Therapeutic Advances in Hematology最新文献

Background: While carfilzomib has shown effectiveness in treating relapsed or refractory multiple myeloma (RRMM), the best frequency of dosing is still debated. This meta-analysis aims to investigate the differences in safety and effectiveness between once-weekly and twice-weekly carfilzomib treatment schedules for patients with RRMM.

Methods: A thorough search of five databases was performed. We calculated pooled relative risks (RRs), hazard ratios (HRs), and 95% confidence intervals (95% CIs), and conducted heterogeneity and sensitivity analyses using StateMP 18 software.

Results: Five studies met the inclusion criteria. Analysis indicated that once-weekly carfilzomib significantly enhanced progression-free survival (HR: 0.80, 95% CI: 0.69-0.94, p = 0.007). However, no statistical difference was observed in the pooled RRs for overall response rate (RR: 1.13, 95% CI: 0.94-1.38, p = 0.198) and complete response or better (RR: 2.08, 95% CI: 0.65-6.65, p = 0.217). The once-weekly regimen was notably associated with a reduction in adverse events (RR: 0.98, 95% CI: 0.96-1.00, p = 0.047) relative to the twice-weekly regimen.

Conclusion: The results propose once-weekly carfilzomib as a viable alternative treatment option for RRMM.

Background: Waldenström's macroglobulinemia (WM) is a B-cell neoplasia characterized by the infiltration of lymphoplasmacytic lymphoma cells in the bone marrow and abnormal secretion of IgM paraprotein. Ibrutinib, a Bruton tyrosine kinase inhibitor (BTKi), showed high efficacy in WM clinical trials. However, there is limited real-world data regarding its effectiveness and safety in routine clinical practice.

Objectives: The MACRO study aimed to investigate the clinical, genetic, and demographic characteristics of WM patients treated with ibrutinib-based therapies in Spain. Key secondary objectives included describing effectiveness and safety profile.

Design: Retrospective observational.

Methods: This multicenter, observational, retrospective study included adult patients diagnosed with symptomatic WM treated with ibrutinib since its commercial approval in Spain in 2016. Data were collected from 19 hospitals through retrospective medical chart reviews.

Results: Fifty-two eligible patients were recruited. The median age at the start of ibrutinib treatment was 74 years. Most of patients were male (65.4%) and had an Eastern Cooperative Oncology Group performance status of 0-1 (89.7%). Overall response rate was 92.2%, with a major response rate of 80.5%. Median progression-free survival (PFS) was 57.2 months, and the estimated 2-year overall survival rate was 89.2%. No significant differences in PFS were identified based on the parameters defining risk subgroups, nor did they vary according to treatment line, initial dose, or treatment schedule. Most common adverse events included bleeding (30.8%), diarrhea (23.1%), and infections (15.4%), with most of them being grades 1-2. No new safety signs were identified.

Conclusion: This study presents real-world evidence on the characteristics and outcomes of WM patients treated with ibrutinib in Spain, showing it to be effective with a manageable safety profile consistent with clinical trial results. These findings support ibrutinib as a valuable treatment option for WM in real-world settings.

Background: Marital status has been demonstrated to impact the outcomes of several malignancies. The prognostic role of marital status in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) has not been determined.

Methods: We identified 67,238 patients with CLL/SLL from the Surveillance, Epidemiology, and End Results (SEER) database. The patients were randomly divided into the training and validation cohorts. The univariate and multivariate Cox regression analyses were performed to screen the predictors for overall survival (OS) and disease-specific survival (DSS). The nomograms were developed and validated by the C-index, calibration curve, receiver-operating characteristic (ROC) curve, and decision curve analysis.

Results: Marital status was an independent predictor of OS and DSS, with married patients having the best survival compared to single, divorced, and widowed patients. The nomograms for OS and DSS containing marital status were constructed, respectively. The C-index and ROC curve indicated that the models have favorable discrimination. The calibration curve showed good predictive accuracy. Decision curve analysis demonstrated considerable clinical net benefits. According to the points of the nomograms, patients were divided into three risk groups with distinct outcomes.

Conclusion: Married marital status correlated with better survival in patients with CLL/SLL. The integration of marital status into validated nomograms provides a clinically accessible tool for improved risk stratification. Identifying widowed patients as a high-risk subgroup enables targeted interventions and optimized surveillance strategies in CLL/SLL management.

Background: Crovalimab is a novel C5 inhibitor that enables rapid and sustained C5 inhibition with every 4-week subcutaneous maintenance dosing, with the possibility for self-administration. When switching from another C5 inhibitor (binds to a different epitope than crovalimab) to crovalimab and vice versa, transient immune complexes will form and may cause transient immune complex reactions (TICRs).

Objectives: To assess TICR occurrence, manifestation, and management in patients with paroxysmal nocturnal hemoglobinuria (PNH) who switched from another C5 inhibitor to crovalimab.

Design: COMMODORE 1 and 2 randomized C5 inhibitor-experienced and -naïve patients, respectively, to receive crovalimab or eculizumab. The COMMODORE 1 nonrandomized, descriptive cohort included patients who previously received ravulizumab or approved or higher-than-approved doses of eculizumab.

Methods: Pooled data of patients who switched from eculizumab or ravulizumab to crovalimab were evaluated for TICR incidence and severity. TICR treatments and TICR durations were assessed by severity.

Results: This descriptive analysis included 201 patients who switched from eculizumab (n = 174) or ravulizumab (n = 27) to crovalimab. Baseline characteristics were generally balanced between patients with and without a TICR. Thirty-nine of 201 patients (19%) experienced TICRs (11% Grades 1-2; 8% Grade 3; no Grades 4-5). Median time to onset and median TICR duration were 1.6 (range, 0.7-4.4) and 1.7 weeks (range, 0.4-34.1), respectively. The most common symptoms were arthralgia (45%), rash (34%), and pyrexia (21%), with no evidence of renal manifestations. Oral corticosteroids were the most common TICR treatment. Grade 3 TICRs were treated with higher oral corticosteroid dose but did not take longer to resolve than Grades 1-2 TICRs.

Conclusion: Pooled COMMODORE 1 and 2 data show that TICRs from switching between C5 inhibitors were generally mild to moderate and resolved with appropriate treatment. These results further confirm that crovalimab is well tolerated in patients with PNH.

Trial registration: NCT04432584; NCT04434092.

Chronic graft-versus-host disease (cGVHD) is a potentially life-threatening complication of hematopoietic stem cell transplantation (HSCT). The global incidence of cGVHD remains high, despite prophylactic regimens for patients undergoing HSCT. Systemic corticosteroids are the standard first-line treatment for cGVHD, but most treated individuals will require second-line or further treatment because of suboptimal disease control or toxicity from long-term corticosteroid use. No standard treatment algorithm exists for steroid-refractory cGVHD, with similar response rates and poor outcomes across different pharmacologic regimens. The pathogenesis of cGVHD is driven by an imbalance in effector T helper 17/T follicular helper cells and regulatory T-cells that leads to an inability to reverse a proinflammatory environment and the loss of immune tolerance, which causes irreversible fibrosis in target organs. Rho-associated coiled-coil-containing protein kinase 2 (ROCK2) signaling plays key roles in regulating T-cell-mediated immune responses, promoting the differentiation of fibroblasts into myofibroblasts, and stimulating transforming growth factor β-induced fibrosis. Belumosudil, an oral selective ROCK2 inhibitor, targets the ROCK2 pathway, thus correcting disrupted immune homeostasis, downregulating proinflammatory cytokines, and reversing fibrosis in cGVHD. Clinical trials demonstrated rapid and sustained overall response with belumosudil, and a favorable adverse effects profile with a low risk of infection and cytopenia in pretreated and multiorgan involved cGVHD patients, resulting in its approval for use in cGVHD. This narrative review provides an overview of the pathophysiology of cGVHD and the limitations of current treatment, and describes the pharmacologic activity, clinical studies, and real-world data supporting belumosudil use in patients with cGVHD.

Background: Azacitidine (AZA) plus venetoclax (VEN) has emerged as a widely accepted treatment option for acute myeloid leukemia (AML), particularly in older patients or those unfit for intensive chemotherapy. However, real-world data on AZA + VEN efficacy and safety in Southeast Asia remain limited.

Objectives: To evaluate the real-world effectiveness and safety of AZA + VEN in newly diagnosed (ND) and relapsed/refractory (R/R) AML patients in Thailand.

Design: A retrospective observational multicenter study.

Methods: This is a multicenter retrospective study included ND and R/R AML patients treated between 2021 and 2024 at three tertiary hospitals in Thailand. All patients received AZA at 75 mg/m² for 7 days per cycle. VEN dosing and duration were individualized based on physician judgment, drug availability, and patient affordability. Data collection included clinical characteristics, cytogenetics, treatment details, response rates, survival outcomes, and toxicities.

Results: A total of 81 patients were analyzed, included 54 ND and 27 R/R AML cases, with a median age of 65 years. Based on European LeukemiaNet 2022 classification, 51.9% had intermediate risk, and 33.3% had adverse risk. The composite complete remission was 56.8% (ND: 64.8%, R/R: 40.7%). VEN was administered at a median dose of 100 mg for 28 days, combined with potent CYP3A4 inhibitor of antifungal prophylaxis (posaconazole 51.0%, voriconazole 30.4%, itraconazole 17.7%). The median overall survival was 9.2 months and relapse-free survival was 8.1 months. Grades 3-4 neutropenia and febrile neutropenia occurred in 93.8% and 60.5% of patients, respectively.

Conclusion: This real-world practice highlights the feasibility and effectiveness of AZA-VEN in combination with antifungal prophylaxis for elderly or unfit AML patients in resource-limited countries. However, infectious complications remain a concern with this low-intensity regimen.

Myelodysplastic syndromes (MDS), particularly in older adults aged 60 years and above, present significant therapeutic challenges due to poor prognosis and limited treatment options. Higher-risk MDS (HR-MDS), defined by the Revised International Prognostic Scoring System score of ⩾3.5, is characterized by increased myeloblasts, severe cytopenia, and a median survival of <2 years. The pathogenesis involves complex genetic mutations, cytogenetic abnormalities, and a dysregulated bone marrow microenvironment. Current standard therapies, such as hypomethylating agents and allogeneic stem cell transplantation, are often inadequate, especially in older patients with comorbidities and limited clinical trial eligibility. This review highlights emerging targeted therapies for older HR-MDS patients, focusing on small-molecule agents for their critical advantages like patient-friendly oral delivery, lower production barriers, improved access to intracellular targets, and flexible dosing strategies. Venetoclax, an oral B-cell lymphoma-2 (BCL-2) inhibitor, has shown promise in clinical trials but requires further validation. Isocitrate dehydrogenase 1 (IDH1) inhibitors, including ivosidenib and olutasidenib, have demonstrated efficacy and tolerability, while ongoing investigations explore other novel agents like IDH2 inhibitors and FMS-like tyrosine kinase 3 (FLT3) inhibitors. By summarizing the latest advancements, this review emphasizes the importance of developing safe, effective, and personalized therapies to improve outcomes and quality of life for older patients with HR-MDS, with a focus on age-specific clinical trials.

Background: Venetoclax is the first representative of a new class of targeted therapy, that inhibits selectively B-cell lymphoma-2 (BCL-2), an anti-apoptotic protein, frequently overexpressed in hematological malignancies. Venetoclax was approved by the Food and Drug Administration for chronic lymphocytic leukemia and for acute myeloid leukemia in 2016 and 2021, respectively. Because of its promising role in many hematological malignancies, several clinical trials are in progress and other extensions of indication are expected. An analysis of its long-term safety profile in real life is necessary.

Objectives: The aim of our study was to evaluate all adverse events (AEs) reported to the French national pharmacovigilance database since its approval in France.

Methods: We performed a retrospective study of all cases of AEs occurring under venetoclax recorded in the French national pharmacovigilance database since its market approval until March 2022 in France.

Results: During the period study, a total of 209 AEs were spontaneously reported in 123 patients, of which 173 (82%) were serious. We confirmed that the most frequent toxicities described by the summary of product characteristic (SPC) and literature data on it, including hematological (21%), gastrointestinal (11%), dermatological (9%), infectious (8%) AEs, and tumor lysis syndrome (3%). Seventy-six (36%) AEs were not listed in the SPC for which the causal relationship of venetoclax could not be excluded including autoimmune hemolytic anemias (2%) or cardiac AEs (7%).

Conclusion: These data especially in cardiac events provide important information on the safety of the venetoclax in a real-world setting.

Background: Essential thrombocythemia (ET) is a Philadelphia chromosome-negative myeloproliferative neoplasm that is characterized by thrombocytosis and an elevated risk of thrombosis and hemorrhage. We aimed to ascertain the demographics, treatment patterns, and risk of recurrent thrombosis among patients with ET in Taiwan.

Objectives: To investigate the patient characteristics, proportion of treatment, age-specific treatment pattern, average daily dose, and risk of recurrence of thrombosis in patients with ET.

Design: A population-based cross-sectional study was conducted between January 1, 2020 and December 31, 2021.

Methods: This study utilized data from the National Health Insurance Research Database in Taiwan. Patients with ET were identified based on ICD-10-CM codes, and their demographic, clinical, and treatment data were analyzed. Descriptive and statistical analyses were employed to compare patient characteristics, treatment modalities, and recurrence of thrombotic events.

Results: Among the 4503 patients with ET (prevalence: 19.3 cases per 100,000 population), the mean age was 58.1 years, with a female predominance (60.3%). Thrombosis occurred in 3.8% of patients during the study period, with a recurrence rate of 30.5% in patients with a history of thrombosis. Hydroxyurea (46.8%) and anagrelide (30.2%) were the most common treatments, with younger patients receiving higher therapeutic doses. Despite cytoreductive therapy, younger patients demonstrated higher recurrence rates of thrombosis. The cumulative incidences of secondary myelofibrosis and acute myeloid leukemia were 2.6% and 0.6%, respectively, over 2 years.

Conclusion: This study highlights the burden of ET in Taiwan and reveals significant unmet needs in thrombosis prevention, particularly among younger patients. Real-world treatment patterns diverge from recommendations in guidelines, and this finding emphasizes the need for individualized therapeutic strategies to optimize patient outcomes. Further research, such as a longitudinal study, is warranted to investigate the risk factors of thrombosis, disease progression, and mortality in this cohort.