Low-Dose Antithymocyte Globulin Plus Low-Dose Post-Transplant Cyclophosphamide for Prevention of Graft-Versus-Host Disease after Haploidentical Peripheral Blood Stem Cell Transplants: A Large Sample, Long-Term Follow-up Retrospective Study

Abstract

Background: The use of haploidentical hematopoietic stem cell transplantation (haplo-HSCT) to treat hematological diseases is increasing. Two regimens for in vivo T-cell depletion are currently used in haplo-HSCT for prophylaxis of graft-versus-host disease (GVHD), including anti-thymocyte globulin (ATG)-based and posttransplant cyclophosphamide (PTCy)-based regimens. Our previous studies have demonstrated that low-dose ATG plus low-dose PTCy (low-dose ATG/PTCy) combined with cyclosporine (CSA) and mycophenolate mofetil had promising activity for the prevention of GVHD in haploidentical peripheral blood stem cell transplantation (haplo-PBSCT). Now, the efficacy of the low-dose ATG/PTCy regimen for GVHD prevention in haplo-HSCT was evaluated in a large sample with a long-term follow-up. Methods: The patients undergoing haplo-PBSCT between May 2017 and June 2021 in our center were enrolled in the retrospective study. The study included a variety of hematological diseases, such as acute myeloid leukemia (AML, n=113), acute lymphoblastic leukemia (ALL, n=49), mixed phenotype acute leukemia (MPAL, n=4), myelodysplastic syndromes (MDS, n=18), chronic myeloid leukemia (CML, n=10), non-Hodgkin's lymphoma (NHL, 30) and multiple myeloma (MM, n=1). All patients received low-dose ATG/PTCy regimen for prophylaxis of GVHD including ATG 2.5 mg/kg administered on day −2 to −1 and cyclophosphamide (Cy) 50 mg/kg on day +3, cyclosporine A (CsA) and mycophenolate mofetil (MMF) initiating on day +4. The starting infusion dose of CsA was 2 mg/kg, after which the dose was modified to obtain a nadir serum level between 200 and 300 ng/ml, eventually tapering from day +90 to day +180. MMF was administered orally at 15 mg/kg three times daily (maximum dose of 3 g per day) until day +34 and discontinued if no aGvHD. Mycophenolic acid sodium enteric tablets (MPA) correspond to MMF instead. Grafts were from mobilized peripheral blood stem cells. Family members selected as haploidentical donors were defined on the HLA-A, -B, -C, -DRB1, and -DQB1 locus at the high-resolution level of the recipient donor number of human leukocyte antigen (HLA) mismatches >2. Results: Two hundred and twenty-five patients undergoing haplo-PBSCT were enrolled in the study. There were 144 males and 81 females with a median age of 38 years (range, 6 to 69 years). At the time of transplantation, 146 (64.89%, 146/225) patients were in complete response (CR), while 79 (35.11%, 79/225) patients had active disease. One hundred and five patients received myeloablative conditioning (MAC) regimens, while 40 patients received reduced-intensity conditioning (RIC) regimens. All patients received PBSC grafts with the median CD34+ cells of 10.3 (1.64-46.55) × 108/kg, and the median mononuclear cells (MNCs) was 15.35 (3.48-39.74) × 108/kg. Ten patients failed to engraft, including 6 patients with primary graft failure and 4 with secondary graft failure. The median time for neutrophil engraftment was 12 days (range, 9-28 days), while the median time for platelet engraftment was observed in 13 days (range, 9-87 days). The cumulative incidence (CI) of grades I-IV acute GVHD (aGVHD) was 30.7% (24.6-36.9%). The CIs of grades II-IV and III-IV acute GVHD by 100 days post-transplant were 12.4% (95%CI, 8.0-16.8%) and 4.6% (95%CI, 1.8-7.4%), respectively. While chronic GVHD was 31.2% (95%CI, 24.6-37.9%) and moderate/severe chronic GVHD was 16.4% (95%CI, 11.1%-21.7%). A total of 90 patients died. Fifty-nine patients died of non-relapse causes (NRM 59/225, 26.2%). With a median follow-up of 26 months (range, 0-61 months), 50 cases relapsed. The median time of relapse was 15.5 months (range, 1−46 months). The mean OS and DFS were 38.01 months (95%CI, 34.33-41.6%) and 35.45 months (95%CI, 31.75-39.15%). The 2-year disease-free survival (DFS), overall survival (OS), and GVHD-free, relapse-free survival (GRFS) was 54.8% (95%CI, 48.94-62.26%) and 60.9% (95%CI, 54.24-67.56%) and 48.0% (95%CI, 41.14-54.86%), respectively. The 2-year CI of relapse was 26.6% and NRM was 16.6%. All patients were included in immune reconstitution studies and 81 cases were analyzed at each endpoint. On days +120, median CD3+, CD4+, CD8+, CD19+ and CD56/CD16+ counts were 954 (95-4891), 180 (8-743),754 (73-4272), 34 (1-276) and 215 (19-2539)/μl, respectively. Conclusion: The low-dose ATG/PTCy regimen presented a high efficacy for prophylaxis of GVHD in haplo-PBSCT.