A phase 2, open-label study of ibrutinib plus rituximab in Japanese patients with Waldenstrom's macroglobulinemia.

Ibrutinib is a first-in-class Bruton kinase inhibitor against B-cell neoplasms including Waldenström macroglobulinemia (WM). This study evaluated the efficacy and safety of ibrutinib-rituximab in Japanese patients with WM. Patients received ibrutinib 420 mg orally once daily plus weekly rituximab 375 mg/m2 IV (8 infusions total). The primary end point was major response rate (MRR; PR or better) by Independent Review Committee assessment. Secondary endpoints were progression-free survival (PFS), safety, pharmacokinetics, and biomarkers. Primary analysis was conducted in 16 patients [baseline, treatment naïve: 8 (50.0%); relapsed/refractory WM: 8 (50.0%)] who received ibrutinib-rituximab, after all patients completed Week 57 or end of treatment. At primary analysis, MRR was 87.5% [14/16 patients; 95% CI: 61.7, 98.4%; p < 0.0001 (null hypothesis: 32% response rate)]. At final analysis (median study intervention duration: 34.4 months, median follow-up: 35.0 months), MRR was unchanged at 87.5%, but VGPR [6/16 (37.5%)] and PR [8/16 (50.0%)] improved. Prior treatment status did not affect response. At final analysis, median PFS was not reached [36-month PFS rate: 86% (95% CI: 55, 96%)]. No critical safety signals were reported. This study demonstrated a positive benefit/risk profile of ibrutinib-rituximab in Japanese patients with WM, consistent with the iNNOVATE study.

Fatal outcome of BK virus encephalitis in an allogeneic stem cell transplantation recipient.

BK virus (BKV) encephalitis is a rare complication after hematopoietic stem cell transplantation (HSCT). A 43-year-old woman with recurrent follicular lymphoma after autologous HSCT received allogeneic bone marrow transplantation from a human leukocyte antigen-matched related donor. Neutrophil engraftment was achieved on post-transplant day 13. Memory loss and noncooperative attitude toward the medical staff were observed on day 16, and her mental status worsened progressively. Magnetic resonance imaging (MRI) showed nonspecific findings on day 19; however, cerebrospinal fluid (CSF) analysis including real-time polymerase chain reaction on day 20 revealed elevated levels of BKV 4.67 × 104 copy/mL. BKV encephalitis was diagnosed based on CSF findings, intravenous administration of immunoglobulin and cidofovir was started, and the immunosuppressive agent dose was reduced. Diffusion-weighted MRI on day 28 showed signal abnormalities in the bilateral periventricular white matter. Although the follow-up CSF analysis on day 35 was negative for BKV, her mental status and MRI findings did not improve, and she died on day 55 because of respiratory failure. This case emphasizes the importance of considering BKV encephalitis as a differential diagnosis of post-transplant encephalitis, considering the central nervous system-associated immune reconstitution inflammatory syndrome in patients with worsening central nervous system findings after eradication of BKV in the CSF.

Characteristics of chronic lymphocytic leukemia in Japan: Comprehensive analysis of the CLLRSG-01 study.

Chronic lymphocytic leukemia (CLL) is rare in Japan. We conducted the nationwide, prospective observational study CLLRSG-01 to clarify the current state of CLL in Japan and to make accurate international comparisons by preparing naturally air-dried smears like those used in other countries. Of the 201 untreated patients enrolled and evaluated, 119 were diagnosed with CLL and 82 with non-CLL mature B-cell neoplasms, based on the WHO classification. Of the 119 CLL patients, 90 were classified as typical and 29 as atypical according to FAB classification morphology, with the proportion of atypical CLL consistent with reports from other countries. Immunophenotypic analyses by flow cytometry showed that 55% of Japanese CLL patients had a Matutes score of 4 or higher, which is lower than the rate of about 90% in Europeans. Mutated IGHV was identified in 80% of Japanese CLL patients, which is a higher rate than in Western patients. The most frequent IGHV gene was VH3-30 (15%), followed by VH3-23 (12%) and VH4-34 (10%). VH1-69, the most common gene in Western countries, was identified in only one patient. These results indicate that the pattern of immunophenotypes and IGHV gene usage in Japanese CLL patients differs from that in Western patients.

End-of-treatment 18[F]-FDG PET can predict early progression in patients receiving bendamustine-rituximab for follicular lymphoma in first relapse: a prospective West Japan hematology Study Group (W-JHS) NHL01 trial.

Response determined by 18[F]-fluoro-2-deoxy-D-glucose (18F-FDG) positron emission tomography (PET)-CT after induction therapy can predict progression-free survival (PFS) in follicular lymphoma (FL). However, little prospective research has examined the significance of PET after second-line therapy. We conducted a prospective multicenter phase II trial (W-JHS NHL01) of bendamustine plus rituximab (BR) without rituximab maintenance for FL in first relapse. This study aimed to evaluate the usefulness of end-of-treatment (EOT)-PET for predicting PFS in FL patients in first relapse. EOT-PET examinations were performed between 6 and 8 weeks from the start of the last BR cycle. The primary endpoint was 1-year PFS. Key secondary endpoints were overall response rate (ORR), complete response rate (CRR), and 1-year overall survival (OS). Seventy-five patients were enrolled, and 8 were excluded from analysis. ORR was 86.6% and CRR was 59.7%. One-year PFS was 88.9% (95% confidence interval [CI] 80.7-94.3%) and 1-year OS in 75 patients was 97.3% (95% CI 89.6-99.3%). One-year PFS was significantly inferior in EOT-PET-positive patients (n = 9) compared with PET-negative patients (n = 58) (77.8% vs. 93.1%; p = 0.02). We confirmed that EOT-PET after second-line BR therapy could predict early progression in FL patients in first relapse.

Plain language summary of the TRANSFORM study primary analysis results: lisocabtagene maraleucel as a second treatment regimen for large B-cell lymphoma following failure of the first treatment regimen.

WHAT IS THIS SUMMARY ABOUT?: People diagnosed with a disease called large B-cell lymphoma (LBCL) may experience return, or early relapse, of their disease within the first year after receiving and responding to their first (first-line) treatment regimen. Others may have primary refractory disease, meaning that the disease either did not respond to first-line treatment at all or only responded for a very brief period. Second (second-line) treatment includes immunotherapy followed by high-dose chemotherapy and ASCT, which has the potential to cure LBCL. However, if the disease does not respond to immunotherapy, people cannot receive ASCT, and less than 30% of people are cured. Therefore, new second-line treatment options are required, such as CAR T cell therapy, which uses a person's own genetically engineered lymphocytes, also called T cells, to fight their lymphoma. In this article, we summarize the key results of the phase 3 TRANSFORM clinical study that tested if liso-cel, a CAR T cell treatment, can safely and effectively be used as a second-line treatment for people with early relapsed or primary refractory (relapsed/refractory) LBCL. A total of 184 adults with relapsed/refractory LBCL who were able to receive ASCT were randomly treated with either liso-cel or standard of care (SOC) as second-line treatment. SOC included immunochemotherapy followed by high-dose chemotherapy and ASCT. WHAT WERE THE KEY TAKEAWAYS?: Almost all (97%) people in the liso-cel group completed treatment, whereas 53% of people in the SOC group did not complete treatment, mostly due to their disease not responding or relapsing, and therefore they were not able to receive ASCT. People who received liso-cel as a second-line treatment lived longer without the occurrence of an unfavorable medical event or worsening of the disease and had a better response to treatment than those who received SOC as second-line treatment. People who received liso-cel reported side effects that researchers considered to be manageable, and that were known to occur with CAR T cell treatment. WHAT WERE THE MAIN CONCLUSIONS REPORTED BY THE RESEARCHERS?: Results from the TRANSFORM study support the use of liso-cel as a more effective second-line treatment compared with SOC that is safe for people with relapsed/refractory LBCL. Clinical Trial Registration: NCT03575351 (TRANSFORM study) (ClinicalTrials.gov).

Post-marketing surveillance of the safety and effectiveness of nivolumab for classic Hodgkin lymphoma in Japan.

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%) male patients, median age was 64.0 years, and 54 patients (18.8%) had performance status ≥ 2. Treatment-related adverse events (TRAEs) were reported in 183 (63.5%) patients, with grade 3-5 TRAEs in 86 (29.9%). The most common TRAEs were infusion reaction (14.6%), hepatic function abnormal (5.9%), interstitial lung disease (ILD) (5.6%), and hypothyroidism (5.2%). TRAEs of special interest in ≥ 5% of patients were infusion reaction (15.6%), hepatic failure/hepatic dysfunction/hepatitis/cholangitis sclerosing (13.2%), thyroid dysfunction (9.7%), and ILD (7.3%). In multivariable analyses, prior allogeneic hematopoietic stem cell transplantation was a risk factor for hepatic failure/hepatic dysfunction/hepatitis/cholangitis sclerosing, and prior thyroid gland disorders was a risk factor for thyroid dysfunction. The overall response rate was 61.7%. In conclusion, nivolumab showed a similar safety profile and comparable effectiveness to that reported in clinical trials for relapsed/refractory cHL (CheckMate 205, ONO-4538-15).

Glasdegib with intensive/nonintensive chemotherapy in Japanese patients with untreated acute myeloid leukemia or high-risk myelodysplastic syndromes.

Glasdegib is a potent, selective, oral inhibitor of the hedgehog signaling pathway. In this phase I study, previously untreated Japanese patients with acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes were treated with glasdegib (100 mg once daily) combinations: low-dose cytarabine (20 mg twice daily; cohort 1, n = 6; expansion cohort, n = 15); daunorubicin and cytarabine (60 mg/m2 i.v.; cohort 2, n = 6); or azacitidine (100 mg/m2 i.v.; cohort 3, n = 6). Patients, except cohort 2, were ineligible for intensive chemotherapy. The primary end-point was dose-limiting toxicity in cohorts 1-3 and disease-modifying response in the expansion cohort. Disease-modifying response rate was tested with the null hypothesis of 6.8%, which was set based on the results from the phase II BRIGHT AML 1003 study (NCT01546038). No dose-limiting toxicities were observed in cohorts 1 or 3; one patient in cohort 2 experienced a dose-limiting toxicity of grade 3 erythroderma. The most common grade ≥3 treatment-related adverse events were neutropenia and thrombocytopenia (66.7% each) in cohort 1 and thrombocytopenia (60.0%) in the expansion cohort. In the expansion cohort, the disease-modifying response rate was 46.7% (90% confidence interval, 24.4-70.0; p < 0.0001), with all patients achieving either a complete response or complete response with incomplete blood count recovery. Median overall survival was 13.9 months. In this study, the primary disease-modifying response end-point with glasdegib plus low-dose cytarabine was met. The study confirms the safety and efficacy of glasdegib plus low-dose cytarabine in Japanese patients with AML ineligible for intensive chemotherapy.

Loss of or decrease in CD30 expression in four patients with anaplastic large cell lymphoma after brentuximab vedotin-containing therapy.

Brentuximab vedotin (BV), CD30 specific antibody drug conjugate, has been used to treat anaplastic large cell lymphoma (ALCL) and classic Hodgkin lymphoma (CHL); it is also used in the treatment of other CD30-positive peripheral T-cell lymphomas. We aimed to investigate the incidence and clinicopathological characteristics of patients with ALCL or CHL with loss of or decrease in CD30 expression after BV-containing therapy. Twelve and nine patients with refractory/relapsed CHL and ALCL, respectively, were analyzed after receiving BV-containing therapy. In four ALCL patients (44%), CD30 expression was lost/decreased in re-biopsy materials, including one with complete loss and three with a reduction of less than 20%. All 12 CHL patients showed consistent CD30 expression levels after BV treatment. Compared with five ALCL patients with consistent CD30 expression, four ALCL patients with a loss of/decrease in CD30 expression received a higher cumulative dose of BV (P = 0.014) and revealed a lower intensity of CD30 expression in initial biopsy materials (P = 0.017). The subtypes of ALCL (ALK positive, ALK negative, and primary cutaneous) were not related to the loss of/decrease in CD30 expression. In conclusion, 44% of ALCL patients, regardless of histological subtypes, showed a loss of/decrease in CD30 expression after receiving BV-containing therapy, but this phenomenon was not observed in CHL patients. A higher cumulative dose of BV and a lower amount of CD30 antigen in tumor cells in the initial biopsy materials might be predictors of a loss of/decrease in CD30 expression in ALCL patients.

Real-world effectiveness and safety of ibrutinib in relapsed/refractory mantle cell lymphoma in Japan: post-marketing surveillance.

Efficacy and safety data for ibrutinib in Japanese patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL) were limited at the time of its approval in Japan. All-case post-marketing surveillance was conducted in Japanese R/R MCL patients who began ibrutinib treatment between December 2016 and December 2017, and patients were followed until 30 June 2020. In the effectiveness analysis set (n = 202), the overall response rate was 59.9%, 52-week progression-free survival was 47.5%, and overall survival was 69.3%. Safety was assessed in 248 patients (median age 74.0 years). When ibrutinib treatment was started, patients had received a median of three prior lines of therapy. The overall incidence of adverse events (AE) was 74.6%, and AE frequency and severity grade distribution were similar between patients with 1 versus more than 1 prior line of therapy. The most common AE was platelet count decreased (all grades; 10.4%), similarly to previous observations in patients with R/R chronic lymphocytic leukemia/small lymphocytic lymphoma. Five patients (2.0%) developed atrial fibrillation. The effectiveness and safety of ibrutinib were consistent with its known profile at approval in Japan. These results suggest that ibrutinib is effective and safe in Japanese R/R MCL patients in routine clinical practice.

A phase II Japanese trial of 90-minute rituximab infusion for untreated B-cell lymphoma.

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.

Phase 2 study of ibrutinib plus venetoclax in Japanese patients with relapsed/refractory mantle cell lymphoma.

BACKGROUND: Despite high response rates to initial therapy, most patients with mantle cell lymphoma (MCL) experience relapsed or refractory (R/R) disease. Here, we report the efficacy, safety, and pharmacokinetics of the Phase 2, single-arm M20-075 study (NCT04477486) of ibrutinib and venetoclax combination therapy in Japanese patients with R/R MCL. METHODS: Patients received 560 mg ibrutinib and 400 mg venetoclax (after a 5-week ramp-up from 20 mg) once daily for up to 104 weeks. Primary endpoint was complete response (CR) rate by independent review committee (IRC). Secondary endpoints included overall response rate (ORR), duration of response (DOR), undetectable minimal residual disease (uMRD) rate, progression-free survival (PFS), overall survival (OS), safety including dose-limiting toxicity (DLT) assessment in the first six patients, and pharmacokinetic parameters. Full analysis set (FAS) comprised all treated patients. Per protocol set (PPS) excluded treated patients with non-evaluable disease at baseline by IRC. RESULTS: Thirteen patients were treated (FAS n = 13; PPS, n = 12). Median age was 71 years, patients had a median of two prior treatments. After a median follow-up of 9.6 months, IRC-assessed CR rate and ORR were both 83% (PPS). All six MRD-evaluable patients had uMRD. Median DOR, PFS, and OS were unreached. The most common Grade ≥ 3 treatment-emergent adverse event (TEAE) was neutropenia (23%); 1 patient discontinued due to squamous cell carcinoma of the lung. No DLTs, tumor lysis syndrome, or deaths related to TEAEs were observed. CONCLUSION: Ibrutinib plus venetoclax exhibited high response rates and a well-tolerated safety profile in Japanese patients with R/R MCL.

Japanese phase Ib study of the oral PI3K-δ and -γ inhibitor duvelisib in patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma.

This phase Ib, open-label, single-arm, multicenter study assessed the efficacy and safety of duvelisib, an oral dual inhibitor of phosphatidylinositol 3-kinase-δ and -γ, in Japanese patients with relapsed or refractory (r/r) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Duvelisib was administered orally at 25 mg twice a day (BID) until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) and all responses were assessed by an independent review committee. Nine CLL patients and 1 SLL patient were enrolled. ORR was 80% (95% confidence interval 44.4, 97.5) for all 10 patients. All 6 patients previously treated with a Bruton's tyrosine kinase (BTK) or BCL2 inhibitor achieved a partial response. The most common adverse events were neutropenia (50%), diarrhea (40%), anemia, hypokalemia, constipation and rash (30% each). The most common grade ≥ 3 adverse events were neutropenia (50%), anemia (30%) and thrombocytopenia (20%). Duvelisib 25 mg BID showed favorable efficacy and a manageable safety profile in selected Japanese patients with r/r CLL/SLL, including patients previously treated with BTK or BCL2 inhibitors (Clinical trial registration: jRCTs2080224791).

Subcutaneous epcoritamab monotherapy in Japanese adults with relapsed/refractory diffuse large B-cell lymphoma.

Epcoritamab is a subcutaneously administered CD3xCD20 bispecific Ab that showed deep, durable responses with a manageable safety profile in patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) in the global multicenter pivotal phase II trial EPCORE NHL-1. Here, we present results from the similar EPCORE NHL-3 phase I/II trial evaluating epcoritamab monotherapy in Japanese patients with R/R CD20+ B-cell non-Hodgkin's lymphoma previously treated with two or more lines of therapy. Epcoritamab was dosed subcutaneously in 28-day cycles; once weekly during cycles 1-3, every 2 weeks during cycles 4-9, and every 4 weeks from cycle 10 until disease progression or unacceptable toxicity. Step-up dosing and cytokine release syndrome (CRS) prophylaxis were used during treatment cycle 1. As of January 31, 2022, 36 patients received treatment with 48 mg epcoritamab monotherapy. At a median follow-up of 8.4 months, overall response and complete response rates by independent review committee were 55.6% and 44.4%, respectively. The median duration of response, duration of complete response, and overall survival were not reached at the time of data cut-off. The most common treatment-emergent adverse events of any grade were CRS (83.3%), injection-site reactions (69.4%), infections (44.4%), neutropenia (38.9%), hypokalemia (27.8%), and decreased lymphocyte count (25.0%). Cytokine release syndrome occurrence was predictable; events were primarily low grade (grade 1-2), all resolved, and none led to treatment discontinuation. These encouraging results are consistent with previous findings and support the ongoing clinical evaluation of epcoritamab for the treatment of R/R DLBCL, including in earlier treatment lines.

Pathogenesis of Gastrointestinal Follicular Lymphomas: Consideration Based on Histopathology and Endoscopic Findings.

Gastrointestinal (GI) follicular lymphoma (FL) is the most frequently diagnosed extranodal FL; however, its pathogenesis is debatable. We investigated the distribution, endoscopic, and histopathologic findings of 366 GI FL samples obtained from 298 patients. FLs were most frequently observed in the small intestine (71%), including the duodenum (52%), but were also commonly found in the stomach (15%) and colon (12%). The proportion of granular lesions in the duodenum, terminal ileum, colon, and stomach was 74%, 39%, 24%, and 0%, respectively. Submucosal or ulcerated tumors were frequently observed in the stomach (48%) and colon (52%). Most GI FL showed grade 1 to 2 histology (89%) as well as CD10 + (93%) and BCL2 + (98%) positivity. There were no significant differences in the endoscopic or histologic findings between primary and secondary GI FLs. As known, the mucosa of the small intestine is thin and villous, while the mucosa of the stomach and colon is thicker and has a smooth surface. Granular lesions corresponding to very small FL were detected in the former but rarely in the latter. Nine (7%) patients with primary GI FL developed histologic transformation to diffuse large B-cell lymphoma (n=8) or high-grade B-cell lymphoma (n=1) 10 months to 14 years after the diagnosis of FL. Two patients died of lymphoma. In conclusion, the incidence and endoscopic findings differed, but the histopathology was similar in FLs in each site. These differences might be attributed to variations in each GI site's mucosal structure and the neoplastic follicles' size. Due to its characteristic structure, very small classic FLs might be detectable mainly in the small intestine.

Dose-escalation part of Phase I study of single-agent mosunetuzumab in Japanese patients with relapsed/refractory B-cell non-Hodgkin lymphoma.

OBJECTIVE: This dose-escalation part of an ongoing Phase I study assessed the tolerability, safety and pharmacokinetics of mosunetuzumab in Japanese patients with relapsed/refractory B-cell non-Hodgkin lymphoma (NHL). METHODS: Mosunetuzumab was administered intravenously, with step-up dosing in a 3 + 3 design, on Days 1, 8 and 15 of Cycle 1, and Day 1 of each subsequent 21-day cycle for up to 17 cycles to patients across five cohorts with different target doses (2.8, 6.0, 13.5, 27.0 or 60.0 mg). RESULTS: As of 5 July 2022, 23 patients had received mosunetuzumab. The median patient age was 63.0 years, 56.5% of patients were male, and 69.6% of patients had diffuse large B-cell lymphoma, 17.4% had transformed follicular lymphoma (FL) and 13.0% had FL. The median number of prior lines of therapy was 4. Mosunetuzumab was well tolerated and there were no deaths. The most common adverse events (any grade) were neutropenia/neutrophil count decreased (47.8%) and cytokine release syndrome (34.8%). Most cytokine release syndrome events were Grade 1/2 (one Grade 3), and most occurred within 24 hours of the first dose of mosunetuzumab. The apparent half-life of mosunetuzumab was 4.1-5.0 days. Two patients achieved a complete response, and 11 patients achieved a partial response. CONCLUSIONS: This study demonstrated that mosunetuzumab has an acceptable safety profile and antitumor activity in Japanese patients with relapsed/refractory B-cell NHL. The recommended Phase II dose of 1.0/2.0/60.0/60.0/30.0 mg was tolerable and there were no new or different safety signals compared with the global Phase I study.

Japanese subgroup analysis in the Asian phase II study of darinaparsin in patients with relapsed or refractory peripheral T-cell lymphoma.

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.

Pirtobrutinib in Covalent Bruton Tyrosine Kinase Inhibitor Pretreated Mantle-Cell Lymphoma.

PURPOSE: Pirtobrutinib is a highly selective, noncovalent (reversible) Bruton tyrosine kinase inhibitor (BTKi). We report the safety and efficacy of pirtobrutinib in patients with covalent Bruton tyrosine kinase inhibitor (cBTKi) pretreated mantle-cell lymphoma (MCL), a population with poor prognosis. METHODS: Patients with cBTKi pretreated relapsed/refractory (R/R) MCL received pirtobrutinib monotherapy in a multicenter phase I/II trial (BRUIN; ClinicalTrials.gov identifier: NCT03740529). Efficacy was assessed in the first 90 consecutively enrolled patients who met criteria for inclusion in the primary efficacy cohort. The primary end point was overall response rate (ORR). Secondary end points included duration of response (DOR) and safety. RESULTS: The median patient age was 70 years (range, 46-87), the median prior lines of therapy was 3 (range, 1-8), 82.2% had discontinued a prior cBTKi because of disease progression, and 77.8% had intermediate- or high-risk simplified MCL International Prognostic Index score. The ORR was 57.8% (95% CI, 46.9 to 68.1), including 20.0% complete responses (n = 18). At a median follow-up of 12 months, the median DOR was 21.6 months (95% CI, 7.5 to not reached). The 6- and 12-month estimated DOR rates were 73.6% and 57.1%, respectively. In the MCL safety cohort (n = 164), the most common treatment-emergent adverse events (TEAEs) were fatigue (29.9%), diarrhea (21.3%), and dyspnea (16.5%). Grade ≥3 TEAEs of hemorrhage (3.7%) and atrial fibrillation/flutter (1.2%) were less common. Only 3% of patients discontinued pirtobrutinib because of a treatment-related adverse event. CONCLUSION: Pirtobrutinib is a first-in-class novel noncovalent (reversible) BTKi and the first BTKi of any kind to demonstrate durable efficacy after prior cBTKi therapy in heavily pretreated R/R MCL. Pirtobrutinib was well tolerated with low rates of treatment discontinuation because of toxicity.