This interim analysis of a phase 1/2, open-label, single-arm study assessed the safety, efficacy, and pharmacokinetics of gilteritinib plus chemotherapy in adults with newly diagnosed FLT3 mutation-positive acute myeloid leukemia.

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.

Despite the introduction of new drugs, multiple myeloma (MM) still remains incurable. We previously reported that CD34 MM cells, which are clonogenic and self-renewing, are therapy-resistant and persist as a major component of minimal residual disease, expanding during relapse. To investigate the effects of immunotherapies such as immune-checkpoint inhibitors, CAR-T therapy, and bispecific antibodies on CD34 MM cells, we analyzed immune profiles of both MM cells and T cells from MM patients using microarrays and flow cytometry. Ingenuity pathway analysis revealed 14 out of 289 canonical pathways were more active in CD34 MM cells compared to CD34 cells, many of which were involved in inflammation and immune responses. Notably, PD-1 signaling-related genes were highly expressed in CD34 MM cells. Among 10 immune-checkpoint molecules, CD34 cells more frequently expressed CD112, CD137L, CD270, CD275, and GAL9 than CD34 cells in both newly diagnosed and relapsed/resistant patients. In addition, CD4 and CD8 T cells more frequently expressed TIGIT and CD137, suggesting that CD112/TIGIT and CD137L/CD137 interactions may suppress T-cell activity against CD34 MM cells. Furthermore, our finding of higher FcRH5 expression on CD34 MM cells is encouraging for future research into the efficacy of FcRH5-targeted therapy in MM.

Polycythemia vera (PV) is a myeloproliferative neoplasm that is associated with an elevated risk of thrombosis. Treatment strategies are based on thrombosis risk classification. Phlebotomy is a commonly recommended treatment for all patients with PV, regardless of their risk classification, and reduces the incidence of thrombosis by lowering hematocrit levels. However, patients with PV frequently present with iron deficiency at diagnosis due to increased erythropoiesis, which repeated phlebotomy can exacerbate. This can produce symptoms that diminish quality of life, such as fatigue, lethargy, and impaired concentration. Recently, hepcidin mimetics have been developed to suppress iron utilization in erythropoiesis. Among them, rusfertide has been shown to control hematocrit levels without requiring phlebotomy. Further studies are needed to identify new treatment strategies for PV that also consider iron deficiency.

Ganciclovir and foscarnet are two representative anti-cytomegalovirus (CMV) agents. A previous regional study revealed a lower risk of chronic graft-versus-host disease (GVHD) in patients who received pre-emptive foscarnet. We conducted a retrospective nationwide study to confirm the results. A total of 8890 patients aged 16 or older with hematological malignancies who received foscarnet (n = 1555) or ganciclovir (n = 7335) during their first hematopoietic stem cell transplantation (HSCT) were included. The risks of chronic GVHD (hazard ratio [HR], 1.26; 95% confidence interval [CI], 1.13-1.40; P < 0.001) and extensive chronic GVHD (HR, 1.16; 95% CI, 1.01-1.33; P = 0.033) were higher with ganciclovir. Among male patients with a female donor, the incidence of extensive chronic GVHD 3 years after HSCT was clearly lower with foscarnet (13%; 95% CI, 9-16%) than with ganciclovir (27%; 95% CI, 25-29%; P < 0.001). In male patients who received HSCT from female donors, foscarnet recipients showed significantly lower incidence of extensive chronic GVHD than ganciclovir recipients, regardless of donor source or previous acute GVHD. While caution is necessary, these results indicate that foscarnet affects alloimmunization and might reduce the incidence of chronic GVHD.

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.

Lenalidomide is an oral immunomodulatory agent approved for the treatment of relapsed/refractory adult T-cell leukemia/lymphoma (ATLL) in Japan. Post-marketing surveillance (PMS) was conducted to confirm its safety and effectiveness. From April 2017 until April 2020, safety data were obtained for 77 patients and effectiveness data for 65 patients (31.2% of patients had progressive disease as the best response to their most recent prior regimen). Forty-nine patients (63.6%) in the safety analysis set experienced an adverse drug reaction (ADR). Grade ≥ 3 ADRs occurred in 42.9%. The most common Grade ≥ 3 ADRs were neutrophil count decreased/neutropenia and platelet count decreased/thrombocytopenia (11.7% each). Serious ADRs occurred in 26 patients. Five patients had previously received allogeneic hematopoietic stem cell transplantation. Among these, one experienced acute graft versus host disease (GvHD) during lenalidomide administration and two responded to lenalidomide. Effectiveness analysis showed that an objective response was achieved in 29.2% of patients. No statistically significant differences were observed in the objective response rates of patients aged < 70 versus those aged ≥ 70 years (33.3% vs 28.0%, respectively; p = 0.6904). No new safety signals were observed in this PMS, and lenalidomide demonstrated a favorable benefit-risk balance in Japanese patients with ATLL.

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.

Luspatercept has shown durable clinical efficacy for the treatment of anemia in transfusion-dependent patients with lower-risk myelodysplastic syndromes (LR-MDS). We report the results of a prespecified primary analysis of a phase 2 trial of luspatercept in non-transfusion-dependent (NTD) Japanese patients with anemia due to LR-MDS. Luspatercept (starting dose 1.0 mg/kg) was administered subcutaneously once every 3 weeks. The primary endpoint was the proportion of patients who achieved hematological improvement-erythroid (HI-E) response (≥ 1.5 g/dL increase in hemoglobin level for 8 weeks) without transfusions within the first 24 weeks of treatment. At the primary analysis data cutoff, 21 patients had been enrolled/treated; 17 and 10 patients had completed 24 and 48 weeks of treatment, respectively. HI-E response occurred within 24 weeks in 10 patients (47.6%; 95% confidence interval, 25.7-70.2; P < 0.0001), which was significantly higher than the predefined threshold (10%). By week 48, HI-E response occurred in 12 patients (57.1%) and 17 patients (81.0%) remained NTD. Luspatercept was well tolerated. Three patients (14.3%) had grade 3-4 treatment-related treatment-emergent adverse events. Luspatercept resulted in statistically and clinically significant improvements in hemoglobin levels, and may help delay the need for transfusions in NTD patients with LR-MDS.

Due to the poor prognosis of adult T-cell leukemia/lymphoma (ATL), new treatments are urgently needed, especially for elderly patients with aggressive ATL. The anti-CCR4 antibody drug mogamulizumab (MOG) has been approved for the treatment of untreated ATL. To analyze the impact of MOG on elderly patients, we conducted a retrospective analysis of patients aged 70 years and older with aggressive ATL diagnosed at our institution between 2015 and 2021. Among 32 patients, including those who received best supportive care, the median survival time (MST) and 2-year overall survival (OS) rate were 14.6 months (range, 0.0-83.7), and 34.7% [95% confidence interval (CI), 18.2-51.9], respectively, which were better than outcomes in our previous study. The MST and 2-year OS for patients treated with MOG-containing chemotherapy were 18.1 months (range, 4.0-83.7) and 45.0% (95%CI, 23.1-64.7), respectively, demonstrating clear improvement. Adverse events observed with MOG-containing treatment, such as myelosuppression and skin rash, were similar to those reported previously. Univariate analysis identified comorbidity as a predictor of poor outcomes, but not intensity of MOG-containing treatment, suggesting a different mechanism of action than that of classical chemotherapy. Our study suggests that MOG-containing treatments are an option for elderly patients with ATL.

The recently developed platelet aggregation technique based on low-angle light scattering (LaSca) in diluted platelet-rich plasma (PRP) requires only a small sample volume and provides information about platelet aggregation and shape change. This study aimed to investigate the influence of preanalytical and analytical variables and to validate the method in a real-life pediatric hematology hospital setting.

Sutimlimab, a complement inhibitor, has recently been approved in Japan for treating cold agglutinin disease (CAD). We report the safety and efficacy of sutimlimab in Japanese patients with CAD who completed a global phase 3 clinical trial (CARDINAL/CADENZA: 26-week treatment with 1-2 years of open-label extension [OLE] periods) and subsequently participated in the Japanese OLE study. Patients with a recent history of blood transfusion (CARDINAL, n = 3) and those without (CADENZA, n = 4) were analyzed (71.4% female; median [range] baseline age: 70 [46-83] years). For CARDINAL/CADENZA, the treatment duration (median [range]) was 140.9 (104.9-157.3) weeks, and the cessation period was 70 (61-133) weeks. For the Japanese OLE study, the treatment duration was 47.1 (15.1-49.1) weeks. Three (42.9%) patients experienced treatment-related and treatment-emergent adverse events (TEAEs): injection site erythema, cystitis bacterial, viral infection, and blood pressure increased during CARDINAL/CADENZA. One (14.3%) patient experienced one treatment-related TEAE (urinary tract infection) during the Japanese OLE study. One patient died of renal failure, considered unrelated to sutimlimab, that was exacerbated by hepatorenal syndrome due to liver cirrhosis and bacterial peritonitis, in addition to CKD. Hemoglobin and bilirubin levels improved during treatment but deteriorated after withdrawal and recovered on retreatment. Sutimlimab was well tolerated over a median of 3.8 years, with no new safety concerns identified during retreatment.

In the diagnosis and treatment of acquired von Willebrand syndrome (AVWS), von Willebrand factor (VWF) antigen levels (VWF:Ag) are helpful for quantifying blood VWF-protein levels. Most clinical laboratories measure VWF:Ag by latex immunoassay (LIA), but underlying diseases of AVWS may influence LIA results. A 60 year-old AVWS patient with immunoglobulin G (IgG) kappa-type monoclonal gammopathy of undetermined significance (MGUS) showed reduced VWF activity but normal levels of VWF:Ag. His VWF multimers were broadly decreased, which represented a large discrepancy with VWF:Ag. To investigate the mechanism of this discrepancy, we measured the patient's plasma VWF:Ag by in-house enzyme-linked immunosorbent assay (ELISA) and LIA. We also purified the IgG fraction from the patient's serum and measured VWF:Ag in VWF-deficient plasma supplemented with this fraction. VWF:Ag measured by in-house ELISA (VWF:Ag) was much lower than that measured by LIA (VWF:Ag), which indicated reduced VWF-protein volume in blood. Indeed, VWF:Ag was detected by LIA in VWF-deficient plasma spiked with a patient-derived IgG fraction. These results suggest that LIA detected a non-specific immunoreaction and overestimated the patient's VWF:Ag. Clinicians should be aware that underlying diseases of AVWS could influence the LIA system, and interpret VWF:Ag cautiously.

FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD)-positive acute myeloid leukemia (AML) has a poor prognosis, particularly with DNMT3A and NPM1 mutations. Quizartinib, a FLT3 inhibitor showing clinical benefit in FLT3-ITD-positive AML, has unclear safety and efficacy when combined with donor lymphocyte infusion (DLI). We report a case of FLT3-ITD-positive AML with DNMT3A and NPM1 mutations that relapsed after allogeneic hematopoietic stem cell transplantation (allo-HCT) and was treated with quizartinib and DLI. A 49-year-old man was diagnosed with AML. Target-sequencing analysis of the bone marrow revealed FLT3-ITD, DNMT3A R882, and NPM1 mutations. Although the patient achieved complete remission (CR) through induction therapy and received allo-HCT, he relapsed on day 71. Quizartinib was initiated on day 79, and the patient achieved CR with incomplete recovery on day 106. He did not desire a second allo-HCT and continued quizartinib in combination with DLI, which was started on day 156 and administered eight times every 2 to 3 months. The patient achieved hematological CR on day 163 and remained in molecular CR 3 years after allo-HCT without adverse effects. Quizartinib combined with DLI may be a feasible treatment for early relapse of FLT3-ITD-positive AML after allo-HCT, even with concurrent DNMT3A and NPM1 mutations.

We report the first large-scale retrospective cohort study on adolescent and young adult (AYA) polycythemia vera (PV) and essential thrombocythemia (ET) in Japan, a subgroup analysis using Japanese multicenter registry data (JSH-MPN-R18). This study included patients with PV (n = 31) or ET (n = 141) aged 20 to 39 years at the initial visit. Hemorrhage-free survival (HFS) was better in AYA ET than in non-AYA ET (5-year HFS: 100% vs. 88.6%, p < 0.01), which might be attributed to differences in antithrombotic treatment rates between AYA and non-AYA patients. Although thrombosis-free survival did not differ statistically, the percentage of venous thrombotic events (TEs) among total TEs was higher in AYA compared to non-AYA PV and ET in Japan (26.0% vs. 6.0%, p < 0.01), but much lower than figures reported in European or US cohorts. Cytoreductive therapy (CRT) was administered to 25.8% of AYA patients with PV and 43.3% of AYA patients with ET, and the reason was usually unrelated to high risk of thrombosis. These results could be used to develop a more appropriate strategy for managing PV and ET in the Japanese AYA population.

In patients with hemophilia A with inhibitor (PwHA-I), emicizumab drastically reduces bleeding events. However, few studies have investigated the behavior and effects of factor X (FX) in patients who require intensive treatment with factor VIII-bypassing agents (BPA) and emicizumab. A 59-year-old man with HA-I receiving emicizumab prophylaxis was admitted to our hospital because of acute gangrenous cholecystitis. He received percutaneous transhepatic gallbladder drainage and laparoscopic cholecystectomy along with repeated administration of recombinant activated factor VII (rFVIIa). On day 10, a large hematoma developed around the residual gallbladder. Rotational thromboelastometry (ROTEM) suggested poor effect of rFVIIa and reduced activity of emicizumab. Considering that this could be due to consumption of FX, plasma-derived FVIIa/FX agent (pdFVIIa/X) was administered, and ROTEM parameters recovered considerably. The patient was discharged on day 19 uneventfully. Plasma assays revealed that FX antigen level (FX:Ag) was 107.5% at baseline but then decreased. Administration of pdFVIIa/FX restored FX:Ag (pre/post 47.2%/125.5%). ROTEM and thrombin generation assay with in vitro addition of anti-emicizumab antibody suggested that low FX:Ag was responsible for attenuating the effect of emicizumab, and pdFVIIa/FX administration restored coagulation potentials. In PwHA-I receiving intensive treatment with rFVIIa under emicizumab prophylaxis, FX consumption might attenuate the effect of emicizumab.

Recombinant porcine factor VIII (rpFVIII) is a hemostatic agent for acquired hemophilia A (AHA). Cross-reaction of auto-antibodies against rpFVIII has been reported, although no data are available in Japanese patients. This study investigated the cross-reactivity and coagulation potential of rpFVIII in plasma samples from Japanese patients with AHA. Cross-reactivity was calculated as the ratio of anti-porcine FVIII inhibitor titer (pFVIII-INH) to human FVIII inhibitor titer. Comprehensive coagulation potential was assessed by clot waveform analysis (CWA) and thrombin generation assay (TGA) in samples spiked with rpFVIII (equivalent to 200 U/kg). Nine of 16 plasma samples (56.3%) had positive pFVIII-INH, with a median cross-reactivity of 1.2%. FVIII activity (FVIII:C) was restored to > 100% in all samples upon spiking with rpFVIII, but was weakly correlated with pFVIII-INH. CWA parameters and most TGA parameters were restored to normal upon spiking with rpFVIII; correlation of these parameters with FVIII:C was similar to that observed in controls. Overall, cross-reactivity to rpFVIII in Japanese patients was similar to that reported in Caucasian patients. Our results suggest that an initial clinical dose of 200 U/kg rpFVIII could restore coagulation potential to normal, and that FVIII:C monitoring after rpFVIII administration may be more informative than pFVIII-INH before administration.