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Leukemic Transformation in Myeloproliferative Neoplasms

A Literature Review on Risk, Characteristics, and Outcome

      Abstract

      Myeloproliferative neoplasms (MPNs) operationally include essential thrombocythemia, polycythemia vera, primary myelofibrosis (PMF), and prefibrotic PMF. All 4 MPN variants might progress into blast-phase disease (MPN-BP). For essential thrombocythemia, reported risk factors for leukemic transformation include advanced age, extreme thrombocytosis, anemia, leukocytosis, and sequence variants/mutations involving TP53 and EZH2 (for expansion of gene symbols, see www.genenames.org); for polycythemia vera, advanced age, leukocytosis, abnormal karyotype, mutations involving SRSF2 and IDH2, and treatment with pipobroman, chlorambucil, or P32; and for PMF, increased blast percentage, thrombocytopenia, abnormal karyotype, triple-negative driver mutational status, and sequence variants/mutations involving SRSF2, RUNX1, CEBPA, and SH2B3. The reported median survival figures for MPN-BP range from 1.5 to 2.5 months in patients treated with supportive care only, from 2.5 to 10 months in those receiving hypomethylating agents or low-dose chemotherapy, and from 3.9 to 9.4 months in those receiving induction chemotherapy. Three-year survival after allogeneic stem cell transplant was reported in 16% to 33% of patients. These observations validate the extremely poor prognosis associated with MPN-BP and the lack of effective drug therapy and highlight the need for urgent assessment of therapeutic values of investigational agents. In the meantime, affected patients might be best served with aggressive chemotherapy followed by allogeneic stem cell transplant after adequate blast clearance.

      Abbreviations and Acronyms:

      AML (acute myeloid leukemia), ASCT (allogeneic stem cell transplant), BETi (bromodomain and extra terminal domain inhibitor), CR (complete remission), DIPSS (Dynamic International Prognostic Scoring System), ET (essential thrombocythemia), FAB (French-American-British), MDS (myelodysplastic syndrome), MF (myelofibrosis), MPN (myeloproliferative neoplasm), MPN-BP (blast-phase myeloproliferative neoplasm), PMF (primary myelofibrosis), PV (polycythemia vera), RBC (red blood cell), WHO (World Health Organization)
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      Learning Objectives: On completion of this article, you should be able to (1) describe risk factors for leukemic transformation in myeloproliferative neoplasms; (2) review current experience in the outcome of patients with blast-phase myeloproliferative neoplasms; and (3) discuss current challenges in the treatment of blast-phase myeloproliferative neoplasms.
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      Myeloproliferative neoplasms (MPNs) are clonal hematopoietic stem cell disorders characterized by proliferative bone marrow with varying degrees of reticulin/collagen fibrosis, extramedullary hematopoiesis, abnormal peripheral blood count, and constitutional symptoms that are presumed to be secondary to abnormally expressed inflammatory cytokines.
      • Tefferi A.
      Myelofibrosis with myeloid metaplasia.
      • Hasselbalch H.C.
      The role of cytokines in the initiation and progression of myelofibrosis.
      The classical categories of MPN consists of chronic myeloid leukemia, primary myelofibrosis (PMF), essential thrombocythemia (ET), and polycythemia vera (PV). Chronic myeloid leukemia is invariably associated with a specific genetic abnormality (BCR-ABL1) (for expansion of gene symbols, see www.genenames.org)
      • Verfaillie C.M.
      Biology of chronic myelogenous leukemia.
      • Faderl S.
      • Talpaz M.
      • Estrov Z.
      • O'Brien S.
      • Kurzrock R.
      • Kantarjian H.M.
      The biology of chronic myeloid leukemia.
      ; accordingly, the other MPNs are operationally labeled as “BCR-ABL1–negative MPN,” and the World Health Organization (WHO) classification system currently recognizes 4 variants of BCR-ABL1–negative MPN: ET, PV, PMF, and prefibrotic PMF.
      • Arber D.A.
      • Orazi A.
      • Hasserjian R.
      • et al.
      The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia.
      There is considerable overlap among the 4 MPN variants in terms of symptomatology, laboratory findings, bone marrow morphology, and mutations, however, with marked differences in natural history and survival outcomes.
      • Arber D.A.
      • Orazi A.
      • Hasserjian R.
      • et al.
      The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia.
      Accordingly, diagnostic accuracy is prognostically relevant, especially in terms of differentiating WHO-defined ET from prefibrotic PMF and masked PV, which displays a higher risk of leukemic transformation.
      • Barbui T.
      • Thiele J.
      • Passamonti F.
      • et al.
      Survival and disease progression in essential thrombocythemia are significantly influenced by accurate morphologic diagnosis: an international study.
      • Barbui T.
      • Thiele J.
      • Gisslinger H.
      • et al.
      Masked polycythemia vera (mPV): results of an international study.
      In general, the natural history of MPN might be interrupted by thrombohemorrhagic complications
      • Elliott M.A.
      • Tefferi A.
      Thrombosis and haemorrhage in polycythaemia vera and essential thrombocythaemia.
      or disease transformation into post-ET or post-PV myelofibrosis (MF)
      • Barosi G.
      • Mesa R.A.
      • Thiele J.
      • et al.
      International Working Group for Myelofibrosis Research and Treatment (IWG-MRT)
      Proposed criteria for the diagnosis of post-polycythemia vera and post-essential thrombocythemia myelofibrosis: a consensus statement from the International Working Group for Myelofibrosis Research and Treatment.
      or post-MPN acute leukemia, also known as blast-phase myeloproliferative neoplasms (MPN-BP).
      • Tefferi A.
      • Guglielmelli P.
      • Larson D.R.
      • et al.
      Long-term survival and blast transformation in molecularly annotated essential thrombocythemia, polycythemia vera, and myelofibrosis.
      • Noor S.J.
      • Tan W.
      • Wilding G.E.
      • et al.
      Myeloid blastic transformation of myeloproliferative neoplasms—a review of 112 cases.
      The typical definition of MPN-BP includes the documentation of 20% or more blasts in the peripheral blood or bone marrow.
      • Mesa R.A.
      • Verstovsek S.
      • Cervantes F.
      • et al.
      International Working Group for Myelofibrosis Research and Treatment (IWG-MRT)
      Primary myelofibrosis (PMF), post polycythemia vera myelofibrosis (post-PV MF), post essential thrombocythemia myelofibrosis (post-ET MF), blast phase PMF (PMF-BP): consensus on terminology by the international working group for myelofibrosis research and treatment (IWG-MRT).
      However, discordance in the content of peripheral blood vs bone marrow blasts is often seen.
      • Mascarenhas J.
      • Navada S.
      • Malone A.
      • Rodriguez A.
      • Najfeld V.
      • Hoffman R.
      Therapeutic options for patients with myelofibrosis in blast phase.
      The propensity for leukemic transformation in MPN varies according to the MPN variant and is highest in PMF, with an incidence of 10% to 20% in the first 10 years of the disease
      • Abdulkarim K.
      • Girodon F.
      • Johansson P.
      • et al.
      AML transformation in 56 patients with Ph- MPD in two well defined populations.
      • Cervantes F.
      • Tassies D.
      • Salgado C.
      • Rovira M.
      • Pereira A.
      • Rozman C.
      Acute transformation in nonleukemic chronic myeloproliferative disorders: actuarial probability and main characteristics in a series of 218 patients.
      • Tam C.S.
      • Nussenzveig R.M.
      • Popat U.
      • et al.
      The natural history and treatment outcome of blast phase BCR-ABL myeloproliferative neoplasms.
      ; lower in PV, with an estimated risk of 2.3% at 10 years and 7.9% at 20 years
      • Tefferi A.
      • Rumi E.
      • Finazzi G.
      • et al.
      Survival and prognosis among 1545 patients with contemporary polycythemia vera: an international study.
      ; and lowest in ET, with less than 1% in the first decade of the disease.
      • Barbui T.
      • Thiele J.
      • Passamonti F.
      • et al.
      Survival and disease progression in essential thrombocythemia are significantly influenced by accurate morphologic diagnosis: an international study.
      • Vardiman J.W.
      • Thiele J.
      • Arber D.A.
      • et al.
      The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes.
      This varying incidence of MPN-BP was recently highlighted in a large study by Tefferi et al.
      • Tefferi A.
      • Guglielmelli P.
      • Larson D.R.
      • et al.
      Long-term survival and blast transformation in molecularly annotated essential thrombocythemia, polycythemia vera, and myelofibrosis.

      Characteristics of MPN-BP

      Blast-phase myeloproliferative neoplasms commonly involve the myeloid lineage with rare involvement of the lymphoid lineage. The characteristics of MPN-BP have been reported to be different, both morphologically and cytogenetically, from primary (de novo) acute myeloid leukemia (AML). According to the French-American-British (FAB) classification of AML, erythroleukemia (FAB-M6) and megakaryoblastic leukemia (FAB-M7) were the most common subtypes reported in MPN-BP.
      • Abdulkarim K.
      • Girodon F.
      • Johansson P.
      • et al.
      AML transformation in 56 patients with Ph- MPD in two well defined populations.
      • Mesa R.A.
      • Li C.Y.
      • Ketterling R.P.
      • Schroeder G.S.
      • Knudson R.A.
      • Tefferi A.
      Leukemic transformation in myelofibrosis with myeloid metaplasia: a single-institution experience with 91 cases.
      A Mayo Clinic study of patients with PMF found M7 (25.4%) to be the most common subtype followed by M0 (22.4%) and M2 (17.9%).
      • Mesa R.A.
      • Li C.Y.
      • Ketterling R.P.
      • Schroeder G.S.
      • Knudson R.A.
      • Tefferi A.
      Leukemic transformation in myelofibrosis with myeloid metaplasia: a single-institution experience with 91 cases.
      The incidence of AML in post-ET or post-PV MF is similar to that of post-PMF AML.
      • Mesa R.A.
      • Li C.Y.
      • Ketterling R.P.
      • Schroeder G.S.
      • Knudson R.A.
      • Tefferi A.
      Leukemic transformation in myelofibrosis with myeloid metaplasia: a single-institution experience with 91 cases.
      Patients with PV and ET can also directly develop AML without going through the fibrotic phase of the disease.
      • Tam C.S.
      • Nussenzveig R.M.
      • Popat U.
      • et al.
      The natural history and treatment outcome of blast phase BCR-ABL myeloproliferative neoplasms.
      • Passamonti F.
      • Rumi E.
      • Arcaini L.
      • et al.
      Leukemic transformation of polycythemia vera: a single center study of 23 patients.
      A karyotype in MPN-BP is often complex, and a favorable karyotype is infrequent. Common mutations described in MPN-BP include JAK2, IDH1/2, TP53, ASXL1, and TET2, whereas their counterparts in primary AML include N/KRAS, DNMT3a, NPM1, and FLT3.
      • Green A.
      • Beer P.
      Somatic mutations of IDH1 and IDH2 in the leukemic transformation of myeloproliferative neoplasms.
      • Abdel-Wahab O.
      • Manshouri T.
      • Patel J.
      • et al.
      Genetic analysis of transforming events that convert chronic myeloproliferative neoplasms to leukemias.
      • Zhang S.J.
      • Rampal R.
      • Manshouri T.
      • et al.
      Genetic analysis of patients with leukemic transformation of myeloproliferative neoplasms shows recurrent SRSF2 mutations that are associated with adverse outcome.
      • Rampal R.
      • Ahn J.
      • Abdel-Wahab O.
      • et al.
      Genomic and functional analysis of leukemic transformation of myeloproliferative neoplasms.
      A study that analyzed genetic information in paired samples of chronic MPN-BP reported acquisition of TET2 mutation during blast transformation and presence of ASXL1 in both phases of the disease.
      • Abdel-Wahab O.
      • Manshouri T.
      • Patel J.
      • et al.
      Genetic analysis of transforming events that convert chronic myeloproliferative neoplasms to leukemias.
      JAK2 mutations are important in MPN pathogenesis, and clonal changes in JAK2 clones, during leukemic transformation, have been observed with acquisition of new mutations and, in certain instances, loss of the prevailing mutations.
      • Campbell P.J.
      • Baxter E.J.
      • Beer P.A.
      • et al.
      Mutation of JAK2 in the myeloproliferative disorders: timing, clonality studies, cytogenetic associations, and role in leukemic transformation.
      • Theocharides A.
      • Boissinot M.
      • Girodon F.
      • et al.
      Leukemic blasts in transformed JAK2-V617F-positive myeloproliferative disorders are frequently negative for the JAK2-V617F mutation.

      Risk Factors for Leukemic Transformation in MPN

      Various clinical and genetic risk factors have been identified as being useful in predicting leukemic transformation in MPN (Table 1).
      Table 1Risk Factors for Leukemic Transformation
      Risk factorsEssential thrombocytosisPolycythemia veraMyelofibrosis
      ClinicalAge ≥60 y
      • Passamonti F.
      • Rumi E.
      • Arcaini L.
      • et al.
      Prognostic factors for thrombosis, myelofibrosis, and leukemia in essential thrombocythemia: a study of 605 patients.
      • Gangat N.
      • Wolanskyj A.P.
      • McClure R.F.
      • et al.
      Risk stratification for survival and leukemic transformation in essential thrombocythemia: a single institutional study of 605 patients.


      Thrombosis
      • Barbui T.
      • Thiele J.
      • Passamonti F.
      • et al.
      Survival and disease progression in essential thrombocythemia are significantly influenced by accurate morphologic diagnosis: an international study.
      Age >70 y
      • Marchioli R.
      • Finazzi G.
      • Landolfi R.
      • et al.
      Vascular and neoplastic risk in a large cohort of patients with polycythemia vera.


      Age >61 y
      • Tefferi A.
      • Rumi E.
      • Finazzi G.
      • et al.
      Survival and prognosis among 1545 patients with contemporary polycythemia vera: an international study.
      Age >65 y
      • Barbui T.
      • Carobbio A.
      • Finazzi G.
      • et al.
      Elevated C-reactive protein is associated with shortened leukemia-free survival in patients with myelofibrosis.


      Red blood cell transfusion dependency
      • Passamonti F.
      • Rumi E.
      • Elena C.
      • et al.
      Incidence of leukaemia in patients with primary myelofibrosis and RBC-transfusion-dependence.
      LaboratoryPlatelets (≥1000×109/L)
      • Barbui T.
      • Thiele J.
      • Passamonti F.
      • et al.
      Survival and disease progression in essential thrombocythemia are significantly influenced by accurate morphologic diagnosis: an international study.
      • Gangat N.
      • Wolanskyj A.P.
      • McClure R.F.
      • et al.
      Risk stratification for survival and leukemic transformation in essential thrombocythemia: a single institutional study of 605 patients.


      Anemia
      • Gangat N.
      • Wolanskyj A.P.
      • McClure R.F.
      • et al.
      Risk stratification for survival and leukemic transformation in essential thrombocythemia: a single institutional study of 605 patients.
      • Tefferi A.
      • Gangat N.
      • Wolanskyj A.P.
      • et al.
      20+ yr without leukemic or fibrotic transformation in essential thrombocythemia or polycythemia vera: predictors at diagnosis.


      Leukocytosis (≥15×109/L)
      • Chim C.S.
      • Kwong Y.L.
      • Lie A.K.
      • et al.
      Long-term outcome of 231 patients with essential thrombocythemia: prognostic factors for thrombosis, bleeding, myelofibrosis, and leukemia.
      • Abdulkarim K.
      • Ridell B.
      • Johansson P.
      • Kutti J.
      • Safai-Kutti S.
      • Andréasson B.
      The impact of peripheral blood values and bone marrow findings on prognosis for patients with essential thrombocythemia and polycythemia vera.
      Leukocytes (15×109)
      • Tefferi A.
      • Rumi E.
      • Finazzi G.
      • et al.
      Survival and prognosis among 1545 patients with contemporary polycythemia vera: an international study.
      White blood cells (>30×109/L)
      • Dupriez B.
      • Morel P.
      • Demory J.L.
      • et al.
      Prognostic factors in agnogenic myeloid metaplasia: a report on 195 cases with a new scoring system.


      Platelets (<50×109/L)
      • Tam C.S.
      • Kantarjian H.
      • Cortes J.
      • et al.
      Dynamic model for predicting death within 12 months in patients with primary or post-polycythemia vera/essential thrombocythemia myelofibrosis.


      Peripheral blast (≥3%) and/or platelets (<100×109/L)
      • Huang J.
      • Li C.Y.
      • Mesa R.A.
      • et al.
      Risk factors for leukemic transformation in patients with primary myelofibrosis.


      IL-8, IL-2R
      • Tefferi A.
      • Vaidya R.
      • Caramazza D.
      • Finke C.
      • Lasho T.
      • Pardanani A.
      Circulating interleukin (IL)-8, IL-2R, IL-12, and IL-15 levels are independently prognostic in primary myelofibrosis: a comprehensive cytokine profiling study.


      C-reactive protein (>7 mg/L) and peripheral blast (>1%)
      • Barbui T.
      • Carobbio A.
      • Finazzi G.
      • et al.
      Elevated C-reactive protein is associated with shortened leukemia-free survival in patients with myelofibrosis.
      Bone marrowPrefibrotic primary myelofibrosis morphology, reticulin grading, and bone marrow cellularity
      • Barbui T.
      • Thiele J.
      • Passamonti F.
      • et al.
      Survival and disease progression in essential thrombocythemia are significantly influenced by accurate morphologic diagnosis: an international study.
      • Abdulkarim K.
      • Ridell B.
      • Johansson P.
      • Kutti J.
      • Safai-Kutti S.
      • Andréasson B.
      The impact of peripheral blood values and bone marrow findings on prognosis for patients with essential thrombocythemia and polycythemia vera.
      Bone marrow blasts (≥10%)
      • Tam C.S.
      • Kantarjian H.
      • Cortes J.
      • et al.
      Dynamic model for predicting death within 12 months in patients with primary or post-polycythemia vera/essential thrombocythemia myelofibrosis.
      Previous therapyCytoreductive agents, pipobroman, P32, chlorambucil
      • Finazzi G.
      • Caruso V.
      • Marchioli R.
      • et al.
      ECLAP Investigators
      Acute leukemia in polycythemia vera: an analysis of 1638 patients enrolled in a prospective observational study.
      Cytogenetic abnormalitiesNoneAbnormal karyotype
      • Tefferi A.
      • Rumi E.
      • Finazzi G.
      • et al.
      Survival and prognosis among 1545 patients with contemporary polycythemia vera: an international study.
      Abnormal karyotype
      • Dupriez B.
      • Morel P.
      • Demory J.L.
      • et al.
      Prognostic factors in agnogenic myeloid metaplasia: a report on 195 cases with a new scoring system.


      Chromosome 17 aberrations
      • Tam C.S.
      • Kantarjian H.
      • Cortes J.
      • et al.
      Dynamic model for predicting death within 12 months in patients with primary or post-polycythemia vera/essential thrombocythemia myelofibrosis.


      Monosomal karyotype (1q, 7q, 5q, 6p, 7p, 19q, 22q, and 3q, del17p, −5, −7) and/or complex
      • Vaidya R.
      • Caramazza D.
      • Begna K.H.
      • et al.
      Monosomal karyotype in primary myelofibrosis is detrimental to both overall and leukemia-free survival.


      Unfavorable karyotype (complex karyotype or sole or 2 abnormalities that include +8, −7/7q-, i(17q), −5/5q-, 12p-, inv(3), or 11q23 rearrangement)
      • Gangat N.
      • Caramazza D.
      • Vaidya R.
      • et al.
      DIPSS plus: a refined Dynamic International Prognostic Scoring System for primary myelofibrosis that incorporates prognostic information from karyotype, platelet count, and transfusion status.
      • Caramazza D.
      • Begna K.H.
      • Gangat N.
      • et al.
      Refined cytogenetic-risk categorization for overall and leukemia-free survival in primary myelofibrosis: a single center study of 433 patients.


      Del17p, −5, −7, and/or complex
      • Quintás-Cardama A.
      • Kantarjian H.
      • Pierce S.
      • Cortes J.
      • Verstovsek S.
      Prognostic model to identify patients with myelofibrosis at the highest risk of transformation to acute myeloid leukemia.
      MutationsTP53, EZH2
      • Chim C.S.
      • Kwong Y.L.
      • Lie A.K.
      • et al.
      Long-term outcome of 231 patients with essential thrombocythemia: prognostic factors for thrombosis, bleeding, myelofibrosis, and leukemia.
      SRSF2, IDH2
      • Chim C.S.
      • Kwong Y.L.
      • Lie A.K.
      • et al.
      Long-term outcome of 231 patients with essential thrombocythemia: prognostic factors for thrombosis, bleeding, myelofibrosis, and leukemia.
      Triple-negative mutational status
      • Tefferi A.
      • Guglielmelli P.
      • Larson D.R.
      • et al.
      Long-term survival and blast transformation in molecularly annotated essential thrombocythemia, polycythemia vera, and myelofibrosis.


      ASXL1, SRSF2, IDH1, or IDH2
      • Vannucchi A.M.
      • Lasho T.L.
      • Guglielmelli P.
      • et al.
      Mutations and prognosis in primary myelofibrosis.
      IL-2R = interleukin 2 receptor; IL-8 = interleukin 8.

      Risk Factors for Leukemic Transformation in PMF

      Conventional drug therapies have not resulted in prolongation of survival in PMF, and allogeneic stem cell transplant (ASCT) remains the definitive treatment for purposes of cure or prolongation of survival. Accordingly, identification of risk factors for inferior overall and leukemia-free survival is a critical step in the management of patients with PMF or post-ET or post-PV MF.
      In a study of 311 patients with PMF, independent risk factors for leukemic transformation included circulating blast of more than 3% and platelet count of less than 100×109/L.
      • Huang J.
      • Li C.Y.
      • Mesa R.A.
      • et al.
      Risk factors for leukemic transformation in patients with primary myelofibrosis.
      The same study also found no increased leukemogenicity from treatment with hydroxyurea, thalidomide, or many other drugs, although a potential detrimental effect from erythropoiesis stimulating agents, and danazol was suggested. Using the aforementioned 2 risk factors, the rate of leukemic transformation was only 6% in the absence of both risk factors and 18% in the presence of one or both risk factors. Leukocytosis (>30×109/L) was also identified as a risk factor for leukemic transformation in another study.
      • Dupriez B.
      • Morel P.
      • Demory J.L.
      • et al.
      Prognostic factors in agnogenic myeloid metaplasia: a report on 195 cases with a new scoring system.
      In a study by Passamonti et al,
      • Passamonti F.
      • Rumi E.
      • Elena C.
      • et al.
      Incidence of leukaemia in patients with primary myelofibrosis and RBC-transfusion-dependence.
      red blood cell (RBC) transfusion need was also identified as an independent risk factor for leukemic transformation, with an incidence of leukemic transformation at 7.4×100 persons per year in RBC-transfused patients vs 1.5×100 persons per year in nontransfused patients (P<.001). Other reported risk factors for leukemic transformation include increased serum interleukin 8 levels,
      • Tefferi A.
      • Vaidya R.
      • Caramazza D.
      • Finke C.
      • Lasho T.
      • Pardanani A.
      Circulating interleukin (IL)-8, IL-2R, IL-12, and IL-15 levels are independently prognostic in primary myelofibrosis: a comprehensive cytokine profiling study.
      C-reactive protein level of greater than 7 mg/L, age greater than 65 years, and peripheral blast count of more than 1%.
      • Barbui T.
      • Carobbio A.
      • Finazzi G.
      • et al.
      Elevated C-reactive protein is associated with shortened leukemia-free survival in patients with myelofibrosis.
      The International Prognostic Scoring System
      • Cervantes F.
      • Dupriez B.
      • Pereira A.
      • et al.
      New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment.
      and the Dynamic International Prognostic Scoring System (DIPSS)
      • Passamonti F.
      • Cervantes F.
      • Vannucchi A.M.
      • et al.
      A dynamic prognostic model to predict survival in primary myelofibrosis: a study by the IWG-MRT (International Working Group for Myeloproliferative Neoplasms Research and Treatment).
      are currently used to risk stratify patients with PMF and predict survival. The DIPSS was further modified to DIPSS plus
      • Gangat N.
      • Caramazza D.
      • Vaidya R.
      • et al.
      DIPSS plus: a refined Dynamic International Prognostic Scoring System for primary myelofibrosis that incorporates prognostic information from karyotype, platelet count, and transfusion status.
      by including thrombocytopenia, unfavorable karyotype, and RBC transfusion need as additional risk factors. An analysis of risk factors for leukemic transformation, in the context of DIPSS plus, identified unfavorable karyotype and platelet count less than 100×109/L as being the most important: patients with no risk factors had a risk of leukemic transformation at 5 years of 6% and at 10 years of 12%, whereas the risk was substantially higher in patients with 1 or more risk factors at 18% and 31% at 5 and 10 years, respectively.
      • Dupriez B.
      • Morel P.
      • Demory J.L.
      • et al.
      Prognostic factors in agnogenic myeloid metaplasia: a report on 195 cases with a new scoring system.
      Subsequent studies have confirmed the adverse effect of specific cytogenetic abnormalities, including monosomal and complex karyotypes.
      • Vaidya R.
      • Caramazza D.
      • Begna K.H.
      • et al.
      Monosomal karyotype in primary myelofibrosis is detrimental to both overall and leukemia-free survival.
      In a study of 793 patients with PMF, the 2-year rate of leukemic transformation was 29.4% in patients with monosomal karyotype compared with 8.3% in patients with complex karyotype.
      • Vaidya R.
      • Caramazza D.
      • Begna K.H.
      • et al.
      Monosomal karyotype in primary myelofibrosis is detrimental to both overall and leukemia-free survival.
      Mutually exclusive driver mutations up-regulating the JAK-STAT signaling pathway are frequent in MPN. JAK2 mutations are almost always present in patients with PV, whereas their incidence in PMF and ET is similar and estimated at 60%.
      • Tefferi A.
      • Vainchenker W.
      Myeloproliferative neoplasms: molecular pathophysiology, essential clinical understanding, and treatment strategies.
      In ET and PMF, the remaining 40% of patients harbor either CALR (25%-35%)
      • Klampfl T.
      • Gisslinger H.
      • Harutyunyan A.S.
      • et al.
      Somatic mutations of calreticulin in myeloproliferative neoplasms.
      • Nangalia J.
      • Massie C.E.
      • Baxter E.J.
      • et al.
      Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2.
      • Rotunno G.
      • Mannarelli C.
      • Guglielmelli P.
      • et al.
      Associazione Italiana per la Ricerca sul Cancro Gruppo Italiano Malattie Mieloproliferative Investigators
      Impact of calreticulin mutations on clinical and hematological phenotype and outcome in essential thrombocythemia.
      • Rumi E.
      • Pietra D.
      • Ferretti V.
      • et al.
      Associazione Italiana per la Ricerca sul Cancro Gruppo Italiano Malattie Mieloproliferative Investigators
      JAK2 or CALR mutation status defines subtypes of essential thrombocythemia with substantially different clinical course and outcomes.
      • Tefferi A.
      • Lasho T.L.
      • Finke C.M.
      • et al.
      CALR vs JAK2 vs MPL-mutated or triple-negative myelofibrosis: clinical, cytogenetic and molecular comparisons.
      • Tefferi A.
      • Wassie E.A.
      • Lasho T.L.
      • et al.
      Calreticulin mutations and long-term survival in essential thrombocythemia.
      • Fu R.
      • Xuan M.
      • Zhou Y.
      • et al.
      Analysis of calreticulin mutations in Chinese patients with essential thrombocythemia: clinical implications in diagnosis, prognosis and treatment.
      or MPL (3%-8%) mutations.
      • Tefferi A.
      • Vainchenker W.
      Myeloproliferative neoplasms: molecular pathophysiology, essential clinical understanding, and treatment strategies.
      Approximately 10% to 15% of patients with ET or PMF do not express any one of the aforementioned 3 driver mutations and are often referred to as being “triple negative.”
      • Tefferi A.
      • Guglielmelli P.
      • Larson D.R.
      • et al.
      Long-term survival and blast transformation in molecularly annotated essential thrombocythemia, polycythemia vera, and myelofibrosis.
      • Vannucchi A.M.
      • Guglielmelli P.
      Molecular pathophysiology of Philadelphia-negative myeloproliferative disorders: beyond JAK2 and MPL mutations.
      The prognostic role of driver mutations, in terms of leukemic transformation, is best recognized for PMF where a higher risk has been associated with triple negative and a lower risk with CALR type 1 mutation status.
      • Tefferi A.
      • Guglielmelli P.
      • Larson D.R.
      • et al.
      Long-term survival and blast transformation in molecularly annotated essential thrombocythemia, polycythemia vera, and myelofibrosis.
      The most elaborate studies assessing the prognostic role of mutations comes from 2 patient cohorts from Mayo Clinic and Florence, Italy.
      • Vannucchi A.M.
      • Lasho T.L.
      • Guglielmelli P.
      • et al.
      Mutations and prognosis in primary myelofibrosis.
      These studies identified ASXL1, SRSF2, IDH1, or IDH2 mutations as independent risk factors for leukemic transformation. The contribution of these mutations in conferring high risk for leukemic transformation was reported in other studies as well.
      • Tefferi A.
      • Guglielmelli P.
      • Lasho T.L.
      • et al.
      CALR and ASXL1 mutations-based molecular prognostication in primary myelofibrosis: an international study of 570 patients.
      • Tefferi A.
      • Lasho T.
      • Finke C.
      • et al.
      Targeted deep sequencing in primary myelofibrosis.
      • Tefferi A.
      • Lasho T.L.
      • Abdel-Wahab O.
      • et al.
      IDH1 and IDH2 mutation studies in 1473 patients with chronic-, fibrotic- or blast-phase essential thrombocythemia, polycythemia vera or myelofibrosis.
      • Pardanani A.
      • Lasho T.L.
      • Finke C.M.
      • Mai M.
      • McClure R.F.
      • Tefferi A.
      IDH1 and IDH2 mutation analysis in chronic- and blast-phase myeloproliferative neoplasms.
      A Genetics-Based Prognostic Scoring System for PMF that integrated karyotype information and mutation status was recently reported in an abstract form at the American Society of Hematology annual meeting.
      • Tefferi A.
      • Guglielmelli P.
      • Finke C.
      • et al.
      Integration of mutations and karyotype towards a Genetics-Based Prognostic Scoring System (GPSS) for primary myelofibrosis.
      Cytogenetic risk categorization included very high (monosomal karyotype, inv(3), i(17q), −7/7q-, 11q, or 12p abnormalities), high (complex nonmonosomal, 2 abnormalities not included in the very high risk category, 5q-, +8, other autosomal trisomies except +9, and other sole abnormalities not included in other risk categories), intermediate (sole abnormalities of 20q-, 1q+ or any other sole translocation, and -Y or other sex chromosome abnormality), and low (normal or sole abnormalities of 13q- or +9). Mutational status was considered favorable in the presence of CALR type 1/type 1–like variants and unfavorable in the presence of ASXL1, SRSF2, EZH2, and IDH1/2 mutations. The integration of karyotype and mutational status allowed risk stratification into high, intermediate 2, intermediate 1, and low risk groups, with the Genetics-Based Prognostic Scoring System–identified high-risk group displaying the highest risk of leukemic transformation; leukemia-free survival was significantly different between the high-intermediate 2 group vs low-intermediate 1 group (median, 11.6 years vs not reached), and this was validated in another independent cohort.
      • Tefferi A.
      • Guglielmelli P.
      • Finke C.
      • et al.
      Integration of mutations and karyotype towards a Genetics-Based Prognostic Scoring System (GPSS) for primary myelofibrosis.
      Most recently, a Mayo Clinic study of targeted sequencing in PMF identified ASXL1, SRSF2, CBL, and KIT mutations as interindependent risk factors for overall survival.
      • Tefferi A.
      • Lasho T.
      • Finke C.
      • et al.
      Targeted deep sequencing in primary myelofibrosis.
      Univariate analysis for leukemia-free survival identified SRSF2, RUNX1, CEBPA, SH2B3, and IDH2 mutations as risk factors, and the first 4 remained significant in that regard in multivariate analysis.

      Risk Factors for Leukemic Transformation in PV

      It is now well established that treatment of patients with PV treated with P32, chlorambucil, or pipobroman results in a higher risk of leukemic transformation.
      • Finazzi G.
      • Caruso V.
      • Marchioli R.
      • et al.
      ECLAP Investigators
      Acute leukemia in polycythemia vera: an analysis of 1638 patients enrolled in a prospective observational study.
      • Berk P.D.
      • Wasserman L.R.
      • Fruchtman S.M.
      • Goldberg J.D.
      Treatment of polycythemia vera: a summary of clinical trials conducted by the Polycythemia Vera Study Group.
      Older age,
      • Tefferi A.
      • Rumi E.
      • Finazzi G.
      • et al.
      Survival and prognosis among 1545 patients with contemporary polycythemia vera: an international study.
      • Marchioli R.
      • Finazzi G.
      • Landolfi R.
      • et al.
      Vascular and neoplastic risk in a large cohort of patients with polycythemia vera.
      leukocytosis,
      • Tefferi A.
      • Rumi E.
      • Finazzi G.
      • et al.
      Survival and prognosis among 1545 patients with contemporary polycythemia vera: an international study.
      • Gangat N.
      • Strand J.
      • Li C.Y.
      • Wu W.
      • Pardanani A.
      • Tefferi A.
      Leucocytosis in polycythaemia vera predicts both inferior survival and leukaemic transformation.
      and abnormal karyotype
      • Tefferi A.
      • Rumi E.
      • Finazzi G.
      • et al.
      Survival and prognosis among 1545 patients with contemporary polycythemia vera: an international study.
      have also been associated with a higher risk of leukemic transformation. A recent Mayo Clinic study evaluated 133 patients with PV, in which 5.4% had documented leukemic transformation.
      • Tefferi A.
      • Lasho T.
      • Guglielmelli P.
      • et al.
      Targeted deep sequencing in polycythemia vera and essential thrombocythemia.
      Sequence variants or mutations in PV other than JAK2, CALR, or MPL were seen in 52.6% of patients. ASXL1, SRSF2, and IDH2 were identified as adverse variants or mutations on the basis of their effect on overall, leukemia-free, or MF-free survival. In particular, SRSF2, IDH2, and RUNX1 mutations were associated with shortened leukemia-free survival in univariate analysis; SRSF2 and IDH2 mutations remained significant in multivariate analysis.

      Risk Factors for Leukemic Transformation in ET

      The reported incidence of leukemic transformation in ET has varied from less than 1% to almost 10% in some studies. In this regard, the 10-year rates from earlier studies have ranged from 2.6%
      • Passamonti F.
      • Rumi E.
      • Arcaini L.
      • et al.
      Prognostic factors for thrombosis, myelofibrosis, and leukemia in essential thrombocythemia: a study of 605 patients.
      to 8.3%-9.7%.
      • Chim C.S.
      • Kwong Y.L.
      • Lie A.K.
      • et al.
      Long-term outcome of 231 patients with essential thrombocythemia: prognostic factors for thrombosis, bleeding, myelofibrosis, and leukemia.
      • Girodon F.
      • Dutrillaux F.
      • Broséus J.
      • et al.
      Leukocytosis is associated with poor survival but not with increased risk of thrombosis in essential thrombocythemia: a population-based study of 311 patients.
      • Cervantes F.
      • Alvarez-Larrán A.
      • Talarn C.
      • Gómez M.
      • Montserrat E.
      Myelofibrosis with myeloid metaplasia following essential thrombocythaemia: actuarial probability, presenting characteristics and evolution in a series of 195 patients.
      More recent studies that have carefully excluded patients with prefibrotic PMF from their study population suggest a remarkably lower rate of less than 1% at 10 years and 2% in 15 years in WHO-defined ET.
      • Barbui T.
      • Thiele J.
      • Passamonti F.
      • et al.
      Survival and disease progression in essential thrombocythemia are significantly influenced by accurate morphologic diagnosis: an international study.
      • Passamonti F.
      • Rumi E.
      • Pungolino E.
      • et al.
      Life expectancy and prognostic factors for survival in patients with polycythemia vera and essential thrombocythemia.
      In regard to risk factors for leukemic transformation in ET, Gangat et al
      • Gangat N.
      • Wolanskyj A.P.
      • McClure R.F.
      • et al.
      Risk stratification for survival and leukemic transformation in essential thrombocythemia: a single institutional study of 605 patients.
      studied 605 consecutive patients and identified anemia with hemoglobin levels below sex-adjusted normal values, extreme thrombocytosis (≥1000×109/L), and age as continuous variables for leukemic transformation; the first 2 risk factors were included in a prognostic model that predicted leukemic transformation, and the particular risk was low at 0.4% when both risk factors were absent and was significantly higher at 4.8% and 6.5% in the presence of one or both risk factors, respectively (P<.001).
      Other risk factors for leukemic transformation in ET identified by other studies include leukocytosis (≥15×109/L),
      • Chim C.S.
      • Kwong Y.L.
      • Lie A.K.
      • et al.
      Long-term outcome of 231 patients with essential thrombocythemia: prognostic factors for thrombosis, bleeding, myelofibrosis, and leukemia.
      • Abdulkarim K.
      • Ridell B.
      • Johansson P.
      • Kutti J.
      • Safai-Kutti S.
      • Andréasson B.
      The impact of peripheral blood values and bone marrow findings on prognosis for patients with essential thrombocythemia and polycythemia vera.
      extreme thrombocytosis (≥1000×109/L),
      • Barbui T.
      • Thiele J.
      • Passamonti F.
      • et al.
      Survival and disease progression in essential thrombocythemia are significantly influenced by accurate morphologic diagnosis: an international study.
      • Gangat N.
      • Wolanskyj A.P.
      • McClure R.F.
      • et al.
      Risk stratification for survival and leukemic transformation in essential thrombocythemia: a single institutional study of 605 patients.
      anemia,
      • Gangat N.
      • Wolanskyj A.P.
      • McClure R.F.
      • et al.
      Risk stratification for survival and leukemic transformation in essential thrombocythemia: a single institutional study of 605 patients.
      • Tefferi A.
      • Gangat N.
      • Wolanskyj A.P.
      • et al.
      20+ yr without leukemic or fibrotic transformation in essential thrombocythemia or polycythemia vera: predictors at diagnosis.
      • Abdulkarim K.
      • Ridell B.
      • Johansson P.
      • Kutti J.
      • Safai-Kutti S.
      • Andréasson B.
      The impact of peripheral blood values and bone marrow findings on prognosis for patients with essential thrombocythemia and polycythemia vera.
      older age,
      • Passamonti F.
      • Rumi E.
      • Arcaini L.
      • et al.
      Prognostic factors for thrombosis, myelofibrosis, and leukemia in essential thrombocythemia: a study of 605 patients.
      • Gangat N.
      • Wolanskyj A.P.
      • McClure R.F.
      • et al.
      Risk stratification for survival and leukemic transformation in essential thrombocythemia: a single institutional study of 605 patients.
      and increased reticulin content or bone marrow cellularity
      • Barbui T.
      • Thiele J.
      • Passamonti F.
      • et al.
      Survival and disease progression in essential thrombocythemia are significantly influenced by accurate morphologic diagnosis: an international study.
      • Abdulkarim K.
      • Ridell B.
      • Johansson P.
      • Kutti J.
      • Safai-Kutti S.
      • Andréasson B.
      The impact of peripheral blood values and bone marrow findings on prognosis for patients with essential thrombocythemia and polycythemia vera.
      ; it is possible that the last 2 parameters segregated with incorrectly diagnosed cases with prefibrotic PMF. The effect of cytoreductive drugs in leukemic transformation of patients with ET was examined in several studies including a cohort of 338 patients
      • Palandri F.
      • Catani L.
      • Testoni N.
      • et al.
      Long-term follow-up of 386 consecutive patients with essential thrombocythemia: safety of cytoreductive therapy.
      in which single agent treatment with hydroxyurea or busulfan did not appear to increase the risk of leukemic transformation. Many other retrospective studies have also validated the absence of convincing evidence for drug leukemogenicity in ET, although reports to the contrary are also noted.
      • Chim C.S.
      • Kwong Y.L.
      • Lie A.K.
      • et al.
      Long-term outcome of 231 patients with essential thrombocythemia: prognostic factors for thrombosis, bleeding, myelofibrosis, and leukemia.
      Regardless, there is general agreement on the absence of controlled data that implicate any 1 drug or combination thereof as being leukemogenic in ET.
      More recent studies have examined the role of driver and other mutations in the development of leukemia in ET. Among the 3 MPN-associated driver mutations, MPL mutations have been associated with a higher risk of fibrotic progression but their effect on leukemic transformation was either not apparent
      • Beer P.A.
      • Campbell P.J.
      • Scott L.M.
      • et al.
      MPL mutations in myeloproliferative disorders: analysis of the PT-1 cohort.
      • Vannucchi A.M.
      • Antonioli E.
      • Guglielmelli P.
      • et al.
      Characteristics and clinical correlates of MPL 515W>L/K mutation in essential thrombocythemia.
      or noted during longer-term follow-up.
      • Tefferi A.
      • Wassie E.A.
      • Lasho T.L.
      • et al.
      Calreticulin mutations and long-term survival in essential thrombocythemia.
      A Mayo Clinic study
      • Tefferi A.
      • Lasho T.
      • Guglielmelli P.
      • et al.
      Targeted deep sequencing in polycythemia vera and essential thrombocythemia.
      of targeted sequencing recently identified TP53, EZH2, SRSF2, and IDH2 variants or mutations as being associated with a higher risk of leukemic transformation in univariate analysis; TP53 and EZH2 remained significant in multivariate analysis.

      Outcome of Patients With MPN-BP

      The survival of patients with MPN-BP is generally considered to be extremely poor (Table 2). This is not unexpected, given its high-risk morphological and cytogenetic features compared with those of both chronic phase MPN and primary AML. Blast-phase myeloproliferative neoplasms are often, but not always, preceded by a fibrotic phase of the disease.
      • Tam C.S.
      • Kantarjian H.
      • Cortes J.
      • et al.
      Dynamic model for predicting death within 12 months in patients with primary or post-polycythemia vera/essential thrombocythemia myelofibrosis.
      In the largest retrospective review of 273 patients with MPN-BP treated with hypomethylating agents (n=99), high-dose cytarabine (n=71), or low-dose cytarabine (n=52),
      • Chihara D.
      • Kantarjian H.M.
      • Newberry K.J.
      • et al.
      Survival outcome of patients with acute myeloid leukemia transformed from myeloproliferative neoplasms.
      progression-free or overall survival did not differ among the treatment groups; 46 patients subsequently received ASCT, with 27 in complete remission (CR), and median survival was longer in patients in CR vs patients not in CR (35.1 months vs 8.9 months). The authors also noted that treatment outcome had not changed between 1989 and 2016. In a similarly large study,
      • Mesa R.A.
      • Li C.Y.
      • Ketterling R.P.
      • Schroeder G.S.
      • Knudson R.A.
      • Tefferi A.
      Leukemic transformation in myelofibrosis with myeloid metaplasia: a single-institution experience with 91 cases.
      we reported on 91 consecutive cases of MPN-BP; the overall outcome was poor, with a median survival of 2 to 3 months of the subgroup who received induction chemotherapy and responded faring a little better with a median survival of 6.2 months as opposed to 2.7 months of patients who did not respond to treatment (P=NS). Only 1 patient had received ASCT and survived for more than 2 years.
      • Mesa R.A.
      • Li C.Y.
      • Ketterling R.P.
      • Schroeder G.S.
      • Knudson R.A.
      • Tefferi A.
      Leukemic transformation in myelofibrosis with myeloid metaplasia: a single-institution experience with 91 cases.
      Table 2Survival Outcomes of Blast-Phase Myeloproliferative Neoplasms
      Reference, studyNSupportive care: n, mOSHMA or low-dose chemotherapy: n, mOSJAK2 inhibitor ruxolitinibInduction chemotherapy: n, mOSAllogeneic stem cell transplant: n, mOS or survival
      Passamonti et al,
      • Passamonti F.
      • Rumi E.
      • Arcaini L.
      • et al.
      Leukemic transformation of polycythemia vera: a single center study of 23 patients.
      2005
      237 pts, 2.5 mo8 pts, 2.5 mo, low dose8 pts, 5.6 mo1 pt, survived >70 d
      Mesa et al,
      • Mesa R.A.
      • Li C.Y.
      • Ketterling R.P.
      • Schroeder G.S.
      • Knudson R.A.
      • Tefferi A.
      Leukemic transformation in myelofibrosis with myeloid metaplasia: a single-institution experience with 91 cases.
      2005
      9148 pts, 2.1 mo19 pts, 2.9 mo, low dose24 pts, 3.9 mo1 pt, survived >57 mo
      Tam et al,
      • Tam C.S.
      • Nussenzveig R.M.
      • Popat U.
      • et al.
      The natural history and treatment outcome of blast phase BCR-ABL myeloproliferative neoplasms.
      2008
      7419 pts, 1.5 mo12 pts, 7 mo, low dose36 pts, 6 mo8 pts, 73% survival, median follow-up 31 mo
      Thepot et al,
      • Thepot S.
      • Itzykson R.
      • Seegers V.
      • et al.
      Groupe Francophone des Myelodysplasies (GFM)
      Treatment of progression of Philadelphia-negative myeloproliferative neoplasms to myelodysplastic syndrome or acute myeloid leukemia by azacitidine: a report on 54 cases on the behalf of the Groupe Francophone des Myelodysplasies (GFM).
      2010
      2626 pts, 8 mo, azacitidine
      Mascarenhas et al,
      • Mascarenhas J.
      • Navada S.
      • Malone A.
      • Rodriguez A.
      • Najfeld V.
      • Hoffman R.
      Therapeutic options for patients with myelofibrosis in blast phase.
      2010
      116 pts, >9 mo, decitabine5 pts, >20 mo
      Ciurea et al,
      • Ciurea S.O.
      • de Lima M.
      • Giralt S.
      • et al.
      Allogeneic stem cell transplantation for myelofibrosis with leukemic transformation.
      2010
      1414 pts, 31 mo
      Noor et al,
      • Noor S.J.
      • Tan W.
      • Wilding G.E.
      • et al.
      Myeloid blastic transformation of myeloproliferative neoplasms—a review of 112 cases.
      2011
      2320 pts, 6 mo3 pts, 10.5 mo
      Cherington et al,
      • Cherington C.
      • Slack J.L.
      • Leis J.
      • et al.
      Allogeneic stem cell transplantation for myeloproliferative neoplasm in blast phase.
      2012
      138 pts, 75% 2-y PFS
      Eghtedar et al,
      • Eghtedar A.
      • Verstovsek S.
      • Estrov Z.
      • et al.
      Phase 2 study of the JAK kinase inhibitor ruxolitinib in patients with refractory leukemias, including postmyeloproliferative neoplasm acute myeloid leukemia.
      2012
      1818 pts, 17% response
      Kennedy et al,
      • Kennedy J.A.
      • Atenafu E.G.
      • Messner H.A.
      • et al.
      Treatment outcomes following leukemic transformation in Philadelphia-negative myeloproliferative neoplasms.
      2013
      7515 pts, 6.6 mo13 pts, 9.4 mo17 pts, 47 mo
      Alchalby et al,
      • Alchalby H.
      • Zabelina T.
      • Stübig T.
      • et al.
      Chronic Malignancies Working Party of the European Group for Blood and Marrow Transplantation
      Allogeneic stem cell transplantation for myelofibrosis with leukemic transformation: a study from the Myeloproliferative Neoplasm Subcommittee of the CMWP of the European Group for Blood and Marrow Transplantation.
      2014
      4646 pts, 33% 3-y OS
      Cahu et al,
      • Cahu X.
      • Chevallier P.
      • Clavert A.
      • et al.
      Allo-SCT for Philadelphia-negative myeloproliferative neoplasms in blast phase: a study from the Societe Française de Greffe de Moelle et de Therapie Cellulaire (SFGM-TC).
      2014
      6060 pts, 16% 3-y OS
      Badar et al,
      • Badar T.
      • Kantarjian H.M.
      • Ravandi F.
      • et al.
      Therapeutic benefit of decitabine, a hypomethylating agent, in patients with high-risk primary myelofibrosis and myeloproliferative neoplasm in accelerated or blastic/acute myeloid leukemia phase.
      2015
      2121 pts, 6.9 mo, decitabine
      Pemmaraju et al,
      • Pemmaraju N.
      • Kantarjian H.
      • Kadia T.
      • et al.
      A phase I/II study of the Janus kinase (JAK)1 and 2 inhibitor ruxolitinib in patients with relapsed or refractory acute myeloid leukemia.
      2015
      1818 pts, 0% response
      Andriani et al,
      • Andriani A.
      • Montanaro M.
      • Voso M.T.
      • et al.
      Azacytidine for the treatment of retrospective analysis from the Gruppo Laziale for the study of Ph-negative MPN.
      2015
      1919 pts, 9.9 mo, azacytidine
      Shanavas et al,
      • Shanavas M.
      • Popat U.
      • Michaelis L.C.
      • et al.
      Outcomes of allogeneic hematopoietic cell transplantation in patients with myelofibrosis with prior exposure to Janus kinase 1/2 inhibitors.
      2016
      1313 pts, 32% 2-y OS
      Chihara et al,
      • Chihara D.
      • Kantarjian H.M.
      • Newberry K.J.
      • et al.
      Survival outcome of patients with acute myeloid leukemia transformed from myeloproliferative neoplasms.
      2016
      27399 pts, 7.8 mo, HMA, 52 pts, 8 mo, low dose71 pts, 7.1 mo46 pts, 15.3 mo
      HMA = hypomethylating agent; mOS = median overall survival; OS = overall survival; PFS = progression-free survival; pts = patients.
      There are several other reports in the literature on MPN-BP. Tam et al
      • Tam C.S.
      • Nussenzveig R.M.
      • Popat U.
      • et al.
      The natural history and treatment outcome of blast phase BCR-ABL myeloproliferative neoplasms.
      reported on 74 patients and also documented responses to AML-like induction chemotherapy that were not, however, durable but with improved survival as compared with supportive care (median, 6 months vs 1.5 months); of note, patients who received ASCT at any point during their treatment had better survival than did those who did not receive ASCT, and the survival advantage was even more evident for early transplant with 73% survival at a median follow-up of 31 months; the authors identified older age, peripheral blasts of 20% or more, and previous splenectomy as independent risk factors for survival.
      • Tam C.S.
      • Nussenzveig R.M.
      • Popat U.
      • et al.
      The natural history and treatment outcome of blast phase BCR-ABL myeloproliferative neoplasms.
      Passamonti et al
      • Passamonti F.
      • Rumi E.
      • Arcaini L.
      • et al.
      Leukemic transformation of polycythemia vera: a single center study of 23 patients.
      reported the outcome of MPN-BP after PV and found similar survival between patients who had received AML-like induction chemotherapy (median, 5.6 months) or palliation with low-dose chemotherapy (cytarabine or 6-thioguanine) or supportive care (median, 2.5 months). Noor et al
      • Noor S.J.
      • Tan W.
      • Wilding G.E.
      • et al.
      Myeloid blastic transformation of myeloproliferative neoplasms—a review of 112 cases.
      studied 23 patients with MPN-BP, among whom 20 received AML-like induction chemotherapy, with 12 achieving remission; median survival was higher in responding patients at 12.8 months compared with 2.9 months in patients who did not achieve remission; 3 patients underwent ASCT with a median survival of 10.5 months. The authors subsequently scanned the literature and gathered information on 112 patients with MPN-BP to identify favorable risk factors for survival: antecedent diagnosis of ET, absence of complex karyotype, age less than 60 years, and less than 3 previous therapies. In yet another study of 13 patients with MPN-BP, 11 were treated with AML-like induction chemotherapy, with 8 patients achieving complete response, reversal to chronic phase disease, or marrow blast clearance
      • Cherington C.
      • Slack J.L.
      • Leis J.
      • et al.
      Allogeneic stem cell transplantation for myeloproliferative neoplasm in blast phase.
      ; 8 patients underwent ASCT, including 5 patients with less than 5% blood and bone marrow blast, 2 patients with peripheral blasts, and 1 patient with more than 5% bone marrow blast; outcome in this small study was better in the absence of excess bone marrow blast, but patients with circulating blasts were still salvageable.
      Hypomethylating agents, such as azacitidine and decitabine, have also been shown to have activity in MPN-BP; in a study of 26 patients treated with azacitidine, a 38% response rate (median time to response, 9 months) with an overall median survival of 8 months was reported.
      • Thepot S.
      • Itzykson R.
      • Seegers V.
      • et al.
      Groupe Francophone des Myelodysplasies (GFM)
      Treatment of progression of Philadelphia-negative myeloproliferative neoplasms to myelodysplastic syndrome or acute myeloid leukemia by azacitidine: a report on 54 cases on the behalf of the Groupe Francophone des Myelodysplasies (GFM).
      In that study, the authors observed better responses in post-ET, as opposed to post-PV, MPN-BP, with no significant difference in overall survival.
      • Thepot S.
      • Itzykson R.
      • Seegers V.
      • et al.
      Groupe Francophone des Myelodysplasies (GFM)
      Treatment of progression of Philadelphia-negative myeloproliferative neoplasms to myelodysplastic syndrome or acute myeloid leukemia by azacitidine: a report on 54 cases on the behalf of the Groupe Francophone des Myelodysplasies (GFM).
      Another study reviewed patients with MPN-BP treated with azacytidine (75 mg/m2) and found that the observed median survival of 9.9 months was better than that of their historical controls
      • Andriani A.
      • Montanaro M.
      • Voso M.T.
      • et al.
      Azacytidine for the treatment of retrospective analysis from the Gruppo Laziale for the study of Ph-negative MPN.
      ; once again, the median survival of patients who achieved CR was even better at 19.6 months. In a retrospective comparison to 6 patients treated with decitabine, the 5 who received low-intensity ASCT survived longer, with a median survival of more than 20 months.
      • Mascarenhas J.
      • Navada S.
      • Malone A.
      • Rodriguez A.
      • Najfeld V.
      • Hoffman R.
      Therapeutic options for patients with myelofibrosis in blast phase.
      Similar observations were noted in another study of 14 patients with MPN-BP who received ASCT after first being chemotherapy-induced and 2-year survival was reported at 49%.
      • Ciurea S.O.
      • de Lima M.
      • Giralt S.
      • et al.
      Allogeneic stem cell transplantation for myelofibrosis with leukemic transformation.
      Badar et al
      • Badar T.
      • Kantarjian H.M.
      • Ravandi F.
      • et al.
      Therapeutic benefit of decitabine, a hypomethylating agent, in patients with high-risk primary myelofibrosis and myeloproliferative neoplasm in accelerated or blastic/acute myeloid leukemia phase.
      studied the use of decitabine in 21 patients with MPN-BP; 6 patients responded (3 CR, 2 near CR, and 1 partial response), and survival was better in responders vs nonresponders (median, 10.5 months vs 4 months); the authors did not find survival difference between decitabine-treated patients and historical controls treated with AML-like induction chemotherapy without ASCT.
      Kennedy et al
      • Kennedy J.A.
      • Atenafu E.G.
      • Messner H.A.
      • et al.
      Treatment outcomes following leukemic transformation in Philadelphia-negative myeloproliferative neoplasms.
      adopted an approach of using curative intent treatment with induction chemotherapy followed by ASCT in fit and transplant-eligible patients. Seventy-five patients were included in the study, with 39 patients receiving AML-like induction chemotherapy followed by ASCT in eligible patients (17 of 39). The 36 other patients were treated with noncurative intent using hypomethylating agents, novel agents, or supportive care. Two-year survival was superior at 25.6% vs 3.1% in patients treated with curative intent. Furthermore, median survival was impressive at 47 months in patients who received ASCT and was not affected by the type of conditioning regimen. Induction chemotherapy without ASCT was unable to induce long-term remissions and resulted in a median survival of 9.4 months. The transplant cohort and the induction chemotherapy arm with responses but without transplant were compared, and survival was significantly better in the transplant group (2-year survival of 47% vs 15%; P=.03). The median survival for low-intensity regimens was 6.6 months. This study further stressed the importance of ASCT as an adjunct to induction chemotherapy.
      The MPN Subcommittee of the Chronic Malignancies Working Party of the European Society for Blood and Marrow Transplantation studied 46 patients with MPN-BP who received ASCT.
      • Alchalby H.
      • Zabelina T.
      • Stübig T.
      • et al.
      Chronic Malignancies Working Party of the European Group for Blood and Marrow Transplantation
      Allogeneic stem cell transplantation for myelofibrosis with leukemic transformation: a study from the Myeloproliferative Neoplasm Subcommittee of the CMWP of the European Group for Blood and Marrow Transplantation.
      At a median follow-up of 37.4 months, progression-free survival and overall survival at 3 years were 26% and 33%, respectively. The major determinant of survival after ASCT was achievement of CR before transplant (69% vs 22%; P=.008). A study in France analyzed the outcomes of ASCT in patients with MPN-BP or myelodysplastic syndrome (MDS)/MPN-BP
      • Cahu X.
      • Chevallier P.
      • Clavert A.
      • et al.
      Allo-SCT for Philadelphia-negative myeloproliferative neoplasms in blast phase: a study from the Societe Française de Greffe de Moelle et de Therapie Cellulaire (SFGM-TC).
      ; 60 patients were studied and overall survival and leukemia-free survival at 3 years were 16% and 9%, respectively. As expected, outcome was better in patients receiving transplant in CR, while intensity of the conditioning regimen did not affect survival.
      • Cahu X.
      • Chevallier P.
      • Clavert A.
      • et al.
      Allo-SCT for Philadelphia-negative myeloproliferative neoplasms in blast phase: a study from the Societe Française de Greffe de Moelle et de Therapie Cellulaire (SFGM-TC).
      A Canadian MPN group conducted a study to evaluate the survival effect of ASCT in patients with MF previously exposed to JAK inhibitors
      • Shanavas M.
      • Popat U.
      • Michaelis L.C.
      • et al.
      Outcomes of allogeneic hematopoietic cell transplantation in patients with myelofibrosis with prior exposure to Janus kinase 1/2 inhibitors.
      ; their patient cohort of 100 included 13 who progressed into MPN-BP while receiving JAK inhibitor; patients with MPN-BP received AML-like induction chemotherapy or hypomethylating agents before transplant; 2-year post-ASCT survival was worst in patients with MPN-BP (32%), and the poor outcome was attributed to a higher relapse rate. In regard to ruxolitinib activity in MPN-BP, a phase 2 study was conducted in refractory AML, including 18 patients with MPN-BP and exhibited limited activity.
      • Eghtedar A.
      • Verstovsek S.
      • Estrov Z.
      • et al.
      Phase 2 study of the JAK kinase inhibitor ruxolitinib in patients with refractory leukemias, including postmyeloproliferative neoplasm acute myeloid leukemia.

      Investigational Agents

      Blast-phase myeloproliferative neoplasms are relatively resistant to conventional chemotherapy with the only curative hope being ASCT, as discussed above, necessitating the need to develop novel therapies. Bromodomain and extra terminal domain inhibitors (BETis) target epigenetic proteins in cancer and were studied in patient-derived MPN blast progenitor cells and exhibited activity inducing apoptosis and inhibiting growth
      • Saenz D.T.
      • Fiskus W.
      • Manshouri T.
      • et al.
      BET protein bromodomain inhibitor-based combinations are highly active against post-myeloproliferative neoplasm secondary AML cells.
      ; furthermore, synergism was observed when BETis were combined with ruxolitinib. In another study, combination of BETi with heat shock protein 90 inhibitor exerted effects on ruxolitinib-persisting or ruxolitinib-resistant MPN blast cells. This was based on a previous finding reported by this team that heat shock protein 90 inhibitor reduces mutant JAK2, AKT, and c-RAF as well as induces apoptosis in JAKi-resistant MPN blast cells.
      • Fiskus W.
      • Verstovsek S.
      • Manshouri T.
      • et al.
      Heat shock protein 90 inhibitor is synergistic with JAK2 inhibitor and overcomes resistance to JAK2-TKI in human myeloproliferative neoplasm cells.
      CPX-351 is a liposome formulation of cytarabine and daunorubicin and recently received breakthrough therapy designation in May 2016 for therapy-related AML or AML with myelodysplasia-related changes. Ex vivo sensitivity using CPX-351 in leukemia cells from different sources exhibited activity against myeloid blasts derived from patients with MPN/MDS overlap.
      • Gordon M.J.
      • Tardi P.
      • Loriaux M.M.
      • et al.
      CPX-351 exhibits potent and direct ex vivo cytotoxicity against AML blasts with enhanced efficacy for cells harboring the FLT3-ITD mutation.
      Moreover, the improved survival (median, ∼10 months with CPX-351 vs ∼6 months with the standard “7+3” AML therapy; P=.005) reported in the relevant phase III trial of CPX-351 involved older patients and high-risk AML, including therapy related and with antecedent MDS or chronic myelomonocytic leukemia.
      • Lancet J.E.
      • Uy G.L.
      • Cortes J.E.
      • et al.
      Final results of a phase III randomized trial of CPX-351 versus 7+3 in older patients with newly diagnosed high risk (secondary) AML.
      Accordingly, it makes sense to investigate the therapeutic value of CPX-351 in MPN-BP, which happens to be a form of secondary AML and usually affects older patients.

      Conclusion

      The prognosis of MPN- BP remains dismal and appears to be worse than that of primary AML. Drug therapy alone, although capable of inducing CRs in a minority of patients, is ineffective in securing long-term remissions. Furthermore, despite increasing information on mutational repertoire in MPN-BP, the promise for targeted therapy in the near future is currently slim. Durable remissions have been noted in few patients who managed to receive ASCT, but the overall experience with the particular treatment modality has been less than impressive. It is possible that one can reduce the case numbers with MPN-BP using MPN treatment that modifies the natural history of disease, but the particular scenario has yet to be realized. Current prognostic models for MPN are useful in predicting leukemic transformation, and incorporation of molecular information might lead to further refinement of these models. For now, the only hope for cure or long-term remission in MPN-BP remains ASCT, and every effort should be made to identify patients with MPN who are at high risk for leukemic transformation so that they can be offered treatment with ASCT sooner rather than later.

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