Risk Factors for Poor Survival after Hematopoietic Stem Cell Transplantation in Inherited Bone Marrow Failure Syndromes

Introduction: Inherited bone marrow failure syndromes (IBMFS) are characterized by single or multi-lineage cytopenias as well as non-hematologic manifestations. Hematopoietic stem cell transplantation (HSCT) is the only curative therapy for the hematological abnormalities. However, high rates of mortality and morbidity from this procedure have been reported in patients with IBMFSs.

Objective: The study aim was to investigate the impact of patient, donor and treatment-related variables on the outcome of HSCT in IBMFS patients.

Methods: Data of patients who were prospectively enrolled in the Canadian Inherited Marrow Failure Registry (CIMFR) from 2001 to 2012 and underwent HSCT were analyzed. The CIMFR is a population-based multicenter study, which includes all 16 pediatric tertiary care centers across all provinces in Canada. These centers care for >95% of the eligible pediatric IBMFS population in Canada. Descriptive analyses, as well as univariate and multivariate analyses (using a Cox proportional hazards model) were performed to assess the impact of multiple factors on probability of survival following transplant.

Results: Among 363 patients enrolled in CIMFR, 65 underwent allogeneic HSCT. Thiry-four patients were male and 30 were female (gender unknown for 1 patient). Median age at diagnosis with IBMFS was 3.0 years (range: prenatal diagnosis to 32.0 years) and median age at HSCT was 6.5 years (range: 0.25-20.1 years). Median follow-up time post-HSCT (time to death or last follow-up) was 2.8 years (range 0.01–15.9 years). Indications for transplant included severe cytopenia (n=44), myelodysplastic syndrome (n=18) acute myeloid leukemia (n=2) and unavailable cause (n=1). Cell type were bone marrow (n=40), cord blood (n=17), peripheral blood (n=5), unknown (n=3). Sixty-two percent of patients (n=40) received cells from an unrelated donor. Seventy-four percent (n=47) of patients had a full HLA-matched donor; 19 of those were related and 28 were unrelated donors. The most common conditioning regimen combined high dose cyclophosphamide, fludarabine and anti-thymocyte globulin (n=17). Incidence of graft failure, acute (grade II-IV) graft versus host disease (GVHD) and chronic GVHD was 14%, 30% and 22%, respectively. Five-year probability of survival for HSCT recipients was 73.4% ± 6.1% (SE). Causes of death included infections (CMV, fungal infections and bacterial), GVHD, lymphoproliferative disorder and congestive heart failure, pulmonary fibrosis, bronchiolitis obliterans. In the univariate analysis, factors significantly associated with increased mortality post-HSCT included ≥20 pre-HSCT platelet transfusions, pre-transplant administration of granulocyte colony-stimulating factor, 1 or more HLA mismatches, donor type (divided into four categories: matched related, partially matched related, matched unrelated, partially matched unrelated) and conditioning regimens combining high doses of cyclophosphamide with fludarabine and anti-thymocyte globulin (while comparing this combination against all others). The former 3 variables remained significant in the multivariate analysis.

Conclusion: Number of pre-transplant platelet transfusions, use of granulocyte colony-stimulating factor and one or more donor-recipient HLA mismatches were shown to increase the risk of mortality in patients with IBMFSs undergoing HSCT. Novel strategies are needed to improve outcome in patients with a high risk of HSCT-related complications.