Unmanipulated Peripheral Blood Stem Cells Can be Safely Used to Allograft Patients with Severe Aplastic Anemia; The Impact of ATG in Latin American Experience

Severe aplastic anemia (SAA) is characterized by the absence of progenitor hematopoietic cells in bone marrow caused mainly by autoimmunity. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the treatment of choice for young newly diagnosed patients with SAA. The preferred source of stem cells is bone marrow (BM) due to improved overall survival (OS) and lower incidence of graft versus host disease (GVHD).

In Latin American countries, many patients have received peripheral blood stem cell transplantation (PBSCT) for several reasons: lower cost, apheresis without anesthesia, no bone punctures and faster hematological recovery. Moreover, due to patient family or donors idiosyncratic factors, there is a lack of acceptance to surgical harvesting of bone marrow. Therefore we describe the Latin American experience with allo-HSCT using PBSC in SAA patients.

One hundred and ninety patients with acquired SAA that received allo-HSCT using PBSC between 1997- 2014 were included. The allo-HSCT was performed at 4 centers of Perú, Colombia and México. All donors were HLA-identical siblings mobilized with G-CSF. The choice of the conditioning regimens was made on each institution. Primary outcome was OS; incidence of GVHD, outcome of patients > 40 years old and effect of conditioning regimens on survival were studied.

The median of CD 34+ cells administered was 4.22 X 10⁶/kg (range 0.70-22.28). Median of neutrophil and platelet recovery was 11 days (range 7-35) and 12 days (range 8-25) respectively. Neutrophil recovery for anti-thymocyte globulin (ATG)-based regimens presented at a median of 11 days (range 7-28) and for non-ATG based regimens 14 days (range 9-35) (P<0.001). Median platelet recovery for ATG based regimens was 10 days (range 8-17) and 14 days (range 8-25) for non ATG based regimens. (P=0.02) Engraftment did not occur in 5% of recipients (n=10).

The incidence of acute graft versus host disease (aGVHD) was 19.5% (8.4% was grade III-IV). Chronic GVHD (cGVHD) was 24.7% and extensive manifestations presented in 5.9% of patients. No relation between the conditioning regimen used (ATG vs non-ATG based regimens) and the incidence of aGVHD (P=0.066) or cGVHD (p=0.613) was found. The administration of ≥3.0X10⁶ CD 34/Kg related to higher incidence of aGVHD grade III and IV (P=0.05), but not cGVHD (P=0.709) or extensive cGVHD (P=0.428). The presence of aGVDH and cGVHD was associated with higher mortality (P<0.0001 and P=0.0001 respectively). OS was 71% at 10-years follow-up. OS for patients ≥40 years was 75%; similar than those younger (P=0.661).Comparing ATG based regimens (n=127) vs non-ATG based regimens (n= 63) OS was 82% vs 59% respectively (P=.001). Mortality within the first 100 days post-transplant was 7%.

Time from diagnosis to transplant ≥ 100 days was not a predictor of death (P=0.458). A total of 63% of patients were considered heavily transfunded and this factor was not related to relapse (P=0.96), aGVHD (P=0.75) or cGVHD (P=0.39). Nineteen patients (10%) lost their grafts; most of them had received non-ATG conditioning regimens (P=.016). Four patients (2%) developed secondary malignancies after transplant: acute myeloid leukemia (2), myelodisplastic syndrome (1) and hairy cell leukemia (1).

In multivariate analysis, the use of non-ATG based regimens (P<0.0001), presence of grade III-IV aGVHD (P<0.0001), extensive cGVHD (P=0.009) and >3 X10⁶/kg CD34(P=0.04) were independent negative predictors of survival.

Infections were the leading cause of death. The second cause was GVDH and related complications. The transplant was successful in 95% of patients. The OS achieved in this study at 10 years with ATG-based regimens and PBSC (82%) is comparable to that (84%) reported from the WPSAA-EBMT (Haematologica 2009) using BM. In the study reported by EBMT-CIBMTR (Blood 2007) the 5 years OS was 85% using BM in patients ≤20 years and 64% in patients > 20 years. In our study the incidence of aGVHD and cGVHD was similar the aforementioned study of WPSAA-EBMT using PBSC (19.5% vs 17%) and (24.5 vs 22%) respectively.

In conclusion allo-HSCT in SAA patients using PBSC is an effective treatment resulting in cure in the majority of cases. Patients conditioned with ATG had a 10-year OS similar to that reported with BM as the source of stem cells, a prospective and comparative study is needed to definitively establish if it is safe to perform a HSCT using peripheral blood as a source of stem cells.