Haematologica最新文献

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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We previously used a disease-specific B cell receptor (BCR) point mutation (IGLV3-21R110) for selective targeting of a highrisk subset of chronic lymphocytic leukemia (CLL) with chimeric antigen receptor (CAR) T cells. Since CLL is a disease of the elderly and a significant fraction of patients is not able to physically tolerate CAR T-cell treatment, we explored bispecific antibodies as an alternative for precision targeting of this tumor mutation. Heterodimeric IgG1-based antibodies consisting of a fragment crystallizable region (Fc) attached to both an anti-IGLV3-21R110 Fab and an anti-CD3 (UCHT1) single chain variable fragment (R110-bsAb) selectively killed cell lines engineered to express high levels of the neoepitope as well as primary CLL cells using healthy donor and CLL patient-derived T cells as effectors. R110-bsAb spared polyclonal human B cells (as opposed to CD19-targeting blinatumomab) as well as CD34+ human stem cells. Yet, R110-bsAb induced lower T-cell activation than blinatumomab with primary CLL cells likely due to lower expression of target antigen. In vivo, R110- bsAb specifically killed IGLV3-21R110-expressing cell lines and CLL cells while sparing peripheral blood mononuclear cells. These findings highlight bispecific antibodies as a potential off-the-shelf immunotherapy for high-risk CLL patients, offering selective targeting while preserving healthy B cells.