Myeloablative Allogeneic Bone Marrow Transplantation (AlloBMT) with T Cell Depletion (TCD) and Post-Transplant GM-CSF for Patients with High Risk MDS.

Myelodysplastic syndromes (MDS) are a complex and heterogeneous group of hematopoietic stem cell malignancies that are generally incurable outside allo BMT. The toxicities of allo BMT, specifically graft-vs-host disease (GVHD) and end organ toxicity, have limited its use in this traditionally older group of patients (pts) who often have medical co-morbidities. Efforts to apply allo BMT to more pts have focused on reducing the toxicities. Graft manipulation, including TCD, and reduced-intensity conditioning (RIC) regimens have been shown to decrease the upfront mortality of allo BMT; yet improvements in overall survival have been limited due to associated increased post-BMT relapse rates and increased graft failure. Myeloid growth factors have been used commonly, though not systematically, following allo BMT to speed engraftment. Our data, and that of others, suggest that myeloid growth factors may also have anti-tumor properties in MDS by impacting differentiation pathways and/or through their immunomodulatory effects. We developed a clinical trial to determine if the addition of GM-CSF could safely decrease the relapse rate following a TCD allo BMT in pts with high risk MDS. Pts with MDS ≤ 65 undergoing evaluation for a matched sibling allo BMT at the Sidney Kimmel Cancer Center at Johns Hopkins were considered eligible. Pts received a TCD allograft (elutriation and CD34 isolation) following a myeloablative busulfan/cytoxan preparative regimen; GM-CSF @ 250 mcg/m²/day from Day +5 until ANC >2000/m³ × 3 days and then 125mcg/m²/day subcutaneously thru Day +60. A total of 43 pts were treated on the protocol with a median age of 56 (range 30 to 65) yrs. Forty pts had poor risk MDS (cytogenetics and IPSS) and 3 pts had AML upon retrospective pathology review. The addition of GM-CSF was well tolerated post-allo BMT with only 1 pt unable to complete the full dose, planned therapy. The overall survival @ 1 and 3 years was 54% and 50% respectively while the event free survival @ 1 and 3 years was 47% and 33% respectively with median follow-up in the surviving group of 37.5 months. Treatment related toxicity was low with a 9% cumulative incidence of grade III/IV aGVHD and a transplant-related mortality (TRM) of 21% (9/43) with 4 deaths related to GVHD, 4 related to engraftment, and 1 secondary to venoocclusive disease. Cumulative incidence of relapse at data analysis was 40% (17/43) with one patient achieving remission after donor lymphocyte infusion. Engraftment failure was seen in only 9% (4/43) of pts. Taken together, ablative preparative regimens followed by TCD allo BMT can safely be used in older MDS pts with the addition of GM-CSF resulting in acceptable engraftment without increased toxicity. Myeloablative conditioning with TCD and prolonged post-transplant GM-CSF produced favorable results in this group of older, high-risk MDS patients. The role of high dose conditioning for alloBMT for MDS is unclear, but the TRM was similar to the low mortality reported with RIC regimens, and the graft failure and relapse rates may be superior.