Comprehensive Clinical-Molecular Transplant Risk Model for Myelofibrosis Undergoing Allogeneic Stem Cell Transplantation

Background The dynamic International Prognostic Scoring System (DIPSS) is commonly applied to predict survival among patients with primary myelofibrosis (PMF) but has been shown to perform less precisely in secondary myelofibrosis (SMF) and after transplantation. Furthermore, the prognostic relevance of mutation profile resulted in the mutation-enhanced IPSS (MIPSS) in PMF, as well as in a model specific to SMF (MYSEC-PM) after essential thrombocythemia (ET) or polycythemia vera (PV). The aim of the current study was to develop a comprehensive prognostic system including clinical and molecular information, specifically in myelofibrosis undergoing transplantation. Methods Previously published methods were used to sequence myelofibrosis-associated genes (i.a. CALR1/2, JAK2, MPL,ASXL1, SRSF2, EZH2, IDH1/2, DNMT3A, TET2, TP53). Outcome was calculated from date of transplant (95% confidence interval). Variables associated with overall survival (OS) constructed a Cox regression with a stepwise selection procedure. Hazard ratios (HR) were used as weights for model development. Validation was done using repeated random subsampling. Performance of the model was verified via Harrel's concordance index C and was also tested in predefined cohorts: disease (PMF, SMF), conditioning, and ruxolitinib pretreatment. Results Population. The total cohort consisted of 361 patients from four different centers in Germany and France (260 PMF, 101 SMF). Median age at transplant was 57 years (range, 22-75), 58% were male and 42% had a Karnofsky performance score (KPS) Factors on outcome. In univariate analysis, mutations in CALR and MPL showed better OS (79% and 76%) vs. JAK2 (53%) and triple negative (50%; p=0.001). Outcome was similar according to CALR type (p=0.99). ASXL1 and DNMT3A mutations also entered the multivariate model. The following eight clinical, molecular and transplant-related variables were identified (corresponding HR): leukocytes >25x109/l (1.71), platelets 57 years (1.69), recipient/donor CMV serostatus (+/- vs. other, 1.68), ASXL1 (1.74), JAK2/triple negative (2.10), and MMUD (2.11). Myelofibrosis Transplant Scoring System (MTSS). A weighted score of 1 was assigned to leukocytosis, thrombocytopenia, KPS 57, recipient/donor CMV serostatus (+/-), and ASXL1 mutation, whereas 2 points were assigned to JAK2/triple negative and MMUD. Four risk groups constructed the MTSS: low (score 0-2), intermediate (score 3-4), high (score 5-6), and very high (score 7-9). The 5-year OS according to risk groups was 88%, 71%, 50%, and 20% (Figure 1). The hazard for death (with low-risk as reference) was 2.36 for intermediate-risk, 4.65 for high-risk, and 9.72 for very high-risk. The score was predictive of OS overall as well as for PMF and SMF (p Conclusions The new MTSS includes modern disease- and transplant-associated risk variables pertinent to both PMF and SMF. This proposed system consistently predicts outcome facilitating posttransplant decision-making and can be applied to different conditioning settings and to patients receiving ruxolitinib pretreatment. Figure 1. Figure 1. Disclosures Beelen: Medac: Consultancy, Other: Travel Support. Kroeger:Novartis: Honoraria, Research Funding; Riemser: Honoraria, Research Funding; Neovii: Honoraria, Research Funding; Sanofi: Honoraria; JAZZ: Honoraria; Celgene: Honoraria, Research Funding.