- Email: [email protected]
PV MF: Different from Primary MF
Extended Abstract: 013-MTPIV-01
Management of Post ET/PV MF: Different from Primary MF Extended Abstract Clinical features of MF: PMF and SMF Information on the clinical presentation of primary myelofibrosis (PMF) and post polycythemia (PV) and post essential thrombocythemia (ET) MF, from now on named secondary myelofibrosis (SMF), are mainly obtained from the largest cohorts of patients as the IPSS (International Prognostic scoring System) for PMF,1-3 and the MYSEC project (MYelofibrosis SECondary to PV and ET) for SMF.4,5
Francesco Passamonti, MD University of Insubria, Varese, Italy [email protected]
Concerning PMF,1,6 median age of the IPSS cohort (N¼1054) was 64 years with 17% of the patients younger than 50 years, and 5% younger than 40 year. Males are predominant (61%). Ninety percent of the patients presented with splenomegaly. Bone marrow or blood karyotype showed abnormalities in 30% of PMF and 60% of the patients carried the JAK2 mutation. The incidence of thrombosis in PMF was 2.2 x100 patients/year at 10 years.7 Among 278 patients in whom the final cause of death was known, transformation to acute myeloid leukemia (AML) was the most frequent cause (31%), followed by PMF progression without AML (18%), thrombosis and cardiovascular complications (13%), infection (10%) or bleeding (5%) out of the setting of AML, portal hypertension (5%) and secondary cancer (4%). A subsequent analysis demonstrated that overall survival of PMF improved in the last decades, mainly due to better survival in lower risk patients.8
Barbara Mora, MD Ospedale di Circolo, Varese, Italy [email protected]
Margherita Maffioli, MD Ospedale di Circolo, Varese, Italy margherita.maffi[email protected]
The need for clinical and molecular information in SMF led to the development of the MYSEC project,4,5 an international effort generated in 2014 to collect retrospective data on SMF. This is the largest cohort to date of SMF patients, including 781 consecutive patients collected from 16 international centers. Among these, 685 (333 PET MF, 352 PPV MF) patients were with phenotype driver mutations available. Compared to PETMF, patients with PPV MF were older, had higher values of white blood cells and hemoglobin, larger spleen size and lower platelet count. At diagnosis, patients with PPV MF had significantly higher frequency of constitutional symptoms, abnormal karyotype and prior thrombosis than those with PET MF. Thrombotic events occurred in 67 SMF (12%), blast phase in 52 SMF (7.5%) and death in 169 SMF (25%). Cause of death was known in 136 of the 169 patients who died: non-clonal disease progression in 52 (38%), AML in 43 (32%), second malignancy in 10 (7%), infection in 12 (9%), heart failure in 11 (8%), vascular complications in seven (5%), and other in one (1%). Median survival was 14.5 years in PET MF and 8.1 years in PPV MF, with a borderline difference.4
Keywords Polycythemia, thrombocythemia, myelofibrosis, prognosis, JAK2 S24
Mutations in PMF and SMF The driver mutations of JAK2, MPL and CALR genes are present in MF (PMF and SMF) and patients without these mutations (1015%, overall) are conventionally called triple negative (TN).9 The JAK2 mutation has been detected in 60% of MF, MPL mutations in 5-10% of MF,10, while mutations in the CALR gene have been mainly identified in PMF patients without JAK2 or MPL mutations, 11,12 covering 70% of the mutational profile in JAK2/MPL-negative patients. Additional mutations of CBL, TET2, SF3B1, SRSF2, DNMT3A, IDH1/2, EZH2, and ASXL1 genes are variably reported in MPN, although mainly in patients with PMF.13
The MYSEC project has provided the ideal framework to develop a prognostic system specifically tailored for PPV- and PET-MF, named MYSEC-PM (Myelofibrosis Secondary to PV and ETPrognostic Model).4 The median survival of overall SMF was 9.3 years. Ad hoc statistical analyses have been employed to select the following subset of significant covariates: hemoglobin level below 11 g/dL, platelet count lower than 150 x109/L, circulating blasts equal to or higher than 3%, CALR-unmutated genotype, presence of constitutional symptoms. Age at diagnosis was also found to be an important predictor for survival according to multivariate models and was retained as a continuous covariate. Each discrete variable was assigned a risk point: 0.15 points per each year of age, two points to hemoglobin level below 11 g/dL, to circulating blasts equal to or higher than 3%, and to CALR-unmutated genotype; one point to platelet count lower than 150 x109/L and to the presence of constitutional symptoms. The sum of risk points and age-related risk were mapped into four risk categories with different median overall survival: low-risk (score less than 11), median survival not reached; intermediate-1 risk (score equal to or higher than 11 and lower than 14), median survival 9.3 years (95% CI: 8.1-NR); intermediate-2 risk (score equal to or higher than 14 and less than 16) median survival 4.4 years (95% CI: 3.2-7.9); and high risk (score equal to or higher than 16), median survival 2 years (95% CI: 1.73.9). A nomogram to facilitate the use of the model has been developed. The large set of SMF patients included in the MYSEC project allowed for the development of this model with superior discriminatory power with respect to IPSS in this specific subset of MF.
The MYSEC project recently disclosed genotype-phenotype associations in SMF.5 At presentation JAK2-mutated patients had higher white blood cell count and greater splenomegaly than CALR-mutated patients and that CALR type 1/type 1-like and CALR type 2/type 2-like were similar in terms of clinical presentation and outcome. AML incidence was higher in JAK2-mutated PET MF and TN patients (triple negative, i.e. without JAK2, MPL, CALR mutations) when compared with CALR-mutated patients. In SMF ASXL1, EZH2, SRSF2, IDH1, and IDH2 account for 25% of patients. Differently from PMF,10 these mutations have no implication on SMF outcome prediction, with the exception of SRSF2 mutations, which correlate with reduced survival.6 Prognostic score to predict survival in PMF and SMF The IPSS model was defined in 2009 on a basis of 1054 patients with PMF, excluding post-PV and post-ET MF and prefibrotic PMF.1 Median survival was 69 months in the whole series. Median survivals were 135 months in low risk, 95 in intermediate-1 risk, 48 in intermediate-2 risk, and 27 in high risk. The DIPSS was subsequently developed on 525 PMF patients regularly followed, using the same IPSS risk factors but with a different scoring system.14 Median survival referring to patients maintaining the same risk category over time was not reached in low risk, 14.2 years in intermediate-1 risk, 4 years in intermediate-2 risk, and 1.5 years in high risk. The DIPSS-plus model was produced by the analysis of 793 patients with PMF of which 428 were referred within and 365 after their first year of diagnosis.15 Unfavorable cytogenetics, red blood cell transfusion need, low platelet counts were added to DIPSS categories. Median survival was 185 months in low risk, 78 in intermediate-1 risk, 35 in intermediate-2 risk and 16 in high risk.
Copyrights & Permissions Authors transfer copyright to the publisher
Acknowledgements This work was supported by a grant from the Associazione Italiana per la Ricerca sul Cancro (AIRC; Milano, Italy), Special Program Molecular Clinical Oncology 5x1000 to AIRC-Gruppo Italiano Malattie Mieloproliferative (AGIMM) project #1005. Was also supported by grants from the Fondazione Matarelli (Milano, Italy), Fondazione Rusconi (Varese, Italy) and AIL Varese ONLUS.
References 1. 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. Blood. 2009;113(13):2895-2901. 2. Passamonti F, Alessandro V, Domenica C, et al. A New International Multicenter-Based Model to Predict Survival in Myelofibrosis Secondary to Polycythemia and Thrombocythemia: The Mysec Prognostic Model (MYSEC-PM). Blood. 2014;124(21):1826-1826. 3. Passamonti F, Cervantes F, Vannucchi AM, et al. Dynamic International Prognostic Scoring System (DIPSS) predicts progression to acute myeloid leukemia in primary myelofibrosis. Blood. 2010;116(15):2857-2858. 4. Passamonti F, Giorgino T, Mora B, et al. A clinical-molecular prognostic model to predict survival in patients with
Starting from the IPSS and DIPSS prognostic models and the data provided on mutational platform available,16 it seemed obvious to combine different clinical-molecular parameters with the aim to recognize higher risk patients among low risk patients. To reinforce the role of mutations in disease prediction, the additional prognostic value of the number of mutated genes has been taken into account.17 The presence of two or more mutations predicted worst outcome. Median survival was 2.6 years, 7.0 years and 12.3 years for patients with 2, 1 or no mutations respectively. Two or more mutations were also associated with shortened leukemia-free survival.
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post polycythemia vera and post essential thrombocythemia myelofibrosis. Leukemia. 2017. Passamonti F, Mora B, Giorgino T, et al. Driver mutations’ effect in secondary myelofibrosis: an international multicenter study based on 781 patients. Leukemia. 2017;31(4):970-973. Cervantes F, Passamonti F, Barosi G. Life expectancy and prognostic factors in the classic BCR/ABL-negative myeloproliferative disorders. Leukemia. 2008;22(5):905-914. Barbui T, Carobbio A, Cervantes F, et al. Thrombosis in primary myelofibrosis: incidence and risk factors. Blood. 2010;115(4):778-782. Cervantes F, Dupriez B, Passamonti F, et al. Improving survival trends in primary myelofibrosis: an international study. J Clin Oncol. 2012;30(24):2981-2987. Passamonti F, Maffioli M. Update from the latest WHO classification of MPNs: a user’s manual. Hematology Am Soc Hematol Educ Program. 2016;2016(1):534-542. Rumi E, Pietra D, Guglielmelli P, et al. Acquired copyneutral loss of heterozygosity of chromosome 1p as a molecular event associated with marrow fibrosis in MPLmutated myeloproliferative neoplasms. Blood. 2013;121(21):4388-4395. Klampfl T, Gisslinger H, Harutyunyan AS, et al. Somatic Mutations of Calreticulin in Myeloproliferative Neoplasms. N Engl J Med. 2013. Nangalia J, Massie CE, Baxter EJ, et al. Somatic CALR Mutations in Myeloproliferative Neoplasms with Nonmutated JAK2. N Engl J Med. 2013. Passamonti F, Maffioli M, Caramazza D. New generation small-molecule inhibitors in myeloproliferative neoplasms. Curr Opin Hematol. 2012;19(2):117-123. Passamonti F, Cervantes F, Vannucchi AM, 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). Blood. 2010;115(9):1703-1708. 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. J Clin Oncol. 2011;29(4):392-397. Vannucchi AM, Lasho TL, Guglielmelli P, et al. Mutations and prognosis in primary myelofibrosis. Leukemia. 2013;27(9):1861-1869. Guglielmelli P, Lasho TL, Rotunno G, et al. The number of prognostically detrimental mutations and prognosis in primary myelofibrosis: an international study of 797 patients. Leukemia. 2014.
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Management of Post ET/PV MF: Different from Primary MF Extended Abstract Clinical features of MF: PMF and SMF Information on the clinical presentation of primary myelofibrosis (PMF) and post polycythemia (PV) and post essential thrombocythemia (ET) MF, from now on named secondary myelofibrosis (SMF), are mainly obtained from the largest cohorts of patients as the IPSS (International Prognostic scoring System) for PMF,1-3 and the MYSEC project (MYelofibrosis SECondary to PV and ET) for SMF.4,5
Francesco Passamonti, MD University of Insubria, Varese, Italy [email protected]
Concerning PMF,1,6 median age of the IPSS cohort (N¼1054) was 64 years with 17% of the patients younger than 50 years, and 5% younger than 40 year. Males are predominant (61%). Ninety percent of the patients presented with splenomegaly. Bone marrow or blood karyotype showed abnormalities in 30% of PMF and 60% of the patients carried the JAK2 mutation. The incidence of thrombosis in PMF was 2.2 x100 patients/year at 10 years.7 Among 278 patients in whom the final cause of death was known, transformation to acute myeloid leukemia (AML) was the most frequent cause (31%), followed by PMF progression without AML (18%), thrombosis and cardiovascular complications (13%), infection (10%) or bleeding (5%) out of the setting of AML, portal hypertension (5%) and secondary cancer (4%). A subsequent analysis demonstrated that overall survival of PMF improved in the last decades, mainly due to better survival in lower risk patients.8
Barbara Mora, MD Ospedale di Circolo, Varese, Italy [email protected]
Margherita Maffioli, MD Ospedale di Circolo, Varese, Italy margherita.maffi[email protected]
The need for clinical and molecular information in SMF led to the development of the MYSEC project,4,5 an international effort generated in 2014 to collect retrospective data on SMF. This is the largest cohort to date of SMF patients, including 781 consecutive patients collected from 16 international centers. Among these, 685 (333 PET MF, 352 PPV MF) patients were with phenotype driver mutations available. Compared to PETMF, patients with PPV MF were older, had higher values of white blood cells and hemoglobin, larger spleen size and lower platelet count. At diagnosis, patients with PPV MF had significantly higher frequency of constitutional symptoms, abnormal karyotype and prior thrombosis than those with PET MF. Thrombotic events occurred in 67 SMF (12%), blast phase in 52 SMF (7.5%) and death in 169 SMF (25%). Cause of death was known in 136 of the 169 patients who died: non-clonal disease progression in 52 (38%), AML in 43 (32%), second malignancy in 10 (7%), infection in 12 (9%), heart failure in 11 (8%), vascular complications in seven (5%), and other in one (1%). Median survival was 14.5 years in PET MF and 8.1 years in PPV MF, with a borderline difference.4
Keywords Polycythemia, thrombocythemia, myelofibrosis, prognosis, JAK2 S24
Mutations in PMF and SMF The driver mutations of JAK2, MPL and CALR genes are present in MF (PMF and SMF) and patients without these mutations (1015%, overall) are conventionally called triple negative (TN).9 The JAK2 mutation has been detected in 60% of MF, MPL mutations in 5-10% of MF,10, while mutations in the CALR gene have been mainly identified in PMF patients without JAK2 or MPL mutations, 11,12 covering 70% of the mutational profile in JAK2/MPL-negative patients. Additional mutations of CBL, TET2, SF3B1, SRSF2, DNMT3A, IDH1/2, EZH2, and ASXL1 genes are variably reported in MPN, although mainly in patients with PMF.13
The MYSEC project has provided the ideal framework to develop a prognostic system specifically tailored for PPV- and PET-MF, named MYSEC-PM (Myelofibrosis Secondary to PV and ETPrognostic Model).4 The median survival of overall SMF was 9.3 years. Ad hoc statistical analyses have been employed to select the following subset of significant covariates: hemoglobin level below 11 g/dL, platelet count lower than 150 x109/L, circulating blasts equal to or higher than 3%, CALR-unmutated genotype, presence of constitutional symptoms. Age at diagnosis was also found to be an important predictor for survival according to multivariate models and was retained as a continuous covariate. Each discrete variable was assigned a risk point: 0.15 points per each year of age, two points to hemoglobin level below 11 g/dL, to circulating blasts equal to or higher than 3%, and to CALR-unmutated genotype; one point to platelet count lower than 150 x109/L and to the presence of constitutional symptoms. The sum of risk points and age-related risk were mapped into four risk categories with different median overall survival: low-risk (score less than 11), median survival not reached; intermediate-1 risk (score equal to or higher than 11 and lower than 14), median survival 9.3 years (95% CI: 8.1-NR); intermediate-2 risk (score equal to or higher than 14 and less than 16) median survival 4.4 years (95% CI: 3.2-7.9); and high risk (score equal to or higher than 16), median survival 2 years (95% CI: 1.73.9). A nomogram to facilitate the use of the model has been developed. The large set of SMF patients included in the MYSEC project allowed for the development of this model with superior discriminatory power with respect to IPSS in this specific subset of MF.
The MYSEC project recently disclosed genotype-phenotype associations in SMF.5 At presentation JAK2-mutated patients had higher white blood cell count and greater splenomegaly than CALR-mutated patients and that CALR type 1/type 1-like and CALR type 2/type 2-like were similar in terms of clinical presentation and outcome. AML incidence was higher in JAK2-mutated PET MF and TN patients (triple negative, i.e. without JAK2, MPL, CALR mutations) when compared with CALR-mutated patients. In SMF ASXL1, EZH2, SRSF2, IDH1, and IDH2 account for 25% of patients. Differently from PMF,10 these mutations have no implication on SMF outcome prediction, with the exception of SRSF2 mutations, which correlate with reduced survival.6 Prognostic score to predict survival in PMF and SMF The IPSS model was defined in 2009 on a basis of 1054 patients with PMF, excluding post-PV and post-ET MF and prefibrotic PMF.1 Median survival was 69 months in the whole series. Median survivals were 135 months in low risk, 95 in intermediate-1 risk, 48 in intermediate-2 risk, and 27 in high risk. The DIPSS was subsequently developed on 525 PMF patients regularly followed, using the same IPSS risk factors but with a different scoring system.14 Median survival referring to patients maintaining the same risk category over time was not reached in low risk, 14.2 years in intermediate-1 risk, 4 years in intermediate-2 risk, and 1.5 years in high risk. The DIPSS-plus model was produced by the analysis of 793 patients with PMF of which 428 were referred within and 365 after their first year of diagnosis.15 Unfavorable cytogenetics, red blood cell transfusion need, low platelet counts were added to DIPSS categories. Median survival was 185 months in low risk, 78 in intermediate-1 risk, 35 in intermediate-2 risk and 16 in high risk.
Copyrights & Permissions Authors transfer copyright to the publisher
Acknowledgements This work was supported by a grant from the Associazione Italiana per la Ricerca sul Cancro (AIRC; Milano, Italy), Special Program Molecular Clinical Oncology 5x1000 to AIRC-Gruppo Italiano Malattie Mieloproliferative (AGIMM) project #1005. Was also supported by grants from the Fondazione Matarelli (Milano, Italy), Fondazione Rusconi (Varese, Italy) and AIL Varese ONLUS.
References 1. 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. Blood. 2009;113(13):2895-2901. 2. Passamonti F, Alessandro V, Domenica C, et al. A New International Multicenter-Based Model to Predict Survival in Myelofibrosis Secondary to Polycythemia and Thrombocythemia: The Mysec Prognostic Model (MYSEC-PM). Blood. 2014;124(21):1826-1826. 3. Passamonti F, Cervantes F, Vannucchi AM, et al. Dynamic International Prognostic Scoring System (DIPSS) predicts progression to acute myeloid leukemia in primary myelofibrosis. Blood. 2010;116(15):2857-2858. 4. Passamonti F, Giorgino T, Mora B, et al. A clinical-molecular prognostic model to predict survival in patients with
Starting from the IPSS and DIPSS prognostic models and the data provided on mutational platform available,16 it seemed obvious to combine different clinical-molecular parameters with the aim to recognize higher risk patients among low risk patients. To reinforce the role of mutations in disease prediction, the additional prognostic value of the number of mutated genes has been taken into account.17 The presence of two or more mutations predicted worst outcome. Median survival was 2.6 years, 7.0 years and 12.3 years for patients with 2, 1 or no mutations respectively. Two or more mutations were also associated with shortened leukemia-free survival.
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post polycythemia vera and post essential thrombocythemia myelofibrosis. Leukemia. 2017. Passamonti F, Mora B, Giorgino T, et al. Driver mutations’ effect in secondary myelofibrosis: an international multicenter study based on 781 patients. Leukemia. 2017;31(4):970-973. Cervantes F, Passamonti F, Barosi G. Life expectancy and prognostic factors in the classic BCR/ABL-negative myeloproliferative disorders. Leukemia. 2008;22(5):905-914. Barbui T, Carobbio A, Cervantes F, et al. Thrombosis in primary myelofibrosis: incidence and risk factors. Blood. 2010;115(4):778-782. Cervantes F, Dupriez B, Passamonti F, et al. Improving survival trends in primary myelofibrosis: an international study. J Clin Oncol. 2012;30(24):2981-2987. Passamonti F, Maffioli M. Update from the latest WHO classification of MPNs: a user’s manual. Hematology Am Soc Hematol Educ Program. 2016;2016(1):534-542. Rumi E, Pietra D, Guglielmelli P, et al. Acquired copyneutral loss of heterozygosity of chromosome 1p as a molecular event associated with marrow fibrosis in MPLmutated myeloproliferative neoplasms. Blood. 2013;121(21):4388-4395. Klampfl T, Gisslinger H, Harutyunyan AS, et al. Somatic Mutations of Calreticulin in Myeloproliferative Neoplasms. N Engl J Med. 2013. Nangalia J, Massie CE, Baxter EJ, et al. Somatic CALR Mutations in Myeloproliferative Neoplasms with Nonmutated JAK2. N Engl J Med. 2013. Passamonti F, Maffioli M, Caramazza D. New generation small-molecule inhibitors in myeloproliferative neoplasms. Curr Opin Hematol. 2012;19(2):117-123. Passamonti F, Cervantes F, Vannucchi AM, 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). Blood. 2010;115(9):1703-1708. 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. J Clin Oncol. 2011;29(4):392-397. Vannucchi AM, Lasho TL, Guglielmelli P, et al. Mutations and prognosis in primary myelofibrosis. Leukemia. 2013;27(9):1861-1869. Guglielmelli P, Lasho TL, Rotunno G, et al. The number of prognostically detrimental mutations and prognosis in primary myelofibrosis: an international study of 797 patients. Leukemia. 2014.
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