Postgrafting Immune Suppression Combined With Nonmyeloablative Conditioning For Transplantation Of HLA-Matched Related Or Unrelated Hematopoetic Cell Grafts: Preliminary Results Of A Phase II Study For Treatment Of Primary Immunodeficiency Disorders

Myeloablative conditioning regimens may cause life threatening transplant related toxicities in patients with primary immunodeficiency disorders (PID), particularly in patients with co-morbid conditions. We previously reported the outcomes of a phase I study using nonmyeloablative conditioning in 14 high-risk patients and demonstrated low transplant related mortality (TRM; 3-year, 23%); however there was a high incidence of chronic GVHD (1-year 47%). We reasoned that the incidence of GVHD could be reduced if marrow was used instead of PBSC; however, previous experience showed marrow to be associated with a higher risk for rejection. Therefore our standard nonmyeloablative regimen of 90 mg/m2 fludarabine and 2 Gy total body irradiation (TBI) was somewhat intensified to include either Campath 1-H, or, for patients with infections for whom Campath 1-H was contraindicated, an additional 2 Gy TBI. Sixteen patients with PID and significant underlying infections and/or other co-morbidities were given HLA-matched related (n=7) or unrelated (n=9) marrow grafts following nonmyeloablative conditioning modified with either Campath 1-H (n=3) or 4 Gy TBI (n=13). All patients were given postgrafting immunosuppression with MMF and CSP. Of the 15 patients evaluable for engraftment, mixed (50-95%; n=8) or full (>95%; n=6) donor CD3+T-cell chimerism was established in 14 patients. Two patients required a 2nd myeloablative HCT due to graft rejection or loss of the granulocyte and NK cell components of the graft despite stable mixed T-cell chimerism. The cumulative incidence of extensive chronic GVHD at 1 year was 29%. With a median follow-up of 19 (range, 3 – 36) months the 1-year overall survival and TRM were 87% and 14%, respectively. One patient with disseminated CMV and adenovirus before HCT died from these infections at day +1 and one patient with pre existing renal failure died at day +222 from complications of renal failure. Five patients were not evaluable for disease response due to less than 100 days of follow-up (n=2), 2nd HCT (n=2), or death prior to day 100 following HCT (n=1). Eleven patients had improvement in or correction of their underlying immunodeficiency. Although preliminary, these results indicate that outcome can be improved for high-risk patients with PID using a modified nonmyeloablative conditioning regimen and marrow grafts, resulting in reduction of chronic GVHD, stable donor engraftment, low TRM, and correction of underlying disease processes.