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Arber, Daniel A.; Orazi, Attilio
doi: 10.1002/ajh.27656pmid: 40056065
With the recent publication of new classification systems of hematopoietic neoplasms, understanding how recognition of disease entities has occurred over time and the subsequent development of formal disease classifications is of importance. This review focuses on the early recognition of myeloid disorders, especially chronic myeloid disorders, and how clinical observations became associated with specific cytologic, histologic, immunophenotypic, and eventually genetic features. This combined approach to disease classification is of particular importance in the evaluation of chronic myeloid neoplasms and has resulted in the definition of clinicopathologic disease entities that allow for more customized treatment approaches. The constant incorporation of ever‐increasing information related to these disorders illustrates that disease classification is a constantly evolving process that requires constant updates as we strive to better understand the disorders we diagnose and treat.
Gagelmann, Nico; Kröger, Nicolaus
doi: 10.1002/ajh.27660pmid: 40079242
Allogeneic hematopoietic stem‐cell transplantation (HCT) remains the only potentially curative therapy for patients with myelodysplastic neoplasms (MDS) and myelofibrosis (MF) and is the standard care for eligible patients with higher‐risk disease. Despite significant advancements, both diseases pose unique challenges due to their clinical and molecular heterogeneity, necessitating personalized approaches to patient selection, timing, and transplant management. For MDS, genomic profiling has revolutionized prognostic frameworks such as IPSS‐M, enabling tailored therapeutic decisions. In MF, driver mutations (e.g., JAK2, CALR, MPL) and additional high‐risk molecular markers provide critical insights into disease biology and transplant outcomes. Optimal timing of HCT is critical, and recent models might help personalize treatment approaches. Molecular measurable residual disease monitoring has demonstrated prognostic value in both diseases, guiding preemptive strategies to mitigate relapse risk. Harnessing molecular technologies, clinical expertise, patient‐centered decision‐making, and innovative pharmaceutical strategies offers an exciting opportunity to shape a transformative and curative treatment framework. Here, we provide a contemporary review on HCT for MDS and MF, highlighting up‐to‐date insights into disease biology, standard of care, and recommendations, as well as open avenues.
Loscocco, Giuseppe G.; Guglielmelli, Paola
doi: 10.1002/ajh.27658pmid: 40062529
Myelofibrosis (MF) is a myeloproliferative neoplasm that is accompanied by driver JAK2, CALR, or MPL mutations in more than 90% of cases, leading to constitutive activation of the JAK–STAT pathway. MF is a multifaceted disease characterized by trilineage myeloid proliferation with prominent megakaryocyte atypia and bone marrow fibrosis, as well as splenomegaly, constitutional symptoms, ineffective erythropoiesis, extramedullary hematopoiesis, and a risk of leukemic progression and shortened survival. Therapy can range from observation alone in lower‐risk and asymptomatic patients to allogeneic hematopoietic stem cell transplantation, which is the only potentially curative treatment capable of prolonging survival, although burdened by significant morbidity and mortality. The discovery of the JAK2 V617F mutation prompted the development of JAK inhibitors (JAKi) including the first‐in‐class JAK1/JAK2 inhibitor ruxolitinib and subsequent approval of fedratinib, pacritinib, and momelotinib. The latter has shown erythropoietic benefits by suppressing hepcidin expression via activin A receptor type 1 (ACVR1) inhibition, as well as reducing splenomegaly and symptoms. However, the current JAKi behave as anti‐inflammatory drugs without a major impact on survival or disease progression. A better understanding of the genetics, mechanisms of fibrosis, cytopenia, and the role of inflammatory cytokines has led to the development of numerous therapeutic agents that target epigenetic regulation, signaling, telomerase, cell cycle, and apoptosis, nuclear export, and pro‐fibrotic cytokines. Selective JAK2 V617F inhibitors and targeting of mutant CALR by immunotherapy are the most intriguing and promising approaches. This review focuses on approved and experimental treatments for MF, highlighting their biological background.
Gangat, Naseema; Tefferi, Ayalew
doi: 10.1002/ajh.27659pmid: 40056069
Anemia in myeloid neoplasms is multifaceted, with heterogeneous pathogenetic mechanisms that include ineffective erythropoiesis, hepcidin‐induced iron‐restricted erythropoiesis, and abnormal inflammatory cytokine production. Current management of anemia is challenged by limited approved drugs that specifically treat anemia in myelofibrosis (MF) and myelodysplastic syndrome (MDS). Newer therapies target the transforming growth factor beta (TGF‐β)‐bone morphogenic protein/sons of mothers against decapentaplegic (BMP‐SMAD) signaling pathway, which plays a significant role in ineffective erythropoiesis (SMAD 2/3) and abnormal hepcidin production (SMAD 1/5/8). These include TGF‐β ligand traps (luspatercept, elritercept), activin A receptor type 1 (ACVR1)/activin receptor‐like kinase 2 (ALK2) inhibitors (momelotinib, zilurgisertib), and anti‐hemojuvelin antibody‐based therapies (DISC‐0974). Luspatercept and momelotinib are approved for anemia related to lower‐risk MDS and MF, respectively, and represent an important addition to the treatment armamentarium, along with imetelstat, a telomerase inhibitor, recently ratified for anemia in lower‐risk MDS. A promising strategy to overcome the limitations of existing anemia‐directed therapies includes the use of drug combinations with complementary mechanisms (luspatercept + erythropoiesis stimulating agents, luspatercept + momelotinib, DISC‐0974 + momelotinib), and harnessing the erythropoietic potential of sodium‐glucose co‐transporter‐2 inhibitors (SGLT‐2I). Future research should address the complex pathophysiology of anemia, standardize definitions for anemia with gender‐specified cutoffs, implement uniform erythroid response criteria, and consider early therapeutic intervention in clinical trials for anemia‐directed therapies.
Barbui, Tiziano; Stefano, Valerio De; Rossi, Elena; Ghirardi, Arianna; Carobbio, Alessandra; Loscocco, Giuseppe Gaetano; Condorelli, Annalisa; Guglielmelli, Paola
doi: 10.1002/ajh.27657pmid: 40062566
This paper explores emerging therapies in polycythemia vera and essential thrombocythemia, focusing on thrombosis as a driver of disease progression leading to myelofibrosis, blast phase, second cancers, and mortality. While the thrombosis rate in high‐risk patients has declined, it remains persistently high in low‐risk individuals, with most events being arterial. Inflammation driven by JAK2 V617F mutation plays a primary role in pathogenesis, and mounting evidence suggests arterial thrombosis itself can fuel a self‐sustaining cycle of inflammation, thereby accelerating hematologic and systemic complications. Early intervention with cytoreductive and anti‐inflammatory drugs may not only prevent incidental thrombosis but also disrupt this inflammatory circuit.
Shah, Mithun Vinod; Arber, Daniel A.; Hiwase, Devendra K.
doi: 10.1002/ajh.27655pmid: 40066944
Alterations in the tumor suppressor gene TP53 are common in human cancers and are associated with an aggressive nature. Approximately 8%–12% of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) harbor TP53 mutations (TP53 mut) and present immense challenges due to inherent chemoresistance and poor outcomes. As TP53 mut are more common in older individuals and those with secondary/therapy‐related myeloid neoplasms (MN), their incidence is expected to increase with an aging population and rising proportion of cancer survivors. Treatments used for other MN—intensive chemotherapy, hypomethylating agents, and the BCL‐2 inhibitor venetoclax—do not improve the survival of TP53 mut MN patients meaningfully. Additionally, further development of many promising agents has been discontinued, highlighting the challenges. Widespread acknowledgment of these problems led to the recognition of TP53 mut MN as a distinct entity in the 5th edition of the World Health Organization and International Consensus Classifications. However, critical discrepancies between the two classifications may lead to under‐ or overestimation of the prognostic risk. Here, we review recent advances in the biology, diagnosis, and treatment of TP53 mut MN. The development of TP53 mut MN is positioned at the intersection of age, hereditary predisposition, and anti‐cancer therapies. Precursor TP53 mut clones can be detected years prior to the eventual leukemic transformation—raising the possibility of early intervention. We discuss the two classification systems and the bearing of the discrepancies between the two on timely and effective management. We provide novel evidence in the areas of discrepancies. Finally, we review the current therapeutic landscape and the obvious limitations of the currently used therapies.
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