In order to improve survival outcomes of patients with relapsed or refractory acute lymphoblastic leukaemia (R/R ALL), there is a high need for novel and durable treatment regimens. A recent study of a relatively large patient series (N= 52) now demonstrated that CAR-T therapy bridged to haploidentical haematopoietic stem cell transplantation (haplo-HSCT) could improve the survival of children and young adult R/R B-ALL patients, without increased transplant-related mortality rates.
EXPERT OPINION OF PROF. DR. BARBARA DE MOERLOOSE, HAEMATOLOGIST, UNIVERSITY HOSPITAL GHENT
“In this study, the used CAR-T construct contains a CD28 co-stimulatory domain. For these products, it is known that they have a shorter persistence as compared to 4-1BB co-stimulatory domains. As such, they can make the ‘bridge’ to haematopoietic stem cell transplantation in patients who achieve remission following these CD28-based CAR-T cells.”
Despite the fact that the prognosis of patients with acute lymphoblastic leukaemia (ALL) has significantly improved over the past decades, patients with relapsed/refractory (R/R) ALL still have a dismal survival rate. For these patients, allogeneic haematopoietic stem cell transplantation (allo-HSCT) can improve survival outcomes. However, persistent measurable residual disease (MRD) before HSCT is an important prognostic factor in determining HSCT outcomes and the MRD of some children cannot be completely eradicated before allo-HSCT. In contrast, chimeric antigen receptor T-cell (CAR-T) therapy can produce high rates of complete remission among these patients while frequent relapse (30-50% of patients) remains an issue. A recent study by Hu et al. now is the first to report on a combined CAR-T therapy and haplo-HSCT strategy to treat children and young adults with R/R ALL. With this strategy, using CAR-T therapy as bridging to allo-HSCT has the potential to reduce relapse rates.
In total, 52 Chinese patients with R/R Philadelphia chromosome-negative B-cell ALL who underwent haplo-HSCT after CAR-T therapy were included in the analysis. All patients were between 0 and 18 years old. Anti-CD19 CAR-T cells constructed with a 4-1BB (63.5%) or CD28 (36.5%) costimulatory domain were generated via lentiviral vector from fresh leukapheresis material. Prior to CAR-T infusion, 95.2% patients received lymphodepleting chemotherapy, including fludarabine (25 mg/m2 per day, days −5 to −3) and cyclophosphamide (250 mg/m2 per day, days −5 to −3). The conditioning regimen for haplo-HSCT consisted of cytarabine (4 g/m2/d) from days −10 to −9, busulfan (3.2 mg/kg/d) from days −8 to −6, cyclophosphamide (1.8 g/m2/d) from days −5 to −4, simustine (250 mg/kg/d) on day −3, and anti-thymocyte globulin (2.5 mg/kg/d) from days −5 to −2. In addition, all patients received cyclosporin A, mycophenolate mofetil, and short-term methotrexate to prevent graft versus- host disease (GVHD). Methotrexate was given as 15 mg/m2/d on day +1, and 10 mg/m2/d on days +3, +5, and +11. G-CSF was subcutaneously administered to donors from day −3 to transplantation day. All recipients received 5 μg/kg/d of either fresh unmanipulated G-CSF mobilised bone marrow cells plus peripheral blood stem cells (PBSCs) or PBSCs alone. G-CSF (5 μg/kg/d) was provided from day +6 until the white blood cell count ≥2 × 109/L and absolute neutrophil count ≥0.5 × 109/L for three consecutive days.
Median age of patients enrolled in the study was 8 years, 53.8% had refractory and 46.2% had relapsed disease. In total, 45 patients (86.5%) achieved MRD-negative complete remission (CR) or CR with partial haematologic recovery (CRh) at one month after anti-CD19 CAR-T cell therapy. Cytokine release syndrome (CRS) of any grade was reported in 30 (57.7%) patients, including 4 patients with CRS of grade 3-4. Furthermore, neurotoxicity syndromes occurred in 8 (15.4%) patients, all of low grade. No CAR-T treatment-related mortality was observed. The median time from CAR-T therapy to haplo-HSCT was 61 days (range: 29–130 days) and all patients achieved CR/CRh before haplo-HSCT. After a median follow-up of 24.6 months after haplo-HSCT, the one-year probabilities of event-free survival (EFS), and overall survival (OS), were 80.1% and 92.3% respectively, while the one-year probability of cumulative incidence of relapse was 14.1%. Corresponding 2-year probabilities were 76.0%, 84.3% and 19.7% respectively. A pre-HSCT measurable residual disease-positive status was found to be an independent factor associated with poor overall survival (HR[95%CI]: 4.201[1.034–17.063]; p= 0.045). Except for three patients who were ineligible for chronic GVHD (cGVHD) evaluation due to a follow-up of less than 100 days, the 2-year cumulative incidence of cGVHD and moderate-to-severe cGVHD was 35% and 9%, respectively. No increased risk of treatment-related mortality or infection was observed.
In this study, a significant percentage of patients achieved MRD-negative CR/CRh at one month after anti-CD19 CAR T-cell therapy, and the 1-year and 2-year EFS and OS after haplo-HSCT indicated that the combined CAR-T therapy and haplo-HSCT strategy can improve the prognosis of patients with R/R ALL. Haplo-HSCT may therefore be a safe and effective treatment strategy to improve event-free survival and overall survival after CAR-T therapy.
Hu G-H, Zhao X-Y, Zuo Y-X, et al. Unmanipulated haploidentical hematopoietic stem cell transplantation is an excellent option for children and young adult relapsed/refractory Philadelphia chromosome-negative B-cell acute lymphoblastic leukemia after CAR-T-cell therapy. Leukemia. 2021;35(11):3092-100.