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Summary: Background: Cutaneous T‐cell lymphoma (CTCL) negatively impacts quality of life (QoL), but existing QoL questionnaires may not comprehensively reflect patients' experience. Objectives: To identify the aspects of QoL that are most meaningful to patients with CTCL and to evaluate existing QoL instruments in this context. Methods: Semistructured interviews were conducted between May and June 2019 using purposive sampling of patients with CTCL. Data were analysed by an inductive thematic approach using Dedoose Version 8.0.35. Results: One‐on‐one interviews lasting a median of 43 min were completed by 18 patients [median age 62 years (interquartile range 52–70); 39% advanced‐stage (IIB–IV)]. Itch was the most common clinical symptom reported (16 of 18 patients), followed by pain (12 of 18), skin breaks (11 of 18) and skin flaking (10 of 18). Eleven patients reported that their symptoms interfered with sleep, which impacted daily functioning. Patients also noted a lack of understanding of the disease in the community and felt uncertain (12 of 18), depressed (11 of 18), suicidal (four of 18) and hopeless (nine of 18). Nearly all patients (17 of 18) reported a sense of 'otherness' (not feeling 'normal' or 'like themselves'), and most patients (16 of 18) specifically mentioned concern about their physical appearance. Patients also noted substantial treatment burden. Salient patient concerns, including individual clinical symptoms, concern about appearance and problems with sleep, were not adequately or consistently represented in generic, skin‐specific or CTCL‐specific QoL measures. Conclusions: Incorporating the concerns and priorities that distinguish patients with CTCL from other patient populations will be of paramount importance in developing a comprehensive CTCL‐specific measure of QoL that adequately captures patients' experience. What is already known about this topic? Cutaneous T‐cell lymphoma (CTCL) negatively impacts quality of life (QoL). What does this study add? Our findings demonstrate that existing QoL instruments, including an instrument specific to CTCL, do not adequately reflect patient concerns, including specific symptoms, problems with sleep and concern about appearance. What are the clinical implications of this work? Including the concerns and priorities that distinguish patients with CTCL from other patient populations will be of paramount importance in developing a more comprehensive CTCL‐specific measure of QoL that adequately captures patients' illness experience.Specific assessment of these concerns should be included in routine clinical practice. Linked Comment: Gabes. Br J Dermatol 2021; 184:195. Plain language summary available online [ABSTRACT FROM AUTHOR]

Summary: Background: Cutaneous T‐cell lymphoma (CTCL) has been associated with considerable physical, psychological and financial burden. However, its impact on health‐related quality of life (QoL) and economic costs are not well studied. Objectives: To measure the QoL impact and financial burden of CTCL. Methods: A cross‐sectional survey of 67 patients with CTCL was conducted using the Ontario Health Utilities Index Mark 3 (HUI3) questionnaire. Normative population data (n = 3310) were obtained from the 2002–2003 Joint Canada/United States Survey of Health. Economic cost was estimated using quality‐adjusted life‐year (QALY) loss derived from HUI3 scores. Results: Patients with CTCL had significantly lower aggregate HUI3 scores than the general population (0·68 vs. 0·87, P < 0·001). Multivariable regression analysis adjusting for demographics and comorbidities showed CTCL was associated with significantly poorer performance overall (–0·13, 95% CI –0·21 to –0·06, P < 0·001) and in domains of speech (–0·03, 95% CI –0·05 to –0·01, P = 0·01), ambulation (–0·04, 95% CI –0·08 to 0·00, P = 0·03), emotion (–0·07, 95% CI –0·12 to –0·02, P = 0·01), and pain (–0·07, 95% CI –0·13 to –0·01, P = 0·03). These health utility decrements yielded an average loss of 1·48 QALYs per patient. Using a $50 000 per QALY willingness‐to‐pay threshold, CTCL was associated with an individual lifetime burden of $73 889 and U.S. societal burden of $2·86 billion. Conclusions: These findings suggest CTCL has a pervasive impact on QoL, comparable with debilitating conditions such as end‐stage renal disease. The substantial economic burden of CTCL underscores the potential societal benefit of prompt diagnosis and effective management. What's already known about this topic? Cutaneous T‐cell lymphoma is associated with physical, psychological and financial burden. What does this study add? The overall quality‐of‐life impact of cutaneous T‐cell lymphoma has not previously been measured using a generic health utility instrument.In this study, we compare the overall quality‐of‐life burden of patients with cutaneous T‐cell lymphoma with that of other populations and calculate the economic burden of the disease. Linked Comment: Rosenthal and Kim. Br J Dermatol 2020; 182:20–21. Plain language summary available online Respond to this article [ABSTRACT FROM AUTHOR]

B Conclusions: b Golidocitinib demonstrated its potential as a novel targeted therapy for the treatment of I r i / I r i PTCL. Among them, 35 patients achieved tumor response (ORR = 43.8%), including 20 patients (25.0%) achieved complete responses. B Introduction: b Currently there is no consensus on the treatment of relapsed/refractory ( I r i / I r i ) PTCL, and patient prognosis was poor. [Extracted from the article]

Duvelisib in patients with relapsed/refractory peripheral T-cell lymphoma from the phase 2 PRIMO Trial Expansion Phase: outcomes by baseline histology Based on dose optimization results, the EP dose was DUV 75 mg BID for 2 cycles, to maximize disease control, followed by 25 mg BID, to mitigate late toxicities, until progressive disease/unacceptable toxicity. B Introduction: b Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of aggressive lymphomas with a poor prognosis for relapsed/refractory disease. [Extracted from the article]

B Conclusion: b Within the heavily pre-treated MF population enrolled in TELLOMAK, Lacutamab shows clinical activity in KIR3DL2 expressing MF pts, with higher global ORR according to updated LN evaluation. MF pts are allocated to one of two cohorts: KIR3DL2 >=1% MF (Cohort 2) and KIR3DL2 <1% MF (Cohort 3). [Extracted from the article]

Diffuse large B-cell lymphoma (DLBCL) is typically treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). However, only 60% of patients are cured with R-CHOP. Polatuzumab vedotin is an antibody--drug conjugate targeting CD79b, which is ubiquitously expressed on the surface of malignant B cells. METHODS We conducted a double-blind, placebo-controlled, international phase 3 trial to evaluate a modified regimen of R-CHOP (pola-R-CHP), in which vincristine was replaced with polatuzumab vedotin, as compared with standard R-CHOP, in patients with previously untreated intermediate-risk or high-risk DLBCL. Patients 18 to 80 years of age were randomly assigned in a 1:1 ratio to receive six cycles of either pola-R-CHP or R-CHOP, plus two cycles ofrituxinlab alone. The primary end point was investigator-assessed progression-free survival. Secondary end points included overall survival and safety. RESULTS Overall, 879 patients underwent randomization: 440 were assigned to the pola-R-CHP group and 439 to the K-CHOP group. After a median follow-up of 28.2 months, the percentage of patients surviving without progression was significantly higher in the pola-R-CHP group than in the R-CHOP group (76.7% [95% confidence interval (CI), 72.7 to 80.8] vs. 70.290 [95% CI, 65.8 to 74.6] at 2 years; stratified hazard ratio for progression, relapse, or death, 0.73 by Cox regression; 95% CI, 0.57 to 0.95; P=0.02). Overall survival at 2 years did not differ significantly between the groups (88.7% [95% CI, 85.7 to 91.6] in the pola-R-CHP group and 88.6% [95% CI, 85.6 to 91.6] in the R-CHOP group; hazard ratio for death, 0.94,95% CI, 0.65 to 1.37; P=0.75). The safety profile was similar in the two groups. CONCLUSIONS Among patients with previously untreated intermediate-risk or high-risk DLBCL, the risk of disease progression, relapse, or death was lower among those who received pola-R-CHP than among those who received R-CHOP. (Funded by F. Hoffmann-La Roche/Genentech; POLARIX ClinicalTrials.gov number, NCT03274492.) [ABSTRACT FROM AUTHOR]

Cutaneous T-cell lymphoma (CTCL) remains a challenging disease due to its significant heterogeneity, therapy resistance, and relentless progression. Multi-omics technologies offer the potential to provide uniquely precise views of disease progression and response to therapy. We present here a comprehensive multi-omics view of CTCL clonal evolution, incorporating exome, whole genome, epigenome, bulk-, single cell (sc) VDJ-, and scRNA-sequencing of 114 clinically annotated serial skin, peripheral blood, and lymph node samples from 35 CTCL patients. We leveraged this extensive dataset to define the molecular underpinnings of CTCL progression in individual patients at single cell resolution with the goal of identifying clinically useful biomarkers and therapeutic targets. Our studies identified a large number of recurrent progression-associated clonal genomic alterations; we highlight mutation of CCR4, PI3K signaling, and PD-1 checkpoint pathways as evasion tactics deployed by malignant T cells. We also identified a gain of function mutation in STAT3 (D661Y) and demonstrated by CUT&RUN-seq that it enhances binding to transcription start sites of genes in Rho GTPase pathways, which we previously reported to have activated chromatin and increased expression in HDACi-resistant CTCL. These data provide further support for a previously unrecognized role for Rho GTPase pathway dysregulation in CTCL progression. A striking number of progression-associated mutations occurred in chromatin methylation modifiers, including EZH2, suggesting that EZH1/2 inhibition may also benefit patients with CTCL. Knowledge of these molecular changes should be leveraged for improved disease monitoring, biomarker-informed clinical trial design, and new therapeutic strategies in this challenging and incurable cancer.

Abstract: Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of mature T-cell neoplasms that represent ∼10% of all non-Hodgkin lymphoma. Outcomes for the majority of patients with PTCL are poor, and treatment approaches have been relatively uniform using cyclophosphamide, doxorubicin, vincristine, and prednisone-based therapy. For example, large registry studies consistently demonstrate 5-year overall survival of ∼30% to 40%. However, as our understanding of the biology underpinning the heterogeneity of PTCL improves and as treatments specifically for PTCL are developed, risk stratification has become a more relevant question. Tools including positron emission tomography-computed tomography and minimal residual disease (MRD) monitoring offer the potential for dynamic risk stratification. In this review, we first summarize registry data describing outcomes in the most common subtypes of PTCL: PTCL not otherwise specified, nodal T-follicular helper cell lymphoma including angioimmunoblastic T-cell lymphoma, and anaplastic large cell lymphoma. We describe current clinically based prognostic indices validated for PTCL and highlight emerging tools for prognostication including novel molecular biomarkers, imaging-based metrics, and MRD dynamics., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Peripheral T-cell lymphomas (PTCLs) are a heterogenous yet aggressive group of lymphomas that arise from mature T- or NK-cell precursors. Nodal PTCLs include anaplastic large-cell lymphoma, PTCL not otherwise specified, and follicular helper T-cell lymphomas. Recent advances in understanding these heterogenous diseases have prompted investigation of novel agents to improve on treatment. Brentuximab vedotin, a CD30 antibody-drug conjugate, has been incorporated into frontline treatment regimens of CD30-expressing PTCLs based on the ECHELON-2 trial. Multiple ongoing trials are evaluating the addition of other targeted agents in the frontline and relapsed/refractory setting. These include single-agent brentuximab vedotin, histone deacetylase inhibitors, duvelisib, ruxolitinib, EZH2 inhibitors, and azacitidine, among others. Follicular helper T-cell lymphomas, given frequent mutations in epigenetic regulator genes, may preferentially respond to agents such as histone deacetylase inhibitors, EZH2 inhibitors, and hypomethylating agents. As these therapies evolve in their use for both relapsed/refractory disease and then into frontline treatment, subtype-specific therapy will likely help personalize care for patients with PTCL., (Copyright © 2024 by The American Society of Hematology.)

Introduction: Histone deacetylase inhibitors (HDACi) and combination chemotherapy are independently used to treat relapsed/refractory (R/R) lymphoma. In vitro studies suggest that the addition of HDACi to platinum-based chemotherapy is synergistic., Patients and Methods: We conducted a phase I study of romidepsin, gemcitabine, oxaliplatin and dexamethasone (Romi-GemOxD) in R/R aggressive lymphomas with an expansion cohort in T-cell lymphomas. A total of 24 patients were enrolled with median age 70; 6 patients had diffuse large B-cell lymphoma (DLBCL) and 18 patients had peripheral T-cell lymphomas (PTCL-NOS: 10; angioimmunoblastic T-cell lymphoma [AITL]: 7; ALK-negative anaplastic large cell lymphoma: 1). Patients had received a median of 2 prior lines of therapy and 10 patients were refractory to last line of therapy., Results: Using a standard 3 + 3 dose escalation design, the maximum tolerated dose of romidepsin was determined to be 10 mg/m 2 in combination with GemOxD. There were no unexpected toxicities. The most common grade ≥ 3 treatment-emergent adverse events were thrombocytopenia (79%) and lymphopenia (46%). The overall response rate for Romi-GemOxD was 52% (12/23) with complete response (CR) rate of 43% (10/23). All 6 patients with AITL evaluable for efficacy achieved CR. Durable responses were seen in patients with AITL, PTCL-NOS and DLBCL. Without additional therapy, 4 patients remained in remission for more than 2 years, with 3 patients progressing at 46.5, 30.8, and 32.6 months and 1 remission ongoing at 83 months. A total of 4 patients proceeded to consolidative stem cell transplant following induction., Conclusion: Romi-GemOxD represents a well-tolerated, time-limited, effective option for patients, particularly for those with AITL in which durable responses were seen. NCT02181218., Competing Interests: Disclosure Neha Mehta-Shah has served as a consultant for Kyowa Hakko Kirin, Secura Bio, AstraZeneca, Genentech/Roche, Janssen Oncology, Pfizer. Neha Mehta-Shah has institutional research funding Bristol Myers Squibb, Genentech/Roche, Celgene, Innate Pharma, Corvus Pharmaceuticals, AstraZeneca, C4 Therapeutics, Daiichi Sankyo, Yingli Pharma, Dizal Pharma, Secura Bio, and Morphosys. Nancy L. Bartlett has served as a consultant for ADC Therapeutics, Roche/Genentech and Seattle Genetics. Nancy L. Bartlett has institutional research funding from Autolous, BMS, Gilead Sciences, Janssen Biotech, Parmacyclics, Millennium Pharmaceuticals. Brad S Kahl has served as a consultant for AbbVie, Acerta Pharma, ADC Therapeutics, BeiGene, BMS, Celgene, Genentech, Incyte, Roche, Kite Pharma, Seattle Genetics. Todd A. Fehniger has research funding from ImmunityBio, Affimed, Wugen, and HCW Biologics; consults for Wugen, Gamida Cell, Takeda, Nkarta, Indapta, and Orca Bio; and has equity and potential royalty interest in Wugen. Peter A Riedell has served as a consultant and/or advisory board member for AbbVie, ADC Therapeutics, BeiGene, Bristol Myers Squibb (BMS), CVS Caremark, Genentech/Roche, Genmab, Intellia Therapeutics, Janssen, Kite/Gilead, Nektar Therapeutics, Novartis, Pharmacyclics, and Sana Biotechnology and has received honoraria from Adaptive Biotechnologies and institutional research support from AstraZeneca, BMS, Calibr, CARGO Therapeutics, Cellectis, CRISPR Therapeutics, Fate Therapeutics, Genentech/Roche, Kite Pharma, Novartis, and Xencor. AC has institutional research funding from Secura bio. KC, NF, AF, CM, JL and MW have no relevant conflicts of interest to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Peripheral T-cell lymphomas are aggressive non-Hodgkin lymphomas with few treatment options for relapsed or refractory disease. Valemetostat tosylate (valemetostat) is a potent, novel, dual inhibitor of EZH2 and EZH1. We investigated the clinical activity and safety of valemetostat in patients with relapsed or refractory peripheral T-cell lymphoma, and its safety in patients with relapsed or refractory adult T-cell leukaemia/lymphoma., Methods: VALENTINE-PTCL01 was a multicentre, open-label, single-arm, phase 2 trial performed at 47 hospitals in 12 countries across Asia, Europe, North America, and Oceania. Patients with either peripheral T-cell lymphoma or adult T-cell leukaemia/lymphoma, aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-2 received oral valemetostat at 200 mg per day in continuous 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint for patients with peripheral T-cell lymphoma was the CT-based objective response rate by blinded independent central review (BICR) using 2014 Lugano response criteria. Patients who received valemetostat and had a confirmed eligible peripheral T-cell lymphoma subtype on central review were included in the efficacy analysis. The primary endpoint for patients with adult T-cell leukaemia/lymphoma was the safety and tolerability of valemetostat. Safety in both cohorts was assessed in all patients who received at least one dose of valemetostat. The trial is registered with ClinicalTrials.gov, NCT04703192, and EudraCT, 2020-004954-31, and is closed to enrolment., Findings: Between June 16, 2021, and Aug 10, 2022, 133 patients with relapsed or refractory peripheral T-cell lymphoma (median age 69·0 years [IQR 58·0-74·0]; 91 [68%] were male, and 42 [32%] were female) and 22 patients with adult T-cell leukaemia/lymphoma (66·5 years [54·0-73·0]; 15 [68%] were male, and seven [32%] were female) were enrolled. The median follow-up time was 12·3 months (95% CI 11·8-13·8). 52 (44%; 95% CI 35-53) of 119 efficacy-evaluable patients with relapsed or refractory peripheral T-cell lymphoma had an objective response. The most common grade 3-4 adverse events were thrombocytopenia (31 [23%] of 133 patients in the peripheral T-cell lymphoma group and 11 [50%] of 22 patients in the adult T-cell leukaemia/lymphoma group), anaemia (25 [19%] and ten [46%]), and neutropenia (23 [17%] and four [18%]). Serious treatment-emergent adverse events were reported in 53 (40%) patients with peripheral T-cell lymphoma and 15 (68%) patients with adult T-cell leukaemia/lymphoma; nine (7%) patients and one (5%) patient had a serious treatment-emergent adverse event considered to be treatment related, respectively. No treatment-related deaths were reported., Interpretation: These data show that treatment with valemetostat leads to durable responses in patients with relapsed or refractory peripheral T-cell lymphoma, with a manageable safety profile., Funding: Daiichi Sankyo., Competing Interests: Declaration of interests PLZ has received consulting fees from lncyte, Novartis, BeiGene, and SOBI, and honoraria from Takeda, AstraZeneca, MSD, Bristol Myers Squibb (BMS), lncyte, Roche, Gilead, Recordati, Kyowa Kirin, Novartis, BeiGene, Janssen, and SOBI, unrelated to this study. KIz has received manuscript support from Daiichi Sankyo to their institution, related to this work; research funding Chugai, BMS, Incyte, Genmab, LOXO Oncology, Daiichi Sankyo, BeiGene, AbbVie, AstraZeneca, Regeneron, Yakult, Chugai, Otsuka, Novartis, Pfizer, MSD, Bayer, Kyowa Kirin, Eisai, Janssen, Ono Pharmaceutical, Gilead, Astellas, and Amgen to their institution, unrelated to this work; consulting fees from AstraZeneca, Ono Pharmaceutical, Mitsubishi Tanabe, Eisai, Chugai, BMS, AbbVie, Takeda, Zenyaku, Genmab, Kyowa Kirin, MSD, Carna Biosicences, Novartis, Yakult, Nihon Shinyaku, Novartis, and BeiGene, unrelated to this work; and honoraria from AstraZeneca, Ono Pharmaceutical, Eisai, Chugai, Janssen, Symbio, BMS, Daiichi Sankyo, Otsuka, AbbVie, Takeda, Eli Lilly, Genmab, Kyowa Kirin, MSD, Astellas, Pfizer, Meiji Seika Pharma, Novartis, Nihon Kayaku, and Gilead, unrelated to this work. NM-S has received research funding from AstraZeneca, BMS, C4 Therapeutics, Celgene, Corvus Pharmaceuticals, Daiichi Sankyo, Dizal Pharmaceuticals, Genetech/Roche, Incyte, Innate Pharmaceuticals, Secura Bio, Verastem, and Yingli Pharmaceuticals, to their institutions, unrelated to this work; consulting fees from AstraZeneca, Kyowa Hakka Kirin, Karyopharm, Ono Pharmaceuticals, Secura Bios, Daiichi Sankyo, Genentech, and Janssen, unrelated to this work; and participated on a data safety monitoring board and an advisory board for Daiichi Sankyo, unrelated to this work. SKB received manuscript support from Daiichi Sankyo, related to this work; consulting fees and honoraria from Acrotech, Kyowa Kirin, and Seagen, unrelated to this work; and participated on a data safety monitoring board or advisory board for Janssen, unrelated to this work. KIs has received manuscript support from Daiichi Sankyo, related to this work; research funding from Ono Pharmaceutical and Kyowa Kirin to their institutions, unrelated to this work; honoraria from Kyowa Kirin, Takeda, Chugai Pharmaceutical, Celgene, BMS, Daiichi Sankyo, Ono Pharmaceutical, Astellas, Eisai, Pfizer, Otsuka, Sanofi, CSL Behring, AbbVie, Yakult, Janssen Pharmaceutical, and Nippon Shinyaku, unrelated to this work; participated on data safety monitoring board or advisory board for Meiji Seika Pharma and Daiichi Sankyo, unrelated to this work; and received materials from Ono Pharmaceutical to their institution, unrelated to this work. SK has received support from Daiichi Sankyo, related to this work; research funding from Chugai, Kyowa Kirin, and Janssen, unrelated to this work; and honoraria from Daiichi Sankyo, Chugai, Kyowa Kirin, and Janssen, unrelated to this work. EB has received research funding from Amgen and BMS, to their institution, unrelated to this work; honoraria from Novartis, Kite/Gilead, Roche, Takeda, Janssen, and AbbVie, unrelated to this work; support for attending meetings or travel from Roche and Kite/Gilead, unrelated to this work; and participated on data safety monitoring board or advisory board from Novartis, Kite/Gilead, Roche, Incyte, ADC Therapeutics, and AbbVie, unrelated to this work. KC received consulting fees from Roche, Takeda, Celgene, and AbbVie, unrelated to this work; honoraria from Roche and Takeda, unrelated to this work; support for attending meetings or travel from Roche, Takeda, and BMS, to their institution; and participated on data safety monitoring board or advisory board for Daiichi Sankyo, unrelated to this work. GG received honoraria from Ideogen and Takeda, unrelated to this work; support for attending meetings or travel from Roche, Kite-Gilead, Sandoz, BeiGene, and Janssen, unrelated to this work; and participated on data safety monitoring board or advisory board for AbbVie, Roche, Takeda, Kite-Gilead, Italfarmaco, Ideogen, and Genmab, unrelated to this work. EJ received research funding from Celgene, Merck, Pharmacyclics, and F Hoffman-LaRoche, unrelated to this work; honoraria from Merck, Daiichi, BMS, and Bayer, unrelated to this work; and has patents planned, issued, or pending with UpToDate, unrelated to this work. TF has received research funding from ADCT, AstraZeneca, BMS, Corvus, Daiichi, Genmab, Kymera, Merck, Seagen, TESSA, Trillium, Alexion, and Portola, unrelated to this work; consulting fees from ADCT, AstraZeneca, BMS, Epizyme, Genmab, Seagen, Pharmacyclics, and Celgene, unrelated to this work; honoraria from Takeda, Seagen, Genmab, Epizyme, ADCT, AstraZeneca, BMS, Pharmacyclics, AbbVie, and Pfizer, unrelated to this work; and owns stock in OMI and Genomic Testing Cooperative, unrelated to this work. DE received research funding from Nippon Shinyaku Pharmaceutical, Chugai Pharmaceutical, and Eisai Pharmaceutical, to their institution, unrelated to this work; and honoraria from Eisai Pharmaceutical, Chugai Pharmaceutical, SymBio Pharmaceuticals, BMS, Kyowa Kirin Pharmaceutical, and Nippon Shinyaku Pharmaceutical, unrelated to this work. EDD received consulting fees from Takeda, unrelated to this work; honoraria from Takeda and BeiGene, unrelated to this work; and funding for attending meetings or travel from Takeda, unrelated to this work. JZ received research funding from Secura Bio, Astex, CRSPR, Myeloid Therapeutics, and Daichi Sankyo, unrelated to this work; consulting fees from Seattle genetics, Secura Bio, Kyowa Kirin, and Myeloid Therapeutics, unrelated to this work; and honoraria from Kyowa Kirin, unrelated to this work. JJ, SW, TM, AI, and KN are employed by Daiichi Sankyo. TM has received support for attending meetings or travel from Daiichi Sankyo, unrelated to this work. AI, TM, and YC own stock options in Daiichi Sankyo, unrelated to this work. KN owns stock in Daiichi Sankyo, unrelated to this work. SH received research funding from the US National Institutes of Health/National Cancer Institute Cancer Center, (support grant P30 CA008748); research funding from ADC Therapeutics, Affimed, Aileron, Celgene, Crispr Therapeutics, Daiichi Sankyo, Forty Seven, Kyowa Hakko Kirin, Takeda, Seattle Genetics, Trillium Therapeutics, and SecuraBio; and honoraria from Abcuro, Autolus, Auxilius Pharma, Corvus, Cimeio Therapeutics, Daiichi Sankyo, Dren Bio, Kyowa Hakko Kirin, March, Bio, Ono Pharmaceuticals, SecuraBio, Shore line, Biosciences, Takeda, Tubulis and Yingli Pharma. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

In the last decade, there has been increased understanding of the pathologic features and biology of peripheral T cell lymphomas (PTCLs) through development of multi omics and molecular profiling techniques. In addition, international collaborations through multi center trials as well as prospective registry studies have improved our knowledge of host and tumor genomic factors and treatment factors affecting disease outcomes. In our review today, we aim to highlight the current epidemiology, latest advances in classification, disease biology and the evolving treatment landscape for nodal PTCLs., (© 2023 John Wiley & Sons Ltd.)

Mycosis fungoides (MF) and Sézary syndrome (SS) are the most common subtypes of cutaneous T-cell lymphoma (CTCL). While MF generally follows an indolent course, a subset of patients will experience progressive and/or treatment-refractory disease; Sézary syndrome is an aggressive lymphoma associated with high morbidity and mortality. Although allogeneic hematopoietic cell transplant (allo-HCT) is the only currently available potentially curative treatment modality for MF/SS there is no published guidance on referral criteria, transplant timing orallo-HCT approach. To develop consensus clinical practice recommendations, we performed a Delphi survey of 32 specialists in dermatology (n = 9), transplant hematology/oncology (n = 10), non-transplant hematology/oncology (n = 8), and radiation oncology (n = 5) from across the United States. Consensus required agreement of ≥75% of participants. Sixteen consensus statements were generated on four topics: (1) criteria for referral for consideration for allo-HCT, (2) allo-HCT preparative regimens and procedures (3) disease status at the time of allo-HCT, and (4) multidisciplinary management in the pre- and post-transplant settings. These clinical practice guidelines provide a framework for decision-making regarding allo-HCT for MF/SS and highlight areas for future prospective investigation., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Post-transplant lymphoproliferative disorders (PTLDs) remain a feared complication of transplantation, with significant morbidity and mortality. The oncogenic Epstein-Barr virus (EBV) is a key pathogenic driver in 50%-80% of cases. Numerous prognostic indices, comprising multiple clinical, epidemiological and tumor characteristics, including EBV tumor positivity, do not consistently associate with worse patient survival, suggesting a potential role for EBV genome variants in determining outcome. However, the precision medicine tools for determining if a viral genome variant is pathogenic are very limited compared with human genome variants. Further, targeted studies have not implicated a specific viral etiological agent in EBV-negative PTLD. Using novel cutting-edge technologies, we are extracting viral nucleic acids from formalin-fixed, paraffin-embedded archived, or frozen PTLD tissues or plasma, to test for all vertebrate viruses simultaneously in an unbiased fashion, using metagenomic shotgun sequencing (MSS). We are collecting such samples from multiple transplant centers to address the following specific aims and close the following knowledge gaps: (1) Validate our novel observation that PTLD tissue positivity by MSS for anellovirus (and confirmed by PCR) serves as a biomarker for higher transplant recipient mortality after the diagnosis of PTLD; (2) determine the role of other oncogenic viruses in EBV-negative PTLD by unbiased MSS of multiple viral groupings, confirmed by other techniques; and (3) develop the necessary computational, algorithmic and software analytic tools required to determine association of EBV genome variants with worse presentations or outcomes in PTLD. Study completion will contribute to better patient care and may provide avenues for novel therapies., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

PI3K-δ inhibitors have shown impressive activity in lymphoid malignancies but have been hampered by autoimmune and infectious toxicities, leading to market withdrawals. We previously demonstrated activity of the PI3K-δγ inhibitor duvelisib in T cell lymphomas (TCLs) that was associated with inflammatory adverse events. As reported here, we conducted a phase 1b/2a study of duvelisib in combination with either romidepsin (n = 66) or bortezomib (n = 32) in patients with relapsed/refractory TCL and found that the addition of romidepsin, but not bortezomib, appeared to increase efficacy while attenuating PI3K inhibitor-driven toxicity. The primary endpoint of the study was to determine the safety and maximum tolerated dose of duvelisib, which was 75 mg twice daily when combined with romidepsin versus 25 mg twice daily when combined with bortezomib. The most common adverse events were neutropenia (42%, 25/59) and fatigue (37%, 22/59) in patients treated with duvelisib and romidepsin and diarrhea (48%, 11/23) and neutropenia (30%, 7/23) in patients treated with duvelisib and bortezomib. Duvelisib and romidepsin resulted in less grade 3/4 hepatotoxicity (14%, 8/59) compared to 40% (14/35) in our previous study with duvelisib monotherapy. This was associated with reductions in circulating inflammatory mediators and myeloid cell inflammatory gene expression. Secondary endpoints of overall and complete response rates were 55% (35/64) and 34% (22/64) for patients treated with duvelisib and romidepsin and 34% (11/32) and 13% (4/32) for patients treated with duvelisib and bortezomib. Among patients with peripheral T cell lymphomas (PTCLs), overall and complete response rates of duvelisib and romidepsin were 56% (27/48) and 44% (21/48), respectively, with exploratory analyses showing increased response rates in patients with a follicular helper T cell subtype. These findings support further development of combined PI3K and histone deacetylase (HDAC) inhibition in TCLs and suggest a unique strategy to enable PI3K inhibitor-based combinations for additional patient populations. ClinicalTrials.gov identifier: NCT02783625 ., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Abstract: Personalized cancer vaccines designed to target neoantigens represent a promising new treatment paradigm in oncology. In contrast to classical idiotype vaccines, we hypothesized that "polyvalent" vaccines could be engineered for the personalized treatment of follicular lymphoma (FL) using neoantigen discovery by combined whole-exome sequencing (WES) and RNA sequencing (RNA-seq). Fifty-eight tumor samples from 57 patients with FL underwent WES and RNA-seq. Somatic and B-cell clonotype neoantigens were predicted and filtered to identify high-quality neoantigens. B-cell clonality was determined by the alignment of B-cell receptor (BCR) CDR3 regions from RNA-seq data, grouping at the protein level, and comparison with the BCR repertoire from healthy individuals using RNA-seq data. An average of 52 somatic mutations per patient (range, 2-172) were identified, and ≥2 (median, 15) high-quality neoantigens were predicted for 56 of 58 FL samples. The predicted neoantigen peptides were composed of missense mutations (77%), indels (9%), gene fusions (3%), and BCR sequences (11%). Building off of these preclinical analyses, we initiated a pilot clinical trial using personalized neoantigen vaccination combined with PD-1 blockade in patients with relapsed or refractory FL (#NCT03121677). Synthetic long peptide vaccines targeting predicted high-quality neoantigens were successfully synthesized for and administered to all 4 patients enrolled. Initial results demonstrate feasibility, safety, and potential immunologic and clinical responses. Our study suggests that a genomics-driven personalized cancer vaccine strategy is feasible for patients with FL, and this may overcome prior challenges in the field. This trial was registered at www.ClinicalTrials.gov as #NCT03121677., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Abstract: Little is known about risk factors for central nervous system (CNS) relapse in mature T-cell and natural killer cell neoplasms (MTNKNs). We aimed to describe the clinical epidemiology of CNS relapse in patients with MTNKN and developed the CNS relapse In T-cell lymphoma Index (CITI) to predict patients at the highest risk of CNS relapse. We reviewed data from 135 patients with MTNKN and CNS relapse from 19 North American institutions. After exclusion of leukemic and most cutaneous forms of MTNKNs, patients were pooled with non-CNS relapse control patients from a single institution to create a CNS relapse-enriched training set. Using a complete case analysis (n = 182), including 91 with CNS relapse, we applied a least absolute shrinkage and selection operator Cox regression model to select weighted clinicopathologic variables for the CITI score, which we validated in an external cohort from the Swedish Lymphoma Registry (n = 566). CNS relapse was most frequently observed in patients with peripheral T-cell lymphoma, not otherwise specified (25%). Median time to CNS relapse and median overall survival after CNS relapse were 8.0 and 4.7 months, respectively. We calculated unique CITI risk scores for individual training set patients and stratified them into risk terciles. Validation set patients with low-risk (n = 158) and high-risk (n = 188) CITI scores had a 10-year cumulative risk of CNS relapse of 2.2% and 13.4%, respectively (hazard ratio, 5.24; 95% confidence interval, 1.50-18.26; P = .018). We developed an open-access web-based CITI calculator (https://redcap.link/citicalc) to provide an easy tool for clinical practice. The CITI score is a validated model to predict patients with MTNKN at the highest risk of developing CNS relapse., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Patients with cutaneous T cell lymphoma (CTCL) experience high morbidity and mortality due to S. aureus skin infections and sepsis, but the causative immune defect is unclear. We previously identified high levels of LAIR2, a decoy protein for the inhibitory receptor LAIR1, in advanced CTCL. Mice do not have a LAIR2 homolog, so we used Lair1 knock-out (KO) mice to model LAIR2 overexpression. In a model of subcutaneous S. aureus skin infection, Lair1 KO mice had significantly larger abscesses and areas of dermonecrosis compared to WT. Lair1 KO exhibited a pattern of increased inflammatory responses in infection and sterile immune stimulation, including increased production of proinflammatory cytokines and myeloid chemokines, neutrophil ROS, and collagen/ECM remodeling pathways. Notably, Lair1 KO infected skin had a similar bacterial burden and neutrophils and monocytes had equivalent S. aureus phagocytosis compared to WT. These findings support a model in which lack of LAIR1 signaling causes an excessive inflammatory response that does not improve infection control. CTCL skin lesions harbored similar patterns of increased expression in cytokine and collagen/ECM remodeling pathways, suggesting that high levels of LAIR2 in CTCL recapitulates Lair1 KO, causing inflammatory tissue damage and compromising host defense against S. aureus infection., Competing Interests: Conflict of Interest Statement: The authors declare no conflict of interest.

Abstract: Outcomes in patients with relapsed diffuse large B-cell lymphoma (DLBCL) who undergo autologous stem cell transplant (auto-SCT) are poor. Blinatumomab is a CD3/CD19 bispecific T-cell engager that directs cytotoxic T cells to CD19+ cells. Here, we performed a pilot study of blinatumomab consolidation after auto-SCT for 14 patients with DLBCL or transformed follicular lymphoma. All patients underwent standard-of-care auto-SCT with carmustine, etoposide, cytarabine, and melphalan (BEAM) conditioning followed by 1 cycle (4 weeks continuous infusion) of blinatumomab consolidation starting at day 42 after auto-SCT. All 14 patients treated on study completed BEAM auto-SCT and 1 cycle of posttransplant blinatumomab. Five patients developed grade 1 cytokine release syndrome (CRS), with no grade 2 or higher CRS. Immune effector cell-associated neurotoxicity syndrome was not observed. Patients were followed up for 3 years after auto-SCT, with median follow-up of 37 (range, 12-65) months. One-hundred days after auto-SCT (1 month after blinatumomab consolidation), 12 patients (86%) had achieved complete remission. At 1 year after auto-SCT, 7 patients (50%) remained in CR, and 1 patient had died of progressive disease. Patients who relapsed had a lower CD8:CD4 T-cell ratio before starting blinatumomab than patients who remained in remission. This pilot study demonstrates blinatumomab consolidation after auto-SCT is safe and well tolerated. Strategies to increase the CD8:CD4 ratio and use additional cycles of consolidation in a larger randomized trial are needed to confirm the efficacy of consolidation with blinatumomab after auto-SCT. This trial was registered at www.clinicaltrials.gov as #NCT03072771., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Although a rare subset of non-Hodgkin lymphomas, peripheral T-cell lymphomas (PTCL) account for a disproportionate proportion of patient mortality. Conventional therapies are derived from experience treating aggressive B-cell lymphomas and center around CHOP-based chemotherapy. However, due to the unique biology and diverse subtypes of PTCL, most patients fail to durably respond to this approach and 5-year survival is only 20% to 30%. There have been multiple attempts to improve outcomes for patients with PTCL. Among the more successful strategies are the use of consolidative autologous stem cell transplant, the augmentation of CHOP with etoposide (CHOEP), and the use of brentuximab vedotin in CD30-positive PTCL. Advances in the understanding of histology-specific biology has cultivated enthusiasm to evaluate hypomethylating agents, histone deacetylate inhibitors, and phosphoinositol-3-kinase inhibitors in the frontline setting. Improvements in monitoring disease response and prognostication including the use of cell-free DNA, mutational profiling, and interim PET/CT imaging are also on the horizon. For patients with acute T-cell leukemia/lymphoma, the use of mogamulizumab-based therapy in the frontline setting may lead to advances in care. The true impact of these new-era therapies will only be elucidated as clinical practices incorporate the rapidly changing evidence., Competing Interests: Disclosure NMS has received institutional clinical trial funding from AstraZeneca, Bristol Myers-Squibb, Celgene, C4 Therapeutics, Corvus Pharmaceuticals, Daiichi Sankyo, Genentech/Roche, Innate Pharmaceuticals, Secura Bio/Verastem, Yingli Pharmaceuticals and Dizal pharmaceuticals. She has received compensation for service as a consultant for Astrazeneca, Secura Bio/Verastem, Daiichi Sankyo, C4 Therapeutics, Genentech, Karyopharm Therapeutics, and Kyowa Hakko Kirin. JSB and NCF have no relevant conflicts of interest to disclose. NMS is a clinical research scholar of the Leukemia & Lymphoma Society., (Copyright © 2023. Published by Elsevier Inc.)

Gamma Delta (γδ) T-cell lymphomas are uncommon and aggressive neoplasms originating from the γδ receptor-bearing lymphocytes. The most frequent entities include primary hepatosplenic γδ T-cell lymphomas, primary cutaneous γδ lymphoma, and monomorphic epitheliotropic T-cell lymphoma. F-18 fluorodeoxyglucose (FDG) PET/CT is an important modality in the staging of Hodgkin's and various non-Hodgkin's lymphoma. However, literature is scare on imaging findings of γδ lymphoma on F-18 FDG PET/CT. In this review, we discuss briefly the clinical and biological features and present the spectrum of F-18 FDG PET/CT findings of γδ lymphoma., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Institute of Radiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Golidocitinib, a selective JAK1 tyrosine-kinase inhibitor, has shown encouraging anti-tumour activity in heavily pre-treated patients with relapsed or refractory peripheral T-cell lymphoma in a phase 1 study (JACKPOT8 Part A). Here, we report the full analysis of a phase 2 study, in which we assessed the anti-tumour activity of golidocitinib in a large multinational cohort of patients., Methods: We did a single-arm, multinational, phase 2 trial (JACKPOT8 Part B) in 49 centres in Australia, China, South Korea, and the USA. Eligible patients were adults (aged ≥18 years) with relapsed or refractory peripheral T-cell lymphoma who had received at least one previous line of systemic therapy and an Eastern Cooperative Oncology Group performance status of 0-2. Patients were given oral golidocitinib 150 mg once daily until disease progression or other discontinuation criteria were met. The primary endpoint was the CT-based objective response rate, assessed by an independent review committee (IRC) per Lugano 2014 classification. The activity analysis set included all patients who received at least one dose and whose pathological diagnosis of peripheral T-cell lymphoma had been retrospectively confirmed by a central laboratory and who had at least one measurable lesion at baseline assessed by IRC. The safety analysis set included all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT04105010, and is closed to accrual and follow-up is ongoing., Findings: Between Feb 26, 2021, and Oct 12, 2022, we assessed 161 patients for eligibility, of whom 104 (65%) were enrolled and received at least one dose of study drug; the activity analysis set included 88 (85%) patients (median age 58 years [IQR 51-67], 57 [65%] of 88 were male, 31 [35%] were female, and 83 [94%] were Asian). As of data cutoff (Aug 31, 2023; median follow-up was 13·3 months [IQR 4·9-18·4]), per IRC assessment, the objective response rate was 44·3% (95% CI 33·7-55·3; 39 of 88 patients, p<0·0001), with 21 (24%) patients having a complete response and 18 (20%) having a partial response. In the safety analysis set, 61 (59%) of 104 patients had grade 3-4 drug-related treatment-emergent adverse events. The most common grade 3-4 drug-related treatment-emergent adverse events were neutrophil count decreased (30 [29%]), white blood cell count decreased (27 [26%]), lymphocyte count decreased (22 [21%]), and platelet count decreased (21 [20%]), which were clinically manageable and reversible. 25 (24%) patients had treatment-related serious adverse events. Deaths due to treatment-emergent adverse events occurred in three (3%) patients: two (2%) due to pneumonia (one case with fungal infection [related to golidocitinib] and another one with COVID-19 infection) and one (1%) due to confusional state., Interpretation: In this phase 2 study, golidocitinib showed a favourable benefit-risk profile in treating relapsed or refractory peripheral T-cell lymphoma. The results of this study warrant further randomised clinical studies to confirm activity and assess efficacy in this population., Funding: Dizal Pharmaceutical., Competing Interests: Declaration of interests LM reports research support outside the scope of this work from Dizal Pharmaceutical. NM-S has received institutional clinical trial funding from AstraZeneca, Bristol Myers Squibb, Celgene, C4 Therapeutics, Corvus Pharmaceuticals, Daiichi Sankyo, Genentech/Roche, Innate Pharmaceuticals, Secura Bio/Verastem, Yingli Pharmaceuticals, and Dizal Pharmaceuticals. YK reports consulting fees or personal fees from Janssen, Novartis, and Beigene; and honoraria from Antengene, Janssen, Roche, and Novartis. PA reports data safety monitoring board or advisory board participation for Seattle Genetics, BostonGene, Kyowa Kirin, and Daichii Sankyo. ZY reports employment by Dizal Pharmaceutical. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Antibodies targeting PD-1 or 4-1BB achieve objective responses in follicular lymphoma (FL), but only in a minority of patients. We hypothesized that targeting multiple immune receptors could overcome immune resistance and increase response rates in patients with relapsed/refractory FL. We therefore conducted a phase 1b trial testing time-limited therapy with different immunotherapy doublets targeting 4-1BB (utomilumab), OX-40 (ivuxolimab), and PD-L1 (avelumab) in combination with rituximab among patients with relapsed/refractory grade 1-3A FL. Patients were enrolled onto 2 of 3 planned cohorts (cohort 1 - rituximab/utomilumab/avelumab; cohort 2 - rituximab/ivuxolimab/utomilumab). 3+3 dose escalation was followed by dose expansion at the recommended phase 2 dose (RP2D). Twenty-four patients were enrolled (16 in cohort 1 and 9 in cohort 2, with one treated in both cohorts). No patients discontinued treatment due to adverse events and the RP2D was the highest dose level tested in both cohorts. In cohort 1, the objective and complete response rates were 44% and 19%, respectively (50% and 30%, respectively, at RP2D). In cohort 2, no responses were observed. The median progression-free survivals in cohorts 1 and 2 were 6.9 and 3.2 months, respectively. In cohort 1, higher density of PD-1+ tumor-infiltrating T-cells on baseline biopsies and lower density of 4-1BB+ and TIGIT+ T-cells in on-treatment biopsies were associated with response. Abundance of Akkermansia in stool samples was also associated with response. Our results support a possible role for 4-1BB agonist therapy in FL and suggest that features of the tumor microenvironment and stool microbiome may be associated with clinical outcomes (NCT03636503)., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The malignant Hodgkin and Reed Sternberg (HRS) cells of classical Hodgkin lymphoma (cHL) are scarce in affected lymph nodes, creating a challenge to detect driver somatic mutations. As an alternative to cell purification techniques, we hypothesized that ultra-deep exome sequencing would allow genomic study of HRS cells, thereby streamlining analysis and avoiding technical pitfalls. To test this, 31 cHL tumor/normal pairs were exome sequenced to approximately 1,000× median depth of coverage. An orthogonal error-corrected sequencing approach verified >95% of the discovered mutations. We identified mutations in genes novel to cHL including: CDH5 and PCDH7, novel stop gain mutations in IL4R, and a novel pattern of recurrent mutations in pathways regulating Hippo signaling. As a further application of our exome sequencing, we attempted to identify expressed somatic single-nucleotide variants (SNV) in single-nuclei RNA sequencing (snRNA-seq) data generated from a patient in our cohort. Our snRNA analysis identified a clear cluster of cells containing a somatic SNV identified in our deep exome data. This cluster has differentially expressed genes that are consistent with genes known to be dysregulated in HRS cells (e.g., PIM1 and PIM3). The cluster also contains cells with an expanded B-cell clonotype further supporting a malignant phenotype. This study provides proof-of-principle that ultra-deep exome sequencing can be utilized to identify recurrent mutations in HRS cells and demonstrates the feasibility of snRNA-seq in the context of cHL. These studies provide the foundation for the further analysis of genomic variants in large cohorts of patients with cHL., Significance: Our data demonstrate the utility of ultra-deep exome sequencing in uncovering somatic variants in Hodgkin lymphoma, creating new opportunities to define the genes that are recurrently mutated in this disease. We also show for the first time the successful application of snRNA-seq in Hodgkin lymphoma and describe the expression profile of a putative cluster of HRS cells in a single patient., (© 2023 The Authors; Published by the American Association for Cancer Research.)

Patients with relapsed/refractory primary mediastinal large B-cell lymphoma (R/R PMBL) have poor responses to salvage therapy. Nivolumab and brentuximab vedotin (BV) showed promising early efficacy in patients with R/R PMBL in the phase 1/2 open-label, multicenter CheckMate 436 study; we report safety and efficacy findings from the 3-year follow-up. Patients who were eligible were aged ≥15 years with R/R PMBL previously treated with either high-dose chemotherapy plus autologous hematopoietic cell transplantation (HCT) or ≥2 prior multiagent chemotherapies, and had Eastern Cooperative Oncology Group performance status scores of 0 to 1 and CD30 expression of ≥1%. Patients were treated with nivolumab 240 mg and BV 1.8 mg/kg once every 3 weeks until disease progression or unacceptable toxicity. Primary end point was objective response rate (ORR); secondary end points included complete response rate, duration of response, progression-free survival (PFS), and overall survival (OS). Safety was monitored throughout. At final database lock (30 March 2022), 29 patients had received nivolumab plus BV; median follow-up was 39.6 months. Investigator-assessed ORR was 73.3%; median time to response was 1.3 months (range, 1.1-4.8). Median PFS was 26.0 months; median OS was not reached. PFS and OS rates at 24 months were 55.5% (95% confidence interval [CI], 32.0-73.8) and 75.5% (95% CI, 55.4-87.5), respectively. The most frequently occurring grade 3/4 treatment-related adverse event was neutropenia. Consolidative HCT was received by 12 patients, with a 100-day complete response rate of 100.0%. This 3-year follow-up showed long-term efficacy for nivolumab plus BV in R/R PMBL, with no new safety signals. This trial was registered at www.clinicaltrials.gov as #NCT02581631., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)