New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment

Abstract

Therapeutic decision-making in primary myelofibrosis (PMF) is becoming more challenging because of the increasing use of allogeneic stem cell transplantation and new investigational drugs. To enhance this process by developing a highly discriminative prognostic system, 1054 patients consecutively diagnosed with PMF at 7 centers were studied. Overall median survival was 69 months (95% confidence interval [CI]: 61-76). Multivariate analysis of parameters obtained at disease diagnosis identified age greater than 65 years, presence of constitutional symptoms, hemoglobin level less than 10 g/dL, leukocyte count greater than 25 ؋ 10 9 /L, and circulating blast cells 1% or greater as predictors of shortened survival. Based on the presence of 0 (low risk), 1 (intermediate risk-1), 2 (intermediate risk-2) or greater than or equal to 3 (high risk) of these variables, 4 risk groups with no overlapping in their survival curves were delineated; respective median survivals were 135, 95, 48, and 27 months (P < .001). Compared with prior prognostic models, the new risk stratification system displayed higher predictive accuracy, replicability, and discriminating power. In 409 patients with assessable metaphases, cytogenetic abnormalities were associated with shorter survival, but their independent contribution to prognosis was restricted to patients in the intermediate-risk groups. JAK2V617F did not cluster with a specific risk group or affect survival. IntroductionPrimary myelofibrosis (PMF) 1 is classified as a chronic myeloproliferative disorder and characterized by variable degrees of cytopenia(s) and/or cytosis, a leukoerythroblastic blood picture, bone marrow fibrosis, and extramedullary hematopoiesis often resulting in hepatosplenomegaly. 2 From a pathogenesis standpoint, the disease features clonal proliferation involving pluripotent hematopoietic stem cells, 3,4 and clonal cell-derived cytokines are implicated for some of the disease aspects such as bone marrow fibrosis and extramedullary hematopoiesis. 2 Most recently, JAK2 5-7 and MPL 8-10 mutations were described in approximately 50% and 10% of patients with PMF, respectively. However, the precise pathogenetic contribution of these mutations is currently not well defined.PMF usually affects subjects with advanced age, 11 but young people are not necessarily spared. 12 Reported median survivals are variable and in the range of 4-7 years. 13,14 Previous studies have identified several adverse prognostic factors for survival, including advanced age, [15][16][17][18][19] marked anemia, 13-22 leukocytosis or leukopenia, 14,16,18,22 abnormal karyotype, 18,23-25 constitutional symptoms, 13,14,17,22 and presence of circulating blasts. 13,14,22 Based on some of these variables, several prognostic scoring systems have been proposed. 12,13,18,19,22,26 More recently, the prognostic value of blood CD34 ϩ cell count 27,28 and JAK2 mutational status [29][30][31] has also been evaluated.Current drug therapy for PMF has not been shown to influence survival and is often used for pal...

One Thousand Patients With Primary Myelofibrosis: The Mayo Clinic Experience

“…Information regarding presenting clinical and laboratory features was available in all 1000 patients for most parameters (Table 1). 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.…”

“…[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.…”

How to manage children and young adults with myeloproliferative neoplasms

“…The onset of the MPNs is often a very slowly advancing process and both in the WHO-defined PV and ET, disease-specific survival (loss in life expectancy) is not substantially different from that of a control population, especially in younger adults. 14 PMF is a more serious disease with expected median observed survival of about 6 years, 15 whereas in prefibrotic myelofibrosis median survival is about 10 years. 14 Information on the genetic abnormalities most commonly encountered in MPNs has to be explicitly discussed.…”

“…14 The International Prognostic Scoring System (IPSS) for classical-advanced PMF uses five independent predictors of inferior survival (age 465 years, hemoglobin o10 g/100 ml, leukocyte count 425 Â 109/l, circulating blasts 41% and presence of constitutional symptoms) to stratify patients into low, intermediate-1, intermediate-2 and high-risk categories based on the presence of 0, 1, 2 or 43 risk factors, respectively; the corresponding median observed survivals are estimated at 135, 95, 48 and 27 months. 15 On the other hand, it has to be tested whether this International Prognostic Scoring System may be also applicable on patients with early PMF that infrequently present with constitutional symptoms.…”