Peripheral T-cell Lymphoma Research Articles

A Phase 2 study of acimtamig (AFM13) in patients with CD30-positive, relapsed or refractory peripheral T-cell lymphomas.

Patients with relapsed or refractory (R/R) peripheral T-cell lymphoma (PTCL) generally have poor prognoses and limited treatment options. This study evaluated the efficacy of a novel CD30/CD16A bispecific innate cell engager, acimtamig (AFM13), in patients with R/R PTCL. Patients included those with CD30 expression in ≥1% of tumor cells and who were R/R following ≥1 prior line of systemic therapy. Acimtamig (200 mg) was administered once weekly in 8-week cycles. The primary endpoint was overall response rate (ORR) by fluorodeoxyglucose-positron emission tomography per independent review committee; secondary and exploratory endpoints included duration of response (DoR), safety, progression-free survival, and overall survival. The ORR in 108 patients was 32.4% (95% CI: 23.7, 42.1) with a complete response rate of 10.2% (95% CI: 5.2, 17.5); median DoR was 2.3 months (95% CI: 1.9, 6.5). Patients with R/R angioimmunoblastic T-cell lymphoma exhibited the greatest number of responses (53.3% [95% CI: 34.3, 71.7]). Responses were independent of CD30 expression level, prior brentuximab vedotin treatment, or steroid premedication. Acimtamig exhibited a tolerable safety profile; the most common treatment-related adverse events were infusion-related reactions in 27 patients (25.0%) and neutropenia in 11 patients (10.2%). No cases of cytokine release syndrome or acimtamig-related deaths were reported. Despite exhibiting promising clinical activity and tolerable safety in a heavily pretreated PTCL population, the study did not meet the criteria for the primary endpoint. The promising clinical efficacy observed warrants further investigation, and development of acimtamig for patients with R/R CD30+ lymphomas continues in combination with allogeneic natural killer cells.

TRBC1-CAR T cell therapy in peripheral T cell lymphoma: a phase 1/2 trial.

Relapsed/refractory peripheral T cell lymphomas (PTCLs) are aggressive tumors with a poor prognosis. Unlike B cell lymphomas, treatment of PTCL has not benefited from advances in immunotherapy. This is largely due to a lack of suitable target antigens that discriminate malignant from normal T cells, thus avoiding severe immunosuppression consequent to depletion of the entire T cell compartment. We recently described a targeting strategy based on the mutually exclusive expression of T cell antigen receptor beta-chain constant domain (TRBC) 1 and 2. Selective targeting of the T cell antigen receptor beta-chain expressed by the (clonal) malignancy spares normal T cells expressing the other chain. The LibraT1 study is an ongoing, multicenter, international, single-arm phase 1/2 study of TRBC1-directed autologous chimeric antigen receptor (CAR) T cells (AUTO4) in relapsed/refractory TRBC1-positive PTCL. Primary objectives were assessment of safety and tolerability of AUTO4 infusion. Key secondary endpoints included efficacy, CAR T cell expansion and persistence. Here we describe the findings from dose escalation in LibraT1 in the first ten patients, in a non-prespecified interim analysis. AUTO4 resulted in low frequency of severe immunotoxicity, with one of ten patients developing grade 3 cytokine release syndrome. Complete metabolic response was observed in four of ten evaluable patients, with remissions being durable beyond 1 year in two patients. While an absence of circulating CAR T cells was observed, CAR T cells were readily detected in lymph node biopsy samples from sites of original disease suggesting homing to tumor sites. These results support the continuing exploration of TRBC1 targeting in PTCL. ClinicalTrials.gov registration: NCT03590574 .

Intermediate results of efficacy and safety of combined treatment with brentuximab vedotin and bendamustine for refractory and relapsed forms of peripheral T-cell lymphoma: A retrospective study

Aim. To evaluate the efficacy and safety profile of the BvB combination in the treatment of R/R nPTCL, the complete response (CR) and partial response (PR) rates, overall survival (OS), and progression-free survival (PFS). Materials and methods. The analysis included 39 patients with R/R forms of nPTCL who underwent treatment in state budgetary institutions of the Moscow Department of Health (06.2008–08.2024). The efficacy (CR, PR, OS, PFS) and safety profile of the BvB combination were evaluated. Results. The best efficacy was noted when the BvB regimen was prescribed as a 2nd-line therapy compared to 3rd and subsequent lines. The overall response rate (ORR) when prescribed as 2nd-line therapy was 57% (n=13) of cases, CR – in 39.1% (n=9), PR – in 8.7% (n=2). The use of the BvB regimen as 3rd and subsequent lines of therapy led to ORR in 5 (31.3%) patients, CR – in 2 (12.5%), PR – in 2 (12.5%) patients. Statistically significant differences were obtained for the median PFS of patients who received the BvB regimen in the 2nd vs 3rd and subsequent lines of therapy: 6.5 and 2.5 months, respectively (p=0.0304). The BvB combination was characterized by an acceptable safety profile. Conclusion. The use of the BvB regimen in R/R forms of nPTCL demonstrated high efficacy and an optimal safety profile. The obtained results indicate the need to continue the study on a larger group of patients.

Enteropathy-associated T-cell lymphoma: from indolent to aggressive.

Abstract Enteropathy-associated T-cell lymphoma (EATL) is a rare neoplasm that accounts for <5% of peripheral T-cell lymphomas. EATL is derived from malignant transformation of intestinal intraepithelial lymphocytes and is the most common neoplastic complication of celiac disease. It is rare in patients diagnosed at a young age, although in long-standing coeliac disease it may be the debut of the disease. Its diagnosis involves imaging techniques, biopsies and immunohistochemistry, the main tool needed being a high diagnostic suspicion. The prognosis is poor and there is currently no consensus on the best therapeutic approach.

Refining Diagnostic Subtypes of Peripheral T-cell Lymphoma Using a Multiparameter Approach

Peripheral T-cell lymphoma (PTCL) is a heterogeneous category, and many cases are unclassifiable and designated as PTCL-not otherwise specified (PTCL-NOS). Gene expression profiling (GEP) has delineated two prognostic subtypes within PTCL-NOS, PTCL-TBX21, and PTCL-GATA3, characterized by distinctive transcriptomes and a different prognosis. To further evaluate the pathologic features of these subgroups, 101 PTCL cases that did not meet specific criteria for well-defined T-cell lymphoma entities underwent detailed pathologic, immunophenotypic (including TFH biomarkers) and GEP analyses, separating them into PTCL-NOS (n=63) and PTCL-TFH (a.k.a. nodal PTCL-TFH, NOS, and TFH lymphoma, NOS) (n=38). PTCL-NOS cases were further categorized into PTCL-GATA3 (n=22; 34%) and PTCL-TBX21 (n=41; 66%), and a significant association (p < 0.02) with overall survival (OS) was reaffirmed. Histopathological assessment showed PTCL-GATA3 cases were characterized by monotonous medium-sized or large transformed cells with a minimal tumor microenvironment (TME) compared to PTCL-TBX21 cases, which consisted of pleomorphic cells in a polymorphous TME (p < 0.05). GEP analysis validated these TME distinctions. Immunophenotypic analysis showed that PTCL-GATA3 cases were predominantly CD4+CD8- and associated with significantly higher LEF1, MYC, and CD30 expression (p < 0.05). PTCL-TBX21 displayed a more diverse biomarker profile with two subgroups: one expressing cytotoxic antigens and enriched in CD8+CD4- or CD8-CD4- phenotype, and another lacking cytotoxic markers but showing a CD4+CD8- phenotype with increased ICOS expression, but devoid of other TFH markers. The PTCL-TFH cases correlated with an angioimmunoblastic T-cell lymphoma (AITL) gene signature, had more EBER-positive cells than the PTCL-GATA3 and PTCL-TBX21 cases, and a subset had some morphologic features of AITL (p < 0.01). This study highlights the unique morphologic and phenotypic variations within the newly-identified PTCL subtypes and should enable more precise diagnosis and tailored therapeutic strategies in the future.

Pralatrexate Injection Combined with Oral Leucovorin for Mucositis Management in the Treatment of Peripheral and Cutaneous T-Cell Lymphomas–Results from a Multicenter Phase 2 Trial

Pralatrexate (Folotyn®) is an antifolate indicated for treatment of relapsed/refractory peripheral T-cell lymphoma (PTCL), and although durable clinical benefit has been demonstrated, oral and gastrointestinal mucositis and/or skin reactions are frequent toxicity complications associated with pralatrexate treatment. Leucovorin (d,l-folinic acid) administration has been used as standard rescue for patients receiving high dose methotrexate therapy and has recently been studied in patients with PTCL and cutaneous T-cell lymphoma (CTCL) receiving pralatrexate. We describe results from a multi-center, phase 2, single-arm, open-label trial, conducted with the primary objective to evaluate the effect of leucovorin in preventing or reducing the incidence of Grade 2 or higher oral mucositis associated with pralatrexate treatment in Cycle 1. Patients were administered pralatrexate, 30 mg/m2 as an intravenous (IV) push, once weekly for 6 weeks in each cycle, followed by a week of rest (no treatment). Leucovorin 25 mg tablets were administered three times daily (tid) for two days (a total of six doses [150 mg cumulative weekly dose]), initiated 24 hours (±2 hours) after each pralatrexate dose. The evaluable population included 34 patients, mean age 63.7 year, 60% male, of which two (5.9%) developed Grade 2 oral mucositis during the study period (p<0.0001) and no reports of Grade ≥3. Dose modifications, including omissions, delays or reductions, due to oral mucositis were limited to one patient. Co-administration of leucovorin resulted in a significant reduction in mucositis and can be considered a prophylactic therapy in patients receiving pralatrexate treatment. Clinical trial # NCT02106650

Dual epigenetic therapy plus chemotherapy in peripheral T cell lymphoma with T follicular helper phenotype

The nonrandomized phase II study by Ding etal. explored the combination of azacitidine and chidamide with or without GemOx chemotherapy in relapsed/refractory peripheral Tcell lymphoma and demonstrated that the dual epigenetic therapy is safe and efficacious, particularly in the angioimmunoblastic Tcell lymphoma subset.1 Further investigation into adding chemotherapy is warranted, building on the promising results seen in this trial.

Comparison of tucidinostat with CHOP-like versus CHOP-like in first-line treatment of peripheral T-cell lymphoma: a single-center real-world study.

Tucidinostat has been approved by the Chinese FDA for relapsed/refractory Peripheral T cell lymphoma (PTCL), but its efficacy in newly diagnosed PTCL has not been confirmed. In this study, we aimed to compare the efficacy of tucidinostat combined with CHOP-like (C + CHT) versus CHOP-like alone (CHT) in newly diagnosed PTCL patients. Of the PTCL patients, 109 were newly diagnosed. Patients in the C + CHT group who achieved objective response received tucidinostat maintenance therapy. A total of 36 pairs (n = 72) were matched at a ratio of 1:1 using propensity scoring. The matching criteria included: whether the Prognostic index for the peripheral T-cell lymphoma-not otherwise specified subtype (PIT) was ≥ 2, the pathological subtype, age > 60 years, and gender (matching tolerance = 0.024). A significantly higher objective response rate (ORR) (P = 0.016), 2-year progression-free survival (PFS) (P = 0.026), and 2-year survival rate (P = 0.017) was observed for the C + CHT group as compared to the CHT group. After propensity score matching (PSM), the C + CHT group as compared to the CHT group displayed significantly longer PFS (P = 0.035) and overall survival (OS) (P = 0.029). For the C + CHT group in the per-protocol set, the effect values showed a significant benefit in terms of both PFS (P = 0.027) and OS (P = 0.019). Common grade 3-4 haematological adverse events (AEs), had comparable incidence in each group; while common non-haematological AEs, including elevated AST and ALT were higher in the C + CHT group than in the CHT group. Our study suggests that the tucidinostat with CHOP-like regimen and sequential tucidinostat maintenance after objective remission provides a promising therapeutic approach for treating newly diagnosed PTCL patients.

Genome-wide CRISPR screen identifies MAD2L1BP and ANAPC15 as targets for brentuximab vedotin sensitivity in CD30+ peripheral T-cell lymphoma.

Genome-wide CRISPR screen identifies MAD2L1BP and ANAPC15 as targets for brentuximab vedotin sensitivity in CD30+ peripheral T-cell lymphoma.

Maintenance Therapy Post-Stem Cell Transplantation for Patients with T-Cell Lymphomas.

Given the poor outcomes for peripheral T-cell lymphomas (PTCL), stem cell transplant (SCT) remains an important therapeutic approach. Post-SCT relapse is common and maintenance therapy post-SCT is increasingly being utilized. Here we review the use of post-SCT maintenance therapy for PTCL patients. Maintenance therapy is increasingly utilized to decrease post-SCT relapse and improve outcomes in PTCL. Ongoing and completed post-SCT maintenance trials utilizing agents such as romidepsin, brentuximab vedotin, duvelisib, and pembrolizumab have shown efficacy in decreasing relapse. Further, additional agents with efficacy in PTCL have emerged that may inform future maintenance approaches. Maintenance therapy is a promising approach to maintain response after SCT in PTCL. While several trials are ongoing to evaluate maintenance therapy in PTCL, current data suggests this may be an effective method to decrease post-SCT relapse.

Multicenter randomized phase III study of high-dose therapy with autologous stem cell transplantation versus observation for patients with newly diagnosed peripheral T-cell lymphoma who achieved complete metabolic response after induction therapy (JCOG2210, TRANSFER study).

Patients with peripheral T-cell lymphoma demonstrated a poor prognosis after obtaining a complete response with induction treatment compared to those with B-cell lymphoma. Once it relapsed, curative treatment is frequently limited to invasive treatments with significant treatment-related mortality, including allogeneic stem cell transplantation. The limitations of these treatment choices indicate the necessity for developing optimal consolidation therapies to prevent relapse. This multicenter randomized phase III trial aims to confirm the superiority of the high-dose therapy with autologous stem cell transplantation over observation alone in terms of progression-free survival for patients with newly diagnosed peripheral T-cell lymphoma who achieved complete metabolic response after induction therapy. A total of 140 patients from 52 hospitals will be enrolled in Japan over 5.5years. This trial is registered in the Japan Registry of Clinical Trials as jRCTs031240169 (https://jrct.niph.go.jp/latest-detail/jRCTs031240169).

Two Atypical Clinical Cases of a Rare Lymphoma: Peripheral T-Cell Lymphoma

Two Atypical Clinical Cases of a Rare Lymphoma: Peripheral T-Cell Lymphoma

TRIP13 is Critical for the Survival of B-cell Lymphomas and Myeloid Leukemias In Vitro

Hematologic malignancies represent a diverse group of blood tumors accounting for approximately 10% of all cancer cases in the US. Based on the site of manifestation, presumed cell of origin, genetic abnormalities, and clinical features, we recognize more than 100 clinically important subtypes of hematologic malignancies broadly categorized into three main groups: leukemia, lymphoma, and multiple myeloma. While the prognosis for patients with specific subtypes of hematologic malignancies, such as Hodgkin lymphomas or chronic lymphocytic leukemia has significantly improved over the last several years, other subtypes such as acute myeloid leukemia or non-Hodgkin lymphomas still present with significant treatment challenges. A better understanding of molecular drivers of tumor maintenance is needed to improve existing therapies. Thyroid hormone receptor interactor 13 (TRIP13) is an AAA + ATPase that plays an important yet poorly understood role in the regulation of the mammalian cell cycle. The TRIP13 gene is highly expressed in various human tumors including colorectal carcinoma and glioblastoma, and it seems to promote tumorigenesis. Recently, we identified TRIP13 as a gene overexpressed in Peripheral T-cell lymphomas where it plays a critical role in tumor maintenance by regulating the G2-M phase of the cell cycle. However, the biological activities of TRIP13 in non-T cell hematologic malignancies have not been investigated to date. Here we used shRNA-mediated knockdown and a small molecule inhibitor to downregulate TRIP13 in B-cell lymphoid and myeloid lineages. We found genetic downregulation inhibited the proliferation of both B-cell lymphomas and acute myeloid leukemia cell lines in vitro. The pharmacologic inhibition of TRIP13 effectively induced the G0/G1 cell cycle arrest and apoptosis of B-cell lymphomas. Altogether these data demonstrate that TRIP13 is critical for the maintenance of hematologic malignancies of B-cell and myeloid malignancies in vitro. Thus, TRIP13 might be a good target in the treatment of various types of hematologic malignancies.

Antibody-Based Therapies for Peripheral T-Cell Lymphoma.

While antibody-based immunotherapeutic strategies have revolutionized the treatment of B-cell lymphomas, progress in T-cell lymphomas has suffered from suboptimal targets, disease heterogeneity, and limited effective treatment options. Nonetheless, recent advances in our understanding of T-cell biology, the identification of novel targets, and the emergence of new therapies provide hope for the future. In this review, we explore four areas of current and evolving antibody-based strategies for the treatment of peripheral T-cell lymphoma (PTCL): monoclonal antibodies (mAbs), bispecific antibodies (BsAs), chimeric antigen receptor T-cell therapy (CAR-T), and antibody-drug conjugates (ADCs). As part of this discussion, we will also include limitations, lessons learned, and potential future directions.

Rapidly Progressive Primary Cutaneous Gamma Delta T-Cell Lymphoma With FYN Gene Alteration.

Primary cutaneous gamma delta T-cell lymphoma (PCGDTCL) is a rare type of non-Hodgkin lymphoma accounting for <1% of primary cutaneous T-cell lymphomas. The exact cause of PCGDTCL is not known, however, it is thought that chronic antigen exposure in the skin may lead to immune dysregulation at the site, resulting in abnormal proliferation of mature, post-thymic cytotoxic gamma delta T cells. Mutations are the most common genetic alteration seen in PCGDTCL, while structural abnormalities such as gene fusions are not common. We report a case of PCGDTCL with atypical immunophenotypic features, including expression of CD5 with lack of cytotoxic marker expression, and a structural alteration leading to FYN deletion at exon 8. Recently, it was described that a deletion of the area between FYN exon 8 and TRAF3IP2 intron 2 results in a novel FYN::TRAF3IP2 fusion in peripheral T-cell lymphoma, not otherwise specified. We describe our patient's clinical course, differential diagnosis, and potential implications of FYN deletion on disease pathogenesis. To our knowledge, this is the first report of an FYN structural alteration to be described in PCGDTCL.

Aggressive Lymphoma after CD19 CAR T-Cell Therapy

SummaryThe development of a fatal, clonal, autonomously proliferating CD4−CD8− chimeric antigen receptor (CAR)+ peripheral T-cell lymphoma (PTCL) occurred 1 month after a patient received treatment with tisagenlecleucel for relapsed primary central nervous system lymphoma. The PTCL had a clonal T-cell receptor rearrangement, which was already detectable in the apheresis product for CAR T-cell manufacturing and 7 months earlier for autologous transplantation. Somatic DNMT3A and TET2 mutations in CD34+ stem cells and their progeny were detected in the PTCL, in the apheresis specimen that was obtained for CAR T-cell production, and in the autotransplant. The PTCL harbored an additional somatic TET2 mutation, which was already detectable in the CAR T-cell apheresis product and the final CAR T-cell product at very low frequencies, providing evidence that clonal hematopoiesis had contributed to lymphomagenesis.

Lack of SMARCB1 expression characterizes a subset of human and murine peripheral T-cell lymphomas

Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) is a heterogeneous group of malignancies with poor outcome. Here, we identify a subgroup, PTCL-NOSSMARCB1-, which is characterized by the lack of the SMARCB1 protein and occurs more frequently in young patients. Human and murine PTCL-NOSSMARCB1- show similar DNA methylation profiles, with hypermethylation of T-cell-related genes and hypomethylation of genes involved in myeloid development. Single-cell analyses of human and murine tumors revealed a rich and complex network of interactions between tumor cells and an immunosuppressive and exhausted tumor microenvironment (TME). In a drug screen, we identified histone deacetylase inhibitors (HDACi) as a class of drugs effective against PTCL-NOSSmarcb1-. In vivo treatment of mouse tumors with SAHA, a pan-HDACi, triggered remodeling of the TME, promoting replenishment of lymphoid compartments and reversal of the exhaustion phenotype. These results provide a rationale for further exploration of HDACi combination therapies targeting PTCL-NOSSMARCB1- within the TME.

The Impact of Social Determinants of Health on Peripheral T Cell Lymphoma Outcomes: Treatment Center-Type Emerges as a Powerful Prognostic Indicator

BackgroundPrognostic models in peripheral T cell lymphoma (PTCL) have identified biological factors including age, performance status, LDH, and bone marrow involvement as prognostic for survival. The association of nonbiological factors, termed social determinants of health (SDH), on PTCL outcomes remains unexplored. MethodsTo evaluate the impact of actionable SDH on PTCL mortality across race groups, we conducted a retrospective cohort study that included all White, Hispanic, Asian/Pacific Islander (PI) and Black adult patients with PTCL (AITL, ALCL, NKTCL and PTCL, NOS), diagnosed from 2000 to 2020, in California. We utilized Chi2 and Wilcoxon rank-sum tests for descriptive metrics and Kaplan-Meier statistics for mortality estimation. Regression models included patient- (age, sex, race, stage, Charlson Comorbidity Index, histology, treatment type, treatment at an academic center, payer), and neighborhood-level factors (socioeconomic (SES) quintile, proportion without a high school diploma, and rural/urban). Risk factors significant in univariate regression at a P-value < .10 were incorporated into the multivariable model. FindingsOur analysis included 6158 patients: 51.8% White, 25.8% Hispanic, 14.7% Asians/PI, and 7.6% Black. Hispanics exhibited the longest median survival (33 months) followed by Whites, Blacks, and Asian/PI (25, 20, and 14 months, respectively; P = .011). Risk factors independently associated with inferior lymphoma-specific survival (LSS) included Asian/PI compared with NH White race (HR, 1.23; 95% CI, 1.10-1.34; P = .0002), AITL and ALCL compared with PTCL, NOS histology (AITL HR, 1.14; 95% CI, 1.02-1.25; P = .011; ALCL HR, 1.15; 95% CI, 1.04-1.26; P = .004), academic compared to nonacademic facility-type (HR 0.71; 95% CI, 0.64-0.77; P < .01), Medicare compared with uninsured status (HR 1.48, 95% CI, 1.25-1.73; P < .01), and the lowest 3 education quartiles compared to the highest education quartile (Q2 HR 1.13; 95% CI, 1.01-1.25; P = .021; Q3 HR 1.14; 95% CI, 1.02-1.26; P = .018; Q4 HR 1.22; 95% CI, 1.08-1.36; P < .001). In the least resourced patients, histology, treatment, treatment facility-type, payer and education were independently prognostic for LSS. Treatment at an academic institution was associated with a striking improvement in LSS (academic institution: yes = 101 months, no = 17 months; P < .01). InterpretationThese data identify treatment facility-type, payer and education, as an independent actionable SDH for PTCL mortality. Treatment center-type had the strongest prognostic association with LSS in our PTCL cohort, conferring a risk reduction of PTCL mortality by nearly 30%. Interventions targeted at improving access to academic centers may improve outcomes for all PTCL patients.

Valemetostat for patients with relapsed or refractory peripheral T-cell lymphoma (VALENTINE-PTCL01): a multicentre, open-label, single-arm, phase 2 study.

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. 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. 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. 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. Daiichi Sankyo.

Valemetostat monotherapy in patients with relapsed or refractory non-Hodgkin lymphoma: a first-in-human, multicentre, open-label, single-arm, phase 1 study.

Few treatment options exist for patients with non-Hodgkin lymphoma, and outcomes remain poor for relapsed or refractory disease. We evaluated the safety and preliminary clinical activity of valemetostat, a novel inhibitor of EZH2 and EZH1, in patients with relapsed or refractory non-Hodgkin lymphomas. This first-in-human, multicentre, open-label, single-arm, phase 1, dose-escalation and dose-expansion trial was done in 19 hospitals across Japan and the USA. Patients were included if they were aged 18 years or older in the USA or 20 years or older in Japan with a primary diagnosis of relapsed or refractory non-Hodgkin lymphoma and an Eastern Cooperative Oncology Group performance status of 0 or 1. In the dose-escalation part, patients received oral valemetostat at doses of 150 mg per day, 200 mg per day, 250 mg per day, and 300 mg per day continuously in 28-day cycles until progressive disease or unacceptable toxicities. All patients received 200 mg per day in the dose-expansion part. The primary endpoints were safety, pharmacokinetics, and the recommended phase 2 dose; the secondary endpoints were the maximum tolerated dose and the antitumour activity of valemetostat. Responses were assessed in patients who received at least one dose, with measurable lesions at baseline according to the International Working Group 2007 revised criteria for malignant lymphoma (peripheral T-cell lymphoma and B-cell non-Hodgkin lymphoma) and the modified 2009 criteria for adult T-cell leukaemia/lymphoma. The trial is registered with ClinicalTrials.gov, NCT02732275, and is currently active, but not recruiting. Between April 7, 2016, and June 10, 2021, 90 patients (53 [59%] males and 37 [41%] females; 49 [54%] Asian, 33 [37%] White, and eight [9%] Black) were enrolled and treated with valemetostat and included in the safety analysis set. 57 (63%) patients had peripheral T-cell lymphoma, 14 (16%) had adult T-cell leukaemia/lymphoma, and 19 (21%) had B-cell non-Hodgkin lymphoma. Seven (8%) patients received valemetostat 150 mg per day, 74 (82%) received 200 mg per day, seven received 250 mg per day, and two received 300 mg per day. Median follow-up was 7·4 months (IQR 3·4-17·6). All patients had at least one treatment-emergent adverse event; the most common treatment-emergent adverse events of any grade were decreased platelet count (52 [58%] of 90 patients), dysgeusia (45 [50%]), and anaemia (38 [42%]). The most common grade 3-4 adverse events were decreased neutrophil count (21 [23%]), decreased platelet count (18 [20%]), and decreased lymphocyte count (17 [19%]). The most common serious adverse event of any grade was Pneumocystis jirovecii pneumonia (four [4%]). No treatment-related deaths occurred. The overall response rate was 54·5% (48 of 88; 95% CI 43·6-65·2) for patients in the efficacy analysis set. The maximum tolerated dose was not reached; the recommended phase 2 dose of 200 mg per day was determined. Valemetostat exposure was variable between patients and was overlapped over the dose range of 150-250 mg per day. The safety profile of valemetostat monotherapy was acceptable in these patients with relapsed or refractory non-Hodgkin lymphoma. Favourable clinical activity was observed. These findings support a new indication for valemetostat in this setting. Daiichi Sankyo.