Infections Are the Major Cause of Non Relapse Mortality (NRM) after T Cell Depleted (TCD) Allogeneic Hematopoietic Stem Cell Transplantation for Advanced Myelodysplastic Syndrome

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative treatment for MDS.  GVHD is one of the main causes of NRM in unmodified allo-HSCT. We aimed to study causes of NRM after TCD transplant.

108 patients with MDS underwent TCD allo-HSCT at MSKCC between 1/2001- 4/2012.  Median age was 57.6 (18.1-73.0).  WHO subtypes at diagnosis were: RA/RCMD 30, RAEB-I 34 & RAEB-II 44. In 73 pts disease progressed prior to transplant. 101 pts were treated before transplant (hypomethylating agents 27, induction chemotherapy 73, syngeneic transplant 1). All pts underwent conditioning with a myeloablative regimen and received ATG to prevent graft rejection (other than 4 pts).    Hematopoietic stem cells source was PB in 102 pts and BM in 6 pts. BM grafts were depleted of T-cells by soybean agglutinin  followed by sheep RBC rosetting, and PB graft by immunomagnetic CD34+ selection (Isolex initially and CliniMACS after 09/2011). Donors were HLA matched (79; 39 related and 40 unrelated) or mismatched (29).

The OS (with 95% confidence interval) at 1 year was 70.2% (60.5-77.9) and at 3 years 50.0 % (39.9-59.2). Cumulative incidence (CI) at 1 year of grade III-IV acute GvHD was 12.1% (6.8-19.1) and of chronic GvHD 2.8% (0.8-7.4). CI of relapse at 1 year was 11.2 % (6.1-18.0) and at 2 years 16.0% (9.7-23.6). 106 patients engrafted (2 died early and were not evaluable). 

The CI of NRM at 1 year was 23.3% (15.8-31.7) and at 2 years 31.8 % (23.2-40.7). The causes of death were defined according to Copelan’s criteria (BBMT 2007).  Infections accounted for 51% of NRM; 32% bacterial, 16% viral and 3% fungal.  In a univariate landmark analysis, the only factor associated with increased NRM was a low CD4 at 3 months (p=0.012). For patients with CD4<100 vs ≥100 at 3 months post transplant, the 1 year NRM was 21.9% (9.5-37.5) vs 8.6% (2.1-20.8) and at 3 years 35.4% (18.9-52.3) vs 8.6% (2.1-20.8). The CI of death due to infection was significantly higher in patients with CD4<100 vs ≥100 (p=0.019): 15.2% (5.4-29.5) vs 2.9% (0.2-12.9) at 1 year and 21.3% (9.2-36.8) vs 2.9% (0.2-12.9) at 3 years.  There was a trend for higher NRM in older patients (>50) (p=0.094), with estimated incidence of 34.9% vs 20.8% at two years.  The following factors were not associated with an increased NRM: etiology (de-novo vs therapy related), conditioning regimen (chemotherapy vs TBI), pretransplant therapy (hypomethylating vs induction chemotherapy), donor (MRD vs MUD vs MM donor and mixed T cell chimerism (<50% donor chimerism) on day 100 post transplant and BM chimerism at 6 months (<95% donor chimerism).

Infections were the main cause for NRM followed by GVHD. Low CD4 count at 3 months post transplant was a strong predictor for NRM and in particular for infection related mortality. TCD allo-HSCT associated with low incidence of GvHD can serve as a platform to enhance immunity against specific common infections etiologies with viral or fungal specific cytotoxic T cells.