Immunotherapy with Autologous Anti-CD19 Chimeric Antigen Receptor T Cells Followed By Allogeneic Hematopoietic Stem Cell Transplantation Has Remarkably Improved Leukemia-Free Survival in Refractory/Relapsed B-Cell Acute Lymphoblastic Leukemia

Introduction: The prognosis of refractory/relapsed acute lymphoblastic leukemia (ALL) is poor with chemotherapy or even allogeneic hematopoietic stem cell transplantation (HSCT). Although our immunotherapy with autologous anti-CD19 chimeric antigen receptor T cells (CART) has resulted in 88.6% complete remission (CR) in refractory/relapsed B-cell ALL (B-ALL), many patients relapsed at around 2 months after CART therapy (unpublished data). Our current strategy is to perform HSCT for refractory/relapsed B-ALL in CR by CART therapy to attain continuous leukemia-free survival (LFS). However, majority of the patients with CART therapy developed cytokine release syndrome which may increase transplant-related mortality (TRM). Moreover, all patients with CART therapy have very tough diseases which could result in higher relapse rate after transplant. Objective: In current study, the safety and efficacy of HSCT for refractory/relapsed B-ALL after CART therapy were investigated. The patients with B-ALL who received HSCT during the same time period without CART therapy were as control. Patients and Methods: Between July 2015 and May 2016, consecutive 22 patients with refractory/relapsed CD19+ B-ALL in CR by CART therapy followed by allogeneic HSCT in our hospital were analyzed as CART group; and consecutive 89 patients with B-ALL in CR who received allogeneic HSCT in our hospital during the same time period but without previous CART therapy were as control group. Clinical characteristics between two groups was comparable except more CR1 (22.7% vs. 57.3%) in control group and more CD3+ cells infused (1.93x10⁸/kg vs. 1.46 x10⁸/kg, p=0.026) in CART group. The median age was 8 (2-44) years, 15 (2-52) years in CART and control groups (p=0.147). The median disease course was 19.1 (3.9-53.7) months, 10.6 (3.7-123.0) months in CART and control groups (p=0.385). The median time from CART therapy to HSCT was 86 (31-172) days. Disease status was 22.7% cases in CR1, 54.5% in CR2, 18.2% in CR3 and 4.5% in CR4 in CART group; and 57.3% cases in CR1, 36.0% in CR2 and 6.7% in CR3 in control group (p=0.08). Minimal residual disease pre-conditioning by flow cytometry was positive in 22.7%, 31.5% patients in CART and control groups (p=0.422). Donor source was identical sibling (IS) in 13.6%, unrelated (UR) in 31.8% and haploidentical (HI) in 54.5% in CART group; and IS in 14.6%, UR in 16.9% and HI in 68.5% in control group (p=0.313). Myeloablative conditioning regimens were administered with either total body irradiation (TBI) plus cyclophosphamide (Cy)/ fludarabine (Flu)-based in 90.9% cases or busulfan (Bu) plus Cy/ Flu-based in 9.1% cases in CART group; and TBICY/Flu-based in 85.4% cases or BuCy/Flu-based in 14.6% cases in control group (p=0.498). Antithymocyte globulin was used in UR and HI transplants. Cyclosporine, short-term methotrexate, and mycophenolate mofetil were employed for GVHD prophylaxis. Results: The median time to neutrophil engraftment was similar between two groups (14 days vs. 13 days, p=0.196), but platelet engraftment was slower in CART group (14 days vs. 12 days, p=0.031). Cumulative incidence of grade II-IV acute GVHD (aGVHD) was higher in CART group (57.6% vs. 33.1%, p=0.009), which may related to higher CD3+ cells infused in CART cohort; but the incidences of grade III-IV aGVHD were no statistical significance (25.1% vs. 15.7%, p=0.564) in two groups. No remarkable differences were seen in CMV reactivation (45% vs. 51.7%, p=0.601) and transplant-associated thrombotic microangiopathy (13.6% vs. 9.0%, p=0.514) in two groups. No significant difference was found in TRM between CART and control groups (7.1% vs. 15.2%, p=0.808). Relapse rates were similar in two groups (5.0% vs. 6.9%, p=0.888). With a median follow-up 9 (2-12) months, LFS was comparable in CART and control groups (84.8% vs. 80.9%, p=0.937). Conclusions: Our preliminary results have shown that the strategy with CART therapy followed by allogeneic HSCT in refractory/relapsed B-ALL is very safe and effective with similar outcomes in TRM, relapse rate and LFS compared with control group. CART therapy has resulted in very good CR in refractory/relapsed B-ALL and allowed the patients to achieve continuous LFS by subsequent allogeneic HSCT, which is revolutionary modality for those patients who have otherwise incurable diseases.