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Spivak JL. Myeloproliferative Neoplasms: Challenging Dogma. J Clin Med 2024; 13:6957. [PMID: 39598101 PMCID: PMC11595126 DOI: 10.3390/jcm13226957] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Revised: 11/09/2024] [Accepted: 11/10/2024] [Indexed: 11/29/2024] Open
Abstract
Myeloproliferative neoplasms, polycythemia vera, essential thrombocytosis, and primary myelofibrosis are a unique group of clonal hematopoietic stem cell neoplasms that share somatic, gain-in-function driver mutations in JAK2, CALR, and MPL. As a consequence, these disorders exhibit similar phenotypic features, the most common of which are the ceaseless production of normal erythrocytes, myeloid cells, platelets alone or in combination, extramedullary hematopoiesis, myelofibrosis, and a potential for leukemic transformation. In the case of polycythemia vera and essential thrombocytosis, however, prolonged survival is possible. With an incidence value in the range of 0.5-2.0/100,000, myeloproliferative neoplasms are rare disorders, but they are not new disorders, and after a century of scrutiny, their clinical features and natural histories are well-defined, though their individual management continues to be controversial. With respect to polycythemia vera, there has been a long-standing dispute between those who believe that the suppression of red blood cell production by chemotherapy is superior to phlebotomy to prevent thrombosis, and those who do not. With respect to essential thrombocytosis, there is a similar dispute about the role of platelets in veinous thrombosis, and the role of chemotherapy in preventing thrombosis by suppressing platelet production. Linked to these disputes is another: whether therapy with hydroxyurea promotes acute leukemia in disorders with a substantial possibility of longevity. The 21st century revealed new insights into myeloproliferative neoplasms with the discovery of their three somatic, gain-of-function driver mutations. Almost immediately, this triggered changes in the diagnostic criteria for myeloproliferative neoplasms and their therapy. Most of these changes, however, conflicted with prior well-validated, phenotypically driven diagnostic criteria and the management of these disorders. The aim of this review is to examine these conflicts and demonstrate how genomic discoveries in myeloproliferative neoplasms can be used to effectively complement the known phenotypic features of these disorders for their diagnosis and management.
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Affiliation(s)
- Jerry L Spivak
- Hematology Division, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
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Patel AB, Masarova L, Mesa RA, Hobbs G, Pemmaraju N. Polycythemia vera: past, present and future. Leuk Lymphoma 2024; 65:1552-1564. [PMID: 38871488 DOI: 10.1080/10428194.2024.2361836] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Revised: 05/16/2024] [Accepted: 05/26/2024] [Indexed: 06/15/2024]
Abstract
There has been remarkable progress in the development of novel therapeutic approaches for patients with polycythemia vera (PV). Historically, therapy goals in PV were to mitigate thrombotic risks and control blood counts and symptoms. There is now increased focus on disease modification through progressive attrition of JAK2-mutant stem/progenitor cells. The approval of ropeginterferon, a novel monoPEGylated interferon, coupled with findings from LOW-PV and longer-term data from CONTINUATION-PV that strongly support a disease-modifying effect for interferon therapy, have transformed the treatment paradigm for this disorder. Results from MAJIC-PV demonstrate that disease modification can also be induced with JAK inhibitors, suggesting an urgent need to incorporate prospective molecular monitoring into PV trials. Novel agents, such as hepcidin mimetics, aim to help patients with PV restore normal hematocrit levels and become phlebotomy-free. In this review, we will summarize past, current and future approaches to PV management and highlight findings from key clinical studies.
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Affiliation(s)
- Ami B Patel
- Division of Hematology and Hematologic Malignancies, The University of Utah, Salt Lake City, UT, USA
| | - Lucia Masarova
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ruben A Mesa
- Atrium Health Wake Forest Baptist Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston Salem, NC, USA
| | - Gabriela Hobbs
- Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Naveen Pemmaraju
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Martinez J, Handa S, Skorodinsky A, Kremyanskaya M. The evolving landscape of polycythemia vera therapies. Expert Opin Pharmacother 2024; 25:1439-1452. [PMID: 39106053 DOI: 10.1080/14656566.2024.2387681] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2024] [Revised: 07/24/2024] [Accepted: 07/30/2024] [Indexed: 08/07/2024]
Abstract
INTRODUCTION The treatment landscape of polycythemia vera (PV) has seen major advancements within the last decade including approval of ruxolitinib in the second line setting after hydroxyurea, ropegylated interferon-α2b, and advanced clinical development of a novel class of agents called hepcidin mimetics. AREAS COVERED We provide a comprehensive review of the evidence discussing the risk stratification, treatment indications, role and limitations of phlebotomy only approach and pivotal trials covering nuances related to the use of interferon-α (IFN-α), ruxolitinib, hepcidin mimetics, and upcoming investigational agents including HDAC and LSD1 inhibitors. EXPERT OPINION The research paradigm in PV is slowly shifting from the sole focus on hematocrit control and moving toward disease modification. The discovery of hepcidin mimetics has come as a breakthrough in restoring iron homeostasis, achieving phlebotomy-independence and may lead to improved thrombosis-free survival with stricter hematocrit control. On the other hand, emerging data with IFN- α and ruxolitinib as well as combination of the two agents suggests the potential for achieving molecular remission in a subset of PV patients and long-term follow-up is awaited to validate the correlation of molecular responses with clinically relevant outcomes of progression-free and thrombosis-free survival.
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Affiliation(s)
- Juana Martinez
- Department of Internal Medicine, NYC Health + Hospitals/Elmhurst, Icahn School of Medicine at Mount Sinai, Queens, NY, USA
| | - Shivani Handa
- Department of Internal Medicine, Division of Hematology, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
| | | | - Marina Kremyanskaya
- Department of Internal Medicine, Division of Hematology & Medical Oncology, Tisch Cancer Institute/Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Tefferi A, Vannucchi AM, Barbui T. Essential thrombocythemia: 2024 update on diagnosis, risk stratification, and management. Am J Hematol 2024; 99:697-718. [PMID: 38269572 DOI: 10.1002/ajh.27216] [Citation(s) in RCA: 24] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Accepted: 01/08/2024] [Indexed: 01/26/2024]
Abstract
OVERVIEW Essential thrombocythemia is a Janus kinase 2 (JAK2) mutation-prevalent myeloproliferative neoplasm characterized by clonal thrombocytosis; clinical course is often indolent but might be interrupted by thrombotic or hemorrhagic complications, microcirculatory symptoms (e.g., headaches, lightheadedness, and acral paresthesias), and, less frequently, by disease transformation into myelofibrosis (MF) or acute myeloid leukemia. DIAGNOSIS In addition to thrombocytosis (platelets ≥450 × 109 /L), formal diagnosis requires the exclusion of other myeloid neoplasms, including prefibrotic MF, polycythemia vera, chronic myeloid leukemia, and myelodysplastic syndromes with ring sideroblasts and thrombocytosis. Bone marrow morphology typically shows increased number of mature-appearing megakaryocytes distributed in loose clusters. GENETICS Approximately 80% of patients express myeloproliferative neoplasm driver mutations (JAK2, CALR, MPL), in a mutually exclusive manner; in addition, about 50% harbor other mutations, the most frequent being TET2 (9%-11%), ASXL1 (7%-20%), DNMT3A (7%), and SF3B1 (5%). Abnormal karyotype is seen in <10% of patients and includes +9/20q-/13q-. SURVIVAL AND PROGNOSIS Life expectancy is less than that of the control population. Median survival is approximately 18 years but exceeds >35 years in younger patients. The triple A survival risk model, based on Age, Absolute neutrophil count, and Absolute lymphocyte count, effectively delineates high-, intermediate-1-, intermediate-2-, and low-risk disease with corresponding median survivals of 8, 14, 21, and 47 years. RISK FACTORS FOR THROMBOSIS Four risk categories are considered: very low (age ≤60 years, no thrombosis history, JAK2 wild-type), low (same as very low but JAK2 mutation present), intermediate (same as low but age >60 years), and high (thrombosis history or age >60 years with JAK2 mutation). MUTATIONS AND PROGNOSIS MPL and CALR-1 mutations have been associated with increased risk of MF transformation; spliceosome with inferior overall and MF-free survival; TP53 with leukemic transformation, and JAK2V617F with thrombosis. Leukemic transformation rate at 10 years is <1% but might be higher in JAK2-mutated patients with extreme thrombocytosis and those with abnormal karyotype. TREATMENT The main goal of therapy is to prevent thrombosis. In this regard, once-daily low-dose aspirin is advised for all patients and twice daily for low-risk disease. Cytoreductive therapy is advised for high-risk and optional for intermediate-risk disease. First-line cytoreductive drugs of choice are hydroxyurea and pegylated interferon-α and second-line busulfan. ADDITIONAL CONTENT The current review includes specific treatment strategies in the context of extreme thrombocytosis, pregnancy, splanchnic vein thrombosis, perioperative care, and post-essential thrombocythemia MF, as well as new investigational drugs.
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Affiliation(s)
- Ayalew Tefferi
- Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Alessandro Maria Vannucchi
- CRIMM, Center Research and Innovation of Myeloproliferative Neoplasms, University of Florence, AOU Careggi, Florence, Italy
| | - Tiziano Barbui
- Research Foundation, Papa Giovanni XXIII Hospital, Bergamo, Italy
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Tefferi A, Barbui T. Polycythemia vera: 2024 update on diagnosis, risk-stratification, and management. Am J Hematol 2023; 98:1465-1487. [PMID: 37357958 DOI: 10.1002/ajh.27002] [Citation(s) in RCA: 71] [Impact Index Per Article: 35.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2023] [Accepted: 06/12/2023] [Indexed: 06/27/2023]
Abstract
DISEASE OVERVIEW Polycythemia vera (PV) is a JAK2-mutated myeloproliferative neoplasm characterized by clonal erythrocytosis; other features include leukocytosis, thrombocytosis, splenomegaly, pruritus, constitutional symptoms, microcirculatory disturbances, and increased risk of thrombosis and progression into myelofibrosis (post-PV MF) or acute myeloid leukemia (AML). DIAGNOSIS A working diagnosis is considered in the presence of a JAK2 mutation associated with hemoglobin/hematocrit levels of >16.5 g/dL/49% in men or 16 g/dL/48% in women; morphologic confirmation by bone marrow examination is advised but not mandated. CYTOGENETICS Abnormal karyotype is seen in 15%-20% of patients with the most frequent sole abnormalities being +9 (5%), loss of chromosome Y (4%), +8 (3%), and 20q- (3%). MUTATIONS Over 50% of patients harbor DNA sequence variants/mutations other than JAK2, with the most frequent being TET2 (18%) and ASXL1 (15%). Prognostically adverse mutations include SRSF2, IDH2, RUNX1, and U2AF1, with a combined incidence of 5%-10%. SURVIVAL AND PROGNOSIS Median survival is ⁓15 years but exceeds 35 years for patients aged ≤40 years. Risk factors for survival include older age, leukocytosis, abnormal karyotype, and the presence of adverse mutations. Twenty-year risk for thrombosis, post-PV MF, or AML are ⁓26%, 16% and 4%, respectively. RISK FACTORS FOR THROMBOSIS Two risk categories are considered: high (age >60 years or thrombosis history) and low (absence of both risk factors). Additional predictors for arterial thrombosis include cardiovascular risk factors and for venous thrombosis higher absolute neutrophil count and JAK2V617F allele burden. TREATMENT Current goal of therapy is to prevent thrombosis. Periodic phlebotomy, with a hematocrit target of <45%, combined with once- or twice-daily aspirin (81 mg) therapy, absent contraindications, is the backbone of treatment in all patients, regardless of risk category. Cytoreductive therapy is reserved for high-risk disease with first-line drugs of choice being hydroxyurea and pegylated interferon-α and second-line busulfan and ruxolitinib. In addition, systemic anticoagulation is advised in patients with venous thrombosis history. ADDITIONAL TREATMENT CONSIDERATIONS At the present time, we do not consider a drug-induced reduction in JAK2V617F allele burden, which is often incomplete and seen not only with peg-IFN but also with ruxolitinib and busulfan, as an indicator of disease-modifying activity, unless accompanied by cytogenetic and independently-verified morphologic remission. Accordingly, we do not use the specific parameter to influence treatment choices. The current review also includes specific treatment strategies in the context of pregnancy, splanchnic vein thrombosis, pruritus, perioperative care, and post-PV MF.
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Affiliation(s)
- Ayalew Tefferi
- Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Tiziano Barbui
- Research Foundation, Papa Giovanni XXIII Hospital, Bergamo, Italy
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Palumbo GA, Breccia M, Baratè C, Bonifacio M, Elli EM, Iurlo A, Pugliese N, Rossi E, Guglielmelli P, Palandri F. Management of polycythemia vera: A survey of treatment patterns in Italy. Eur J Haematol 2023; 110:161-167. [PMID: 36319575 PMCID: PMC10100449 DOI: 10.1111/ejh.13889] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Revised: 10/24/2022] [Accepted: 10/26/2022] [Indexed: 11/07/2022]
Abstract
OBJECTIVES Polycythemia vera (PV) is an acquired clonal hematopoietic stem cell disorder characterized by the overproduction of red blood cells. It has long been underlined that there are differences in treatment patterns in routine practice. Therapeutic strategies have also expanded, and in recent years the JAK1/JAK2 inhibitor ruxolitinib has emerged as a second-line therapeutic option in patients who are intolerant to or resistant to hydroxyurea. Determining the impact of changes on practice patterns is of interest, especially for aspects that lack detailed guidance for management. METHODS To gain insights into treatment patterns by clinicians treating patients with PV in Italy, we carried out a survey of 60 hematologists and transfusion specialists. The questions covered: treatment of low-risk patients, definition of significant leukocytosis, splenomegaly and excessive phlebotomies, resistance/intolerance to hydroxyurea, use of ruxolitinib, cytoreductive therapy, and vaccines. RESULTS In general, the results of the survey indicate that there is a large heterogeneity in management of patients with PV across these areas. CONCLUSIONS While helping to provide greater understanding of treatment patterns for patients with PV in Italy, our survey highlights the need for additional clinical studies to obtain more precise guidance for the routine care of patients with PV.
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Affiliation(s)
- Giuseppe Alberto Palumbo
- Dipartimento di Scienze Mediche, Chirurgiche e Tecnologie Avanzate "G.F. Ingrassia", University of Catania, Catania, Italy
| | - Massimo Breccia
- Hematology, Department of Precision and Translational Medicine, Policlinico Umberto 1, Sapienza University, Rome, Italy
| | - Claudia Baratè
- Department of Clinical and Experimental Medicine, Section of Hematology, University of Pisa, Pisa, Italy
| | - Massimiliano Bonifacio
- Department of Medicine, Section of Hematology, University of Verona and AOUI Verona, Verona, Italy
| | - Elena Maria Elli
- Hematology Division and Bone Marrow Transplant Unit, Ospedale San Gerardo, ASST Monza, Monza, Italy
| | - Alessandra Iurlo
- Hematology Division, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Novella Pugliese
- Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Elena Rossi
- Section of Hematology, Department of Radiological and Hematological Sciences, Catholic University, Fondazione Policlinico A. Gemelli IRCCS, Rome, Italy
| | - Paola Guglielmelli
- Center of Research and Innovation of Myeloproliferative Neoplasms, AOU Careggi, University of Florence, Florence, Italy
| | - Francesca Palandri
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia "Seràgnoli", Bologna, Italy
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Saliba AN, Gangat N. Accelerated and blast phase myeloproliferative neoplasms. Best Pract Res Clin Haematol 2022; 35:101379. [DOI: 10.1016/j.beha.2022.101379] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2022] [Accepted: 08/23/2022] [Indexed: 11/29/2022]
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Appropriate management of polycythaemia vera with cytoreductive drug therapy: European LeukemiaNet 2021 recommendations. Lancet Haematol 2022; 9:e301-e311. [DOI: 10.1016/s2352-3026(22)00046-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 01/28/2022] [Accepted: 01/31/2022] [Indexed: 02/06/2023]
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Barbui T, Carobbio A, De Stefano V. Thrombosis in myeloproliferative neoplasms during cytoreductive and antithrombotic drug treatment. Res Pract Thromb Haemost 2022; 6:e12657. [PMID: 35155976 PMCID: PMC8822262 DOI: 10.1002/rth2.12657] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 12/31/2021] [Accepted: 01/12/2022] [Indexed: 12/16/2022] Open
Abstract
A state-of-the-art lecture titled "Myeloproliferative Neoplasm-associated Thrombosis" was presented at the ISTH congress in 2021. We summarize here the main points of the lecture with two purposes: to report the incidence rates of major thrombosis in polycythemia vera and essential thrombocythemia and to discuss to what extent cytoreductive therapy and antithrombotic drugs have reduced the incidence of these events. Unfortunately, the incidence rate of thrombosis remains high, ranging between 2 and 5/100 person-years. It is likely that new drugs such as interferon and ruxolitinib can be more efficacious given their cytoreductive and anti-inflammatory activities. Despite prophylaxis with vitamin K antagonists and direct oral anticoagulants after venous thrombosis in either common sites or splanchnic or cerebral sites, the incidence rate is still elevated, as high as 4 to 5/100 person-years. Future studies with new drugs or new strategies should consider thrombosis as the primary endpoint or surrogate biomarkers only if previously validated.
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Affiliation(s)
- Tiziano Barbui
- FROM Research FoundationPapa Giovanni XXIII HospitalBergamoItaly
| | | | - Valerio De Stefano
- Section of HematologyDepartment of Radiological and Hematological SciencesCatholic UniversityFondazione Policlinico A. Gemelli IRCCSRomeItaly
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Running interferon interference in treating PV/ET: meeting unmet needs. Hematology 2021; 2021:463-468. [DOI: 10.1182/hematology.2021000280] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Abstract
Enthusiasm about interferons for the treatment of myeloproliferative neoplasms has recently arisen. How does a nontargeted therapy selectively target the malignant clone? Many foundational questions about interferon treatment are unanswered, including who, when, and for how long do we treat. Using an individual case, this review touches on gaps in risk assessment in polycythemia vera (PV) and essential thrombocythemia (ET) and the history of treatment with interferons. How is it that this proinflammatory cytokine effectively treats ET and PV, themselves proinflammatory states? We summarize existing mechanistic and clinical data, the molecular context as a modifier for treatment response, the establishment of treatment goals, and the challenges that lie ahead.
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Spivak JL. Advances in polycythemia vera and lessons for acute leukemia. Best Pract Res Clin Haematol 2021; 34:101330. [PMID: 34865702 DOI: 10.1016/j.beha.2021.101330] [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: 10/20/2022]
Abstract
The myeloproliferative neoplasms (MPN), polycythemia vera (PV), essential thrombocytosis and primary myelofibrosis, are an unusual group of myeloid neoplasms, which arise in a pluripotent hematopoietic stem cell (HSC) due to gain of function driver mutations in the JAK2, CALR and MPL genes that constitutively activate JAK2, the cognate tyrosine kinase of the type 1 hematopoietic growth factor (HGF) receptors. PV is the ultimate phenotypic expression of constitutive JAK2 activation since it alone of the three MPN is characterized by overproduction of normal red cells, white cells and platelets. Paradoxically, however, although PV is a panmyelopathy involving myeloid, erythroid and megakaryocytic progenitor cells, pluripotent HSC only express a single type of HGF receptor, the thrombopoietin receptor, MPL. In this review, the basis for how a pluripotent HSC with one type of HGF can give rise to three separate types of myeloid cells will be explained and it will be demonstrated that PV is actually a hormone-sensitive disorder, characterized by elevated thrombopoietin levels. Finally, it will be shown that the most common form of acute leukemia in PV is due to the inappropriate use of chemotherapy, including hydroxyurea, which facilitates expansion of DNA-damaged, mutated HSC at the expense of their normal counterparts.
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Affiliation(s)
- Jerry L Spivak
- Division of Hematology, Johns Hopkins University School of Medicine, Traylor 924, 720 Rutland Avenue, Baltimore, MD, 20037, USA.
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Tefferi A, Vannucchi AM, Barbui T. Polycythemia vera: historical oversights, diagnostic details, and therapeutic views. Leukemia 2021; 35:3339-3351. [PMID: 34480106 PMCID: PMC8632660 DOI: 10.1038/s41375-021-01401-3] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 08/17/2021] [Accepted: 08/23/2021] [Indexed: 02/07/2023]
Abstract
Polycythemia vera (PV) is a relatively indolent myeloid neoplasm with median survival that exceeds 35 years in young patients, but its natural history might be interrupted by thrombotic, fibrotic, or leukemic events, with respective 20-year rates of 26%, 16%, and 4%. Current treatment strategies in PV have not been shown to prolong survival or lessen the risk of leukemic or fibrotic progression and instead are directed at preventing thrombotic complications. In the latter regard, two risk categories are considered: high (age >60 years or thrombosis history) and low (absence of both risk factors). All patients require phlebotomy to keep hematocrit below 45% and once-daily low-dose aspirin, in the absence of contraindications. Cytoreductive therapy is recommended for high-risk or symptomatic low-risk disease; our first-line drug of choice in this regard is hydroxyurea but we consider pegylated interferon as an alternative in certain situations, including in young women of reproductive age, in patients manifesting intolerance or resistance to hydroxyurea therapy, and in situations where treatment is indicated for curbing phlebotomy requirement rather than preventing thrombosis. Additional treatment options include busulfan and ruxolitinib; the former is preferred in older patients and the latter in the presence of symptoms reminiscent of post-PV myelofibrosis or protracted pruritus. Our drug choices reflect our appreciation for long-term track record of safety, evidence for reduction of thrombosis risk, and broader suppression of myeloproliferation. Controlled studies are needed to clarify the added value of twice- vs once-daily aspirin dosing and direct oral anticoagulants. In this invited review, we discuss our current approach to diagnosis, prognostication, and treatment of PV in general, as well as during specific situations, including pregnancy and splanchnic vein thrombosis.
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Affiliation(s)
- Ayalew Tefferi
- Division of Hematology, Department of 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
| | - Tiziano Barbui
- Research Foundation, Papa Giovanni XXIII Hospital, Bergamo, Italy
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The Development of Primary Effusion Lymphoma-Like Lymphoma in a Patient with Preexisting Essential Thrombocythemia. Case Rep Hematol 2021; 2021:5237986. [PMID: 34552800 PMCID: PMC8452419 DOI: 10.1155/2021/5237986] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Accepted: 08/26/2021] [Indexed: 12/22/2022] Open
Abstract
A 71-year-old Japanese male was diagnosed with essential thrombocythemia (ET) with the JAK2 V617F mutation variation, in April 2011. He was mainly treated with hydroxyurea following which the number of platelets was maintained within the normal limit. At age 80, he was hospitalized due to cardiac tamponade. Computed tomography showed no evidence of tumor masses or lymphadenopathy. Pericardial drainage was performed, and cytopathologic examination of the fluid revealed atypical lymphoid cells consistent with an effusion lymphoma of B cell lineage. The pericardial effusion was completely drained, and complete remission was achieved. Ultimately, the patient was diagnosed with primary effusion lymphoma-like lymphoma (PEL-LL). To the best of our knowledge, this is the first report of PEL-LL following ET.
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14
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Clinical insights into the origins of thrombosis in myeloproliferative neoplasms. Blood 2021; 137:1145-1153. [PMID: 33237986 DOI: 10.1182/blood.2020008043] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Accepted: 11/18/2020] [Indexed: 02/06/2023] Open
Abstract
Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), polycythemia vera, essential thrombocythemia, and primary myelofibrosis, are hematopoietic stem cell disorders that are defined by activating mutations in signal transduction pathways and are characterized clinically by the overproduction of platelets, red blood cells, and neutrophils, significant burden of disease-specific symptoms, and high rates of vascular events. The focus of this review is to critically reevaluate the clinical burden of thrombosis in MPNs, to review the clinical associations among clonal hematopoiesis, JAK2V617F burden, inflammation, and thrombosis, and to provide insights into novel primary and secondary thrombosis-prevention strategies.
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Castillo Tokumori F, Komrokji R, Kuykendall AT. Stepping out of antiquity: An update on emerging drugs for the treatment of polycythemia vera. Expert Opin Emerg Drugs 2021; 26:209-218. [PMID: 34139920 DOI: 10.1080/14728214.2021.1945579] [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: 10/21/2022]
Abstract
Introduction: Polycythemia vera is a chronic hematologic malignancy frequently presented with constitutional symptoms and associated with an increased risk of thrombosis, hemorrhage, and progression to myelofibrosis or acute myeloid leukemia. Current treatment strategies reduce thrombohemorrhagic risk by controlling blood counts and inhibiting platelets, but often fail to address disease-related symptoms or biologically modify the disease.Areas covered: We review the current paradigm for treating polycythemia vera, highlight areas of unmet need, review therapeutic agents in late stage clinical development, and provide an overarching view of how these emerging agent may fit into the future armamentarium of polycythemia vera treatments.Expert opinion: The shift from focusing solely on secondary prevention of thrombohemorrhagic events to a comprehensive treatment strategy that additionally aims to improve quality of life and prevent disease progression has resulted in a rapidly evolving therapeutic landscape that promises to move the treatment of polycythemia vera out of antiquity into the modern age.
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Affiliation(s)
| | - Rami Komrokji
- Department of Malignant Hematology, H. Lee Moffitt Cancer Center, Tampa, USA
| | - Andrew T Kuykendall
- Department of Malignant Hematology, H. Lee Moffitt Cancer Center, Tampa, USA
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Constanzo J, Faget J, Ursino C, Badie C, Pouget JP. Radiation-Induced Immunity and Toxicities: The Versatility of the cGAS-STING Pathway. Front Immunol 2021; 12:680503. [PMID: 34079557 PMCID: PMC8165314 DOI: 10.3389/fimmu.2021.680503] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2021] [Accepted: 04/26/2021] [Indexed: 12/20/2022] Open
Abstract
In the past decade, radiation therapy (RT) entered the era of personalized medicine, following the striking improvements in radiation delivery and treatment planning optimization, and in the understanding of the cancer response, including the immunological response. The next challenge is to identify the optimal radiation regimen(s) to induce a clinically relevant anti-tumor immunity response. Organs at risks and the tumor microenvironment (e.g. endothelial cells, macrophages and fibroblasts) often limit the radiation regimen effects due to adverse toxicities. Here, we reviewed how RT can modulate the immune response involved in the tumor control and side effects associated with inflammatory processes. Moreover, we discussed the versatile roles of tumor microenvironment components during RT, how the innate immune sensing of RT-induced genotoxicity, through the cGAS-STING pathway, might link the anti-tumor immune response, radiation-induced necrosis and radiation-induced fibrosis, and how a better understanding of the switch between favorable and deleterious events might help to define innovative approaches to increase RT benefits in patients with cancer.
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Affiliation(s)
- Julie Constanzo
- IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, Institut régional du Cancer de Montpellier, Montpellier, France
| | - Julien Faget
- IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, Institut régional du Cancer de Montpellier, Montpellier, France
| | - Chiara Ursino
- IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, Institut régional du Cancer de Montpellier, Montpellier, France
| | - Christophe Badie
- Cancer Mechanisms and Biomarkers Group, Radiation Effects Department, Centre for Radiation, Chemical & Environmental Hazards Public Health England Chilton, Didcot, United Kingdom
| | - Jean-Pierre Pouget
- IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, Institut régional du Cancer de Montpellier, Montpellier, France
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17
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Spivak JL, Moliterno AR. The Thrombopoietin Receptor, MPL, Is a Therapeutic Target of Opportunity in the MPN. Front Oncol 2021; 11:641613. [PMID: 33777803 PMCID: PMC7987816 DOI: 10.3389/fonc.2021.641613] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Accepted: 01/28/2021] [Indexed: 12/12/2022] Open
Abstract
The myeloproliferative neoplasms, polycythemia vera, essential thrombocytosis and primary myelofibrosis share driver mutations that either activate the thrombopoietin receptor, MPL, or indirectly activate it through mutations in the gene for JAK2, its cognate tyrosine kinase. Paradoxically, although the myeloproliferative neoplasms are classified as neoplasms because they are clonal hematopoietic stem cell disorders, the mutations affecting MPL or JAK2 are gain-of-function, resulting in increased production of normal erythrocytes, myeloid cells and platelets. Constitutive JAK2 activation provides the basis for the shared clinical features of the myeloproliferative neoplasms. A second molecular abnormality, impaired posttranslational processing of MPL is also shared by these disorders but has not received the recognition it deserves. This abnormality is important because MPL is the only hematopoietic growth factor receptor expressed in hematopoietic stem cells; because MPL is a proto-oncogene; because impaired MPL processing results in chronic elevation of plasma thrombopoietin, and since these diseases involve normal hematopoietic stem cells, they have proven resistant to therapies used in other myeloid neoplasms. We hypothesize that MPL offers a selective therapeutic target in the myeloproliferative neoplasms since impaired MPL processing is unique to the involved stem cells, while MPL is required for hematopoietic stem cell survival and quiescent in their bone marrow niches. In this review, we will discuss myeloproliferative neoplasm hematopoietic stem cell pathophysiology in the context of the behavior of MPL and its ligand thrombopoietin and the ability of thrombopoietin gene deletion to abrogate the disease phenotype in vivo in a JAK2 V617 transgenic mouse model of PV.
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Affiliation(s)
- Jerry L Spivak
- Hematology Division, Department of Medicine, Johns Hopkins University School of Medicine Baltimore, Baltimore, MD, United States
| | - Alison R Moliterno
- Hematology Division, Department of Medicine, Johns Hopkins University School of Medicine Baltimore, Baltimore, MD, United States
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18
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Abstract
Accelerated and blast phase myeloproliferative neoplasms are advanced stages of the disease with historically a poor prognosis and little improvement in outcomes thus far. The lack of responses to standard treatments likely results from the more aggressive biology reflected by the higher incidence of complex karyotype and high-risk somatic mutations, which are enriched at the time of transformation. Treatment options include induction chemotherapy (7 + 3) as that used on de novo acute myeloid leukemia or hypomethylating agent-based therapy, which has shown similar outcomes. Allogeneic stem cell transplantation remains the only potential for cure.
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Affiliation(s)
- Tania Jain
- Division of Hematological Malignancies and Stem Cell Transplantation, Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, 1650 Orleans Street, Baltimore, MD 21287, USA.
| | - Raajit K Rampal
- Leukemia Service, Department of Medicine, Memorial Sloan Kettering, 530 East 74th Street, New York, NY 10021, USA. https://twitter.com/RaajitRampal
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19
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Tefferi A, Barbui T. Polycythemia vera and essential thrombocythemia: 2021 update on diagnosis, risk-stratification and management. Am J Hematol 2020; 95:1599-1613. [PMID: 32974939 DOI: 10.1002/ajh.26008] [Citation(s) in RCA: 219] [Impact Index Per Article: 43.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Accepted: 09/21/2020] [Indexed: 12/25/2022]
Abstract
DISEASE OVERVIEW Polycythemia vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms (MPN) respectively characterized by clonal erythrocytosis and thrombocytosis; other disease features include leukocytosis, splenomegaly, thrombosis, bleeding, microcirculatory symptoms, pruritus and risk of leukemic or fibrotic transformation. DIAGNOSIS Bone marrow morphology remains the cornerstone of diagnosis. In addition, the presence of JAK2 mutation is expected in PV while approximately 90% of patients with ET express mutually exclusive JAK2, CALR or MPL mutations (so called driver mutations). In ET, it is most important to exclude the possibility of prefibrotic myelofibrosis. SURVIVAL Median survivals are approximately 15 years for PV and 18 years for ET; the corresponding values for patients age 40 or younger were 37 and 35 years. Certain mutations (mostly spliceosome) and abnormal karyotype might compromise survival in PV and ET. Life-expectancy in ET is inferior to the control population. Driver mutations have not been shown to affect survival in ET but risk of thrombosis is higher in JAK2 mutated cases. Leukemic transformation rates at 10 years are estimated at <1% for ET and 3% for PV. THROMBOSIS RISK In PV, two risk categories are considered: high (age > 60 years or thrombosis history present) and low (absence of both risk factors). In ET, four risk categories are considered: very low (age ≤ 60 years, no thrombosis history, JAK2 wild-type), low (same as very low but JAK2 mutation present), intermediate (age > 60 years, no thrombosis history, JAK2 wild-type) and high (thrombosis history present or age > 60 years with JAK2 mutation). RISK-ADAPTED THERAPY The main goal of therapy in both PV and ET is to prevent thrombohemorrhagic complications. All patients with PV require phlebotomy to keep hematocrit below 45% and once-daily or twice-daily aspirin (81 mg), in the absence of contraindications. Very low risk ET might not require therapy while aspirin therapy is advised for low risk disease. Cytoreductive therapy is recommended for high-risk ET and PV, but it is not mandatory for intermediate-risk ET. First-line drug of choice for cytoreductive therapy, in both ET and PV, is hydroxyurea and second-line drugs of choice are interferon-α and busulfan. We do not recommend treatment with ruxolutinib in PV, unless in the presence of severe and protracted pruritus or marked splenomegaly that is not responding to the aforementioned drugs. NEW TREATMENT DIRECTIONS Controlled studies are needed to confirm the clinical outcome value of twice-daily vs once-daily aspirin dosing and the therapeutic role of pegylated interferons and direct oral anticoagulants.
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Affiliation(s)
- Ayalew Tefferi
- Division of Hematology, Department of Medicine Mayo Clinic Rochester Minnesota
| | - Tiziano Barbui
- Research Foundation Papa Giovanni XXIII Hospital Bergamo Italy
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20
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Subtelna I, Kryshchyshyn-Dylevych A, Jia R, Lelyukh M, Ringler A, Kubicek S, Zagrijtschuk O, Kralovics R, Lesyk R. 5-Arylidene-2-(4-hydroxyphenyl)aminothiazol-4(5H)-ones with selective inhibitory activity against some leukemia cell lines. Arch Pharm (Weinheim) 2020; 354:e2000342. [PMID: 33241558 DOI: 10.1002/ardp.202000342] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Revised: 10/31/2020] [Accepted: 11/07/2020] [Indexed: 11/07/2022]
Abstract
The data on the pharmacology of 4-thiazolidinones showed that 5-ene-2-(imino)amino-4-thiazolidinones are likely to comprise one of the most promising groups of compounds possessing anticancer properties. A series of 5-arylidene-2-(4-hydroxyphenyl)aminothiazol-4(5H)-ones was designed, synthesized, and studied against 10 leukemia cell lines, including the HL-60, Jurkat, K-562, Dami, KBM-7, and some Ba/F3 cell lines. The structure-activity relationship analysis shows that almost all tested 5-arylidene-2-(4-hydroxyphenyl)aminothiazol-4(5H)-ones were characterized by ІС50 values lower or comparable to that of the control drug chlorambucil. Among the tested compounds, (5Z)-5-(2-methoxybenzylidene)- (12), (5Z)-(2-ethoxybenzylidene)- (21), (5Z)-5-(2-benzyloxybenzylidene)- (25), and (5Z)-5-(2-allyloxybenzylidene)-2-(4-hydroxyphenylamino)thiazol-4(5H)-ones (28) possessed the highest antileukemic activity at submicromolar concentrations (ІС50 = 0.10-0.95 µM).
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Affiliation(s)
- Ivanna Subtelna
- Department of Pharmaceutical, Organic, and Bioorganic Chemistry, Danylo Halytsky Lviv National Medical University, Lviv, Ukraine
| | - Anna Kryshchyshyn-Dylevych
- Department of Pharmaceutical, Organic, and Bioorganic Chemistry, Danylo Halytsky Lviv National Medical University, Lviv, Ukraine
| | - Ruochen Jia
- MyeloPro Diagnostics and Research GmbH, Vienna, Austria.,Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
| | - Maryan Lelyukh
- Department of Pharmaceutical, Organic, and Bioorganic Chemistry, Danylo Halytsky Lviv National Medical University, Lviv, Ukraine
| | - Anna Ringler
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Stefan Kubicek
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | | | - Robert Kralovics
- Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.,CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Roman Lesyk
- Department of Pharmaceutical, Organic, and Bioorganic Chemistry, Danylo Halytsky Lviv National Medical University, Lviv, Ukraine.,Department of Public Health, University of Information Technology and Management in Rzeszow, Rzeszow, Poland
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21
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Brabrand M, Frederiksen H. Risks of Solid and Lymphoid Malignancies in Patients with Myeloproliferative Neoplasms: Clinical Implications. Cancers (Basel) 2020; 12:cancers12103061. [PMID: 33092233 PMCID: PMC7589412 DOI: 10.3390/cancers12103061] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 10/05/2020] [Accepted: 10/19/2020] [Indexed: 01/21/2023] Open
Abstract
Simple Summary Patients with chronic myeloproliferative neoplasms (MPNs) such as polycythemia vera and essential thrombocythemia have an elevated risk of acute leukemia. Recently, it has been recognized that the risk of solid cancers is also increased. In the past decade, several studies have compared cancer frequency in patients with MPNs with the general population. In our study, we present results sampled from 12 previous studies, totaling more than 65,000 patients with MPNs identified through large registries. Patients with MPNs were compared to the age/sex-matched general population. Our results show that risk of new cancers is 1.5–3.0-fold elevated in patients with MPNs. In particular, lymphomas and cancers of the skin, lung, kidney, and thyroid gland occur more frequently. The difference in cancer occurrence is highest in the age group 60–79 years. Our results indicate that clinical follow up of patients with MPNs should include awareness of the increased cancer risk. Abstract In the past decade, several studies have reported that patients with chronic myeloproliferative neoplasms (MPNs) have an increased risk of second solid cancer or lymphoid hematological cancer. In this qualitative review study, we present results from studies that report on these cancer risks in comparison to cancer incidences in the general population or a control group. Our literature search identified 12 such studies published in the period 2009–2018 including analysis of more than 65,000 patients. The results showed that risk of solid cancer is 1.5- to 3.0-fold elevated and the risk of lymphoid hematological cancer is 2.5- to 3.5-fold elevated in patients with MPNs compared to the general population. These elevated risks apply to all MPN subtypes. For solid cancers, particularly risks of skin cancer, lung cancer, thyroid cancer, and kidney cancer are elevated. The largest difference in cancer risk between patients with MPN and the general population is seen in patients below 80 years. Cancer prognosis is negatively affected due to cardiovascular events, thrombosis, and infections by a concurrent MPN diagnosis mainly among patients with localized cancer. Our review emphasizes that clinicians caring for patients with MPNs should be aware of the very well-documented increased risk of second non-myeloid cancers.
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Affiliation(s)
- Mette Brabrand
- Department of Haematology, Odense University Hospital, 5000 Odense, Denmark;
- Academy of Geriatric Cancer Research (AgeCare), Odense University Hospital, 5000 Odense, Denmark
- Department of Clinical Research, University of Southern Denmark, 5000 Odense, Denmark
| | - Henrik Frederiksen
- Department of Haematology, Odense University Hospital, 5000 Odense, Denmark;
- Department of Clinical Epidemiology, Aarhus University Hospital, 8200 Aarhus, Denmark
- Correspondence:
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22
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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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23
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Current management strategies for polycythemia vera and essential thrombocythemia. Blood Rev 2020; 42:100714. [DOI: 10.1016/j.blre.2020.100714] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Revised: 08/02/2019] [Accepted: 05/11/2020] [Indexed: 02/06/2023]
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24
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Spivak JL. Polycythaemia vera, ruxolitinib, and hydroxyurea: where do we go now? LANCET HAEMATOLOGY 2020; 7:e184-e185. [PMID: 31982040 DOI: 10.1016/s2352-3026(19)30262-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Revised: 12/04/2019] [Accepted: 12/04/2019] [Indexed: 10/25/2022]
Affiliation(s)
- Jerry L Spivak
- Hematology Division, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
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25
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Azrakhsh NA, Mensah-Glanowska P, Sand K, Kittang AO. Targeting Immune Signaling Pathways in Clonal Hematopoiesis. Curr Med Chem 2019; 26:5262-5277. [PMID: 30907306 DOI: 10.2174/0929867326666190325100636] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2018] [Revised: 03/05/2019] [Accepted: 03/12/2019] [Indexed: 12/15/2022]
Abstract
BACKGROUND Myeloid neoplasms are a diverse group of malignant diseases with different entities and numerous patho-clinical features. They arise from mutated clones of hematopoietic stem- and progenitor cells which expand by outperforming their normal counterparts. The intracellular signaling profile of cancer cells is the sum of genetic, epigenetic and microenvironmental influences, and the multiple interconnections between different signaling pathways make pharmacological targeting complicated. OBJECTIVE To present an overview of known somatic mutations in myeloproliferative neoplasms (MPN), myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) and the inflammatory signaling pathways affected by them, as well as current efforts to therapeutically modulate this aberrant inflammatory signaling. METHODS In this review, we extensively reviewed and compiled salient information with ClinicalTrials.gov as our source on ongoing studies, and PubMed as our authentic bibliographic source, using a focused review question. RESULTS Mutations affecting immune signal transduction are present to varying extents in clonal myeloid diseases. While MPN are dominated by a few common mutations, a multitude of different genes can be mutated in MDS and AML. Mutations can also occur in asymptomatic persons, a finding called clonal hematopoiesis of indeterminate potential (CHIP). Mutations in FLT3, JAK, STAT, CBL and RAS can lead to aberrant immune signaling. Protein kinase inhibitors are entering the clinic and are extensively investigated in clinical trials in MPN, MDS and AML. CONCLUSION In summary, this article summarizes recent research on aberrant inflammatory signaling in clonal myeloid diseases and the clinical therapeutic potential of modulation of signal transduction and effector proteins in the affected pathways.
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Affiliation(s)
| | - Patrycja Mensah-Glanowska
- Department of Hematology, Jagiellonian University Medical College / University Hospital, Krakow, Poland
| | - Kristoffer Sand
- Clinic of Medicine and Rehabilitation, More and Romsdal Hospital Trust, Alesund, Norway
| | - Astrid Olsnes Kittang
- Department of Clinical Science, University of Bergen, Bergen, Norway.,Department of Medicine, Section for Hematology, Haukeland University Hospital, Bergen, Norway
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26
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Affiliation(s)
- Ayalew Tefferi
- From the Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN
| | - Animesh Pardanani
- From the Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN
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27
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Abstract
Since its discovery, polycythemia vera (PV) has challenged clinicians responsible for its diagnosis and management and scientists investigating its pathogenesis. As a clonal hematopoietic stem cell (HSC) disorder, PV is a neoplasm but its driver mutations result in overproduction of morphologically and functionally normal blood cells. PV arises in an HSC but it can present initially as isolated erythrocytosis, leukocytosis, thrombocytosis, or any combination of these together with splenomegaly or myelofibrosis, and it can take years for a true panmyelopathy to appear. PV shares the same JAK2 mutation as essential thrombocytosis and primary myelofibrosis, but erythrocytosis only occurs in PV. However, unlike secondary causes of erythrocytosis, in PV, the plasma volume is frequently expanded, masking the erythrocytosis and making diagnosis difficult if this essential fact is ignored. PV is not a monolithic disorder: female patients deregulate fewer genes and clinically behave differently than their male counterparts, while some PV patients are genetically predisposed to an aggressive clinical course. Nevertheless, based on what we have learned over the past century, most PV patients can lead long and productive lives. In this review, using clinical examples, I describe how I diagnose and manage PV in an evidence-based manner without relying on chemotherapy.
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28
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Therapy-associated leukemic transformation in myeloproliferative neoplasms – What do we know? Best Pract Res Clin Haematol 2019; 32:65-73. [DOI: 10.1016/j.beha.2019.02.004] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Revised: 02/02/2019] [Accepted: 02/07/2019] [Indexed: 12/22/2022]
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29
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Targeted next-generation sequencing in blast phase myeloproliferative neoplasms. Blood Adv 2019; 2:370-380. [PMID: 29467191 DOI: 10.1182/bloodadvances.2018015875] [Citation(s) in RCA: 91] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2018] [Accepted: 01/24/2018] [Indexed: 11/20/2022] Open
Abstract
Among 248 consecutive patients with blast phase myeloproliferative neoplasm (MPN-BP), DNA collected at the time of blast transformation was available in 75 patients (median age, 66 years; 64% men). MPN-BP followed primary myelofibrosis in 39 patients, essential thrombocythemia in 20 patients, and polycythemia vera in 16 patients. A myeloid neoplasm-relevant 33-gene panel was used for next-generation sequencing. Driver mutation distribution was JAK2 57%, CALR 20%, MPL 9%, and triple-negative 13%. Sixty-four patients (85%) harbored other mutations/variants, including 37% with ≥3 mutations; most frequent were ASXL1 47%, TET2 19%, RUNX1 17%, TP53 16%, EZH2 15%, and SRSF2 13%; relative mutual exclusivity was expressed by TP53, EZH2, LNK, RUNX1, SRSF2, and NRAS/KRAS mutations. Paired chronic-blast phase sample analysis was possible in 19 patients and revealed more frequent blast phase acquisition of ASXL1, EZH2, LNK, TET2, TP53, and PTPN11 mutations/variants. In multivariable analysis, RUNX1 and PTPN11 mutations/variants were associated with shorter survival duration; respective hazard ratios (HRs) (95% confidence interval [CI]) were 2.1 (95% CI, 1.1-3.8) and 3.0 (95% CI, 1.1-6.6). An all-inclusive multivariable analysis confirmed the prognostic relevance of RUNX1 mutations (HR, 1.9; 95% CI, 1.5-5.5) and also showed additional contribution from a treatment strategy that includes transplant or induction of complete or near-complete remission (HR, 0.3; 95% CI, 0.2-0.5). The current study points to specific mutations that might bear pathogenetic relevance for leukemic transformation in MPN and also suggest an adverse survival effect of RUNX1 mutations.
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30
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Tefferi A, Barbui T. Polycythemia vera and essential thrombocythemia: 2019 update on diagnosis, risk-stratification and management. Am J Hematol 2019; 94:133-143. [PMID: 30281843 DOI: 10.1002/ajh.25303] [Citation(s) in RCA: 151] [Impact Index Per Article: 25.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2018] [Accepted: 09/26/2018] [Indexed: 12/15/2022]
Abstract
Disease Overview: Polycythemia vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms respectively characterized by erythrocytosis and thrombocytosis; other disease features include leukocytosis, splenomegaly, thrombosis, bleeding, microcirculatory symptoms, pruritus, and risk of leukemic or fibrotic transformation. Diagnosis: Bone marrow morphology remains the cornerstone of diagnosis. In addition, the presence of JAK2 mutation is expected in PV while approximately 90% of patients with ET express mutually exclusive JAK2, CALR, or myeloproliferative leukemia mutations. In ET, it is most important to exclude the possibility of prefibrotic myelofibrosis. Survival: Median survivals are 14 years for PV and 20 years for ET; the corresponding values for younger patients are 24 and 33 years. Certain mutations (mostly spliceosome) and abnormal karyotype might compromise survival in PV and ET. Life-expectancy in ET is inferior to the control population. Driver mutations have not been shown to affect survival in ET. Risk of thrombosis is higher in JAK2-mutated ET. Leukemic transformation rates at 10 years are estimated at <1% for ET and 3% for PV. Thrombosis Risk: In PV, 2 risk categories are considered: high (age > 60 years or thrombosis history present) and low (absence of both risk factors); in ET, 4 risk categories are considered: very low (age ≤ 60 years, no thrombosis history, JAK2 wild-type), low (same as very low but JAK2 mutation present), intermediate (age > 60 years, no thrombosis history, JAK2 wild-type) and high (thrombosis history present or age > 60 years with JAK2 mutation). Risk-Adapted Therapy: The main goal of therapy in both PV and ET is to prevent thrombohemorrhagic complications. All patients with PV require phlebotomy to keep hematocrit below 45% and once- or twice-daily aspirin (81 mg), in the absence of contraindications. Very low-risk ET might not require therapy while aspirin therapy is advised for low-risk disease. Cytoreductive therapy is recommended for high-risk ET and PV but it is not mandatory for intermediate-risk ET. First-line drug of choice for cytoreductive therapy, in both ET and PV, is hydroxyurea and second-line drugs of choice are interferon-α and busulfan. We do not recommend treatment with ruxolutinib in PV, unless in the presence of severe and protracted pruritus or marked splenomegaly that is not responding to the aforementioned drugs.
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Affiliation(s)
- Ayalew Tefferi
- Division of Hematology, Department of Medicine; Mayo Clinic; Rochester Minnesota
| | - Tiziano Barbui
- Research Foundation, Papa Giovanni XXIII Hospital; Bergamo Italy
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31
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32
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How I treat the blast phase of Philadelphia chromosome–negative myeloproliferative neoplasms. Blood 2018; 132:2339-2350. [DOI: 10.1182/blood-2018-03-785907] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2018] [Accepted: 10/06/2018] [Indexed: 12/30/2022] Open
Abstract
The classic Philadelphia chromosome (Ph)–negative myeloproliferative neoplasms (MPNs) are a heterogeneous group of hematopoietic stem-cell diseases, characterized by activated JAK/STAT signaling and significant phenotypic mimicry, including a propensity for evolution to myeloid blast phase disease. Effective therapeutic options are limited for patients with Ph− MPNs in the blast phase (MPN-BP), and allogeneic stem-cell transplantation is the only known cure. Our increasing understanding of the molecular pathogenesis of this group of diseases, coupled with the increasing availability of targeted agents, has the potential to inform new subset-specific therapeutic approaches. Ultimately, progress in MPN-BP will hinge on prospective clinical and translational investigations with the goal of generating more effective treatment interventions. This case-based review highlights the molecular and clinical heterogeneities of MPN-BP and incorporates a treatment algorithm that underscores the importance of a personalized approach to this challenging group of diseases.
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Dickersin K, Dixon D, Ferris F, Goldberg J, Kimmel S, Lachin J. University of Pennsylvania 10th annual conference on statistical issues in clinical trials: Current issues regarding data and safety monitoring committees in clinical trials (afternoon panel session). Clin Trials 2018; 15:366-385. [PMID: 30021497 DOI: 10.1177/1740774518781849] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
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Burgstaller S, Buxhofer-Ausch V, Sliwa T, Beham-Schmid C, Gastl G, Geissler K, Melchardt T, Krauth M, Krippl P, Petzer A, Rumpold H, Wölfler A, Gisslinger H. Austrian recommendations for the management of polycythemia vera. Wien Klin Wochenschr 2018; 130:535-542. [PMID: 30027395 DOI: 10.1007/s00508-018-1359-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2018] [Accepted: 06/22/2018] [Indexed: 01/07/2023]
Abstract
Polycythemia vera (PV) is a clonal disease arising from hematopoietic stem cells. Erythrocytosis is the hallmark of the disease but leukocytosis, thrombocytosis and splenomegaly may also be present. Thromboembolic complications occur in about 20% of patients. Circulatory disturbances as well as pruritus represent frequent symptoms of the disease. Mutations in the JAK2 gene are present in 95% of patients in exon 14 (V617F) and in 3% in exon 12. The main goal of the treatment for patients with PV is the prevention of thromboembolic events, transformation to myelofibrosis and acute myeloid leukemia. Interferon alpha and hydroxyurea are used as first-line treatment for high risk patients. For patients unresponsive to first-line therapy ruxolitinib is available.
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Affiliation(s)
- Sonja Burgstaller
- Department of Internal Medicine IV, Klinikum Wels-Grieskirchen, Wels, Austria.
| | | | - Thamer Sliwa
- 3rd Medical Department, Hanusch Hospital, Vienna, Austria
| | | | - Günther Gastl
- Division of Hematology and Oncology, Innsbruck Medical University, Innsbruck, Austria
| | - Klaus Geissler
- 5th Medical Department with Hematology, Oncology and Palliative Medicine, Hospital Hietzing, Vienna, Austria
| | - Thomas Melchardt
- 3rd Medical Department with Hematology and Medical Oncology, Hemostaseology, Rheumatology and Infectiology, Laboratory for Immunological and Molecular Cancer Research, Paracelsus Medical University Hospital Salzburg, Salzburg, Austria
| | - Maria Krauth
- Department of Internal Medicine I, Division of Hematology and Blood Coagulation, Medical University of Vienna, Vienna, Austria
| | - Peter Krippl
- Department of Internal Medicine with Hematology and Oncology, Steiermärkische Krankenanstaltengesellschaft m. b. H. Krankenhausverbund Feldbach-Fürstenfeld, Fürstenfeld, Austria
| | - Andreas Petzer
- Department of Internal Medicine I, Ordensklinikum Barmherzige Schwestern, Linz, Austria
| | - Holger Rumpold
- Department of Internal Medicine II, Landeskrankenhaus Feldkirch, Feldkirch, Austria
| | - Albert Wölfler
- Division of Hematology, Medical University of Graz, Graz, Austria
| | - Heinz Gisslinger
- Department of Internal Medicine I, Division of Hematology and Blood Coagulation, Medical University of Vienna, Vienna, Austria
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Salvagno L, Simonato L, Sorarù M, Bianco A, Chiarion-Sileni V, Aversa SM, Camporese R, Garofolin P, Fiorentino M. Secondary Leukemia following Treatment for Hodgkin's Disease. TUMORI JOURNAL 2018; 79:103-7. [PMID: 8346559 DOI: 10.1177/030089169307900204] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Aims and Background Patients treated for Hodgkin's disease with chemotherapy or with the association of chemotherapy and radiotherapy have an increased risk of secondary leukemia. The aim of this study was to evaluate the leukemogenic risk due to these treatment modalities. Methods We performed a case-control study on a population of 1410 patients treated for Hodgkin's disease from 1970 to 1990 in our Institute. Among these patients, we identified 25 cases of secondary leukemia and 3 cases of myelodysplasia, all occurring more than one year after the diagnosis of Hodgkin's disease. Three cases occurred among the patients treated with radiotherapy alone. When we analyzed the risk in relation to the type of treatment (radiotherapy, chemotherapy, or both), the comparisons were relative to patients treated with radiotherapy alone. Results We found that chemotherapy alone is associated with a fivefold increased risk (odds ratio = 5.4) compared with radiotherapy alone. When both treatments are used, the risk is not further increased (odds ratio = 4.4). Patients receiving more than 6 courses of chemotherapy have an excess risk (relative risk = 2.5) compared with those treated with 6 courses or less. No increased risk was observed after splenectomy. Conclusions This study confirms an increased incidence of secondary leukemia occurring in patients treated for Hodgkin's disease. The increased risk seems to be correlated with the number of courses of alkylating agent therapy, whereas it is unaffected by the addition of radiotherapy.
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Affiliation(s)
- L Salvagno
- Divisione di Oncologia Medica, Centro Oncologico Regionale, Padua, Italy
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Navone R. Bone Marrow Histopathology of Acute Nonlymphocytic Leukemia following Therapy for Primary Malignancies. TUMORI JOURNAL 2018; 70:363-70. [PMID: 6474585 DOI: 10.1177/030089168407000411] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Therapy-related acute nonlymphocytic leukemias occur with increasing frequency owing to modern aggressive antineoplastic therapies. Out of 3,138 bone marrow trephine biopsies, there were 148 cases of acute nonlymphocytic leukemias. Of these, 14 cases occurred 30–156 months following chemotherapy or radiotherapy or both for malignant disease. The male/female ratio was 0.27 (vs. 1.6 of « de novo » leukemias). Primary malignancies (7 Hodgkin's disease, 1 fibrosarcoma and 6 carcinomas) had been treated with chemotherapy+radiotherapy (10 cases), with chemotherapy alone (3 cases) or with radiotherapy alone (1 case) and were apparently cured. All therapy-related leukemias were heralded by a preleukemic cytopenic phase. Response to therapy was poor (mean survival 3.9 months). Bone marrow histopathological findings showed in 13 cases acute myelo- or monoblastic leukemia and in 1 case erythroleukemia. Out of 21 biopsies, there were increased numbers of abnormal megakaryocytes in 10, megaloblastic dyserythropoiesis in 7, and fibrosis in 13 (moderate in 11 cases and severe in 2, with dry tap). Therapy-related acute leukemia appears to be a distinct clinical-pathological entity. Bone marrow trephine biopsy is useful because of the frequency of fibrosis, the possibility of dry tap, and the characteristic histopathological findings that make diagnosis possible also in the preleukemic phase.
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Karantanos T, Moliterno AR. The roles of JAK2 in DNA damage and repair in the myeloproliferative neoplasms: Opportunities for targeted therapy. Blood Rev 2018; 32:426-432. [PMID: 29627078 DOI: 10.1016/j.blre.2018.03.007] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2017] [Revised: 03/03/2018] [Accepted: 03/27/2018] [Indexed: 02/09/2023]
Abstract
The JAK2V617F-positive myeloproliferative neoplasms (MPN) serve as an excellent model for the study of genomic instability accumulation during cancer progression. Recent studies highlight the implication of JAK2 activating mutations in the development of DNA damage via reactive oxygen species (ROS) production, replication stress induction and the accumulation of genomic instability via the increased degradation of p53 and acquisition of a "mutagenic" phenotype. The accumulation of genomic instability and acquisition of mutations in critical DNA damage repair (DDR) mediators appears to be implicated in the progression of JAK2V617F-positive MPN. On the other hand, JAK2 signaling normally induces DDR through activation of repair mediators such as Chk1, RAD51 and RECQL5. These opposing effects on DNA integrity in the setting of JAK2V617F have significant clinical implications and have led to the introduction of novel combinational therapies for these diseases. The inhibition of MDM2 with Nutlin-3 improves the efficacy of IFN-α via decreased p53 degradation, the combination of hydroxyurea with Ruxolitinib, and their combination with PARP inhibitors have significant anti-tumor effects. A better understanding of the implication of JAK2 in the development and repair of DNA damage can improve our understanding of the biology of these neoplasms, meliorate the risk stratification of our patients and enrich our therapeutic armamentarium.
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Affiliation(s)
| | - Alison R Moliterno
- Division of Hematology, Department of Medicine, The Johns Hopkins University School of Medicine, USA.
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Tefferi A, Vannucchi AM, Barbui T. Polycythemia vera treatment algorithm 2018. Blood Cancer J 2018; 8:3. [PMID: 29321547 PMCID: PMC5802495 DOI: 10.1038/s41408-017-0042-7] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2017] [Revised: 07/27/2017] [Accepted: 07/27/2017] [Indexed: 12/18/2022] Open
Abstract
Recently reported mature survival data have confirmed the favorable prognosis in polycythemia vera (PV), with an estimated median survival of 24 years, in patients younger than age 60 years old. Currently available drugs for PV have not been shown to prolong survival or alter the natural history of the disease and are instead indicated primarily for prevention of thrombosis. Unfortunately, study endpoints that are being utilized in currently ongoing clinical trials in PV do not necessarily target clinically or biologically relevant outcomes, such as thrombosis, survival, or morphologic remission, and are instead focused on components of disease palliation. Even more discouraging has been the lack of critical appraisal from "opinion leaders", on the added value of newly approved drugs. Keeping these issues in mind, at present, we continue to advocate conservative management in low-risk PV (phlebotomy combined with once- or twice-daily aspirin therapy) and include cytoreductive therapy in "high-risk" patients; in the latter regard, our first, second, and third line drugs of choice are hydroxyurea, pegylated interferon-α and busulfan, respectively. In addition, it is reasonable to consider JAK2 inhibitor therapy, in the presence of protracted pruritus or markedly enlarged splenomegaly shown to be refractory to the aforementioned drugs.
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Affiliation(s)
- Ayalew Tefferi
- Division of Hematology, Department of 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
| | - Tiziano Barbui
- Research Foundation, Papa Giovanni XXIII Hospital, Bergamo, Italy
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Khan M, Siddiqi R, Gangat N. Therapeutic options for leukemic transformation in patients with myeloproliferative neoplasms. Leuk Res 2017; 63:78-84. [PMID: 29121538 DOI: 10.1016/j.leukres.2017.10.009] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2017] [Revised: 10/12/2017] [Accepted: 10/25/2017] [Indexed: 12/12/2022]
Abstract
Approximately 5-10% of patients with Philadelphia chromosome negative myeloproliferative neoplasms (MPN) comprising of essential thrombocythemia, polycythemia vera and primary myelofibrosis) experience transformation to acute myeloid leukemia (AML, ≥20% blasts). Treatment options for post-MPN AML patients are limited, as conventional approaches like standard chemotherapy, fail to offer long-term benefit. Median survival for secondary AML is ∼2.4 months. Post-MPN AML therefore represents an area of urgent clinical need. At present, allogeneic stem cell transplant (ASCT) following induction therapy is the best therapeutic option. Patients ineligible for ASCT are treated with hypomethylating agents. New agents under investigation include histone deacetylase inhibitors, JAKinhibitors and agents targeting the BRD4 protein. Combined treatment strategies involving these novel agents are being tested. In this review we present the current evidence regarding treatment options for post-MPN AML patients.
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Affiliation(s)
- Maliha Khan
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Rabbia Siddiqi
- Department of Internal Medicine, Dow University of Health Sciences, Karachi, Pakistan
| | - Naseema Gangat
- Division of Hematology, Mayo Clinic, Rochester, MN, United States.
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Low-burden TP53 mutations in chronic phase of myeloproliferative neoplasms: association with age, hydroxyurea administration, disease type and JAK2 mutational status. Leukemia 2017; 32:450-461. [PMID: 28744014 PMCID: PMC5808067 DOI: 10.1038/leu.2017.230] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2016] [Revised: 06/30/2017] [Accepted: 07/05/2017] [Indexed: 12/19/2022]
Abstract
The multistep process of TP53 mutation expansion during myeloproliferative neoplasm (MPN) transformation into acute myeloid leukemia (AML) has been documented retrospectively. It is currently unknown how common TP53 mutations with low variant allele frequency (VAF) are, whether they are linked to hydroxyurea (HU) cytoreduction, and what disease progression risk they carry. Using ultra-deep next-generation sequencing, we examined 254 MPN patients treated with HU, interferon alpha-2a or anagrelide and 85 untreated patients. We found TP53 mutations in 50 cases (0.2–16.3% VAF), regardless of disease subtype, driver gene status and cytoreduction. Both therapy and TP53 mutations were strongly associated with older age. Over-time analysis showed that the mutations may be undetectable at diagnosis and slowly increase during disease course. Although three patients with TP53 mutations progressed to TP53-mutated or TP53-wild-type AML, we did not observe a significant age-independent impact on overall survival during the follow-up. Further, we showed that complete p53 inactivation alone led to neither blast transformation nor HU resistance. Altogether, we revealed patient's age as the strongest factor affecting low-burden TP53 mutation incidence in MPN and found no significant age-independent association between TP53 mutations and hydroxyurea. Mutations may persist at low levels for years without an immediate risk of progression.
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Affiliation(s)
- Jerry L Spivak
- From the Hematology Division, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore
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Grinfeld J, Godfrey AL. After 10 years of JAK2V617F: Disease biology and current management strategies in polycythaemia vera. Blood Rev 2017; 31:101-118. [DOI: 10.1016/j.blre.2016.11.001] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2016] [Revised: 11/08/2016] [Accepted: 11/14/2016] [Indexed: 12/12/2022]
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Tefferi A, Barbui T. Polycythemia vera and essential thrombocythemia: 2017 update on diagnosis, risk-stratification, and management. Am J Hematol 2017; 92:94-108. [PMID: 27991718 DOI: 10.1002/ajh.24607] [Citation(s) in RCA: 139] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2016] [Accepted: 11/11/2016] [Indexed: 12/12/2022]
Abstract
DISEASE OVERVIEW Polycythemia Vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms respectively characterized by erythrocytosis and thrombocytosis; other disease features include leukocytosis, splenomegaly, thrombosis, bleeding, microcirculatory symptoms, pruritus, and risk of leukemic or fibrotic transformation. DIAGNOSIS PV is defined by a JAK2 mutation, whose absence, combined with normal or increased serum erythropoietin level, makes the diagnosis unlikely. JAK2, CALR, and MPL mutations are the mutually exclusive "driver" mutations in ET with respective incidences of 55%, 25%, and 3%; approximately 17% are triple-negative. However, the same molecular markers might also be present in prefibrotic myelofibrosis, whose morphological distinction from ET is prognostically relevant. SURVIVAL AND LEUKEMIC/FIBROTIC TRANSFORMATION Median survivals are approximately 14 years for PV and 20 years for ET; the corresponding values for younger patients (age <60 years) are 24 and 33 years. Life-expectancy in ET is inferior to the control population. Driver mutational status has not been shown to affect survival in ET whereas the presence of JAK2/MPL mutations has been associated with higher risk of arterial thrombosis and that of MPL with higher risk of fibrotic progression. Risk factors for overall survival in both ET and PV include advanced age, leukocytosis and thrombosis. Leukemic transformation rates at 20 years are estimated at <10% for PV and 5% for ET; fibrotic transformation rates are slightly higher. Most recently, ASXL1, SRSF2, and IDH2 mutations have been associated with inferior overall, leukemia-free or fibrosis-free survival in PV; similarly adverse mutations in ET included SH2B3, SF3B1, U2AF1, TP53, IDH2, and EZH2. THROMBOSIS RISK STRATIFICATION Current risk stratification in PV and ET is designed to estimate the likelihood of recurrent thrombosis. Accordingly, PV includes two risk categories: high-risk (age >60 years or thrombosis history) and low-risk (absence of both risk factors). In ET, risk stratification includes four categories: very low risk (age ≤60 years, no thrombosis history, JAK2/MPL un-mutated), low risk (age ≤60 years, no thrombosis history, JAK2/MPL mutated), intermediate risk (age >60 years, no thrombosis history, JAK2/MPL un-mutated), and high risk (thrombosis history or age >60 years with JAK2/MPL mutation). In addition, presence of extreme thrombocytosis (platelets >1000 × 10(9)/L) might be associated with acquired von Willebrand syndrome (AvWS) and, therefore, risk of bleeding. RISK-ADAPTED THERAPY The main goal of therapy in PV and ET is to prevent thrombohemorrhagic complications. All patients with PV require phlebotomy to keep hematocrit below 45% and once-daily aspirin (81 mg). In addition, high-risk patients with PV require cytoreductive therapy. Very low risk ET patients might not require any form of therapy while low-risk patients require at least once-daily aspirin therapy. Cytoreductive therapy is also recommended for high-risk ET patients but it is not mandatory for intermediate-risk patients. First-line drug of choice for cytoreductive therapy, in both ET and PV, is hydroxyurea and second-line drugs of choice are interferon-α and busulfan. We currently do not recommend treatment with ruxolutinib or other JAK2 inhibitors in PV or ET, unless in the presence of severe and protracted pruritus or marked splenomegaly that is not responding to the aforementioned drugs. Screening for AvWS is recommended before administrating aspirin, in the presence of extreme thrombocytosis. Am. J. Hematol. 92:95-108, 2017. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Ayalew Tefferi
- Division of Hematology, Department of Medicine; Mayo Clinic; Rochester Minnesota USA
| | - Tiziano Barbui
- Research Foundation, Papa Giovanni XXIII Hospital; Bergamo Italy
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Spivak JL. Polycythaemia vera and precision medicine: a prescription for the 21st century. Lancet Oncol 2017; 18:9-11. [DOI: 10.1016/s1470-2045(16)30591-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2016] [Accepted: 10/20/2016] [Indexed: 10/20/2022]
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Vannucchi AM. From leeches to personalized medicine: evolving concepts in the management of polycythemia vera. Haematologica 2016; 102:18-29. [PMID: 27884974 DOI: 10.3324/haematol.2015.129155] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2016] [Accepted: 09/22/2016] [Indexed: 01/14/2023] Open
Abstract
Polycythemia vera is a clonal disorder of hematopoietic stem/progenitor cells. It manifests as an expansion of red cell mass. It is the most common chronic myeloproliferative neoplasm. In virtually all cases, it is characterized by a V617F point mutation in JAK2 exon 14 or less common mutations in exon 12. The landmark discovery of the autonomously activated JAK/STAT signaling pathway paved the way for the clinical development of the first target drug, the JAK1 and JAK2 inhibitor ruxolitinib. This is now approved for patients with resistance or intolerance to hydroxyurea. Phlebotomies and hydroxyurea are still the cornerstone of treatment, and aim to prevent the first appearance or recurrence of cardiovascular events that, together with progression to post-polycythemia vera myelofibrosis and leukemia, represent the main causes of death. Interferon-α is an alternative drug and has been shown to induce molecular remissions. It is currently undergoing phase III trials that might eventually lead to its approval for clinical use. The last few years have witnessed important advances towards an accurate early diagnosis of polycythemia vera, greater understanding of its pathogenesis, and improved patient management. This review will focus on the most recent achievements and will aim to unify the different concepts involved in a personalized approach to the patient with polycythemia vera. In spite of many recent advances in the understanding of its pathogenesis and improved disease management, polycythemia vera remains a life-threatening myeloproliferative neoplasm for which there is no cure. This review will present a critical overview of evolving concepts in diagnosis and treatment of this disease.
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Affiliation(s)
- Alessandro M Vannucchi
- CRIMM, Centro di Ricerca e Innovazione per le Malattie Mieloproliferative, Azienda Ospedaliera Universitaria Careggi, Dipartimento di Medicina Sperimentale e Clinica, Università degli Studi, Firenze, DENOTHE Excellence Center, Italy
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Analysis of thrombosis and bleeding complications in patients with polycythemia vera: a Turkish retrospective study. Int J Hematol 2016; 105:70-78. [PMID: 27699575 DOI: 10.1007/s12185-016-2105-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2016] [Revised: 09/26/2016] [Accepted: 09/26/2016] [Indexed: 12/20/2022]
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Kiso S, Naito R, Fukao K, Hiki M, Miyazaki T, Takagi A, Miyauchi K, Daida H. Rapidly progressed aortic stenosis in a patient with previous diagnosis of polycythemia vera and post‐polycythemia vera myelofibrosis. Clin Case Rep 2016; 4:589-92. [PMID: 27398203 PMCID: PMC4891485 DOI: 10.1002/ccr3.568] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2015] [Revised: 03/14/2016] [Accepted: 04/03/2016] [Indexed: 11/27/2022] Open
Abstract
Polycythemia vera (PV) is a chronic myeloproliferative disease that is often complicated with thromboembolism. However, aortic stenosis (AS) could be a manifestation of the cardiovascular complications of PV possibly through shear stress and atherosclerosis. We report a rare case of rapidly progressed AS in a patient with PV.
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Affiliation(s)
- Shohei Kiso
- Department of Cardiovascular MedicineJuntendo University Graduate School of Medicine2‐1‐1 Hongo Bunkyo‐kuTokyo113‐8421Japan
| | - Ryo Naito
- Department of Cardiovascular MedicineJuntendo University Graduate School of Medicine2‐1‐1 Hongo Bunkyo‐kuTokyo113‐8421Japan
| | - Kosuke Fukao
- Department of Cardiovascular MedicineJuntendo University Graduate School of Medicine2‐1‐1 Hongo Bunkyo‐kuTokyo113‐8421Japan
| | - Makoto Hiki
- Department of Cardiovascular MedicineJuntendo University Graduate School of Medicine2‐1‐1 Hongo Bunkyo‐kuTokyo113‐8421Japan
| | - Tetsuro Miyazaki
- Department of Cardiovascular MedicineJuntendo University Graduate School of Medicine2‐1‐1 Hongo Bunkyo‐kuTokyo113‐8421Japan
| | - Atsutoshi Takagi
- Department of Cardiovascular MedicineJuntendo University Graduate School of Medicine2‐1‐1 Hongo Bunkyo‐kuTokyo113‐8421Japan
| | - Katsumi Miyauchi
- Department of Cardiovascular MedicineJuntendo University Graduate School of Medicine2‐1‐1 Hongo Bunkyo‐kuTokyo113‐8421Japan
| | - Hiroyuki Daida
- Department of Cardiovascular MedicineJuntendo University Graduate School of Medicine2‐1‐1 Hongo Bunkyo‐kuTokyo113‐8421Japan
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Blackadar CB. Historical review of the causes of cancer. World J Clin Oncol 2016; 7:54-86. [PMID: 26862491 PMCID: PMC4734938 DOI: 10.5306/wjco.v7.i1.54] [Citation(s) in RCA: 155] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2015] [Revised: 10/31/2015] [Accepted: 11/24/2015] [Indexed: 02/06/2023] Open
Abstract
In the early 1900s, numerous seminal publications reported that high rates of cancer occurred in certain occupations. During this period, work with infectious agents produced only meager results which seemed irrelevant to humans. Then in the 1980s ground breaking evidence began to emerge that a variety of viruses also cause cancer in humans. There is now sufficient evidence of carcinogenicity in humans for human T-cell lymphotrophic virus, human immunodeficiency virus, hepatitis B virus, hepatitis C virus, human papillomavirus, Epstein-Barr virus, and human herpes virus 8 according to the International Agency for Research on Cancer (IARC). Many other causes of cancer have also been identified by the IARC, which include: Sunlight, tobacco, pharmaceuticals, hormones, alcohol, parasites, fungi, bacteria, salted fish, wood dust, and herbs. The World Cancer Research Fund and the American Institute for Cancer Research have determined additional causes of cancer, which include beta carotene, red meat, processed meats, low fibre diets, not breast feeding, obesity, increased adult height and sedentary lifestyles. In brief, a historical review of the discoveries of the causes of human cancer is presented with extended discussions of the difficulties encountered in identifying viral causes of cancer.
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