A Prospective Multicenter Study of Nonmyeloablative Conditioning with TBI or Fludarabine/TBI for HLA-Matched Related Hematopoietic Cell Transplantation for Treatment of Hematologic Malignancies with Post Grafting Immunosuppression with Tacrolimus and Mycophenolate Mofetil: 10-Year Experience

Background:  Nonmyeloablative conditioning with 2-Gy TBI alone or in combination with fludarabine (FLU/TBI) and HLA-matched related donor peripheral blood allografts followed by cyclosporine (CSP) and mycophenolate mofetil (MMF) for the prophylaxis of graft-versus-host disease (GVHD) is an effective therapy for many hematologic malignancies with reliable engraftment and moderate toxicity. The major causes of non-relapse mortality (NRM) are the development of acute and chronic GVHD. Several studies have demonstrated that tacrolimus may offer advantages compared with CSP for the prevention of GVHD in patients treated with myeloablative conditioning. The combination of tacrolimus and MMF, which has been used for GVHD prophylaxis after myeloablative hematopoietic cell transplantation (HCT), was well tolerated with low toxicity. Pilot data suggested an improved and perhaps superior GVHD prophylaxis with tacrolimus/MMF compared to our extensive historical experience using CSP/MMF with nonmyeloablative HCT. The purpose of this study is to evaluate the incidence of grade III‑IV and II-IV acute GVHD, extensive chronic GVHD, along with the rate of NRM, relapse/progression, and overall survival after nonmyeloablative conditioning and post-grafting immunosuppression with tacrolimus and MMF.

Methods:  In a phase II multicenter clinical trial we evaluated the effect of post grafting immunosuppression with tacrolimus and MMF for the prophylaxis of GVHD following nonmyeloablative conditioning with 2-Gy TBI alone or in combination with 90mg/m² FLU (FLU/TBI) for patients with hematologic malignancies. Patients at low risk of graft rejection (preceding autologous HCT within 6 months) received TBI alone (n=50) while the remaining patients received FLU/TBI conditioning (n=100). Tacrolimus was administered orally (0.06 mg/kg, Q12 hr) from days -3 to +56 and in the absence of GVHD tapered off by day +180. Tacrolimus was targeted to 15-20 ng/ml for the first 28 days and 10-20 ng/ml subsequently while on full dose. MMF was given orally (15 mg/kg, Q12 hr) from day 0 until day 27.

Results:  150 patients were enrolled from 2004 to 2013 and received peripheral blood stem cells (median doses of 8.1×10⁶ CD34⁺ cells/kg and 3.5×10⁸ CD3⁺ cells/kg) from HLA-matched related donors. Diagnosis at transplant included AML (n=42), ALL (n=6), CLL (n=2), MDS/MPD (n=12), NHL (n=25), HL (n=8), and MM (n=55). Median patient age was 56 (range 19-74) years. Sixty-one percent of patients had an HCT comorbidity index (HCT-CI) score of greater than 2. Five percent of patients had failed a prior autologous HCT in FLU/TBI group. Median follow-up was 5.2 years. One graft failure was observed in the FLU/TBI group and no patients rejected their graft. The early NRM at day 100 was 1%. The cumulative incidences of grade II-IV and grade III-IV acute GVHD at 120 days were 26% (FLU/TBI 25%; TBI 28%) and 4% (FLU/TBI 2%; TBI 8%), respectively. Only one patient developed grade IV acute GVHD. Forty-eight percent of patients had chronic GVHD by 5 years (FLU/TBI 44%; TBI 54%). Five-year NRM was low at 12%. The overall cumulative incidence of relapse/progression at 5 years was 52%. Five-year overall and progression-free survivals were 51% and 37%, respectively.

Conclusions:  Post-grafting immunosuppression and GVHD prophylaxis with tacrolimus/MMF resulted in a low risk of acute and chronic GVHD, which compares favorably with our experience in a concurrent trial using CSP/MMF with FLU/TBI conditioning (46% grades II-IV acute and 72% chronic GVHD with CSP/MMF, respectively; BBMT, 2013, 19: 1340-1347). Furthermore, we recently reported that the active metabolite of MMF (MPA) concentration at steady state (MPA Css) was lower in patients who received concomitant CSP than patients receiving tacrolimus. Low total MPA Css was associated with an increased risk of severe acute GVHD following nonmyeloablative HCT (BBMT 2013, 19: 1159-1166).Together these data warrant consideration of a randomized phase III trial to investigate the role of tacrolimus/MMF versus CSP/MMF in nonmyeloablative HCT.

Figure 1. Cumulative incidences of grade II to IV acute GVHD (A) and chronic GVHD (B)