Background: Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative option currently offered to patients with high-risk or relapsed acute lymphoblastic leukemia (ALL). However, active disease or minimal residual disease (MRD) prior to HSCT is associated with early relapse and poor prognosis with long-term survival less than 30%. We have confirmed that chidamide, a selective histone deacetylase inhibitor (HDACi), work synergistically with cytotoxic agents such as combination of cladribine, gemcitabine and busulfan as conditioning therapy against lymphocytic malignancies. Here, we conducted a clinical trial to evaluate the efficacy of chidamide containing conditioning allo-HSCT in patients with these high-risk ALLs.
Methods: Patients with active ALL or MRD received a myeloablative conditioning consisting of chidamide, fludarabine, cytarabine and busulfan (ChiFAB), followed by infusion of peripheral blood hematopoietic stem cells from related or unrelated donors. The ChiFAB was administered as following: chidamide was given orally at 20 mg twice weekly started from D-7 for 3 weeks; fludarabine was given intravenously at 30 mg/m2 D-6 to D-2; cytarabine was given 4 hours after the finish of fludarabine at 1 g/m2 D-6 to D-2; and busulfan was given intravenously once daily at 3.2 mg/kg D-6 to -3. Prophylaxis of acute graft-versus-host-disease were posttransplant cyclophosphamide plus cyclosporine for matched donor transplants, and additional post-transplant anti-thymocyte globulin and mycophenolate mofetil for haplo-HSCT. Donor lymphocyte infusion was not routinely administered in this trial.
Results: Twenty-four patients were enrolled with median age of 24.5 (16-61 years). Male to female ratio was 3:1. Six (25%) had a diagnosis of Philadelphia positive acute B cell lymphoblastic leukemia (Ph+B-ALL), 8 (33.3%) had Ph-B-ALL, and 10 (41.7%) had T-ALL. Nineteen (79.2%) patients were MRD positive (blast cells <5% in the bone marrow), while five (20.8%) were with active disease (blast cells ≥5%). Eleven (45.8%) patients underwent matched sibling donor transplant, 4 (16.7%) underwent matched unrelated donor transplant, and 9 (37.5%) received haplo-HSCT. Neutrophils and platelets engrafted at a median of 14 days (12-20 days) and 16 days (12-46 days) post-transplant, respectively. Twenty (83.3%) patients reached MRD negative at 30 days. The median follow-up time of the whole cohort was 9.2 months (2-43.8), estimated 1-year progression free survival (PFS) and overall survival (OS) are 53.1% and 59.4% (Figure-1 A&B). For patients with MRD or active disease, estimated 1-year PFS are 67% and 0% (Figure-1 C), and estimated 1-year OS of these 2 groups of patients are 67.7% and 30% (Figure-1D), respectively. Only one patient (4.2%) developed II° aGvHD within 100 days post-transplant (Figure-1 E). The incidence of non-relapse mortality is 24.6% (Figure -1 F).
Conclusions: Chidamide-containing conditioning allo-HSCT may improve the prognosis of ALL with MRD.
Liu:West China Hospital of Sichuan University: Employment.
Asterisk with author names denotes non-ASH members.