Post-Transplant Cyclophosphamide and Tacrolimus—Mycophenolate Mofetil Combination Governs GVHD and Immunosuppression Need, Reducing Late Toxicities in Allogeneic Peripheral Blood Hematopoietic Cell Transplantation from HLA-Matched Donors

Abstract

Combined direct antineoplastic activity and the long-lasting immunological effects of allogeneic hematopoietic cell transplant (HCT) can cure many hematological malignancies, but broad adoption requires non-relapse mortality (NRM) rates and graft-versus-host disease (GVHD) control. Recently, posttransplant cyclophosphamide (PTCy) given after a bone marrow transplant significantly reduced GVHD-incidence, while PTCy given with tacrolimus/mofetil mycophenolate (T/MMF) showed activity following allogeneic peripheral blood stem cell transplantation (alloPBSCT). Here, we report the experience of a larger cohort (85 consecutive patients) and expanded follow-up period (03/2011–12/2019) with high-risk hematological malignancies who received alloPBSCT from Human-Leukocyte-Antigens HLA-matched unrelated/related donors. GVHD-prophylaxis was PTCy 50 mg/kg (days+3 and +4) combined with T/MMF (day+5 forward). All patients stopped MMF on day+28 with day+110 = median tacrolimus discontinuation. Cumulative incidences were 12% for acute and 7% for chronic GVHD- and no GVHD-attributed deaths. For surviving patients, the 12, 24, and 36-month probabilities of being off immunosuppression were 92, 96, and 96%, respectively. After a 36-month median follow-up, NRM was 4%; median event-free survival (EFS) and overall survival (OS) had yet to occur. One- and two-year chronic GVHD-EFS results were 57% (95% CI, 46–68%) and 53% (95% CI, 45–61%), respectively, with limited late infections and long-term organ toxicities. Disease relapse caused the most treatment failures (38% at 2 years), but low transplant toxicity allowed many patients (14/37, 38%) to receive donor lymphocyte infusions as a post-relapse strategy. We confirmed that PTCy+T/MMF treatment effectively prevented acute and chronic GVHD and limited NRM to unprecedented low rates without loss of disease control efficacy in an expanded patient cohort. This trial is registered at U.S. National Library of Medicine as #NCT02300571.

Post-Transplant Cyclophosphamide and Thymoglobulin, a Graft-Versus-Host Disease Prophylaxis in Matched Sibling Donor Peripheral Blood Stem Cell Transplantations

“…Extensive chronic GvHD was also significantly reduced (28% vs 46%) 15,16 . Prior studies of MSD PBSCTs in patients with hematologic malignancies using PTCy as a GvHD prophylaxis indicate that other drugs such as bortezomib, sirolimus, and tacrolimus-mycophenolate mofetil need to be combined with PTCy in order to reduce the incidence of GvHD [17][18][19][20] . The use of PTCy and low-dose ATG as a GvHD prophylaxis in MSD PBSCTs showed more favorable outcomes.…”

Risk factors for graft-versus-host-disease after donor lymphocyte infusion following T-cell depleted allogeneic stem cell transplantation

“…In 2016, we introduced the endpoint treatment success, which equals cGRFS ( 10 ). During the last years, cGRFS and current immunosuppression-relapse-free survival have become more popular as outcome measures ( 11 , 12 , 55 – 58 ). However, to our knowledge, we are the first who have applied semi-parametric multi-state modeling in this context.…”

Post‐transplant cyclophosphamide as sole GHVD prophylaxis after matched reduced‐intensity conditioning allotransplant

“…It could allow also to shorten the time for immune reconstitution. The three‐drug prophylaxis (PTCY/CsA or tacrolimus/MMF) in PB matched Allo‐HSCT is generally associated with good survivals and low NRM and GVHD incidences 32–34 . The combination of PTCY with two drugs is also supported by a retrospective study from the European Society for Blood and Marrow Transplantation (EBMT) 35 .…”

“…The three-drug prophylaxis (PTCY/CsA or tacrolimus/MMF) in PB matched Allo-HSCT is generally associated with good survivals and low NRM and GVHD incidences. [32][33][34] The combination of PTCY with two drugs is also supported by a retrospective study from the European Society for Blood and Marrow Transplantation (EBMT). 35 However, short courses of bortezomib 36,37 or sirolimus 38 with PTCY alone have been proven to provide similar results.…”