ORLANDO – A combination of venetoclax (Venclexta) and the experimental BCL-2 inhibitor navitoclax showed good activity and acceptable safety in both children and adults with relapsed or refractory acute lymphoblastic leukemia or lymphoblastic lymphoma, investigators in a phase 1 trial reported.
The overall rate of combined complete response (CR), CR with incomplete marrow recovery (CRi) or incomplete platelet recovery (CRp) was 49% among 45 patients: 24 with acute lymphoblastic leukemia of B-cell lineage (B-ALL), 18 with T-cell lineage ALL (T-ALL), and 3 with lymphoblastic lymphoma, reported, from Stanford (Calif.) University.
“Venetoclax, navitoclax, and chemotherapy is well tolerated with few discontinuations for dose reductions due to adverse events in patients with relapsed/refractory ALL or lymphoblastic lymphoma. The preliminary efficacy was promising in this heavily pretreated population of patients, including pediatric patients and patients with prior stem cell transplantation of CAR [chimeric antigen receptor] T-cell therapy,” he said at the annual meeting of the American Society of Hematology.
Venetoclax is a highly selective inhibitor of the B-cell lymphoma 2 (BCL-2) pathway. Navitoclax inhibits BCL-2, the BCL–extra large (BCL-XL) transmembrane molecule, and the apoptotic protein BCL-W, but was associated with dose-limiting toxicities when used at standard doses in monotherapy, he noted.
To see whether adding venetoclax to low-dose navitoclax could be safe and have synergistic activity against BCL-2, Dr. Lacayo and colleagues are conducting aof patients aged 4 years and older with relapsed/refractory ALL or lymphoblastic lymphoma.
Patients receive the weight-adjusted equivalent of 200 mg venetoclax on day 1, and 400 mg equivalent daily thereafter. Beginning on day 3, patients receive oral navitoclax daily at doses of 25, 50, or 100 mg for patients weighing 45 kg or more, or 25 or 50 mg for patients weighing from 20 to less than 45 kg.
Patients can also receive two cycles of chemotherapy with asparaginase, vincristine, and dexamethasone, with additional cycles allowed at the investigators’ discretion.
The patients reported on at ASH 2019 had received a median of 4 prior lines of therapy (range, 1-10).
After a median time on study of 8 months, preliminary efficacy – a secondary endpoint of this phase 1 trial – was promising, Dr. Lacayo said. The CR rate was 25% among patients with B-ALL, 11% in patients with T-ALL, and 67% (two of three patients) with lymphoblastic lymphoma. The respective CRi rates were 13%, 17%, and 0%, and respective CRp rates were 17%, 11%, and 0%.
In addition, 3 of 24 patients (13%) with B-ALL had a partial response, as did 1 patient with lymphoblastic lymphoma.
The median time to first response was about 1.1 months. The median duration of response was 9.1 months for patients with B-ALL, 4.2 months for patients with T-ALL, and had not been reached among patients with lymphoblastic leukemia.
The median overall survival was 9.7 months for patients with B-ALL, 6.8 months for those with T-ALL, and not reached for those with lymphoblastic leukemia.
In all, 6 of 24 patients with B-ALL, 3 of 18 with T-ALL, and 2 of 3 with lymphoblastic leukemia survived long enough to proceed to stem cell transplantation or CAR T-cell therapy.
Analysis of the combination’s safety, the primary endpoint, showed that 58% of patients had grade 3-4 adverse events (AEs) related to venetoclax, and 42% had grade 3-4 AEs related to navitoclax. Four patients had to discontinue the combination because of treatment-related AEs.
Dose-limiting toxicities, which occurred in seven patients, included delayed count recovery, drug-induced liver injury, intestinal ischemia, and increase in serum bilirubin.
One patient died from an intestinal ischemic event deemed to be related to the combination, and seven other patients had fatal adverse events considered not related to the study drugs. The causes of death included sepsis, septic shock, cardiac arrest, and neurotoxicity.
The investigators are enrolling an expansion cohort to see whether a 21-day dosing schedule of venetoclax with 50 mg navitoclax, or 25 mg for patients under 45 kg, could improve count recovery time.
The study was funded by AbbVie. Dr. Lacayo reported having no conflict of interests to disclose. Several coauthors are AbbVie employees.
SOURCE: Lacayo NJ et al. ASH 2019, Abstract 285.