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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 -
Virchows Archiv : An International... Jan 2023The myelodysplastic syndrome/myeloproliferative neoplasms (MDS/MPN) category includes a heterogeneous group of diseases characterized by the co-occurrence of clinical... (Review)
Review
The myelodysplastic syndrome/myeloproliferative neoplasms (MDS/MPN) category includes a heterogeneous group of diseases characterized by the co-occurrence of clinical and pathologic features of both myelodysplastic and myeloproliferative neoplasms. The recently published International Consensus Classification of myeloid neoplasms revised the entities included in the MDS/MPN category as well as criteria for their diagnosis. In addition to the presence of one or more increased peripheral blood cell counts as evidence of myeloproliferative features, concomitant cytopenia as evidence of ineffective hematopoiesis is now an explicit requirement to diagnose the diseases included in this category. The increasing availability of modern gene sequencing has allowed better understanding of the biologic characteristics of these myeloid neoplasms. The presence of specific mutations in the appropriate clinicopathologic context is now included in the diagnostic criteria for some of MDS/MPN entities. In this review, we highlight what has changed in the diagnostic criteria of MDS/MPN from the WHO 2016 classification while providing practical guidance in diagnosing these diseases.
Topics: Humans; Neoplasms; Myelodysplastic-Myeloproliferative Diseases; Myeloproliferative Disorders; Mutation
PubMed: 36469102
DOI: 10.1007/s00428-022-03465-7 -
American Journal of Hematology Apr 2024Essential thrombocythemia is a Janus kinase 2 (JAK2) mutation-prevalent myeloproliferative neoplasm characterized by clonal thrombocytosis; clinical course is often... (Review)
Review
OVERVIEW
Essential thrombocythemia is a Janus kinase 2 (JAK2) mutation-prevalent myeloproliferative neoplasm characterized by clonal thrombocytosis; clinical course is often indolent but might be interrupted by thrombotic or hemorrhagic complications, microcirculatory symptoms (e.g., headaches, lightheadedness, and acral paresthesias), and, less frequently, by disease transformation into myelofibrosis (MF) or acute myeloid leukemia.
DIAGNOSIS
In addition to thrombocytosis (platelets ≥450 × 10 /L), formal diagnosis requires the exclusion of other myeloid neoplasms, including prefibrotic MF, polycythemia vera, chronic myeloid leukemia, and myelodysplastic syndromes with ring sideroblasts and thrombocytosis. Bone marrow morphology typically shows increased number of mature-appearing megakaryocytes distributed in loose clusters.
GENETICS
Approximately 80% of patients express myeloproliferative neoplasm driver mutations (JAK2, CALR, MPL), in a mutually exclusive manner; in addition, about 50% harbor other mutations, the most frequent being TET2 (9%-11%), ASXL1 (7%-20%), DNMT3A (7%), and SF3B1 (5%). Abnormal karyotype is seen in <10% of patients and includes +9/20q-/13q-.
SURVIVAL AND PROGNOSIS
Life expectancy is less than that of the control population. Median survival is approximately 18 years but exceeds >35 years in younger patients. The triple A survival risk model, based on Age, Absolute neutrophil count, and Absolute lymphocyte count, effectively delineates high-, intermediate-1-, intermediate-2-, and low-risk disease with corresponding median survivals of 8, 14, 21, and 47 years.
RISK FACTORS FOR THROMBOSIS
Four risk categories are considered: very low (age ≤60 years, no thrombosis history, JAK2 wild-type), low (same as very low but JAK2 mutation present), intermediate (same as low but age >60 years), and high (thrombosis history or age >60 years with JAK2 mutation).
MUTATIONS AND PROGNOSIS
MPL and CALR-1 mutations have been associated with increased risk of MF transformation; spliceosome with inferior overall and MF-free survival; TP53 with leukemic transformation, and JAK2V617F with thrombosis. Leukemic transformation rate at 10 years is <1% but might be higher in JAK2-mutated patients with extreme thrombocytosis and those with abnormal karyotype.
TREATMENT
The main goal of therapy is to prevent thrombosis. In this regard, once-daily low-dose aspirin is advised for all patients and twice daily for low-risk disease. Cytoreductive therapy is advised for high-risk and optional for intermediate-risk disease. First-line cytoreductive drugs of choice are hydroxyurea and pegylated interferon-α and second-line busulfan.
ADDITIONAL CONTENT
The current review includes specific treatment strategies in the context of extreme thrombocytosis, pregnancy, splanchnic vein thrombosis, perioperative care, and post-essential thrombocythemia MF, as well as new investigational drugs.
Topics: Humans; Middle Aged; Thrombocythemia, Essential; Microcirculation; Polycythemia Vera; Thrombocytosis; Thrombosis; Myeloproliferative Disorders; Primary Myelofibrosis; Mutation; Risk Assessment; Abnormal Karyotype; Janus Kinase 2; Calreticulin
PubMed: 38269572
DOI: 10.1002/ajh.27216 -
Blood Jul 2020Secondary acute myeloid leukemias (AMLs) evolving from an antecedent myeloproliferative neoplasm (MPN) are characterized by a unique set of cytogenetic and molecular... (Review)
Review
Secondary acute myeloid leukemias (AMLs) evolving from an antecedent myeloproliferative neoplasm (MPN) are characterized by a unique set of cytogenetic and molecular features distinct from de novo AML. Given the high frequency of poor-risk cytogenetic and molecular features, malignant clones are frequently insensitive to traditional AML chemotherapeutic agents. Allogeneic stem cell transplant, the only treatment modality shown to have any beneficial long-term outcome, is often not possible given the advanced age of patients at time of diagnosis and frequent presence of competing comorbidities. Even in this setting, relapse rates remain high. As a result, outcomes are generally poor and there remains a significant unmet need for novel therapeutic strategies. Although advances in cancer genomics have dramatically enhanced our understanding of the molecular events governing clonal evolution in MPNs, the cell-intrinsic and -extrinsic mechanisms driving leukemic transformation at this level remain poorly understood. Here, we review known risk factors for the development of leukemic transformation in MPNs, recent progress made in our understanding of the molecular features associated with leukemic transformation, current treatment strategies, and emerging therapeutic options for this high-risk myeloid malignancy.
Topics: Abnormal Karyotype; Allografts; Antineoplastic Agents; Cell Transformation, Neoplastic; Chromosome Aberrations; Clonal Evolution; Combined Modality Therapy; Comorbidity; Disease Progression; Drug Resistance, Neoplasm; Drugs, Investigational; Genes, Neoplasm; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Models, Biological; Mutation; Myeloproliferative Disorders; Neoplasm Proteins; Recurrence; Risk Factors; Single-Cell Analysis; Therapies, Investigational
PubMed: 32430500
DOI: 10.1182/blood.2019000943 -
Virchows Archiv : An International... Jan 2023This review addresses changes and updates in eosinophilic disorders under the International Consensus Classification (ICC). The previous category of myeloid/lymphoid... (Review)
Review
This review addresses changes and updates in eosinophilic disorders under the International Consensus Classification (ICC). The previous category of myeloid/lymphoid neoplasm with eosinophilia (M/LN-eo) and a specific gene rearrangement is changed to M/LN-eo with tyrosine kinase gene fusions to reflect the underlying genetic lesions. Two new members, M/LN-eo with ETV6::ABL1 fusion and M/LN-eo with various FLT3 fusions, have been added to the category; and M/LN-eo with PCM1::JAK2 and its genetic variants ETV6::JAK2 and BCR::JAK2 are recognized as a formal entity from their former provisional status. The updated understanding of the clinical and molecular genetic features of PDGFRA, PDGFRB and FGFR1 neoplasms is summarized. Clear guidance as to how to distinguish these fusion gene-associated disorders from the overlapping entities of Ph-like B-acute lymphoblastic leukemia (ALL), de novo T-ALL, and systemic mastocytosis is provided. Bone marrow morphology now constitutes one of the diagnostic criteria of chronic eosinophilic leukemia, NOS (CEL, NOS), and idiopathic hypereosinophilia/hypereosinophilic syndrome (HE/HES), facilitating the separation of a true myeloid neoplasm with characteristic eosinophilic proliferation from those of unknown etiology and not attributable to a myeloid neoplasm.
Topics: Humans; Hypereosinophilic Syndrome; Leukemia; Myeloproliferative Disorders; Receptor, Platelet-Derived Growth Factor beta; Bone Marrow; Oncogene Proteins, Fusion
PubMed: 36068374
DOI: 10.1007/s00428-022-03402-8 -
Acta Haematologica 2021Myeloproliferative neoplasms (MPNs) can transform into blast phase MPN (leukemic transformation; MPN-BP), typically via accelerated phase MPN (MPN-AP), in ∼20-25% of... (Review)
Review
BACKGROUND
Myeloproliferative neoplasms (MPNs) can transform into blast phase MPN (leukemic transformation; MPN-BP), typically via accelerated phase MPN (MPN-AP), in ∼20-25% of the cases. MPN-AP and MPN-BP are characterized by 10-19% and ≥20% blasts, respectively. MPN-AP/BP portend a dismal prognosis with no established conventional treatment. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the sole modality associated with long-term survival.
SUMMARY
MPN-AP/BP has a markedly different mutational profile from de novo acute myeloid leukemia (AML). In MPN-AP/BP, TP53 and IDH1/2 are more frequent, whereas FLT3 and DNMT3A are rare. Higher incidence of leukemic transformation has been associated with the most aggressive MPN subtype, myelofibrosis (MF); other risk factors for leukemic transformation include rising blast counts above 3-5%, advanced age, severe anemia, thrombocytopenia, leukocytosis, increasing bone marrow fibrosis, type 1 CALR-unmutated status, lack of driver mutations (negative for JAK2, CALR, or MPL genes), adverse cytogenetics, and acquisition of ≥2 high-molecular risk mutations (ASXL1, EZH2, IDH1/2, SRSF2, and U2AF1Q157). The aforementioned factors have been incorporated in several novel prognostic scoring systems for MF. Currently, elderly/unfit patients with MPN-AP/BP are treated with hypomethylating agents with/without ruxolitinib; these regimens appear to confer comparable benefit to intensive chemotherapy but with lower toxicity. Retrospective studies in patients who acquired actionable mutations during MPN-AP/BP showed positive outcomes with targeted AML treatments, such as IDH1/2 inhibitors, and require further evaluation in clinical trials. Key Messages: Therapy for MPN-AP patients represents an unmet medical need. MF patients, in particular, should be appropriately stratified regarding their prognosis and the risk for transformation. Higher-risk patients should be monitored regularly and treated prior to progression to MPN-BP. MPN-AP patients may be treated with hypomethylating agents alone or in combination with ruxolitinib; also, patients can be provided with the option to enroll in rationally designed clinical trials exploring combination regimens, including novel targeted drugs, with an ultimate goal to transition to transplant.
Topics: Allografts; Blast Crisis; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Mutation; Myeloproliferative Disorders; Neoplasm Proteins
PubMed: 33882481
DOI: 10.1159/000512929 -
Journal of Hematology & Oncology Jun 2021The Philadelphia negative myeloproliferative neoplasms (MPN) compromise a heterogeneous group of clonal myeloid stem cell disorders comprising polycythaemia vera,... (Review)
Review
The Philadelphia negative myeloproliferative neoplasms (MPN) compromise a heterogeneous group of clonal myeloid stem cell disorders comprising polycythaemia vera, essential thrombocythaemia and primary myelofibrosis. Despite distinct clinical entities, these disorders are linked by morphological similarities and propensity to thrombotic complications and leukaemic transformation. Current therapeutic options are limited in disease-modifying activity with a focus on the prevention of thrombus formation. Constitutive activation of the JAK/STAT signalling pathway is a hallmark of pathogenesis across the disease spectrum with driving mutations in JAK2, CALR and MPL identified in the majority of patients. Co-occurring somatic mutations in genes associated with epigenetic regulation, transcriptional control and splicing of RNA are variably but recurrently identified across the MPN disease spectrum, whilst epigenetic contributors to disease are increasingly recognised. The prognostic implications of one MPN diagnosis may significantly limit life expectancy, whilst another may have limited impact depending on the disease phenotype, genotype and other external factors. The genetic and clinical similarities and differences in these disorders have provided a unique opportunity to understand the relative contributions to MPN, myeloid and cancer biology generally from specific genetic and epigenetic changes. This review provides a comprehensive overview of the molecular pathophysiology of MPN exploring the role of driver mutations, co-occurring mutations, dysregulation of intrinsic cell signalling, epigenetic regulation and genetic predisposing factors highlighting important areas for future consideration.
Topics: Animals; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Genetic Predisposition to Disease; Humans; Mutation; Myeloproliferative Disorders
PubMed: 34193229
DOI: 10.1186/s13045-021-01116-z -
Blood Aug 2022Germline DDX41 variants are the most common mutations predisposing to acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) in adults, but the causal variant (CV)...
Germline DDX41 variants are the most common mutations predisposing to acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) in adults, but the causal variant (CV) landscape and clinical spectrum of hematologic malignancies (HMs) remain unexplored. Here, we analyzed the genomic profiles of 176 patients with HM carrying 82 distinct presumably germline DDX41 variants among a group of 9821 unrelated patients. Using our proposed DDX41-specific variant classification, we identified features distinguishing 116 patients with HM with CV from 60 patients with HM with variant of uncertain significance (VUS): an older age (median 69 years), male predominance (74% in CV vs 60% in VUS, P = .03), frequent concurrent somatic DDX41 variants (79% in CV vs 5% in VUS, P < .0001), a lower somatic mutation burden (1.4 ± 0.1 in CV vs 2.9 ± 0.04 in VUS, P = .012), near exclusion of canonical recurrent genetic abnormalities including mutations in NPM1, CEBPA, and FLT3 in AML, and favorable overall survival (OS) in patients with AML/MDS. This superior OS was determined independent of blast count, abnormal karyotypes, and concurrent variants, including TP53 in patients with AML/MDS, regardless of patient's sex, age, or specific germline CV, suggesting that germline DDX41 variants define a distinct clinical entity. Furthermore, unrelated patients with myeloproliferative neoplasm and B-cell lymphoma were linked by DDX41 CV, thus expanding the known disease spectrum. This study outlines the CV landscape, expands the phenotypic spectrum in unrelated DDX41-mutated patients, and underscores the urgent need for gene-specific diagnostic and clinical management guidelines.
Topics: Aged; DEAD-box RNA Helicases; Female; Germ Cells; Germ-Line Mutation; Humans; Leukemia, Myeloid, Acute; Male; Mutation; Myelodysplastic Syndromes; Myeloproliferative Disorders
PubMed: 35671390
DOI: 10.1182/blood.2021015135 -
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 -
Seminars in Diagnostic Pathology May 2023Myelodysplastic/ Myeloproliferative neoplasms (MDS/MPN) demonstrate overlapping pathologic and molecular features of myelodysplastic (MDS) and myeloproliferative (MPN)... (Review)
Review
Myelodysplastic/ Myeloproliferative neoplasms (MDS/MPN) demonstrate overlapping pathologic and molecular features of myelodysplastic (MDS) and myeloproliferative (MPN) neoplasms. Diagnosis is difficult based on morphology alone, requiring exclusion of various non-neoplastic causes for CBC abnormalities and morphologic findings and other myeloid neoplasms. Identifying a clonal abnormality by cytogenetics or molecular studies has vastly improved our ability to diagnose MDS/MPN and has been incorporated in the different classification schemas. Currently two separate classification systems are in use- The 5 edition WHO and international consensus classification. The two competing classifications emphasize genetic work-up and are similar on many levels; however, they do introduce diagnostic dilemma when diagnosing certain entities such as chronic myelomonocytic leukemia in the presence of NPM1 mutations. The genetic profile overlaps among different subentities; however, the combination and the incidence of mutations; together with the clinical features and morphology helps in further subclassification. In this review, we discuss the advances in molecular characterization of MDS/MPN. We attempt to summarize the differences between the various classification schemes, and highlight the changes made in the diagnostic criteria.
Topics: Humans; Myelodysplastic-Myeloproliferative Diseases; Myeloproliferative Disorders; Mutation; Genomics; Neoplasms
PubMed: 37105794
DOI: 10.1053/j.semdp.2023.04.005