2025+JDA指南：原发性皮肤淋巴瘤管的管理（大纲）

Correspondence: Toshihisa Hamada(thamada@ihwg.jp)

Received:3 October 2025| Revised:13 October 2025| Accepted:17 October 2025

Keywords: clinical guideline| cutaneous lymphoma| GRADE| skin-directed therapy| systemic therapy

ABSTRACT

Since the publication of the Japanese guidelines for the management of cutaneous lymphomas in 2020, the WHO classification of hematolymethyl neoplasms has been updated, and a number of novel systemic drugs for cutaneous T-cell lymphoma have been approved in Japan. In 2025, we revised the Japanese guidelines for the management of cutaneous lymphomas in consider-ation of recent advances in our understanding of the pathophysiology and classification of cutaneous lymphomas, together with the update in treatment strategies reflecting the advent of novel drugs. This revision was also conducted under the Japanese Dermatological Association's commission, incorporating expert reviews and public comments. In addition to a brief explanation of the epidemiology,diagnosis, staging system, prognosis, and management of the different types of cutaneous lymphomas, we herein provide recommendations for 12 clinical questions(CQs) regarding treatment options that may vary even among experts.A systematic review process and the selection of recommendations to individual CQs were conducted in accordance with the Grading of Recommendations, Assessment, Development and Evaluation(GRADE) scheme by a multidisciplinary expert panel

This is a secondary publication of the guidelines published in Vol. 135(6), ISSN 0021-499X, pages 1433-1529 of The Japanese Journal of Dermatology. These guidelines are excerpts from the full version of the Japanese guidelines. Therefore,figures,tables, and references that are not relevant to these excerpts have been omitted.The authors have obtained permission for this publication from the Editor of The Japanese Journal of Dermatology. All the authors have agreed on this secondary

©2025 Japanese Dermatological Association.

consisting of dermatologists, hematologists, and a radiation oncologist. In these guidelines, we present outlines of the revised Japanese guidelines for the management of cutaneous lymphomas.

1| Introduction

Cutaneous lymphomas have a wide variety of subtypes with diverse clinicopathological features and prognosis. Since individual types of cutaneous lymphoma are rare disease entities with a small number of patients, we emphasize the importance of clinical guidelines based on the latest knowl-edge and evidence. A number of guidelines on the manage-ment of cutaneous lymphomas have been published in Europe and North America[1-4]. The prevalence and types of cuta-neous lymphomas may vary among different ethnic groups and healthcare systems in different countries. Therefore, it is essential to develop clinical guidelines that are in line with the actual social and medical backgrounds in Japan. These guidelines provide basic as well as the latest information on the treatment of cutaneous lymphoma and propose treatment strategies(algorithms) according to recent evidence for crucial treatment choices.

In 2009, the Japanese Skin Cancer Society(JSCS)-Lymphoma Study Group published the first edition of clinical guidelines for the management of cutaneous lymphomas in Japan. The 4th edition of the WHO classification of hematopoietic tumors was published, and the staging classification was revised. With the addition of new findings, the second edition of clinical guide-lines was published in 2011[5]. Since the development of the sec-ond edition, a number of novel drugs have been approved for the treatment of cutaneous T-cell lymphoma(CTCL). In addition,the fourth edition of the WHO classification of hematopoietic tumors was revised in 2017[6]. Following these developments,the third edition of clinical guidelines was published in 2020[7]. Since then, new evidence has been continuously accumu-lated, and additional treatment options have been approved in Japan. In consideration of these conditions, the current re-vision was conducted under the commissioning of the Japanese Dermatological Association and JSCS and in collaboration with the entire skin cancer field.

These clinical guidelines apply to patients with cutaneous lymphoma. The intended users include all healthcare pro-fessionals who treat cutaneous lymphoma, including nurses,pharmacists, and other medical professionals, and healthcare policymakers. They will also help general clinicians deal with cutaneous lymphoma efficiently and appropriately. The Skin Cancer Management Guidelines Revision Committee was es-tablished in the current revision, consisting of seven working groups for skin malignancies: melanoma, basal cell carcinoma,extramammary Paget's disease, cutaneous lymphoma, squa-mous cell carcinoma, cutaneous angiosarcoma, and Merkel cell carcinoma.

The current edition of the clinical guidelines for cutaneous lymphomas consists of three parts as before. The first part pro-vides basic knowledge covering diagnostic procedures, a staging evaluation, and prognostic information. The second part gives more detailed information on the individual types of cutaneous

lymphoma, including treatment options with a proposal of treatment algorithms. The third part includes clinical questions(CQs) and recommendations in accordance with the Grading of Recommendations, Assessment, Development and Evaluation(GRADE) scheme. The processes for guidelines development were aligned with the Minds 2020 Clinical Practice Guideline Development Manual[8]. A literature search was conducted with the assistance of professional librarians and the coopera-tion of the Japan Medical Library Association. Committee mem-bers were divided into teams responsible for CQ development and a systematic literature review.

2| Literature Search

We referred to the previous Japanese and European/North American versions of the clinical guidelines to identify key clinical issues concerning the treatment of cutaneous lympho-mas and formulated CQs accordingly. To set CQs, we assessed each item according to the PICO framework-patients/problem/population(P), interventions(I), comparisons/controls/compar-ators(C), and outcomes(O)-and conducted a comprehensive literature search. The Japan Medical Library Association was commissioned to perform a literature search for these guide-lines and conducted searches for each CQ using the Cochrane Library,PubMed, and Ichushi-Web from January 1966 up to the cut-off date of July 2023(Table S1). Manual searches were also conducted to include reports not available in these databases or presented at major international conferences, when necessary.After the literature search, retrieved articles were independently screened(secondary screening) by two systematic reviewers for each CQ to assess outcomes related to benefits and harms and to select which articles to include.

3| Current Understanding of Cutaneous Lymphomas CTCL

3.1| Mycosis Fungoides(MF)/Sezary Syndrome(SS)

MF is the most common subtype of CTCL, accounting for approx-imately 50% of cases[9, 10]. It typically shows the epidermotropic infiltration of CD4-positive neoplastic T-cells and progresses slowly over years and decades from patches to plaques and, in some cases, tumors. Sudden tumor development without preced-ing lesions suggests other lymphoma subtypes. MF has various clinical and histological variants, each with a distinct prognosis.S, a rare leukemic form of CTCL, is diagnosed when erythrod-erma is accompanied by the same neoplastic T-cells in both skin and peripheral blood, often with lymphadenopathy. Although specific genetic drivers remain unclear, MF/SS cells are consid-ered to originate from undifferentiated hematopoietic stem cells accumulating multiple mutations over time. Unlike other lympho-mas with characteristic chromosomal translocations, MF/SS cells exhibit heterogeneous genetic alterations across cases. Reported

mutations involve the JAK-STAT, MAPK, T-cell receptor, TNF

A treatment algorithm for MF is shown in Figure 1.

3.1.1| Need for an Intervention for Early-Stage MF

No prospective cohort studies have evaluated the prognosis of MF patients under observation without treatment. Retrospective stud-ies previously found no significant differences in survival rates between patients with stage IA(or T1) MF and controls matched for race,age, and sex[15-18]. Based on these findings, observation(watchful waiting) is considered to be reasonable for stage IA MF.In a cohort study on 395 patients with early-stage MF, 7.3% were managed without any treatment[19]. However, a disease-specific mortality rate of 2% was reported in a long-term follow-up study of patients with stage IA MF[15], underscoring the importance of regular follow-ups. Other studies showed that overall survival(OS)was shorter in patients with stage T2a than in those with stage IA[20,21]. Therefore, observation(watchful waiting) is generally not recommended for stage IB and higher MF.

3.1.2| Topical Treatment

Randomized controlled trials(RCTs) have yet to assess the efficacy of topical corticosteroids for MF/SS. One prospective study on the efficacy of topical corticosteroids(strong class) demonstrated that the response and complete response(CR) rates for patients with stage IA were 94% and 63%, respectively, while those for patients with stage IB were 82% and 25%, respectively[22]. Although no clinical evidence has been reported for advanced-stage disease,topical corticosteroids are one of the useful options for palliative or adjunctive local therapy across all disease stages.

In Europe and the United States, 0.01%-0.02% mechloreth-amine(HN2) solution or ointment has conventionally been used[23,24], and gel formulations are now widely available[25]. An RCT comparing 0.02% HN2 gel and ointment demonstrated a higher response rate(59% vs.48%) and shorter time to a response(26 weeks vs. 42 weeks) for HN2 gel[25]. The most common ad-verse event(AE) of HN2 gel was irritant or allergic contact der-matitis.Bexarotene gel, a topical retinoid available in the United States, was evaluated in a phase III trial on 50 patients with stage IA-IIA MF, showing response rates of 44% by the Physician's Global Assessment, 46% by the Composite Assessment of Index Lesion Disease Severity, and 54% by the primary endpoint clas-sification, which represented the final evaluation based on pre-defined criteria integrating these two measures[26]. The most common AEs included irritant dermatitis, pruritis, and burn-ing sensation[26]. Carmustine(BCNU) topical therapy achieved CR rates of 86% for stage IA, 47% for stage IB, and 55% for stage IIA, with erythema being the most frequent AE and allergic contact dermatitis occurring in less than 10% of cases[27, 28].Co-administration with O[6]-benzylguanine may enhance the efficacy of BCNU[29]. Since HN2 gel, bexarotene gel, and BCNU are not approved in Japan,0.2%-0.4% nimustine solution

 FIGURE 1| Treatment algorithm for mycosis fungoides.

has been used off-label[30]. However, no clinical trials have been conducted to evaluate its efficacy or safety.

3.1.3| Phototherapy

To date, no RCTs have directly compared UV phototherapy with other skin-directed treatments for MF/SS. In Japan, the most widely used phototherapy modalities are psoralen plus UVA(PUVA) and narrow band(NB)-UVB. NB-UVB achieved CR rates of 54%-83% for stage IA/IB MF[31-33]. Other studies showed CR rates of 70%-90% for stage IA/IB and 100% for stage IIA[34-38]. PUVA alone has shown CR rates ranging from 58%to 100% for stage IA-IIA or T1/T2 MF[39-45]. Although PUVA is generally less effective for stage IIB(T3), CR was reported in 33%-100% of patients with stage III(T4)[41-43, 45]. However,PUVA alone is not effective for SS[42, 43]. Non-randomized comparative studies on stage IA/IB MF reported similar CR rates with NB-UVB(60%-81%) and PUVA(62%-71%)[46-48].Bath-PUVA has also been evaluated as an alternative to oral PUVA[49-53]. In a large cohort study comparing 158 patients treated with bath-PUVA and 109 patients with NB-UVB, both groups achieved a CR rate of 88%; however, disease-free sur-vival(DFS) was significantly longer in the bath-PUVA group(43.2 months vs.14.9months,p<0.0001)[53].

The efficacy of maintenance PUVA therapy after CR remains controversial: some studies reported a reduced risk of relapse$[42,43,54], while others showed no prolongation of relapse-free survival[55]. Given the malignant nature of MF/SS, treatment discontinuation based solely on the total dose of UV or total number of treatments may be inappropriate. However, after long-term phototherapy, careful monitoring for skin cancer is essential[55]. Further discussions on NB-UVB vs. PUVA, as well as combination therapy with borexotane, may be found in CQ1 and CQ2 of these guidelines.

IFN-IFN-α and IFN-γ may be used as systemic treatments for MF/SS. In Europe and North America, IFN-α-2a or IFN-α-2b is commonly available, whereas no IFN-α formulations in Japan are approved for MF/SS. Although RCTs have yet to evaluate the efficacy of IFN-α monotherapy, multiple studies reported an overall response rate(ORR) of 54% and a CR rate of 17%, with median response durations ranging from 5 to 41 months[56, 57].A retrospective study on low-dose IFN-α reported an ORR of 67%, with higher response rates in early-stage disease[58].These findings suggest that IFN-α is an effective systemic treat-ment for MF/SS refractory to skin-directed therapies. Regarding IFN-γ, which is approved in Japan, a multicenter, open-label,non-randomized, single-arm phase II study was conducted to assess its efficacy and safety in 15 patients with stage IA-IIIA MF[59]. An objective response was observed in 73% of patients and was sustained beyond 5.7 months. These findings suggest that IFN-γ is also an effective systemic option for MF, with sim-ilar efficacy to IFN-α.

3.2| Small Molecule Compounds

Retinoids-Retinoids are a group of compounds that are struc-turally related to vitamin A. In Europe and North America,

retinoic acid receptor agonists, such as retinoin(all-trans ret-noic acid: ATRA), isotretinoin(13-cis-retinoic acid), and etret-inate, as well as retinoid X receptor(RXR) agonists, such as bexarotene, have been used to treat MF/SS. Among these, only bexarotene is approved for the treatment of CTCL, having re-ceived approval in the United States in 1999, Europe in 2001,and Japan in 2016. Eretinate, which has long been used mainly in combination with phototherapy, is not approved in Japan for the treatment of MF/SS.

Isotretinoin-The response rate of oral isotretinoin for MF/SS has been reported to range between 43% and 100%, while that of oral etretinate ranges between 55% and 67%[60]. In a non-randomized comparative study, no significant differences were observed in ORR(59% vs. 67%), the CR rate(both 21%), or AEs between isotretinoin and etretinate[61]. During treatment, re-currence was detected in 26% of patients receiving isotretinoin and 22% of those receiving etretinate[61]. The duration of re-sponse(DOR) with oral isotretinoin or etretinate was previously reported to range between 3 and 13 months[62].

Bexarotene-Bexarotene is a synthetic retinoid and selective RXR agonist. Clinical studies examined its efficacy in patients with MF/SS. In a phase II/III trial on 58 patients with early-stage MF(stage IA-IIA) who were refractory to prior therapies,including phototherapy, topical chemotherapy, and total skin electron beam therapy(TSEBT), the ORR was 54% and the CR rate was 7% in the group receiving the recommended dose of 300mg/m2/day(n=28), with a recurrence rate of 13%. In con-trast, in the group receiving higher doses exceeding 300mg/m2(n=15), the ORR and CR rate increased to 67% and 27%, re-spectively, although the recurrence rate was also higher(50%)[63]. The most common AEs included hyperlipidemia and hypo-thyroidism. In the 300mg/m2 group, hypercholesterolemia, hy-pertriglyceridemia, and hypothyroidism occurred in 36%, 71%,and 29%, respectively. These rates increased in the higher-dose group to 80%,100%, and 53%, respectively[63].

In patients with advanced-stage MF/SS(stage IIB-IVB), the ORR was 45%(n=56) with 300 mg/m2/day, including 57% in stage IIB, 32% in stage III(including SS), 44% in stage IVA2,40% in stage IVB, and 24% in patients with SS. The CR rate was 2%, and recurrence was detected in 36% of patients. The me-dian DOR was 10.0 months[64]. In a separate cohort receiving>300mg/m2/day(n=38), the ORR, CR rate, and recurrence rate were 55%,13%, and 38%, respectively, with a median DOR of 12.8months. The incidence and type of AEs were similar to those reported in early-stage patients[64].

In Japan, a phase I/II clinical trial was conducted to evaluate the safety and efficacy of oral bexarotene in 16 patients with CTCL,including 12 with MF(stage IB-IVB) and 1 with primary cuta-neous anaplastic large-cell lymphoma(pcALCL). After confirm-ing safety and tolerability at 150mg/m2/day in three patients,the remaining 13 patients received 300mg/m2/day[65]. The ORR was 66% in both the 150 and 300mg/m2 groups. Despite the small sample size, these findings suggested similar efficacy at the lower dose. Among all 16 patients, hypothyroidism and dyslipidemia were reported in 94% and 80%, respectively. Grade≥3 AEs occurred in 50%(8/16) of patients, including six with lipid abnormalities, two with hepatic dysfunction, and one with

neutropenia. Dose-limiting toxicity was observed in 31%(4/13)of patients receiving 300 mg/m2/day, but not in those receiving 150mg/m2/day[65]. Although 300mg/m2/day is the approved starting dose in Japan, some institutions initiate treatment at 150mg/m2/day to reduce AEs, resulting in variability in initial dosing practices.

A non-randomized comparative study on ATRA and bexarotene in patients with refractory MF/SS(stage IB-IVB) showed no sig-nificant differences in ORR, DOR, OS, or toxicity between the two agents[66]. Notably, ATRA is not approved for the treat-ment of MF or SS in Japan.

Histone deacetylase inhibitors(HDACi)-Two HDACi, vorinos-tat and romidepsin, have been used for the treatment of CTCL.HDACi are considered to exert antitumor effects by promoting the transcription of genes involved in differentiation, apoptosis,cell cycle arrest, and the inhibition of angiogenesis by maintain-ing the acetylation status of histone and non-histone proteins;however, the underlying mechanisms remain unclear.

Vorinostat was approved by the FDA in 2006 and by the Pharmaceuticals and Medical Devices Agency in Japan in 2011 for the treatment of CTCL. In a pivotal phase IIB trial conducted in the United States, 74 patients with MF/SS(13 with stage IB-IIA and 61 with stage IIB-IVB), all of whom were refractory to two or more prior systemic therapies, were treated with 400mg oral vorinostat once daily. The ORR was 29.7%, with a median time to response of 1.8 months. The ORR in patients with stage IIB or higher was 29.5%, with a median time to response of 1.9months, indicating similar efficacy across disease stages.In patients with SS, the ORR was 33%[67]. Common AEs in-cluded thrombocytopenia(25%), often occurring within the first 2 weeks of treatment, as well as gastrointestinal symptoms, such as hyperglycemia, diarrhea, nausea, and dehydration. Although rare(approximately 1%), deep vein thrombosis and pulmonary embolism were also reported[67].

In a Japanese phase I trial on six patients with stage IIB or higher MF who were refractory to at least one systemic therapy, no ob-jective responses were observed(ORR 0%), and stable disease was achieved by 66% of patients, as assessed by the modified Severity-weighted Assessment Tool(mSWAT)[68].

Romidepin was approved by the FDA in 2009 for CTCL, but is currently approved in Japan only for peripheral T-cell l-ymphoma(PTCL). In a US phase II trial on 71 patients with MF/SS(9 with stage IA-IIA and 62 with stage IIB-IVB) refractory to at least two systemic therapies,romidepsin was administered intravenously at 14mg/m2 on days 1,8, and 15 of a 28-day cycle.The ORR was 34%, the CR rate was 6%, and the median DOR was 13.7 months. In patients with stage IIB or higher, the ORR was 30% and the CR rate was 7%[69].

In an international multicenter phase II trial conducted in 33 centers across eight countries, 96 patients with stage IB-IVA MF/SS(28 with stage IB-IIA and 68 with stage IIB-IVA) re-ceived the same dosing regimen. The ORR was 34%, the CR rate was 6%, the median time to response was 2 weeks, and the median DOR was 15 months. Among patients with stage IIB or higher, the ORR was 38% and the CR rate was 7%. In 37 patients

with blood involvement, the ORR was 32%[70]. Reported AEs were similar to those observed with vorinostat and included hematological toxicities, such as thrombocytopenia, anemia,and leukopenia, as well as gastrointestinal symptoms(e.g., di-arrhea and nausea), fatigue, and electrocardiographic changes,including QT prolongation. In Japan, romidepsin was approved for PTCL based on a domestic phase I/II study including only two patients with CTCL[71]; therefore, data on romidepsin for CTCL in Japan are limited.

3.3| Antibodies and Antibody-Drug Conjugates

Mogamulizumab-Mogamulizumab is a humanized IgG1x monoclonal antibody targeting C-C chemokine receptor 4(CCR4), which is expressed on Th2 cells and regulatory T-cells(Tregs). Under physiological conditions, CCR4 plays a critical role in the homing of memory T-cells to peripheral tissues, such as the skin.CCR4 is also highly expressed on tumor cells in CTCL and adult T-cell leukemia/lymphoma(ATL). Mogamulizumab exerts its antitumor effects by binding to CCR4 and inducing antibody-dependent cellular cytotoxicity. In addition, the de-pletion of CCR4-expressing Tregs is considered to enhance its antitumor activity.

Mogamulizumab was approved in Japan in 2012 for relapsed or refractory ATL, and in 2014 for CCR4-positive PTCL and CTCL.The indication initially required the confirmation of CCR4 ex-pression on peripheral blood lymphocytes or biopsy specimens using a companion diagnostic kit. However, in 2018, the re-quirement for CCR4 expression was removed for CTCL, and the dosing schedule was revised. The previous regimen of 1 mg/kg weekly for up to 8 doses was replaced with weekly dosing for 5 weeks followed by biweekly administration, with no limit on the number of doses.

A Japanese phase II clinical trial evaluated mogamulizumab in 29 patients with PTCL and 8 with CTCL(7 with advanced-stage MF[stage IIB or higher] and 1 with pcALCL). In patients with MF, the ORR was 29%(partial responses[PRs] only), as assessed by mSWAT[72].

An overseas phase II trial was conducted on 38 patients with CTCL(21 with MF and 17 with SS, including four with stage IB-IIA and 34 with stage IIB or higher). Clinical responses were assessed by sWMAT for skin, PET/CT for lymph nodes, and flow cytometry for peripheral blood. In patients with MF, ORRs were 33% for skin, 15% for lymph nodes, and 100%(n=2) for blood.In SS, ORRs were 53%, 33%, and 94%, respectively, indicating greater efficacy for SS than for MF[73]. In the Japanese trial,common AEs included hematological toxicity, fever, and skin rash. Among patients with PTCL and CTCL, lymphopenia oc-curred in 81%(grade≥3 in 73%), fever in 30%(no grade≥3), and rash in 51%(grade≥3 in 11%)[72]. Although rare, serious AEs,such as toxic ermaldermal necrolysis, the reactivation of hepatitis B, and tumor lysis syndrome, developed.

In a pivotal open-label, randomized, phase III trial comparing magomulizum and vorinostat, 372 patients with previously treated CTCL(204 with MF and 168 with SS) were enrolled re-gardless of CCR4 expression. Patients were randomized to receive

mogamulizumab at 1 mg/kg weekly for 5 doses followed by every 2weeks, or oral vorinostat at 400 mg daily. The primary endpoint was progression-free survival(PFS), and secondary endpoints in-cluded the ORR, which was assessed by mSWAT for skin, imaging for nodal/visceral lesions, and flow cytometry for blood. Median PFS for mgamulizumab was 7.7 months, and that for vorinostat was 3.1 months(p<0.0001). ORRs were 28% for mogamulizumab(52/186) and 5% for vorinostat(9/186)(p<0.0001)[14]. A subgroup analysis showed no significant differences in ORRs according to CCR4 expression levels in lesional skin for either treatment.

Although these findings support the clinical benefits of magam-ulizumab in CTCL, caution is warranted in patients who are can-didates for allogeneic hematopoietic stem-cell transplantation(allo-HSCT). In ATL patients, pretransplant magomulizumab has been associated with severe acute graft-versus-host disease(GVHD)[74,75]. This risk markedly increased when mogamuli-zumab was administered within 50 days prior to transplantation[74]. However, in a retrospective study on eight patients with MF/SS who underwent allo-HSCT more than 200days after the last dose of mogamulizumab,only one(with a HLA-mismatched unrelated donor) developed grade 4 gastrointestinal GVHD[76].Therefore, when mogamulizumab is considered for patients el-igible for allo-HSCT, an advanced consultation with transplant physicians is strongly recommended.

BV-BV is an antibody-drug conjugate consisting of a chimeric anti-CD30 monoclonal antibody linked to monomethyl aurista-tin E(MMAE), the microtubule polymerization inhibitor. Upon binding to CD30 on the surface of tumor cells, BV is internalized via endocytosis, and MMAE is subsequently released intracel-lularly, where it disrupts microtubule formation and arrests cell division. BV was approved in the United States in 2011 and in Japan in 2014 for the treatment of relapsed or refractory CD30-positive Hodgkin lymphoma and systemic anaplastic large-cell lymphoma(ALCL). In the United States in 2017, indications were expanded to include relapsed or refractory CD30-positive pcALCL and MF. In Japan, the approved indication was broad-ened in December 2019 from relapsed/refractory CD30-positive ALCL to include CD30-positive PTCL, and CD30-positive re-lapsed or refractory CTCL was also added in November 2023.These expansions have broadened the clinical application of BV across various subtypes of CTCL.

The ORR of BV in patients with Hodgkin lymphoma was previ-ously reported to be 53%-75%, with CR rates of 18%-46%, while ORR and CR rates in patients with systemic ALCL were 63%-100% and 57%-80%, respectively[77]. In a phase II study on 32 patients with MF/SS, the ORR was 70%. The median percentage of CD30-positive cells in these cases was 13%(range:0%-100%),and patients with<5% CD30-positive cells had significantly lower response rates than those with≥5%[78].

In a pivotal open-label, randomized phase III trial comparing BV with either bexarotene or methotrexate in patients with CD30-positive CTCL(MF or pcALCL), ORRs lasting≥4 months were 56.3% in the BV group and 12.5% in the control group(p<0.001)[13]. Among patients with MF, the ORR, durable response rate(≥4 months), and CR rate were 65%, 50%, and 10%, respectively.In patients with pcALCL, these rates were 75%, 75%, and 31%,respectively[13].

In contrast, among patients treated with bexarotene or metho-treate, the ORR in MF was 16%, with a durable response rate of 10% and a CR rate of 0%; for pcALCL, they were 33%, 20%, and 7%, respectively. BV showed not only superior response rates to standard therapies, but also longer DOR and PFS. The most frequent AE in the BV group was peripheral neuropathy, occur-ring in 45% of patients(grade≥3 in 5%). Other reported AEs included nausea(30%), diarrhea(30%), and rash(11%). Rare, but important AEs were progressive multifocal leukoeencephalopa-thy, tumor lysis syndrome, and Stevens-Johnson syndrome[13].

Denileukin diftitox-Denileukin diftitox is a recombinant fusion toxin composed of interleukin-2, which binds to CD25, and the cytotoxic domain of diphtheria toxin. It exerts its antitumor ac-tivity by selectively targeting CD25-positive cells. Denileukin diftoxit was approved in the United States for the treatment of relapsed or refractory CD25-positive CTCL and in Japan in March 2021 for the treatment of relapsed or refractory PTCL or CTCL.

In a phase III randomized trial conducted in the United States,patients with CD25-positive MF/SS(stage IB-IVA) who re-lapsed or were refractory received either 9 or 18μg/kg/day of denileukin diftitox via intravenous infusions on 5 consecutive days every 21 days for up to 8 cycles[79]. No significant differ-ences were observed in efficacy between the two dosing groups.The ORR was 30%, the CR rate was 10%, and the median DOR was 6.9months. The most commonly observed AEs were acute hypersensitivity-type infusion reactions and delayed-onset cap-illary leak syndrome.

In another randomized placebo-controlled trial involving pa-tients with CD25-positive MF/SS(stage IA-III, based on the former staging system), ORR and PFS rates were significantly higher with denileukin diftitox than with a placebo[80]. While no significant difference was observed in CR rates between CD25-positive and CD25-negative patients, the DOR was slightly longer in CD25-positive cases[81].

In a Japanese phase II trial on patients with relapsed or refrac-tory PTCL and CTCL, the ORR for CTCL was 31.6%, and the median PFS was 4.2months[82]. The most frequent AEs in-cluded elevated AST/ALT, hypoalbuminemia, lymphopenia,and fever. One treatment-related death due to rhabdomolysis was reported as a serious AE. Among patients who had received previous therapies, the ORR was 53.8%(50%[4/8] for CTCL and 60%[3/5] for PTCL), suggesting that denileukin diftitox was also effective for heavily pretreated patients with relapsed or refrac-tory disease.

3.3.1| Chemotherapy

In MF, chemotherapy using cytotoxic agents may be consid-ered depending on a number of factors, such as the disease stage and presence of large-cell transformation. However,since maintaining efficacy generally requires prolonged treat-ment, single-agent chemotherapy with favorable tolerability is typically selected. Multi-agent chemotherapy is used restric-tively for selected cases, such as those with large-cell trans-formation, visceral involvement, or for disease control before

allo-HSCT. Classical agents, including methotrexate, have not been extensively evaluated in controlled clinical trials.It is important to note that although clinical trials have been conducted, they did not adopt the current consensus response criteria.

Regarding advanced-stage MF/SS, the goal of treatment other than allo-HSCT may primarily be symptom palliation. The pro-longation of PFS with chemotherapy, whether single- or multi-agent, is generally not expected. It is an established consensus not to utilize chemotherapy as the initial treatment modality for SS[83]. In advanced-stage MF, in addition to methotrexate and etoposide, which have been frequently selected in the past,various systemic therapies and molecular targeted drugs are in-creasingly being used as treatment options. Further discussions regarding systemic treatments may be found in CQ3 to CQ6 of these guidelines.

Although methotrexate is one of the most commonly used sys-temic drugs in Western countries, there are no RCTs. In two retrospective cohort studies on low-dose methotrexate(median weekly dose: 25mg), the ORR and CR rate for T2 disease were 33% and 12%, respectively, and DFS was 15 months, while the ORR and CR rate for T4 disease were 58% and 41%, respectively[84,85].

Etoposide is generally used intravenously as combination ther-apy for non-Hodgkin lymphomas, including CTCL. Limited data are available on the efficacy of oral etoposide for MF/SS. In a recent retrospective study on 13 patients, low-dose oral etopo-side(50 mg every other day to 100mg daily) achieved an ORR of 69%[86]. In Japan, oral etoposide(25-50mg daily for 3 weeks followed by an interval of 1 week) alone or in combination with oral prednisolone has been used for advanced-stage MF/SS;however, clinical trials have yet to be performed[87].

Gemcitabine has been used for the treatment of a number of malignant tumors, including CTCL. In a phase II trial targeting stage IIB/III MF that had been refractory to previous treatments,gemcitabine showed an ORR of 70% with a CR rate of 10%[88].Another phase II study on gemcitabine for previously-untreated advanced-stage MF(stage IIIB/III) demonstrated that the ORR and CR rate were 73% and 23%, respectively. However, it was ineffective for SS[89]. Similar findings were reported in another phase II study at another institution and, thus, gemcitabine may be promising as single-agent chemotherapy for advanced-stage MF/SS[90]. Gemcitabine is approved for relapsed or refractory lymphoma in Japan.

Pegylated liposomal doxorubicin is also a therapeutic option for advanced-stage MF/SS. Two phase II trials and two retrospec-tive trials showed ORRs of 56%-87% and CR rates of 20%-42%[91-94]. These findings suggest the potential of pegylated lipo-somal doxorubicin as a single-agent chemotherapy, although it is not approved for hematological malignancies in Japan.

Pralatrexate is approved for relapsed or refractory PTCL in Japan based on the findings of a phase I/II study for PTCL, showing an ORR of 45%; however, CTCLs were not examined in that study[95]. Another phase I/II study(30mg/m2 weekly) and a dose de-escalation study(starting dose of 30mg/m2 and subsequently

reduced to 20-10mg/m2 depending on dose-limiting toxicities)in United States showed that pralatrexate was effective for re-lapsed or refractory MF(ORR: 45%) and even for transformed MF(ORR:25%)[96-98].

Pentostatin, a purine analog, was investigated for its efficacy in MF/SS in the 1990s. In one retrospective study and two single-arm phase II trials, pentostatin showed ORRs of 0%-57% and CR rates of 0%-14% for MF, and ORRs of 33%-71% and CR rates of 5%-29% for SS[99-101]. It is not approved in Japan, and its manufacturing and sales have been discontinued.

3.3.2| Radiotherapy(RT)

Cutaneous lymphoma is a radiosensitive neoplasm.Traditionally, a total dose of 20-36Gy(1.8-2.0Gy per fraction)has been applied. Depending on the extent of the disease, local-ized or total skin irradiation is used. Guidelines published by the International Lymphoma Radiation Oncology Group(ILROG,2015)[102], NCCN(Version 2, 2024)[4], and the up-dated European Organization for Research and Treatment of Cancer(EORTC)(2023)[2] provide useful recommendations regarding dose and field settings. Low-dose regimens(8-12Gy)have recently been reevaluated, chiefly for safety reasons.However, it remains unclear whether low-dose or conventional-dose RT is preferable. For further details, refer to CQ7 of the cur-rent guidelines.

Local RT-Local RT is applicable to all stages(I-IV) and lesion types,including patches, plaques, and tumors. Electron beams with an appropriate bolus are commonly used depending on le-sion thickness, while X-rays may be selected for deeper or com-plex areas. Treatment fields are generally set with a margin of 1-2cm around the lesion, and a margin of≥2cm is recommended for solitary lesions treated with curative intent[103, 104]. In the curative treatment of solitary lesions, conventionally fraction-ated RT of 24-30Gy(1.8-2.0Gy per fraction) is generally used.However, since most lesions respond to lower doses, ILROG recommends a dose range of 20-24Gy[102]. Although 4-12Gy may be considered for palliative purposes, doses of 8-12Gy are preferable due to a response rate>90%[105-107], in contrast to<30% with ultralow-dose regimens, such as 4Gy(2Gyx2)[105]. Doses≥8Gy are considered appropriate; see CQ7 for fur-ther details. Re-treatment with 8-12Gy is considered to be safe[104]. Fractionation schedules need to be tailored based on the skin condition, the cumulative dose to the site, and the patient's prognosis because a higher dose per fraction increases the risk of late toxicities. Common toxicities include erythema, erosions,ulcers, blisters, pigmentation, and telangiectasia. Alopecia and corneitis may occur depending on the area of irradiation.

TSEBT-TSEBT is one of the treatment options for cutaneous lymphomas across stages I to IV. The most commonly used technique is the Stanford method, in which patients undergo irradiation in six different body positions using a long source-to-surface distance approach[108]. Supplemental boosts or shielding are applied to areas at risk of under- or overdosing.In recent years, total skin irradiation using helical tomother-apy has also been performed. This method allows treatment in the supine position and enables dose delivery to deeper

lesions, but is associated with a risk of bone marrow suppres-sion. The total dose typically ranges between 8 and 36 Gy, with 30-36Gy being the standard regimen[109]; however, recent studies reported high response rates even with low-dose reg-imens of 8-12Gy[110-114]; see CQ7 for details. AEs include dermatitis, alopecia, edema, salivary gland dysfunction, and secondary malignancies.

3.3.3| Hematopoietic Stem-Cell Transplantation(HSCT)

HSCT includes autologous HSCT following high-dose chemo-therapy and allo-HSCT. Allo-HSCT is the preferred approach for MF/SS. The development of reduced-intensity condition-ing regimens, which retain potent immunosuppressive effects while minimizing toxicity, has expanded eligibility to patients up to approximately 70 years of age. However, the non-relapse mortality(NRM) rate remains high at approximately 20% due to complications, such as regimen-related toxicity,GVHD, and infections, and chronic GVHD significantly impairs quality of life(QOL). The prognosis of advanced-stage cases(stage IIB or higher) is generally poor, and allo-HSCT has demonstrated potential benefits in this setting. In a retrospective analysis by the European Society for Blood and Marrow transplantation(n=113), 1- and 3-year NRM, PFS, and OS rates were 26% and 28%,34% and 26%, and 56% and 38%, respectively. The relapse rate was 44%, with a median time to relapse of 3.5 months[115].In a study by the Center for International Blood and Marrow Transplant Research(n=129), 5-year NRM, PFS, and OS rates were 22%,17%, and 32%, respectively. One- and 5-year relapse rates were 50% and 61%, respectively[116]. A Japanese registry analysis(n=48) reported 3-year PFS and OS rates of 19% and 30%, respectively. Two-year NRM and relapse rates were 15.4%and 65.9%, respectively[117]. In 2023, the CUTALLO prospec-tive matched cohort study showed that median PFS was signifi-cantly longer in the transplant group than in the nontransplant group(9.0months vs.3.0months,p<0.0001), and QOL was also significantly better in the transplant group(p=0.005)[118].These findings demonstrate the promising efficacy of allo-HSCT for patients with advanced MF/SS; however, the high NRM rate remains a major concern. Disease control before transplantation is also recommended[115, 117]. Allo-HSCT is one of the key treatment options for transplant-eligible patients with advanced-stage MF/SS; see CQ8 for details.

3.4| Primary Cutaneous CD30+ T-Cell Lymphoproliferative Disorders(CD30+ LPD)

Primary cutaneous CD30+ T-cell LPD is the second most common form of CTCL, and represents a spectrum including pcALCL, lymphomatoid papulosis(LyP), and borderline lesions.A common feature is that a majority of neoplastic cells express CD30. Histologically, pcALCL and LyP sometimes exhibit sim-ilar morphological and immunophenotypic findings, whereas they significantly differ in their clinical presentation and course.

Clinically, pcALCL exhibits a slight male predominance and may affect a wide age range[9, 10]. It presents with solitary or mul-tiple red nodules, tumors, indurulated plaques, or subcutaneous

masses, sometimes accompanied by ulceration[119]. In some cases, annular or horseshoe-shaped infiltrative erythema may also be observed. Even in multifocal presentations, a symmetri-cal distribution, as observed in LyP, is uncommon. Spontaneous regression may occur, and some cases show repeated cycles of the appearance and disappearance of lesions.

Histologically,pcALCL shows the nodular sheet-like infiltration of large lymphoid cells extending into the deep dermis or subcu-tis. Epidermotropism is typically absent or subtle[119]. Tumor cells exhibit a pleomorphic, anaplastic, or immunoblastic mor-phology with irregularly shaped nuclei and an abundant cyto-plasm. Some tumor cells have the appearance of Reed-Sternberg cells. Neutrophils or eosinophils may also be observed. Tumor cells are generally positive for CD30, CD4, and cutaneous lym-phocyte antigen and negative for CD8 and anaplastic lymphoma kinase. CD3 is often positive, although negative cases are not uncommon. Additionally, CD25, cytotoxic molecules(T-cell intracellular antigen 1,granzyme B, and perforin), and CCR4 are often expressed. CD30 is also expressed in MF, ATL, and extranodal NK/T-cell lymphoma, which require different treat-ments; therefore, careful differentiation is essential. Useful di-agnostic methods include an assessment of characteristic skin lesions, such as erythematous patches or plaques, the detection of monoclonal HTLV-1 proviral integration, and Epstein-Barr virus-encoded small nuclear RNA(EBER) in situ hybridization.Unlike systemic ALCL, anaplastic lymphoma kinase expression is lacking in tumor cells. Rearrangements of the IRF4-DUSP22 locus on 6p25.3 were identified in approximately 20% of pcALCL cases and some LyP cases, but have rarely been reported in cases of transformed MF[120,121].

Regarding treatment strategies(Figure 2), no comparative studies have been conducted, except for a randomized clini-cal trial including BV[13]. Generally, pcALCL has a favorable prognosis, with a 5-year survival rate of 66%-77% even in mul-tifocal cases[122, 123]. Although cyclophosphamide+ doxo-rubicin+ vincristine+ prednisolone(CHOP) therapy achieves a high CR rate of 90%, the recurrence rate is as high as 62%and, thus, it is not regarded as curative[124]. Moreover, the initial treatment of solitary or localized cases with chemother-apy has been associated with faster disease progression than with local RT[125]. Consequently, for skin-limited pcALCL,local therapy is preferred over intensive systemic therapy.Observation using topical or intralesional corticosteroids may be considered for cases susceptible to spontaneous regression.However, the standard first-line option for solitary or local-ized disease is surgical excision or local RT. Although direct comparative studies have yet to be conducted, both therapies achieve similarly high CR rates(95%-100%) with a recurrence rate of approximately 40%[124]. Since local skin recurrence is not associated with a poor prognosis, repeated surgical exci-sion or RT is recommended. Local RT may be considered for patients with multifocal lesions. A dose of 20 Gy(2.5Gyx8 fractions) is recommended for solitary or localized lesions,while 8Gy(4Gyx2 fractions) is considered sufficient for mul-tifocal or rescaled cases[126]. When local treatment is insuf-ficient, systemic therapy needs to be considered. Low-dose methorextate(5-25mg/week) has been widely used as first-line therapy[124, 127]. The phase III ALCANZA trial demon-strated that BV had a higher response rate than methotrexate

T1N0M0 T3N0M0 anyTN1-3M0 T2N0M0 anyTanyNM1

Topical/ Intra-lesional corticosteroids

 FIGURE 2| Treatment algorithm for primary cutaneous anaplastic large-cell lymphoma.

or bexarotene(75% vs.20%)[13]. In Japan, BV was approved after a phase II physician-initiated trial[128], as discussed in CQ9. Chemotherapy regimens including BV, such as BV+cy-clophosphamide+ doxorubicin+ prednisolone(BV-CHP),may be used for refractory cases. Chemotherapy is generally recommended for cases with lymph node or visceral involve-ment[124, 127, 129]. Mogamulizumab may also be considered for CCR4-positive cases.

Although LyP mostly occurs in adults, children may also be affected. It presents with disseminated papules or small nodules that appear and spontaneously regress within a few weeks to a few months[119]. These lesions are generally dis-tributed symmetrically with a predisposition to the extremi-ties. The number of lesions varies from only a few to hundreds of lesions. Histologically, LyP exhibits highly variable mor-phological features[119, 124]. Type A is the most common variant, accounting for 75% of all LyP biopsies, and shows scattered medium-sized to large CD30+ lymphoid cells in a background of various inflammatory infiltrates, such as lym-phocytes, neutrophils, eosinophils, and histiocytes, in the dermis. Type B is characterized by the dermal infiltration and epidermotropism of small to medium-sized lymphocytes sim-ilar to MF/SS, and CD30 expression is sometimes lacking in this variant. The histological findings of type C are identical to those of pcALCL. Type D shows the prominent epidermot-ropism of CD8+CD30+ small to large lymphocytes, resem-bling primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma. Type E exhibits the angiocentric and angiodestructive infiltration of medium-sized CD30+lymphocytes. In addition to histological variants, LyP with the 6p25.3 rearrangement is currently defined as a distinct type in the WHO classification 2024[130]. LyP generally per-sists for years to decades, but is not associated with mortality.On the other hand, secondary lymphomas, such as MF and cutaneous and systemic ALCL, have been reported in some LyP cases[131]. Even taking the secondary lymphomas into account, the prognosis of LyP is good, with a disease-specific mortality rate of 4%-6%[132, 133]. Although the histological subtype does not affect the clinical course or prognosis of LyP,secondary lymphomas are more frequently associated with types B and C and less frequently with type D[133]. A wait-and-see strategy is recommended because no therapy changes

the clinical course or prevents secondary lymphomas. UV or systemic therapy is considered for cases with impaired QOL due to disseminated lesions, multiple erosions, or severe pru-ritus. Among systemic therapies, low-dose methotrexate is the most frequently used[124].

3.5| Subcutaneous Panniculitis-Like T-Cell Lymphoma(SPTCL)

SPTCL is a rare subtype of cutaneous lymphoma that prefer-entially involves subcutaneous tissue. By definition, neoplastic lymphocytes in SPTCL are CD8-positive cytotoxic T-cells ex-pressing alpha/beta T-cell receptors. Latent EB virus infection is typically negative[130]. SPTCL is estimated to account for 1%-2% of cutaneous lymphoma cases[9, 119]. It affects indi-viduals of all ages, but is generally more common in patients younger than 40years and shows a female predominance.Clinically, it presents as multiple subcutaneous nodules resem-bling erythema nodosum, typically on the lower extremities, but also on the trunk and face[6]. Ulceration is rare, occurring in approximately 6% of cases[134]. Systemic symptoms, including fever, leukopenia, thrombocytopenia, and liver function abnor-malities, are frequently observed. Autoantibodies may be pres-ent, with approximately 10%-19% of cases being associated with autoimmune diseases, such as systemic lupus erythematosus,Sjogren's syndrome, or rheumatoid arthritis[135]. Similarities with lupus profundus have also been reported both clinically and histopathologically[136, 137]. Although SPTCL generally shows an indolent clinical behavior, cases complicated by he-mophagocytic syndrome(HPS) often have a fatal outcome. A previous study reported 5-year OS rates of 91% and 46% in pa-tients without and with HPS, respectively[134].

Histologically,SPTCL is characterized by the infiltration of neo-plastic lymphocytes into subcutaneous fat, with minimal or no involvement of the dermis. Neoplastic lymphocytes are small to medium in size and infiltrate the fat lobules, forming a lobular panniculitis pattern. A classic“lace-like” or“rimming” pattern,where lymphoma cells surround individual adipocytes, is often observed, but is not specific to SPTCL. The necrosis of adipose tissue, nuclear debris, and hemophagocytosis by histiocytes are frequently observed. Immunohistochemically, tumor cells

are typically positive for CD3, CD8, granzyme B, and TIA-1,but negative for CD4 and CD56. CD30-positive cells may also be observed in some cases[6]. Gamma/delta T-cell lymphomas,which used to be classified under the same category, may be histologically indistinguishable from SPTCL on H&E staining[138]. Therefore, demonstrating βF1 positivity may be useful for confirming the alpha/beta T-cell origin. Whole-body imaging(CT or PET/CT) is recommended to rule out other lymphomas and to detect occult lesions. PET/CT is particularly useful for identifying subclinical disease. If lymphadenopathy or visceral involvement is suspected based on physical or imaging findings,a tissue biopsy needs to be performed. Bone marrow biopsy is not routinely needed unless HPS is suspected or other lym-phoma subtypes cannot be excluded.

While SPTCL is generally negative for EBER, EBER-positive cases have been reported in Asia[130, 135]. EBER positivity alone does not exclude SPTCL; however, a careful differential diagnosis is needed. Furthermore, recent studies reported that germline mutations in HAVCR2 were frequently detected in pa-tients with SPTCL, particularly in cases with early onset and/or relapsing disease courses. These mutations may be associ-ated with disease severity and shorten recurrence-free survival[139-141].

Treatment approaches for SPTCL without HPS are described below. In SPTCL, clinical trials or case-control studies on ther-apeutic interventions are still lacking. Among international guidelines, only those from ESMO[3] and BAD[1] describe spe-cific approaches for SPTCL. The ESMO guidelines recommend corticosteroids or immunosuppressive agents as the first-line treatment for HPS-negative patients, and suggest RT for solitary or localized disease. The BAD guidelines also note the effective-ness of systemic corticosteroids. However, no studies have di-rectly compared the efficacy or DOR between these treatment options; current evidence is limited to case reports and case series.

Corticosteroids and immunosuppressive agents are commonly used as first- or second-line treatments in SPTCL, including re-lapsed cases. However, no studies have directly compared the ef-ficacy of corticosteroids versus other immunosuppressive drugs or chemotherapy. In a European multicenter study by Willemze et al.,24 of 63 patients(38%) received non-chemotherapy sys-temic treatments, including corticosteroids(n=19), cyclospo-rine, chloramclucib, or methotrexate.The ORR was 88%, with 16 achieving CR and five PR. Nine of the CR cases relapsed, while five regained remission with re-treatment. Chemotherapy was used for relapse in eight patients, with three achieving CR[134].A literature review by Go et al. found that among 20 patients treated initially with corticosteroids, the response rate was 50%[142]. Lower efficacy may be due to the inclusion of gamma/delta T-cell lymphomas. Some patients without HPS achieved long-term remission(median 36.5months). Additional studies described the successful use of corticosteroids or immunosup-pressants in patients with relapsed or refractory disease[134].These findings support corticosteroids as a reasonable initial treatment for HPS-negative SPTCL due to their low toxicity.However, the optimal dosage and duration remain unclear, and multi-agent chemotherapy may be considered for unrespon-sive cases.

RT was previously shown to be effective for SPTCL with local-ized lesions. In a multicenter study by Willemze et al., three pa-tients received radiation as the initial treatment and all achieved CR; however, the duration of remission was not reported. One patient achieved a second CR after re-irradiation for relapse[134]. A review by Go et al.[142] reported a response rate of 81% in 11 patients treated with radiation, including CR in four and PR in five. One patient maintained remission for more than 1 year, while another relapsed within months; data were un-available for the other patient. Although long-term disease con-trol with radiation alone may be limited, its high initial response rate supports its use in patients with localized disease and no systemic symptoms, such as fever, cytopenia, or HPS.

In patients with SPTCL complicated by HPS, multi-agent che-motherapy and corticosteroid therapy have both shown limited efficacy[134, 142]. To date, no study has demonstrated that chemotherapy is clearly superior to corticosteroids in this pop-ulation. However, disease-related mortality in SPTCL is largely attributable to HPS, and successful treatment with multi-agent chemotherapy or chemotherapy combined with HSCT has been reported[134, 142]. Depending on the clinical context, cytotoxic chemotherapy or immunosuppressive therapy, such as cortico-steroids or immunosuppressive agents, may be selected. A treat-ment algorithm for SPTCL is presented in Figure 3.

3.6| ATL

3.6.1| Diagnosis,Subtype, and Prognosis of ATL

ATL is a form of T-cell malignancy caused by human T-lymphotropic virus type I(HTLV-1). It is characterized by lymphadenopathy, hepatospenomegaly, hypercalcemia, skin lesions, and the presence of abnormal peripheral blood lympho-cytes with multibulated nuclei. Skin lesions are observed in approximately 50% of ATL patients[119, 143]. The diagnosis of ATL is based on the following criteria:(i) positive serum anti-HTLV-1 antibody;(ii) abnormal peripheral blood lymphocytes with convoluted or lobulated nuclei or histological findings of ATL in biopsy specimens from the lymph nodes, gastrointestinal-ral tract, or skin;(iii) tumor cells exhibiting a mature CD4+ T-cell phenotype; and(iv) the monoclonal integration of HTLV-1 proviral DNA into tumor cells confirmed by a Southern blot analysis[144]. Of these, criterion(iv) is important for differenti-ating ATL from other cutaneous lymphomas that may occur in HTLV-1 carriers, such as MF.

 *HPS, hemophagocytic syndrome

FIGURE3| Treatment algorithm for subcutaneous panniculitis-like T-cell lymphoma.

ATL is classified into four clinical subtypes, namely, the acute,lymphoma, chronic, and smoldering types, based on organ in-volvement, peripheral blood findings, and laboratory data[144].The chronic type is further divided into two subgroups accord-ing to the presence of the following unfavorable prognostic fac-tors:(i) serum lactate dehydrogenase> the upper limit of normal(ULN);(ii) serum blood urea nitrogen<ULN; and(iii) serum albumin<the lower limit of normal. Unfavorable chronic ATL has at least one of these factors. Smoldering-type ATL primarily manifesting with skin lesions is sometimes classified as the“cu-taneous type”[145,146].

The treatment strategy for ATL is selected according to the clini-cal subtype(Figure 4). In Japan, aggressive ATL, which includes the acute, lymphoma, and unfavorable chronic types, is gener-ally treated with combination chemotherapy, such as vincristine+ cyclophosphamide+ doxorubicin+ prednisolone-doxoru-bicin+ raminustime+ prednisolone-vindesine+ etoposide+carboplatin+ prednisolone, based on the modified LSG-15 protocol, CHOP, or CHOP-like regimens. In eligible younger patients, allo-HSCT is considered following induction therapy.Mogamulizumab is often added; however, its use prior to allo-HSCT requires caution due to the risk of severe GVHD[147].In CD30-positive cases, regimens containing BV(e.g., BV-CHP)have been reported[148]. IFN-α with zidovudine(IFN/AZT)therapy has been suggested as a treatment option for patients without bulky masses; however, neither IFN-α nor AZT is ap-proved for the treatment of ATL in Japan. Regarding indolent ATL, including the favorable chronic and smoldering types,watchful waiting is the standard approach for asymptomatic cases. In patients with cutaneous lesions, SDTs(skin-directed therapies), such as phototherapy, local RT, and systemic ther-apies,including oral retinoids,IFN-y,or single-agent oral che-motherapy, are used[7]. Clinical trials have yet to evaluate mogamulizumab for indolent ATL and, thus, its efficacy or prognostic impact remains unproven. In smoldering-type ATL,patients who develop cutaneous tumors without leukemic man-ifestations or visceral involvement often exhibit rapid disease progression and a poor prognosis. When the disease shows

progression, systemic chemotherapy similar to that used for ag-gressive ATL needs to be initiated[149].

Treatment strategies for ATL with systemic involvement beyond the skin need to be developed in collaboration with hematolo-gists, oncologists, and radiologists. Therefore, these guidelines focus on therapeutic options for patients with cutaneous lesions who do not require intensive systemic therapies.

SDT. SDTs, such as UV phototherapy and local RT, are typi-cally used for indolent ATL with cutaneous lesions. Although neither randomized nor non-randomized trials have evaluated UV phototherapy for ATL-specific skin lesions, PUVA therapy has shown favorable outcomes in case series. In a study on 22 patients, including those with extracutaneous involvement, all four untreated cases achieved PR. Seven of nine relapsed cases showed PR, and two had stable disease[150]. However, there is no evidence to show that UV phototherapy improves the overall prognosis of patients. NB-UVB therapy is easier to administer than PUVA therapy, with limited case reports suggesting effi-cacy for ATL-specific skin lesions[151-153]. Local RT is also considered to be effective, despite the absence of controlled stud-ies. In one case series of five patients with erythema, nodules, or tumors, complete remission was achieved in all cases, including untreated and relapsed patients[150]. Another study evaluated ten cutaneous lesions in three ATL patients(one with the acute type and two with the smoldering type) and found a response rate of 100%, with no in-field recurrence during the follow-up[154]. Therefore, RT is considered to be useful for tumor reduc-tion and local control.

Systemic therapy. Systemic therapy needs to be considered for patients refractory to SDTs as an additional treatment.Etretine is not approved in Japan for ATL, but was shown to be effective for cutaneous lesions and is often used off-label in combination with phototherapy[155]. Bexarotene, a selec-tive RXR agonist, was approved in June 2024 for ATL with cutaneous lesions based on the findings of a phase II trial in Japan.The study enrolled 32 patients with indolent ATL and

 FIGURE 4| Treatment algorithm for adult T-cell leukemia-lymphoma.

aggressive-type ATL that relapsed with cutaneous lesions after achieving remission through chemotherapy. ORRs based on mSWAT were 50.0% in the 100mg/m2 group and 70.6% in the 300 mg/m2 group. Common AEs included hypothyroidism and hypertriglyceridemia[156]. The efficacy of combination therapy with retinoids and SDTs for indolent ATL is discussed in CQ10 of these guidelines.IFN-y has shown efficacy for ATL with skin-limited involvement. In a case series of 22 patients,the ORR was 54.5%, with a CR rate of 22.7%[157]. Although IFN-y is currently approved for MF/SS, no IFNs are currently approved in Japan for ATL. Lenalidomide, an immunomod-ulatory drug approved for relapsed/refractory ATL, achieved a response rate of 42% in a phase II trial, but has not been evaluated for indolent ATL[158]. Hematological AEs are common and require close monitoring. Tucdinostat and vale-metostat are newly approved agents for relapsed/refractory ATL. Both exhibit activity against skin and peripheral blood lesions; however, their efficacy for indolent ATL has not yet been evaluated[159, 160]. The main AEs include cytopenias.Mogamulizumab has exhibited high efficacy for relapsed/re-fractory ATL, particularly in skin and peripheral blood; how-ever, its use for indolent ATL remains unestablished[161].Severe skin reactions, including Stevens-Johnson syndrome,have been reported, particularly after repeated administra-tion. In refractory cases with skin lesions and a poor progno-sis, single-agent chemotherapy is an option when multi-agent regimens are feasible. Oral etolopide achieved response rates of up to 71.4% in small case series, and retrospective studies suggested that its combination with SDTs prolonged OS and PFS[162, 163]. Although evidence is limited, sobuxozane has also shown responses in relapsed ATL with cutaneous in-volvement[164-167]. In cases of nodulotumoral disease with rapid progression or resistant to single-agent treatments such as oral retinoids or IFN-y, multi-agent chemotherapy follow-ing aggressive ATL protocols may be needed.

4| Cutaneous B-Cell Lymphomas(CBCL)

In the revised 2018 WHO-EORTC classification, CBCLs are categorized into five subtypes: primary cutaneous marginal zone lymphoma(PCMZL), primary cutaneous follicle center lymphoma(PCFCL), primary cutaneous diffuse large B-cell lymphoma, leg type(PCLBCL,LT),EB virus-positive mucuoc-taneous ulcer, and intravascular large B-cell lymphoma[168]. In this section, we provide an overview of the three major entities,PCMZL, PCFCL, and PCLBCL, LT, and discuss their therapeu-tic strategies.

4.1| Indolent CBCL, PCMZL, and PCFCL

Local RT is recommended as the first-line treatment for solitary(T1) or localized(T2) lesions[4]. Surgical excision may also be considered for solitary skin lesions smaller than 5cm in diameter(T1a) if there are no significant cosmetic concerns. Additionally,although not approved in Japan, SDTs, such as intralesional or topical corticosteroids, imiquimod, nitrogen mustard, and topical beaxarotene, may show efficacy[4]. Given the generally favorable prognosis, a watchful waiting approach may also be appropriate in consideration of factors such as patient age, lesion

location, number, and distribution[4]. Treatment options for cases with multiple lesions involving anatomically noncontigu-ous areas(T3) include local RT, intralesional corticosteroids, the systemic administration of the anti-CD20 monoclonal antibody rituximab,intralesional rituximab,combination chemotherapy,or SDTs[3, 4]. In asymptomatic cases, observation may be se-lected[4]. In patients with extracutaneous involvement, treat-ment strategies align with those for follicular lymphoma in the case of PCFCL and for nodal marginal zone lymphoma in the case of PCMZL[4]. The reevaluation of lesions is needed for re-lapsed, refractory, or advanced disease before the selection of treatment options(Figure 5).

Local RT. Radical irradiation with a total dose of 24-30 Gy and a margin of 1.0-1.5cm is recommended for treatment[102].Alternatively, palliative low-dose irradiation using 4Gy in 2 fractions is also applicable[102]. In a literature review and ret-rospective cohort study by Senff et al., standard-dose RT(typi-cally 30-45Gy) for the indolent group achieved a high CR rate of 99%; however, recurrence rates were 46%-60% in PCMZL and 29%-47% in PCFCL, with most relapses occurring in skin lesions outside the irradiated field[169, 170]. In a retrospective cohort study by Hamilton et al., the CR rate in patients who re-ceived standard-dose RT(25-35 Gy) was 94%, with an in-field re-lapse rate of 2%, whereas the recurrence rate from the resection site in the surgery-only group was 33%[171]. Gauci et al.[172]conducted a retrospective cohort study and reported a CR rate of 100% with standard-dose RT(18-30Gy), an in-field relapse rate of 39%, a median DFS of 44 months, 3- and 5-year DFS rates of 56% and 51%, respectively, and 3- and 5-year OS rates of 100%.In a retrospective cohort study by Neelis et al., the CR rate with low-dose irradiation(4Gy in 2 fractions) was low at 75%, with 29.5% of patients experiencing persistent or recurrent in-field after disease after 6.3 months that required additional irradiation with 20Gy[105]. In a retrospective cohort study by Goyal et al.,comparing low-dose(2-4Gy) and standard-dose(24-40Gy) RT for the indolent group, CR rates were 94.1% and 97.3%, respec-tively, with no significant difference. However, the rate of local recurrence was slightly higher in the low-dose group(p=0.07).Acute and late skin toxicities were significantly more frequent in the standard-dose group than in the low-dose group(acute toxicity: 15.7% vs.78.4%,p<0.0001; late toxicity:7.8% vs.40.5%,p<0.0036)[173]. These findings indicate that radical RT for the indolent group achieves high response rates, although in-field recurrence is frequent. The choice between radical and pallia-tive RT may depend on the distribution and number of lesions,whether the disease is initial or recurrent, and patient factors,such as age and systemic medical conditions.

4.1.1| Surgical Therapy

Surgery yields a high response rate similar to RT, although local recurrence rates are high. No recommended surgical margin has been established. In consideration of cosmetic outcomes,surgical treatment for the indolent group is generally applied to small, solitary lesions[3,4].

A literature review by Senff et al., including 75 PCMZL and 93 PCFCL cases, reported CR rates of 99% and 98%, respectively,although approximately 40% of patients experienced recurrence

 FIGURE 5| Treatment algorithm for primary cutaneous B-cell lymphoma.

[169]. Hamilton et al.[171] reported a 33% recurrence rate at the resection site in the surgery-only group. In contrast, a literature review by Parbhakar et al.[174] comparing RT(30-40Gy) and surgery for the indolent group found no significant difference in DFS over a median follow-up of 3.6 years, with only one case of cutaneous recurrence in the RT group. In a retrospective co-hort study on 137 PCMZL patients treated initially with surgery,local RT, or a combination of both, Servitjet et al. reported a CR rate of 88%, a recurrence rate of 44%(32% at the treated site,62% at distant skin sites, and 5.8% at both), and a median DFS of 47 months. No significant difference in recurrence rates was ob-served between the surgery(45.2%) and RT(37.7%) groups[175].

4.1.2| Systemic Monotherapy With Rituximab(Intravenous Administration)

In retrospective cohort studies investigating the efficacy of sys-temic rituximab monotherapy in the indolent group, including patients with both solitary/localized and multiple lesions, CR rates ranged between 60% and 90%, with ORR of 87%-100%[176-180]. Recurrence rates also widely varied among studies,ranging between 27% and 82%[176-180]. In one retrospective cohort study on 26 cases(9 PCMZL and 17 PCFCL), rituximab was administered at 375mg/m2 weekly for 4 weeks. The ORR was 100%(CR: 77%, PR: 23%); however, recurrence rates were 88.9% in PCMZL and 52.9% in PCFCL. The median DOR among patients who achieved CR was 13.4years[181]. Therefore, sys-temic rituximab monotherapy is one of the promising options for the treatment of patients with multiple lesions who are con-traindicated for RT or surgery. Although a high recurrence rate is expected, this treatment may offer high response rates and long DOR in CR cases. The comparative efficacy of rituximab

monotherapy versus rituximab-based combination chemother-apy in indolent CBCL refractory to SDTs is addressed in CQ11.

4.1.3| Topical and Intralesional Therapies

Topical and intralesional therapies are treatment options for sol-itary or localized lesions in the indolent group[3,4]. Few studies have reported the efficacy of topical steroids with sufficient sta-tistical power. One retrospective cohort study on nine patients with CBCL who received lesional triamcinolone showed a CR rate of 44% and a PR rate of 56% with a median DOR of 47 months[182]. With various injection protocols for intralesional ritux-imab,most studies have used the protocol of a lesional injection 1-3 times a week at 3-week intervals[169, 183-187]. A literature review and cohort studies showed that intralesional rituximab treatment was highly effective, with CR rates ranging between 45% and 100% and response rates ranging between 72% and 100%. However, recurrence rates were also high, ranging be-tween 40% and 67%[169, 183-187]. Studies on the topical admin-istration of IFN-α(not approved in Japan) for indolent CBCL are limited. Cozzio et al. reported the efficacy of topical IFN-α-2a at a dose of 3 million IU, administered three times per week in eight cases of PCMZL. The CR rate was 100%, and two patients who experienced local relapse after CR were readadministered IFN- $\alpha$ and achieved CR again[188]. In one retrospective cohort study on 15 patients with indolent CBCL who received IFN-α therapy, the ORR was 66.7%, with a median DOR of 15.5 months.However, 90% of patients experienced relapse during a median follow-up period of 40months[189]. Regarding topical imiqui-mod(not approved in Japan), one retrospective cohort study on 16 patients with indolent CBCL who received 5% imiquimod cream applied to lesions showed an ORR of 62.5%(CR: 31.25%,

PR: 31.25%) with a median treatment duration of 4.6 months[190]. All cases that achieved CR had solitary T1a lesions.The only AE was local skin irritation at the application site[190].In summary, topical and intralesional therapies may offer high response rates and favorable safety profiles, particularly in pa-tients with solitary lesions.

4.1.4| Combination Chemotherapy

No specific combination chemotherapy regimen is recom-mended for the treatment of indolent CBCL. Literature reviews on the efficacy of combination chemotherapy showed that the most commonly used regimen was CHOP. An analysis of CHOP therapy in 33 PCMZL patients showed a CR rate of 85% with a relapse rate of 57%[169]. In a cohort of 104 PCFCL patients who were treated with CHOP or CHOP-like regimens, the CR rate was 85% and the relapse rate was 48%[169]. Of note, most patients who received combination chemotherapy had multiple lesions or large tumor masses[169].

4.1.5| Other Therapies

In a multicenter, randomized, phase III trial comparing 178 pa-tients treated with lenalidomide plus rituximab(not approved in Japan) to 180 patients treated with placebo plus rituximab,the former group showed significantly prolonged PFS(median PFS: 39.4 months vs. 14.1 months; hazard ratio 0.46; 95% confi-dence interval[CI]: 0.34-0.62)[191]. Although grade 3/4 neu-tropenia and lymphopenia were more frequently observed in the combination arm, the safety profile was acceptable[191].TG1042(not approved in Japan) is a nonreplicating adenovi-rus serotype 5 vector carrying human IFN-γ cDNA. In a phase II clinical trial, 13 patients with relapsed CBCL(including six PCMZL, six PCFCL, and one PCLBCL other than LT) received local TG1042 injections. This study reported a CR rate of 54%,PR rate of 31%, and ORR of 85%[192]. The median DOR was 23.5 months, and the main AEs included flu-like symptoms, fa-tigue, and injection-site reactions[192].

4.2| PCLBCL,LT

PCLBCL, LT is a group of the activated B-cell(ABC) subtype of diffuse large B-cell lymphoma(DLBCL). According to the NCCN Guidelines(Version 2, 2024), it is categorized as an ag-gressive lymphoma, and its treatment follows that of nodal DLBCL[4]. ESMO guidelines recommend the addition of local RT(36-40Gy) to R-CHOP(CHOP chemotherapy plus rituximab-imab) for solitary or localized lesions[3]. Options for patients for whom chemotherapy is not feasible may include local RT at a total dose of 40Gy or the systemic administration of rituximab monotherapy[3]. Systemic rituximab monotherapy is also se-lected for patients with multiple lesions for whom chemotherapy is not feasible[3]. Treatment strategies have yet to be established for relapsed or refractory cases. In these cases, the treatment strategy generally follows that of nodal DLBCL.

Combination chemotherapy with rituximab±local RT.Combination chemotherapy with rituximab is recommended as

the first-line treatment[3]. Previous case series reported high CR rates with rituximab-containing combination chemotherapy,par-ticularly R-CHOP therapy[193,194]. A multi-institutional retro-spective study on 115 patients demonstrated that the prognosis of the rituximab-containing combination chemotherapy group was significantly better than that of the other treatment groups(com-bination chemotherapy without rituximab, RT, corticosteroids,single-agent chemotherapy, or rituximab monotherapy)(3-year DFS:80% vs.48%,p<0.001;5-year DFS:74% vs.38%,p<0.001)[195]. A multivariate analysis revealed that combination chemo-therapy without rituximab was an independent poor prognostic factor(odds ratio 4.6,95% CI 2.4-9.1,p<0.001)[195].In one retro-spective cohort study, a comparison between R-CHOP plus local RT and R-CHOP alone revealed the significant prolongation of PFS(median PFS: 58 vs. 14 months, p=0.04), although no sig-nificant difference in OS was observed[196]. This disease pre-dominantly affects elderly patients, many of whom have a poor performance status and comorbidities, making the treatment with combination chemotherapy challenging for safety reasons.In these cases, surgical treatment, RT, rituximab monotherapy, or combinations thereof may be selected according to the conditions of individual patients. Recommendations on treatment selection among these modalities are discussed in CQ12.

4.2.1| Pegylated Liposomal Doxorubicin(Not Approved in Japan)

Combination chemotherapy for elderly patients with PCLBCL,LT is often difficult to introduce due to concerns over AEs, including cardiotoxicity and hematological toxicity. Pegylated liposomal doxorubicin is a formulation in which doxorubicin is encapsulated in polyethylene glycol-modified liposomes, enhancing tumor tis-sue penetration and thereby improving antitumor efficacy while reducing AEs. Pulini et al. administered pegylated liposomal doxorubicin to four PCLBCL, LT cases, reporting a median time to response of 3 months and a CR rate of 100%[197]. Fabbri et al.reported on rituximab plus pegylated liposomal doxorubicin combination therapy in three PCLBCL, LT cases, observing CR in one case,PR in one case, and progression in one case[198].AEs related to this treatment were limited to grade 2 or lower, and this therapy may be considered for cases where combination chemo-therapy including CHOP is difficult to administer[198].

Lenalidomide(not approved in Japan). There are currently no established treatment guidelines for relapsed/refractory PCLBCL,LT. Lenalidomide is a thalidomide analogue classified as an immunomodulatory drug, exerting antitumor effects via the inhibition of hematological tumor cell proliferation. A multi-institutional phase II trial on lenalidomide in 19 relapsed/refrac-tory PCLBCL, LT cases reported an ORR of 26.3% at 6 months(CR: 21.1%, PR: 5.2%), with median PFS, OS, and disease-specific survival of 4,19.4, and 23.8 months, respectively[199].

4.2.2| Other Treatments(Not Approved in Japan)

MYD88 gene mutations promote the survival of ABC-type DLBCL lymphoma cells via NF-xB signaling, which may be inhibited by targeting Bruton's tyrosine kinase(BTK), a key mediator of B-cell receptor signaling[200]. The BTK inhibitor brutinib has exhibited

efficacy for relapsed/refractory PCLBCL, LT cases, including CR cases[201-203]. Furthermore, therapeutic effects from combi-nations of britinib with other agents, such as rituximab, lena-lidomide, or R-EPCH, have been reported[204, 205]. Ibrutinib appears to be effective for refractory cases harboring the MYD88 L265P mutation[202,204,205]. Other reported treatments for re-lapsed/refractory cases include the BCL-2 inhibitor venetoclax and the immune checkpoint inhibitor pembrolizumab[206,207].

5| CQ and RECOMMENDATIONS

CQ1: Is PUVA therapy recommended over narrow-band UVB therapy for MF/SS?

Recommendation

We weakly recommend PUVA therapy, if available, over NB-UVB therapy for MF/SS.

● Recommendation: 2

· Evidence level:D

•Agreement Rate:100%(7/7)

Voting Results

|1. Recommend "PUVA"|2. Suggest "PUVA"|3. Suggest "NB-UVB"|4. Recommend| |---|---|---|---| ||||| |$$CQ1\text{(1st vote)}$$|||100%| ||||(7/7)| ||||Total votes 7(Abstention 3)|

5.1| Background and Objectives

UV phototherapy is a standard treatment for early-stage MF and is widely used for advanced-stage MF and SS in combination with systemic therapy. UV phototherapy includes PUVA therapy, NB-UVB therapy, broad-band UVB therapy, and UVA1 therapy, with the former two mainly being used in Japan. Due to its longer wave-length, UVA reaches a deeper part of the skin than UVB, which may be beneficial for the treatment of advanced-stage MF. It re-mains unclear whether PUVA or NB-UVB therapy needs to be rec-ommended for MF/SS in consideration of its clinical effects, AEs,patient values and preferences, costs, and other factors. This CQ aims to evaluate the benefits and disadvantages of the two types of UV phototherapy and clarify whether PUVA or NB-UVB therapy needs to be recommended for MF/SS.

5.2| Evidence

Each factor of PICO was set as follows: P(target population),patients with MF/SS; I(intervention), PUVA therapy; C(com-parator), NB-UVB therapy; O(outcome), the response rate(im-portance rating: 8 points), DOR(8 points), AEs(7 points), the recurrence rate(7 points), and dosage before response(6 points).One semi-RCT(intra-individual right-left comparative study)

[208], one prospective cohort study[209], one meta-analysis tar-geting patients at stage IA and IB[210], and 14 retrospective co-hort studies[46, 47, 53, 211-221], one of which evaluated only AEs[211], compared the clinical effects of PUVA and NB-UVB therapies on MF/SS; however, an RCT has yet to be conducted. All studies were from outside Japan, and the skin colors of patients varied. Regarding the response rate, a meta-analysis of 14 stud-ies[46, 47, 53, 209, 212-221] revealed that CR rates were 68.8%(518/753 cases) for PUVA and 56.8%(235/414 cases) for NB-UVB,which were not significantly different(p=0.1621). One semi-RCT(intra-individual right-left comparative study)[208] was ex-cluded from the meta-analysis because a retrospective study from the same institute[212] appeared to include the same cases. One meta-analysis of studies that enrolled more than ten cases in each group showed that the CR rate for PUVA in patients at stages IA and IB was 73.81%, while that for NB-UVB was 62.15%, with the former being significantly higher than the latter(odds ratio 1.68,p=0.04)[210]. The average duration of PUVA was 23.8months(standard deviation:10.56, range:10-43.25), while that of NB-UVB was 15.2months(standard deviation:6.088, range:5.2-24.5)[46,47,53,213-216].

Regarding AEs in cases treated with PUVA and NB-UVB, carcino-genesis was detected in 0.66%(3/455 cases) and 0%(0/233 cases),skin damage with the discontinuation of treatment in 0.88%(4/455 cases) and 1.29%(3/233 cases), burn/erythema in 4.83%(22/455 cases) and 6.01%(14/233 cases), nausea in 1.10%(5/455 cases),and 0%(0/233 cases), pruritus in 0.44%(2/455 cases) and 0.43%(1/233 cases),respectively[46,47,53,208,213,214,217,218].One retrospective cohort study found secondary amyloidosis after UV phototherapy in 5 of 34 cases in the PUVA-treated group and in 0 of 27 cases in the NB-UVB group. An evaluation of the risk of cancer after UV phototherapy was not sufficient due to the short observation period with a limited number of patients. Recurrence rates using a meta-analysis of four retrospective cohort studies[53,215,216,219] were 33.7%(70/208 cases) for PUVA and 34.6%(44/127 cases) for NB-UVB, which were not significantly different(odds ratio 0.935, p=0.7342). No studies reporting dosages before responses were identified.

5.3| Discussion

All studies cited for response rates, DOR, AE, and recurrence rates were from abroad, with patients of different skin types being en-rolled. No studies investigated dosages before responses. The ev-idence level was D(very weak). The meta-analysis of 14 studies revealed that the CR rate for the intervention group was 68.8%,while that for the control group was 56.8%. There was no signifi-cant difference between the two groups. DOR for the intervention group was 23.8 months, which was longer than that for the control group(15.2months). No significant difference was observed in the recurrence rate in a meta-analysis of 5 cohort studies. The frequen-cies and severities of AEs were similar. Taken together, these find-ings indicate that the intervention group had some advantages in terms of DOR; however, difficulties are associated with deciding which phototherapy to recommend.

Regarding patient values and preferences, few institutions in Japan provide PUVA therapy, which may cause a burden for pa-tients and their families. AEs and the need for photoprotection

by oral medication withoxmethalsen may also be negative fac-tors for PUVA therapy. Although no studies investigated the balance between cost and benefits, PUVA therapy is less expen-sive than NB-UVB therapy. On the other hand, only NB-UVB therapy, which is applicable to various skin diseases, is available in most hospitals in Japan. Furthermore, it is not easy for facil-ities or health insurance providers to introduce UVA systems.The unstable supply of methoxalsen is another issue. In some guidelines abroad, PUVA therapy is recommended over NB-UVB therapy, while both types of phototherapies are listed in other guidelines without any further recommendations[2-4].The risk of skin cancer is low in Japan, and NB-UVB therapy is available in more hospitals than PUVA therapy. The panel ulti-mately concluded that PUVA therapy is weakly recommended,if available, over NB-UVB therapy for MF/SS.

5.4| Clinical Considerations

PUVA and NB-UVB therapies are both listed as recommended phototherapies in the NCCN, ESMO, and EORTC guidelines[2-4].NB-UVB therapy needs to be applied first for early-stage MF because it is less carcinogenic than PUVA therapy, while the latter is better for plaques than the former. However, these com-ments are not evidence-based, just expert opinions. Now that only NB-UVB therapy, which is applicable to various skin dis-eases, is available in most hospitals in Japan, it is not easy for fa-cilities or health insurance providers to introduce UVA systems,although PUVA therapy has the advantage of a longer duration before recurrence[33]. The unstable supply of methoxalsen is another issue that needs to be addressed.

5.5| Future Research Directions

Further clinical studies are needed on the outcomes of UVA and NB-UVB phototherapies for MF plaques, particularly the im-pact of different wavelengths, the effects of which on thick skin lesions may vary. It is ideal to have evidence from a Japanese population because therapeutic effects and AEs are dependent on skin color types.

6| CQ2: Is Combination Therapy With Bexarotene and Phototherapy Recommended Over Bexarotene Monotherapy for Patients With Phototherapy-Refractory MF?

Recommendation

We weakly recommend performing combination therapy with bexarotene and phototherapy rather than switching to bexarotene monotherapy in patients with phototherapy-refractory MF.

● Recommendation level: 2

● Evidence level:C

● Agreement Rate: 100%(3/3)

Voting Results

|1.Recommend|2.Suggest 2.Suggest "performing combination therapy with bexarotene and phototherapy"|3.Suggest 3.Suggest "switching to bexarotene monotherapy"|4.Recommendation| |---|---|---|---| |CQ2 (1st vote)|100% (3/3)||| ||Total votes 3(Abstention 7)|||

6.1| Background and Objectives

Phototherapy is commonly selected for the treatment of early-stage MF, often in combination with topical corticosteroids,and is generally effective. A limited number of patients may have a poor response to phototherapy. In these patients, the oral retinoid exbarotene is frequently selected because it may be administered in an outpatient setting. The effects of the combination of phototherapy plus bexarotene or bexarotene monotherapy remain unclear. This CQ aims to clarify whether the two therapies need to be recommended for patients with phototherapy-refractory MF.

6.2| Evidence

Each factor of PICO was set as follows: P(target population),patients with MF refractory to phototherapy; I(intervention), a combination of phototherapy and bexarotene; C(comparator),bexarotene monotherapy; O(outcome), the ORR(importance rating:8 points),DOR(8 points),AEs(7 points),PFS(7 points),and time to response(6 points).

Regarding the ORR, one RCT[222] and two retrospective co-hort studies[223, 224] compared bexarotene plus phototherapy versus bexarotene monotherapy. This RCT included cases of CTCL other than MF/SS. In addition, one of the cohort studies included CTCL(not MF) cases, with the intervention group re-ceiving a low dose of bexarotene(150-300 mg/m2). These stud-ies included cases regardless of their response to phototherapy,resulting in a high level of indirectness.

A meta-analysis of cohort studies alone showed that in the fixed-effect model, the odds ratio for the overall response was 2.26(95% CI 1.17-4.38), indicating a significantly higher re-sponse rate with combination therapy. However, in the random-effects model, the odds ratio was 0.96(95% CI 0.05-18.98), and no significant difference between the two groups was observed.Response rates were 60.3%(73/121 cases) for the combination group and 50.0%(43/86 cases) for the monotherapy group.

Regarding the CR rate, a meta-analysis of one RCT and one co-hort study showed CR rates of 14.2%(16/113 cases) in the total combination group and 6.2%(4/65 cases) in the total monother-apy group. The odds ratio for achieving CR was 2.28 in the fixed-effect model and 2.29 in the random-effects model; however,neither reached significance.

PFS was reported in only one cohort study[223], showing a me-dian PFS of 19.1 months in the combination group and 6.7 months in the monotherapy group; statistical testing was not performed.

The time to response was evaluated in only one RCT[222], which also included CTCL cases other than MF/SS and was not limited to phototherapy-refractory patients. The median time to response was 21.0days in the combination group and 16.0days in the mono-therapy group, with no significant between-group difference.

One RCT and two cohort studies investigated AEs; however,only one cohort study[224] directly compared the combination of phototherapy and bexarotene with bexarotene monotherapy.This study included patients with CTCL other than MF and cases not limited to phototherapy-refractory disease, indicating high indirectness. The sample size was small, and a difference was observed in bexarotene doses between studies: the interven-tion group received 150-300mg/m2, whereas the control group received the standard 300 mg/m2 dose. Consequently, we con-cluded that the risk of bias was high.

In the cohort study[224], the incidence of serious AEs was 12.5%(1/8 cases) in the group receiving combination therapy with bexaro-tene monotherapy and bexarotene and bexarotene monotherapy group.

No studies that directly compared the DOR between the two groups were identified.

6.3| Discussion

One RCT and two retrospective cohort studies compared combi-nation therapy with bexarotene plus phototherapy to bexarotene monotherapy. The RCT was an open-label trial, and the other two were observational cohort studies, indicating a high risk of bias. We concluded that the strength of evidence was“low(C)." The efficacy of combination therapy was slightly higher for the response rate and DOR, and AEs generally decreased in the combination groups. Based on the limitations in the individual study designs and sample sizes, we concluded that the overall certainty of the evidence was low.

Regarding the balance of benefits and harms, no studies directly investigated which outcome needed to be given more weight. We concluded that uncertainty and inconsistency were both low for key outcomes.

No comparative studies examined the net benefit, cost, or re-source allocation. The medical costs for phototherapy are ap-proximately JPY 1500 per session for PUVA and JPY 3400 per session for NB-UVB. The estimated monthly medical cost of bexarotene, based on a body surface area of 1.6m2, is JPY 512406. Due to the slight difference in medical costs between the two groups, combination therapy may be reasonable for pa-tients and healthcare providers.

The panel ultimately concluded that combination therapy with bexarotene and phototherapy is weakly recommended over bexarotene monotherapy for patients with phototherapy-refractory MF.

6.4| Clinical Considerations

Given the limitations of the evidence, careful evaluations of effi-cacy and safety between the two groups are needed. The NCCN Clinical Practice Guidelines(ver. 2, 2024)[4] list combination therapy with bexarotene and phototherapy as one of the treat-ment options for patients with phototherapy-refractory MF.However, these guidelines do not provide a direct comparison between combination therapy and bexarotene monotherapy[4].Treatment options need to be selected based on the medical con-ditions and needs of individual patients.

6.5| Future Research Directions

To further address this CQ, multicenter, prospective clinical studies comparing combination therapy and bexarotene mono-therapy and evaluating outcomes are needed.

7| CQ3: When Starting Bexarotene for MF/SS,Is a Low-Dose Initiation Recommended Over a Standard-Dose Initiation?

Recommendation

We weakly recommend the initiation of bexarotene at a standard dose over a low dose for MF/SS.

• Strength of recommendation: 3

● Evidence level: D

● Agreement Rate: 80%(4/5)

Voting Results

|1.Recommend|2.Suggest selecting lower- dose regimen|3.Suggest selecting a standard- dose regimen|4.Recommend recommend a standard-dose regimen|5.No recommendation| |---|---|---|---|---| |CQ3(1st vote)||80%(4/5)||| |CQ3(1st vote)|Total votes 5(Abstention 5)||||

7.1| Background and Objectives

Bexarotene, an oral retinoid, is widely used in the treatment of CTCL, including MF/SS. However, frequent AEs associated with bexarotene, particularly hypothyroidism and lipid metabolism dis-orders, necessitate reductions in the standard dose. Therefore, its initiation using a low-dose regimen is expected in clinical practice;however, therapeutic effects remain unclear. Following clarifica-tion of whether the standard- or low-dose initiation of bexarotene is recommended, the appropriate starting dose will be selected in consideration of the balance between safety and cost.

7.2| Evidence

The target population(P) was patients with MF/SS. The inter-vention(I) was low-dose bexarotene(<300mg/m2), and the

comparator(C) was standard-dose bareotene(300 mg/m2).The primary outcomes(O) were the response rate(importance rat-ing:8 points), DOR(8), AEs(8), and PFS(7). After a literature review, we found two RCTs that directly evaluated the initial dose of bareotene, a standard-dose(300 mg/m2) group versus a low-dose(<300mg/m2) group, in patients with MF/SS[63, 65].Three retrospective cohort studies that described the starting doses in both groups have also been reported[223-225]. Six ret-rospective cohort studies that evaluated patients treated with ei-ther the standard or low dose were also found[66,222,226-229].

Regarding response rates, a meta-analysis of two RCTs[63, 65]showed that the low-dose group had a slightly lower response rate than the standard-dose group(27.8% vs. 57.5%, odds ratio 0.31,95% CI 0.09-1.12,p=0.073). A meta-analysis of three retro-spective cohort studies[223-225], which included both starting doses, revealed that the response rate was significantly lower in the low-dose group than in the standard-dose group(25.4% vs.62.2%, odds ratio 0.21, 95% CI 0.10-0.47,p=0.0001). In a meta-analysis combining these five studies[63, 65, 223-225], the re-sponse rate was significantly lower in the low-dose group than in the standard-dose group(26.0% vs.60.9%, odds ratio 0.23,95%CI 0.12-0.43,p<0.0001).

Regarding DOR, only one RCT reported response durations of 103 days in the standard-dose group and 74.5 days in the low-dose group[65]. However, a statistical analysis was not performed.

As for AEs, hypothyroidism, hyperglyceridemia, and neutro-penia were frequently observed. Therefore, individual analyses of these AEs were performed in addition to grade 3 or higher AEs.The incidence of grade 3 or higher AEs in a meta-analysis of three studies(one RCT[65] and two retrospective cohort studies[223, 224]) was significantly lower in the low-dose group than in the standard-dose group(20.0% vs.53.8%, odds ratio 0.19,95% CI 0.09-0.39, p<0.0001). No significant difference was observed in the incidence of hypothyroidism in a meta-analysis of two RCTs[63,65](27.8% vs.48.8%, odds ratio 0.45,95% CI 0.10-2.06,p=0.30). A meta-analysis combining two RCTs[63, 65] and three retrospective cohort studies[223-225] also showed no significant difference in the incidence of hypertriglyceridemia(57.5% vs. 74.7%, odds ratio 0.56, 95% CI 0.24-1.34, p=0.19). A meta-analysis of two RCTs[63, 65] revealed no significant dif-ference in the incidence of neutropenia(16.7% vs. 36.6%, odds ratio 0.38,95% CI 0.09-1.55,p=0.18). However, a meta-analysis of two retrospective cohort studies[223, 224] showed a signifi-cantly lower incidence in the low-dose group(11.7% vs. 28.6%,odds ratio 0.35, 95% CI 0.18-0.67, p=0.0017). In a meta-analysis of these four studies, a significantly lower incidence of neutrope-nia was noted in the low-dose group(12.4% vs. 30.1%, odds ratio 0.35,95% CI 0.19-0.64,p=0.0006).

The only evaluate retrospective cohort study did not find a signif-icant difference in PFS between the two groups(10.2 weeks in the standard-dose group and 11.5weeks in the low-dose group)[223].

7.3| Discussion

Of the two RCTs, one[63] administered a very low dose of bex-arotene(6.5mg/m2) to the low-dose group, while the other[65]

had a limited number of cases, and both were open-label studies.Therefore, we concluded that the evidence level was very low.Furthermore, the cohort study had a small number of cases, and the inclusion criteria for subjects markedly varied. Overall, the risk of bias was considered to be high. Furthermore, the inci-dence of AEs may vary among individual institutions due to dif-ferent baseline values. Based on the above issues, we concluded that the certainty(strength) of the evidence was“D(very weak).”

Regarding the balance between benefits and harms, the response rate was slightly lower in the low-dose group than in the standard-dose group. However, no significant differences were observed in DOR or PFS between the groups. On the other hand, grade 3 or higher AEs were slightly more frequent in the standard-dose group than in the low-dose group. In individual analyses of fre-quent AEs, no significant differences were noted in hypothyroid-ism or hypertricyceridemia between the two groups. However,neutropenia was more common in the standard-dose group.Considering the balance of the above primary outcomes, harms may slightly outweigh benefits in the low-dose group.

Regarding patients' values and preferences, judgments are ex-pected to vary depending on the targeted patients, such as whether to prioritize the response rate or avoid the risk of AEs,including neutropenia.

No studies specifically evaluated the balance between net ben-efits and cost/resources; however, the drug cost must be lower in the low-dose group. Assuming a body surface area of 1.5m2,the standard dose of bexarotene(300mg/m2) requires 450mg6(s capsules) daily, costing JPY 17080, while the low-dose group(150mg/m2) requires 225mg(3 capsules) daily, costing JPY 8540. In the case of severe neutropenia, even after the discontin-uation of bexarotene, the administration of G-CSF is required,resulting in an increase in resources. However, such cases are expected to be rare. Overall, difficulties are associated with es-tablishing the superiority or inferiority of cost-effectiveness in consideration of the balance of the response rate, PFS, and AEs.

At the panel meeting, we achieved a consensus on this CQ,namely, that the initiation of bexarotene at the low dose is not recommended for MF/SS. When comparing the risk of under-estimating the therapeutic effect of bexarotene in a continuous low-dose regimen, with a reduction in the risk of AEs, we con-cluded that the former will be disadvantageous for patients. One of the five panelists judged“strongly recommend(suggest) not to intervene,” whereas the majority of the panelists judged“weakly recommend not to intervene”; therefore, the decision to“condi-tionally recommend against the intervention” was made.

7.4| Clinical Considerations

The certainty(strength) of the evidence for this CQ recommen-dation is low. Therefore, in clinical practice, the initial dose of bexarotene needs to be selected based on the disease condition or patient values. The NCCN guidelines(Version 2, 2024)[4]and ESMO guidelines[3] do not mention the initial dose of bex-arotene. The EORTC guidelines cite a study by Hamada et al.[224] and state that the response rate was significantly lower in patients with treated bexarotene at the low dose than at the

standard dose[2]. On the other hand, the BAD guidelines[1]cited by Scarisbrick et al. describes in detail the management of bexarotene administration. According to this study, the rec-ommended starting dose of bexarotene of 150 mg/m2 once daily needs to be commenced[230]. After 4 weeks of bexarotene at 150mg/m2 daily and when monitored blood tests(free T3, free T4, and lipid metabolism) are stable, the dose of bexarotene needs to be increased to 300 mg/m2 daily[230]. Dose increments of 75 mg(one capsule) per day every 2-4 weeks are also advised for patients with unstable lipid-related AEs[230].

7.5| Future Research Directions

The recommended initial doses of bexarotene may differ be-tween early- and advanced-stage MF or SS. Furthermore, the impact of standard- and low-dose bexarotene on long-term prog-nosis has not been investigated. Further comparative studies are needed to address these issues.

8| CQ4: Is Oral Etoposide Recommended Over Mogamulizumab for CD30-Negative Advanced-Stage MF in Patients With Interferon-y or Retinoid Resistance?

Recommendation

We weakly recommend the use of mogamulizumab over oral etoposide for patients with CD30-negative, advanced MF that is refractory to interferon-γ or retinoids.

● Recommendation: 3

● Evidence level:D

● Agreement Rate: 77.8%(7/9)

Voting Results

|1. Recommend "oral etoposide"|2. Suggest "oral etoposide"|3. Suggest "mogamulizumab"|4. Recommend "mogamulizumab" "mogamulizumab|5.No recommendation| |---|---|---|---|---| |CQ4 (1st vote)||77.8% (7/9)|11.1% (1/9)|11.1% (1/9)| |||Total votes 9(Abstention 1)|||

8.1| Background and Objectives

In patients with advanced-stage MF(stage IIB or higher),SDTs alone, such as topical corticosteroids and phototherapy,are generally insufficient for disease control, and systemic therapy is often required. Intensive multi-agent chemotherapy is not recommended because it rarely achieves long-term re-mission. In consideration of long-term safety, the initial treat-ment typically involves a combination of SDTs with IFN-y or retinoids. In cases that are refractory to or have relapsed after these regimens, multiple treatment options are avail-able, including targeted therapies, such as magomulizumab and denileukinift oxifitox, HDACi, and single-agent chemo-therapy(e.g., oral etoposide). BV is a treatment option when tumor cells express CD30, as observed in cases of large-cell

transformation. However, it is not applicable to CD30-negative cases. Mogamulizumab and oral etoposide are frequently se-lected for patients with CD30-negative disease. However, it remains unclear whether oral etoposide may be recommended over moagulizumab with respect to both efficacy and safety.Further clarification of the preferred treatment in this setting will assist in clinical decision-making.

8.2| Evidence

This CQ focused on patients(P) with CD30-negative, advanced-stage MF refractory to IFN-y or retinoids. The intervention(I) was oral etoposide, and the comparator(C) was mogamu-lizumab. The outcomes(O) identified for assessment included ORR(importance rating:8 points),DOR(8),OS(7), the inci-dence of secondary malignancies(8), AEs(7), and PFS(6). A lit-erature review was conducted based on these outcomes.

No studies that directly compared oral etoposide and mogamuli-zumab for these outcomes were identified. Although single-arm studies were available for both agents, most included heteroge-neous populations, such as patients with early-stage MF or SS,and were not limited to CD30-negative cases. The evidence re-viewed consisted of one RCT using a different comparator and two retrospective cohort studies.

Regarding ORR, one retrospective cohort study included 13 pa-tients treated with oral etoposide, including one who received intravenous administration, and reported an ORR of 69.2%(9 of 13 patients)[86]. An RCT on the effects of magamulizumab in patients with early- and advanced-stage MF and SS reported an ORR of 21%(22 of 105 patients) for MF and a skin-specific ORR of 42%(78 of 186 patients) for the overall MF/SS population[14].One retrospective cohort study on patients with MF and SS re-ported an ORR of 46%(23 of 50 patients) for MF, with the same rate(46%) being observed for skin-specific responses[231]. The CR rate for oral etoposide was evaluated in one retrospective cohort study, which reported 0%(0 of 10 patients)[86]. Regarding mogom-alizumab, the CR rate was 2.6%(5 of 186 patients) in an RCT involving patients with early- and advanced-stage MF and SS[14].One retrospective cohort study on mogamulizumab in early- and advanced-stage MF reported a CR rate of 8%(4 of 50 patients)[231].

The following AEs were reported. One retrospective cohort study on oral etoposide noted serious AEs in 50.0% of patients(5 of 10)[86]. One RCT on mogamulizumab for early- and advanced-stage MF/SS reported grade 3 or 4 AEs, regardless of causality,in 41% of patients(75 of 184)[14]. Serious treatment-related AEs,including pneumonia and fever, occurred in 20% of patients(36 of 184) and treatment-related death in 1%(2 of 184). In a retro-spective cohort study on early- and advanced-stage MF/SS, the rate of serious AEs was 18.5%(23 of 124)[231].

No studies were available to assess PFS for oral etoposide. One retrospective cohort study on mogamulizumab reported a me-dian PFS of 8.8 months(95% CI 4.6-43.0)[231].

Regarding the time to response, oral etoposide was evaluated in one retrospective cohort study, with a median time to response of 12.5 weeks(95% CI 6-25.4)[86]. One RCT on mogamulizumab

for early- and advanced-stage MF/SS reported 3.3 months(95%CI 2.0-6.4)[14], while a retrospective cohort study found that it was 3.1 months(95% CI 0.3-44.3)[231].

Concerning DOR, one retrospective cohort study on oral etopo-side for early- and advanced-stage MF reported a median DOR of 10.8 months[86]. A post hoc analysis of an RCT on mogamu-lizumab reported a median DOR of 13.1 months[232], although this analysis had the drawback of a high drop-out rate.

No studies that reported data on OS or the incidence of second-ary malignancies for either treatment were identified.

8.3| Discussion

Three studies were reviewed: one RCT with a different compara-tor, and two retrospective cohort studies for each treatment arm.However, no study directly compared oral etoposide and mogujalizumab in terms of key outcomes, including ORR, DOR,OS, secondary malignancies, AEs, and PFS.

Although one study on oral etoposide reported a high ORR, the sample size was small, and the incidence of serious AEs was also high, resulting in a low overall level of evidence. In contrast,mogamulizumab was supported by an RCT and larger cohort studies and, thus, was considered to have a higher level of evi-dence than oral etoposide. Nevertheless, none of the studies ex-clusively enrolled patients with CD30-negative, advanced-stage MF, and the therapeutic efficacies of oral etoposide and mogam-ulizumab may vary depending on the CD30 expression status.Given these limitations, the overall certainty of the evidence was downgraded due to the serious risk of bias and indirectness,and was rated as grade D(very low).

With respect to the balance of benefits and harms, a direct comparison between the two agents was not possible due to the absence of head-to-head trials. However, more studies were available for mogamulizumab. In addition, the types of seri-ous AEs differed between oral etoposide and mogamulizumab.Therefore, the benefit-harm balance is considered to vary and be difficult to interpret definitively.

No studies that directly evaluated the net clinical benefit, cost-effectiveness, or resource requirements associated with the interventions were identified. Etoposide is less expensive than magamulizumab. However, due to the lack of comparative data on efficacy and safety, no studies have assessed the relative cost-effectiveness or resource utilization of the two treatments.Therefore, no concrete conclusions regarding the appropriate-ness of the intervention have been reached, and the balance of cost and benefit has yet to be evaluated.

During panel discussions, one member noted that the prolonged use of cytotoxic agents, such as etopide, is generally not pre-ferred in clinical practice. Other members expressed similar concerns, noting that although etopide is used in practice, it rarely achieves long-term remission when used as monotherapy and is likely to lead to treatment resistance. Of the nine voting panel members, one voted for“no recommendation,” one voted to“recommendomulizumab,” and seven voted to“suggest

mogamulizumab." Based on the majority opinion, CQ4 was clas-sified as a conditional recommendation against the intervention.

8.4| Clinical Considerations

No other published guidelines were found to include a CQ that directly compares oral etoposide with mogamulizumab.Therefore, this intervention may not be considered appropriate by patients, physicians, or other healthcare providers due to the lack of comparative evidence.

8.5| Future Research Directions

To date, no RCTs have been conducted to address this clini-cal issue. Given the rarity of the disease and the challenges of performing direct comparisons, future studies need to focus on registry-based analyses or large-scale retrospective studies targeting relevant patient populations. These studies need to evaluate response rates, DOR, and the incidence of secondary malignancies in relation to specific clinical morphologies.

9| CQ5: Is Treatment With BV Recommended Over Oral Etoposide or Mogamulizumab for Patients With Advanced-Stage, CD30-Positive MF Refractory to Interferon-γ or Retinoids?

Recommendation

We weakly recommend BV over oral etoposide or mogam-ulizumab for patients with advanced-stage, CD30-positive MF that is refractory to interferon-γ or retinoids.

● Recommendation: 2

● Evidence level: D

● Agreement Rate:87.5%(7/8)

Voting Results

|1. Recommend $$\left|\begin{array}{l}\text{Brentuximab}\\ \text{vedotin}\end{array}\right|$$ $$\begin{array}{l}\text{B}\text{rentuximab}\\ \text{vedotin}\end{array}$$ $$\begin{array}{l}\text{B}\text{rentuximab}\\ \text{vedotin}\end{array}$$ $$\begin{array}{l}\text{B}\text{rentuximab}\\ \text{vedotin}\end{array}$$ $$\begin{array}{l}\text{B}\text{rentuximab}\\ \text{vedotin}\end{array}$$ $$\begin{array}{l}\text{B}\text{rentuximab}\\ \text{vedotin}\end{array}$$ $$\begin{array}{l}\text{B}\text{not}$$|2. Suggest "brentuximab vedotin"|3. Suggest "oral etoposide or magamulizumab"|4. Recommend|| |---|---|---|---|---| |CQ5|12.5%|87.5%|"oral etoposide or|magamulizumab"| |(1st vote)|(1/8)|(7/8)||magamulizumab"| ||||Total votes 8(Abstention 2)||

9.1| Background and Objectives

After the initial treatment with retinoids or IFN-y, multiple ther-apeutic options are available for relapsed or refractory MF with poor disease control. These include molecular targeted thera-pies, such as mogumulizumab and denileukin diftitox, HDACi,and single-agent chemotherapies, including oral etoposide. In some of these cases, tumor cells express CD30. BV, an anti-CD30 antibody-drug conjugate, has been approved for systemic ALCL expressing CD30, and an increasing number of studies are re-porting its efficacy for CD30-positive MF. However, it remains

unclear whether treatment with BV for CD30-positive MF needs to be recommended over commonly used therapies, such as oral etoposide and mogamulizumab, based on considerations of effi-cacy and safety. Further clarification of its utility and selection of the preferred option among these treatments may be of great value in guiding therapeutic decision-making.

9.2| Evidence

This CQ targeted patients(P) with advanced-stage, CD30-positive MF refractory to IFN-y or retinoids.The intervention(I)was treatment with BV, and the comparison(C) was oral etopo-side or magomulizumab. A literature review was conducted with the following outcomes(O): ORR(importance rating: 8 points),DOR(8),OS(8),AEs(7),the relapse rate(6),and PFS(7).

No studies that directly compared BV with oral etoposide or mog-amulizumab in patients with MF were identified. Furthermore,most studies lacked clear descriptions of a previous treatment history or did not perform stratified analyses based on the treat-ment history. Therefore, it was not possible to extract data spe-cifically for patients with advanced-stage MF refractory to IFN-y or retinoids. In addition, many studies did not limit inclusion to stage IIB or higher; consequently, data including stage IIA or lower were also used. No large-scale studies on oral etoposide were identified. The relevant literature included two single-arm prospective studies[78,233], five case series[86,234-237], and three RCTs[13,14,238].

Regarding ORR, there were two single-arm prospective studies[78,233],one RCT[13], and four case series[234-237] for BV.The pooled response rate from the two interventional studies,one RCT, and two case series with a low risk of bias was 63.4%(92/145 patients)[234, 235]. One RCT on magamulizumab[14]reported a response rate of 21%(22/105 patients), although this included patients with stage IIA or lower. Only one small case series[86] was available for oral etoposide, with a reported re-sponse rate of 75%(6/8 patients).

Available data on AEs were derived from heterogeneous cohorts that included patients with early-stage MF, pcALCL, and SS.The incidence of grade 3 or higher AEs was similar between groups: 37.8%(37/98 patients) for BV and 41%(76/184 patients)for mogamulizumab[13, 14, 78, 236-239]. No AE data on oral etoposide were available due to the small number of cases and limited scope of existing case series.

Regarding relapse rates, one case series[235] reported data for BV.However, this cohort included patients with MF, SS, and CD30-positive LPD.Of these,13 patients were retreated with BV, and the ORR upon re-treatment was 54%, with a CR rate of 23%.

Concerning PFS, two studies on BV[233, 238] reported median PFS of 13.2 and 16.7 months, respectively. Median PFS with mogamulizumab was 6.7 months(95% CI 5.6-9.4); however, this was derived from pooled data including patients with MF and SS across all stages[14].

Regarding DOR and OS, no studies that provided extractable data limited to CD30-positive, stage IIB or higher MF were found.

9.3| Discussion

No head-to-head comparisons of ORR, DOR, OS, AEs, or PFS were identified. Furthermore, it was not possible to extract data specifically for advanced-stage MF refractory to IFN-y or reti-noids. No data were available for DOR or OS. The certainty of the evidence was rated as“D(very low).”

Regarding the balance of benefits and harms, BV may be supe-rior to magamulizumab in terms of the objective response rate,although comparisons with oral etoposide were difficult. No significant differences were observed in PFS or the incidence of grade 3 or higher AEs. Therefore, the intervention group ap-peared to have slightly higher response rates, and the interven-tion may be associated with improved clinical outcomes.

Oral agents offer advantages in terms of economic burden and the frequency of hospital visits. Regarding patient(or caregiver)preferences for this treatment, there is significant uncertainty and heterogeneity in preferences. Although no studies have ex-amined the net benefit, cost, or resource utilization, standard dosing regimens are as follows: BV(50mg for intravenous in-fusion, JPY 388958 per vial) is administered at a dose of 2-3 vials per infusion every 3 weeks; mogamulizumab(20mg for intravenous infusion, JPY 171219 per vial) is administered with 3-4 vials per infusion weekly for the first five doses, followed by biweekly infusions; and oral etoposide(50mg capsules, JPY 1040.8 per capsule) is typically given at 50 mg daily for 21 consec-utive days followed by a rest period of 1-2 weeks. The required resources and costs of BV and mogamulizumab are considered to be similar. Oral etoposide is relatively inexpensive.

In the panel discussion, it was noted that BV may be superior to magomulizumab in terms of the ORR. Although a com-parison with oral etoposide was difficult, no objections were raised to using the antibody-drug BV before chemotherapeutic agents. Among the eight participants voting, one strongly rec-ommended performing the intervention, while seven recom-mended performing the intervention conditionally. Based on this, CQ5 was concluded as a“weak recommendation to per-form the intervention."

9.4| Clinical Considerations

In the NCCN Guidelines(Version 2.2024)[4], BV and mogam-ulizumab are listed in parallel; however, for MF with large-cell transformation, BV is prioritized above mogamulizumab. Oral etoposide is positioned as a lower-priority option than BV and mogamulizumab. In contrast, in the EORTC[2] and ESMO[3]guidelines, BV and mogamulizumab are listed as parallel treat-ment options; however, there is no mention of oral etoposide.

9.5| Future Research Directions

The present recommendation was primarily based on the objec-tive response rate; however, no data were available on DOR or OS, and no high-level evidence was found for PFS. In MF, which typically follows a prolonged clinical course, it remains unclear which treatment sequence, BV or magamulizumab, needs to be

prioritized. Clinical studies are warranted to evaluate the effi-cacy of initiating treatment with one agent and switching to the other upon treatment failure.

10| CQ6: In the First-Line Treatment of SS, Is Mogamulizumab Recommended Over Retinoids?

Recommendation

Due to limited evidence from comparisons of magomuli-zumab and retinoids as first-line therapy for SS, no recom-mendation was made.

● Recommendation: None

•Evidence level: D

•Agreement Rate:80%(4/5)

Voting Results

||1.Recommend|2. Suggest "mogamulizumab"|3. Suggest "retinoids"|4. 3. Resinoids"|5.No "retinoids"| |---|---|---|---|---|---| |CQ6||80.0%(4/5)|20.0%(1/5)||| |(1st vote)|||Total votes 5(Abstention 5)||| |CQ6 (second vote)|80.0%(4/5)|20.0%(1/5)|||| ||||Total votes 5(Abstention 5)|||

10.1| Background and Objectives

SS is characterized by erythroderma, lymphadenopathy, and leu-kemic involvement, indicating that the disease affects the skin and systemic compartments. Although SS is a systemic disease,multi-agent chemotherapy is not recommended due to its lim-ited DOR, high relapse rates, and safety reasons. As a result, first-line community standard treatment has included a combination of SDTs and retinoids. Mogamulizumab has been recognized as a treatment option because of its proven efficacy, particularly in managing blood involvement. However, it remains unclear whether mogamulizumab may be recommended over retinoids when considering both efficacy and safety. Further clarifica-tion of preferred agents in this setting may greatly aid in clinical decision-making.

10.2| Evidence

This CQ focused on patients(P) with SS scheduled to receive first-line treatment. The intervention(I) was mogamulizumab,and the comparator(C) was retinoids. Outcomes(O) consid-ered in the literature review included ORR(importance rating:8 points),DOR(8),OS(7), the relapse rate(7),AEs(7), and PFS(6).

The evidence base for magomulizumab included one RCT with a different comparator[14], one phase I/II single-arm trial[73], and two case series[232, 240]. Available evidence for retinoids(bexar-otene) consisted of one cohort study[64] and one case series[227].

The reported ORR for mogamulizumab was 37% in the RCT[14],47.1% in the cohort study by Duvic et al.[73],and 62.5[239]and 69.5%[231] in the two respective case series. Regarding ret-inoids, Duvic et al. reported a response rate of 24% in a phase II/III interventional trial focused on SS[64], and Abbott et al.showed a 44% response rate in a case series that included both MF and SS[226].

The median DOR for mogamulizumab was 17.3 months in one RCT[14]. In a cohort study by Duvic et al., which included both MF and SS, the median DOR was 10.4 months[14]. Concerning retinoids(bexarotene), the median DOR was longer than 10.0months in a cohort that included both MF and SS[64],while a case series by Abbott et al. reported a median DOR of 8 months[226].

As for relapse rates, no studies reporting relapse data for mogam-ulizumab were identified. In contrast, for retinoids(bexarotene),a cohort study by Duvic et al. involving patients with MF and SS reported a relapse rate≥36%[64].

No studies were identified that directly compared AEs between magomulizumab and retinoids. The incidence of grade≥3 or serious AEs for magomulizumab was 41% in the RCT by Kim et al.[14], 23.8% in the cohort study by Duvic et al.[73], and 47.6[239] and 18.5%[231] in two case series. In comparison,a case series by Abbott et al. reported a rate of 15% for bexar-otene[226].

Among serious AEs, in the RCT by Kim et al., the most fre-quently observed AEs for mogamulizumab included fever in 8 of 184 patients(4%) and cellulitis in five(3%)[14]. There were three AE-related deaths(2%), two of which(1%), sepsis and poly-myositis, were considered to be related to the treatment. Other observational studies on mogamulizumab showed variability in reported AEs, with no consistent high-frequency events. In contrast, for retinoids(bexarotene), the cohort study by Duvic et al.[64] and the case series by Abbott et al.[226] both reported similar frequently occurring AEs: hyperlipidemia(82%[64] and 100%[226], respectively) and hypothyroidism(29%[64] and 100%[226], respectively). One treatment-related death was re-ported in the cohort study[64].

Median PFS for magamulizumab was 7.7 months in the RCT[14],11.4 months in the cohort study by Duvic et al.[73], and 22[239] and 20.3 months[231] in the two case series. A case series by Abbott et al. reported a median PFS of 7 months for bexaro-tene[226].

10.3| Discussion

No studies that directly compared the key outcomes of interest between mogulizumab and retinoids were identified. One RCT with a different comparator was available for mogamuli-zumab[14]. Additional evidence for the intervention arm con-sisted of one cohort study[73] and two case series[231, 239]. One cohort study[64] and one case series[226] were identified for the comparator(retinoid), with both using single-arm observational designs.

However, these studies included heterogeneous populations in which MF and SS were often enrolled, the initial treatment status was not always specified, and concurrent therapies were some-times used. These factors contribute to a very serious concern regarding indirectness. Additionally, the route of administration differed between the two treatments, which may result in varia-tions and uncertainty depending on patient characteristics and clinical settings. Based on these limitations, the overall certainty of the evidence was rated as D(very low).

The balance of benefits and harms was not definitively assessed due to the lack of head-to-head comparative studies. While avail-able studies more frequently reported favorable clinical out-comes with omogamulizumab than with bearotexene, the types of AEs differed between the two agents. Mogamulizumab was associated with treatment-related deaths in a small number of cases; therefore, its potential risks may slightly outweigh those of bexarotene, although this conclusion is limited by the quality and indirectness of the available evidence.

No studies that assessed the net benefit, cost-effectiveness, or resource utilization associated with either intervention were identified. However, the use of magomulizumab was consid-ered to require greater healthcare resources than retinoids in Japan.

In the first round of panel voting, four of the five members voted to make a weak recommendation in favor of the intervention,while one member voted for a weak recommendation against the intervention. Although multiple studies supported the efficacy of the intervention arm, concerns were raised about the lack of di-rect comparative evidence, leading one member to question the strength of the evidence supporting the intervention. Following additional discussions, a second round of voting was conducted,which yielded the same result. Since a consensus exceeding 80%was not achieved, the panel reached a final decision of“no rec-ommendation" for CQ6. One panel member noted that mogamu-lizumab may still be a reasonable treatment option in cases with a high burden of circulating tumor cells.

10.4| Clinical Considerations

No other published guidelines that directly compared mogam-ulizumab with retinoids were found. As a reference, the NCCN guidelines(Version 2.2024)[4] for SS stratify treatment rec-ommendations according to the peripheral blood tumor bur-den, using 5000 Sézary cells/μL as the threshold between low and high tumor burden groups. According to these guidelines,bexarotene monotherapy is listed as a recommended first-line treatment option only in the low tumor burden group, whereas mogamulizumab monotherapy is recommended as a first-line option in both the low and high tumor burden groups.

10.5| Future Research Directions

Given the rarity of SS, conducting large-scale RCTs is likely to be difficult. A reasonable approach may be to perform prospective cohort studies comparing mogamulizumab and retinoids, fol-lowed by appropriate analytical evaluations.

11| CQ7: Is Low-Dose Electron Beam Therapy(Total Dose of 4-20 Gy) Recommended Over Conventional-Dose Electron Beam Therapy(Total Dose of 20-40 Gy) in the Management of MF?

1. In patients with plaque or tumor-stage lesions, is low-dose total skin electron beam therapy recommended over conventional-dose therapy?

Recommendation

We weakly recommend low-dose total skin electron beam therapy for patients with plaque or tumor-stage lesions.

● Recommendation: 2

● Evidence level: D

•Agreement Rate:88.9%(8/9)

Voting Results

|1. Recommend “low-dose “low-dose irradiation”|2. Suggest "low- dose irradiation”|3. Suggest “conventional- dose irradiation”|4. Recommend “conventional- dose irradiation”| |---|---|---|---| |CQ7-1 (1st vote)|11.1%(1/9)|88.9%(8/9)||

2. In patients with plaque or tumor-stage lesions, is low-dose local electron beam therapy recommended over conventional-dose therapy?

Recommendation

We weakly recommend low-dose local electron beam ther-apy for patients with plaque or tumor-stage lesions.

● Recommendation: 2

● Evidence level:D

● Agreement Rate: 100%(9/9)

Voting Results

|1. Recommend|2. Suggest|3. Suggest|4. Recommend| |---|---|---|---| |“low-dose|"low-dose|"conventional-|"conventional-dose| |irradiation"|irradiation"|dose irradiation"|irradiation"| |CQ7-2||100%(9/9)|| |(1st||Total votes 9(Abstention 1)|| |vote)||||

11.1| Background and Objectives

MF is a malignancy with high radiosensitivity, and RT utilizing electron beams has demonstrated excellent clinical effectiveness.Local electron beam therapy is employed for residual lesions or newly emerging lesions refractory to other treatments, irrespec-tive of the timing of occurrence. In cases involving disseminated cutaneous involvement, TSEBT represents a therapeutic option.Conventional electron beam therapy has employed total doses of 20-40Gy, with lower fraction sizes in consideration of minimiz-ing cutaneous toxicity. However, low-dose fractionated regimens,

with total doses ranging between 4 and 20Gy, have been reported.Nevertheless, the optimal dosing strategy for local and total skin radiation therapies remains unclear in terms of balancing thera-peutic efficacy and the risk of AEs. The establishment of the most appropriate dosing regimen may provide meaningful guidance in clinical decision-making regarding treatment selection.

11.2| Evidence

1. TSEBT

Patients(P) with plaque or tumor-stage MF were targeted, with the intervention(I) being low-dose TSEBT(total dose 4-20Gy)and the control(C) being conventional-dose TSEBT(total dose 20-40Gy). The outcomes(O) assessed were OS, ORR, DOR, the CR rate, AEs, recurrence rate, and PFS. A systematic literature review did not identify any RCTs. Five prospective cohort stud-ies[110-114], eight retrospective cohort studies[240-247], one pooled analysis[248], and one meta-analysis[249] were included.

A pooled analysis of four retrospective studies[242, 244, 245, 247]comparing low- and conventional-dose groups showed no signif-icant differences in ORR(96.4% vs. 94.4%; odds ratio 0.618, 95%CI 0.150-2.554) or the CR rate(32.7% vs. 43.1%; odds ratio 1.554,95% CI 0.842-2.870).

Outcomes including DOR, the recurrence rate, and AEs were reported in a single retrospective study on 26 patients(12 low-dose, 14 conventional-dose), which showed no significant differ-ences in median DOR(4 months vs. 7 months), the recurrence rate(100% in both groups), or the incidence of grade 3 AEs(0%vs.7.1)[245].

Similarly, one retrospective study including 25 patients(12 low-dose,13 conventional-dose) reported no significant difference in mean PFS(5.3 months vs.15.7 months,p=0.28)[247].

No comparative data on OS were available.

2. Local electron beam therapy

Patients(P) with plaque or tumor-stage MF were targeted, with the intervention(I) being low-dose local electron beam therapy(total dose 4-20 Gy) and the control(C) being conventional-dose local electron beam therapy trial of dose 40-256.8) and the control(C) being conventional-dose local electron beam therapy (total dose 20-40 Gy). The outcomes(O) assessed were OS, ORR, DOR, the CR rate, AEs, the recur-rence rate, and PFS. No comparative studies were found. Three retrospective cohort studies[105-107] evaluating low-dose regi-mens for palliative intent were included.

Among these, an 8Gy in 2 fractions regimen in 24 MF patients with 65 plaque or tumor lesions achieved an ORR of 98% and a CR rate of 92%[105]. Another study on 46 CTCL patients with 242 lesions receiving a single 8-Gy dose reported an ORR of 99%and a CR rate of 84% among 156 plaque or tumor lesions[107].A third study on 41 patients with CTCL(97.5% MF) and 225 le-sions(67.6% plaque/tumor lesions) evaluated varying regimens(4Gy in 2 fractions, 8Gy in 2-4 fractions, and 12Gy in 3-6 frac-tions), and reported an ORR of 87% with a 6-month CR rate of 46%[106].

AEs were minimal, limited to acute dermatitis(grade≥2 in 7.1%)[106] or localized erythema[107]. No late AEs were ob-served[107].

The recurrence rate was 0% in the single 8Gy treatment study[107].

No studies evaluated OS, DOR, or PFS.

11.3| Discussion

1. TSEBT

Four retrospective cohort studies comparing low-dose and conventional-dose TSEBT were identified; however, each was limited by a small sample size. The quality of evidence for assess-able outcomes was compromised by a substantial risk of bias, in-consistency, imprecision, and indirectness, leading to a GRADE assessment of“D(very low certainty).”

No significant or clinically significant differences were observed in favorable outcomes, such as ORR or the CR rate, or in un-favorable outcomes, including the recurrence rate or treatment-related AEs.

While no studies explicitly examined the net clinical benefit,cost-effectiveness, or resource utilization, low-dose TSEBT is expected to provide practical advantages, including reduced treatment sessions, shortened hospitalization or outpatient care periods, decreased resource demands, and the feasibility of re-irradiation in cases of relapse.

Taking these considerations into account, the expert panel reached consensus in favor of the intervention. However, given the extremely limited quality of evidence, the recommendation was classified as a“weak recommendation(suggestion)."

2. Local electron beam therapy

No studies directly comparing low-dose and conventional-dose local electron beam therapy were identified. Only three ret-rospective cohort studies examining low-dose therapy alone were available, resulting in a GRADE rating of“D(very low certainty)."

Since direct comparisons were not possible, a definitive assess-ment of the balance between benefits and harms was not possi-ble. Nevertheless, since AEs are generally dose-dependent, it is reasonable to infer that low-dose therapy may result in a reduced incidence and severity of treatment-related toxicity.

Although no studies addressed cost-benefit analyses or resource implications, low-dose therapy is anticipated to reduce treatment frequency, potentially alleviating the burden on patients and healthcare systems, while also allowing for re-irradiation in the event of disease recurrence.

Based on a comprehensive panel discussion, there was unani-mous agreement to issue a“weak recommendation(suggestion)”in support of low-dose local electron beam therapy.

11.4| Clinical Considerations

A standardized definition of“low-dose” has not yet been estab-lished for total skin or local electron beam therapy. Prospective co-hort studies on TSEBT evaluated doses, such as 10Gy[110], 12Gy[111-113], and 8Gy in 2 fractions[114], while the majority of retro-spective cohort studies utilized doses of 10 or 12Gy[242, 244-246].A retrospective cohort study comparing a 4-Gy regimen with the conventional 30-Gy regimen demonstrated a significantly lower CR rate in the former(10% vs.68.0%,p<0.01), leading to its discon-tinuation. In light of these findings, a dose of 8-12Gy is considered to be appropriate when implementing low-dose TSEBT.

Regarding local electron beam therapy, 4Gy in 2 fractions was reported to fail at achieving CR in approximately 70% of lesions,necessitating early re-irradiation[105]. Furthermore, another study indicated a slightly lower ORR for 4Gy than for 8Gy(82.8%vs.91.5%,p=0.057), and the 1-year rate of freedom from local re-treatment was significantly higher with 8Gy or 12Gy than with 4Gy(92% or 96% vs.77%,p=0.034)[106].Therefore, when considering low-dose local electron beam therapy, clinicians need to recognize that the 4Gy in 2 fractions regimen may be inferior in efficacy to the 8 or 12Gy regimen and need to select the dose accordingly. It is also important to note that all referenced studies were conducted with palliative intent and, thus, the reported dosing strategies can-not be extrapolated to curative settings for solitary lesions.

11.5| Future Research Directions

TSEBT remains a technically challenging modality for the treat-ment of extensive cutaneous involvement, primarily due to the limited number of facilities equipped to deliver this therapy. The commonly used Stanford technique requires patients to remain standing with their arms away from the body for a prolonged pe-ri, thereby imposing a substantial physical burden on patients.Additionally, radiation dose distributions may vary depending on anatomical regions. In contrast, total skin irradiation using intensity-modulated RT with TomoTherapy, a technique that has recently been developed, allows for treatment in the supine posi-tion and improves dose homogeneity. However, the use of X-rays in this approach introduces potential risks, such as bone marrow sup-pression, an uncommon AE in electron beam therapy. To date, no direct comparative studies between these two modalities have been reported. Since the availability of RT equipment differs by institu-tion, a multicenter prospective cohort study comparing these two treatment methods by selecting facilities capable of delivering ei-ther TSEBT or TomoTherapy-based irradiation may be warranted.

12| CQ8: Is Allogeneic Hematopoietic Stem-Cell Transplantation Recommended Over Other Pharmacological Therapies for Patients With Advanced-Stage MF(Stage IIB or Higher)?

Recommendation

Allogeneic hematopoietic stem-cell transplantation may be proposed as a treatment option for patients with advanced-stage MF who are eligible for transplantation over other pharmacological therapies in terms of suppressing relapse or disease progression.

Supporting Information: Patients with MF or SS with one or more of the following three poor prognostic factors were in-cluded in the quasi-RCT[118].

1. Refractory or relapsed disease after one or more lines of sys-temic therapy.

2. Large-cell transformation within 2years of diagnosis.

3. N3 lymph node involvement or visceral involvement according to the International Society for Cutaneous Lymphoma(ISCL) and EORTC classification.

● Recommendation: 2

· Evidence level: C

•Agreement Rate: 100%(9/9)

Voting Results

|1. Recommend "allogeneic hematopoietic stem cell transplantation" transplantation"|2. Suggest "allogeneic hematopoietic stem cell transplantation"|3. Suggest "other pharmacological therapies"|4. Recommend "other pharmacological therapies"| |---|---|---|---| |$$CQ8$$|100%||| |(1st vote)|(9/9)||| |||Total votes 9(Abstention 1)||

12.1| Background and Objectives

There is no established standard treatment for advanced MF(stage IIB or higher), the effects of pharmacological therapy are transient, and the overall prognosis remains poor. Allo-HSCT may provide long-term remission in patients with MF.The usefulness of allo-hSCT with reduced-intensity condi-tioning has been demonstrated in this setting, enabling trans-plantation in a broader age range. However, allo-HSCT is associated with NRM due to GVHD, conditioning-related tox-icity, and infections. Moreover, disease relapse after transplan-tation is not uncommon, and the overall benefit of allo-HSCT for advanced-stage MF remains unclear. Treatment selection will be strongly supported by establishing whether allogeneic transplantation needs to be recommended over nontransplant pharmacological therapies.

12.2| Evidence

This CQ targeted patients with advanced MF(stage IIB or higher)(P), with the intervention(I) defined as allo-HSCT,and the comparator(C) being other pharmacological thera-pies. A literature review was conducted for this CQ using the following primary outcomes(O): OS(importance rating: 9 points),PFS(8),NRM(7), the relapse rate(7),GVHD(7), and QOL(8).

The literature search and screening identified one quasi-RCT[118] that directly compared the intervention group and control group, as well as eight case series studies[115-117, 250-254]with more than 10 cases in the intervention group, which were included in the analysis.

In the quasi-RCT[118], OS was slightly longer in the interven-tion group than in the control group(median OS: not reached vs.26.9 months, p=0.092). A post hoc intent-to-treat(ITT) analysis of the ITT population limited to patients with MF also showed no significant differences(hazard ratio 0.43, 95% CI 0.16-1.17).

In contrast, PFS was significantly longer in the intervention group in the quasi-RCT[118](median PFS:9 months vs.3 months, haz-ard ratio 0.38,95% CI 0.21-0.69,p<0.0001).

In the quasi-RCT, NRM was significantly higher in the interven-tion group(8.5% vs.0%,p=0.0171)[118]. In the seven case series of the intervention group alone[115-117, 251-254], treatment-related mortality or NRM varied depending on the evaluation method and timing and, thus, were not pooled; however, re-ported rates ranged between 10.4% and 35.9%.

The relapse rate was significantly lower in the intervention group in the quasi-RCT[118](45.4% vs. 86%, hazard ratio 0.29, 95% CI 0.17-0.58). Among the eight case series of the intervention group[115-117,250-254], the combined relapse rate in the two studies was 38.7%. In the six studies that reported relapse or progres-sion rates, the combined rate of relapse or progression was 53.3%[115-117,250-252].

In the quasi-RCT, the cumulative incidence of acute GVHD of all grades was 55.9% and 1-year chronic GVHD was 31.4% in the in-tervention group. No GVHD occurred in the control group[118].In the eight case series of the intervention group[115-117,250-254], the pooled cumulative incidence of grade 2-4 acute GVHD was 39.9% and chronic GVHD ranged between 32% and 86%.

QOL was assessed in the quasi-RCT[118]. Using the EORTC Quality of Life Questionnaire C30, the intervention group showed a mean increase of 0.62(standard deviation 0.22) per hospital visit. In addition, the Skindex 29 score decreased by a mean of 3.4(standard deviation 1.2) per visit in the interven-tion group.

12.3| Discussion

Only one quasi-RCT[118] directly compared allo-HSCT with other pharmacological therapies for advanced-stage MF. This study was unblinded, presenting a risk of bias. In addition, the observational studies[115-117, 250-254] included in the anal-ysis were all single-arm case series of the intervention group,which also carry a high risk of bias. Based on these factors, the strength of evidence for this CQ is rated as“C(weak)."

In terms of the balance of benefits and harms, the quasi-RCT[118] showed that the intervention group had favorable out-comes in terms of PFS and QOL. However, the intervention group also exhibited a higher NRM rate and experienced GVHD,which was not observed in the control group. Therefore, while the intervention(allo-HSCT) may increase desirable effects in terms of disease control, it may also increase undesirable effects in terms of AEs.

No studies have directly compared the net benefit and the bal-ance of costs and resources between the two approaches. The

implementation of the intervention requires the use of a number of medications, including conditioning regimen agents, immuno-suppressive agents, and medications for infection prevention and treatment, as well as frequent blood transfusions during periods of cytopenia. Therefore, substantial costs are incurred during the intervention period. However, if remission is achieved through the intervention, a subsequent reduction in long-term treatment costs may be expected. In contrast, in the control group, the im-mediate costs associated with the intervention may be avoided;however, ongoing treatment-related expenses are likely to con-tinue over an extended period. Due to these factors, it is difficult to confirm a clear advantage in terms of cost-effectiveness.

In the panel discussion, the findings of the quasi-RCT served as the main basis for deliberation. The panel carefully weighed the benefits of the intervention, such as prolonged PFS and improved QOL, against its harms, including increased NRM[118]. All members agreed that the intervention may be conditionally rec-ommended, provided that its indication is carefully considered.Accordingly, CQ8 was concluded to represent a“conditional rec-ommendation in favor of the intervention." In addition, it was decided that the key eligibility criteria for the quasi-RCT forming the basis for this recommendation will be listed as Supporting Information.

12.4| Clinical Considerations

According to the guidelines of BAD[1], EORTC[2], ESMO[3],and NCCN(Version 2. 2024)[4], allo-HSCT is described as a treatment option to be considered for patients with MF and SS at stage IIB or higher who are refractory to various therapies.

While the intervention offers the potential for long-term remis-sion, it also carries risks, such as NRM and GVHD, and, thus,requires careful decision-making based on individual patient values and preferences. During the panel discussion, a patient representative shared the following perspective:“Due to the poor prognosis of the disease, I was very anxious, but ultimately chose transplantation. If there is a high likelihood of death from the underlying disease even after nontransplant therapies, I would still prefer to undergo transplantation despite the risk of treatment-related mortality. I discussed the need for a leave of absence with my workplace prior to transplantation; they were supportive, but I ultimately had to take 1.5 years off from work."This highlights the importance of providing thorough pretreat-ment explanations to ensure patient understanding and the need for close collaborations with hematologists. The implementation of the intervention needs to be limited to facilities with hema-tologists who are experienced in allo-HSCT. It is also important to note that donor coordination may require a certain amount of time.

12.5| Future Research Directions

The primary body of evidence, aside from the single quasi-RCT,currently consists solely of single-arm case series of the inter-vention group. Further comparative studies between the inter-vention and control groups are needed to establish whether OS,DFS, and the relapse rate may be improved without increasing

NRM in the intervention group. Detailed data on patients who have received the intervention are being accumulated in the Transplant Registry Unified Management Program managed by the Japanese Society for Transplantation and Cellular Therapy and the Japanese Data Center for Hematopoietic Cell Transplantation. In addition, the Japanese Society for Cutaneous Malignancies launched a prospective registry of major skin can-cers,including cutaneous lymphoma, in 2024.These patient reg-istries are expected to serve as valuable resources for building future evidence.

13| CQ9: Is Treatment With Brentuximab Vedotin Recommended Over Oral Retinoids or Methotrexate for Patients With pcALCL for Whom Skin-Directed Therapy Is Ineffective?

Recommendation

We recommend treatment with trexubimax vedotin over oral retinoids or methotrexate for patients with pcALCL who are unresponsive to skin-directed therapy.

• Recommendation: 1

- Evidence level: C

•Agreement Rate:100%(5/5)

Voting Results

|1. Recommend "performing treatment with Brentuximab treatment with Brentuximab vedotin" vedotin"|2. Suggest "performing treatment with Brentuximab vedotin"|3. Suggest "performing treatment with Brentuximab vedotin"|4. Recommend "not performing treatment with bentuximab vedotin"| |---|---|---|---| |CQ9 (1st vote)|100% (5/5)|Total votes 5(Abstention 5)||

13.1| Background and Objectives

Frequently, pcALCL is managed with SDTs, such as surgery or RT. Even in cases of recurrence, disease control may frequently be achieved by repeating SDTs. In patients with extensive cutaneous involvement or lymph node metastasis, SDT alone may be insuf-ficient to control the disease. Under these conditions, systemic treatments, such as oral retinoids, methotrexate, or multi-agent chemotherapy(e.g.,CHOP), may be considered. In the field of he-matological oncology, the anti-CD30 antibody-drug conjugate BV has been approved for systemic ALCL expressing CD30, and its efficacy is being increasingly recognized. Evidence supporting the utility of BV for pcALCL is also accumulating. Therefore, a com-parison between BV and conventionally used treatments, such as oral retinoids and methotrexate, may clarify which to recom-mend, thereby informing optimal treatment selection.

13.2| Evidence

The patients(P) targeted in this CQ comprised patients with pcALCL. The intervention(I) was treatment with BV, and the

comparison(C) was oral retinoids or methotrexate. The out-compos) evaluated included OS(importance rating: 8 points),ORR(8),DOR(8),AEs(8), the relapse rate(7), and PFS(7).

Relevant literature included two interventional studies(one being a single-arm phase II trial on BV[233], and the other an open-label phase III RCT comparing BV with bexarotene or meth-otrexate[13]), along with four case series[234, 235, 255, 256].However, in the RCT, subgroup analyses comparing bexarotene versus methotrexate were not conducted, and some patients re-ceived higher-than-standard doses of methotrexate.

Based on pooled data from the two interventional studies[13,233], the ORR in the BV arm was 77.8%(14/18), whereas that in the comparator arm was 33%(5/15). Among the case se-ries[234,235,255,256], pooled findings from two studies each on BV and methotrexate showed an ORR of 75%(9/12) in the BV group and 81.8%(9/11) in the methotrexate group.

In an RCT[13], the median DOR was 15.1 months in the inter-vention group(43 responders) and 18.3 months in the control group(13 responders), without statistical testing for significance.However, this dataset included combined cases of MF. No case series mentioned the DOR.

Regarding AEs, although the data contained mixed data includ-ing cases of MF, the combined analysis of two interventional studies[13, 233] showed that the incidence of grade 3 or higher AEs was 46.8%(29/62) in the control group and 40.9%(27/66) in the intervention group. In one case series[235], which included data from patients with MF and SS, the incidence of AEs in the intervention group was 6.0%(4/67).

Interventional studies did not report relapse rates. However, a pooled analysis of two observational studies[235, 255] showed that the relapse rate was 71.4%(5/7) in the control group and 54%(36/67) in the intervention group. It is important to note that the data for the intervention group included patients with MF and SS.

In an RCT[13], median PFS was significantly longer in the in-tervention group(12 responders) than in the control group(5 responders): 27.5 months vs. 5.3 months, with a hazard ratio of 0.252(95% CI 0.081-0.790). No case series mentioned PFS.

No studies that addressed OS were identified.

13.3| Discussion

One RCT comparing BV with bexarotene or oral methotrexate was identified; however, no subgroup analysis was conducted to compare bexarotene and methotrexate separately. Furthermore,the methotrexate group included cases treated with high doses.The RCT was not blinded, and other studies had small sample sizes and a high risk of bias. Therefore, the certainty of the evi-dence was rated as“C(low).

Regarding the balance of benefits and harms, the interventional group showed superiority in terms of the response rate and PFS in the RCT, whereas the incidence of AEs was similar be-tween groups. Therefore, the intervention appears to be superior

overall. Nevertheless, BV carries a risk of peripheral neuropathy,which may be a critical factor in treatment selection depending on the patient's occupation or daily functional activities.

Concerning patient values and preferences, the intervention and control groups in the studies included both comprised patients with relapsed or refractory disease, suggesting that many patients are seeking treatment efficacy. However, BV is an intravenous drug requiring regular hospital visits, while bexarotene and meth-otrexate are oral agents that allow for longer intervals between visits. In addition, BV is associated with peripheral neuropathy,which may be a significant consideration depending on the pa-tient's occupation or lifestyle. These factors indicate that there may be considerable variabilities in patients' values and preferences.

Although no studies have evaluated net benefits, costs, or resource use, BV(50mg) costs JPY 388958 per vial, with 3-2 vials typically used per dose every 3 weeks. Methotrexate(2mg) costs JPY 87.2 per tablet, with a usual dosage of 3-6 tablets per week. Bexarotene(75mg) costs JPY 2846.7 per capsule, with a typical daily dosage of 4-8 capsules. Therefore, the three-week cost of BV is estimated at JPY 777916 to 1166874, while methotrexate costs approximately JPY 784.8 to 1569.6, and bexarotene IPY 239122.8 to 478245.6. BV is the most expensive, followed by bexarotene, with methotrexate being the least expensive among the three treatments.

In the panel discussion, all members agreed to strongly recommend the intervention based on the findings of the RCT, particularly the improved response rate and prolonged PFS, which were deemed to outweigh potential AEs. Based on this, CQ9 was concluded with a strong recommendation to perform the intervention.

13.4| Clinical Considerations

According to the NCCN Guidelines(Version 2. 2024)[4], BV,methotrexate, administered at doses up to 50 mg/week, which exceed those typically used in Japan, and the systemic admin-istration of retinoids(bexarotene) are listed equally as first-line treatment options for multifocal lesions.

The BAD guidelines[1] list chemotherapy, including methotrex-tate and BV, in parallel as treatment options for extensive skin involvement and progression to visceral organs or lymph nodes.There is no mention of retinoids.

The ESMO guidelines[3] describe low-dose methotrexate(5-20mg/week) and low-dose RT as first-line treatments for multifocal lesions, while BV is listed as a second-line treatment.No recommendations regarding retinoids are provided.

Accordingly, none of the guidelines recommend BV over other agents for pcALCL. In clinical practice, treatment decisions need to consider not only efficacy and safety, but also economic factors and patient preferences.

13.5| Future Research Directions

All studies addressing this CQ, including both interventional and observational studies, have been limited to Western populations.

Previous studies suggested that the prognosis of pcALCL in Japan was inferior to that in Western populations[257, 258]. Although further data from Japanese and Asian populations are needed,given the rarity of the disease, it is considered more feasible to collect retrospective studies comparing intervention and control treatments under this CQ.

14| CQ10: Is Skin-Directed Therapy in Combination With Oral Retinoids Recommended Over Skin-Directed Therapy Alone for Indolent ATL With Skin Lesions(Smoldering and Chronic Types Without Poor Prognostic Factors)?

Recommendation

We weakly recommend a combination of oral retinoids and skin-directed therapy instead of skin-directed therapy alone for indolent ATL with skin lesions(smoldering and chronic types without poor prognostic factors).

● Recommendation: 2

● Evidence level: D

● Agreement Rate: 100%(6/6)

Voting Results

|1. Recommend|2. Suggest|3. Suggest|4. Recommend| |---|---|---|---| |"skin-directed therapy in combination with|"skin-directed therapy in|"skin-directed therapy alone|| |oral retinoids"|oral retinoids"|oral retinoids"|therapy alone"| |Con|100%|(1st vote)|(6/6)| |Total votes 6(Abstention 4)||||

14.1| Background and Objectives

The standard treatment for indolent ATL(smoldering and chronic types without poor prognostic factors) in the“Guidelines for the Treatment of Hematopoietic Malignancy" of the Japanese Society of Hematology is watchful waiting[259]. However, this recommen-dation is based on a lack of evidence to show that the introduction of conventional chemotherapy, such as combination chemother-apy,in patients with indolent ATL improves their prognosis. On the other hand, the skin lesions of indolent ATL are regarded as lesions that require treatment in dermatology because of pruritus and cos-metic aspects that affect the QOL of patients. SDTs, such as UV light irradiation and local RT, are commonly used for local control.Another promising treatment, currently not covered by insurance,is oral retinoids; it is not known whether the combination of SDTs and oral retinoids on ATL skin lesions is superior to SDTs alone.Further clarification of whether SDTs in combination with oral ret-inoids is recommended will greatly aid in treatment selection.

14.2| Evidence

Indolent ATL with skin lesions(smoldering and chronic types without poor prognostic factors) was included(P), with SDTs

plus oral retinoids as the intervention(I) and SDTs alone as the control(C). A literature review was conducted on CQs with the response rate(importance rating: 8 points), DOR(7), PFS(7),AEs(6), and time to response(5) as the major outcomes(O).

After a literature search and screening, four case-control studies[155,163,260,261] were selected for analyses.

In a case-control study on nine patients(five with and four with-out SDT) treated with retetrate for the smoldering type with skin lesions, one CR and seven PRs(89% response rate) were observed at 3 months[155]. In a case-control study on retinotin(ATRA) in six indolent ATL patients with skin lesions by Maeda et al., two achieved PR and four stable disease(SD)(33% response rate)[260, 261]. In a case-control study by Sawada et al.[163] on pa-tients with BSA<10% and<2 nodules or tumors, 12 CR, 15 PR,and 2 SD(93% response rate) were reported among 29 patients in the SDT alone group. Although no studies have directly compared the two groups, the combination of SDTs and oral retinoids may achieve a high response rate even in a short period of time.

In a case-control study on nine patients(five with and four with-out SDT) treated with retetrate for smoldering-type skin lesions by Yonekura et al., 100%(9/9, nine with grade 2 cheilitis, four with grade 3 onychomycosis, and one with grade 2 back pain) of patients developed AEs. In the study on ATRA by Maeda et al., including the acute, lymphoma, chronic, and smoldering types, 50% of cases(10/20, five headache, two liver dysfunction, two hyperlipidemia,and one anorexia) developed AEs, of which one was grade 3 or higher. No studies on the incidence of AEs in the control group are available for comparison; however, an increase in AEs may occur.

No studies that examined DOR, PFS, or time to response were identified.

14.3| Discussion

No studies directly compared any outcomes between the two groups. As noted above, there was no evidence of a“benefit” in the intervention group for the response rate. The strength of the evidence was assigned a“D”(very weak).

There is no high-quality evidence comparing desirable effects with regard to the balance of benefits and harms; however,case-control studies on the intervention group have shown some responses. In terms of undesirable effects, studies on the inter-vention group reported AEs, mostly grade 1 or 2.Therefore, it is possible that the desirable effects of the intervention outweighed the undesirable effects.

No studies on the importance of patient values and intentions with respect to the response rate(benefit; importance 8 points),DOR(benefit; 7), PFS(benefit; 7), AEs(harm; 6), and time to re-sponse(benefit; 5) were identified. There may be important un-certainty and variability in these key outcomes in terms of age,frequency of hospital visits, and cost.

Although there are no comparative studies on the balance be-tween net benefit and cost/resource, the intervention group requires more money than the control group due to the use of

medications. The intervention group may also require more resources than the control group because of the use of drugs;however, the control group may also require more resources depending on the frequency of visits, making an evaluation dif-ficult. In other words, although the intervention group has to pay for drugs, the intervention may reduce the frequency of UV irradiation in control SDT, which may also reduce the cost of treatment.

The panel discussed the potential for a higher short-term re-sponse rate with the combination of oral retinoids and SDTs, and also that AEs are considered to be acceptable. Therefore, it was agreed that the combination of oral retinoids and SDTs needs to be used, particularly for patients who are refractory to SDT.All six voting members voted“weakly recommend,” and since there was unanimous agreement, CQ10 was decided as the“con-ditional recommendation for this intervention.”

14.4| Clinical Considerations

The 2023 edition of the“Guidelines for the Treatment of Hematology Malignancy” of the Japanese Society of Smoldering and chronic types without poor prognostic factors)[259], and referring to the Guidelines for Cutaneous Lymphomas for the smoldering type with skin lesions only. In other words,SDTs are recommended for patients with skin lesions, and reti-noids and IFN are listed as treatment options for patients refrac-tory to SDTs.

14.5| Future Research Directions

There are currently no reported prospective studies on the effi-cacy of oral retinoids for this clinical issue. Furthermore, there are no retrospective or prospective studies with large sample sizes of oral retinoids plus SDTs, nor are there any large inte-grated studies or prospective studies on SDTs alone for indolent ATL. After a literature search and panel meeting, there was one phase II study on bexarotene in Japanese patients with indolent ATL and skin lesions and patients with aggressive ATL who had skin relapse after achieving remission following≥1 regimen of systemic chemotherapy[156]. Although large-scale prospective studies are difficult because of the rarity of this disease, the accu-mulation of further evidence through multicenter retrospective studies is desirable in the future.

15| CQ11: Is Rituximab Plus Multi-Agent Chemotherapy Recommended Over Rituximab Monotherapy for Refractory/Multifocal Indolent CBCL(PCMZL and PCFCL) Resistant to Skin-Directed Therapies?

Recommendation

We weakly recommend rituximab monotherapy over ritux-imab plus multi-agent chemotherapy for refractory/mul-tifocal indolent CBCL(PCMZL and PCFCL) resistant to skin-directed therapies.

● Recommendation level: 3

● Evidence level:D

● Agreement Rate:77.8%(7/9)

Voting Results

||1. Recommend "rituximab plus multi-agent chemotherapy"|2. Suggest (rituximab plus multi-agent chemotherapy"|3. Suggest (rituximab monotherapy"|4. Recommend "rituximab monotherapy"| |---|---|---|---|---| |CQ11|||77.8%|22.2%| |(1st vote)|||(7/9)|(2/9)| ||Total votes 9(Abstention 1)||||

15.1| Background and Objectives

PCMZL and PCFCL have a good prognosis and are generally treated with SDTs. Treatment options for these two diseases,which are resistant to SDTs or develop as multifocal cutaneous lesions, include rituximab monotherapy and rituximab plus multi-agent chemotherapy used for aggressive B-cell lymphoma.It is unclear whether rituximab plus multi-agent chemotherapy is recommended over rituximab monotherapy based on efficacy and safety. Further clarification of which treatment is recom-mended based on these points may contribute to selecting be-tween these two treatments.

15.2| Evidence

Patients with PCMZL and PCFCL(P) were included in this CQ.We set the intervention(I) and control(C) as rituximab plus multi-agent chemotherapy and rituximab monotherapy, respec-tively. The primary outcomes(O) included ORR(importance rating:8 points), OS(7), the recurrence rate(7), DOR(7), AEs(8), and PFS(6).

We identified 11 retrospective cohort studies[176-181,198,262-265] and one open-label RCT[266].

One retrospective cohort study compared the response rate be-tween the two groups[262]. Response rates were 90% in the intervention group and 100% in the control group, showing no significant difference. No significant difference in the response rate(92.3% vs.96.9%, odds ratio 0.380, 95% CI 0.041-3.517) was observed in a pooled analysis based on three retrospective cohort studies with an intervention group alone[198, 263, 265], and seven studies with a control group alone[176-181,264]. None of the studies were consistent in the methods of assessing responses or response assessment time points, and the numbers of patients enrolled in the studies were generally small.

AEs were reported in seven cohort studies[176, 178-181, 198,264] and in one open-label RCT[266]. In the RCT, grade>3 AE rates were significantly higher in the intervention group than in the control group(33.3% vs.9.4%). However, no detailed method for randomization was defined, and patients enrolled in this RCT had systemic lymphoma other than cutaneous lymphoma.Grade>3 AE rates were significantly higher in the intervention

group than in the control group(34.4% vs. 5.4% vs. 5.4%, odds ratio 9.236, 95% CI 4.981-17.124) through a pooled analysis based on one retrospective cohort study with an intervention group alone[263], and 6 studies with a control group alone[176,178-181,264].

None of the studies reported OS.

None of the studies reported the recurrence rate, DOR, or PFS in the intervention group.

Consequently, for patients with refractory and/or multifocal in-dolent CBCL, no significant difference was observed in the re-sponse rate between the two groups, and the AE rate was lower in the control group.

15.3| Discussion

Most studies had a single-arm design from a single institute.Therefore, we assessed the quality of evidence as a high risk of bias and indirectness of evidence for both the response rate and AEs, which were verifiable, respectively.

Regarding the balance between desirable and undesirable con-sequences, no significant difference was detected in desirable consequences between the two groups, whereas AEs, one of the undesirable consequences, were significantly higher in the intervention group. The intervention may increase undesirable consequences.

Although an increase was noted in the response rate in the inter-vention group, it is unclear whether OS was extended.

No comparative study on the balance between desirable effects and resource use(OFF) and AEs may generally be higher in the intervention group than in the control group. Drug costs per course in regimens for a body surface area of 1.6m2 are as follows: rituximab JPY 94007x2,cyclophosphamide JPY(1154x2)+(304x2), doxorubicin JPY 6210+(1989x3), vincristine JPY 1988x2, and prednisolone JPY 9.8x12x5, totaling JPY 207671 for the intervention group(R-CHOP therapy) and JPY 188014 for the control group. Based on the number of drugs, the control group is slightly more cost-effective. Resource use as a result of regular blood testing and additional treatments when AEs occur may be higher in the in-tervention group than in the control group.

In the discussion at the panel meeting, we agreed that ritux-imab plus multi-agent chemotherapy is not recommended for refractory/multifocal indolent CBCL for safety and resource use reasons. In voting, seven(77.8%) and two(22.2%) of the nine committee members weakly and strongly recommended ritux-imab monotherapy, respectively. We concluded a weak recom-mendation against the intervention.

15.4| Clinical Considerations

Treatment recommendations for indolent CBCL have been based on the 2008 EORTC and ISCL guidelines[169], which

recommended surgery, RT, topical steroids, local steroid injec-tions, and intravenous rituximab therapy for solitary or grouped lesions of the disease. Other options included topical injections of IFN-α and rituximab, which are not available in Japan. A re-cent review did not recommend the use of rituximab plus multi-agent chemotherapy[267]. AEs were significantly higher in the intervention group. Taking into account the need for counter-measures and testing, additional resource use may be required for the intervention group. Given the balance of benefits, cost-effectiveness, and resource use, the intervention does not ap-pear to be reasonable for patients, physicians, and other medical professionals.

15.5| Future Research Directions

No RCTs have been conducted on this clinical issue. Given the rarity of the disease, integrated research on findings from retro-spective studies comparing intervention and control groups may provide a reasonable solution.

16| CQ12: Is Skin-Directed Therapy± Rituximab Therapy Recommended Over Rituximab Plus Multi-Agent Chemotherapy for PCLBCL, LT in Elderly Cases?

Recommendation

We weakly recommend rituximab plus multi-agent chemo-therapy over skin-directed therapy±rituximab therapy for PCLBCL,LT in elderly cases.

● Recommendation level: 3

● Evidence level:D

● Agreement Rate: 60%(6/10)

Voting Results

|1.Recommend 2. Suggest “skin-directed therapy ± therapy± rituximab therapy± rituximab therapy± therapy± rituximab therapy"|3. Suggest "rituximab plus multi-agent chemotherapy" (6/10)|4.Recommendent 36269. No significant differences were 0.570-2.104) through a pooled analysis based on|| |---|---|---|---| |CQ12|||| |(1st vote)||(6/10)|(4/10)| |||Total votes 10(Abstention 0)||

16.1| Background and Objectives

PCLBCL, LT is an aggressive lymphoma that occurs predomi-nantly in the lower limbs of elderly women. In Japan, the me-dian age at diagnosis is in the 70s, and elderly patients are often encountered as a result of the aging society. In patients with PCLBCL, LT, rituximab plus multi-agent chemotherapy is rec-ommended, according to DLBCL. Regarding elderly patients with multiple comorbidities or with reduced PS, non-intensive treatments, such as SDT alone or in combination with rituximab monotherapy, may be selected for localized lesions in real-world settings. It is unclear whether non-intensive treatments are as effective as rituximab plus multi-agent chemotherapy. Further

clarification of which treatment is recommended based on these points may contribute to selecting between these treatments.

16.2| Evidence

Patients with PCLBCL,LT(P) were included in this CQ. We set the intervention(I) and control(C) as SDTs± rituximab therapy and rituximab plus multi-agent chemotherapy, respectively. The pri-mary outcomes(O) included ORR(importance rating: 8 points),AEs(8),OS(8), the recurrence rate(7),DOR(7),and PFS(7).

We identified 10 retrospective cohort studies[171, 180, 193-196,198,265,268,269] and one review study[169].

Five studies reported response rates[180, 194, 198, 265, 268],while no study compared them between the two groups. Nine studies reported CR rates as a substitute[169, 180, 193-195, 198,265,268,269], and five of the nine compared them between the two groups[169, 193-195, 269]. No significant differences were observed in the CR rate(81.5% vs.82.8%, odds ratio 1.095, 95% CI 0.570-2.104) through a pooled analysis based on the nine studies.

Recurrence rates were reported in three single-arm cohort stud-ies[193,265,268].Through a pooled analysis of the three stud-ies,recurrence rates were significantly higher in the intervention group than in the control group(26.3% vs. 100%, odds ratio 19.600,95% CI 1.905-201.63).

AEs were reported in three single-arm cohort studies[180,194,195].Through a pooled analysis of the three studies, no significant differences were noted in grade>3 AEs between the two groups(32.1% vs.0%, odds ratio 0.422, 95% CI 0.042-4.164).

Median OS was reported in two single-arm cohort studies: one with an intervention group[196] and the other with a control group[268].

PFS and DOR were reported in two single-arm cohort studies with a control group[196, 265], and one single-arm cohort study with an intervention group, respectively[180]. Therefore, we were unable to compare PFS and DOR in the two groups.

Consequently, for elderly patients with PCLBCL, LT, no signif-icant differences were noted in response rates or AEs between the two groups, and the recurrence rate was lower in the con-trol group.

16.3| Discussion

We were unable to compare OS, PFS, and DOR between the two groups. Many biases included a single-arm design from a single institute, and the small number of patients enrolled in individual studies with various chemotherapy regimens and observation periods. We assessed the quality of the evidence as a high risk of bias and the indirectness of evidence for both the response rate and recurrence rate, which were verifiable, respectively.

Regarding the balance of desirable and undesirable conse-quences, no significant differences were observed in desirable

consequences between the two groups, whereas the recurrence rate, one of the undesirable consequences, was significantly higher in the intervention group. Therefore, the intervention may increase undesirable consequences.

No comparative study on the balance between desirable effects and resource use was identified. In the intervention group,medical expenses for local RT(electron beam, total 30 gray, 15 frequencies) are JPY 119600. When combined with rituximab monotherapy, the additional drug cost per course of the regimen for a body surface area of 1.6m2 is JPY 94007x2, totaling JPY 307614. In the control group(R-CHOP therapy), the drug costs per course of the regimen, at a body surface area of 1.6m2, are as follows: rituximab JPY 94007x2, cyclophosphamide JPY(1154x2)+(304x2),dorxorubicin JPY 6210+(1989x3),vinris-tine JPY 1988x2, and prednisolone JPY 9.8x12x5, totaling JPY 207671.Therefore, cost-effectiveness between the two groups de-pends on the choice of treatment options in the intervention group.

In the discussion at the panel meeting, we agreed that SDT±rit-uximab therapy is not recommended for PCLBCL, LT in elderly cases, because of the higher recurrence rate of the intervention group. In voting, six(60%) and four(40%) of the ten commit-tee members weakly and strongly recommended rituximab plus multi-agent chemotherapy, respectively. We concluded a weak recommendation against the intervention.

16.4| Clinical Considerations

Rituximab plus multi-agent chemotherapy(e.g., the R-CHOP regimen) has been recommended for PCLBCL, LT, similar to systemic DLBCL. A recent review recommended the use of rit-uximab plus multi-agent chemotherapy[267]. The intervention group may require multiple treatment interventions depending on the number of skin lesions and recurrence. Given the balance of benefits, cost-effectiveness, and resource use, it is likely that the intervention is not reasonable for patients, physicians, and other medical professionals.

16.5| Future Research Directions

Given the rarity of the disease, integrated research on the find-ings of retrospective studies comparing intervention and control groups will ultimately provide a reasonable solution to this issue.

Acknowledgments

The JDA covered all the costs associated with the creation of these guidelines. The revision committee members received travel expenses,daily allowances, and accommodation support in accordance with the standards set by the JDA. No manuscript fees were paid, and this sup-port did not affect the creation of the guidelines.

Conflicts of Interest

In accordance with the“Guidance on the Criteria for Participation in the Formulation of Clinical Practice Guidelines"(hereafter,“participa-tion criteria guidance") published by the Japan Medical Association in March 2017, members of the guidelines revision committee disclosed their COI for the past 3 years, going back to the previous year, and for

each year up to the publication of the guidelines. When declaring, the following were reported using the COI self-report form stipulated in the participation criteria guidance:(1) the COI of the committee member themselves, and the COI of the committee member's spouse;(2) the COI of first-degree relatives or those who share income or property interests;and(3) the COI of the organization to which the committee member be-longs. The target period was from January 1,2020, to January 31,2024.Four and three committee members subsequently had financial and academic COI, respectively(Table S2). Committee members with finan-cial or academic COI participated in the discussion of COI-related CQs,but obtained from voting on the recommendation decisions(Table S2).Of note, Dr. Tomomitsu Miyagaki is the Associate Editor of The Journal of Dermatology.

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

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Supporting Information

Additional supporting information can be found online in the Supporting Information section. Data S1: jde70037-sup-0001-DataS1.docx.