Survival of Allogeneic Stem Cell Transplantation Vs Conventional Therapies per DIPSS Stratification in Patients with Primary Myelofibrosis Younger Than 65 Years: A Retrospective Analysis on 673 Patients (2014)

Abstract Introduction Primary myelofibrosis (PMF) is a clonal myeloproliferative neoplasm with a high risk of clonal evolution and mortality. Allogeneic stem cell transplantation (ASCT) is currently the only curative treatment approach for myelofibrosis. Due to the inherent complications, careful patient selection is mandatory. Patients and Methods With the goal of refining patient selection for ASCT we compared results of ASCT with non-transplant approaches in 673 patients with PMF stratified according the Dynamic International Prognostic Scoring System (DIPSS), which assigns a time-dependent risk on a scale of low, intermediate (int)-1, int-2, and high. Considering a commonly used age-threshold for indication of ASCT, we restricted the analysis to patients aged 65 years or younger. This included 190 PMF patients (median 50 years at diagnosis) who received ASCT (HLA-matched related, n= 88 [46%] HLA-matched unrelated and mismatched related, n= 102 [54%] donors) after reduced intensity (n=93), or high intensity conditioning (n=97), and 248 patients, median age 55 years, from the DIPSS database (PMF patients not receiving any experimental drug at data cut-off and censored at the time of ASCT). DIPSS scores at ASCT, or, for non-transplanted patients, at diagnosis, were low in 22 (11%) and 125 (49%), int-1 in 38 (20%) and 75 (29%), int-2 in 85 (45%) and 52 (20%), and high in 45 (24%) and 3 (1%) patients, respectively. The median time from diagnosis to ASCT was 1.2 years. In line with the dynamic nature of the DIPSS, risk scores in the non-transplanted cohort change with time and, accordingly, were accounted for as time-dependent covariates. The date of diagnosis was considered as origin of the time scale, and patients entered the analysis when receiving ASCT (ASCT cohort) or at the time of acquisition of a specific DIPSS category of a non-transplant cohort. Therefore, left truncated, right censored data were used for both cohorts. Left truncation (begin of observation) for the ASCT cohort was the time to ASCT after diagnosis, while for the non-transplant cohort it was the time of achieving the respective DIPSS risk category. Cox proportional hazard models were built separately for the four DIPSS stages, considering the cohort as a discrete covariate; the corresponding relative risks (RR) between the two cohorts were computed under the proportional-hazards approximation, and Wald tests were used to report significance. Age at diagnosis was not significant in any model and, therefore, was not included in the regressions. The present study could not address the potentially confounding factor of selection bias regarding ASCT. Results The relative risk (RR) of dying among patients receiving ASCT relative to those receiving conventional therapies was 5.6 (95% CI: 1.7-19, p=0.0051) for low risk DIPSS, 1.6 (95% CI: 0.79-3.2, p=0.19) for int-1 risk DIPSS, 0.55 (95%CI: 0.36-0.83, p=0.005) for int-2 , and 0.37 (95%CI: 0.21-0.66, p=0.0007) for high risk DIPSS patients. The proportions of patients with low risk DPSS surviving at 1, 5 and 10 years were 100%, 69%, and 60%, respectively, for the ASCT cohort, and 98%, 95%, and 92% for the non-transplant cohort. The corresponding figures for patients with int-1 risk were 78%, 52%, and 41%, respectively, after ASCT, and 97%, 77%, and 63% for non-transplanted patients. Among patients with int-2 risk survival after ASCT was 82%, 50%, and 32%, respectively, and 77%, 41% and 11% among non-transplanted patients. The corresponding figures for high risk patients were 65%, 37% and 27% for the ASCT cohort, and 67%, 11% and 1%, respectively, for the non-transplant cohort. It should be noted that hazard ratios are not constant over time, and summarizing the risk in a single “average” RR ignores the specifics of the survival trends. Survival differences became pronounced beyond 5 years following diagnosis for int-2 and high risk patients. Conclusion Patients with PMF who, at any age≤ 65 years, have int-2 or high risk disease by DIPSS have superior survival if receiving ASCT during their disease history. Conversely, conventional therapy appears to result in superior outcome in low risk patients, while intermediate-1 risk patients represent a group in whom individual counseling may be particularly important. Disclosures Vannucchi: Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Research Funding.