Secondary Systemic Immunosuppressants (SSI) After Myeloablative HLA Matched Related And Unrelated Bone Marrow Transplantation (BMT) Using High Dose Cyclophosphamide (HiCy) As Sole GVHD Prophylaxis

The optimal approach for GVHD prophylaxis remains uncertain and novel strategies are needed. It has been argued that, due to subjectivity in scoring clinical signs of GVHD, additional, more objective endpoints should be used. One of more persuasive ones is the use of SSI beyond the originally planned prophylaxis. We retrospectively compared the incidence of GVHD and the use of SSI in 139 consecutive patients with advanced hematologic malignancies treated on a phase II trial using HiCy as a single agent prophylaxis of GVHD following HLA-matched related and unrelated BMT. We hypothesized that use of this prophylactic strategy will promote tolerance induction, improve the control of GVHD, and thereby decrease the overall use of SSI. Patients, median age 49 (21-66), of whom 53% were not in remission at the time of transplant, received HLA-matched related (n=79) or unrelated (n=60) BM after myeloablative BuCy conditioning. HiCy (50 mg/kg/day) was given on days +3, and +4 as only planned GVHD prophylaxis. Patients with acute grade II-IV GVHD were treated with methylprednisolone 1-2.5 mg/kg/day IV as a first line therapy, and those with visceral GVHD also received calcineurin inhibitors (CNI) or other non-CNI immunosuppressants. In the competing risk model (death and graft failure as competing risks), the incidence of acute grade II-IV and III-IV GVHD by day 200 was 50% and 16%, respectively. Thirteen percent of patients who developed acute grade II-IV GVHD were not treated 15% were treated with steroids alone, 63% with steroids plus a CNI and 9% with steroids plus non CNI-based agents. Overall cumulative incidence of SSI use was 45%. Median time to initiation of SSI was 42 (19-142) days and the median duration of SSI use was 152 (13-981) days. At 6 months and 1 year, 63% and 83% of patients were off all immunosuppressive therapy, respectively. With a median follow-up of 26 months, cumulative incidence of chronic GVHD was 10%. Only 3 patients have died with refractory GVHD. These results extend our previous observations that post-transplantation Cy is effective single agent strategy for prophylaxis of acute GVHD with both a low rate of grade III-IV and more than half of the patients never requiring additional SSI. The limited use of SSI may be responsible for low infectious rate and excellent immune reconstitution seen in these patients. This approach also provides novel platform to facilitate the use of post-transplant immunotherapy aimed at reducing relapse.