Sequential Intensiﬁed Conditioning Followed By Tapering Of Prophylactic Immunosupressants and Donor Lymphocyte Infusions In Allogeneic Hematopoietic Stem Cell Transplantation For Refractory Leukemia
Authors: Liu Qifa , Xuan Li , Zhang Yu , Zhou Hongsheng , Huang Fen , Dai Min , Li Yonghua , Nie Danian , Xu Na , Guo Xutao , Lin Dongjun , Xiao Yang , Liu Can , Jiang Qianli , Sun Jing 
Published: October 2019

Abstract

Background
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is perceived as the only curative option for refractory acute leukemia. However, the relapse rate exceeds 50% in these patients undergoing allo-HSCT with standard myeloablative regimen. To improve outcomes of allo-HSCT for refractory leukemia, we previously introduced a strategy of sequential intensified conditioning and early rapid tapering of prophylactic immunosupressants for graft-versus-host disease (GVHD). The results indicated this strategy could improve outcomes of refractory leukemia, with 5-year overall survival (OS) and disease-free survival (DFS) of 44.6% ± 8.1% and 38.2% ± 7.7%. However, the 3-year cumulative incidence of leukemia relapse reached to 33.3%. To reduce the relapse rate but without increasing regimen-related toxicities (RRT), we increased the dose of etoposide (VP-16) in conditioning and infused donor lymphocytes (DLI). The aim of this prospective study was to assess the feasibility and efﬁcacy of this modified strategy in patients with refractory acute leukemia.

Methods
A total of 123 patients with refractory acute leukemia undergoing allo-HSCT from January 2009 to December 2012 were enrolled. Ninety-four patients received related (73 sibling and 21 family donors), 29 unrelated donor transplants; 73 were HLA locus matched, 50 mismatched. Modified sequential intensiﬁed conditioning regimen was: ﬂudarabine (30 mg/m2/day, -10 to -6 days) + cytarabine (2.0 g/m2/day, -10 to -6 days) plus TBI (total body irradiation, 4.5 Gy/day, -5, -4 days) + cyclophosphamide (60 mg/kg/ day, -3, -2 days) + VP-16 (15 mg/kg/day, -3, -2 days). Cyclosporine A (CsA) was withdrawn rapidly in a stepwise fashion (total dose reduced by 20%/week) if patients who did not experience acute GVHD (aGVHD) by day +30 post-transplantation. Donor lymphocytes (1.0×108/kg, once a month, 4 doses totally) would be infused in patients without II° or more than II° aGVHD by day + 60 post-transplantation.

Results
All patients achieved hematopoietic engraftment, except for two who died of infections and one who died of RRT during conditioning. All 120 evaluable patients achieved complete remission (CR) at the time of neutrophil engraftment and achieved complete donor chimerism by day +30 post-transplantation. The incidence of total RRT was 100%, and III-IV RRT was 22.0%. Within the first 100 days post-transplantation, 67 patients developed 95 episodes of infections. Twenty-one had bacterial infections, 7 had invasive fungal infections, 9 had viral infections except cytomegalovirus (CMV) and Epstein-Barr virus (EBV) viremia, 24 had mixed infections and 6 had infections of unknown etiology. Moreover, 48 patients had CMV viremia, 3 developed CMV pneumonia; 41 had EBV viremia, 13 developed EBV-associated diseases. Of the 120 evaluable patients, aGVHD occurred in 31 cases by day +30. Of the 89 patients who did not develop GVHD by day +30, 28 developed aGVHD after CsA withdrawal. Of the 66 patients who received DLI by day +60, 20 developed aGVHD, and 43 developed chronic GVHD (cGVHD, including 13 migrating from aGVHD). cGVHD occurred in 65 of 102 patients who survived more than 100 days, including 43 after DLI. Twenty-three patients experienced leukemia relapse (hematologic in 16, genetic in 4, central nervous system in 2 and extramedullary in 1) at a median time of 165 (range, 28 to 479) days post-transplantation. The 3-year cumulative incidence of relapse was 25.3 ± 4.8%. Of the 23 patients who relapsed, 6 abandoned treatment and 17 received treatment, including 9 with chemotherapy and DLI, 6 only with chemotherapy, 1 only with DLI, and 1 with chemotherapy and radiotherapy. Only two of the 17 cases achieved CR after treatment, and the others all died of disease progress. With a median follow up of 316 (range, 7 to 1589) days post-transplantation, 75 patients survived and 48 died. Causes of death included leukemia relapse (n=21), infections (n=12), GVHD (n=8), EBV-associated diseases (n=5), cerebral hemorrhage (n=1) and secondary dyshematopoiesis (n=1). The 3-year OS and DFS was 58.8% ± 4.7% and 57.0% ± 4.8%.

Conclusions
For patients with refractory leukemia undergoing allo-HSCT, the modified strategy of sequential intensified conditioning followed by tapering of prophylactic immunosupressants and DLI not only improves OS and DFS, but also reduces leukemia relapse.

Disclosures:
Liu: It was supported by 863 Program (No. 2011AA020105).: Research Funding; It was supported by National Public Health Grand Research Foundation (Grant No. 201202017), National Natural Science Foundation of China (Grant No.81000231, No.81270647).: Research Funding; It was supported by Science and Technology Program of Guangzhou of China (11A72121174). : Research Funding.