Annals of Hematology最新文献

Ponatinib, a third-generation tyrosine kinase inhibitor, is effective in patients with chronic myeloid leukemia (CML), particularly in cases of resistance or BCR::ABL1 T315I mutation. However, arterial occlusive events (AOEs) remain an important safety concern. The PONDEROSA registry evaluated ponatinib use under routine clinical conditions in Germany and the Czech Republic. This observational cohort study included 99 adult CML patients treated with ponatinib; patient recruitment took place between 2015 and 2022 at 31 centers. The median follow-up was 22 months (range: 1–83). Among the 99 patients (median age 54 years at CML diagnosis), 91.9% were in chronic phase, 4.0% in accelerated phase, and 4.0% in blast phase. The T315I BCR::ABL1 mutation was detected in 19.2%. Ponatinib starting doses were 45 mg/day (32.3%), 30 mg/day (37.3%), or 15 mg/day (29.3%). Adverse events (AEs) were recorded in 64.6% of patients. Severe cardiovascular or cerebrovascular events occurred in 12.1% of patients, with no fatal events observed. Ponatinib was discontinued in 31.3% of patients, mainly due to intolerance or lack of response. 58.6% of patients achieved or maintained at least a major molecular response (MMR), compared to 19.0% at baseline. Disease progression was observed in 14.1% of patients, and 8.1% underwent allogeneic stem cell transplantation. The estimated 2-year progression-free survival and overall survival rates were 84.4% and 85.7%, respectively. The PONDEROSA study confirms the clinical effectiveness of ponatinib in routine practice. Individualized dosing strategies are essential to balance efficacy and cardiovascular safety. Ponatinib remains a valuable bridging therapy for patients requiring allogeneic transplantation.

Hodgkin’s lymphoma (HL) exhibits genetic susceptibility, but little is known about the pathogenic genes associated with the disease. Herein, we present a case of two siblings from a consanguineous Chinese family who were both diagnosed with nodular sclerosis classical HL. The female child and male child were diagnosed at the ages of 22 and 29, respectively, both presenting with involvement of the neck and mediastinal lymph nodes, and poor response or relapse shortly after the first-line treatment. Whole-exome sequencing of the four family members revealed a novel pathogenic missense mutation in the CD38 gene (c.418 C > T, p.Arg140Trp), which was found to be inherited in an autosomal recessive manner. Herein, we identified a putative pathogenic genetic variant that may be associated with HL, which will contribute to improve the understanding of the genetic molecular mechanisms underlying the disease.

Myeloid/Lymphoid Neoplasms with Eosinophilia and Tyrosine Kinase Gene Fusions (MLN-eo-TK) represent a distinct and heterogeneous group of hematologic malignancies characterized by recurrent gene fusions involving tyrosine kinases, such as PDGFRA, PDGFRB, FGFR1, JAK2, FLT3, ETV::ABL1 and other partner genes/variants. Among these, gene rearrangements involving PCM1::JAK2 are rare and may present diagnostic challenges, particularly when manifesting as acute lymphoblastic leukemia (ALL). We describe a case of a patient who presented with B-cell acute lymphoblastic leukemia (B-ALL) with a JAK2 rearrangement. After the induction therapy, strong myeloid proliferation in bone marrow without evidence of residual lymphoblasts was observed and JAK2 rearrangement was recognized to be a consequence of translocation t(8;9)(p22;p24)] resulting in PCM1::JAK2 fusion. This finding indicated the presence of an underlying chronic myeloid/lymphoid neoplasm, meeting criteria for MLN-eo-TK. Following an inadequate response to standard chemotherapy, salvage regimens incorporating targeted agents (JAK2 and BCL-2 inhibitors) and allogeneic bone marrow transplantation were administered, all of which unfortunately resulted in short-lived clinical benefit. The case highlights the importance of distinguishing de novo lymphoid malignancies from MLN-eo-TK, especially when JAK2 rearrangements are detected. Recognition of the clonal myeloid component during or after lymphoid-directed therapy has important diagnostic and therapeutic implications, supporting the use of targeted JAK2 inhibition in addition to standard chemotherapy.

This study aims to explore the long-term endocrine and gonadal effects of chemotherapy and radiotherapy in female acute lymphoblastic leukemia (ALL) patients. A cohort study included girls diagnosed with ALL and treated between 2000 and 2020. Patients with at least 2 years elapsed since treatment completion were included. Endocrinological evaluations included anthropometric measures and pubertal status, as well as fasting insulin, glucose, lipid levels, and hormone assessments for adrenal, and thyroid functions. Reproductive functions were evaluated based on gonadotropin, estradiol, and anti-Müllerian hormone (AMH) levels. A total of 51 female patients were included. At the time of study participation, the mean age was 14.7 years, and the mean time since treatment completion was 9.4 years. At least one endocrine disorder was present in 39.2% of participants, with dyslipidemia, insulin resistance, and obesity being the most common. Low AMH levels (< 1.1 ng/dL) were found in 41.6%, particularly in those who underwent bone marrow transplantation. A significant positive correlation was found between the time elapsed since treatment and AMH levels (p < 0.001, r = 0.612), while age at diagnosis, risk group (standard, intermediate or high risk), and cranial radiotherapy showed no significant associations. A substantial proportion of ALL survivors developed endocrine complications, with ovarian reserve compromised in over 40% of cases. Notably, this is the first cohort study to demonstrate a significant positive correlation between AMH levels and the time elapsed since treatment, suggesting a potential for gonadal recovery except in those exposed to intensive chemotherapy or transplantation.

Inotuzumab ozogamicin (InO) is effective for relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL) but is associated with hepatotoxicity, particularly sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD), which leads to portal hypertension (PH). We report a case of a 50-year-old woman who, after receiving InO, developed SOS/VOD and subsequent chronic PH, manifesting as recurrent variceal bleeding approximately 18 months post-treatment. A literature review highlights diagnostic advances using non-invasive tools like transient elastography, the central role of calicheamicin-induced endothelial injury and complement activation in pathogenesis, and risk mitigation through ursodiol prophylaxis and avoidance of dual-alkylator conditioning regimens. The case further illustrates that PH can present with atypical hemodynamics, such as preserved portal flow and absence of cirrhosis, and may emerge as a chronic sequela long after acute SOS/VOD resolution. Quantitative risk assessment using a validated model (CIBMTR) revealed a very low pre-treatment SOS/VOD risk (2.64%), highlighting that InO-induced injury can override a favorable baseline risk profile. This underscores the importance of long-term monitoring for PH, even after resolution of acute SOS/VOD and achievement of leukemia remission, to optimize outcomes in InO-treated patients.

To evaluate the long-term efficacy and safety of gilteritinib compared with salvage chemotherapy (SC) in patients with relapsed/refractory FMS-like tyrosine kinase 3 (FLT3)-mutated acute myeloid leukemia (AML). In the phase 3 COMMODORE (NCT03182244) trial, patients with relapsed/refractory FLT3-mutated AML from China, Russia, Singapore, Thailand, and Malaysia were randomized to gilteritinib (120 mg/day) or SC. The long-term follow-up included assessments every 3 months for a maximum of 3 years from the end-of-treatment visit. The primary endpoint was overall survival (OS). Secondary endpoints included event-free survival (EFS), complete remission (CR) rate, hematopoietic stem cell transplantation (HSCT) rate, and transfusion maintenance and conversion rates. Overall, 276 patients (gilteritinib, n = 137; SC, n = 139) completed the long-term follow-up. Most (88.0%) patients were Asian. The median (95% confidence interval [CI]) OS was longer with gilteritinib versus SC (10.3 [8.8, 12.7] vs 5.4 [4.1, 8.1] months, respectively; hazard ratio [HR; 95% CI], 0.612 [0.451, 0.832]), with a median follow-up of 34.6 months. The median (95% CI) EFS was longer with gilteritinib versus SC (2.1 [< 0.1, 3.2] vs 0.6 [0.2, 1.2] months, respectively; HR [95% CI], 0.589 [0.438, 0.792]). The CR rate was 20.4% and 11.5% in the gilteritinib and SC arms, respectively. During the entire study period, 22.6% and 7.9% of patients in the gilteritinib and SC arms underwent HSCT, respectively; 18.2% of patients in the gilteritinib arm received on-study HSCT. No new safety concerns were identified. Long-term gilteritinib treatment improved clinical outcomes compared with SC and was well-tolerated in a predominantly Asian population with relapsed/refractory FLT3-mutated AML.

Sickle cell disease (SCD) is a hereditary hemoglobinopathy that imposes a significant burden on global health. Individuals with SCD often experience multiple nutritional deficiencies, among which vitamin D deficiency has emerged as a critical yet under recognized factor contributing to disease complications. This study aimed to assess the vitamin D status in patients with SCD compared to a matched healthy control group, and to explore its correlation with clinical and biological parameters, including the frequency of vaso-occlusive crises (VOC). A cross-sectional study was conducted between January and June 2024 at Bechir Hamza Children’s Hospital, Tunis. Sixty-four SCD patients and 63 healthy controls were enrolled. Vitamin D [25(OH)D] levels, along with hematologic and biochemical markers, were measured. Statistical analyses included t-tests, chi-square test, ANOVA, and Spearman correlation. Vitamin D levels were significantly lower in the SCD group (15.05 ± 6.6 ng/mL) compared to controls (22.51 ± 12.54 ng/mL, p = 0.026). Among SCD patients, 78.2% (50) had Vitamin D deficiency (< 20ng/mL), 20.3% (13) had Vitamin D insuffisancy (20–30 ng/mL) and only one patient (1.5%) had normal vitamin D status (> 30 ng/mL). Vitamin D levels were inversely correlated with age, total bilirubin, parathyroid hormone (PTH), and frequency of VOC, and positively correlated with hemoglobin concentration and socioeconomic status. SCD patients with vitamin D deficiency experienced significantly more VOC episodes per year. Vitamin D deficiency is highly prevalent among SCD patients and is associated with increased disease severity. Routine screening and appropriate supplementation should be considered as part of comprehensive SCD management strategies.

Hypomethylating agents (HMA) alone or in combination with venetoclax (VEN) are a mainstay for disease control in elderly acute myeloid leukemia (AML). We evaluated the non-inferiority of HMA monotherapy compared to HMA/VEN combination in 227 AML patients aged ≥ 75 years receiving HMA or HMA/VEN combination. No difference in overall survival (OS) was observed between the two groups, with HMA monotherapy demonstrating statistical non-inferiority. HMA-treated patients with favorable performance status had longer OS. The HMA/VEN group experienced higher mortality and worse QoL. HMA monotherapy offers comparable survival outcomes to HMA/VEN with reduced toxicity in elderly AML patients.