Haematologica最新文献

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High-dose methotrexate (HDMTX) is a cornerstone of contemporary treatment protocols for both pediatric and adult acute lymphoblastic leukemia (ALL); however, up to 4% of children and 15% of adults develop renal toxicity with severely delayed MTX elimination (DME). Evidencebased guidance on re-exposure after DME is lacking, and omission of further HDMTX may compromise anti-leukemic efficacy and potentially increase the risk of relapse. This study, conducted within the Ponte di Legno international toxicity working group, aimed to evaluate the safety of HDMTX re-challenge in pediatric patients after DME. National investigators from 12 countries provided case-level data on initial DME events and subsequent HDMTX re-exposures via structured questionnaires. Data from 189 patients treated for ALL who experienced DME were analyzed, of whom 143 were subsequently re-exposed to HDMTX. Clinical toxicities after the initial DME included gastrointestinal complications (vomiting, diarrhea, mucositis), infections, and neurological events (encephalopathy, seizures, MTX stroke-like syndrome). Laboratory toxicities comprised cytopenias and hepatic abnormalities. Two patients transiently required dialysis. DME led to chemotherapy modifications in 73% of the patients. After reexposure, toxicities were similar in spectrum, self-limited, and non-fatal. Twenty children (14%) developed recurrent DME, including three with two additional episodes. Recurrent DME could not be predicted by clinical, pharmacokinetic, or demographic variables, nor by uniform MTX dose reduction during re-exposure. In conclusion, re-exposure to HDMTX following DME is feasible and generally well tolerated, although the risk of recurrence is increased. Re-challenge should be considered once renal function has normalized, with careful monitoring and individualized dose adjustment.

Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), driven by the BCR-ABL1 fusion gene, remains a high-risk malignancy despite therapeutic advances. Tyrosine kinase inhibitors (TKIs) targeting BCR-ABL1 have significantly improved outcomes, but resistance and relapse persist, necessitating novel strategies such as combining TKIs with bispecific T-cell engagers (BiTEs) like blinatumomab. Blinatumomab redirects T cells to eliminate CD19+ leukemia cells and has shown impressive clinical activity in Ph+ ALL when combined with Src+BCR-ABL1 TKIs. However, this contrasts with preclinical observations reporting that Src kinase inhibition by Src/BCR-ABL1 TKIs antagonizes blinatumomabmediated T-cell activation. Consistent with prior preclinical studies, we demonstrate that dasatinib and ponatinib, unlike SRC sparing TKIs (imatinib, nilotinib), antagonize blinatumomab's T-cell engaging efficacy by potently inhibiting LCK Y394 phosphorylation, a critical step in proximal TCR signaling. This inhibition impairs T-cell proliferation, cytokine production, and NFAT activation. To reconcile this in vitro antagonism with favorable clinical combination outcomes, we confirmed that the mechanism of SRC inhibition is T-cell intrinsic and explored the impact of interleukins. We show that TKI-induced T-cell suppression and antagonism can be significantly improved by supplementing co-cultures with common gamma-chain cytokines, particularly IL-7. IL-7 robustly enhances human T-cell proliferation, reduces exhaustion, and significantly improves blinatumomab's cytotoxic efficacy in the presence of Src/BCRABL1 TKIs.

Clonal hematopoiesis (CH) is defined by the clonal expansion of hematopoietic stem and progenitor cells harboring somatic mutations that confer a fitness advantage. CH is common with advancing age and becomes nearly ubiquitous in middle age. Although typically asymptomatic, CH is associated with an increased risk of hematologic malignancies particularly myeloid neoplasms (MN), diverse non-malignant conditions, and all-cause mortality. Over the past decade, research has provided major insights into the origins of CH. In addition to aging, CH is promoted by environmental exposures, inherited genetic predisposition, and acquired conditions. Large-scale population and longitudinal sequencing studies have identified determinants of clonal behavior. Characterization of the natural history of CH has enabled the development of risk stratification models to identify individuals with CH at high risk for progression to MN, thereby providing a rationale for selecting patient populations best suited for therapeutic intervention trials. Emerging strategies include targeting mutation-specific vulnerabilities, modulating inflammatory pathways, reducing genotoxic therapy-induced clonal selection, and repurposing agents with efficacy in MN. In this review, we summarize current knowledge of the risk factors underlying CH development, highlight recent advances in understanding the determinants of clonal behavior including progression to MN, and discuss emerging therapeutic approaches for preventing malignant transformation and clinical trial design considerations.

No standard salvage regimen exists for relapsed/refractory (R/R) pediatric AML. In this prospective, multicenter Phase II trial, 101 evaluable patients (.

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Patients with sickle cell anemia (SCA) have long been discouraged from physical activity (PA). The aim of the present study was to assess the impact of increasing daily step counts on physical fitness, pain and vascular function in patients with SCA. Thirty-eight patients with SCA were recruited and equipped with a Fitbit wrist-worn accelerometer-based PA tracker for 5 weeks to objectively quantify their baseline daily step counts. Patients were then randomly assigned to one of the three groups: 1) control group: no specific information regarding PA was given for 8 weeks (N=12); 2) PA1 group: daily step counts increased by 25% of baseline for 8 weeks (N=12); 3) PA2 group: daily step counts increased by 25% for 4 weeks, then by 50% for 4 additional weeks (N = 14). Pain intensity and frequency decreased after the intervention in the PA1 and PA2 groups. In addition, patients from these two groups increased the distance walked in 6 minutes. Arterial stiffness decreased in both PA1 and PA2 groups, without any change in the autonomic nervous system activity. Several inflammatory markers slightly decreased in the PA2 group. Incubation of cultured endothelial cells with patient plasma showed a decrease in the percentage of ICAM-1 positive cells in the PA2 group. This study is the first to show that increasing daily PA by a simple way (i.e., increasing daily step count of 25-50%) for 8 weeks is sufficient to decrease pain, and improve physical condition and vascular function of patients with SCA.

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