Outcomes of Haploidentical Salvage Transplantation Using Post-Transplant Cyclophosphamide for Graft Failure Following Allogeneic Hematopoietic Stem Cell Transplantation

Abstract

Introduction: Graft failure (GF) is a fatal complication after allogeneic stem cell transplantation (SCT). Although salvage SCT is the only curative therapy for GF, optimal donors and strategies for this procedure have not yet been established. Although in the last decade haploidentical donors have emerged as alternative donors, only limited data are available regarding the outcomes after haploidentical salvage SCT using post-transplant cyclophosphamide (PTCy). Therefore, this nationwide retrospective study aimed to evaluate the transplant outcomes and risk factors for survival after haploidentical salvage SCT using PTCy on behalf of the Transplant Complications Working Group of the Japan Society for Transplantation and Cellular Therapy.Methods: Clinical data were provided by the nationwide database of the Japanese Data Center for Hematopoietic Cell Transplantation. Patients who were diagnosed with GF and underwent a second or higher allogeneic SCT from the haploidentical related donor (≥2 antigen-mismatch), using PTCy as graft-versus-host disease (GVHD) prophylaxis, between 2011 and 2019 were included. Organ failure was defined as either ejection fraction ≤50%, serum creatinine ≥2 mg/dL, bilirubin ≥1.5 × upper limit of normal, or aspartate aminotransferase/alanine aminotransferase ≥2.5 × upper limit of normal. Overall survival (OS) probabilities were estimated using the Kaplan-Meier method and differences among groups were analyzed using the log-rank test. The multivariate analysis for OS was performed using the Cox proportional hazard regression model. Factors from the univariate analysis that demonstrated significance with P values < 0.1 were included in the multivariate analysis.Results: A total of 33 patients were included in the study. The median age was 34 years (range, 2-67), while performance status (PS) was 0-1 in 21 patients (64%). At salvage transplantation, 12 (36%) were receiving treatment for active infection, and 5 (15%) had organ failure. The median interval from SCT to salvage SCT was 49 days (range, 26-1,468), and 21 patients (68%) underwent salvage SCT within 100 days after previous SCT. Conditioning regimens consisted of fludarabine (Flu)/ cyclophosphamide (Cy)-based in 10 (31%), Flu/melphalan (Mel)-based in 10 (31%), and Flu/busulfan (Bu)-based in 7 (21%). The total dose of PTCy was 75-100 mg/kg in 26 patients (84%) and 40-50 mg/kg in 5 patients (16%). Most patients (84%) received tacrolimus plus mycophenolate mofetil as GVHD prophylaxis in addition to PTCy. Previous SCT was cord blood transplantation in 22 patients (67%) and haploidentical transplantation in 6 patients (19%), of which 4 patients (13%) received PTCy. The median time for neutrophil engraftment was 18 days, and the cumulative incidence of neutrophil engraftment at 30 days was 82%. Specifically, a patient who had donor-specific human-leukocyte antigen-antibody successfully achieved neutrophil engraftment at 22 days after salvage SCT. The median OS was 359 days, while the OS at 1 year was 47% (Figure A). In the univariate analysis, the OS of patients who received 75-100 mg/kg PTCy was significantly better than those who received 40-50 mg/kg PTCy (61% vs. 0% at 1 year, P = 0.022, Figure B). After adjusting for PS and the presence of active infection and organ failure, 75-100 mg/kg PTCy was significantly associated with better OS (hazard ratio, 0.30; P = 0.036). Although the differences were not significant, patients who received Flu/Mel-based conditioning exhibited numerically better OS than those who received Flu/Cy- or Flu/Bu-based conditioning (80% vs. 40% vs. 57%, P = 0.21).Conclusions: Haploidentical salvage SCT using PTCy offers promising survival outcomes and can be a substantial option for GF after allogeneic SCT. An adequate dose of PTCy (i.e., 75-100 mg/kg) needs to be administered to achieve long-term survival. [Display omitted] DisclosuresNakamae: PPD-SNBL K.K: Research Funding; Bristol-Myers Squibb Company: Honoraria, Research Funding; Alexion: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; Simon-Kucher & Partners: Honoraria; Takeda Pharmaceutical Company Limited.: Honoraria; Astellas Pharma Inc.: Honoraria; Otsuka Pharmaceutical Co., Ltd: Honoraria; ONO PHARMACEUTICAL CO., LTD.: Honoraria; CMIC HOLDINGS Co., Ltd: Research Funding; Novartis: Honoraria, Research Funding; Pfizer Japan Inc.: Honoraria. Ichinohe: Celgene: Honoraria; Novartis Pharma K.K.: Honoraria; Repertoire Genesis Inc.: Honoraria, Research Funding; Takara Bio Inc.: Research Funding; Zenyaku Kogyo Co.: Research Funding; Taiho Pharmaceutical Co.: Research Funding; Sumitomo Dainippon Pharma Co.: Honoraria, Research Funding; Otsuka Pharmaceutical Co.: Research Funding; Nippon Shinyaku Co: Research Funding; Ono Pharmaceutical Co.: Honoraria, Research Funding; Kyowa Kirin Co.: Honoraria, Research Funding; FUJIFILM Wako Chemicals.: Honoraria, Research Funding; Daiichi Sankyo: Research Funding; Eisai Co.: Honoraria, Research Funding; CSL Behring: Honoraria, Research Funding; Chugai Pharmaceutical: Research Funding; Bristol-Myers Squibb: Honoraria; Takeda Pharmaceutical Co.: Honoraria; AbbVie Pharma: Research Funding; Astellas Pharma: Honoraria, Research Funding. Atsuta: Mochida Pharmaceutical Co., Ltd.: Speakers Bureau; Astellas Pharma Inc.: Speakers Bureau; AbbVie GK: Speakers Bureau; Kyowa Kirin Co., Ltd: Honoraria; Meiji Seika Pharma Co, Ltd.: Honoraria. Nakasone: Takeda Pharmaceutical: Honoraria; Otsuka Pharmaceutical: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Eisai: Honoraria; Chugai Pharmaceutical: Honoraria; Nippon Shinyaku: Honoraria.