Timing of Post-Transplantation Cyclophosphamide Administration in Haploidentical Transplantation: A Comparative Study on Behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation

Abstract

The timing of immunosuppressive therapy used in combination with post-transplantation cyclophosphamide (PTCY) in haploidentical hematopoietic stem cell transplant (haplo-HSCT) is not standardized. We evaluated the schedules of immunosuppression therapy after haplo-HSCT in 509 patients with acute leukemia receiving PTCY on days +3 and +4 along with tacrolimus (group 1; n = 215), with cyclosporine A (CSA) and mycophenolate mofetil (MMF) from day +5 (group 2; n = 170), or CSA + MMF from day 0 or 1 with PTCY on days +3 and +5 (group 3; n = 124). Compared with the other 2 groups, patients in group 3 were younger (median age, 46 years; P = .02) and more often received bone marrow (77%; P < .01) and a regimen containing thiotepa, fludarabine, and busulfan (84%; P< .01). At 2 years, overall survival was 44% was in group 1, 48% in group 2, and 59% in group 3 (P= .15); leukemia-free survival (LFS) was 43%, 46%, and 53% (P= .05); and refined graft-versus-host disease-free, relapse-free survival (rGRFS) was 33%, 39%, and 36% (P = .02). The incidence of grade II-IV acute GVHD was 25% in group 1, 39% in group 2, and 18% in group 3 (P< .01); incidence of chronic GVHD was 25%, 21%, and 24% (P= .50); relapse incidence was 36%, 37%, and 26% (P= .02); and nonrelapse mortality was 26%, 20%, and 21% (P= .35). On multivariate analysis, early start of immunosuppression therapy at day +1 followed by PTCY was associated with a better LFS (hazard ratio [HR], .58; P= .02) and improved rGRFS (HR, .62; P = .02). In this study, the timing of immunosuppression influenced the outcomes of haplo-HSCT with PTCY. An early start of CSA + MMF with PTCY administered on days +3 and +5 improves LFS and rGRFS.

Allogeneic hematopoietic cell transplantation with cord blood versus mismatched unrelated donor with post-transplant cyclophosphamide in acute myeloid leukemia

“…All patients received 50 mg/kg × 2 doses (either Day + 3 and + 4 or day + 3 and + 5). There was heterogeneity in schedule other immunosuppressive drugs based on institutional practice [26]. Grading of acute GVHD was performed using established criteria [27].…”

Timing of Initiation of Calcineurin Inhibitors in Pediatric Haploidentical Transplantation with Post-Transplantation Cyclophosphamide: Effects on Survival, Relapse, and Cytokine Release Syndrome

“…Since factors such as conditioning regimen, stem cell source, donor gender, stem cell count, and duration of immunosuppression affect haplo-HSCTs, the haplo-HSCTs vary between patients, and more importantly, between centers, and thus, it is di cult to draw general conclusions. Our single-center study of 49 patients with leukemia will therefore be a useful standard to compare the results of large multi-center studies, such as the one by Ruggeri et al [2], which included 509 patients with leukemia from 34 centers.…”

“…In this method, after administration of unmanipulated stem cells, proliferation of alloreactive T-cells is allowed for 3 days without any restrictive drugs. On days 3 and 4 or 5, it was assumed that destruction of alloreactive cells occurs by cyclophosphamide (CY), and was followed by continued immunosuppression with a calcineurin inhibitor (CNI) and mycophenolate (MMF) [2,3]. Whether CNIs should be used after cyclophosphamide administration for not inhibiting the development of the alloreactive cell population becomes controversial because recent studies have shown that cyclophosphamide induces alloreactive T cell functional impairment rather than destroying them [4].…”

Does Post-Transplantation Cyclophosphamide Inhibit Graft-versus-Leukemia?

“…The idea behind this modification is that early initiation of the calcineurin inhibitor (CNI) would prevent some of the T cell activation that is required for cyclophosphamide to induce tolerance, and so the graft-versus-leukemia effect would be better preserved. To determine the optimal timing and sequence of CNI and PTCy, Ruggeri et al [8] analyzed outcomes of 509 patients with leukemia in Europe receiving haploBMT incorporating different PTCybased regimens of GVHD prophylaxis. In total, 385 patients received high-dose cyclophosphamide on days 3 and 4 and then started MMF plus a CNI (tacrolimus in 215 and cyclosporine in 170) on day 5, whereas 124 started cyclosporine and MMF on days 0 and 1, respectively, followed by high-dose cyclophosphamide on days 3 and 5.…”

“…The study by Ruggeri et al [8] addresses the important question of the proper timing and sequence of CNI and PTCy administration for optimizing outcomes of haploBMT. While results suggest that CNI initiation before PTCy improves outcomes, this possibility needs to be tested in a prospective, randomized trial to eliminate imbalances in treatment groups.…”