Haematologica最新文献

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Background: Development of inhibitory antibodies (inhibitors) against FVIII is a significant complication of protein replacement therapy in hemophilia A (HA). Platelets, traditionally viewed as mediators of hemostasis, also modulate immune responses through cytokine release and interactions with immune cells. Harnessing these immunomodulatory properties may provide a novel strategy to prevent or suppress inhibitor formation.

Objective: To investigate whether FVIII-engineered platelets and related platelet-based products modulate FVIII immune responses in HA mice.

Methods: FVIII-containing platelets were isolated from 2bF8 transgenic mice. FVIII-deficient mice were infused with intact FVIII-containing platelets, desialylated FVIII-containing platelets (dPlts), or acidified platelet lysates in combination with or before recombinant human FVIII (rhF8) exposure. Anti-FVIII antibody titers were determined by the Bethesda assay and ELISA, and T cell responses were analyzed by flow cytometry and proliferation assays.

Results: Co-infusion of FVIII platelets with rhF8 significantly reduced inhibitor titers compared with rhF8 alone. Acidified FVIII platelet lysates were potent, decreasing inhibitor titers by >20-fold when co-infused with rhF8. In contrast, co-infusion of dPlts with rhF8 did not suppress immune responses. However, repeated pre-sensitization with dPlts alone promoted immune tolerance to FVIII, evidenced by reduced inhibitor titers upon rhF8 immunization and attenuated CD4ô€€€ T cell proliferation upon subsequent rhF8 exposure. These findings reveal a hierarchy of immune modulation, with intact platelets providing partial protection, lysates strongly suppressing immune responses, and dPlts inducing immune tolerance.

Conclusions: FVIII-engineered platelets and platelet-derived products are potent immune modulators. These strategies offer novel and translatable approaches to both restore hemostasis and prevent or eradicate inhibitors in HA.

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Immunomodulatory agents (IMiDs) and the next-generation Cereblon (CRBN) E3 ligase modulators (CELMoDs), targeting the IKZF1/IKZF3-IRF4-MYC axis, are effective therapies for multiple myeloma (MM) across all stages of disease. Resistance to treatment can be acquired following exposure, but a subset of patients have primary resistance, with both states necessitating the development of alternative treatment strategies. Enhancer of zeste homolog 2 (EZH2) has been shown to have increased expression at myeloma relapse and higher expression is associated with a shorter progression free survival from diagnosis. EZH2 inhibitors have been studied as a single agent in myeloma and in combination treatments to overcome drug resistance in other malignancies. In this study KMS-11 and RPMI-8226 myeloma cell lines are used as models of primary IMID resistance, demonstrating persistent Interferon regulatory factor 4 (IRF4) expression after IMiDs/CELMoDs exposure without loss of cell viability. The combination of Tazemetostat, an FDA-approved EZH2 inhibitor, with IMiDs/CELMoDs significantly reduces IRF4 expression, induces apoptosis, and leads to synergistic cell death in these resistant cell lines. Further investigations reveal that the synergistic effect of EZH2 inhibition appears specific to IMiDs/CELMoDs, is CRBN-dependent and rescued by IRF4 overexpression. Mechanistically, Tazemetostat appears to reduce IKZF1 binding to the IRF4 promoter and super-enhancer, explaining how the combination with IMiDs/CELMoDs which also have this effect may reach the threshold required to suppress IRF4 expression and ultimately inhibit MM cell growth in resistant cell lines. Our findings highlight a potential strategy for treating MM patients with IMiD resistance.

The clinical implementation of BCR::ABL1 tyrosine kinase inhibitors (TKIs) for the treatment of chronic myeloid leukemia (CML) represents one of the big successes of mechanism-based cancer therapy. In 2025, survival of patients who start TKI therapy while in the chronic phase is approaching that of age-matched controls. Despite this paradigm shift, significant challenges remain. Some patients still develop overt TKI resistance and progress to bast phase, and the majority continue to harbor residual leukemia and require life-long TKI therapy. Growth and survival signals arising from the microenvironment or from within the leukemia cells confer various degrees of resistance to support a spectrum of leukemic activity ranging from overt acute leukemia in blast phase to persistence of minimal residual disease in patients with a deep molecular response. Here we review cell-intrinsic resistance, covering both reactivation of BCR::ABL1 kinase activity and the less welldefined mechanisms underlying BCR::ABL1-independent TKI resistance. We propose that the pathways used by CML to escape TKI effects reflect the potential and the constraints of BCR::ABL1- driven reprogramming of hematopoietic stem and progenitor cells and that the role of BCR::ABL1 functions other than kinase activity may be underappreciated, providing a rationale for the clinical development of BCR::ABL1 degraders.

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CAR-T has transformed relapsed/refractory LBCL treatment, with CD28-based products yielding rapid responses but higher ICANS rates. With Axicabtagene-ciloleucel and Brexucabtagene-autoleucel, overall and severe ICANS reach 78% and 35%, respectively. Older adults are vulnerable, yet mitigation strategies remain lacking. We aimed to develop and implement a standardized ICANS mitigation protocol for older adults receiving CD28- based anti-CD19 CAR-T, addressing this critical gap. We conducted a single-arm prospective pilot study in patients ≥75yr or ≥65 with additional risk factor receiving CD28-based CAR-T. The protocol included levetiracetam and thiamine prophylaxis, early grade-based corticosteroids and anakinra for grade ≥3 and refractory ICANS - defined as no improvement within 24hr. Endpoints were ICANS duration, refractoriness, response and toxicity. Forty-five patients met eligibility; median age 75 (65-86), 78% had ECOG ≥2 and 42% with neurologic comorbidity. Overall, grade ≥3, and refractory ICANS developed in 67%, 31%, and 20%, respectively. Median ICANS duration was 4 days, shorter than previous cohorts. Disease and patients' characteristics did not predict ICANS metrics, excluding LDH showing trend for severe ICANS (p=0.07). mEASIX and ICANS-PSS scores were not predictive; expansion was not compromised. Cumulative steroids associated with infections (p=.002) and NRM (p.