International Journal of Hematology最新文献

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.

This study investigated the efficacy of tisagenlecleucel (tisa-cel) and allogeneic hematopoietic stem cell transplantation (allo-SCT) for patients with relapsed and/or refractory (r/r) large B-cell lymphoma (LBCL) with poor prognostic factors, defined as performance status (PS) ≥ 2, multiple extranodal lesions (EN), chemorefractory disease, or higher lactate dehydrogenase (LDH). Overall, the allo-SCT group demonstrated worse progression-free survival (PFS), higher non-relapse mortality, and a similar relapse/progression rate. Notably, the tisa-cel group showed better PFS than the allo-SCT group among patients with chemorefractory disease (3.2 vs. 2.0 months, p = 0.092) or higher LDH (4.0 vs. 2.0 months, p = 0.018), whereas PFS in the two cellular therapy groups was similar among those with PS ≥ 2 or multiple EN. Survival time after relapse post-cellular therapy in patients with poor prognostic factors was 1.6 with allo-SCT and 4.6 months with tisa-cel. These findings were confirmed in a propensity score matching cohort. In conclusion, tisa-cel resulted in better survival than allo-SCT in patients with poor prognostic factors. However, patients who relapsed post-cellular therapy had dismal outcomes regardless of therapy. Further strategies are warranted to improve outcomes in these 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.

Therapeutic drug monitoring (TDM) of busulfan (BU) is useful for achieving the target area under the curve (AUC) because its effective plasma-concentration range is narrow. This preliminary observational study evaluated the pharmacokinetic (PK) parameters of BU administered four times daily or once daily to pediatric patients. The plasma concentrations were measured at both the test dose and first dose, and the doses on day 1 and days 2-4 were determined based on each TDM. A comparison of PK parameters between four-times-daily and once-daily administration was performed for both the test dose and first dose of BU. Of the 11 patients, five received four-times-daily BU and six received once-daily BU. The V_d for once-daily administration was higher than that for four-times-daily administration for the first dose but not for the test dose. The ratio of actual AUC for the first dose to estimated AUC guided by the test dose was lower with once-daily administration than with four-times-daily administration. These results indicate that the PK parameters of BU administered once daily are challenging to predict based on the TDM of the test dose. TDM should be considered on day 1 to achieve the target AUC, especially with once-daily administration.

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.