Daratumumab-Primed Venetoclax Combined with Cage for Refractory/Relapsed T-Lymphoblastic Leukemia/Lymphoma Patients: Single-Arm, Open-Label, Phase I Study

Background The anti-CD38 antibody daratumumab, currently approved for the treatment of patients with multiple myeloma, is also being explored for patients with acute lymphoblastic leukemia (ALL), whose blasts commonly express high levels of CD38. We assessed the safety and efficacy of Daratumumab-primed Venetoclax combined with CAGE in patients with relapsed/refractory T-ALL.

Method This single-arm, open-label, phase I study enrolled patients with relapsed/refractory T-ALL who had received at least two lines of previous therapy and whose tumor cells express CD38. Patients received Daratumumab 12mg/kg intravenously on day 0, Venetoclax 100mg per os on days 0 to 7, Granulocyte colony-stimulating factor ( G-CSF) 150ug subcutaneous injection on days 0 to 7, Aclarubicin 7.5mg/m² intravenously on days 1 to 7, Cytarabine 25 mg/m² intravenously on days 1 to 7, Etoposide of 25 mg/m² intravenously on days 1 to 7 of 28-day cycles for a maximum of two cycles or until documentation of minimal residual disease-negative complete response (as assessed by the investigator), disease progression, or unacceptable toxicity. For the CNS leukemia patients, intrathecal injection with dexamethasone 5mg, cytarabine 50mg and methotrexate 15mg should be done on days 1, 3, 5. Primary end point was CR rate and safety.

Result Sixteen eligible patients were enrolled between October 2021 and May 2022, and all were followed up until July 31st, 2022. The median age of the 16 patients was 30 (15-72) years old. Eight patients were diagnosed with R/R T-ALL and 8 with R/R T-LBL at enrollment. High risk subtypes included early T-cell precursor (ETP)-ALL (n=8, 50%) and primary refractory disease (n=11, 68.8%). Eleven patients had a history of transplantation prior to enrollment, seven patients were allo-HSCT and four were auto-HSCT. Patients were heavily pretreated with a median of 7 (3-14) cycles of therapies before enrollment. The median duration from diagnosis to enrollment was 20 months (range 5.2-34.8). At enrollment, eleven patients had tumor cells infiltration of bone marrow. While 14 patients (6 T-ALL and 8 T-LBL) developed extramedullary disease, including diffuse involvement (n=5) or bulky mediastinal masses >7 cm in diameter (n=4), or central nervous system (CNS) involvement (n=6).

For the regimen, the most common adverse events were leukocytopenia and infection. Hematologic grade 4 chemotherapy related adverse events (AE) included leukopenia, thrombocytopenia and neutropenia were observed in all patients (100%). The median duration of leukopenia, thrombocytopenia and neutropenia were 13 days, 14 days and 12 days, respectively. 100% patients experienced agranulocytosis with fever. Bacteremia Infection occurred in 4 patients (25%). Intestinal infection occurred in two patients (12.5%) and pulmonary infection occurred in three patients (18.75%).

The median followed-up time was 4 months. Ten patients received one cycle chemotherapy and six patients received two cycles chemotherapy. Six patients got complete remission (CR) by one cycle chemotherapy. Three patients got complete remission (CR) by two cycles chemotherapy. The rate of CR and the objective remission rate (ORR) were 56.25% (n=9) and 62.5% (n=10) , respectively. Eight of eleven patients who had bone marrow involvement achieved minimal residual disease (MRD) negative CR (n=6, 54.5%) or MRD positive CR (n=2, 18.2%); Two patients (18.2%) with bone marrow involvement achieved partial remission (PR). The rate of ORR and CR for patients with bone marrow involvement were 90.9% and 72.7%, respectively. Six of ten patients who had extramedullar lymph nodes involvement achieved CR (60%); Two patients (20%) achieved PR. For the extramedullar lymph nodes involvement, the rate of ORR and CR were 80% and 60%, respectively. While only two of six patients who had CNS leukemia achieved CR (33.3%).

Conclusions Daratumumab-primed Venetoclax combined with CAGE achieved a high remission rate for refractory/relapsed T-lymphoblastic leukemia/lymphoma patients with acceptable tolerability. The regimen could be a superior selection as tumor reduction bridged to CAR T or allo-HSCT therapy. The regimen presented better efficacy for bone marrow involvement and extramedullar lymph nodes involvement than CNS leukemia, as well should be revised to enhance the CNS prophylaxis.

No relevant conflicts of interest to declare.