International Journal of Hematology最新文献

We characterized the safety and efficacy of the bispecific antibody teclistamab in Japanese patients with relapsed/refractory multiple myeloma (RRMM). Patients were pretreated with a proteasome inhibitor (PI), immunomodulatory drug (IMiD), and anti-CD38 monoclonal antibody (mAb). The primary endpoint was frequency and type of treatment-emergent adverse events (TEAEs) in phase 1, and overall response rate (ORR; ≥ partial response [PR]) in phase 2. In phase 1, 14 patients received once-weekly (QW) subcutaneous teclistamab (0.72 mg/kg [n = 5]; 1.5 mg/kg [n = 5]; 3 mg/kg [n = 4]). No dose-limiting toxicities were observed. As of April 2024, 26 phase-2 patients received the recommended phase-2 dose (QW) (RP2D: 1.5 mg/kg) of teclistamab. Biweekly (Q2W) dosing was allowed after maintaining response for ≥ 6 months. At a median follow-up of 14.32 months, ORR was 76.9% (≥ very good PR: 76.9%; ≥ complete response: 65.4%). Median duration of response, progression-free survival, and overall survival were not reached. Common TEAEs included CRS (grade ≤ 2), neutropenia, and infections. No patient had immune effector cell-associated neurotoxicity syndrome (ICANS) and dose reductions. Teclistamab demonstrated deep and durable responses in Japanese patients with RRMM, consistent with the global pivotal MajesTEC-1 study, supporting the potential for a new standard of care for Japanese RRMM patients.

Ibrutinib is a first-in-class Bruton's tyrosine kinase inhibitor that is approved for the treatment of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) in Japan based on randomized clinical trial data. The aim of the real-world, retrospective Orbit study was to describe long-term clinical outcomes and management in adults (aged ≥ 20 years) with CLL/SLL treated with ibrutinib, either as first-line (1L) treatment or for relapsed or refractory (RR) disease, in routine clinical practice in Japan between July 2018 and December 2020. A total of 246 patients were registered, and the safety and per-protocol sets included 237 and 234 patients, respectively. After a median follow-up of 35.7 months, the 36-month progression-free survival rate was 80.9% in the 1L CLL cohort and 67.2% in the RR CLL cohort, and the 36-month overall survival rates were 90.8% and 83.7%, respectively. Common Terminology Criteria for Adverse Events (CTCAE) Grade ≥ 3 adverse events of special interest were atrial fibrillation (2.1%), infections (herpesvirus infection, fungal infection, or Pneumocystis jiroveci pneumonia; 1.7%), bleeding (3.8%), and second primary malignancy (2.5%). These findings confirm the long-term, real-world effectiveness and safety of ibrutinib for the treatment of Japanese patients with newly diagnosed or RR CLL/SLL.

A 63-year-old man, previously diagnosed with multiple autoimmune diseases, developed life-threatening bleeding after gastrectomy for stomach cancer. He survived due to treatment with factor XIII (FXIII) concentrates immediately after his FXIII antigen (Ag) level was reported to be < 5% of normal. Detailed examination by the Japanese Collaborative Research Group on autoimmune coagulation factor deficiencies revealed the presence of anti-FXIII-A and anti-FXIII-B subunit autoantibodies on immunoblot analyses, and thus autoimmune FXIII deficiency (AiF13D) was diagnosed based on the Japanese and international diagnostic criteria. Antibody eradication therapy with prednisolone was initiated and cyclophosphamide was added later. While FXIII:Ag levels remained at 40-50% of normal, bleeding did not recur even after stomach polypectomy. Experimental studies on patient specimens collected at the initial bleeding and later asymptomatic stages demonstrated the co-existence of clearance-accelerating and inhibitory anti-FXIII autoantibodies. The former type was predominant in both the bleeding and asymptomatic stages, whereas the latter became distinct in the asymptomatic stage. This is the first AiF13D patient to demonstrate such a change in anti-FXIII autoantibody type during the clinical course. This report discusses the relationship between autoantibody type and bleeding phenotype in detail, but future large studies are needed to confirm these observations.

Here, we investigated the clinical significance of NOTCH1 and FBXW7 alterations for adult T-cell leukemia/lymphoma (ATLL) treatment outcomes. NOTCH1 alterations were identified in 37 (14.4%) of 257 patients, of which 33 were single nucleotide variants/insertion-deletions in the PEST domain, and 7 were in the heterodimerization or LIN-12/Notch repeats domains. FBXW7 alterations were observed in nine ATLL patients (3.5%). For patients without allogeneic hematopoietic stem cell transplantation (HSCT), NOTCH1, but not FBXW7, alterations were significantly and independently associated with worse overall survival (median OS 0.5 years, 95% confidence interval [CI] 0.4-0.5 years for 27 patients with NOTCH1 alterations vs 1.8 years, 95% CI 1.3-2.2 years for 170 patients without). Also, for patients receiving mogamulizumab, but not allogeneic-HSCT, NOTCH1, but not FBXW7, alterations were significantly associated with worse survival (median survival from the first dose of mogamulizumab 0.4 years, 95% CI 0.3-0.5 years for 12 patients with NOTCH1 alterations vs 1.4 years, 95% CI 0.9-2.0 years for 87 without). In contrast, NOTCH1 alterations had no significant impact on survival of patients who did receive allogeneic-HSCT. Thus, mogamulizumab-containing treatment was unable to overcome treatment refractoriness of ATLL with NOTCH1 alterations. Therefore, patients with NOTCH1 alterations are recommended for allogeneic-HSCT.

Diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL) represent the two major subtypes of mature B cell lymphoma. A deeper understanding of tumor biology, as well as molecular classification characterized by targetable gene alterations, and the introduction of novel treatment options, including targeted drugs (e.g., antibody-drug conjugates and small molecules [e.g., Bruton tyrosine kinase inhibitor]) and immune therapies (e.g., chimeric antigen receptor [CAR] T cell therapy and bispecific antibody [BsAb]), has changed the treatment paradigms for DLBCL and FL. In clinical practice, however, treatment regimens are determined mainly based on prior treatment history, duration of response after previous treatment, patient age, and patient frailty because there have been few randomized trials to inform treatment selection for patients with relapsed or refractory disease and because there is no single prognostic index that guides suitable treatment for each patient. In this review, we summarize the treatment options for DLBCL and FL and discuss the treatment strategies for these two subtypes. We also discuss future perspectives for the treatment of these subtypes.

Although tyrosine kinase inhibitors (TKIs) have improved the prognosis of chronic myeloid leukemia (CML), some patients do not respond to TKIs. We evaluated 21 patients with CML treated with asciminib, which is effective in heavily pretreated patients. The median age was 63 years (range 25-82). Fourteen patients (67%) had been treated with at least three TKIs (range 2-5 prior lines). The switch to asciminib was due to intolerance in 14 patients (67%) and failure in seven patients (33%). The median duration of asciminib exposure was 237 days. With a median follow-up of 273 days, three patients (14%) discontinued asciminib due to failure and two (10%) due to intolerance. Among the 20 evaluable patients, the cumulative rates of molecular response with a two-log reduction, major molecular response, and four-log reduction were 80%, 60%, and 15%, respectively. The six-month event-free survival rate was 74.7%. The most frequent adverse events were liver dysfunction (29%), elevated amylase levels (14%), and renal dysfunction (10%). No patient experienced cardiovascular events. Six patients (29%) experienced cross-intolerance to asciminib, a rate similar to that for previous TKIs. Our study supports the efficacy and tolerability of asciminib in heavily pretreated CML patients in real-world settings.

The advent of tyrosine kinase inhibitors (TKIs) has revolutionized the treatment of chronic myeloid leukemia (CML), significantly improving patient prognosis. Asciminib, a novel specifically targeting the ABL myristoyl pocket inhibitor, has shown promise for CML patients unresponsive or intolerant to traditional TKIs. However, its use in hemodialysis patients remains underexplored. We present a case of a 71-year-old man with CML undergoing hemodialysis, successfully treated with asciminib. Initial treatment with bosutinib was effective but later failed, prompting a switch to asciminib. The patient achieved a major molecular response within 2 months without adverse effects. Pharmacokinetic analysis revealed significant drug clearance during hemodialysis, necessitating dosage adjustments. This case highlights the potential of asciminib in managing CML in hemodialysis patients, emphasizing the need for individualized treatment plans and close monitoring. Further studies are warranted to establish comprehensive guidelines for asciminib use in this unique patient population.

The Japan Children's Cancer Group Relapsed Acute Lymphoblastic Leukemia (ALL) Committee conducted a prospective observational study (ALL-R14) to explore promising reinduction therapy regimens for relapsed ALL to investigate in future trials. In Japan, clofarabine- and bortezomib-based regimens were of interest since they were newly introduced for ALL in the study period (2015-2018). Seventy-five pediatric patients were enrolled in total. The 2-year event-free/overall survival rates in patients with first (n = 59) or second (n = 11) relapse were 40.1% (95% confidence interval [CI]: 25.5-52.3%)/66.3% (95% CI 52.3-77.0%) and 34.1% (95% CI 9.1-61.6%)/62.3% (95% CI 27.7-84.0%), respectively. Clofarabine- or bortezomib-based regimens were used only in patients with high-risk disease. The first reinduction therapy used in the 41 patients with early or multiple relapsed B-cell precursor ALL was clofarabine in 7 patients and bortezomib in 9 patients. The odds ratio for reinduction failure risk with a clofarabine- or bortezomib-based regimen compared with other regimens was 9.0 (95% CI 0.9-86.4, P = 0.057) or 1.9 (95% CI 0.4-8.7, P = 0.42), respectively. Thus, clofarabine- or bortezomib-based regimens had no obvious advantage as reinduction therapy for relapsed ALL in children.

Mutation profiling by next-generation sequencing (NGS) has facilitated understanding of the molecular pathogenesis of acute myeloid leukemia (AML), and has been incorporated into the new disease classification (International Consensus Classification; ICC) and risk classification (European LeukemiaNet [ELN] 2022; ELN2022). We compared disease subtypes between the previous disease classification (4th edition of the WHO classification; WHO-4) and the ICC in 91 patients with AML diagnosed at our institution. We also compared disease risk classifications using the previous risk classification (ELN2017) and the ELN2022. Targeted sequencing of bone marrow samples was conducted at Kyoto University. We found that entities under AML with recurrent genetic abnormalities were well-established, with almost no change from the WHO-4 to the ICC. In contrast, 16.7% of cases of AML, not otherwise specified in the WHO-4 were reclassified into AML with mutated TP53, and 36.7% were reclassified into AML with myelodysplasia-related gene mutations or cytogenetic abnormalities per the ICC. Meanwhile, the ELN2017 and ELN2022 showed no difference in concordance indexes in multivariate Cox regression analysis for progression-free and overall survival. The superiority of the ELN2022 over the ELN2017 could not be confirmed in our single-center retrospective study, and further investigation including multicenter prospective studies is needed.

Previously, we reported the efficacy and safety of tazemetostat in Japanese patients with relapsed/refractory follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) harboring the EZH2 mutation in a multicenter, open-label, phase II study. Here, we present a follow-up analysis of tazemetostat at a long-term median follow-up of 35.0 months. Twenty patients were enrolled: 17 in the FL cohort and three in the DLBCL cohort. In the FL cohort, the objective response rate was 70.6%, consistent with the primary analysis, and the median progression-free survival (PFS) was not reached. The 24-month and 36-month PFS rates were 72.1% (95% confidence interval [CI] 41.5%-88.6%) and 64.1% (95% CI 33.7%-83.4%), respectively. The median duration of treatment was 30.2 months. After the primary analysis at a median follow-up of 12.9 months, grade 1-2 urinary tract infection, peripheral motor neuropathy, and hypogammaglobulinemia newly emerged, but the incidence of adverse events (AEs) did not increase notably during this follow-up period. No unexpected grade ≥ 3 treatment-related AEs were reported. Long-term oral monotherapy with tazemetostat showed favorable efficacy and safety profiles, indicating that it may be a useful third-line or later treatment option for patients with relapsed/refractory FL harboring the EZH2 mutation. Trial registration: ClinicalTrials.gov: NCT03456726.