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)

Abstract

Age older than 65 years, hemoglobin level lower than 100 g/L (10 g/dL), white blood cell count greater than 25 ؋ 10 9 /L, peripheral blood blasts 1% or higher, and constitutional symptoms have been shown to predict poor survival in primary myelofibrosis (PMF) at diagnosis. To investigate whether the acquisition of these factors during follow-up predicts survival, we studied 525 PMF patients regularly followed. All 5 variables had a significant impact on survival when analyzed as time- IntroductionPrimary myelofibrosis (PMF) is a Philadelphia-negative myeloproliferative neoplasm (MPN) whose diagnostic criteria have been recently updated. 1 Among MPNs, PMF has the most heterogeneous clinical presentation, which may encompass anemia, splenomegaly, leukocytosis or leukopenia, thrombocytosis or thrombocytopenia, and constitutional symptoms. The discovery of the activating mutation JAK2 (V617F) in more than 70% of patients with MPNs 2 led to the development of new biochemically selective JAK2 inhibitors. 3 These agents are currently being tested in clinical trials that usually include patients with long disease history.Advanced age, 4-7 anemia, 4-11 red blood cell transfusion need, 12 leukopenia, 8 leukocytosis, 8 thrombocytopenia, 9 peripheral blast count, 4,6 systemic symptoms, 6,10 degree of microvessel density, 13 and cytogenetic abnormalities 5,7,9,[14][15][16] were shown to be associated with poor outcome in patients with PMF. The presence of the JAK2 (V617F) mutation per se does not seem to imply worse survival, 17 although a low JAK2 (V617F) allele burden seems associated with poorer outcome. 18,19 Recently, Cervantes et al 17 on behalf of the International Working Group for Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) developed a prognostic scoring system to estimate survival of PMF patients. This model uses 5 factors (age older than 65 years, hemoglobin level Ͻ 100 g/L [10 g/dL], white blood cell count Ͼ 25 ϫ 10 9 /L, peripheral blood blasts Ն 1%, and presence of constitutional symptoms) to identify 4 risk categories with different survival.Prognostic models for PMF developed so far are based on the evaluation of risk factors present at diagnosis. However, the acquisition of additional risk factors during the disease course may substantially modify the patients' outcome. A dynamic prognostic model that accounts for modifications of the risk profile after diagnosis may prove useful in clinical practice. On behalf of IWG-MRT, first we investigated whether the acquisition anytime during follow-up of one or more of the prognostic factors identified by Cervantes et al 17 predicts survival. Then, a new prognostic score based on a time-dependent risk evaluation was developed: the Dynamic International Prognostic Scoring System (DIPSS) for PMF. MethodsThe study was carried out through an international cooperation on behalf of the IWG-MRT. An ad hoc database was developed for data collection. For personal use only. on May 12, 2018. by guest www.bloodjournal.org From Study designThe Institutional Rev...

One Thousand Patients With Primary Myelofibrosis: The Mayo Clinic Experience

“…All patients had information on the 5 variables (see Patients and Methods section) that were required for risk stratification according to IPSS 32 or DIPSS. 33 DIPSS-plus 21 and leukemia risk stratification was possible in 967 patients in whom karyotype information was available. Information on JAK2V617F, MPL, and IDH mutations was available in 583, 341, and 305 patients, respectively ( Table 1).…”

“…[26][27][28][29] IDH1 and IDH2 mutations were analyzed by direct sequencing and/or high-resolution melting assay. 30 Unfavorable karyotype designation 31 and International Prognostic Scoring System (IPSS), 32 DIPSS, 33 and DIPSSplus 21 21 Leukemic transformation risk was considered high in the presence of unfavorable karyotype or platelet count less than 100 ϫ 10 9 /L or low in the absence of both of these risk factors. 21 All statistical analyses considered clinical and laboratory parameters obtained at time of first referral to Mayo Clinic.…”

“…In this regard, we also encourage deeper examination of cytogenetic details and degree of elevation in circulating blasts and leukocytes in order to identify patients with a very high risk of early death. 41 In the absence of cytogenetic information, we prefer IPSS 32 for prognostication at time of diagnosis and DIPSS 33 for prognostication at time of referral beyond the time of initial diagnosis. Once accurate prognostication has been accomplished, the excellent prognosis associated with low-risk disease (median survival of Ͼ15 years for all patients and up to 20 years for younger patients) mandates a high threshold for intervening with specific therapy.…”

Safety and efficacy of combination therapy of interferon‐α2 and ruxolitinib in polycythemia vera and myelofibrosis

“…Inclusion criteria were age ≥18 years and a diagnosis of PV or MF of low‐ or intermediate‐1 or ‐2‐risk on the DIPSS scale,16 including PMF, post‐PV MF, and post‐ET MF according to, respectively, the 2008 WHO criteria24 and the International Working Group‐Myeloproliferative Neoplasms Research and Treatment (IWG‐MRT) criteria 25. Evidence of active disease was required, defined by a need for phlebotomy, white blood cell (WBC) count ≥10 × 10 9 /L, platelet count >400 × 10 9 /L, constitutional symptoms, pruritus, symptomatic splenomegaly, or previous thrombosis.…”

“…Pegylated forms of IFNα2 (PEG‐IFNα2) allow administration once weekly and have proven efficacious in ET9, 10, 11, 12 and PV9, 10, 11, 12, 13, 14, 15. Patients in the early phase of MF, defined by low‐ or intermediate‐risk disease on the Dynamic International Prognostic Scoring System (DIPSS) scale,16 have also been shown to benefit from treatment with IFNα2 9, 17, 18. Of note, in a subset of patients, long‐term treatment with IFNα2 induces deep molecular remission sustained even years after cessation of therapy 9, 10, 11, 13, 14, 15.…”