International Journal of Hematology最新文献

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.

Inappropriate discontinuation of immunosuppressive drugs (ISD) following allogeneic hematopoietic cell transplantation (HCT) can lead to the development of chronic graft-versus-host disease (cGVHD) and necessitate the reintroduction of ISD. However, only a few studies have compared the discontinuation rates of secondary steroid for cGVHD between different stem cell sources. We retrospectively evaluated 191 patients who underwent HCT at our institution to determine the discontinuation rates of secondary steroids for cGVHD. 50 patients (26.7%) received secondary steroid for cGVHD. After additional steroid for cGVHD, the 2-year cumulative steroid discontinuation rates were 50.0%, 0%, 8.3%, 44.0%, and 40.0% for MSD, uPBSC, uBM, UCB, PTCy-haplo, respectively (P = 0.0313). Patients transplanted with uBM or uPBSC had significantly lower cumulative discontinuation rates of additional steroids for cGVHD compared to those transplanted with other stem cell sources (P < 0.001). Multivariate analysis indicated that the cumulative steroid discontinuation rate was significantly lower in uPBSC or uBM group compared to in MSD group (uPBSC, HR, 0.10; P = 0.024, uBM, HR, 0.13; P = 0.007). Therefore, careful steroid reduction or additional treatment for cGVHD is necessary in patients transplanted with uBM and uPBSC.

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.

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.

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^ELISA) was much lower than that measured by LIA (VWF:Ag^LIA), 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^LIA. Clinicians should be aware that underlying diseases of AVWS could influence the LIA system, and interpret VWF:Ag cautiously.

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.

This post-marketing surveillance (PMS) assessed the safety and effectiveness of isatuximab plus pomalidomide and dexamethasone (Isa-Pd) for relapsed or refractory multiple myeloma (RRMM) in frail individuals during real-world use in Japan. Data from all individuals with RRMM treated with Isa-Pd in Japan between October 2020 and October 2021 were collected, with follow-up continued up to 12 months after starting Isa-Pd or until discontinuation. In the overall PMS population, 40 participants were classified as frail (33.3%) and 29 as fit/intermediate (24.2%), and 51 had no frailty score (42.5%). Incidence of adverse drug reactions in each group was 77.5%, 65.5%, and 37.3%. In frail versus fit/intermediate participants, bone-marrow suppression occurred in 72.5% versus 44.8%, infectious diseases in 17.5% versus 10.3%, and infusion-related reactions in 7.5% versus 3.5%. Heart failure occurred in one participant with no frailty score. The rates of overall response and very good partial response or better were higher (p = 0.101) in fit/intermediate participants (56.0% and 36.0%) than in frail participants (38.5% and 18.0%). Rates of treatment discontinuation due to disease progression were similar between groups. These findings support the safety and effectiveness of Isa-Pd for frail individuals with RRMM in real-life settings in Japan.

Eltrombopag is used with first-line immunosuppressive therapy for adult aplastic anemia, although its practical utility in childhood remains unclear. We retrospectively analyzed the outcomes of pediatric patients who received eltrombopag in Japan. Of the 27 eligible patients, 23 (85%) were previously treated, and 15 (56%) had severe or very-severe disease. Seventeen (63%) received eltrombopag with or after rabbit anti-thymocyte globulin plus cyclosporin-A. Within the first year of eltrombopag therapy, 12 patients showed a good or partial response, 15 showed no response, and 8 non-responders successfully underwent hematopoietic cell transplantation. Within the first 3 months after eltrombopag therapy, all but one of the transfusion-dependent responders became transfusion-independent. At 12 months, 6 of 12 responders were disease-free off-treatment. The one-year overall response rate was higher for severe or very-severe than non-severe cases (p = 0.006). Multivariable analysis showed that very-severe disease at the start of eltrombopag therapy was a predictor of being disease-free off-treatment (p = 0.03). No cytogenetic abnormalities developed, but myelofibrosis occurred 4 months after eltrombopag therapy in one non-responder with very-severe disease. The first 3 months' response to adjunctive eltrombopag may guide to the safe and effective use for the cure of disease, although prospective trials are needed to determine its long-term effects.