Atsushi Marumo

Background: Venetoclax‐based regimens (VEN) have been widely adopted as frontline therapeutic options for elderly patients with acute myeloid leukemia (AML). However, comprehensive real‐world comparisons of VEN with conventional intensive or reduced‐intensity chemotherapy remain limited. Methods: In this multicenter retrospective study, we evaluated treatment patterns and outcomes in 1370 patients with newly diagnosed AML. Patients were classified into three cohorts according to their frontline treatment: intensive chemotherapy (IC), reduced‐intensity chemotherapy (rIC), or VEN. Analyses were performed in both the overall cohort and elderly patients (aged ≥ 60 years), including baseline comparisons, uni‐ and multivariable analyses, and subgroup analyses. Results: Baseline characteristics differed substantially among treatment cohorts; patients treated with VEN were older and had a higher prevalence of adverse‐risk disease than those receiving IC or rIC . In the overall cohort, VEN achieved an overall response rate ( ORR ) comparable to IC and higher than rIC (74.3% vs. 60.2%, p = 0.034). Among elderly patients, VEN was associated with a higher ORR than rIC (75.7% vs. 50.5%, p = 0.001), and the favorable ORR findings remained significant after correction for multiple testing. VEN was also associated with a lower 60‐day early‐death rate than rIC in elderly patients (1.4% vs. 20.0%, p < 0.001), suggesting better early treatment tolerability. Median event‐free survival was longer with VEN than with rIC in the primary elderly cohort analysis (9.6 vs. 6.6 months, p = 0.031), and this difference persisted in a sensitivity analysis censoring at allogeneic hematopoietic stem cell transplantation, although it was attenuated in landmark and propensity‐score‐based sensitivity analyses. Overall survival did not differ significantly between the two cohorts (15.9 vs. 11.0 months, p = 0.102). Conclusion: The higher response rate and lower early mortality with VEN were the most consistent findings, whereas comparative survival outcomes were considered supportive but exploratory.

BCOR and BCORL1 (BCOR/L1 ) mutations are observed in both myeloid neoplasms (MN) and bone marrow failure syndromes (BMF), but their clinical significance may differ. We analyzed 11 340 patients and identified 418 BCOR/L1 ‐mutated patients, focusing on differences between MN and BMF. Compared with MN, BMF was associated with younger age, a higher frequency of normal karyotype, a greater proportion of missense mutations, and significantly lower variant allele frequencies (VAFs). We next compared BCOR/L1 ‐mutated cases with wild‐type cases. In MN, BCOR/L1 mutations were associated with older age, inferior survival, and a higher number of co‐occurring mutations, whereas in BMF, they were associated with a higher prevalence of PNH clones. Single‐cell DNA sequencing and VAF‐based analysis demonstrated that BCOR/L1 mutations were usually secondary in MN but primary events in BMF. Longitudinal sequencing revealed that BCOR/L1 ‐mutant clones often contracted or disappeared over time, even in progression, suggesting limited clonal fitness of BCOR/L1 mutations themselves; instead, progression was associated with increased mutational burden, particularly in RUNX1 . Prognostically, BCOR/L1 mutations were associated with inferior survival in MN, whereas in BMF they were not associated with prognosis and tended to correlate with a favorable response to immunosuppressive therapy. RNA‐sequencing analyses showed reduced BCOR/L1 expression in BMF, and BCOR knockout was associated with reduced HLA class I expression. Our findings suggest that BCOR/L1 mutations are secondary events in MN and co‐occurring mutations may influence disease progression and prognosis, whereas in BMF they appear to be ancestral events acquired independently of progression to MN, potentially through immune privilege‐related mechanisms.

Summary: Allogeneic haematopoietic stem cell transplantation (allo‐HSCT) offers a curative potential for myelodysplastic syndrome (MDS) and myelodysplastic/myeloproliferative neoplasm (MDS/MPN). We examined survival trends using a nationwide database of 7175 patients who underwent their first allo‐HSCT between 1998 and 2022. Overall mortality decreased over time in patients with early MDS (hazard ratio [HR] 0.79, 95% confidence interval [CI] 0.65–0.97, p = 0.026 in 2013–2017; HR 0.54, 95% CI 0.42–0.70, p < 0.001 in 2018–2022), advanced MDS (HR 0.80, 95% CI 0.71–0.90, p < 0.001 in 2013–2017; HR 0.74, 95% CI 0.65–0.85, p < 0.001 in 2018–2022), chronic myelomonocytic leukaemia (HR 0.45, 95% CI 0.32–0.64, p < 0.001 in 2013–2017; HR 0.53, 95% CI 0.37–0.74, p < 0.001 in 2018–2022) and atypical chronic myeloid leukaemia (HR 0.32, 95% CI 0.13–0.80, p = 0.016 in 2013–2017; HR 0.26, 95% CI 0.10–0.68, p = 0.006 in 2018–2022). These decreases in overall mortality were mainly attributable to reductions in non‐relapse mortality. Meanwhile, no significant difference in overall mortality was observed in patients with MDS/MPN‐unclassified and therapy‐related myeloid neoplasm. Across all disease subtypes, relapse incidence did not significantly decrease over time, highlighting persistent challenges in reducing the risk of post‐transplant relapse.

The role of platelets in coronavirus disease (COVID-19) severity requires further exploration. To determine whether the platelet index is useful in predicting COVID-19 severity, we compared the platelet index in patients with higher and lower oxygen requirements (≥ 4 L/min vs. < 4 L/min) and patients without COVID-19. We also analyzed the time course of the platelet index in each group. A total of 285 patients with COVID-19 and 36 without COVID-19 who were hospitalized at Fussa Hospital were analyzed. After matching for oxygen requirement at admission, multivariate analysis was performed. Platelets (≤ 16.6 × 10⁴/μL) and platelet-large cell ratio (P-LCR) (≥ 27.8%) were significant factors influencing severity. Based on these factors, we created the Fussa platelet score, and the group with a Fussa platelet score ≥ 2 was significantly more likely to reach the 4 L/min oxygen requirement (event-free survival: Fussa platelet score ≥ 2 versus < 2, P < 0.00000001). Analysis of platelet index by time period showed a significant increase from 6–10 days after onset. The Fussa platelet score can be measured quickly, easily, and inexpensively in a clinic and may be useful in determining need for transfer to a critical care hospital.

Acquired hemophilia A (AHA) is a rare disease in which an autoantibody causes bleeding by interacting with and inhibiting the coagulation activity of endogenous factor VIII (FⅧ). Most cases of AHA are idiopathic, and other causes include autoimmune diseases, malignant tumors, pregnancy, drugs, and viral infections. An 86-year-old man was diagnosed with AHA based on the following results: activated partial thromboplastin time (aPTT) extension of 130.7 seconds, inhibitor pattern by mixing study, endogenous factor VIII (FⅧ) level at 5.1 Bethesda units (BU). The activity of von Willebrand factor (vWF) decreased (<10%), which was considered to be a complication of acquired von Willebrand syndrome (AVWS). The patient was started on prednisolone, and the inhibitor level eventually became negative. vWF values also became normal. However, 1 year later, he was hospitalized due to Coronavirus disease 2019 (COVID-19). His blood test showed an aPTT extension of 110.5 seconds, FⅧ level at 4%, and FⅧ inhibitor titer at 0.8 BU; thus, he was diagnosed with a relapse of AHA. After the administration of corticosteroid and remdesivir, he recovered from COVID-19 and AHA. The inhibitor level became negative on the 9th day of admission. Several articles have reported that COVID-19 infection and vaccination are implicated with AHA. We suggest that the aPTT should be measured when patients with AHA are infected with SARS-CoV2 to confirm AHA relapse.

Background: Coronavirus disease 2019 (COVID-19) has rapidly spread worldwide, causing widespread mortality. Many patients with COVID-19 have been treated in homes, hotels, and medium-sized hospitals where doctors were responsible for assessing the need for critical care hospitalization. This study aimed to establish a severity prediction score for critical care triage. Method: We analyzed the data of 368 patients with mild-to-moderate COVID-19 who had been admitted to Fussa Hospital, Japan, from April 2020 to February 2022. We defined a high-oxygen group as requiring ≥4 l/min of oxygen. Multivariable logistic regression was used to construct a risk prediction score, and the best model was selected using a stepwise selection method. Results: Multivariable analysis showed that older age (≥70 years), elevated creatine kinase (≥127 U/L), C-reactive protein (≥2.19 mg/dL), and ferritin (≥632.7 ng/mL) levels were independent risk factors associated with the high-oxygen group. Each risk factor was assigned a score ranging from 0 to 4, and we referred to the final overall score as the Fussa score. Patients were classified into two groups, namely, high-risk (total risk factors, ≥2) and low-risk (total risk score, < 0.0001). Conclusions: The Fussa score might help to identify patients with COVID-19 who require critical care hospitalization.

Cyclophosphamide (CY)‐induced cardiotoxicity involves rare lethal complications. We previously reported the cardiac events of 811 allogeneic hematopoietic stem cell transplant (allo‐HSCT) recipients; 12 out of 811 recipients (1.5%) developed fatal heart failure. The mortality rate was also very high (91.6%, 11/12). CY dose (200 mg/kg or more) was reported as the independent risk factor. The main disease in patients treated with 200 mg/kg or more of CY was severe aplastic anemia (AA). Therefore, we reduced the dose of CY during conditioning for AA (from 200 to 100 mg/kg), and then we analyzed the clinical features of 294 patients who received a total dose of at least 100 mg/kg of CY. We also compared the clinical features between the current study and our previous study. The proportion of patients treated with at least 200 mg/kg of CY was reduced from 4.2% to 0%. However, CY‐induced heart failure occurred in four of the 294 patients (1.4%), which was similar to the finding reported in our previous study (1.5%). Two of these four patients received a post‐transplant CY (PTCy) regimen (CY 100 mg/kg). All four patients were treated in the cardiac intensive care unit (C‐ICU), and two patients survived. In summary, even the CY dose of 120 mg/kg or less would cause cardiotoxicity. We should also carefully monitor patients treated with PTCy, considering the possibility of CY‐induced cardiotoxicity. Early diagnosis and ICU management have contributed to improved outcomes.

Erythropoiesis-stimulating agent (ESA) has been recognized as an effective way in the treatment of anemia due to chronic kidney disease, but we sometimes see intractable hemodialysis (HD) patients. The causes of ESA-resistant anemia in HD patients include deficiency of trace elements. We report the case of an 89-year-old male who developed pancytopenia after taking an excessive amount of zinc formulation for ESA-resistant anemia during maintenance dialysis. He was prescribed zinc acetate hydrate formulation about 6 months before his presentation. He was found to have pancytopenia 1 month before his presentation, at which point he was introduced to our hospital. We suspected a copper deficiency at the first visit and stopped zinc and added copper, and his condition subsequently improved without being handicapped. Zinc antagonizes copper, so we must take care to diagnose patients ingesting zinc supplements.

Background: Liver dysfunction occurring after allogeneic hematopoietic stem cell transplantation (HSCT) may have various causes, but since these causes are difficult to identify in the early stages, therapeutic intervention may be delayed. It is, therefore, important to identify unfavorable prognostic factors of liver dysfunction as soon as possible. The objective of this study was to identify the unfavorable prognostic factors of liver dysfunction in the early post-transplant period. Methods: We defined liver dysfunction as the detection within 30 days of transplantation of elevated liver or biliary enzyme levels corresponding to Grade 2 in the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. We retrospectively investigated 82 patients who had undergone allogeneic HSCT at our institution. Results: Elevated liver or biliary enzyme levels were observed in almost half of the patients studied (n=40, 48.7%). Elevated total bilirubin (T-Bil) level was the most frequently observed unfavorable prognostic factor, having the greatest impact on overall survival (OS), progression-free survival (PFS), and non-relapse mortality (NRM) (probability of unfavorable outcome in patients without elevated T-Bil level versus that in patients with elevated T-Bil level: OS, 58.9% vs. 15.4%, p < 0.001; PFS, 46.4% vs. 15.4%, p < 0.001; NRM, 10.7% vs. 53.8%, p < 0.001). Moreover, the probability of an unfavorable outcome increased in proportion to the degree of T-Bil elevation and the absence of improvements over time in the T-Bil level. Conclusion: Our study showed that elevated T-Bil level is a major unfavorable prognostic factor of liver dysfunction after allogeneic HSCT.