Engraftment Kinetics After Alimtuzumab-Based Allogeneic Stem Cell Transplant (SCT): Full Donor T-Cell Chimerism Did Not Predict for Acute Graft Versus Host Disease (GVHD) or CMV Reactivation

Graft versus host disease (GVHD) remains the leading cause of the treatment failures following an otherwise successful allogeneic Stem Cell Transplant. Alemtuzumab – based prophylactic regimens is evolving as an important option for prevention of this devastating complication. Multiple phase II studies suggested that patients who received Alemtuzumab –containing GHVD prophylactic regimens tends to have less acute GVHD though the utility is limited by increased incidence of mixed chimerism often requiring donor lymphocytes infusion and cytomegalovirus reactivation.

We hypothesize that if we could identify an optimal dose of Alemtuzumab; we could maintain the benefit of lowering the incidence of GVHD and also minimize mixed chimerism and CMV reactivation following the transplant.

To test our hypothesis, we conducted a pilot study utilizing the combination of Alemtuzumab (20 Related Donor: 30 mg on Day -1; 10 Unrelated donor: 30 mg daily on Day -2 & Day -1) and cyclosporine as GVHD prophylaxis. Between 5/11 and 5/12, 28 pts were included in the study. There were 15 females and 13 males. The diagnosis included 16 AML, 3 NHL, 2 MDS, 1 CML, 1 CLL, 1 ALL, 1 HD, 1 PLL, 1 MPD and 1 MM. Conditioning regimens consisted of Fludarabine/Melphalan in 20, Fludarabine/Busulfan in 5, TBI/Cy in 2 and Fludarabine/Clofarabine in 1. Upon achievement of engraftment, we monitor CMV by PCR weekly and engraftment by Short tandem repeat (STR) monthly with T-cell and Myeloid subsets analysis.

26/28 pts achieved neutrophils engraftment except 1 died shortly after SCT from heart failure and 1 experienced primary graft failure with day 30 STR showing only 3% donor T-cell chimerism. On Day 30 post-SCT, all evaluable pts had predominately donor T-cell (median 99%; 19/27 (70%) ≥ 99%; range 82 to > 99%) and Myeloid Chimerism (24/26 (92%) ≥ 99% except one pt who developed rapidly progressive leukemia phase PTLC after transplant. 25 pts (89%) survived beyond Day 90 post-SCT and have engraftment data available for analysis. On Day 90 analysis, while most pts maintain predominant donor myeloid chimerism (> 95%; median 99%); only 10/25 (40%) had maintained 99% donor T-cell chimerism. In addition, 76% pts had their T-cell donor chimerism worsened by Day 90 when compared with Day 30 analysis (9 pts dropped below 80%; range 8–75%). On the other hand, no pt developed secondary graft failure. 5 pts (17%) developed acute GVHD with only 1 (4%) Grade IV aGVHD. 8 pts (29%) developed CMV reactivation within day 100 post-SCT. Full donor T-cell chimerism did not predict for GVHD or CMV reactivation. With longer follow up, some pts' have donor T-Cell chimerism increased with tapering of immunosuppressive therapy with or without GVHD or after receiving DLI.

1. Our preliminary data suggested that using a lower dose of Alemtuzumab (30 mg for RD and 60 mg for MUD) as GVHD prophylaxis is effective to prevent GVHD though still associated with high incidence of CMV reactivation. 2. Most pts achieve predominant Donor T cell chimerism on day 30 though many worsen on subsequent follow-up. 3. Although it appears that there's no impact on durability of engraftment, longer follow-up is required to determine the impact on relapse, chronic GVHD and survival.

Fung:Genzyme: Honoraria. Off Label Use: Alemtuzumab for GVHD prophylaxis.