Daratumumab and Venetoclax-Containing Regimens in the Management of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation in Hematological Malignancies

Background: The prognosis of relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with hematological malignancies is poor with conventional therapies such as immunosuppressant withdrawal, interferon, chemotherapy, donor lymphocyte infusion and second allo-HSCT. Immunotherapy and targeted therapy may bring new hope for this setting.

Objective: In current study, the safety and efficacy of daratumumab and venetoclax-containing regimens in the management of relapse after allo-HSCT in hematological malignancies were evaluated.

Methods: From August 2019 to May 2020, 12 patients with hematological malignancies who relapsed after allo-HSCT were included. The median age was 26 (5-49) years old. The diagnosis included acute myeloid leukemia (AML, n=3), acute lymphoblastic leukemia (B-ALL, n=2), T lymphoblastic lymphoma/leukemia (T-LBL, n=6) and B lymphoblastic lymphoma/leukemia (B-LBL, n=1). The disease status before transplant was complete remission (CR) in 8 cases (minimal residual disease (MRD)+ in 4, MRD- in 4), partial remission (PR) in 1 case and recurrence in 3 cases. The types of transplant were haploidentical in 6 cases (50%), unrelated in 5 cases (41.7%) and matched sibling in 1 case (8.3%). Myeloablative conditioning regimens were used and GVHD prophylaxis was with cyclosporine, short-term methotrexate and mycophenolate mofetil. Anti-thymocyte globulin was applied in haploidentical and unrelated transplants. The median relapse time was 4 (1-10) months after HSCT and the pattern of relapse included hematologic relapse in 11 cases (91.7%), and MRD+ in 1 case (8.3%). The expression of CD38 antigen was detected by flow cytometry. Daratumumab (400mg for children, 800mg for adults at day 0 and 14) and venetoclax (50mg/d, gradually increased to 100-400mg/d, d1-28) were administrated for induction and consolidation therapies.

Results

After 1 cycle of induction therapy, 5 cases achieved CR (41.7%) (4/6 T-LBL, 1/3 AML), 1 case in PR (T-LBL, 8.3%), and 6 cases in non-remission (NR) (2/2 B-ALL, 2/3 AML, 1/1 B-LBL, 1/6 T-LBL, 50%). The median time to achieve CR was 26 (18-42) days. Three of 5 CR patients were treated with daratumumab and venetoclax only, and rest 2 CR patients were treated with daratumumab and venetoclax plus cytarabine (100mg/d for 3-5d) and etoposide (100mg/d for 3-5d). Four patients in CR were consolidated with daratumumab and venetoclax for continuous MRD- CR with the median 263 days(210,335) , while the rest 1 patient in CR underwent the second allo-HSCT.The median consolidation therapies was 2 (1-4) cycles and the interval was 8 weeks. With the median follow-up 236 (138-365) days, eight of 12 patients (66.7%) survived and DFS was 41.7%. Seven patients developed treatment-related neutropenia (58.3%) and 4 patients had infections (33.3%). No severe side effects were noted. No GVHD occurred during treatment with above regimens.

Conclusion: Our pilot clinical study has shown that daratumumab and venetoclax-containing regimens are safe and effective in the management of relapse after allo-HSCT in patients with hematological malignancies. It seems that better response are in T-LBL. It may provide an option for the patients their leukemic cells expressing CD38 with or without chemotherapy-resistant diseases.

[Key words] relapse; allogeneic hematopoietic stem cell transplantation; hematological malignancy; daratumumab; venetoclax