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Holl K, Chatain N, Krapp S, Baumeister J, Maié T, Schmitz S, Scheufen A, Brock N, Koschmieder S, Moreno-Andrés D. Calreticulin and JAK2V617F driver mutations induce distinct mitotic defects in myeloproliferative neoplasms. Sci Rep 2024; 14:2810. [PMID: 38308077 PMCID: PMC10837458 DOI: 10.1038/s41598-024-53240-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Accepted: 01/30/2024] [Indexed: 02/04/2024] Open
Abstract
Myeloproliferative neoplasms (MPNs) encompass a diverse group of hematologic disorders driven by mutations in JAK2, CALR, or MPL. The prevailing working model explaining how these driver mutations induce different disease phenotypes is based on the decisive influence of the cellular microenvironment and the acquisition of additional mutations. Here, we report increased levels of chromatin segregation errors in hematopoietic cells stably expressing CALRdel52 or JAK2V617F mutations. Our investigations employing murine 32DMPL and human erythroleukemic TF-1MPL cells demonstrate a link between CALRdel52 or JAK2V617F expression and a compromised spindle assembly checkpoint (SAC), a phenomenon contributing to error-prone mitosis. This defective SAC is associated with imbalances in the recruitment of SAC factors to mitotic kinetochores upon CALRdel52 or JAK2V617F expression. We show that JAK2 mutant CD34 + MPN patient-derived cells exhibit reduced expression of the master mitotic regulators PLK1, aurora kinase B, and PP2A catalytic subunit. Furthermore, the expression profile of mitotic regulators in CD34 + patient-derived cells allows to faithfully distinguish patients from healthy controls, as well as to differentiate primary and secondary myelofibrosis from essential thrombocythemia and polycythemia vera. Altogether, our data suggest alterations in mitotic regulation as a potential driver in the pathogenesis in MPN.
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Affiliation(s)
- Kristin Holl
- Institute of Biochemistry and Molecular Cell Biology, Faculty of Medicine, RWTH Aachen University, Aachen, Germany
| | - Nicolas Chatain
- Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, Germany
- Center of Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Aachen, Germany
| | - Susanne Krapp
- Institute of Biochemistry and Molecular Cell Biology, Faculty of Medicine, RWTH Aachen University, Aachen, Germany
| | - Julian Baumeister
- Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, Germany
- Center of Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Aachen, Germany
| | - Tiago Maié
- Institute for Computational Genomics, Joint Research Center for Computational Biomedicine, Faculty of Medicine, RWTH Aachen University, Aachen, Germany
| | - Sarah Schmitz
- Institute of Biochemistry and Molecular Cell Biology, Faculty of Medicine, RWTH Aachen University, Aachen, Germany
| | - Anja Scheufen
- Institute of Biochemistry and Molecular Cell Biology, Faculty of Medicine, RWTH Aachen University, Aachen, Germany
| | - Nathalie Brock
- Institute of Biochemistry and Molecular Cell Biology, Faculty of Medicine, RWTH Aachen University, Aachen, Germany
| | - Steffen Koschmieder
- Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, Germany
- Center of Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Aachen, Germany
| | - Daniel Moreno-Andrés
- Institute of Biochemistry and Molecular Cell Biology, Faculty of Medicine, RWTH Aachen University, Aachen, Germany.
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Mora B, Passamonti F. Towards a Personalized Definition of Prognosis in Philadelphia-Negative Myeloproliferative Neoplasms. Curr Hematol Malig Rep 2022; 17:127-139. [PMID: 36048275 PMCID: PMC9499895 DOI: 10.1007/s11899-022-00672-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/22/2022] [Indexed: 11/29/2022]
Abstract
Purpose of Review Philadelphia-negative myeloproliferative neoplasms (MPNs) include polycythemia vera (PV), essential thrombocythemia (ET), prefibrotic (pre-), and overt-primary myelofibrosis (primary MF, PMF). PV and ET could evolve into secondary MF (SMF), whose early diagnosis relies on monitoring signs of possible progression. All MPNs have a risk of blast phase (BP), that is associated with a very dismal outcome. Overall survival (OS) is different among MPNs, and disease-specific prognostic scores should be applied for a correct clinical management. In this review, an overview of current prognostic scores in MPNs will be provided. Recent Findings The biological complexity of MPNs and its role on the trajectory of disease outcome have led to the design of integrated prognostic models that are nowadays of common use in PMF patients. As for PV and ET, splicing gene mutations could have a detrimental role, but with the limit of the not routinary recommended application of extensive molecular analysis in these diseases. SMF is recognized as a distinct entity compared to PMF, and OS estimates should be calculated by the MYSEC-PM (Myelofibrosis SECondary-prognostic model). Both in PMF and SMF, decisions as selection of patients potentially candidates to allogenic stem cell transplant or that could benefit from an early shift from standard treatment are based not only on conventional prognostic scores, but also on multivariable algorithms. Summary The expanding landscape of risk prediction for OS, evolution to BP, and SMF progression from PV/ET informs personalized approach to the management of patients affected by MPNs.
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Affiliation(s)
- Barbara Mora
- Hematology, Ospedale Di Circolo, A.S.S.T. Sette Laghi, Viale Borri 57, 21100, Varese, Italy.,Department of Medicine and Surgery, University of Insubria, Via Guicciardini 9, 21100, Varese, Italy
| | - Francesco Passamonti
- Hematology, Ospedale Di Circolo, A.S.S.T. Sette Laghi, Viale Borri 57, 21100, Varese, Italy. .,Department of Medicine and Surgery, University of Insubria, Via Guicciardini 9, 21100, Varese, Italy.
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3
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Yang C, Zhang Q, Tang X, Wang B, Guan M, Tang G, Wu Z. BRCA2 promoter hypermethylation as a biomarker for the leukemic transformation of myeloproliferative neoplasms. Epigenomics 2022; 14:391-403. [PMID: 35259923 DOI: 10.2217/epi-2022-0025] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Aim: To characterize the actionable biomarker for leukemic transformation (LT) of myeloproliferative neoplasms (MPNs) at the DNA damage repair promoter methylation level. Materials & methods: Bioinformatic analysis and experimental validation were performed to identify the MPNs-LT specific biomarker out of the promoter methylation of 236 DNA damage repair genes with GSE42042 dataset and an in-house cohort of 80 MPNs. Results: Hypermethylation of BRCA2 promoter was characterized as the JAK2 mutation-independent epigenetic marker for MPNs-LT and repressed mRNA and protein expression, leading to olaparib hypersensitivity in the leukemic cells from MPNs-LT. Conclusion: Expressional silence of BRCA2 by promoter methylation compels the homologous recombination deficiency and vulnerability to PARP inhibition and serves as an actionable marker for targeted therapy for MPNs-LT.
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Affiliation(s)
- Can Yang
- Department of Laboratory Medicine, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Qingyun Zhang
- Central Laboratory, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Xuemei Tang
- Central Laboratory, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Binbin Wang
- Department of Hematology Laboratory Center, Changhai Hospital, Navy Military Medical University, Shanghai, 200433, China
| | - Ming Guan
- Department of Laboratory Medicine, Huashan Hospital, Fudan University, Shanghai, 200040, China.,Central Laboratory, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Gusheng Tang
- Department of Hematology Laboratory Center, Changhai Hospital, Navy Military Medical University, Shanghai, 200433, China
| | - Zhiyuan Wu
- Department of Laboratory Medicine, Huashan Hospital, Fudan University, Shanghai, 200040, China.,Central Laboratory, Huashan Hospital, Fudan University, Shanghai, 200040, China
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4
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Wang N, Yuan L, Jing Y, Fan K, Jin H, Lv C, Wang L, Yu L. Double minute chromosomes in acute myeloid leukemia and myelodysplastic syndromes are associated with complex karyotype, monosomal karyotype, TP53 deletion, and TP53 mutations. Leuk Lymphoma 2021; 62:2466-2474. [PMID: 33904352 DOI: 10.1080/10428194.2021.1919663] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Double minute chromosomes (DMs) are rare in hematologic malignancies. We presented the cytogenetic characteristics and clinical features of the largest single-center cohort of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) patients with DMs. A total of 2576 AML patients and 1642 MDS patients were investigated, and 30 patients (AML = 19; MDS = 11) who had DMs were followed up. DMs were more common in primary AML (94.7%) and MDS (90.9%). Monosomal karyotypes (MK) were also the main cytogenetic characteristics, like complex karyotypes (CK). AML with myelodysplasia-related changes (AML-MRC) and MDS-refractory anemia with excess blasts (MDS-RAEB) was common in this cohort. We conclude that DMs-positive AML and DMs-positive MDS are associated with older age, complex karyotypes, monosomal karyotypes, TP53 deletion and TP53 mutations. DMs are a type of chromothripsis, which can be observed by the karyotype analysis. MYC and KMT2A were the most commonly amplified genes in DMs. Most patients with DMs presented an extremely poor prognosis.
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Affiliation(s)
- Nan Wang
- Department of Hematology, Chinese PLA General Hospital, Beijing, China
| | - Lijun Yuan
- Department of Hematology, Chinese PLA General Hospital, Beijing, China
| | - Yu Jing
- Department of Hematology, Chinese PLA General Hospital, Beijing, China
| | - Keke Fan
- Department of Hematology, Chinese PLA General Hospital, Beijing, China
| | - Hongshi Jin
- Department of Hematology, Chinese PLA General Hospital, Beijing, China
| | - Chao Lv
- Department of Hematology, Chinese PLA General Hospital, Beijing, China
| | - Lili Wang
- Department of Hematology, Chinese PLA General Hospital, Beijing, China
| | - Li Yu
- Department of Hematology, Chinese PLA General Hospital, Beijing, China.,Department of Hematology-Oncology, International Cancer Center, Shenzhen University General Hospital, Shenzhen University Health Science Center, Shenzhen, China
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Shahin OA, Chifotides HT, Bose P, Masarova L, Verstovsek S. Accelerated Phase of Myeloproliferative Neoplasms. Acta Haematol 2021; 144:484-499. [PMID: 33882481 DOI: 10.1159/000512929] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Accepted: 11/09/2020] [Indexed: 12/27/2022]
Abstract
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.
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Affiliation(s)
- Omar A Shahin
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Helen T Chifotides
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Prithviraj Bose
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Lucia Masarova
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Srdan Verstovsek
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
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6
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Dunbar AJ, Rampal RK, Levine R. Leukemia secondary to myeloproliferative neoplasms. Blood 2020; 136:61-70. [PMID: 32430500 PMCID: PMC7332899 DOI: 10.1182/blood.2019000943] [Citation(s) in RCA: 98] [Impact Index Per Article: 19.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Accepted: 01/23/2020] [Indexed: 12/11/2022] Open
Abstract
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.
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MESH Headings
- Abnormal Karyotype
- Allografts
- Antineoplastic Agents/therapeutic use
- Cell Transformation, Neoplastic
- Chromosome Aberrations
- Clonal Evolution
- Combined Modality Therapy
- Comorbidity
- Disease Progression
- Drug Resistance, Neoplasm
- Drugs, Investigational/therapeutic use
- Genes, Neoplasm
- Hematopoietic Stem Cell Transplantation
- Humans
- Leukemia, Myeloid, Acute/etiology
- Leukemia, Myeloid, Acute/genetics
- Leukemia, Myeloid, Acute/pathology
- Leukemia, Myeloid, Acute/therapy
- Models, Biological
- Mutation
- Myeloproliferative Disorders/genetics
- Myeloproliferative Disorders/pathology
- Neoplasm Proteins/genetics
- Recurrence
- Risk Factors
- Single-Cell Analysis
- Therapies, Investigational
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Affiliation(s)
- Andrew J Dunbar
- Leukemia Service, Department of Medicine
- Center for Hematologic Malignancies
| | - Raajit K Rampal
- Leukemia Service, Department of Medicine
- Center for Hematologic Malignancies
| | - Ross Levine
- Leukemia Service, Department of Medicine
- Center for Hematologic Malignancies
- Human Oncology and Pathogenesis Program, and
- Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY
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7
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Grinfeld J. Prognostic models in the myeloproliferative neoplasms. Blood Rev 2020; 42:100713. [DOI: 10.1016/j.blre.2020.100713] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2019] [Revised: 02/25/2020] [Accepted: 05/27/2020] [Indexed: 01/09/2023]
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8
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Shaw G, Berg R. Beyond Hemoglobin: When and How to Work Up Possible Polycythemia Vera. Clin Med Res 2020; 18:11-20. [PMID: 31582417 PMCID: PMC7153800 DOI: 10.3121/cmr.2019.1483] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2019] [Revised: 06/13/2019] [Accepted: 08/20/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND World Health Organization (WHO) 2017 diagnostic criteria for hemoglobin levels in polycythemia vera (PV) were lowered from 185 g/L to 165 g/L for men and from 165 g/L to 160 g/L for women, but these cutoffs were not designed for screening. OBJECTIVES The primary aim of this study was to assess the value of laboratory and clinical parameters in deciding whether to further pursue a diagnosis of PV. A secondary aim was to explore the diagnostic utility of bone marrow morphology. METHODS We evaluated clinical and laboratory parameters that may be useful when considering further diagnostic work-up, emphasizing PV vs. secondary erythrocytosis (SE). We classified 200 patients with JAK2 V617F testing using WHO criteria. RESULTS Patients with myeloproliferative neoplasms (MPN) were rarely under age 40 and uncommonly obese (BMI ≥ 30 kg/m2). Current smoking history favored SE, and these patients rarely had a platelet count ≥ 450 × 103/uL. Laboratory parameters suggesting greater PV likelihood were: RBC > 6.8 × 106 for men or > 5.9 × 106 for women; low erythropoietin; and low MCV or low ferritin. Bone marrow morphology (available in 111 cases) was generally more cellular in PV vs. SE and assessed disease progression. CONCLUSIONS Readily accessible clinical and laboratory data can assist in considering a PV workup, and a possible diagnostic algorithm is presented. These preliminary findings warrant larger studies to develop a more formal PV-risk scoring system with optimal cutoffs and weighting.
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Affiliation(s)
- Gene Shaw
- Department of Lab-Pathology, Marshfield Clinic, Marshfield, Wisconsin
| | - Richard Berg
- Biomedical Informatics Research Center, Marshfield Clinic Research Institute, Marshfield, Wisconsin
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9
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Cruz NM, Gergis U, Silver RT. Myelofibrosis: best practices, controversies and 2019 update. Expert Rev Hematol 2019; 13:71-84. [PMID: 31709843 DOI: 10.1080/17474086.2020.1691519] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
Introduction: Recent advances in the prognostic scheme and treatment of primary and secondary myelofibrosis (MF) have resulted in an overwhelming amount of clinical information to assimilate. The authors believe a comprehensive review that summarizes the most recent published literature, could serve as guidelines for the practicing hematologist.Areas covered: The authors provide a summary of landmark articles regarding epidemiology, symptoms, and pathogenesis of disease. The authors conducted a systematic literature review to answer questions regarding differences between primary myelofibrosis (PMF) and secondary myelofibrosis (SMF), appropriate use and selection of the current risk-stratification models, early versus late treatment of MF and current practices in allogeneic hematopoietic stem cell transplantation (allo-HCT) for MF. The authors conclude the article with their clinical opinion based on their experience and literature review. The purpose of this article is to identify current practices, address any variation, identify and investigate conflicting results and produce statements to guide decision-making.Expert opinion: In this section, the authors advocate for and provide examples of a standardized way of incorporating future discoveries in the pathogenesis and risk-stratification models of MF. They also discuss the importance of using only one risk-stratification model for PMF and one for SMF and their reasoning for early instead of late treatment of MF.
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Affiliation(s)
- Nicole M Cruz
- Division of Hematology & Medical Oncology, Weill Cornell Medicine, New York, NY, USA
| | - Usama Gergis
- Division of Hematology & Medical Oncology, Weill Cornell Medicine, New York, NY, USA
| | - Richard T Silver
- Division of Hematology & Medical Oncology, Weill Cornell Medicine, New York, NY, USA.,Richard T. Silver, M.D. Myeloproliferative Neoplasms (MPN) Center, Weill Cornell Medical College, New York, NY, USA
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10
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Iurlo A, Cattaneo D, Gianelli U. Blast Transformation in Myeloproliferative Neoplasms: Risk Factors, Biological Findings, and Targeted Therapeutic Options. Int J Mol Sci 2019; 20:ijms20081839. [PMID: 31013941 PMCID: PMC6514804 DOI: 10.3390/ijms20081839] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2019] [Revised: 04/09/2019] [Accepted: 04/11/2019] [Indexed: 01/24/2023] Open
Abstract
Myeloproliferative neoplasms represent a heterogenous group of disorders of the hematopoietic stem cell, with an intrinsic risk of evolution into acute myeloid leukemia. The frequency of leukemic evolution varies according to myeloproliferative neoplasms subtype. It is highest in primary myelofibrosis, where it is estimated to be approximately 10–20% at 10 years, following by polycythemia vera, with a risk of 2.3% at 10 years and 7.9% at 20 years. In essential thrombocythemia, however, transformation to acute myeloid leukemia is considered relatively uncommon. Different factors are associated with leukemic evolution in myeloproliferative neoplasms, but generally include advanced age, leukocytosis, exposure to myelosuppressive therapy, cytogenetic abnormalities, as well as increased number of mutations in genes associated with myeloid neoplasms. The prognosis of these patients is dismal, with a medium overall survival ranging from 2.6–7.0 months. Currently, there is no standard of care for managing the blast phase of these diseases, and no treatment to date has consistently led to prolonged survival and/or hematological remission apart from an allogeneic stem cell transplant. Nevertheless, new targeted agents are currently under development. In this review, we present the current evidence regarding risk factors, molecular characterization, and treatment options for this critical subset of myeloproliferative neoplasms patients.
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Affiliation(s)
- Alessandra Iurlo
- Hematology Division, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, and University of Milan, 20122 Milan, Italy.
| | - Daniele Cattaneo
- Hematology Division, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, and University of Milan, 20122 Milan, Italy.
| | - Umberto Gianelli
- Division of Pathology, Department of Pathophysiology and Transplantation, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, and University of Milan, 20122 Milan, Italy.
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Abstract
OPINION STATEMENT Acute myeloid leukemia (AML) patients with a complex karyotype (CK-AML) show at least 3 unrelated clonal cytogenetic abnormalities with notoriously poor outcome. Such cases fall into either AML with myelodysplasia-related changes or therapy-related AML in the current World Health Organization classification of AML. Allogeneic stem cell transplantation is one of the only treatment modalities that can provide a long-term survival benefit and is recommended as a consolidative treatment in patients who are able to achieve complete remission. Unfortunately, transplantation is also associated with a higher relapse rate and more than half of CK-AML patients relapse from disease within the first 2 years. The probability of achieving remission with traditional induction using cytarabine and daunorubicin or idarubicin ("7 + 3") is so small that investigational therapies should be considered up front in these patients. Less intensive therapeutic backbones, typically using one of the hypomethylating agents, azacitidine or decitabine, minimize toxicity and show a trend toward the improved overall survival. CPX 351 (Vyxeos) is a liposomal formulation of cytarabine and daunorubicin and this encapsulation leads to prolonged exposure to the two drugs. This drug is approved for AML patients with MDS-related changes and therapy-related AML, both of which are frequently associated with complex karyotype. Such patients show improved outcome in trials using this combination. Combination therapy that includes venetoclax (BCL2 inhibitor) with hypomethylating agents may also be appropriate for such patients.
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12
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Leukemic transformation among 1306 patients with primary myelofibrosis: risk factors and development of a predictive model. Blood Cancer J 2019; 9:12. [PMID: 30683837 PMCID: PMC6347609 DOI: 10.1038/s41408-019-0175-y] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2018] [Accepted: 12/13/2018] [Indexed: 11/08/2022] Open
Abstract
Among 1306 patients with primary myelofibrosis (PMF), we sought to identify risk factors that predicted leukemic transformation (LT) in the first 5 years of disease and also over the course of the disease. 149 (11%) LT were documented; patients who subsequently developed LT (n = 149), compared to those who remained in chronic phase disease (n = 1,157), were more likely to be males (p = 0.02) and display higher circulating blasts (p = 0.03), ASXL1 (p = 0.01), SRSF2 (p = 0.001) and IDH1 (p = 0.02) mutations. Logistic regression analysis identified IDH1, ASXL1 and SRSF2 mutations, very high-risk karyotype, age > 70 years, male sex, circulating blasts ≥ 3%, presence of moderate or severe anemia and constitutional symptoms, as predictors of LT in the first 5 years of diagnosis. Time-to-event Cox analysis confirmed LT prediction for IDH1 mutation (HR 4.3), circulating blasts ≥ 3% (HR 3.3), SRSF2 mutation (HR 3.0), age > 70 years (HR 2.1), ASXL1 mutation (HR 2.0) and presence of moderate or severe anemia (HR 1.9). HR-based risk point allocation resulted in a three-tiered LT risk model: high-risk (LT incidence 57%; HR 39.3, 95% CI 10.8-114), intermediate-risk (LT incidence 17%; HR 4.1, 95% CI 2.4-7.3) and low-risk (LT incidence 8%). The current study provides a highly discriminating LT predictive model for PMF.
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13
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Tefferi A, Guglielmelli P, Pardanani A, Vannucchi AM. Myelofibrosis Treatment Algorithm 2018. Blood Cancer J 2018; 8:72. [PMID: 30065290 PMCID: PMC6068139 DOI: 10.1038/s41408-018-0109-0] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2018] [Revised: 05/15/2018] [Accepted: 05/25/2018] [Indexed: 01/12/2023] Open
Abstract
Two novel prognostic systems for primary myelofibrosis (PMF) were recently unveiled: GIPSS (genetically inspired prognostic scoring system) and MIPSS70 (mutation-enhanced international prognostic scoring system for transplant-age patients). GIPSS is based exclusively on genetic markers: mutations and karyotype. MIPSS70 includes mutations and clinical risk factors. In its most recent adaptation, the prognostic value of MIPSS70 has been bolstered by the inclusion of a three-tiered cytogenetic risk stratification and use of hemoglobin thresholds that are adjusted for sex and severity (MIPSS70+ version 2.0). GIPSS features four, MIPSS70 three, and MIPSS70+ version 2.0 five risk categories. MIPSS70 is most useful in the absence of cytogenetic information. MIPSS70+ version 2.0 is more comprehensive than MIPSS70 and is the preferred model in the presence of cytogenetic information. Both MIPSS70 and MIPSS70+ version 2.0 require an online score calculator (http://www.mipss70score.it). GIPPS offers a lower complexity prognostic tool that reliably identifies candidates for allogeneic stem cell transplant (GIPSS high-risk disease) or long-term observation with little or no therapeutic intervention (GIPSS low-risk disease). Ultimately, we favor a step-wise prognostication approach that starts with GIPSS but also considers MIPSS70+ version 2.0 for confirming the most appropriate treatment approach for the individual patient.
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Affiliation(s)
- Ayalew Tefferi
- Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.
| | - Paola Guglielmelli
- Department of Experimental and Clinical Medicine, CRIMM, Center Research and Innovation of Myeloproliferative Neoplasms, Azienda Ospedaliera Universitaria Careggi, University of Florence, Florence, Italy
| | - Animesh Pardanani
- Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA
| | - Alessandro M Vannucchi
- Department of Experimental and Clinical Medicine, CRIMM, Center Research and Innovation of Myeloproliferative Neoplasms, Azienda Ospedaliera Universitaria Careggi, University of Florence, Florence, Italy
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14
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Post-ET and Post-PV Myelofibrosis: Updates on a Distinct Prognosis from Primary Myelofibrosis. Curr Hematol Malig Rep 2018; 13:173-182. [DOI: 10.1007/s11899-018-0453-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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15
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Tefferi A, Mudireddy M, Mannelli F, Begna KH, Patnaik MM, Hanson CA, Ketterling RP, Gangat N, Yogarajah M, De Stefano V, Passamonti F, Rosti V, Finazzi MC, Rambaldi A, Bosi A, Guglielmelli P, Pardanani A, Vannucchi AM. Blast phase myeloproliferative neoplasm: Mayo-AGIMM study of 410 patients from two separate cohorts. Leukemia 2018; 32:1200-1210. [PMID: 29459662 PMCID: PMC5940634 DOI: 10.1038/s41375-018-0019-y] [Citation(s) in RCA: 105] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2017] [Revised: 12/05/2017] [Accepted: 12/21/2017] [Indexed: 12/29/2022]
Abstract
A total of 410 patients with blast phase myeloproliferative neoplasm (MPN-BP) were retrospectively reviewed: 248 from the Mayo Clinic and 162 from Italy. Median survival was 3.6 months, with no improvement over the last 15 years. Multivariable analysis performed on the Mayo cohort identified high risk karyotype, platelet count < 100 × 109/L, age > 65 years and transfusion need as independent risk factors for survival. Also in the Mayo cohort, intensive chemotherapy resulted in complete remission (CR) or CR with incomplete count recovery (CRi) rates of 35 and 24%, respectively; treatment-specified 3-year/5-year survival rates were 32/10% for patients receiving allogeneic stem cell transplant (AlloSCT) (n = 24), 19/13% for patients achieving CR/CRi but were not transplanted (n = 24), and 1/1% in the absence of both AlloSCT and CR/CRi (n = 200) (p < 0.01). The survival impact of AlloSCT (HR 0.2, 95% CI 0.1–0.3), CR/CRi without AlloSCT (HR 0.3, 95% CI 0.2–0.5), high risk karyotype (HR 1.6, 95% CI 1.1–2.2) and platelet count < 100 × 109/L (HR 1.6, 95% CI 1.1–2.2) were confirmed to be inter-independent. Similar observations were made in the Italian cohort. The current study identifies the setting for improved short-term survival in MPN-BP, but also highlights the limited value of current therapy, including AlloSCT, in securing long-term survival.
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Affiliation(s)
| | | | - Francesco Mannelli
- AGIMM (AIRC-Gruppo Italiano Malattie Mieloproliferative: Rome, Varese, Pavia, Bergamo, Florence, Italy.,CRIMM, Center for Research and Innovation of Myeloproliferative Neoplasms, University of Florence, AOU Careggi, Florence, Italy
| | | | | | | | | | | | - Meera Yogarajah
- Brody School of Medicine, East Carolina University, Greenville, NC, USA
| | - Valerio De Stefano
- AGIMM (AIRC-Gruppo Italiano Malattie Mieloproliferative: Rome, Varese, Pavia, Bergamo, Florence, Italy.,Institute of Hematology, Catholic University, Roma, Italy
| | - Francesco Passamonti
- AGIMM (AIRC-Gruppo Italiano Malattie Mieloproliferative: Rome, Varese, Pavia, Bergamo, Florence, Italy.,Department of Medicine and Surgery, University of Insubria, ASST Settelaghi, Ospedale di Circolo, Varese, Italy
| | - Vittorio Rosti
- AGIMM (AIRC-Gruppo Italiano Malattie Mieloproliferative: Rome, Varese, Pavia, Bergamo, Florence, Italy.,Center for the Study of Myelofibrosis, Laboratory of Biochemistry, Biotechnology and Advanced Diagnosis, Foundation IRCCS Policlinico San Matteo, Pavia, Italy
| | - Maria Chiara Finazzi
- AGIMM (AIRC-Gruppo Italiano Malattie Mieloproliferative: Rome, Varese, Pavia, Bergamo, Florence, Italy.,Department of Oncology and Hemato-oncology University of Milan and Ospedale Papa Giovanni XXIII, Bergamo, Italy
| | - Alessandro Rambaldi
- AGIMM (AIRC-Gruppo Italiano Malattie Mieloproliferative: Rome, Varese, Pavia, Bergamo, Florence, Italy.,Department of Oncology and Hemato-oncology University of Milan and Ospedale Papa Giovanni XXIII, Bergamo, Italy
| | - Alberto Bosi
- AGIMM (AIRC-Gruppo Italiano Malattie Mieloproliferative: Rome, Varese, Pavia, Bergamo, Florence, Italy.,CRIMM, Center for Research and Innovation of Myeloproliferative Neoplasms, University of Florence, AOU Careggi, Florence, Italy
| | - Paola Guglielmelli
- AGIMM (AIRC-Gruppo Italiano Malattie Mieloproliferative: Rome, Varese, Pavia, Bergamo, Florence, Italy.,CRIMM, Center for Research and Innovation of Myeloproliferative Neoplasms, University of Florence, AOU Careggi, Florence, Italy
| | | | - Alessandro M Vannucchi
- AGIMM (AIRC-Gruppo Italiano Malattie Mieloproliferative: Rome, Varese, Pavia, Bergamo, Florence, Italy.,CRIMM, Center for Research and Innovation of Myeloproliferative Neoplasms, University of Florence, AOU Careggi, Florence, Italy
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16
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Mascarenhas J. A Concise Update on Risk Factors, Therapy, and Outcome of Leukemic Transformation of Myeloproliferative Neoplasms. CLINICAL LYMPHOMA MYELOMA & LEUKEMIA 2017; 16 Suppl:S124-9. [PMID: 27521308 DOI: 10.1016/j.clml.2016.02.016] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/09/2016] [Accepted: 02/09/2016] [Indexed: 12/28/2022]
Abstract
Myeloproliferative neoplasms (MPN) in chronic phase that evolve into blast phase (BP) hold a dismal prognosis and represent an urgent unmet clinical need. The mutational landscape of MPN-BP is distinct from de novo acute myeloid leukemia and offers insight into molecular mechanisms contributing to clonal evolution providing potential novel drug targets. A number of retrospective studies have identified patient- and disease-specific variables associated with increased risk of leukemic transformation (LT) of an underlying MPN. Several prognostic models have been developed to identify those MPN patients at highest risk for LT that may warrant early aggressive therapeutic intervention. Acute myeloid leukemia-type induction chemotherapy does not offer a significant survival benefit for MPN-BP unless followed by hematopoietic stem-cell transplantation. Unfortunately, most patients with MPN-BP are not candidates for hematopoietic stem-cell transplantation as a result of advanced age, competing comorbid conditions, or lack of an acceptable donor graft option. JAK2 inhibitor monotherapy is effective in reducing splenomegaly and symptom burden in the majority of treated patients with myelofibrosis, but LT can still occur. High-dose JAK2 inhibitor monotherapy appears tolerable but only modestly active in the treatment of MPN-BP. Current JAK2 inhibitor-based combination therapy approaches are supported by preclinical investigation and are currently being tested in multicenter clinical trials.
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Affiliation(s)
- John Mascarenhas
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY.
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17
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Bose P, Verstovsek S. Prognosis of Primary Myelofibrosis in the Genomic Era. CLINICAL LYMPHOMA MYELOMA & LEUKEMIA 2017; 16 Suppl:S105-13. [PMID: 27521306 DOI: 10.1016/j.clml.2016.02.031] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/09/2016] [Accepted: 02/09/2016] [Indexed: 02/07/2023]
Abstract
Currently, prognostication in primary myelofibrosis (PMF) relies on the International Prognostic Scoring System (IPSS), dynamic IPSS (DIPSS), and DIPSS-plus, which incorporate age, blood counts, constitutional symptoms, circulating blasts, red cell transfusion need, and karyotype. Although the JAK2 V617F mutation was discovered a decade ago and MPL mutations shortly thereafter, it was the recent discovery of CALR mutations in the vast majority of JAK2/MPL-unmutated patients and recognition of the powerful impact of CALR mutations and triple-negative (JAK2/MPL/CALR-negative) status on outcome that set the stage for revision of traditional prognostic models to include molecular information. Additionally, the advent of next-generation sequencing has identified a host of previously unrecognized somatic mutations across hematologic malignancies. As in the myelodysplastic syndromes, the majority of common and prognostically informative mutations in PMF affect epigenetic regulation and mRNA splicing. Thus, a need has arisen to incorporate mutational information on genes such as ASXL1 and SRSF2 into risk stratification systems. Mutations in yet other genes appear to be important players in leukemic transformation, and new insights into disease pathogenesis are emerging. Finally, the number of prognostically detrimental mutations may affect both survival and response to ruxolitinib, which has significant implications for clinical decision making. In this review, we briefly summarize the prognostic models in use today and discuss in detail the somatic mutations commonly encountered in patients with PMF, along with their prognostic implications and role in leukemic transformation. Emerging prognostic models that incorporate new molecular information into existing systems or exclude clinical variables are also presented.
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Affiliation(s)
- Prithviraj Bose
- Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX.
| | - Srdan Verstovsek
- Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX
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18
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Tefferi A, Mudireddy M, Gangat N, Hanson CA, Ketterling RP, Pardanani A, Nagorney DM. Risk factors and a prognostic model for postsplenectomy survival in myelofibrosis. Am J Hematol 2017; 92:1187-1192. [PMID: 28782256 DOI: 10.1002/ajh.24881] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2017] [Accepted: 08/02/2017] [Indexed: 01/04/2023]
Abstract
Palliative treatment in myelofibrosis (MF) includes transfusion support, JAK2 inhibitors, involved field radiotherapy and splenectomy. To assist in selecting patients who are likely to benefit from splenectomy, we looked into risk factors for postsplenectomy survival, in 120 consecutive cases (median age 66 years); at the time of splenectomy, 61% displayed red cell transfusion need, 49% platelet count <100 × 10(9)/L, 25% leukocyte count >25 × 10(9)/L, 60% constitutional symptoms and 13% circulating blasts ≥5%; dynamic international prognostic scoring system risk categories were 21% high, 55% intermediate-2, 21% intermediate-1 and 3% low. Among informative cases, karyotype was abnormal in 60% and driver mutational status was JAK2 75%, CALR 15%, MPL 4% and triple-negative 6%. At median follow-up of 1.3 years, from time of splenectomy, 95 (79%) deaths and 30 (25%) leukemic transformations were recorded. Median postsplenectomy survival was 1.5 years; in multivariable analysis, survival was adversely affected by age >65 years, transfusion need, leukocyte count >25 × 10(9)/L and circulating blasts ≥5%; these variables were subsequently used to devise an HR-weighted scoring system with high (3-4 risk factors), intermediate (2 risk factors) and low (0-1 risk factors) risk categories; the corresponding postsplenectomy median survivals were 0.3 (HR 5.9, 95% CI 3.2-11.0), 1.3 (HR 2.9, 95% CI 1.8-4.6) and 2.9 years. Postsplenectomy survival was not affected by driver mutational status or occurrence of leukemic transformation. Leukemia-free survival was predicted by very high risk karyotype. The observations from the current study might help identify appropriate candidates for splenectomy in MF.
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19
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Yogarajah M, Tefferi A. Leukemic Transformation in Myeloproliferative Neoplasms: A Literature Review on Risk, Characteristics, and Outcome. Mayo Clin Proc 2017; 92:1118-1128. [PMID: 28688466 DOI: 10.1016/j.mayocp.2017.05.010] [Citation(s) in RCA: 78] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2017] [Revised: 05/08/2017] [Accepted: 05/17/2017] [Indexed: 01/01/2023]
Abstract
Myeloproliferative neoplasms (MPNs) operationally include essential thrombocythemia, polycythemia vera, primary myelofibrosis (PMF), and prefibrotic PMF. All 4 MPN variants might progress into blast-phase disease (MPN-BP). For essential thrombocythemia, reported risk factors for leukemic transformation include advanced age, extreme thrombocytosis, anemia, leukocytosis, and sequence variants/mutations involving TP53 and EZH2 (for expansion of gene symbols, see www.genenames.org); for polycythemia vera, advanced age, leukocytosis, abnormal karyotype, mutations involving SRSF2 and IDH2, and treatment with pipobroman, chlorambucil, or P32; and for PMF, increased blast percentage, thrombocytopenia, abnormal karyotype, triple-negative driver mutational status, and sequence variants/mutations involving SRSF2, RUNX1, CEBPA, and SH2B3. The reported median survival figures for MPN-BP range from 1.5 to 2.5 months in patients treated with supportive care only, from 2.5 to 10 months in those receiving hypomethylating agents or low-dose chemotherapy, and from 3.9 to 9.4 months in those receiving induction chemotherapy. Three-year survival after allogeneic stem cell transplant was reported in 16% to 33% of patients. These observations validate the extremely poor prognosis associated with MPN-BP and the lack of effective drug therapy and highlight the need for urgent assessment of therapeutic values of investigational agents. In the meantime, affected patients might be best served with aggressive chemotherapy followed by allogeneic stem cell transplant after adequate blast clearance.
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Affiliation(s)
- Meera Yogarajah
- Division of Hematology and Oncology, Brody School of Medicine, East Carolina University, Greenville, NC
| | - Ayalew Tefferi
- Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN.
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20
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Anelli L, Pasciolla C, Zagaria A, Specchia G, Albano F. Monosomal karyotype in myeloid neoplasias: a literature review. Onco Targets Ther 2017; 10:2163-2171. [PMID: 28461756 PMCID: PMC5404799 DOI: 10.2147/ott.s133937] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
In 2008, the concept of the monosomal karyotype (MK) in adult acute myeloid leukemia (AML) patients was introduced, defined by the presence of a chromosomal aberration pattern characterized by the presence of at least two autosomal monosomies or of one monosomy plus one or more structural aberrations (not including loss of a chromosome). We present a systematic review of the literature about the influence of the MK on the outcome of patients affected by myeloid malignancies (AML, myelodysplastic syndromes, and primary myelofibrosis). For this review, a comprehensive literature search using the term “monosomal karyotype” was performed, considering articles listed in MEDLINE. This analysis of the literature confirms the negative prognostic impact on survival of the MK in myeloid neoplasias. The detrimental effect of MK on AML patients’ outcome is independent of other variables, including adverse cytogenetic features, supporting the identification of this entity as a challenging subgroup of patients with distinct biologic and clinical features.
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Affiliation(s)
- Luisa Anelli
- Department of Emergency and Organ Transplantation (D.E.T.O.), Hematology Section, University of Bari, Bari, Italy
| | - Crescenza Pasciolla
- Department of Emergency and Organ Transplantation (D.E.T.O.), Hematology Section, University of Bari, Bari, Italy
| | - Antonella Zagaria
- Department of Emergency and Organ Transplantation (D.E.T.O.), Hematology Section, University of Bari, Bari, Italy
| | - Giorgina Specchia
- Department of Emergency and Organ Transplantation (D.E.T.O.), Hematology Section, University of Bari, Bari, Italy
| | - Francesco Albano
- Department of Emergency and Organ Transplantation (D.E.T.O.), Hematology Section, University of Bari, Bari, Italy
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21
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Tefferi A. Myeloproliferative neoplasms: A decade of discoveries and treatment advances. Am J Hematol 2016; 91:50-8. [PMID: 26492355 DOI: 10.1002/ajh.24221] [Citation(s) in RCA: 110] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2015] [Accepted: 10/19/2015] [Indexed: 12/14/2022]
Abstract
Myeloproliferative neoplasms (MPN) are clonal stem cell diseases, first conceptualized in 1951 by William Dameshek, and historically included chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). In 1960, Nowell and Hungerford discovered an invariable association between the Philadelphia chromosome (subsequently shown to harbor the causal BCR-ABL1 mutation) and CML; accordingly, the term MPN is primarily reserved for PV, ET, and PMF, although it includes other related clinicopathologic entities, according to the World Health Organization (WHO) classification system. In 2005, William Vainchenker and others described a Janus kinase 2 mutation (JAK2V617F) in MPN and this was followed by a series of additional descriptions of mutations that directly or indirectly activate JAK-STAT: JAK2 exon 12, myeloproliferative leukemia virus oncogene (MPL) and calreticulin (CALR) mutations. The discovery of these, mostly mutually exclusive, "driver" mutations has contributed to revisions of the WHO diagnostic criteria and risk stratification in MPN. Mutations other than JAK2, CALR and MPL have also been described in MPN and shown to provide additional prognostic information. From the standpoint of treatment, over the last 50 years, Louis Wasserman from the Unites States and Tiziano Barbui from Italy had skillfully organized and led a number of important clinical trials, whose results form the basis for current treatment strategies in MPN. More recently, allogeneic stem cell transplant, as a potentially curative treatment modality, and JAK inhibitors, as palliative drugs, have been added to the overall therapeutic armamentarium in myelofibrosis. In the current review, I will summarize the important advances made in the last 10 years regarding the science and practice of MPN.
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Affiliation(s)
- Ayalew Tefferi
- Division of Hematology, Department of Medicine; Mayo Clinic; Rochester Minnesota
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22
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El Fakih R, Popat U. Janus Kinase Inhibitors and Stem Cell Transplantation in Myelofibrosis. CLINICAL LYMPHOMA MYELOMA & LEUKEMIA 2015; 15 Suppl:S34-42. [PMID: 26297276 DOI: 10.1016/j.clml.2015.02.034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/10/2014] [Revised: 02/05/2015] [Accepted: 02/26/2015] [Indexed: 10/23/2022]
Abstract
Myelofibrosis (MF) is characterized by splenomegaly, blood count abnormalities, particularly cytopenias, and a propensity for transformation to acute leukemia. The current treatment approach is to ameliorate symptoms due to these abnormalities. Treatment with Janus kinase 2 inhibitors reduces spleen size and improves symptoms in patients with MF, but most of the patients eventually have disease progression and stop responding. Allogeneic stem cell transplantation remains the only curative option. However, its efficacy must be balanced against the risk of treatment-related death and long-term sequelae of transplant like chronic graft versus host disease. The challenge is to integrate treatment with Janus kinase inhibitors with allogeneic stem cell transplantation.
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Affiliation(s)
- Riad El Fakih
- Department of Stem Cell Transplantation, The University of Texas M.D. Anderson Cancer Center, Houston, TX.
| | - Uday Popat
- Department of Stem Cell Transplantation, The University of Texas M.D. Anderson Cancer Center, Houston, TX
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23
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Gill H, Leung AYH, Chan CC, Lau JSM, Chan C, Yip SF, Liu H, Kho B, Mak V, Lee HKK, Lin SY, Lau CK, Kwong YL. Clinicopathologic features and prognostic indicators in Chinese patients with myelofibrosis. ACTA ACUST UNITED AC 2015; 21:10-8. [PMID: 26292161 DOI: 10.1179/1607845415y.0000000045] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
OBJECTIVE To define the clinicopathologic features, outcome, and prognostic indicators of myelofibrosis (MF) in Asian patients. METHODS Two hundred and seventy consecutive Chinese patients (primary MF, n = 207; post-polycythemia vera MF, n = 27; and post-essential thrombocythemia MF, n = 36) from seven regional referral hospitals were analyzed. RESULTS The median overall survival (OS) for primary MF was 66 months. Multivariate analysis showed that age >65 years (P = 0.02), platelet count <100 × 10(9)/l (P = 0.001), and leukemic transformation (P = 0.001) negatively impacted on OS. The median OS of 63 patients with secondary MF was 44 months. In primary MF, the 10-year cumulative risk of leukemic transformation was 28%. On multivariate analysis, unfavorable karyotypes significantly predicted inferior leukemia-free survival (LFS) (P = 0.03). In secondary MF, the 10-year cumulative risk of leukemic transformation was 31%. Circulating blasts ≥1% significantly predicted inferior LFS (P = 0.04). The international prognostic scoring system (IPSS) and dynamic IPSS were not significant survival predictors in our cohort. Eighteen patients underwent allogeneic hematopoietic stem cell transplantation. The median OS post-transplantation was merely 19 months. DISCUSSION Platelet count <100 × 10(9)/l, unfavorable karyotypes, and circulating blasts >1% were negative prognostic indicators. Conclusion Chinese MF patients were similar to Western patients in clinicopathologic features and outcome.
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24
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Abstract
The classical myeloproliferative neoplasms (MPNs) are a group of clonal diseases comprising essential thrombocythaemia (ET), polycythaemia vera (PV) and primary myelofibrosis (PMF). PMF is the rarest disease sub type and has been challenging to address due to the lack of a specific genetic marker, inadequate risk identification models and a highly variable clinical course. Continuous efforts have over time, seen the inclusion of cytogenetic information in prognostic scoring models that have resulted in improved risk stratification models providing further rationale for therapeutic management. Technological advances using single nucleotide polymorphism arrays increased the detection of known and novel MPN related changes and variant detection by massively parallel sequencing provided a large scale screening tool for the multitude of somatic gene mutations that have more recently been described in MPN. Some of these mutations show an association with specific cytogenetic changes or phenotypes. While PMF occurs mainly in adults, it has also been described in paediatric cases and shows distinct histopathological, genetic and clinical features in comparison. This review provides an overview of the genomics landscape of PMF and current developments in MPN therapy.
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Affiliation(s)
- Nisha R Singh
- 1 Department of Genetics, Pathology North-Sydney, St Leonards, NSW, Australia ; 2 Kolling Institute, University of Sydney, NSW, Australia
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25
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Rago A, Latagliata R, Montanaro M, Montefusco E, Andriani A, Crescenzi SL, Mecarocci S, Spirito F, Spadea A, Recine U, Cicconi L, Avvisati G, Cedrone M, Breccia M, Porrini R, Villivà N, De Gregoris C, Alimena G, D'Arcangelo E, Guglielmelli P, Lo-Coco F, Vannucchi A, Cimino G. Hemoglobin levels and circulating blasts are two easily evaluable diagnostic parameters highly predictive of leukemic transformation in primary myelofibrosis. Leuk Res 2015; 39:314-7. [PMID: 25636356 DOI: 10.1016/j.leukres.2015.01.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2014] [Revised: 12/29/2014] [Accepted: 01/02/2015] [Indexed: 01/06/2023]
Abstract
To predict leukemic transformation (LT), we evaluated easily detectable diagnostic parameters in 338 patients with primary myelofibrosis (PMF) followed in the Latium region (Italy) between 1981 and 2010. Forty patients (11.8%) progressed to leukemia, with a resulting 10-year leukemia-free survival (LFS) rates of 72%. Hb (<10g/dL), and circulating blasts (≥1%) were the only two independent prognostic for LT at the multivariate analysis. Two hundred-fifty patients with both the two parameters available were grouped as follows: low risk (none or one factor)=216 patients; high risk (both factors)=31 patients. The median LFS times were 269 and 45 months for the low and high-risk groups, respectively (P<.0001). The LT predictive power of these two parameters was confirmed in an external series of 270 PMF patients from Tuscany, in whom the median LFS was not reached and 61 months for the low and high risk groups, respectively (P<.0001). These results establish anemia and circulating blasts, two easily and universally available parameters, as strong predictors of LT in PMF and may help to improve prognostic stratification of these patients particularly in countries with low resources where more sophisticated molecular testing is unavailable.
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Affiliation(s)
- Angela Rago
- Hematology Unit (2U) ICOT/S, Maria Goretti Hospital, AUSL Latina, Italy
| | - Roberto Latagliata
- Department of Cellular Biotechnology and Hematology, University of Rome "Sapienza", Italy
| | | | | | | | | | - Sergio Mecarocci
- Hematology Unit (2U) ICOT/S, Maria Goretti Hospital, AUSL Latina, Italy
| | | | - Antonio Spadea
- Department of Hematology, Regina Elena National Cancer Institute, Rome, Italy
| | - Umberto Recine
- Department of Hematology, S. Spirito Hospital, Rome, Italy
| | - Laura Cicconi
- Department of Biomedicine and Prevention, University "Tor Vergata", Rome, Italy
| | - Giuseppe Avvisati
- Hematology, Stem Cell Transplantation, Transfusion Medicine and Cellular Therapy Unit, University "Campus Bio-Medico" of Rome, Italy
| | - Michele Cedrone
- Department of Hematology, S. Giovanni Addolorata Hospital, Rome, Italy
| | - Massimo Breccia
- Department of Cellular Biotechnology and Hematology, University of Rome "Sapienza", Italy
| | | | - Nicoletta Villivà
- Department of Hematology, "Nuovo Regina Margherita" Hospital, Rome, Italy
| | | | - Giuliana Alimena
- Department of Cellular Biotechnology and Hematology, University of Rome "Sapienza", Italy
| | - Enzo D'Arcangelo
- Department of Statistic Science, University of Rome "Sapienza", Italy
| | - Paola Guglielmelli
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Francesco Lo-Coco
- Department of Biomedicine and Prevention, University "Tor Vergata", Rome, Italy; Laboratory of Neuro-Oncohematology, Santa Lucia Foundation, Rome, Italy
| | - Alessandro Vannucchi
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Giuseppe Cimino
- Hematology Unit (2U) ICOT/S, Maria Goretti Hospital, AUSL Latina, Italy; Department of Cellular Biotechnology and Hematology, University of Rome "Sapienza", Italy.
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26
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Li B, Xu J, Li C, Gale RP, Xu Z, Qin T, Zhang Y, Huang G, Fang L, Zhang H, Pan L, Hu N, Qu S, Xiao Z. Cytogenetic studies and their prognostic contribution in 565 Chinese patients with primary myelofibrosis. Am J Hematol 2014; 89:1043-6. [PMID: 25132428 DOI: 10.1002/ajh.23824] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Revised: 07/02/2014] [Accepted: 08/01/2014] [Indexed: 01/22/2023]
Abstract
To study the feature and prognostic contribution of cytogenetic information in Chinese patients with primary myelofibrosis (PMF), we analyzed cytogenetic data from 565 patients with PMF. One hundred and sixty-two subjects (29%) had abnormal karyotypes, including trisomy 8 (45; 28%), deletion of 20q (25; 15%), deletion of 13q (13; 8%), deletion of 11q (12; 7%), and abnormal chromosome 1 (21; 13%); balanced translocations (14; 9%); a complex karyotype (CK; 30; 19%), and a monosomal karyotype (MK; 19; 12%). Using these data, we showed that the Dynamic International Prognostic Scoring System (DIPSS)-plus, which includes cytogenetic information, is a better survival predictor than the DIPSS. We next used our data to construct the following two cytogenetic-based cohorts: (1) favorable karyotype-subjects with a normal karyotype, a CK that is not a MK, +8 only or a balanced translocation only and (2) unfavorable karyotype-all others. The median survival times were not reached and were 52 month (95% CI, 32-72 months; P = 0.01) in patients with favorable and unfavorable karyotypes, respectively. These data provided the detailed cytogenetic information in Chinese patients with PMF and confirmed the impact of cytogenetic abnormalities on survival in Chinese patients.
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Affiliation(s)
- Bing Li
- MDS and MPN Centre; Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College; Tianjin People's Republic of China
- State Key Laboratory of Experimental Hematology; Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College; Tianjin People's Republic of China
| | - Junqing Xu
- MDS and MPN Centre; Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College; Tianjin People's Republic of China
| | - Chengwen Li
- Cytogenetic Laboratory; Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College; Tianjin People's Republic of China
| | - Robert Peter Gale
- Division of Experimental Medicine; Department of Medicine; Haematology Research Center, Imperial College London, London; United Kingdom
| | - Zefeng Xu
- MDS and MPN Centre; Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College; Tianjin People's Republic of China
- State Key Laboratory of Experimental Hematology; Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College; Tianjin People's Republic of China
| | - Tiejun Qin
- MDS and MPN Centre; Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College; Tianjin People's Republic of China
| | - Yue Zhang
- MDS and MPN Centre; Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College; Tianjin People's Republic of China
- State Key Laboratory of Experimental Hematology; Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College; Tianjin People's Republic of China
| | - Gang Huang
- Divisions of Experimental Hematology and Cancer Biology; Cincinnati Children's Hospital Medical Center; Cincinnati Ohio
| | - Liwei Fang
- MDS and MPN Centre; Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College; Tianjin People's Republic of China
| | - Hongli Zhang
- MDS and MPN Centre; Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College; Tianjin People's Republic of China
| | - Lijuan Pan
- MDS and MPN Centre; Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College; Tianjin People's Republic of China
| | - Naibo Hu
- MDS and MPN Centre; Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College; Tianjin People's Republic of China
| | - Shiqiang Qu
- MDS and MPN Centre; Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College; Tianjin People's Republic of China
| | - Zhijian Xiao
- MDS and MPN Centre; Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College; Tianjin People's Republic of China
- State Key Laboratory of Experimental Hematology; Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College; Tianjin People's Republic of China
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Pathogenesis and management of acute myeloid leukemia that has evolved from a myeloproliferative neoplasm. Curr Opin Hematol 2014; 21:65-71. [PMID: 24366192 DOI: 10.1097/moh.0000000000000017] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
PURPOSE OF REVIEW The myeloproliferative neoplasms (MPNs), including essential thrombocythemia, polycythemia vera and primary myelofibrosis (PMF), are a heterogeneous group of myeloid-derived chronic haematopoietic malignancies. Frequent clinical consequences of these diseases include not only an increased risk of thrombosis but also leukemic transformation, which carries a particularly poor prognosis. Here, we discuss the recent identification of risk factors for leukemic transformation, elucidate mechanisms contributing to leukemic transformation, as well as highlight the development of new treatment strategies. RECENT FINDINGS Significant progress in the understanding of the biology of MPNs has been made in recent years, particularly with the discovery that mutations in the JAK-STAT signaling pathway cause unregulated activation. These genetic insights have been extended to leukemic transformation and have revealed a host of genetic alterations that occur at the time of transformation, and that may identify patients at risk for leukemic transformation. Such studies have demonstrated that acute myeloid leukemia (AML) evolved from a chronic phase MPN is distinct from de-novo AML both genetically and clinically given its resistance to conventional antileukemic therapy. SUMMARY Leukemic transformation of an MPN remains a significant clinical challenge. Recent advances in the understanding of the molecular events that contribute to the development of leukemic transformation will need to be utilized in order to produce rational therapeutic approaches for this largely fatal disease.
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Maffioli M, Caramazza D, Mora B, Merli M, Passamonti F. Myelofibrosis: Prognostication and cytoreductive treatment. World J Hematol 2014; 3:85-92. [DOI: 10.5315/wjh.v3.i3.85] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2013] [Accepted: 06/11/2014] [Indexed: 02/05/2023] Open
Abstract
Myeloproliferative neoplasms include three diseases: polycythemia vera, essential thrombocythemia and primary myelofibrosis (PMF), currently diagnosed according to the 2008 World Health Organization criteria. Patients with PMF may encounter many complications, and, among these, disease progression is the most severe. Concerning prognostication of Myelofibrosis (MF), the International Prognostic scoring system (IPSS) (International Prognostic Scoring System) model at diagnosis and the Dynamic IPSS (DIPSS) anytime during the course of the disease may be useful to define survival of MF patients. The IPSS and the DIPSS are based on age greater than 65 years, presence of constitutional symptoms, hemoglobin level less than 10 g/dL, leukocyte count greater than 25 × 109/L, and circulating blast cells 1% or greater. Cytogenetic profile and mutational analysis seem to be the next step to implement MF prognostication. Concerning treatments, hydroxyurea has been considered until now the drug of choice when an anti-myeloproliferative effect is needed, but recent data on JAK inhibitors demonstrated a significant effect of these drugs on splenomegaly and symptoms.
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Björkholm M, Hultcrantz M, Derolf ÅR. Leukemic transformation in myeloproliferative neoplasms: therapy-related or unrelated? Best Pract Res Clin Haematol 2014; 27:141-53. [PMID: 25189725 DOI: 10.1016/j.beha.2014.07.003] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2014] [Accepted: 07/11/2014] [Indexed: 01/25/2023]
Abstract
Polycythemia vera, essential thrombocythemia, and primary myleofibrosis are chronic myeloproliferative neoplasms (MPNs) associated with an increased morbidity and mortality. MPNs are also associated with progression to acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS). The "true" rate of transformation is not known mainly due to selection bias in clinical trials and underreporting in population-based studies. The outcome after transformation is dismal. The underlying mechanisms of transformation are incompletely understood and in part remain an area of controversy. There is an intrinsic propensity in MPNs to progress to AML/MDS, the magnitude of which is not fully known, supporting a role for nontreatment-related factors. High doses of alkylating agents, P(32) and combined cytoreductive treatments undoubtedly increase the risk of transformation. The potential leukemogenic role of hydroxyurea has been a matter of debate due to difficulties in performing large prospective randomized trials addressing this issue. The main focus of this review is to elucidate therapy-related leukemic transformation in MPNs with a special focus on the role of hydroxyurea.
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Affiliation(s)
- Magnus Björkholm
- Department of Medicine, Division of Hematology, Karolinska University Hospital Solna, Karolinska Institutet, SE-171 76 Stockholm, Sweden.
| | - Malin Hultcrantz
- Department of Medicine, Division of Hematology, Karolinska University Hospital Solna, Karolinska Institutet, SE-171 76 Stockholm, Sweden.
| | - Åsa Rangert Derolf
- Department of Medicine, Division of Hematology, Karolinska University Hospital Solna, Karolinska Institutet, SE-171 76 Stockholm, Sweden.
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30
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Zhou A, Oh ST. Prognostication in MF: from CBC to cytogenetics to molecular markers. Best Pract Res Clin Haematol 2014; 27:155-64. [PMID: 25189726 DOI: 10.1016/j.beha.2014.07.008] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2014] [Accepted: 07/11/2014] [Indexed: 01/18/2023]
Abstract
Myelofibrosis (MF) is a clonal stem cell disorder characterized by ineffective erythropoiesis and extramedullary hematopoiesis leading to progressive bone marrow failure, severe anemia, constitutional symptoms, hepatosplenomegaly, and thrombosis. MF can arise following a history of polycythemia vera (PV) or essential thrombocythemia (ET), or can present de novo as primary myelofibrosis (PMF). The disease course is variable with median survival ranging from months to years. Clinical and biological features such as advanced age, leukocytosis, anemia, transfusion dependence, and elevated inflammatory markers can impact prognosis in patients with PMF. Cytogenetic abnormalities and molecular markers such as JAK2 V617F, ASXL1, and CALR mutations have also been identified as prognostic variables. Several different scoring systems have been developed based on these prognostic factors. In this review, we will discuss the clinical, biological, molecular, and cytogenetic prognostic factors that have been identified in PMF, and the current prognostic models that have been developed to guide treatment decisions.
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Affiliation(s)
- Amy Zhou
- Washington University School of Medicine, Division of Hematology, 660 S. Euclid Ave, Campus Box 8056, St. Louis, MO 63110, USA.
| | - Stephen T Oh
- Washington University School of Medicine, Division of Hematology, 660 S. Euclid Ave, Campus Box 8125, St. Louis, MO 63110, USA.
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Tefferi A, Lasho TL, Finke CM, Knudson RA, Ketterling R, Hanson CH, Maffioli M, Caramazza D, Passamonti F, Pardanani A. CALR vs JAK2 vs MPL-mutated or triple-negative myelofibrosis: clinical, cytogenetic and molecular comparisons. Leukemia 2014; 28:1472-7. [PMID: 24402162 DOI: 10.1038/leu.2014.3] [Citation(s) in RCA: 417] [Impact Index Per Article: 37.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2013] [Accepted: 12/31/2013] [Indexed: 12/12/2022]
Abstract
Calreticulin (CALR) mutations were recently described in JAK2 and MPL unmutated primary myelofibrosis (PMF) and essential thrombocythemia. In the current study, we compared the clinical, cytogenetic and molecular features of patients with PMF with or without CALR, JAK2 or MPL mutations. Among 254 study patients, 147 (58%) harbored JAK2, 63 (25%) CALR and 21 (8.3%) MPL mutations; 22 (8.7%) patients were negative for all three mutations, whereas one patient expressed both JAK2 and CALR mutations. Study patients were also screened for ASXL1 (31%), EZH2 (6%), IDH (4%), SRSF2 (12%), SF3B1 (7%) and U2AF1 (16%) mutations. In univariate analysis, CALR mutations were associated with younger age (P<0.0001), higher platelet count (P<0.0001) and lower DIPSS-plus score (P=0.02). CALR-mutated patients were also less likely to be anemic, require transfusions or display leukocytosis. Spliceosome mutations were infrequent (P=0.0001) in CALR-mutated patients, but no other molecular or cytogenetic associations were evident. In multivariable analysis, CALR mutations had a favorable impact on survival that was independent of both DIPSS-plus risk and ASXL1 mutation status (P=0.001; HR 3.4 for triple-negative and 2.2 for JAK2-mutated). Triple-negative patients also displayed inferior LFS (P=0.003). The current study identifies 'CALR(-)ASXL1(+)' and 'triple-negative' as high-risk molecular signatures in PMF.
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Affiliation(s)
- A Tefferi
- Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, USA
| | - T L Lasho
- Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, USA
| | - C M Finke
- Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, USA
| | - R A Knudson
- Division of Cytogenetics, Department of Laboratory Medicine, Mayo Clinic, Rochester, MN, USA
| | - R Ketterling
- Division of Cytogenetics, Department of Laboratory Medicine, Mayo Clinic, Rochester, MN, USA
| | - C H Hanson
- Division of Hematopathology, Department of Laboratory Medicine, Mayo Clinic, Rochester, MN, USA
| | - M Maffioli
- Division of Hematology, Ospedale di Circolo, Fondazione Macchi, Varese, Italy
| | - D Caramazza
- Division of Hematology, Ospedale di Circolo, Fondazione Macchi, Varese, Italy
| | - F Passamonti
- Division of Hematology, Ospedale di Circolo, Fondazione Macchi, Varese, Italy
| | - A Pardanani
- Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, USA
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Polyploidy in myelofibrosis: analysis by cytogenetic and SNP array indicates association with advancing disease. Mol Cytogenet 2013; 6:59. [PMID: 24341401 PMCID: PMC3906908 DOI: 10.1186/1755-8166-6-59] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2013] [Accepted: 11/25/2013] [Indexed: 11/10/2022] Open
Abstract
Background Myelofibrosis occurs as primary myelofibrosis or as a late occurrence in the evolution of essential thrombocythaemia and polycythaemia vera. It is the rarest of the three classic myeloproliferative neoplasms (MPN). Polyploidy has only rarely been reported in MPN despite the prominent involvement of abnormal megakaryocytes. The use of peripheral blood samples containing increased numbers of haematopoietic progenitors has improved the output from cytogenetic studies in myelofibrosis and together with the use of single nucleotide polymorphism arrays (SNPa) has contributed to an improved knowledge regarding the diverse genetic landscape of this rare disease. Results Cytogenetic studies performed on a consecutive cohort of 42 patients with primary or post ET/PV myelofibrosis showed an abnormal karyotype in 24 cases and of these, nine showed a polyploid clone. Six of the nine cases showed a tetraploid (4n) subclone, whereas three showed mixed polyploid subclones with both tetraploid and octoploid (4n/8n) cell lines. The abnormal clone evolved from a near diploid karyotype at the initial investigation to a tetraploid karyotype in follow-up cytogenetic analysis in four cases. In total, six of the nine polyploid cases showed gain of 1q material. The remaining three cases showed polyploid metaphases, but with no detectable structural karyotypic rearrangements. Three of the nine cases showed chromosome abnormalities of 6p, either at diagnosis or later acquired. SNPa analysis on eight polyploid cases showed additional changes not previously recognised by karyotype analysis alone, including recurring changes involving 9p, 14q, 17q and 22q. Except for gain of 1q, SNPa findings from the polyploid group compared to eight non-polyploid cases with myelofibrosis found no significant differences in the type of abnormality detected. Conclusions The study showed the use of peripheral blood samples to be suitable for standard karyotyping evaluation and DNA based studies. The overall profile of abnormalities found were comparable with that of post-MPN acute myeloid leukaemia or secondary myelodysplastic syndrome and cases in the polyploidy group were associated with features of high risk disease. The above represents the first documented series of polyploid karyotypes in myelofibrosis and shows a high representation of gain of 1q.
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Kim S, Kim H, Kang H, Kim J, Eom H, Kim T, Yoon SS, Suh C, Lee D. Clinical significance of cytogenetic aberrations in bone marrow of patients with diffuse large B-cell lymphoma: prognostic significance and relevance to histologic involvement. J Hematol Oncol 2013; 6:76. [PMID: 24220305 PMCID: PMC3851800 DOI: 10.1186/1756-8722-6-76] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2013] [Accepted: 09/30/2013] [Indexed: 11/25/2022] Open
Abstract
Background Although knowledge of the genetics of diffuse large B-cell lymphoma (DLBCL) has been increasing, little is known about the characteristics and prognostic significance of cytogenetic abnormalities and the clinical utility of cytogenetic studies performed on bone marrow (BM) specimens. To investigate the significance of isolated cytogenetic aberrations in the absence of histologic BM involvement, we assessed the implication of cytogenetic staging and prognostic stratification by a retrospective multicenter analysis of newly diagnosed DLBCL patients. Methods We analyzed cytogenetic and clinical data from 1585 DLBCL patients whose BM aspirates had been subjected to conventional karyotyping for staging. If available, interphase fluorescence in situ hybridization (FISH) data were also collected from patients. Results Histologic BM involvement were found in 259/1585 (16.3%) patients and chromosomal abnormalities were detected in 192 (12.1%) patients (54 patients with single abnormalities and 138 patients with 2 or more abnormalities). Isolated cytogenetic aberrations (2 or more abnormalities) without histologic involvement were found in 21 patients (1.3%). Two or more cytogenetic abnormalities were associated with inferior overall survival (OS) compared with a normal karyotype or single abnormality in both patients with histologic BM involvement (5-year OS, 16.5% vs. 52.7%; P < 0.001) and those without BM involvement (31.8% vs. 66.5%; P < 0.001). This result demonstrated that BM cytogenetic results have a significant prognostic impact that is independent of BM histology. The following abnormalities were most frequently observed: rearrangements involving 14q32, 19q13, 19p13, 1p, 3q27, and 8q24; del(6q); dup(1q); and trisomy 18. In univariate analysis, several specific abnormalities including abnormalities at 16q22-q24, 6p21-p25, 12q22-q24, and -17 were associated with poor prognosis. Multivariate analyses performed for patients who had either chromosomal abnormalities or histologic BM involvement, revealed IPI high risk, ≥ 2 cytogenetic abnormalities, and several specific chromosomal abnormalities, including abnormalities at 19p13, 12q22-q24, 8q24, and 19q13 were significantly associated with a worse prognosis. Conclusions We suggest that isolated cytogenetic aberrations can be regarded as BM involvement and cytogenetic evaluation of BM improves staging accuracy along with prognostic information for DLBCL patients.
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Gangat N, Patnaik MM, Begna K, Kourelis T, Knudson RA, Ketterling RP, Hodnefield JM, Hanson CA, Pardanani A, Tefferi A. Evaluation of revised IPSS cytogenetic risk stratification and prognostic impact of monosomal karyotype in 783 patients with primary myelodysplastic syndromes. Am J Hematol 2013; 88:690-3. [PMID: 23686868 DOI: 10.1002/ajh.23477] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2013] [Accepted: 05/02/2013] [Indexed: 11/09/2022]
Abstract
Cytogenetic classification by the revised international prognostic scoring system (IPSS-R) and the prognostic value of monosomal karyotype (MK) were assessed in 783 patients with primary myelodysplastic syndromes (MDS). At 22 months median follow-up, 562 (72%) deaths were recorded. Percentages of patients with IPSS-R "very good," "good," "intermediate," "poor," and "very poor" cytogenetic categories was 5, 63, 18, 4, and 10%, respectively. The corresponding median survivals were 21, 40, 24, 18, and 6.5 months and the inter-group differences (good vs. very good/intermediate/poor vs. very poor; P < 0.01) or similarities (very good vs. intermediate vs. poor; P = 0.79) were not significantly modified in multivariable analysis. Results were similar when analysis was restricted to 602 patients managed by supportive care. MK adversely affected survival in both poor and very poor karyotype groups (P < 0.01). In conclusion, we were unable to confirm the prognostic superiority of IPSS-R-very good karyotype or prognostically distinguish between very good, intermediate and poor karyotypes. Furthermore, we show additional prognostic information from MK in poor/very poor karyotype.
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Affiliation(s)
- Naseema Gangat
- Department of Internal Medicine; Division of Hematology, Mayo Clinic Rochester; Minnesota
| | - Mrinal M. Patnaik
- Department of Internal Medicine; Division of Hematology, Mayo Clinic Rochester; Minnesota
| | - Kebede Begna
- Department of Internal Medicine; Division of Hematology, Mayo Clinic Rochester; Minnesota
| | - Taxiarchis Kourelis
- Department of Internal Medicine; Division of Hematology, Mayo Clinic Rochester; Minnesota
| | - Ryan A Knudson
- Department of Laboratory Medicine; Cytogenetics, Mayo Clinic Rochester; Minnesota
| | - Rhett P. Ketterling
- Department of Laboratory Medicine; Cytogenetics, Mayo Clinic Rochester; Minnesota
| | | | | | - Animesh Pardanani
- Department of Internal Medicine; Division of Hematology, Mayo Clinic Rochester; Minnesota
| | - Ayalew Tefferi
- Department of Internal Medicine; Division of Hematology, Mayo Clinic Rochester; Minnesota
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Kenderian SS, Al-Kali A, Gangat N, Letendre L, Hogan WJ, Litzow MR, Patnaik MM. Monosomal karyotype in Philadelphia chromosome-negative acute lymphoblastic leukemia. Blood Cancer J 2013; 3:e122. [PMID: 23832069 PMCID: PMC3730199 DOI: 10.1038/bcj.2013.21] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Affiliation(s)
- S S Kenderian
- Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA
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36
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Yang XF, Sun AN, Yin J, Cai CS, Tian XP, Qian J, Chen SN, Wu DP. Monosomal karyotypes among 1147 Chinese patients with acute myeloid leukemia: prevalence, features and prognostic impact. Asian Pac J Cancer Prev 2013; 13:5421-6. [PMID: 23317194 DOI: 10.7314/apjcp.2012.13.11.5421] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
A monosomal karyotype (MK), defined as ≥2 autosomal monosomies or a single monosomy in the presence of additional structural abnormalities, was recently identified as an independent prognostic factor conveying an extremely poor prognosis in patients with acute myeloid leukemia (AML). In the present study, after excluding patients with t(15;17), t(8;21), inv(16) and normal karyotypes, 324 AML patients with cytogenetic abnormalities were the main subject of analysis. The incidences of MK were 13% in patients aged 15 to 60 years and 18% in those between 15 and 88 years old. MK was much more prevalent among elderly patients (p<0.001) and was significantly associated with the presence of -7, -5, del(5q), abn12p, abn17p, -18 or 18q-, -20 or 20q- and CK (for all p<0.001 except for abn12p p=0.009), and +8 or +8q was less frequent in MK+ AML(p=0.007). No correlation was noted between monosomal karyotype and FAB subtype (p>0.05); MK remained significantly associated with worse overall survival among patients with complex karyotype (p=0.032); A single autosomal monosomy contributed an additional negative effect in OS of patients with structural cytogenetic abnormalities (P=0.008). This report presents the prevalence, feature and prognostic impact of MK among a large series of Chinese AML patients from a single center for the first time.
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Affiliation(s)
- Xiao-Fei Yang
- The First Affiliated Hospital of Soochow University, Jiangsu Institute of Hematology, Key laboratory of Thrombosis and Hemostasis of Ministry of Health, Suzhou, China
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Wawrzyniak E, Wierzbowska A, Kotkowska A, Siemieniuk-Rys M, Robak T, Knopinska-Posluszny W, Klonowska A, Iliszko M, Woroniecka R, Pienkowska-Grela B, Ejduk A, Wach M, Duszenko E, Jaskowiec A, Jakobczyk M, Mucha B, Kosny J, Pluta A, Grosicki S, Holowiecki J, Haus O. Different prognosis of acute myeloid leukemia harboring monosomal karyotype with total or partial monosomies determined by FISH: Retrospective PALG study. Leuk Res 2013; 37:293-9. [DOI: 10.1016/j.leukres.2012.10.022] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2012] [Revised: 09/25/2012] [Accepted: 10/27/2012] [Indexed: 10/27/2022]
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Valcárcel D, Ademà V, Solé F, Ortega M, Nomdedeu B, Sanz G, Luño E, Cañizo C, de la Serna J, Ardanaz M, Marco V, Collado R, Grau J, Montoro J, Mallo M, Vallespí T. Complex, Not Monosomal, Karyotype Is the Cytogenetic Marker of Poorest Prognosis in Patients With Primary Myelodysplastic Syndrome. J Clin Oncol 2013; 31:916-22. [DOI: 10.1200/jco.2012.41.6073] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Purpose Complex karyotype (CK) is the poorest risk factor in patients with myelodysplastic syndrome (MDS). It has recently been reported that monosomal karyotype (MK) worsens the prognosis of patients with CK. Patients and Methods We analyzed 1,054 adult patients with MDS with an abnormal karyotype from the Spanish Registry of MDS. The aim of the study was to describe the incidence, characteristics, and prognosis of MK; the main end points were overall survival (OS) and leukemia-free survival. Results MK was identified in 172 patients (16%), most of whom (88%) presented with CK. Variables significantly associated with OS were age (hazard ratio [HR], 1.90; P < .001), bone marrow (BM) blast percentage (HR, 1.05; P < .001), hemoglobin level (HR, 1.71; P < .001), platelet count (HR, 1.41; P < .001), karyotype complexity (CK [three abnormalities]: HR, 1.81; P = .003; very CK [> three abnormalities]: HR, 2; P < .001), and abnormalities of chromosome 5 and/or 7 (HR, 1.89; P < .001). Variables significantly related to the risk of transformation to acute myeloid leukemia (AML) were higher BM blast percentage (HR, 1.12; P < .001) and karyotype complexity (CK: HR, 2.53; P = .002; very CK: HR, 2.77; P < .001). Conclusion After accounting for karyotype complexity, MK was not associated with OS or evolution to AML. In conclusion, these results demonstrate that the prognostic value of MK in MDS is not independent and is mainly the result of its strong association with number of chromosomal abnormalities.
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Affiliation(s)
- David Valcárcel
- David Valcárcel, Margarita Ortega, Julia Montoro, and Teresa Vallespí, Hospital Vall d'Hebrón, Universitat Autònoma de Barcelona; Vera Ademà, Francesc Solé, and Mar Mallo, Grup de Recerca Translacional en Neoplàssies Hematològiques, Institut de Recerca Hospital del Mar; Vera Ademà, Facultat de Biociencies, Universitat Aut
- fonoma de Barcelona, Benet Nomdedeu, Hospital Clínic, Barcelona; Guillermo Sanz, Hospital Universitario La Fe; Rosa Collado, Hospital General de Valencia, Valencia; Elisa Luño, Hospital
| | - Vera Ademà
- David Valcárcel, Margarita Ortega, Julia Montoro, and Teresa Vallespí, Hospital Vall d'Hebrón, Universitat Autònoma de Barcelona; Vera Ademà, Francesc Solé, and Mar Mallo, Grup de Recerca Translacional en Neoplàssies Hematològiques, Institut de Recerca Hospital del Mar; Vera Ademà, Facultat de Biociencies, Universitat Aut
- fonoma de Barcelona, Benet Nomdedeu, Hospital Clínic, Barcelona; Guillermo Sanz, Hospital Universitario La Fe; Rosa Collado, Hospital General de Valencia, Valencia; Elisa Luño, Hospital
| | - Francesc Solé
- David Valcárcel, Margarita Ortega, Julia Montoro, and Teresa Vallespí, Hospital Vall d'Hebrón, Universitat Autònoma de Barcelona; Vera Ademà, Francesc Solé, and Mar Mallo, Grup de Recerca Translacional en Neoplàssies Hematològiques, Institut de Recerca Hospital del Mar; Vera Ademà, Facultat de Biociencies, Universitat Aut
- fonoma de Barcelona, Benet Nomdedeu, Hospital Clínic, Barcelona; Guillermo Sanz, Hospital Universitario La Fe; Rosa Collado, Hospital General de Valencia, Valencia; Elisa Luño, Hospital
| | - Margarita Ortega
- David Valcárcel, Margarita Ortega, Julia Montoro, and Teresa Vallespí, Hospital Vall d'Hebrón, Universitat Autònoma de Barcelona; Vera Ademà, Francesc Solé, and Mar Mallo, Grup de Recerca Translacional en Neoplàssies Hematològiques, Institut de Recerca Hospital del Mar; Vera Ademà, Facultat de Biociencies, Universitat Aut
- fonoma de Barcelona, Benet Nomdedeu, Hospital Clínic, Barcelona; Guillermo Sanz, Hospital Universitario La Fe; Rosa Collado, Hospital General de Valencia, Valencia; Elisa Luño, Hospital
| | - Benet Nomdedeu
- David Valcárcel, Margarita Ortega, Julia Montoro, and Teresa Vallespí, Hospital Vall d'Hebrón, Universitat Autònoma de Barcelona; Vera Ademà, Francesc Solé, and Mar Mallo, Grup de Recerca Translacional en Neoplàssies Hematològiques, Institut de Recerca Hospital del Mar; Vera Ademà, Facultat de Biociencies, Universitat Aut
- fonoma de Barcelona, Benet Nomdedeu, Hospital Clínic, Barcelona; Guillermo Sanz, Hospital Universitario La Fe; Rosa Collado, Hospital General de Valencia, Valencia; Elisa Luño, Hospital
| | - Guillermo Sanz
- David Valcárcel, Margarita Ortega, Julia Montoro, and Teresa Vallespí, Hospital Vall d'Hebrón, Universitat Autònoma de Barcelona; Vera Ademà, Francesc Solé, and Mar Mallo, Grup de Recerca Translacional en Neoplàssies Hematològiques, Institut de Recerca Hospital del Mar; Vera Ademà, Facultat de Biociencies, Universitat Aut
- fonoma de Barcelona, Benet Nomdedeu, Hospital Clínic, Barcelona; Guillermo Sanz, Hospital Universitario La Fe; Rosa Collado, Hospital General de Valencia, Valencia; Elisa Luño, Hospital
| | - Elisa Luño
- David Valcárcel, Margarita Ortega, Julia Montoro, and Teresa Vallespí, Hospital Vall d'Hebrón, Universitat Autònoma de Barcelona; Vera Ademà, Francesc Solé, and Mar Mallo, Grup de Recerca Translacional en Neoplàssies Hematològiques, Institut de Recerca Hospital del Mar; Vera Ademà, Facultat de Biociencies, Universitat Aut
- fonoma de Barcelona, Benet Nomdedeu, Hospital Clínic, Barcelona; Guillermo Sanz, Hospital Universitario La Fe; Rosa Collado, Hospital General de Valencia, Valencia; Elisa Luño, Hospital
| | - Consuelo Cañizo
- David Valcárcel, Margarita Ortega, Julia Montoro, and Teresa Vallespí, Hospital Vall d'Hebrón, Universitat Autònoma de Barcelona; Vera Ademà, Francesc Solé, and Mar Mallo, Grup de Recerca Translacional en Neoplàssies Hematològiques, Institut de Recerca Hospital del Mar; Vera Ademà, Facultat de Biociencies, Universitat Aut
- fonoma de Barcelona, Benet Nomdedeu, Hospital Clínic, Barcelona; Guillermo Sanz, Hospital Universitario La Fe; Rosa Collado, Hospital General de Valencia, Valencia; Elisa Luño, Hospital
| | - Javier de la Serna
- David Valcárcel, Margarita Ortega, Julia Montoro, and Teresa Vallespí, Hospital Vall d'Hebrón, Universitat Autònoma de Barcelona; Vera Ademà, Francesc Solé, and Mar Mallo, Grup de Recerca Translacional en Neoplàssies Hematològiques, Institut de Recerca Hospital del Mar; Vera Ademà, Facultat de Biociencies, Universitat Aut
- fonoma de Barcelona, Benet Nomdedeu, Hospital Clínic, Barcelona; Guillermo Sanz, Hospital Universitario La Fe; Rosa Collado, Hospital General de Valencia, Valencia; Elisa Luño, Hospital
| | - Maite Ardanaz
- David Valcárcel, Margarita Ortega, Julia Montoro, and Teresa Vallespí, Hospital Vall d'Hebrón, Universitat Autònoma de Barcelona; Vera Ademà, Francesc Solé, and Mar Mallo, Grup de Recerca Translacional en Neoplàssies Hematològiques, Institut de Recerca Hospital del Mar; Vera Ademà, Facultat de Biociencies, Universitat Aut
- fonoma de Barcelona, Benet Nomdedeu, Hospital Clínic, Barcelona; Guillermo Sanz, Hospital Universitario La Fe; Rosa Collado, Hospital General de Valencia, Valencia; Elisa Luño, Hospital
| | - Victor Marco
- David Valcárcel, Margarita Ortega, Julia Montoro, and Teresa Vallespí, Hospital Vall d'Hebrón, Universitat Autònoma de Barcelona; Vera Ademà, Francesc Solé, and Mar Mallo, Grup de Recerca Translacional en Neoplàssies Hematològiques, Institut de Recerca Hospital del Mar; Vera Ademà, Facultat de Biociencies, Universitat Aut
- fonoma de Barcelona, Benet Nomdedeu, Hospital Clínic, Barcelona; Guillermo Sanz, Hospital Universitario La Fe; Rosa Collado, Hospital General de Valencia, Valencia; Elisa Luño, Hospital
| | - Rosa Collado
- David Valcárcel, Margarita Ortega, Julia Montoro, and Teresa Vallespí, Hospital Vall d'Hebrón, Universitat Autònoma de Barcelona; Vera Ademà, Francesc Solé, and Mar Mallo, Grup de Recerca Translacional en Neoplàssies Hematològiques, Institut de Recerca Hospital del Mar; Vera Ademà, Facultat de Biociencies, Universitat Aut
- fonoma de Barcelona, Benet Nomdedeu, Hospital Clínic, Barcelona; Guillermo Sanz, Hospital Universitario La Fe; Rosa Collado, Hospital General de Valencia, Valencia; Elisa Luño, Hospital
| | - Javier Grau
- David Valcárcel, Margarita Ortega, Julia Montoro, and Teresa Vallespí, Hospital Vall d'Hebrón, Universitat Autònoma de Barcelona; Vera Ademà, Francesc Solé, and Mar Mallo, Grup de Recerca Translacional en Neoplàssies Hematològiques, Institut de Recerca Hospital del Mar; Vera Ademà, Facultat de Biociencies, Universitat Aut
- fonoma de Barcelona, Benet Nomdedeu, Hospital Clínic, Barcelona; Guillermo Sanz, Hospital Universitario La Fe; Rosa Collado, Hospital General de Valencia, Valencia; Elisa Luño, Hospital
| | - Julia Montoro
- David Valcárcel, Margarita Ortega, Julia Montoro, and Teresa Vallespí, Hospital Vall d'Hebrón, Universitat Autònoma de Barcelona; Vera Ademà, Francesc Solé, and Mar Mallo, Grup de Recerca Translacional en Neoplàssies Hematològiques, Institut de Recerca Hospital del Mar; Vera Ademà, Facultat de Biociencies, Universitat Aut
- fonoma de Barcelona, Benet Nomdedeu, Hospital Clínic, Barcelona; Guillermo Sanz, Hospital Universitario La Fe; Rosa Collado, Hospital General de Valencia, Valencia; Elisa Luño, Hospital
| | - Mar Mallo
- David Valcárcel, Margarita Ortega, Julia Montoro, and Teresa Vallespí, Hospital Vall d'Hebrón, Universitat Autònoma de Barcelona; Vera Ademà, Francesc Solé, and Mar Mallo, Grup de Recerca Translacional en Neoplàssies Hematològiques, Institut de Recerca Hospital del Mar; Vera Ademà, Facultat de Biociencies, Universitat Aut
- fonoma de Barcelona, Benet Nomdedeu, Hospital Clínic, Barcelona; Guillermo Sanz, Hospital Universitario La Fe; Rosa Collado, Hospital General de Valencia, Valencia; Elisa Luño, Hospital
| | - Teresa Vallespí
- David Valcárcel, Margarita Ortega, Julia Montoro, and Teresa Vallespí, Hospital Vall d'Hebrón, Universitat Autònoma de Barcelona; Vera Ademà, Francesc Solé, and Mar Mallo, Grup de Recerca Translacional en Neoplàssies Hematològiques, Institut de Recerca Hospital del Mar; Vera Ademà, Facultat de Biociencies, Universitat Aut
- fonoma de Barcelona, Benet Nomdedeu, Hospital Clínic, Barcelona; Guillermo Sanz, Hospital Universitario La Fe; Rosa Collado, Hospital General de Valencia, Valencia; Elisa Luño, Hospital
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Myeloproliferative neoplasms 2012: The John M. Bennett 80th birthday anniversary lecture. Leuk Res 2012; 36:1481-9. [DOI: 10.1016/j.leukres.2012.08.011] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2012] [Revised: 07/30/2012] [Accepted: 08/06/2012] [Indexed: 01/12/2023]
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Vannucchi AM, Pieri L, Susini MC, Guglielmelli P. BCR-ABL1-negative chronic myeloid neoplasms: an update on management techniques. Future Oncol 2012; 8:575-93. [PMID: 22646772 DOI: 10.2217/fon.12.50] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Recent discoveries concerning mutations associated with chronic myeloproliferative neoplasms have modified our understanding of the biology of these incurable diseases and guided us to the development of inhibitors active on the constitutively activated JAK-STAT pathway. Concurrently, numerous studies dealt with clinical issues; it led to a revised WHO classification; clarified the role of mutated JAK2 and leukocytosis in the pathogenesis of cardiovascular events; allowed the development of risk prognostic scores and tools for monitoring response to therapy; and resulted in completion of Phase III trials with JAK2 inhibitor in myelofibrosis. All these results hold the promise of improving patient prognostication and therapeutic approach, with the aim of efficiently preventing disease-associated complications and, hopefully, to improve the dismal survival associated with myelofibrosis. This review discusses how to manage, according to current clinical practice, the steps of diagnosis, prognostication and therapeutic choices in myeloproliferative neoplasm patients.
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Affiliation(s)
- Alessandro M Vannucchi
- Section of Hematology, Department of Critical Care, University of Florence, Largo Brambilla 3, 50134 Florence, Italy.
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Pardanani A, Tefferi A. Cytogenetic Risk Stratification in Myelodysplastic Syndromes: Are We There Yet? J Clin Oncol 2012; 30:2703-4; author reply 2704-5. [DOI: 10.1200/jco.2012.42.5033] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
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Allogeneic hematopoietic cell transplantation for myelofibrosis in the era of JAK inhibitors. Blood 2012; 120:1367-79. [PMID: 22700718 DOI: 10.1182/blood-2012-05-399048] [Citation(s) in RCA: 86] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
The discovery of JAK2617F mutation paved the way for the development of small molecule inhibitors of JAK1/2 resulting in first approved JAK1/2 inhibitor, ruxolitinib, for the treatment of patients with myelofibrosis (MF). Although JAK1/2 inhibitor therapy is effective in decreasing the burden of symptoms associated with splenomegaly and MF-related constitutional symptoms, it is neither curative nor effective in reducing the risk of leukemic transformation. Presently, allogeneic hematopoietic cell transplantation (HCT) is the only curative therapy for MF. A significant risk of regimen-related toxicities, graft failure, and GVHD are major barriers to the success of HCT in MF. Because of significant HCT-associated morbidity and mortality, divergent opinions regarding its appropriate role in this clinical situation have emerged. In this review, the risk-benefit ratios of modern drug therapy compared with HCT in MF patients are analyzed. A risk-adapted approach individualized to each patient's biologic characteristics and comorbidities is described, which is currently warranted in determining optimal treatment strategies for patients with MF. Inclusion of JAK1/2 inhibitor therapy in future transplant conditioning regimens may provide an opportunity to overcome some of these barriers, resulting in greater success with HCT for MF patients.
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DeLario MR, Sheehan AM, Ataya R, Bertuch AA, Vega C, Webb CR, Lopez-Terrada D, Venkateswaran L. Clinical, histopathologic, and genetic features of pediatric primary myelofibrosis--an entity different from adults. Am J Hematol 2012; 87:461-4. [PMID: 22389089 DOI: 10.1002/ajh.23140] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2011] [Revised: 01/25/2012] [Accepted: 01/26/2012] [Indexed: 11/09/2022]
Abstract
Primary myelofibrosis is a chronic myeloproliferative neoplasm characterized by cytopenias, leukoerythroblastosis, extramedullary hematopoiesis, hepatosplenomegaly and bone marrow fibrosis. Primary myelofibrosis is a rare disorder in adults; children are even less commonly affected by this entity, with the largest pediatric case series reporting on three patients. Most literature suggests spontaneous resolution of myelofibrosis without long term complications in the majority of affected children. We describe the clinical, pathologic, and molecular characteristics and outcomes of nineteen children with primary myelofibrosis treated in our center from 1984 to 2011. Most patients had cytopenia significant enough to require supportive therapy. No child developed malignant transformation and only five of the 19 children (26%) had spontaneous resolution of disease. Sequence analyses for JAK2V617F and MPLW515L mutations were performed on bone marrow samples from 17 and six patients, respectively, and the results were negative. In conclusion, analysis of this large series of pediatric patients with primary myelofibrosis demonstrates distinct clinical, hematologic, bone marrow, and molecular features from adult patients.
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Affiliation(s)
- Melissa R DeLario
- Pediatrics, Section of Hematology and Oncology, Baylor College of Medicine, 6701 Fannin Street, Houston, TX 77030-2399, USA
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Ballen K. How to manage the transplant question in myelofibrosis. Blood Cancer J 2012; 2:e59. [PMID: 22829254 PMCID: PMC3317522 DOI: 10.1038/bcj.2012.3] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2011] [Revised: 01/13/2012] [Accepted: 01/17/2012] [Indexed: 01/03/2023] Open
Abstract
Allogeneic stem cell transplantation remains the only curative therapy for myelofibrosis. Despite advances in transplant, the morbidity and the mortality of the procedure necessitate careful patient selection. In this manuscript, we describe the new prognostic scoring system to help select appropriate patients for transplant and less aggressive therapies. We explore the advances in non-transplant therapy, such as with investigational agents. We review the blossoming literature on results of myeloablative, reduced intensity and alternative donor transplantation. Finally, we make recommendations for which patients are most likely to benefit from transplantation.
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Affiliation(s)
- K Ballen
- Division of Hematology/Oncology, Massachusetts General Hospital, Boston, MA, USA
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Leukemia risk models in primary myelofibrosis: an International Working Group study. Leukemia 2012; 26:1439-41. [PMID: 22289985 DOI: 10.1038/leu.2011.374] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
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Tefferi A, Lasho TL, Jimma T, Finke CM, Gangat N, Vaidya R, Begna KH, Al-Kali A, Ketterling RP, Hanson CA, Pardanani A. One thousand patients with primary myelofibrosis: the mayo clinic experience. Mayo Clin Proc 2012; 87:25-33. [PMID: 22212965 PMCID: PMC3538387 DOI: 10.1016/j.mayocp.2011.11.001] [Citation(s) in RCA: 196] [Impact Index Per Article: 15.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2011] [Revised: 10/23/2011] [Accepted: 11/03/2011] [Indexed: 01/05/2023]
Abstract
OBJECTIVE To share our decades of experience with primary myelofibrosis and underscore the importance of outcomes research studies in designing clinical trials and interpreting their results. PATIENTS AND METHODS One thousand consecutive patients with primary myelofibrosis seen at Mayo Clinic between November 4, 1977, and September 1, 2011, were considered. The International Prognostic Scoring System (IPSS), dynamic IPSS (DIPSS), and DIPSS-plus were applied for risk stratification. Separate analyses were included for patients seen at time of referral (N=1000), at initial diagnosis (N=340), and within or after 1 year of diagnosis (N=660). RESULTS To date, 592 deaths and 68 leukemic transformations have been documented. Parameters at initial diagnosis vs time of referral included median age (66 vs 65 years), male sex (61% vs 62%), red cell transfusion need (24% vs 38%), hemoglobin level less than 10 g/dL (38% vs 54%), platelet count less than 100 × 10(9)/L (18% vs 26%), leukocyte count more than 25 × 10(9)/L (13% vs 16%), marked splenomegaly (21% vs 31%), constitutional symptoms (29% vs 34%), and abnormal karyotype (31% vs 41%). Mutational frequencies were 61% for JAK2V617F, 8% for MPLW515, and 4% for IDH1/2. DIPSS-plus risk distributions at time of referral were 10% low, 15% intermediate-1, 37% intermediate-2, and 37% high. The corresponding median survivals were 17.5, 7.8, 3.6, and 1.8 years vs 20.0, 14.3, 5.3, and 1.7 years for patients younger than 60 years of age. Compared with both DIPSS and IPSS, DIPSS-plus showed better discrimination among risk groups. Five-year leukemic transformation rates were 6% and 21% in low- and high-risk patients, respectively. CONCLUSION The current document should serve as a valuable resource for patients and physicians and provides context for the design and interpretation of clinical trials.
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Affiliation(s)
- Ayalew Tefferi
- Division of Hematology, Mayo Clinic, Rochester, MN 55905, USA.
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Abstract
PURPOSE OF REVIEW Identification of the JAK2V617F mutation in 2005 boosted basic and clinical research in primary myelofibrosis (PMF) and other Philadelphia-negative chronic myeloproliferative neoplasms. We herein review the recent contributions to the understanding and management of PMF. RECENT FINDINGS In addition to the JAK2V617F mutation, different genetic markers have recently been discovered in PMF, the most relevant ones being the mutations in the thrombopoietin (MPL), TET2, and EZH2 genes. From the clinical point of view, attention has recently been paid to thrombosis as a relevant complication of PMF and new prognostic models for this disease have been created and refined. Regarding therapy, reduced intensity conditioning regimens have allowed the possibility of performing allogeneic stem cell transplantation in older PMF patients, whereas the first clinical trials with JAK2 inhibitors have shown their efficacy in splenomegaly and constitutional symptoms. SUMMARY The molecular biology of PMF is more complex than initially believed. Due to its associated mortality risk, stem cell transplantation should be restricted to patients with poor prognostic features. The JAK2-inhibitors are promising as a palliative treatment of PMF. In conclusion, the once neglected PMF has become a very active field of research, which will hopefully soon translate into relevant therapeutic advances.
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Gaillard JB, Chiesa J, Reboul D, Arnaud A, Brun S, Donadio D, Exbrayat C, Wickenhauser S, Bourquard P, Jourdan E, Lavabre-Bertrand T. Monosomal karyotype routinely defines a poor prognosis subgroup in acute myeloid leukemia and is frequently associated with TP53 deletion. Leuk Lymphoma 2011; 53:336-7. [PMID: 21823831 DOI: 10.3109/10428194.2011.608453] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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