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Long-term outcome after transplant in MF patients
Introduction
Statistical analysis
The end points of interest were overall survival (OS), disease-free survival (DFS), relapse/progression and non- relapse mortality (NRM) within the first ten years after HSCT for patients alive and disease-free at the 2-year LM after HSCT. For all outcomes, patients were considered to be at risk since this LM. Median follow up was deter- mined using the reverse Kaplan-Meier method. OS was defined as the time since LM until death from any cause, with surviving patients censored at the time of last follow up. Patients still at risk at ten years after HSCT were administratively censored. DFS was defined as time to death or relapse/progression (whichever occurred first). OS and DFS were estimated using the Kaplan-Meier product limit estimation method, and differences in sub- groups were assessed by the Log-rank test. The cumula- tive incidences of relapse/progression (CIR) and NRM were analyzed together in a competing risks framework.25 Competing risks analyses were also applied to estimate the incidences of (extensive) chronic graft-versus-host dis- ease (cGvHD) and secondary malignancies, each with the competing event death, at ten years after HSCT. Previous acute GvHD (aGvHD) in the landmark population was quantified as a simple proportion, since all cases of aGvHD occurred prior to the 2-year LM time point. Cox proportional hazards regression was used to assess the impact of potential risk factors on OS, RFS, CIR and NRM. CIR and NRM were analyzed in a competing risks framework in which the cause-specific hazards (CSH) were modeled.
Methods from relative survival were used to estimate the proportion of the deaths observed in our cohort which could be attributed to population causes (population mor- tality) and which to MF-related causes, including HSCT and pre-treatment (excess mortality).26,27 Patients were matched by age, sex and country and year of HSCT to a cohort from the general population, for whom survival information was available in the population tables in the Human Mortality Database (http:// www.mortality.org/). The excess hazard of death was defined as the difference between the observed hazard in the patient cohort (this myelofibrosis cohort) and the hazard of the matched gen- eral population cohort. For multivariable analyses, we esti- mated Cox proportional hazards models for the excess hazard of death. Risk factors considered were age, sex, MF classification (primary vs. secondary), conditioning inten- sity, total body irradiation (TBI), donor type, stem cell source, and previous GvHD (defined as the development of any type of GvHD between transplantation and the 2- year LM). All estimates are reported with 95% confidence intervals. All analyses were performed in SPSS version 23 and R 3.3.0 (https://cran.r-project.org/), ‘survival’, ‘cmprsk’, ‘prodlim’ and ‘relsurv’ packages.
Results
Characteristics of patients and transplant
Characteristics of the entire patient cohort and the long-term survivors are shown in Table 1. Long-term sur- vivors were transplanted at a median age of 53.5 years; 837 (79%) patients had primary MF at the time of trans- plantation, 645 (63%) patients received a reduced intensi- ty regimen, and 471 (45%) were transplanted using an HLA-matched sibling donor.
Myelofibrosis (MF) is a malignant clonal disease that can be classified as either primary or secondary to either essential thrombocythemia (ET) or polycythemia vera (PV). The clinical phenotype of MF is markedly heteroge- neous and disease severity can be assessed by a number of different prognostic scoring systems. For example, uti- lizing the Dynamic International Prognostic Scoring System (DIPSS-PLUS), low, int-1, int-2 and high-risk patients have a median survival of 15 years, 6.5 years, 35 months and 16 months, repectively.1 JAK-2 inhibitors, specifically ruxolitinib, which remains the only licensed therapeutic agent in MF, alleviate many symptoms and even possibly increase survival, but they are not consid- ered curative.2-4 Only allogeneic hematopoietic stem cell transplantation (HSCT) has been proposed as curative; overall, HSCT has been reported to cure 30-65% of these patients.5-16 One registry paper analyzed the timing to transplant in patients aged <65 years and concluded that those with intermediate-2 or high-risk disease are those who clearly benefit from transplantation strategies.17 This analysis included transplant-episodes prior to the ruxoli- tinib era, and the role of this agent on transplantation strategies remains under debate.18 Early mortality (within 2 years) after transplantation is known to be 10-30%, but so far no study has analyzed the outcome of transplanted MF patients after this early period. In contrast, long-term outcome studies have been published for HSCT recipi- ents who have more common disease types, such as acute leukemia, lymphoma, and chronic myeloid leukemia.19-24 Understanding the long-term outcome for transplanted MF patients will help to improve monitoring and promote increased awareness of the potential risks of relapse or, indeed, mortality, particularly when compared to the general population.
Methods
Patient selection
Only patients from countries for which the population mortality tables are available in a uniform format through the Human Mortality Database, allowing a sex- and age- matched comparison, and contributing more than twenty allogeneic transplantations for MF were included in the study. Patients aged <18 years and those who were trans- planted from an unrelated matched cord blood were excluded. Patients were analyzed at the time of their first allogeneic transplant only. A total of 2,459 patients received a first allogeneic HCT between January 1995 and December 2014 for primary or secondary MF. A total of 1,055 of these 2,459 patients were reported alive and free of their disease at two years after HSCT; these patients were considered for the study and called long-term (dis- ease-free) survivors. These patients were transplanted in 178 centers in 15 countries.
Definitions
Relapse was defined as disease recurrence. Causes of death were classified as related to relapse if the patient expe- rienced a relapse at any period during follow up. Excess mor- tality was defined as the difference between mortality observed in the myelofibrosis landmark (LM) cohort and mortality in a matched cohort of the general population.
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