Therapeutic Advances in Hematology最新文献

Background: Mutations in the FMS-like tyrosine kinase 3 (FLT3) gene are present in approximately 30% of patients with newly diagnosed (ND) acute myeloid leukemia (AML), and are associated with worse therapy outcomes compared to the general AML population. Gilteritinib, a selective oral FLT3 inhibitor, is a promising treatment option for this patient population.

Objectives: To assess the safety and efficacy of gilteritinib in combination with induction and consolidation chemotherapy in Asian patients with ND, FLT3-mutated (FLT3 ^mut+) AML.

Design: This study was a phase I/II open-label, single-arm study. Herein, we present the final results from phase II.

Methods: A total of 84 patients were enrolled in 33 centers across Japan, Korea, and Taiwan. All patients enrolled in phase II received induction and consolidation therapy with gilteritinib 120 mg/day plus chemotherapy (induction: ⩽2 cycles, idarubicin/cytarabine once-daily; consolidation: ⩽4 cycles, cytarabine twice-daily) followed by maintenance with gilteritinib 120 mg/day monotherapy (⩽26 cycles). The primary efficacy endpoint was the complete remission (CR) rate after induction therapy.

Results: The primary endpoint of CR rate after induction was 50.0% (90% CI: 40.4-59.6). Gilteritinib in combination with chemotherapy achieved high composite CR (CRc; 86.6%, 95% CI: 77.3-93.1) rates after induction. The overall survival (OS) rate at 3 years was 71.6%, and the median OS was 48.2 months; however, due to the immaturity of the data, the median OS should be interpreted with caution. In addition, 51.2% of patients underwent hematopoietic stem cell transplantation during the study period. The safety profile of gilteritinib was as expected, and no new safety signals were identified.

Conclusion: Induction and consolidation with gilteritinib plus chemotherapy, and maintenance with gilteritinib monotherapy were well tolerated in ND patients in Asia with FLT3 ^mut+ AML and had favorable efficacy compared with historical data.

Trial registration: This trial was registered with the ClinicalTrials.gov identifier NCT02310321.

Background: Severe hemophilia traditionally requires lifelong prophylactic treatment, which cannot fully prevent joint damage and significantly impacts patients' quality of life. In recent years, gene therapy has been extensively researched as a potential cure with a single infusion, but it has not yet gained widespread acceptance.

Objectives: This study examines the knowledge and attitudes of people with severe hemophilia regarding gene therapy to provide guidance to practitioners in the context of shared decision-making.

Design: Cross-sectional observational study based on a standardized questionnaire.

Methods: A questionnaire developed by Cutica, Ilaria et al. was evaluated in a self-reported, anonymized survey for a German cohort of 59 people with severe hemophilia. It covered sociodemographic and clinical characteristics, knowledge, attitudes, risk tolerance, and decision-making preferences.

Results: Among 59 people with severe hemophilia A and 10 with severe hemophilia B, 59% expressed a predominantly rejective attitude toward gene therapy. Most had only general knowledge of gene therapy. Concerns about long-term side effects (e.g., cancer development) significantly contribute to a negative attitude toward gene therapy (p = 0.005). People with hemophilia and an annual bleeding rate ⩾1 show a significantly higher willingness to consider or accept gene therapy (p = 0.001). Rejection of gene therapy is significantly associated with high expectations regarding its duration of efficacy and the minimum clotting factor level.

Conclusion: Further studies are needed to refine educational concepts for people with hemophilia and clear out misconceptions about gene therapy.

Background: Ixazomib is an oral proteasome inhibitor for relapsed/refractory multiple myeloma (RRMM). Our study aimed to analyze the efficacy and tolerability of ixazomib-based combination therapies.

Methods: We performed a single-center retrospective analysis of 126 patients with RRMM and other plasma cell neoplasms.

Results: The median age was 65 years, with a median of two prior therapy lines, and 16.7% were triple-class refractory. The overall response rate (ORR) was 52.5%; triple-class refractory patients had a significantly lower ORR than non-refractory controls (10.5% vs 60.2%, p < 0.001). After a median follow-up of 27.0 months, the median progression-free survival (PFS) was 7.9 months (95% CI: 6.9-11.0), and the median overall survival (OS) was 84.1 months (95% CI: 68.1-not reached). In multivariate analysis, a glomerular filtration rate of ⩽70 ml/min/1.73 m² was linked to worse PFS (hazard ratio (HR): 2.11, p = 0.008) and OS (HR: 7.27, p = 0.003). Furthermore, triple-class refractory patients showed a trend toward inferior PFS (HR: 3.76, p = 0.05) and significantly worse OS (HR: 20.46, p = 0.002) compared to non-refractory patients. Grade ⩾3 hematologic adverse events occurred in 15.1% patients, while the most common non-hematologic adverse events were fatigue (5.6%) and peripheral neuropathy (26.2%), with the majority classified as grade 1-2.

Conclusion: Altogether, ixazomib regimens are potent in RRMM but are less effective in heavily pretreated patients and those with renal impairment, suggesting earlier use may yield greater benefits.

Background: Connective tissue diseases (CTDs) are a group of autoimmune disorders in which immune thrombocytopenia (ITP) represents a common and important manifestation. Current CTD-ITP management mainly relies on glucocorticoids and immunosuppressive agents.

Objectives: This systematic review and meta-analysis aims to evaluate the efficacy and safety of immunosuppressive agents in patients with CTD-ITP.

Design: Systematic review and meta-analysis.

Methods: This study was conducted using eight databases up to July 22, 2024. Observational studies and experimental trials with relevant efficacy and safety data were included. Methodological quality were evaluated using the Newcastle-Ottawa Scale and the ROBINS-I tool. The Mantel-Haenszel formula with a random effect model was employed to estimate the overall effect size. Subgroup analyses were performed based on the study characteristics, clinical features, and treatment regimen.

Results: Through integrating 24 studies (1 single-arm clinical trial, 1 case-control, and 22 cohort studies) involving 775 CTD-ITP patients, the pooled estimates of the optimal overall and complete response rate for immunosuppressive therapy were 82% (95% CI: 75-88) and 64% (95% CI: 56-72), with stable results after sensitivity analysis. The combined side-effect incidence was 31% (95% CI: 24-39). The pooled relapse rate was 30% (95% CI: 18-43) among 403 immunosuppressive therapy responders.

Conclusion: Immunosuppressive treatments exhibited favorable efficacy and safety in CTD-ITP patients. Future larger-scale multicenter studies are needed.

Acquired thrombotic thrombocytopenic purpura (aTTP) is a very rare life-threatening disorder, which manifests as a profound thrombocytopenia, microangiopathic hemolytic anemia, renal insufficiency, neurological dysfunction, and other ischemic organ damage. It is caused by antibodies blocking ADAMTS13 metalloprotease. The current standard of the treatment is a triple combination consisting of therapeutic plasma exchange (TPE), immunosuppressive therapy, and caplacizumab, an anti-vWF nanobody. We retrospectively analyzed the medical records and management of three patients with newly diagnosed acute form of aTTP. Three Slovak female patients (mean age at onset 57 years) with severe anemia and thrombocytopenia, one with acute renal insufficiency and two with neurological symptoms were admitted to our institution for suspected aTTP. All patients had ADAMTS13 activity below 2%, laboratory signs of hemolysis, and the presence of ADAMTS13 antibodies. In our laboratory, we also examined the ultra-large high-molecular-weight vWF multimers. The patients were urgently indicated for TPE and high-dose immunosuppressive therapy. Shortly thereafter, caplacizumab was added to the treatment. In the following days platelet count stabilized, ADAMTS13 activity increased and biochemical parameters were gradually adjusted. Two patients experienced exacerbations and one patient experienced relapse of aTTP with mild thrombocytopenia and reduced ADAMTS13 activity, without thrombotic microangiopathy. They were successfully treated with rituximab or cyclophosphamide. Clinical remission was achieved later in all patients. Data collected from our center show that addition of caplacizumab to the standard aTTP treatment helps normalize platelet count faster, reduces the number of TPE sessions and length of hospitalizations, and significantly improves the clinical outcome of patients.

Background: Early diagnosis of primary or light chain (AL) amyloidosis is crucial for initiating appropriate therapeutic interventions. However, diagnosis is getting delayed (several months-to-years) in clinical practice.

Objective: To investigate the real-world patterns of clinical procedures until initial diagnosis of AL amyloidosis in Japan.

Design: Retrospective longitudinal, observational cohort study.

Methods: This study included adults with AL amyloidosis using Medical Data Vision claims database (2003-2022). The primary endpoint was time from initial hospital visit until confirmed AL amyloidosis diagnosis. Symptoms, lab tests, and medical department visits until diagnosis, and mortality were analyzed.

Results: Overall, 323 patients with AL amyloidosis were included (median age: 73.0 years). Median time to confirmed diagnosis was 81.5 days; reported longer in patients aged ⩾65 years versus <65 years, and Charlson Comorbidity Index ⩾4 than <4. Specific tests (tissue and bone marrow biopsy) were conducted 28-40 days close to the diagnosis. Patients visited internal medicine (n = 158), hematology medicine (n = 139), dermatology (n = 97), and nephrology (n = 93) departments for confirmed diagnosis. Time to confirmed diagnosis was shorter for patients who visited hematology (median: 7.5 days). Early diagnosed (⩽1 year) patients had longer time-to-in-hospital death than late diagnosis (>1 year).

Conclusion: These real-world data from Japanese AL amyloidosis patients are crucial for early and effective treatment, leading to better prognosis.

Multiple myeloma (MM) is a B-cell malignancy involving monoclonal plasma cells that produce nonfunctional immunoglobulins. It is still incurable due to de novo or acquired resistance of malignant cells to standard chemotherapies. Thus, understanding the mechanism of therapeutic resistance is essential to develop better interventions and identifying new therapeutic targets. MM is a heterogeneous disease characterized by complex genetic alterations, which are critical for prognostic stratification. Due to the heterogeneity and clinical challenges associated with MM, there remains a critical need for novel biomarkers to improve both early diagnosis and prognostic accuracy. Antioxidants participate in protecting cancer cells from the damaging effects of oxidative stress by neutralizing reactive oxygen species. These molecules may have their own role in myeloma progression and drug resistance. However, studies reported contradictory ideas regarding the levels and roles of antioxidants in MM. The main aim of this review is to conceptualize the diagnostic, prognostic, and therapeutic significance of common antioxidants for MM. The most common antioxidant systems discussed in this study were DJ-1, glutathione, thioredoxin, and superoxide dismutase. The review revealed that antioxidants are overexpressed in myeloma cells compared to normal plasma cells. This excess expression of antioxidants increases tumor cells' survival and their chemoresistance leads to poor prognosis and short survival of myeloma patients. Thus, antioxidants and their synthesis pathways may have a promising prognostic, diagnostic, and therapeutic role in MM. Vitamin C (ascorbic acid), on the other hand, has a two-faced role in cancer, including MM. It can function as an antioxidant (increase myeloma cell resistance to chemotherapy) or pro-oxidant (enhance the therapeutic effect of myeloma drugs), depending on its dose and route of administration. Pharmacological (ultra-high) doses of vitamin C administered intravenously may act as a pro-oxidant that can selectively kill myeloma cells by elevating the cellular labile iron pool and generating extracellular H₂O₂.

Background: Decitabine and cedazuridine (DEC-C) is the only oral hypomethylating agent (HMA) approved for myelodysplastic syndromes (MDS) in the United States. The other HMAs approved for MDS, decitabine and azacitidine, are administered intravenously (IV) or subcutaneously (SC).

Objectives: This study examined real-world outcomes among MDS patients treated with oral DEC-C compared to IV/SC HMAs.

Design: Adult patients diagnosed with MDS who received HMAs as their first treatment on or after July 1, 2020 through February 2024 in ConcertAI's RWD360^® electronic medical records dataset linked to open claims were included in the study.

Methods: We used propensity score matching (PSM) to balance potential confounders. Kaplan-Meier survival analysis was utilized to compare real-world overall survival (rwOS), acute myeloid leukemia (AML)-free survival, and time to next treatment (rwTTNT) among patients treated with oral DEC-C and IV/SC HMAs.

Results: A total of 2101 patients with MDS were included, with 405 treated with oral DEC-C and 1696 treated with IV/SC HMA. After PSM, there were 399 patients in each treatment group; demographic and clinical factors were well balanced. Patients treated with oral DEC-C had a similar median rwOS (22.7 months vs 19.5 months; p = 0.57) and AML-free survival (16.1 months vs 14.3 months; p = 0.10) compared with patients who received IV/SC HMA; however, there were nonsignificant trends in favor of oral DEC-C. The median rwTTNT was significantly longer for the oral DEC-C patients than for the IV/SC HMA patients (9.3 months vs 7.8 months, respectively; p = 0.02).

Conclusion: This real-world study is the largest to date to examine clinical outcomes among MDS patients who initiated oral DEC-C compared to IV/SC HMAs. While study results indicate comparable rwOS and AML-free survival among patients treated with oral DEC-C or with IV/SC HMAs, patients treated with oral DEC-C had a significantly longer rwTTNT. These findings support the use of oral DEC-C as an alternative to parenteral HMA therapy.

Background: Hemophilia A (HA) management remains challenging in northeastern India due to limited access to specialized care. Emicizumab, a bispecific monoclonal antibody, offers prophylactic benefits for patients with or without factor VIII (FVIII) inhibitors.

Objectives: The study aimed to assess the long-term effectiveness, safety, and patient-reported outcomes of emicizumab prophylaxis in people with HA with or without inhibitors.

Design: This 12-month follow-up from a noninterventional, real-world observational study builds on previously published 6-month data and was conducted at the Department of General Medicine, Assam Medical College and Hospital, India.

Methods: Forty pediatric patients with moderate-to-severe HA, including those with inhibitors, receiving emicizumab prophylaxis were followed at a treatment center. The outcomes assessed at baseline, 6 months, and 12 months included annualized bleeding rate (ABR), Hemophilia Joint Health Score (HJHS), Functional Independence Score in Hemophilia (FISH), European QoL-5 dimensional-5 level (EQ-5D-5L) score and visual analog scale (VAS). Subgroup analyses explored age- and inhibitor-status based differences. Data were analyzed using appropriate statistical tests to compare outcomes across time points and subgroups.

Results: The mean ABR reduced significantly from 11.48 at baseline to 0.05 at 12 months (p < 0.001), with all patients showing improvement. Joint and target joint bleeds were eliminated. HJHS improved from mean 12.0 ± 5.23 to 4.6 ± 3.13, and FISH increased from 27.5 ± 2.11 to 30.6 ± 1.39 (both p < 0.001). EQ-5D-5L index and VAS scores also showed significant gains. Notably, age-related disparities in ABR, evident with FVIII therapy, were no longer apparent after emicizumab therapy, highlighting its uniform effectiveness from early childhood.

Conclusion: This 12-month follow-up study from northeastern India confirms the sustained efficacy and safety of emicizumab in reducing bleeds and improving outcomes in children with HA. The findings underscore its value in underserved settings, supporting broader implementation in similar healthcare environments.

Von Willebrand disease (VWD) is an inherited bleeding disorder resulting from a deficiency in von Willebrand factor (VWF), either quantitative or qualitative. Recombinant VWF (rVWF) presents a novel therapeutic option for patients with VWD. Produced in Chinese hamster ovary cells, rVWF is free of animal or human plasma proteins, thus eliminating the risk of pathogen transmission. It preserves the full range of VWF multimers, including ultra-large multimers, which are essential for hemostasis. Research indicates that rVWF demonstrates superior pharmacokinetics and pharmacodynamics compared to plasma-derived VWF, offering a longer terminal half-life, enhanced platelet adhesion and aggregation, and more robust factor VIII stabilization. These properties contribute to rVWF's increased hemostatic efficacy in managing bleeding episodes and perioperative surgical bleeding in adults and children with VWD, as well as the routine prophylaxis for adults to reduce the frequency of bleeding episodes. Furthermore, rVWF is well-tolerated with a low thrombotic risk, making it a promising treatment option and addressing a significant clinical need globally.