Experience in the use of 5-azacytidine, bortezomib and valproic acid for the prevention of leukemia relapses in children after ab-T cell-depleted hematopoietic stem cell transplantation
Authors: Ilyushina M. A. , Shelikhova L. N. , Shasheleva D. A. , Khismatullina R. D. , Blagov S. L. , Maschan A. A. , Maschan M. A. 
Published: June 2022

Hematopoietic stem cell transplantation (HSCT) from an allogeneic donor is a standard treatment for high-risk leukemia that makes it possible to cure patients with chemotherapy-resistant leukemia. “Graft-versus-host” disease (GVHD) is the key biological and clinical problem associated with HSCT. Ex vivo depletion of ab-T cells has been used at the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology since 2012 as a means to prevent GVHD after HSCT. The successful application of this approach to GVHD prevention has reduced the risk of clinically significant acute GVHD and chronic GVHD to 15–20 %, and transplant-related mortality – to 5–10 %. The risk of relapse is 20–30 %, but when HSCT is performed in active disease, it increases to 50 %. The role of epigenetic mechanisms in the formation of the tumor phenotype has been established, and pharmacological approaches have been proposed. New drug classes include proteasome inhibitors such as bortezomib. The relatively low toxicity of epigenetic therapy and proteasome inhibitors makes their use in the post-transplant period an attractive approach to relapse prevention. We regarded prophylaxis after HSCT as one of the possible approaches that could help reduce relapse rate. Here we explore the effects of hypomethylation therapy (azacitidine) combined with an HDAC inhibitor (valproic acid) and a proteasome inhibitor (bortezomib). The study was approved by the Independent Ethics Committee and the Scientific Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology. Combination therapy cycles were carried out after engraftment and in some patients, were accompanied by infusions of modified donor lymphocytes enriched in NK cells or memory T cells. The experimental group included 35 pediatric patients with hemoblastoses who had received HSCT from March 2013 to November 2016. The median age was 6.9 years. Twenty-three children had acute myeloid leukemia (AML), 11 patients – acute lymphoblastic leukemia (ALL), and one patient was diagnosed with juvenile myelomonocytic leukemia (JMML). Twenty-one patients were in complete clinical and hematologic remission at the time of HSCT while 14 patients (AML – 12, ALL – 1, JMML – 1) underwent HSCT in active disease. The patients were conditioned with treosulfan and melphalan (n = 26), thiotepa (n = 8), or etoposide (n = 1). Post-transplantation chemotherapy included azacitidine at a dose of 30 mg/m 2 IV for 5 days, bortezomib at a dose of 1.3 mg/m 2 s.c. (No. 2), and valproic acid at a dose of 250 mg 3 times a day р.о. (No. 6). The patients were planned to receive 3 cycles of post-transplantation chemotherapy with a break of 30 days between each treatment. Donor lymphocyte infusions were given on Day 7 of each cycle. A total of 92 cycles were conducted after HSCT. The most common side effect of treatment was hematologic toxicity. Transient visceral toxicity was registered after 46 (50 %) chemotherapy cycles. There were no cases of acute GVHD after donor lymphocyte infusions. At the time of the analysis, the median follow-up was 6.5 years. The cumulative risk of grade II–IV acute GVHD was 19% (95 % confidence interval (CI) 12–32). Nineteen patients relapsed at a median of 6 months after HSCT. Sixteen patients died of disease progression or complications related to subsequent treatment at a median of 11.76 months. The cumulative probability of relapse was 54% (95% CI 40–73). The cumulative probability of relapse in the patients transplanted in clinical and hematologic remission and those in active disease was 48% (95% CI 30–75) and 64 % (95 % CI 43–95), respectively. The event-free survival in the entire group of patients was 46 % (95 % CI 29–62). The event-free survival rates in the patients transplanted in remission and in active disease were 52% (95% CI 31–73) and 36 % (95 % CI 10–60), respectively. There were no deaths of complications of HSCT that were not associated with the recurrence of the disease in the experimental group. The cumulative risk of relapse among the AML patients in clinical and hematologic remission at the time of HSCT and those with advanced stage of the disease was 45 % (95 % CI 40–74) and 58 % (95 % CI 36–94), respectively. The overall survival was 53 % (95 % CI 31–73); the overall survival for the patients transplanted in remission and those who received HSCT in active disease was 63% (95 % CI 35–92) and 41% (95% CI 14–70), respectively. The event-free survival was 54% (95% CI 30–62) in the remission group and 41% (95 % CI 14–69) in the relapse group. In the ALL patients, the cumulative risk of relapse was 54 % (95 % CI 31–93); the overall and event-free survival rates were 72 % (95 % CI 46–91) and 45 % (95 % CI 16–75), respectively. Our analysis of the overall experience of prophylactic treatment with decitabine and azacitidine after ab-T cell-depleted HSCT suggests that this approach should be considered purely experimental and acceptable for prospective clinical studies in clearly defined cohorts of patients.