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Journal of Clinical Oncology : Official... Jul 2023Polycythemia vera (PV) is characterized by JAK/STAT activation, thrombotic/hemorrhagic events, systemic symptoms, and disease transformation. In high-risk PV,... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Polycythemia vera (PV) is characterized by JAK/STAT activation, thrombotic/hemorrhagic events, systemic symptoms, and disease transformation. In high-risk PV, ruxolitinib controls blood counts and improves symptoms.
PATIENTS AND METHODS
MAJIC-PV is a randomized phase II trial of ruxolitinib versus best available therapy (BAT) in patients resistant/intolerant to hydroxycarbamide (HC-INT/RES). Primary outcome was complete response (CR) within 1 year. Secondary outcomes included duration of response, event-free survival (EFS), symptom, and molecular response.
RESULTS
One hundred eighty patients were randomly assigned. CR was achieved in 40 (43%) patients on ruxolitinib versus 23 (26%) on BAT (odds ratio, 2.12; 90% CI, 1.25 to 3.60; = .02). Duration of CR was superior for ruxolitinib (hazard ratio [HR], 0.38; 95% CI, 0.24 to 0.61; < .001). Symptom responses were better with ruxolitinib and durable. EFS (major thrombosis, hemorrhage, transformation, and death) was superior for patients attaining CR within 1 year (HR, 0.41; 95% CI, 0.21 to 0.78; = .01); and those on ruxolitinib (HR, 0.58; 95% CI, 0.35 to 0.94; = .03). Serial analysis of V617F variant allele fraction revealed molecular response was more frequent with ruxolitinib and was associated with improved outcomes (progression-free survival [PFS] = .001, EFS = .001, overall survival = .01) and clearance of V617F stem/progenitor cells. 1 mutations predicted for adverse EFS (HR, 3.02; 95% CI, 1.47 to 6.17; = .003). The safety profile of ruxolitinib was as previously reported.
CONCLUSION
The MAJIC-PV study demonstrates ruxolitinib treatment benefits HC-INT/RES PV patients with superior CR, and EFS as well as molecular response; importantly also demonstrating for the first time, to our knowledge, that molecular response is linked to EFS, PFS, and OS.
Topics: Humans; Polycythemia Vera; Treatment Outcome; Hydroxyurea; Nitriles; Hemorrhage
PubMed: 37126762
DOI: 10.1200/JCO.22.01935 -
Blood Cancer Journal Jul 2023Leukemic transformation in myeloproliferative neoplasms (MPN), also referred to as "blast-phase MPN", is the most feared disease complication, with incidence estimates... (Review)
Review
Leukemic transformation in myeloproliferative neoplasms (MPN), also referred to as "blast-phase MPN", is the most feared disease complication, with incidence estimates of 1-4% for essential thrombocythemia, 3-7% for polycythemia vera, and 9-13% for primary myelofibrosis. Diagnosis of MPN-BP requires the presence of ≥20% circulating or bone marrow blasts; a lower level of excess blasts (10-19%) constitutes "accelerated phase" disease (MPN-AP). Neither "intensive" nor "less intensive" chemotherapy, by itself, secures long-term survival in MPN-BP. Large-scale retrospective series have consistently shown a dismal prognosis in MPN-BP, with 1- and 3-year survival estimates of <20% and <5%, respectively. Allogeneic hematopoietic stem cell transplant (AHSCT) offers the possibility of a >30% 3-year survival rate and should be pursued, ideally, while the patient is still in chronic phase disease. The value of pre-transplant bridging chemotherapy is uncertain in MPN-AP while it is advised in MPN-BP; in this regard, we currently favor combination chemotherapy with venetoclax (Ven) and hypomethylating agent (HMA); response is more likely in the absence of complex/monosomal karyotype and presence of TET2 mutation. Furthermore, in the presence of an IDH mutation, the use of IDH inhibitors, either alone or in combination with Ven-HMA, can be considered. Pre-transplant clearance of excess blasts is desired but not mandated; in this regard, additional salvage chemotherapy is more likely to compromise transplant eligibility rather than improve post-transplant survival. Controlled studies are needed to determine the optimal pre- and post-transplant measures that target transplant-associated morbidity and post-transplant relapse.
Topics: Humans; Blast Crisis; Retrospective Studies; Neoplasm Recurrence, Local; Myeloproliferative Disorders; Polycythemia Vera; Mutation; Chronic Disease
PubMed: 37460550
DOI: 10.1038/s41408-023-00878-8 -
Cancers Jun 2023The myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN) category comprises a varied group of myeloid neoplastic diseases characterized by clinical and... (Review)
Review
The myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN) category comprises a varied group of myeloid neoplastic diseases characterized by clinical and pathologic overlapping features of both myelodysplastic and myeloproliferative neoplasms. For these reasons, these tumors are challenging in terms of diagnosis. The recent World Health Organization (WHO) 2022 classification and the International Consensus Classification (ICC) made changes in the classification of MDS/MPN compared to the previous 2016 WHO classification and improved the diagnostic criteria of these entities. The aim of this review is to describe the main entities reported in the more recent classifications, focusing on chronic myelomonocytic leukemia (CMML), MDS/MPN with neutrophilia (or atypical CML [aCML]), and MDS/MPN with mutation and thrombocytosis/MDS/MPN with ring sideroblasts and thrombocytosis. A particular emphasis is given to the differential diagnosis and analysis of subtle divergences and semantic differences between the WHO classification and the ICC for these entities.
PubMed: 37370785
DOI: 10.3390/cancers15123175 -
Annals of Hematology Aug 2023Myeloid sarcoma (MS) is a distinct entity among myeloid neoplasms defined as a tumour mass of myeloid blasts occurring at an anatomical site other than the bone marrow,... (Review)
Review
Myeloid sarcoma (MS) is a distinct entity among myeloid neoplasms defined as a tumour mass of myeloid blasts occurring at an anatomical site other than the bone marrow, in most cases concomitant with acute myeloid leukaemia (AML), rarely without bone marrow involvement. MS may also represent the blast phase of chronic myeloproliferative neoplasms (MPN) and myelodysplastic syndromes (MDS). However, the clinical and molecular heterogeneity of AML, as highlighted by the 2022 World Health Organization (WHO) and International Consensus (ICC) classifications, indirectly define MS more as a set of heterogeneous and proteiform diseases, rather than a homogeneous single entity. Diagnosis is challenging and relies mainly on histopathology, immunohistochemistry, and imaging. Molecular and cytogenetic analysis of MS tissue, particularly in isolated cases, should be performed to refine the diagnosis, and thus assign prognosis guiding treatment decisions. If feasible, systemic therapies used in AML remission induction should be employed, even in isolated MS. Role and type of consolidation therapy are not univocally acknowledged, and systemic therapies, radiotherapy, or allogeneic hematopoietic stem cell transplantation (allo-HSCT) should be considered. In the present review, we discuss recent information on MS, focusing on diagnosis, molecular findings, and treatments also considering targetable mutations by recently approved AML drugs.
Topics: Humans; Sarcoma, Myeloid; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Myeloproliferative Disorders; Hematopoietic Stem Cell Transplantation
PubMed: 37286874
DOI: 10.1007/s00277-023-05288-1 -
Pathobiology : Journal of... 2024Disease progression in myelodysplastic syndromes (MDS), myelodysplastic-myeloproliferative neoplasms (MDS/MPN), and myeloproliferative neoplasms (MPN), altogether... (Review)
Review
Disease progression in myelodysplastic syndromes (MDS), myelodysplastic-myeloproliferative neoplasms (MDS/MPN), and myeloproliferative neoplasms (MPN), altogether referred to as myeloid neoplasms (MN), is a major source of mortality. Apart from transformation to acute myeloid leukemia, the clinical progression of MN is mostly due to the overgrowth of pre-existing hematopoiesis by the MN without an additional transforming event. Still, MN may evolve along other recurrent yet less well-known scenarios: (1) acquisition of MPN features in MDS or (2) MDS features in MPN, (3) progressive myelofibrosis (MF), (4) acquisition of chronic myelomonocytic leukemia (CMML)-like characteristics in MPN or MDS, (5) development of myeloid sarcoma (MS), (6) lymphoblastic (LB) transformation, (7) histiocytic/dendritic outgrowths. These MN-transformation types exhibit a propensity for extramedullary sites (e.g., skin, lymph nodes, liver), highlighting the importance of lesional biopsies in diagnosis. Gain of distinct mutations/mutational patterns seems to be causative or at least accompanying several of the above-mentioned scenarios. MDS developing MPN features often acquire MPN driver mutations (usually JAK2), and MF. Conversely, MPN gaining MDS features develop, e.g., ASXL1, IDH1/2, SF3B1, and/or SRSF2 mutations. Mutations of RAS-genes are often detected in CMML-like MPN progression. MS ex MN is characterized by complex karyotypes, FLT3 and/or NPM1 mutations, and often monoblastic phenotype. MN with LB transformation is associated with secondary genetic events linked to lineage reprogramming leading to the deregulation of ETV6, IKZF1, PAX5, PU.1, and RUNX1. Finally, the acquisition of MAPK-pathway gene mutations may shape MN toward histiocytic differentiation. Awareness of all these less well-known MN-progression types is important to guide optimal individual patient management.
Topics: Humans; Granulocyte Precursor Cells; Myeloproliferative Disorders; Myelodysplastic Syndromes; Mutation; Myelodysplastic-Myeloproliferative Diseases; Leukemia, Myeloid, Acute
PubMed: 37232015
DOI: 10.1159/000530940 -
Annals of Laboratory Medicine Sep 2023The fifth edition of the WHO classification (2022 WHO) and the International Consensus Classification (2022 ICC) of myeloid neoplasms have been recently published. We...
Implications of the 5 Edition of the World Health Organization Classification and International Consensus Classification of Myeloid Neoplasm in Myelodysplastic Syndrome With Excess Blasts and Acute Myeloid Leukemia.
The fifth edition of the WHO classification (2022 WHO) and the International Consensus Classification (2022 ICC) of myeloid neoplasms have been recently published. We reviewed the changes in the diagnosis distribution in patients with MDS with excess blasts (MDS-EB) or AML using both classifications. Forty-seven patients previously diagnosed as having AML or MDS-EB with available mutation analysis data, including targeted next-generation and RNA-sequencing data, were included. We reclassified 15 (31.9%) and 27 (57.4%) patients based on the 2022 WHO and 2022 ICC, respectively. One patient was reclassified as having a translocation categorized as a rare recurring translocation in both classifications. Reclassification was mostly due to the addition of mutation-based diagnostic criteria (i.e., AML, myelodysplasia-related) or a new entity associated with mutation. In both classifications, MDS diagnosis required the confirmation of multi-hit alterations. Among 14 patients with mutations, 11 harbored multi-hit alterations, including four with mutations and loss of heterozygosity. Adverse prognosis was associated with multi-hit alterations (=0.009) in patients with MDS-EB, emphasizing the importance of detecting the mutations at diagnosis. The implementation of these classifications may lead to the identification of different subtypes from previously heterogeneous diagnostic categories based on genetic characteristics.
Topics: Humans; Consensus; Myelodysplastic Syndromes; Leukemia, Myeloid, Acute; Myeloproliferative Disorders; Mutation; World Health Organization
PubMed: 37080752
DOI: 10.3343/alm.2023.43.5.503 -
Cancer Research Sep 2023Identifying mechanisms underlying relapse is a major clinical issue for effective cancer treatment. The emerging understanding of the importance of metastasis in...
UNLABELLED
Identifying mechanisms underlying relapse is a major clinical issue for effective cancer treatment. The emerging understanding of the importance of metastasis in hematologic malignancies suggests that it could also play a role in drug resistance and relapse in acute myeloid leukemia (AML). In a cohort of 1,273 AML patients, we uncovered that the multifunctional scavenger receptor CD36 was positively associated with extramedullary dissemination of leukemic blasts, increased risk of relapse after intensive chemotherapy, and reduced event-free and overall survival. CD36 was dispensable for lipid uptake but fostered blast migration through its binding with thrombospondin-1. CD36-expressing blasts, which were largely enriched after chemotherapy, exhibited a senescent-like phenotype while maintaining their migratory ability. In xenograft mouse models, CD36 inhibition reduced metastasis of blasts and prolonged survival of chemotherapy-treated mice. These results pave the way for the development of CD36 as an independent marker of poor prognosis in AML patients and a promising actionable target to improve the outcome of patients.
SIGNIFICANCE
CD36 promotes blast migration and extramedullary disease in acute myeloid leukemia and represents a critical target that can be exploited for clinical prognosis and patient treatment.
Topics: Humans; Animals; Mice; Leukemia, Myeloid, Acute; Treatment Outcome; Prognosis; Recurrence; Blast Crisis; Chronic Disease
PubMed: 37327406
DOI: 10.1158/0008-5472.CAN-22-3682 -
Leukemia Nov 2023From the laboratory perspective, effective management of patients with chronic myeloid leukemia (CML) requires accurate diagnosis, assessment of prognostic markers,... (Review)
Review
From the laboratory perspective, effective management of patients with chronic myeloid leukemia (CML) requires accurate diagnosis, assessment of prognostic markers, sequential assessment of levels of residual disease and investigation of possible reasons for resistance, relapse or progression. Our scientific and clinical knowledge underpinning these requirements continues to evolve, as do laboratory methods and technologies. The European LeukemiaNet convened an expert panel to critically consider the current status of genetic laboratory approaches to help diagnose and manage CML patients. Our recommendations focus on current best practice and highlight the strengths and pitfalls of commonly used laboratory tests.
Topics: Humans; Protein Kinase Inhibitors; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Recurrence
PubMed: 37794101
DOI: 10.1038/s41375-023-02048-y -
Blood Advances Jul 2023Momelotinib is the first inhibitor of Janus kinase 1 (JAK1) and JAK2 shown to also inhibit activin A receptor type 1 (ACVR1), a key regulator of iron homeostasis, and...
Momelotinib is the first inhibitor of Janus kinase 1 (JAK1) and JAK2 shown to also inhibit activin A receptor type 1 (ACVR1), a key regulator of iron homeostasis, and has demonstrated improvements in splenomegaly, constitutional symptoms, and anemia in myelofibrosis (MF). This long-term analysis pooled data from 3 randomized phase 3 studies of momelotinib (MOMENTUM, SIMPLIFY-1, and SIMPLIFY-2), representing MF disease from early (JAK inhibitor-naive) to late (JAK inhibitor-experienced) stages. Patients in the control arms (danazol in MOMENTUM, ruxolitinib in SIMPLIFY-1, and best available therapy in SIMPLIFY-2) could cross over to receive momelotinib at the end of the 24-week randomized period, and all patients could continue momelotinib treatment after the completion of these studies via an extended access protocol (XAP). Across these studies, 725 patients with MF received momelotinib; 12% remained on therapy for ≥5 years, with a median treatment exposure of 11.3 months (range, 0.1-90.4 months). The most common nonhematologic treatment-emergent adverse event (AE) occurring in ≥20% of patients was diarrhea (any grade, 27% and grade ≥3, 3%). Any-grade thrombocytopenia, anemia, and neutropenia occurred in 25%, 23%, and 7% of patients, respectively. The most common reason for momelotinib discontinuation was thrombocytopenia (4% discontinuation rate). The incidence of AEs of clinical importance (eg, infections, malignant transformation, peripheral neuropathy, and hemorrhage) did not increase over time. This analysis of one of the largest randomized trial databases for a JAK inhibitor to date in MF demonstrated a consistent safety profile of momelotinib without long-term or cumulative toxicity. These trials were registered at www.clinicaltrials.gov as: MOMENTUM (#NCT04173494), SIMPLIFY-1 (#NCT01969838), SIMPLIFY-2 (#NCT02101268), and XAP (#NCT03441113).
Topics: Humans; Primary Myelofibrosis; Janus Kinase Inhibitors; Protein Kinase Inhibitors; Randomized Controlled Trials as Topic; Anemia; Thrombocytopenia
PubMed: 37042865
DOI: 10.1182/bloodadvances.2022009311