Shortened-Duration Tacrolimus after Nonmyeloablative, HLA-Haploidentical Bone Marrow Transplantation

Abstract

With post-transplantation cyclophosphamide (PTCy) as graft-versus-host disease (GVHD) prophylaxis, nonmyeloablative HLA-haploidentical (NMA haplo) and HLA-matched blood or marrow transplantation (BMT) have comparable outcomes. Early discontinuation of immunosuppression may reduce the risk of relapse and improve immune reconstitution, but may increase the risk of GVHD. We conducted a prospective trial of NMA haplo BMT for patients with hematologic malignancies (median age, 61 years), evaluating the safety of early discontinuation of tacrolimus. All patients received T cell-replete bone marrow followed by high-dose PTCy, mycophenolate mofetil, and tacrolimus. Tacrolimus was prespecified to stop without taper at day +90, +60, or +120, contingent on having ≥5% donor T cells, no relapse, and no grade II-IV acute or significant chronic GVHD. Safety stopping rules were based on ≥5% graft failure, ≥10% nonrelapse mortality (NRM), or a ≥20% combined incidence of severe acute and chronic GVHD from the tacrolimus stop date through day +180. Of the 47 patients in the day +90 arm, 23 (49%) stopped tacrolimus as planned. Of the 55 patients in the day +60 arm, 38 (69%) stopped as planned. Safety stopping criteria were not met. In both arms, at day +180, the probability of grade II-IV acute GVHD was <40%, that of grade III-IV acute GVHD was <8%, and that of NRM was <5%. The 1-year probabilities of chronic GVHD and NRM were <15% and <10%, respectively, in both arms. The 1-year GVHD-free relapse-free survival was higher in the day 60 arm. Thus, stopping tacrolimus as early as day +60 is feasible and carries acceptable risks after NMA haplo BMT with PTCy. This approach may facilitate post-transplantation strategies for relapse reduction. © 2018 Published by Elsevier Inc. on behalf of the American Society for Blood and Marrow Transplantation.

Development of Grade II Acute Graft-versus-Host Disease Is Associated with Improved Survival after Myeloablative HLA-Matched Bone Marrow Transplantation using Single-Agent Post-Transplant Cyclophosphamide

“…This supports the avoidance of systemic immunosuppression to treat skin-only grade II aGVHD, when possible, because most cases can be watched expectantly without necessitating the reinitiation of immunosuppression; such an approach could limit side effects, infectious risk, and maintain the graft-versus-tumor effects of GVHD. We have previously shown that PTCy minimizes the global immunosuppressive burden experienced by patients undergoing HLA-matched BMT [15], and this work emphasizes the importance of exploring the further minimization of pharmacologic agents post-transplant in other platforms such as reported recently by our group in haplo BMT with PTCy [39]. Although this and other recent studies [9,15,39,40] suggest that potent anti-tumor immune responses are maintained with PTCy, fully deciphering these interactions requires further mechanistic studies.…”

Sequential HLA‐haploidentical transplantation utilizing post‐transplantation cyclophosphamide for GvHD prophylaxis in high‐risk and relapsed/refractory AML/MDS

“…Additionally, it is of note that GFRS in our cohort compared favorably to the one in AML patients treated with ATG instead of PTCY for GvHD prophylaxis in TCR haplo-HSCT, 45 Recently, Kasamon et al reported on the safety of early cessation of postgrafting immunosuppression in the TCR haplo-setting using PTCY for GvHD prophylaxis. If using this safe platform, 49 we might get in the favorable position to apply pDLI earlier in the course after haplo-HSCT. However, their experience is not so easy to translate into ours in patients with high-risk, r/r AML/MDS: BM was the only graft source used, whereas we used PBSCs in~50% of the cases which is associated with a higher GvHD incidence per se in TCR haplo-HSCT.…”

“…Estimates for 1-, 2-, and 3-year DFS were 49% (95% CI: 46-52), 46% (95% CI: [43][44][45][46][47][48][49], and 40% (95% CI: 37-43), respectively. Out of six patients who did not develop aGvHD, five died due to early relapse within the first year (1-year DFS: 70% vs 0%; P < .0001) (Supporting Information, Table 3).…”

How we perform haploidentical stem cell transplantation with posttransplant cyclophosphamide

“…As such, for patients with MRD in whom additional pretransplantation therapy is not pursued, we prefer allografting with PBSCTs and/or for early cessation of immunosuppression, which was associated with less relapse in a small study of BM allografts. 62 In addition, a clinical trial using maintenance therapies (eg, enasidenib, ivosidenib, idelalisib, gilteritinib, blinatumomab, venetoclax, and APR-246) or prophylactic posttransplantation immunotherapy (donor lymphocyte or natural killer cell infusion) to prevent relapse should be considered in these high-risk patients.…”

“…In a recent publication, after haplo-BM allografting with PTCy, tacrolimus could be stopped as early as day 60 after transplantation. 62 Clinical trials are ongoing in patients who have undergone allografting using haplo-PBSCT with PTCy to examine whether immunosuppression can safely be discontinued on day 90.…”