Therapeutic Advances in Hematology最新文献

Background: Crizanlizumab is a novel inhibitor of P-selectin, a key player in multicellular adhesion and inflammatory signaling, that leads to vaso-occlusion in sickle cell disease (SCD).

Objectives: The SOLACE-adults study evaluated the pharmacokinetics, pharmacodynamics (P-selectin inhibition), safety, and efficacy of crizanlizumab, with or without hydroxyurea/hydroxycarbamide, in patients with SCD.

Design: Phase II, single-arm, multicenter study.

Methods: Patients with SCD aged 16-70 years, with ⩾1 vaso-occlusive crisis (VOC) within 12 months before screening, received crizanlizumab 5.0 or 7.5 mg/kg intravenous infusion every 4 weeks; dose groups were enrolled sequentially.

Results: Of 57 patients enrolled, 45 received crizanlizumab 5.0 mg/kg and 12 received 7.5 mg/kg for a median duration of 206 and 170 weeks, respectively. Crizanlizumab concentrations reached maximum levels after a 30-min infusion and remained steady for 6 h, without significant accumulation. P-selectin inhibition was nearly complete for both doses. The median (interquartile range) absolute change in the annualized rate of VOCs leading to healthcare visit from baseline was -0.79 (-3.04, 2.01) in the 5.0 mg/kg group and -0.98 (-1.11, -0.41) in the 7.5 mg/kg group. All patients experienced at least one adverse event (AE), with no apparent differences between the two doses in the frequency and severity of AEs. Grade ⩾3 AEs occurred in 60% of the 5.0 mg/kg group and 58% of the 7.5 mg/kg group. Two patients in the 5.0 mg/kg group and one in the 7.5 mg/kg group had severe crizanlizumab-related infusion-related reactions, which resolved with treatment. No patients developed antibodies against crizanlizumab.

Conclusion: Crizanlizumab 5.0 and 7.5 mg/kg demonstrated a dose-proportional increase in exposure, sustained P-selectin inhibition, a tolerable safety profile, and a sustained reduction in VOCs leading to healthcare visit. This suggests that crizanlizumab is a useful treatment option for patients with SCD who have experienced VOCs.

Trial registration: NCT03264989.

Background: The myeloproliferative neoplasm (MPN) is a heterogeneous group of clonal hyperplasia hematopoietic stem cell disorders, predominantly affecting middle-aged and elderly individuals, with a slow disease progression. With advancements in disease-related research, the survival rates of MPN patients have significantly improved. This research primarily focuses on cardiovascular disease mortality (CVM) and prognostic factors in MPN patients, aiming to provide clinicians with more comprehensive references.

Methods: A total of 24,277 patients were included in the Surveillance, Epidemiology, and End Results (SEER) database. Cumulative mortality was assessed using a competing risk model, univariate and multivariate regression analysis of cardiovascular disease (CVD) mortality risk factors, and a comparison of standardized mortality ratio (SMR) and general population CVM.

Results: Among the 24,277 patients included in this study, a total of 8841 deaths occurred during the follow-up period, with 2429 attributed to CVD. Notably, the risk of CVM was found to be significantly higher in patients with MPNs compared to the general population. Furthermore, this risk increased over time. CVD emerged as the predominant cause of death among individuals aged over 80 years and younger patients exhibited a significantly elevated SMR. Additionally, age, race, marital status, and insurance status were identified as independent prognostic factors for CVM.

Conclusion: The incidence of cardiovascular events in patients with MPNs is significantly higher compared to the general population. Early screening and assessment of cardiac health should be implemented in MPN patients to prevent the occurrence of cardiovascular events and enhance their prognosis.

Background: Secondary myelofibrosis (SMF) is characterized by the excessive deposition of fibrous tissue on top of the primary disease, often causing clinical manifestations to be overshadowed by the primary disease. Unfortunately, current staging systems do not incorporate myelofibrosis, leading to potential treatment delays for SMF.

Objectives: To evaluate the prognosis of patients with multiple myeloma (MM) complicated with myelofibrosis.

Design: The study included the clinical data and treatment results of 208 newly diagnosed multiple myeloma (NDMM) patients who were treated in the Affiliated Hospital of Qingdao University from January 2014 to August 2020, and performed a retrospective analysis.

Methods: All patients underwent bone marrow biopsy, and MF severity was classified into grades 0-3 according to the 2016 WHO criteria. Treatment efficacy was evaluated based on the International Myeloma Working Group (IMWG) standard and SPSS was used for analysis.

Results: The MM patients without SMF exhibited better treatment response (p < 0.05). Importantly, increasing degrees of myelofibrosis were associated with a significant reduction in median progression-free survival (PFS; p < 0.05). MM-SMF patients exhibited significantly shorter median PFS and overall survival (OS; p < 0.05). In the MM-SMF group, neutrophil-lymphocyte ratio >2.39, monocyte-lymphocyte ratio ⩽0.18, and platelet-lymphocyte ratio ⩽61.6 were associated with significantly reduced median PFS and OS (p < 0.05). Notably, the use of bortezomib-based regimens did not significantly impact prognosis in MM-SMF patients, while lenalidomide-based regimens significantly extended median OS but did not significantly affect median PFS.

Conclusion: Myelofibrosis emerges as an important prognostic indicator for predicting the survival outcomes of NDMM patients. In the era of new therapeutics, there is a pressing need to explore novel treatment strategies in order to improve the prognosis of patients with multiple myeloma complicated by myelofibrosis.

Background: Approximately 20%-30% of diffuse large B-cell lymphoma (DLBCL) cases are classified as double-expressor lymphoma (DEL), characterized by the co-expression of the MYC and BCL2 proteins. However, the most effective therapeutic strategy for DEL remains unidentified.

Objectives: To evaluate the efficacy of a novel histone deacetylase inhibitor, chidamide, in combination with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (CR-CHOP) in the treatment of DEL.

Design: This was a retrospective study.

Methods: This study included 62 DEL patients from December 2016 to December 2020. All patients were administered a first-line treatment with CR-CHOP. The short-term efficacy, survival status, and adverse reactions in this population were observed, and the prognostic factors were analyzed.

Results: The median age was 53.9 years (range, 19-77). All patients received a median of six cycles (range, 1-8) of treatment, with 79.0% achieving complete response (CR) and an overall response rate of 88.7%. With a median follow-up of 45.5 months (range, 1-82), the median progression-free survival (PFS) and median overall survival (OS) had not yet been reached. However, the 3-year PFS rate was 71% (95% CI: 61-83), the 3-year OS rate was 87% (95% CI: 79-96), the 5-year PFS rate was 67% (95% CI: 55-80), and the 5-year OS rate was 85% (95% CI: 77-95). Age and autologous stem cell transplantation after CR or partial response were independent prognostic factors for PFS, while various clinical factors were not associated with OS outcomes. The most common grades 3-4 hematologic and nonhematologic toxicity were leukopenia (46.7%) and infection (21%), respectively.

Conclusion: This long-term follow-up study indicates that CR-CHOP in untreated DLBCL with the DEL phenotype demonstrates high short-term efficacy and safety as well as promising survival outcomes.

Dasatinib is a second-generation tyrosine kinase inhibitor employed for chronic myeloid leukemia (CML) treatment that achieves high rates of prolonged and complete molecular responses (MR). Among the adverse effects reported, it has been associated with hemorrhagic complications, mainly due to its inhibiting effects on platelet functions. In addition, immune alterations induced by dasatinib may elevate the risk of bleeding and cytomegalovirus (CMV) infection, particularly in the gastrointestinal tract, thus contributing to the development of hemorrhagic colitis. In this case report, we highlight three cases of CML receiving treatment with dasatinib where CMV hemorrhagic colitis occurred. All of them exhibited iron deficiency anemia as a premature clinical manifestation in the absence of intestinal symptoms, unlike cases previously reported in the literature. CMV infection was confirmed with stool samples or tissue quantitative polymerase chain reaction and/or immunohistochemistry staining in colon biopsies. All three cases could be managed with valganciclovir and iron supplements in an outpatient setting. Management strategies of dasatinib during and after CMV infection varied, as they are not yet established and need to be individualized based on the gravity of symptoms and disease state. Iron deficiency anemia during dasatinib treatment should raise suspicion for the potential presence of CMV colitis, prompting endoscopic studies to rule out this complication, even if intestinal symptoms are not present.

Acute leukemia (AL) is a rare yet perilous malignancy. Currently, the primary treatment for AL involves combination chemotherapy as the cornerstone of comprehensive measures, alongside hematopoietic stem cell transplantation as a radical approach. However, despite these interventions, mortality rates remain high, particularly among refractory/recurrent patients or elderly individuals with a poor prognosis. Acetylation, a form of epigenetic regulation, has emerged as a promising therapeutic avenue for treating AL. Recent studies have highlighted the potential of acetylation regulation as a novel treatment pathway. Histone deacetylase inhibitors (HDACis) play a pivotal role in modulating the differentiation and development of tumor cells through diverse pathways, simultaneously impacting the maturation and function of lymphocytes. HDACis demonstrate promise in enhancing survival rates and achieving a complete response in both acute myeloid leukemia and acute T-lymphoblastic leukemia patients. This article provides a comprehensive review of the advancements in HDACi therapy for AL, shedding light on its potential implications for clinical practice.

[This corrects the article DOI: 10.1177/20406207241260332.].

Over recent decades, management of people with hemophilia (PwH) has been greatly improved by scientific advances that have resulted in a rich and varied therapeutic landscape. Nevertheless, treatment limitations continue to drive innovation, and emerging options have the potential to realize further improvement. We advocate four general principles to optimize benefits from innovation: individualizing the treatment approach, targeting 'normal,' making the most of available resources, and considering treatment affordability. Ultimately, all PwH-men and women, of all ages and severities, and worldwide-should have access to treatment that fully prevents bleeding, while allowing personal, social, family, and professional lives of choice. Clearly, we are not there yet, but developing goals/milestones based on the principles we describe may help to achieve this.

Background: There is limited data on third-party umbilical cord blood (UCB) or mesenchymal stem cell (MSC) transplantation-assisted haploidentical hematopoietic stem cell transplantation (haplo-HSCT) in pediatric patients.

Objective: To evaluate the efficacy and safety of UCB and MSC transplantation-assisted haplo-HSCT in pediatric patients with acute leukemia (AL).

Design: Observational study.

Methods: Clinical data of 152 children with AL undergoing haplo-HSCT at the Children's Hospital of Soochow University between January 2020 and June 2022 were collected. The patients were divided into the haplo-HSCT + UCB group (n = 76), haplo-HSCT + MSC group (n = 31), and haplo-HSCT group (n = 45). Hematopoietic reconstruction time, complications within 30 days after transplantation, and survival and recurrence at 3 years after transplantation were compared among the groups.

Results: Multivariate analysis revealed that haplo-HSCT with MSC and human leukocyte antigen (HLA) matching ⩾6/10 were independent factors reducing engraftment syndrome (ES) incidence. There were no significant differences among the groups in the hematopoietic reconstruction time or incidence of complications within 30 days after transplantation (p > 0.05). Overall survival, relapse-free survival, cumulative incidence of relapse, cumulative incidence of hematological relapse, and 3-year transplant-related mortality were not significantly different (p > 0.05). The incidence of adverse reactions in the haplo-HSCT + UCB group was 97.3% within 4 h after UCB infusion, with a particularly high occurrence rate of 94.7% for hypertension. No transfusion-related adverse reactions occurred after the transfusion of umbilical cord MSC in the haplo-HSCT + MSC group.

Conclusion: MSC-assisted haplo-HSCT can reduce ES incidence after transplantation in pediatric patients with AL. UCB infusion is associated with a high incidence of reversible hypertension. However, no adverse reactions were observed in umbilical cord MSC transfusion.

Background: Interleukin-7 receptor (IL7R) mutation has been demonstrated to be an adverse prognostic factor in acute lymphoblastic leukemia (ALL) patients. However, the effects of the IL7R mutation on acute myeloid leukemia (AML) have rarely been reported. Here, we investigated IL7R mutations and their effects on AML patients.

Methods: A total of 346 newly diagnosed AML patients from January 2017 to July 2020 at Nanfang Hospital were analyzed in this study. A genomic panel of 167 gene targets was detected by next-generation sequencing.

Results: Among 346 patients, 33 (9.5%) AML patients carried IL7R mutations. With a median follow-up of 50.7 months (95% confidence interval (CI) 17.3-62.2), the 5-year overall survival (OS) rates were 51.5% (95% CI 37.0%-71.0%) and 72.2% (95% CI 67.4%-77.3%; p = 0.008), the 5-year event-free survival (EFS) rates were 36.1% (95% CI 23.2%-57.1%) and 58.1% (95% CI 52.9%-63.8%; p = 0.005), the 5-year non-relapse mortality (NRM) were 21.4% (95% CI 8.5%-38.2%) and 6.2% (95% CI 3.7%-9.5%; p = 0.004) in the IL7R mutant (IL7R ^MUT ) group and non-IL7R mutant (IL7R ^WT ) group, respectively. There is no significant difference in the disease-free survival (75.1% vs 73.5%, p = 0.885) and cumulative incidence of relapse (25.7% vs 25.2%, p = 0.933) between IL7R ^MUT and IL7R ^WT group. Furthermore, patients who underwent hematopoietic stem cell transplantation (HSCT) still had more adverse outcomes in the IL7R ^MUT group than in the IL7R ^WT group (5-year OS: 61.9% vs 85.3%, p = 0.003). In the TET2 (p = 0.013) and DNA methyltransferase 3A (DNMT3A; p = 0.046) mutation subgroups, the presence of IL7R mutations was associated with worse OS than in AML patients without IL7R mutations.

Conclusion: Our study demonstrated that the IL7R mutation is associated with an inferior prognosis for AML patients. Patients with IL7R mutations have higher NRM, shorter OS, and EFS than patients without IL7R mutations, even patients who have undergone HSCT. Future larger and multicentric prospective studies will be explored.