Hematology:

No abstract available

As survival of HCT recipients continues to improve, late treatment effects gain importance. We demonstrate that pediatric HCT recipients show increased risk of CH compared with age-matched controls. Prospective studies are crucial to understand the clinical implications of posttransplant CH in this young population.

In recent years, remarkable technological advances have illuminated aspects of the pathogenesis of myeloid malignancies-yet outcomes for patients with these devastating diseases have not significantly improved. We posit that a synthesized view of the three dimensions through which hematopoietic cells transit during their healthy and diseased life-clonal evolution, stem cell hierarchy, and ontogeny-promises high yields in new insights into disease pathogenesis and new therapeutic avenues.

Thyroid cancer (TC) is the most common endocrine malignancy. Most patients will be treated and cured by surgery but a low percentage will develop advanced disease. The treatment of advanced disease is at first the use of radioiodine treatment in differentiated cancer then at progression will rely on molecular alterations and consequently in targeted treatments. In this review, we will explore the most frequent molecular alterations of each histological subtype: differentiated thyroid cancer (DTC), anaplastic thyroid cancer (ATC), medullary thyroid cancers (MTC) and clinically tested and approved treatment. We will also report the clinical and preclinical perspective in this field.

No abstract available

Macrophages execute core functions in maintaining tissue homeostasis, in which their extensive plasticity permits a spectrum of functions from tissue remodeling to immune defense. However, perturbations to tissue-resident macrophages during disease, and the subsequent emergence of monocyte-derived macrophages, can hinder tissue recovery and promote further damage through inflammatory and fibrotic programs. Gaining a fundamental understanding of the critical pathways defining pathogenic macrophage populations enables the development of targeted therapeutic approaches to improve disease outcomes. In the setting of chronic graft-versus-host disease (cGVHD), which remains the major complication of allogeneic hematopoietic stem cell transplantation, colony-stimulating factor 1 (CSF1)-dependent donor-derived macrophages have been identified as key pathogenic mediators of fibrotic skin and lung disease. Antibody blockade of the CSF1 receptor (CSF1R) to induce macrophage depletion showed remarkable capacity to prevent fibrosis in preclinical models and has subsequently demonstrated impressive efficacy for improving cGVHD in ongoing clinical trials. Similarly, macrophage depletion approaches are currently under investigation for their potential to augment responses to immune checkpoint inhibition. Moreover, both monocyte and tissue-resident macrophage populations have recently been implicated as mediators of the numerous toxicities associated with chimeric antigen receptor T-cell therapy, further highlighting potential avenues of macrophage-based interventions to improve clinical outcomes. Herein, we examine the current literature on basic macrophage biology and contextualize this in the setting of cellular and immunotherapy. Additionally, we highlight mechanisms by which macrophages can be targeted, largely by interfering with the CSF1/CSF1R signaling axis, for therapeutic benefit in the context of both cellular and immunotherapy.

The outcome of venous thromboembolism in patients with cancer is worse than in patients without cancer, with a higher risk of recurrences, bleeding and death. However, these risks appear to vary depending on the cancer type. While in some tumours the risk of recurrences outweighs the risk of bleeding, in others the risk of major bleeding (MB) during the anticoagulation markedly exceeds the risk of a recurrent event. Balancing these risks could be helpful to tailor the management of cancer-associated thrombosis (CAT) and improve outcomes. In this article, published data from recent randomized clinical trials as well as from some large registries that have reported separated outcomes of CAT depending on cancer type were reviewed. A careful balance of the risk of recurrences and MB events could provide useful insights for clinicians for individualizing treatment strategies in order to improve the outcomes of CAT, as well as for the design of future clinical trials.

No abstract available

No abstract available

Not available.

Not available.

Approximately 30% of patients with acute myeloid leukemia (AML) express CD7 on their myeloblasts. We have previously demonstrated that single-chain variable fragment (scFv)-based "naturally selected" CD7 chimeric antigen receptor T-cell (NS7CAR-T) therapy shows significant efficacy, with a favorable safety profile in T-cell lymphoid malignancies. Here, we derived dual variable heavy-chain domain of a heavy-chain antibody (dVHH) NS7CAR-Ts that have superior CD7 binding specificity, affinity to their scFv-based counterparts, and improved proliferative capability. In this phase 1 clinical trial, we evaluated the efficacy and safety of nanobody-based dVHH NS7CAR-Ts for patients with CD7+ refractory/relapsed AML. A cohort of 10 patients received dVHH NS7CAR-Ts across 2 dosage levels of 5 × 105/kg and 1 × 106/kg. Before enrollment, patients had undergone a median of 8 (range, 3-17) prior lines of therapy. Seven patients had prior transplants. After NS7CAR-T infusion, 7 of 10 (70%) patients achieved complete remission (CR). The median observation time was 178 days (range, 28-776). Among 7 patients who achieved CR, 3 who relapsed from prior transplants underwent a second allogeneic hematopoietic stem cell transplant (allo-HSCT). One patient remained leukemia free on day 401, and the other 2 died on day 241 and day 776, respectively, from nonrelapse-related causes. Three CR patients without consolidative (allo-HSCT) relapsed within 90 days. All the nonresponders and relapsed patients had CD7 loss. The treatment was well tolerated, with 80% experiencing mild cytokine release syndrome and none had neurotoxicity. This trial underscores the potential promising treatment of dVHH NS7CAR-Ts in providing clinical benefits with a manageable safety profile to patients with CD7+ AML, warranting further investigation. This trial was registered at www.clinicaltrials.gov as #NCT04938115.

No abstract available

Hematological involvement (HI) is one of the life-threatening risk organs (ROs) in Langerhans cell histiocytosis (LCH). Lahey criteria have defined HI since 1975 as hemoglobin <10 g/dL, platelets <100 × 109/L, leukopenia (white blood cell count <4 × 109/L), and/or neutrophils <1.5 × 109/L. Among the 2313 patients aged <18 years enrolled in the French National Histiocytosis Registry (1983-2023), 331 developed HI (median age at diagnosis, 1 year); median follow-up lasted 8.1 years. Bone marrow aspirate smears and biopsies may show reactive histiocytes, hemophagocytosis, or myelofibrosis but never confirm the diagnosis. Fifty-eight patients (17%) developed macrophage-activation syndrome, sometimes related to acute Epstein-Barr virus or cytomegalovirus infection, sometimes months before typical LCH manifestations appeared. Hemoglobin and platelet thresholds for initiating transfusion(s) appear to accurately distinguish 2 groups: mild HI (MHI; >7 g/dL and >20 × 109/L, respectively) and severe HI (SHI; ≤7 g/dL and/or ≤20 × 109/L). Each entity has different organ involvements, laboratory parameters, mutational status, blood BRAFV600E loads, drug sensitivities, and outcomes (MHI and SHI 10-year survival rates, 98% and 73%, respectively). Since 1998, mortality first declined with combination cladribine-cytarabine therapy and then with MAPK inhibitors since 2014. Forty-one patients (12%) developed neurodegenerative complications that have emerged as a risk for long-term survivors. These results suggest limiting the HI-RO definition to SHI, because it encompasses almost all medical complications of LCH. Future clinical trials might demonstrate that targeted therapy approaches would be better adapted for these patients, whereas MHI can be managed with classic therapies.

Myeloid differentiation primary response protein 88 (MYD88) is a key adaptor molecule in the signaling pathways of toll-like receptor and interleukin-1 receptor. A somatic mutation resulting in a leucine-to-proline change at position 265 of the MYD88 protein (MYD88 L265P) is one of the most prevalent oncogenic mutations found in patients with hematological malignancies. In this study, we used high-throughput screening to identify lasalocid A as a potent small molecule that selectively inhibited the viability of lymphoma cells expressing MYD88 L265P and the associated activation of NF-κB. Further investigations using CRISPR-CRISPR-associated protein 9 genetic screening, proteomics, and biochemical assays revealed that lasalocid A directly binds to the MYD88 L265P protein, enhancing its interaction with the ubiquitin ligase RNF5. This interaction promotes MYD88 degradation through the ubiquitin-dependent proteasomal pathway, specifically in lymphomas with the MYD88 L265P mutation. Lasalocid A exhibited strong antitumor efficacy in xenograft mouse models, induced disease remission in ibrutinib-resistant lymphomas, and showed synergistic activity with the B-cell lymphoma 2 inhibitor venetoclax. This study highlights the potential of inducing MYD88 L265P degradation using small molecules, offering promising strategies for treating lymphomas that harbor the MYD88 L265P mutation.

Abstract: The hematopoietic stem cell (HSC) niche in the bone marrow (BM) supports HSC function, fate and numbers [1]. Sympathetic fibres innervate the BM and are components of the hematopoietic stem and progenitor cell (HSPC) niche [2]. Neuropathy of the HSPC niche is present and essential for disease development in experimental models of JAK2 myeloproliferative neoplasms (MPN) and MLL-AF9 acute myeloid leukemia (AML), and it is present in the BM of human MPN and AML patients [3-6]. Neuropathy contributes to mutant HSC expansion and represents an effective therapeutic target to block disease progression in JAK2 MPN mice [3]. The sympathomimetic agonist mirabegron restored nestin cells and reduced reticulin fibrosis in MPN patients [7]. Here, we show that neuropathy of the HSPC niche emerges in two additional experimental models of hematological disease including pre-leukemic myelopoiesis driven by NRAS and lymphoma/lymphoblastic leukemia driven by p53 deletion. Neuropathy involves severe ultrastructural damage in NRAS mice and AML patients as shown by electron microscopy. When further reinforced chemically, neuropathy has a profound impact on the experimental NRAS mouse model, promoting myeloid bias, reducing HSPC numbers and inducing changes in the stem cell microenvironment that include reduced numbers of mesenchymal stromal cells (MSC) and increased presence of morphologically abnormal blood vessels in BM. Together, BM neuropathy is a prevalent factor in hematopoietic malignancies that involves important degradation of sympathetic fibres and contributes to disease in a different manner depending on the driver mutation. This should be taken in consideration in the clinic, given that chemotherapy induces neuropathy of the HSC niche [8] and it is the most frequent first line treatment for AML, acute lymphoblastic leukemia and MPN patients.

Cullin-5 (Cul5) coordinates the assembly of cullin-RING-E3 ubiquitin ligase complexes that include the suppressors of cytokine signaling (SOCS)-box-containing proteins. The SOCS-box proteins function to recruit specific substrates to the complex for ubiquitination and degradation. In hematopoiesis, SOCS-box proteins are best known for regulating the actions of cytokines that utilize the JAK-STAT signaling pathway. However, the roles of most SOCS-box proteins have not been studied in physiological contexts and any actions for Cul5/SOCS complexes in signaling by several hematopoietic cytokines, including thrombopoietin (TPO) and interleukin-3 (IL-3), remain unknown. To define additional potential roles for Cul5/SOCS complexes, we generated mice lacking Cul5 in hematopoiesis; the absence of Cul5 is predicted to impair the SOCS-box-dependent actions of all proteins that contain this motif. Here, we show that Cul5-deficient mice develop excess megakaryopoiesis and thrombocytosis revealing a novel mechanism of negative regulation of megakaryocyte-committed stem cells, a distinct population within the hematopoietic stem cell pool that have been shown to rapidly, perhaps directly, generate megakaryocytes, and which are produced in excess in the absence of Cul5. Cul5-deficient megakaryopoiesis is distinctive in being largely independent of TPO/myeloproliferative leukemia protein and involves signaling via the β-common and/or β-IL-3 receptors, with evidence of deregulated responses to IL-3. This process is independent of the interferon-α/β receptor, previously implicated in inflammation-induced activation of stem-like megakaryocyte progenitor cells.

Bruton tyrosine kinase inhibitors (BTKis) are an established standard of care in chronic lymphocytic leukemia. The covalent BTKis ibrutinib, acalabrutinib, and zanubrutinib bind to BTK C481 and are all susceptible to the C481S mutation. Noncovalent BTKi, including pirtobrutinib, overcome C481S resistance but are associated with multiple variant (non-C481) BTK mutations, including those associated with resistance to acalabrutinib and zanubrutinib (T474 codon and L528W mutations). We review the current knowledge on variant BTK mutations, discuss their clinical implications, and consider their impact on clinical trials.

Not available.

No abstract available