Background: With traditional therapies, the prognosis of relapsed acute lymphoblastic leukemia (ALL) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is extremely poor. Since single-target CART therapy usually could not maintain a long-term remission, we sequentially applied CD19- and CD22-CART cells to treat relapsed B-ALL post-HSCT.
Methods: From June 30, 2017 through October 31, 2018, 32 B-ALL patients relapsing after allo-HSCT with both antigens CD19 and CD22 expression on blasts were enrolled, the median age was 22 (2.3-55) years. Twenty-one relapsed with bone marrow (BM) only, 4 with extramedullary disease (EMD) only and 7 with both BM and EMD. Eighteen of them failed previous therapies including chemotherapy, donor lymphocyte infusion, interferon and even murinized CD19-CART. Recipient-derived T cells were collected and transfected by a lentiviral vector encoding the CAR composed of CD3ζand 4-1BB. Either humanized (for patients being received murinized CD19-CART previously) or murinized CD19-CART and humanized CD22-CART were used. The time interval between two kinds of CART cell infusions was 1.5-6 months. All patients received fludarabine with or without cyclophosphamide prior to each infusion. The efficacy was evaluated on day 30 and then monthly after each CART infusion. Minimal residual disease (MRD) was detected by flow cytometry and quantitative PCR for fusion genes. EMD was examined by PET-CT, CT or MRI. Cytokine release syndrome (CRS) was monitored.
Results: On day 30 after first CART cell infusion, 27/32 (84.4%) patients achieved complete remission (CR) or CR with incomplete count recovery (CRi). MRD-negative was 100% in evaluable CR/CRi patients. Four cases (12.5%) with multiple EMD obtained partial remission (PR) and 1 (3.1%) died of severe CRS and acute hepatic GVHD. Twenty-four patients finished sequential CD19- and CD22-CART therapies, 4 cases could not undergo the second CART infusion (1 died as mentioned above, 1 died of extensive chronic GVHD, 1 gave up and 1 suffered severe neurologic damage), the rest of 4 patients are waiting for the second CART infusion. As of 31 October 2018, at a median follow-up of 10 (4.5-15) months, among 24 patients who received both CD19- and CD22-CART infusions, 3 died of disease progression, 7 relapsed, and 14 maintained disease-free survival (DFS). The overall survival (OS) rate was 87.5% (21/24), and DFS was 58.3% (14/24). Except for CRS, GVHD induced by CART therapy was a major adverse event in these post-HSCT patients. 8/32 (25%) patients experienced GVHD, of them, 5 presented with mild skin and oral mucosal GVHD, 2 with severe hepatic GVHD (1 recovered and 1 died), and 1 developed extensive chronic GVHD then died.
Conclusions: Our study has showed that, for B-ALL patients relapsed post allo-HSCT, single CART infusion has resulted in a high CR rate of 84.4%. Sequentially combined CD19- and CD22-CART therapies significantly improved survival with the rate of OS and DFS being 87.5% and 58.3%, respectively, at a median follow-up of 10 months. The efficacy of CART on multiple EMD is not good and CART induced GVHD needs to be cautious.
Disclosure: Nothing to declare