Because primary ocular adnexal mucosa-associated lymphoid tissue lymphoma (POAML) is rare, key clinical questions, including the best treatment strategy and the validity of watchful waiting (WW), remain unresolved. Although radiotherapy (RT) is the standard treatment for localized POAML, it is commonly associated with acute and late toxicities. Overall, 128 patients with localized POAML diagnosed and managed at our institution between 1998 and 2015 were retrospectively analyzed. Forty-two patients were initially managed with WW, and 86 received immediate RT. During a median follow-up of 7.2 years (range 0.1–18.4), no patients died of lymphoma progression. Seven patients in the WW group experienced disease progression at the primary site. In the RT group, almost all patients (97.7

BACKGROUND:Despite several attempts to improve the prognosis of patients with diffuse large B-cell lymphoma (DLBCL), the rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) regimen remains the standard of care in previously untreated DLBCL. A randomized phase II/III study (JCOG0601) was performed to investigate the efficacy of dose-dense weekly rituximab combined with standard CHOP (RW-CHOP). Herein, we report the final results of JCOG0601 as a post hoc assessment after an 8-year follow-up. METHODS:Patients aged 20-79 years with previously untreated DLBCL (stages I-IV, performance status 0-2) were randomized to either standard R-CHOP or RW-CHOP. RESULTS:Between December 2007 and December 2014, 421 patients were randomly assigned to R-CHOP (n = 213) or RW-CHOP (n = 208). With a median follow-up of 9.6 years, no meaningful differences were found in progression-free survival (PFS) and overall survival (OS) [hazard ratio (HR) in PFS, 0.94; 95% confidence interval (CI), 0.67-1.32; HR in OS, 0.94; 95% CI, 0.63-1.41]. The median PFS and OS were not estimable in both arms. Twenty-one (5.0%) cases of grade ≥ 3 cardiac toxicity were observed. The cumulative incidence rates of secondary malignancy were 14.6% and 16.8% in the R-CHOP and RW-CHOP arms, respectively. The median time from study enrollment to the onset of secondary malignancy was 4.5 years, and the incidence was time-dependent. No unexpected adverse events, including opportunistic infections, occurred. CONCLUSION:These final follow-up data confirmed the nonsuperiority of RW-CHOP in terms of PFS and OS. Standard R-CHOP remains the standard of care for untreated DLBCL.

Context Treatments are limited and prognosis is often poor for patients with relapsed/refractory (R/R) non-Hodgkin lymphomas (NHLs). Valemetostat tosylate (valemetostat), a novel, potent, and selective dual inhibitor of EZH2 and EZH1, suppresses aberrant H3K27me3, thereby promoting antitumorigenic processes. The open-label, multicenter, first-in-human DS3201-A-J101 (NCT02732275) trial assessed valemetostat safety and efficacy in patients with R/R NHLs. Patients Patients were ≥18 (US) or ≥20 (Japan) years of age and R/R or ineligible for standard treatment. Interventions Valemetostat monotherapy: 150-300 mg/day (escalation) and 200 mg/day (expansion). Main Outcome Measures Safety, recommended phase 2 dose, maximum tolerated dose, and clinical efficacy. Results At the primary cutoff (Dec 31, 2022), safety and efficacy analyses included 90 patients (57, peripheral T-cell lymphoma [PTCL]; 14, adult T-cell leukemia/lymphoma [ATLL]; and 19, B-cell NHL [B-NHL]). Median age was 67.5 (range, 26–88) years. Median number of prior therapies was 2 (range, 0–8). Eighteen patients with PTCL or ATLL had previously undergone transplant. All experienced ≥1 treatment-emergent adverse event (TEAE); 78 (87%) had ≥1 treatment-related adverse event. The most common TEAEs (any grade) were decreased platelet count (58%), dysgeusia (50%), and anemia (42%). The most common grade ≥3 TEAEs were decreased neutrophil (23%), platelet (20%), and lymphocyte (19%) counts. TEAEs required dose reduction, interruption, and discontinuation for 9 (10%), 42 (47%), and 7 (8%) patients, respectively. Overall response rates were 55% (30/55; 95% confidence interval [CI], 40.6–68.0) in patients with PTCL, 64% (9/14; 95% CI, 35.1–87.2) in patients with ATLL, and 47% (9/19; 95% CI, 24.4–71.1) in patients with B-NHL. Median durations of response in patients with PTCL, ATLL, and B-NHL were 21.9 (95% CI, 10.2–not reached [NR]), 21.2 (95% CI, 1.4–38.7), and 18.4 (95% CI, 5.3–NR) months, respectively. One patient with R/R follicular lymphoma had a gain-of-function EZH2 mutation and achieved a partial response. Partial responses were also observed in 3 patients with B-NHL without EZH2 mutations. Target engagement was broadly confirmed in tested tissues; higher AUC during the dosing interval of valemetostat was associated with marginal H3K27me3 reductions in normal granulocytes. Conclusions Valemetostat was well tolerated with encouraging clinical activity in patients with R/R NHLs.

Follicular lymphoma (FL) is an indolent lymphoma that becomes aggressive due to histological transformation (HT), leading to reduced survival. Patients with FL have different clinical courses and various treatment options. Some patients exhibit shorter survival and experience disease progression within 24 months of diagnosis/treatment (POD24); the optimal treatment remains an unmet needs. Thus, identifying factors that predict shorter survival is essential to stratify treatment and prolong the survival of patients with FL. To analyze risk factors for POD24 and HT in patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) as first-line treatment, we performed this post-hoc analysis of patients with advanced indolent B-cell lymphoma in a randomized clinical trial wherein six cycles of R-CHOP were administered every 2-3 weeks. The primary analysis showed no differences in outcomes, which enabled the analysis of 248 patients with FL, assigned to two arms. All histopathological specimens from the 300 enrolled patients were reviewed by three expert hematopathologists. Multivariable analysis implicated Follicular Lymphoma International Prognostic Index (FLIPI) intermediate (odds ratio [OR] 2.531, 95% confidence interval [CI] 0.676-9.466) and high- (OR 2.236, 95% CI 0.160-31.226) risks, B symptoms (OR 2.091, 95% CI 0.747-5.851), and grade 3A (G3A) (OR 1.833, 95% CI 0.634-5.299) as risk factors for POD24. Furthermore, multivariable analysis through a median follow-up of 15.9 years implicated G3A (OR 2.628, 95% CI 0.806-8.575) and high-risk FLIPI (OR 4.401, 95% CI 0.186-104.377) as risk factors for HT. However, an analysis limited to the first 10 years revealed that the prognostic factors elucidated from the longer-term analysis had a greater impact on HT. G3A and high-risk FLIPI may independently predict POD24 and HT, thereby informing treatment stratification of patients with untreated advanced-stage FL in future trials, particularly to address the unmet needs of patients with POD24.

BACKGROUND: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. METHODS: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. FINDINGS: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. INTERPRETATION: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. FUNDING:Daiichi Sankyo.

Objective This phase II clinical trial evaluated feasibility and tolerability of 90-minute rituximab infusion and a concentration of 4 mg/mL rituximab infusion in Japanese patients with previously untreated follicular lymphoma or diffuse large B-cell lymphoma.Methods Treatment was rituximab with cyclophosphamide, doxorubicin, vincristine and prednisolone. In cycle 1, rituximab at a dose of 375 mg/m2 (4 mg/mL) was administered at the standard infusion rate stipulated in the package insert. On confirmed tolerance of rituximab, patients received 90-minute infusion in second and subsequent cycles. The primary endpoint was incidence of grade 3 or higher infusion-related reactions during 90-minute rituximab infusion in cycle 2 of rituximab with cyclophosphamide, doxorubicin, vincristine and prednisolone.Results All 32 patients (median age 61.5 years, 16 males, 24 with diffuse large B-cell lymphoma) completed the prescribed six or eight cycles of treatment. One patient withdrew consent after cycle 1, and another developed grade 2 erythema and continued receiving 4 mg/mL at the standard infusion rate for cycle 2. The remaining 30 patients received 90-minute rituximab infusion; 28 (93.3%) completed cycle 2 at the scheduled infusion rate and dosage. No grade 3 or higher infusion-related reactions were associated with a concentration of 4 mg/mL rituximab dose or 90-min rituximab infusion in cycle 2. The most common infusion-related reaction symptoms were pruritus, hypertension and oropharyngeal discomfort. During the study, toxicities and adverse events were as expected, with no new safety signals.Conclusion High-concentration dosing (4 mg/mL) and 90-minute infusion of rituximab are feasible and tolerable in Japanese patients with previously untreated follicular lymphoma or diffuse large B-cell lymphoma.Clinical trial number JapicCTI-173 663. High-concentration dosing (4 mg/mL) and 90-min infusion of rituximab are feasible and tolerable in Japanese patients with previously untreated FL or DLBCL.

Nivolumab was approved for relapsed/refractory classic Hodgkin lymphoma (cHL) in Japan in 2016. After its approval, a prospective, non-interventional, observational post-marketing surveillance was initiated to evaluate the safety and effectiveness of nivolumab treatment for up to 12 months in patients with relapsed/refractory cHL. Of 304 registered patients, 288 were included in safety analyses and 282 in effectiveness analyses. There were 191 (66.3

Patients with relapsed or refractory (R/R) mature natural killer cell and T-cell lymphoma have limited treatment options. To evaluate pralatrexate's performance and factors influencing its safety and efficacy in R/R peripheral T-cell lymphoma (PTCL), we performed a pooled analysis of data from 4 similarly designed, regulatory-mandated prospective clinical trials. Of 221 patients (median age, 59 years; 67.0% male) in the study population, 48.9% had PTCL not otherwise specified (PTCL-NOS), 21.3% angioimmunoblastic T-cell lymphoma, and 11.8% ALK-negative anaplastic large cell lymphoma (ALCL). Patients received pralatrexate for a median of 2.56 months (range, 0.03-24.18) and had a 40.7% objective response rate with a median duration of response of 9.1 months, progression-free survival 4.6 months, and overall survival 16.3 months. The most common treatment-related all-grade adverse events were stomatitis, thrombocytopenia, white blood cell count decrease, pyrexia, and vomiting. Subgroup exploratory analyses suggest improved efficacy with 1 prior line of chemotherapy vs 2 or >= 4 prior lines; PTCL-NOS or ALCL vs transformed mycosis fungoides; chemotherapy and transplant before pralatrexate vs chemotherapy alone or chemotherapy with other nontransplant treatments. In conclusion, these pooled analysis results further support using pralatrexate in patients with R/R PTCL. Prospective studies are needed to confirm the findings of subgroups analyses.

Tucidinostat (formerly known as chidamide) is an orally available, novel benzamide class of histone deacetylase (HDAC) inhibitor that selectively blocks class I and class IIb HDAC. This multicenter phase IIb study aimed to investigate the efficacy and safety of tucidinostat, 40 mg twice per week (BIW), in patients with relapsed/refractory (R/R) peripheral T-cell lymphoma (PTCL). The primary endpoint was overall response rate (ORR) assessed by an independent overall efficacy review committee. Between March 2017 and March 2019, 55 patients were treated, and 46 and 55 were evaluated for efficacy and safety, respectively. Twenty-one of 46 patients achieved objective responses with an ORR of 46% (95% confidence interval : 30.9-61.0), including five patients with complete response (CR). Responses were observed across various PTCL subtypes. In angioimmunoblastic T-cell lymphoma, there were two CR and five partial responses (PR) among eight patients, achieving an ORR of 88%. The disease control rate (CR + PR + stable disease) was 72% (33/46). The median progression-free survival, duration of response, and overall survival were 5.6 months, 11.5 months, 22.8 months, respectively. The most common adverse events (AE) (all grades) were thrombocytopenia, neutropenia, leukopenia, anemia, and diarrhea. The grade ≥3 AE emerging in ≥20% of patients included thrombocytopenia (51%), neutropenia (36%), lymphopenia (22%), and leukopenia (20%). Importantly, most of the AE were manageable by supportive care and dose modification. In conclusion, the favorable efficacy and safety profiles indicate that tucidinostat could be a new therapeutic option in patients with R/R PTCL (clinicaltrials gov. Identifier: NCT02953652).

Background: Despite several attempts of randomized phase III trial to overcome R-CHOP in overall survival (OS), R-CHOP has been continued to be a standard of care in previously untreated DLBCL. We conducted a randomized phase II/III study (JCOG0601, jRCTs031180139) that investigated the efficacy of dose-dense weekly rituximab combined with standard CHOP regimen (RW-CHOP) during the early treatment period for previously untreated DLBCL and published the results (Ohmachi K, et al. Blood Adv. 2021). Here in, we report the long-term efficacy and safety of the JCOG 0601 trial after 8 years follow-up from the end of accrual. Methods: Patients aged 20-79 years with previously untreated CD20-positive DLBCL (stage I-IV, performance status 0-2) were randomized to standard R-CHOP (CHOP-21 with eight doses of rituximab, once every 3 weeks) or RW-CHOP (CHOP-21 with eight doses of weekly rituximab). The primary endpoint of phase III part was progression-free survival (PFS). Required sample size was 422 patients, an accrual period of 7 years, and a follow-up period of 3 years with the primary analysis. An additional follow-up period was added to assess long-term outcomes, for a total of 8 years of follow-up. Results: Between December 2007 and December 2014, 422 patients were enrolled, but primary analysis was performed on 421 patients after one patient withdrew consent: 213 in the R-CHOP arm and 208 in the RW-CHOP arm. The baseline characteristics were as follows (R-CHOP arm vs. RW-CHOP arm): median age, 61 vs. 62 years; male sex, 54.5% vs. 55.8%; Ann Arbor stage I/II/III/IV, 14.6/32.9/26.8/25.8% vs. 16.3/42.8/20.2/20.7%; and International Prognostic Index score ≤2, 77.0% vs. 87.5%. At a primary analysis, there was no significant difference in PFS between the arms. At the time of final analysis with a median follow-up of 9.6 years (range: 0.3-14.9) among all patients, meaningful differences were not found in PFS and OS as well as the primary analysist (hazard ratio [HR] in PFS of RW-CHOP against R-CHOP, 0.94; 95% confidence interval [CI], 0.67 to 1.32, one-sided log-rank, P = 0.36 and HR in OS, 0.94; 95% CI, 0.63 to 1.41). Median PFS and OS were not estimable in both arms. Estimated 10 years PFS and OS of all patients was 66.9% (95% CI, 62.1 to 71.3) and 78.0% (95% CI, 73.6 to 81.7). After the first relapse or refractoriness, 126 patients received post-protocol salvage therapy: 66 in the R-CHOP arm and 60 in the RW-CHOP arm. In each arm, 3 patients received high-dose chemotherapy followed by autologous stem cell transplantation. One patient in the R-CHOP arm proceeded to allogeneic stem cell transplantation from a sibling donor. Ann Arbor stage I to II disease tended to have more favor prognosis than Ann Arbor stage III to IV disease, and no sustained relapse was observed in either stage. Of the 401 patients who underwent central pathological review, 125 were diagnosed with germinal center B-cell-like (GCB) type and 216 with non-GCB type by immunohistochemistry analysis. There was no remarkable difference in PFS between the arms for GCB type and non-GCB type. Death occurred in 95 patients: 56 from DLBCL, 2 from treatment-related cardiac toxicity, 9 from treatment-related mortality caused by salvage treatment, 14 from secondary malignancies, and 11 from other diseases or reasons. There were 34 secondary malignancies in 31 patients (14.6%) in the R-CHOP arm, and 39 cases in 35 patients (16.8%) in the RW-CHOP arm. The most common secondary malignancies were lung cancer (2.6%), colon cancer (1.9%), prostate cancer (1.7%) and gastric cancer (1.9%). Three cases of acute myeloid leukemia (0.7%) and three of myelodysplastic syndromes (0.7%) were observed. The median age of patients who developed secondary malignancy was 72 years (range: 49-84) at the onset. The median time from study enrollment to the onset of secondary malignancy was 4.5 (range: 0.1-13.1) years and the incidence was time dependent. There were no unexpected adverse events, including late opportunistic infections. Conclusion: This final-follow up data demonstrated again no superiority of RW-CHOP in PFS and OS. Standard R-CHOP remains a standard of care for untreated DLBCL.

Table S1. Dose Escalation of C (3 levels) or InO (2 levels) and Treatment Schedule Used to Determine the MTD Based on a Standard 3+3 Design; Table S2. AEs Leading to Permanent Discontinuation or Modification of the MTD

Introduction: Treatment (Tx) options for T-cell non-Hodgkin lymphomas (T-NHLs) are limited and prognosis is too often poor for patients (pts) with relapsed or refractory (R/R) disease. Enhancer of zeste homolog (EZH)2 and EZH1 are methyltransferases that catalyze trimethylation of histone H3 at lysine 27 (H3K27me3); this repressive transcriptional profile is broadly associated with gene silencing. Valemetostat tosylate (valemetostat) is a novel, potent, and selective dual inhibitor of EZH2 and EZH1 that prevents H3K27me3 and increases expression of genes involved in immune function ( SLA, PAG1) that can be silenced by H3K27me3. Valemetostat was approved in Japan for the Tx of R/R adult T-cell leukemia/lymphoma (ATLL) in 2022. The clinical activity of valemetostat in pts with R/R NHLs was investigated in the phase 1 DS3201-A-J101 (“J101”; NCT02732275) trial. Interim data were reported previously. Here we report primary outcomes for pts in J101 with R/R T-NHLs treated with valemetostat. Methods: This open-label, multicenter study was conducted in Japan and the United States (US). Eligible pts were ≥ 18 (US) or ≥ 20 (Japan) years (y) of age and relapsed from, refractory to, or ineligible for standard therapies. The trial included a dose-escalation phase (Japan only) followed by a dose-expansion phase (Japan & US). Enrollment in the expansion phase was limited to pts with R/R peripheral T-cell lymphoma (PTCL) or ATLL. Pts received valemetostat once daily in continuous 28-day (d) Tx cycles at 150-300 mg/d in the escalation phase and 200 mg/d in the expansion phase until disease progression or intolerance. Key endpoints for the dose-escalation and dose-expansion cohorts were safety and PK parameters. Preliminary efficacy assessment included objective response rate (ORR), complete response (CR) rate, duration of response (DOR), and progression-free survival (PFS). DOR and PFS were estimated using Kaplan-Meier methods. Results for PTCL and ATLL are reported separately. Results: At the primary data cutoff (Dec 31, 2022), 71 pts were included in the efficacy and safety analyses; 57 with PTCL and 14 with ATLL. Median age at baseline was 68.0 (range 26-83) y in the PTCL group and 66.5 (37-78) y in the ATLL group, and median prior therapies were 2.0 (1-8) and 2.5 (1-8), respectively; 16 (28%; 14 autologous, 2 allogeneic) pts with PTCL and 2 (14%, both allogeneic) with ATLL had previously undergone transplant. The most common PTCL subtypes were PTCL, not otherwise specified (PTCL, NOS; n = 26, 46%) and angioimmunoblastic T-cell lymphoma (AITL; n = 23, 40%). Tx was ongoing for 8 (11%) pts at data cutoff. All 71 pts included at data cutoff experienced ≥ 1 Tx-emergent adverse event; 59 (83%) pts had a Tx-related adverse event (TRAE). The most common all-grade TRAEs were cytopenias, dysgeusia, and alopecia; the most frequent grade ≥ 3 TRAEs were decreased neutrophil (17%), lymphocyte (11%), and platelet (14%) counts ( Table 1). TRAEs led to Tx discontinuation for 4 (6%) pts (1 each: acute myeloid leukemia, myelodysplastic syndrome, colitis, and acute kidney injury), dose reduction for 5 (7%) pts, and Tx interruption for 18 (25%) pts. The ORR was 55% (30/55) in the PTCL group and 64% (9/14) in the ATLL group, with CR rates of 31% (17/55) and 29% (4/14), respectively; within the PTCL group, the ORR among evaluable pts was 50% (13/26) for PTCL, NOS and 64% (14/22) for AITL ( Table 2). Median times to response were 1.8 (range 1.0-5.6) months (mo) in the PTCL group and 1.9 (1.7-19.4) mo in the ATLL group. Median DOR was 21.9 mo (95% confidence interval [CI], 10.2 mo to not reached [NR]) in the PTCL group (median follow-up 16.4 mo) and 21.2 (95% CI, 1.4 to 38.7) mo in the ATLL group (median follow-up 23.0 mo). Median PFS was 7.7 and 4.1 mo, respectively (median follow-up 18.2 mo and NR). Conclusions: Valemetostat was well tolerated and showed encouraging clinical activity in pts with R/R T-NHLs. Cytopenias were common but could usually be managed without Tx discontinuation. Valemetostat induced durable responses, with median DOR of > 1.5 y in both the PTCL and ATLL groups. Results for pts in this trial with R/R B-NHLs (Izutsu et al) and from a phase 2 trial in R/R T-NHLs (Horwitz et al) are reported separately.

Introduction: B-cell non-Hodgkin lymphomas (B-NHLs), including diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL), are among the most common NHLs. Enhancer of zeste homolog (EZH)2 and EZH1 are methyltransferases that catalyze the trimethylation of histone H3 at lysine 27 (H3K27me3); this repressive transcriptional mark is broadly associated with gene silencing. EZH2 is involved in mediating B-cell development. Valemetostat tosylate (valemetostat) is a novel, potent, and selective dual inhibitor of EZH2 and EZH1. The clinical activity of valemetostat in patients (pts) with relapsed or refractory (R/R) NHL was investigated in the phase 1 DS3201-A-J101 (“J101”; NCT02732275) trial. Interim data were reported previously. Here we report primary clinical outcomes for the subgroup of pts in J101 with R/R B-NHLs, including DLBCL and FL. Methods: This phase 1, open-label, multicenter study was conducted in Japan and the United States (US). Eligible pts were aged ≥ 18 years (y; US) or ≥ 20 y (Japan), had confirmed B-NHL or T-cell NHL (T-NHL), and were relapsed from, refractory to, or ineligible for standard therapies. The trial included a dose-escalation portion (Japan only) followed by a dose-expansion phase (Japan & US). Pts with a histological diagnosis of B-NHL were enrolled in the dose-escalation phase and received valemetostat once daily at doses of 150-300 mg/day (d) in continuous 28-d treatment (Tx) cycles. Preliminary efficacy assessment included objective response rate (ORR), complete response (CR) rate, and duration of response (DOR). DOR was estimated for responding pts using Kaplan-Meier methods. Due to the small number of pts with B-NHL, safety was assessed among all enrolled pts, including those with T-NHL in the dose-escalation and dose-expansion cohorts. Results: At the primary trial cutoff (Dec 31, 2022), 19 pts with R/R B-NHLs were registered and had received ≥ 1 dose of study drug, including 7 with DLBCL, 7 with FL, 3 with indolent B-NHL, and 2 with other B-NHLs. Median age was 66 (range 44-88) y. Most (79%) pts had an Eastern Cooperative Oncology Group performance status score of 0. Median number of prior therapies was 2.0 (range 0-6); no pt in this cohort had received prior hematopoietic cell transplantation. Overall, 90 pts with R/R NHLs were enrolled. All pts experienced at least 1 treatment-emergent adverse event (TEAE), including 78 (87%) who had treatment-related TEAEs. The most common TEAEs (any grade) were decreased platelet count (64%), dysgeusia (50%), anemia (43%), decreased neutrophil count (34%), and alopecia (33%). The most common grade ≥ 3 TEAEs were cytopenias, including decreased neutrophil count (24%), platelet count (24%), and lymphocyte count (19%). TEAEs required Tx interruption for 42 (47%) pts, dose reduction for 9 (10%) pts, and Tx discontinuation for 7 (8%) pts. The overall response rate in pts with R/R B-NHL was 47% (9/19; 95% confidence interval [CI], 24.4-71.1). Clinical responses were seen in 3/7 pts with DLBCL and 4/7 pts with FL; 1 pt in each of these groups achieved CR ( Table). Of 19 pts, 9 (47%) achieved reductions of ≥ 50% from baseline in the sum of target lesion areas during valemetostat Tx ( Figure). A gain-of-function EZH2 mutation was identified in 1 pt with FL, and this pt achieved a partial response. Median time to response overall was 3.7 (range 1.9-10.1) months (mo) and estimated median DOR for the 9 responding pts was 18.4 mo (95% CI, 5.3 mo to not reached). Among all pts who received valemetostat 200 mg/d with pharmacokinetic (PK) data available (n = 74), mean [standard deviation; SD] maximum plasma concentration (C max) on cycle 1 day 1 was 2140 [1620] ng/mL, with a median time to C max (T max) of 3.9 (range 0.2-27.8) h and a mean [SD] AUC tau of 17,500 [21,400] ng × h/mL. Conclusions: Valemetostat demonstrated encouraging clinical activity in pts with R/R B-NHLs. The safety profile of valemetostat was acceptable; cytopenias were common but manageable and did not require Tx discontinuation between 150-300 mg/d. Clinical responses were durable, with a median DOR of > 1.5 y. Results for pts in this trial with R/R T-NHLs are presented in another abstract (Jacobsen et al.) at this congress. Ongoing trials of valemetostat in pts with R/R B-NHLs include a phase 2 monotherapy trial in France and Belgium (NCT04842877) and a phase 1/2 trial of valemetostat plus rituximab and lenalidomide (R 2) in the US (NCT05683171).

Adult T-cell leukemia/lymphoma (ATL) is an aggressive non-Hodgkin lymphoma with poor prognosis and few treatment options for patients with relapsed, recurrent, or refractory disease. We evaluated the efficacy and safety of valemetostat, a potent enhancer of zeste homolog 2 (EZH2) and EZH1 inhibitor, in treating relapsed or refractory (R/R) ATL. This multicenter phase 2 trial enrolled patients with R/R aggressive ATL (acute, lymphoma, unfavorable chronic type). Patients received valemetostat 200 mg/day orally until pro-gressive disease or unacceptable toxicity. The primary end point was overall response rate (ORR) centrally assessed by an independent efficacy assessment committee (IEAC). Secondary end points included best response in disease compartments, duration of response (DOR), pharmacokinetics, and safety. Twenty-five patients (median age, 69.0 years) with a median of 3 prior lines of therapy were enrolled; 24 had prior mogamuli-zumab treatment. The primary end point was met with a centrally reviewed ORR of 48.0% (90% confidence interval [CI], 30.5-65.9), including 5 complete and 7 partial remissions. Patients pretreated with mogamulizumab had an ORR of 45.8% (4 complete and 7 partial remissions). IEAC-assessed median DOR was not reached (NR) (95% CI, 1.87 to NR; months). Treatment-emergent adverse events (TEAEs) were manageable. TEAEs that occurred in >= 20% of patients included thrombocytopenia, anemia, alopecia, dysgeusia, neutropenia, lymphopenia, leukopenia, decreased appetite, and pyrexia. Grade >= 3 TEAEs included thrombocytopenia, anemia, lymphopenia, leukopenia, and neutropenia. Valemetostat demonstrated promising efficacy and tolerability in heavily pretreated patients, warranting further investigation in treating R/R ATL. This trial was registered at www.clinicaltrials.gov as #NCT04102150.

Anti-CD20 antibody in combination with chemotherapy extends overall survival (OS) in untreated advanced-stage follicular lymphoma (FL), yet the optimal associated therapy is unclear. Data on the cumulative incidence of secondary malignancies postrelapse after conventional immunochemotherapy are scarce. A long-term analysis of rituximab combined with cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) as first-line treatment was conducted in a randomised clinical trial. A six-cycle R-CHOP regimen was administered every 2 or 3 weeks without rituximab maintenance. A prespecified evaluation was conducted 15 years after the completion of enrolment, following initial analysis results that showed no significant differences in outcomes at the 3-year mark. In-depth analyses were performed on the cohort of 248 patients with FL who were allocated to the two treatment arms. With a median follow-up period of 15.9 years, the 15-year OS was 76.2%. There were no protocol treatment-related deaths, nor were there any fatal infections attributable to subsequent lymphoma treatment. At 15 years, the cumulative incidence of non-haematological and haematological malignancies was 12.8% and 3.7% respectively. Histological transformation appeared after a median of 8 years. R-CHOP maintains safety and efficacy in patients with advanced FL over extended follow-up, making it a viable first-line option for patients with advanced-stage FL.

Progression-free survival after R-High CHOP/CHASER/LEED with auto-PBSCT in untreated mantle cell lymphoma in JCOG0406 study. A continuous pattern of relapse was observed.

The safety, efficacy, and pharmacokinetics of copanlisib were evaluated in this phase Ib/II study in Japanese patients with relapsed/refractory indolent non-Hodgkin lymphoma (NHL). The primary endpoint was safety at the recommended dose; efficacy endpoints included objective response rate (ORR), progression-free survival (PFS), and overall survival. In phase Ib, patients received copanlisib 45 mg intravenously on days 1, 8, and 15 of a 28-day cycle, and when tolerated, consecutive patients received copanlisib 60 mg. As no dose-limiting toxicities occurred at the 45 mg ( n = 3) or 60 mg ( n = 7) dose in phase Ib, the recommended dose for Japanese patients was determined to be 60 mg, and this dose was used in phase II ( n = 15). Although all patients experienced at least one treatment-emergent adverse event (TEAE), with hyperglycemia being the most common AE, no AE-related deaths were reported. The ORR was 68.0% (17/25 patients), median PFS was 302 (95% CI 231–484) days, and the duration of response was 330 (range 65–659) days. The pharmacokinetic properties of copanlisib were similar between Japanese and non-Japanese patients. Overall, copanlisib 60 mg had an acceptable safety profile and showed promising antitumor activity in Japanese patients with relapsed/refractory indolent NHL.

A Japanese subgroup analysis from the Asian phase II study of darinaparsin in patients with relapsed or refractory peripheral T-cell lymphoma (PTCL) was performed to evaluate the efficacy and safety outcomes of the Japanese population. In this Asian phase II study, darinaparsin was administered to 65 patients, including 37 Japanese patients. In the Japanese population, the histopathological type of PTCL was PTCL, not otherwise specified in 26 patients (70.3%), angioimmunoblastic T-cell lymphoma in 9 patients (24.3%) and anaplastic large cell lymphoma, anaplastic lymphoma kinase (ALK) -negative in 2 patients (5.4%), and the median patient age was 70.0 (range: 43-85). 94.6% and 35.1% of the Japanese population had previously received multi-agent and single-agent regimen, respectively. The efficacy and safety were summarized and compared between the overall and Japanese populations. Based on central assessment, the overall response rate was 22.2% (8/36; 90% confidence interval [CI]: 11.6-36.5) in the Japanese population and 19.3% (11/57; 90% CI: 11.2-29.9) in the overall population. There were no essential differences in the safety profile of darinaparsin between the Japanese population and the overall population. The results of this subgroup analysis indicate that the efficacy and safety profiles of the Japanese subpopulation were broadly consistent with that of the overall population, and that darinaparsin is potentially an effective treatment with a manageable safety profile in Japanese patients with relapse or refractory PTCL.

Darinaparsin is a novel organic arsenical compound of dimethylated arsenic conjugated to glutathione, with antitumor activity and a mechanism of action markedly different from other available agents. This phase 2, nonrandomized, single-arm, open-label study evaluated the efficacy and safety of intravenous darinaparsin (300 mg/m2 over 1 hour, once daily for 5 consecutive days, per 21-day cycle) and its pharmacokinetics at multiple doses in 65 Asian patients with relapsed or refractory peripheral T-cell lymphoma (PTCL). The primary end point was the overall response rate (ORR). The ORR based on central assessment was 19.3% (90% confidence interval, 11.2-29.9), which was significantly higher than the predefined threshold of 10% (P = .024). The ORR was 16.2% in patients with PTCL-not otherwise specified and 29.4% in patients with angioimmunoblastic T-cell lymphoma. Tumor size decreased in 62.3% of patients. Treatment-emergent adverse events (TEAEs) were observed in 98.5% of patients. Grade ≥3 TEAEs with an incidence rate of ≥5% included anemia (15.4%), thrombocytopenia (13.8%), neutropenia (12.3%), leukopenia (9.2%), lymphopenia (9.2%), and hypertension (6.2%). Darinaparsin is effective and well tolerated, with TEAEs that were clinically acceptable and manageable with symptomatic treatment and dose reductions. This trial was registered at www.clinicaltrials.gov as #NCT02653976.