Early-Phase Study Shows Promising Response Rates With Venetoclax Plus Navitoclax in ALL

Nearly half of patients with relapsed/refractory acute lymphocytic leukemia (ALL) had a complete response (CR) after treatment with a combination of venetoclax and navitoclax, according to findings from a phase I study presented at the 2019 ASH Annual Meeting. While nearly all patients experienced at least one grade 3/4 adverse event (AE), the investigators, led by Norman Lacayo, MD, from Stanford University and Lucile Packard Children’s Hospital in Palo Alto, California, noted that there was no unexpected toxicity with this combination.

“Venetoclax is a highly selective BCL2 inhibitor, and navitoclax is also a BCL2 inhibitor, but also inhibits BCLXL and BCLW,” Dr. Lacayo explained. “BCL2 and BCLXL inhibitors synergize to reduce growth of ALL xenografts; in addition, combining venetoclax and navitoclax may mitigate dose-limiting toxicities previously observed with standard-dose navitoclax monotherapy.”

In this phase I, multicenter, open-label, dose-escalation study, investigators evaluated a weight-adjusted regimen of venetoclax plus navitoclax in patients with B-cell ALL, T-cell ALL, or lymphocytic lymphoma (LL). Patients were excluded if they had received chimeric antigen receptor (CAR) T-cell therapy, a biologic agent, or inotuzumab within 30 days or any other anti-cancer therapy within 14 days.

As of the data presentation, 45 patients with B-cell ALL (n=24), T-cell ALL (n=18), or LL (n=3) were enrolled in the trial. The median age was 29 years (range = 6-72) and the median number of prior therapies was 4 (range = 1-10). “Many patients had [disease that] failed prior cellular therapies or immunotherapies,” Dr. Lacayo noted. “Of patients with B-cell ALL, 50% had prior blinatumomab, 29% had prior inotuzumab, and 29% had prior CAR T-cell therapy.” Approximately one-third had prior hematopoietic cell transplantation.

Per study protocol, patients received an initial ramp-up dose of venetoclax 200 mg (or weight-adjusted equivalent) on day 1, and 400 mg thereafter. Navitoclax was added at day 3, at doses of 25, 50, or 100 mg for patients weighing ≥45 kg or at doses of 25 or 50 mg for patients weighing 20 to <45 kg. Participants also received 2 cycles of backbone chemotherapy (asparaginase, vincristine, and dexamethasone), with additional cycles allowed at the investigators’ discretion.

The median time on study was 8 months (range = 6-12). Nearly all patients (98%) experienced an any-grade treatment-emergent AE, and many experienced a grade 3/4 AE (93%). The most common grade 3/4 AEs included:

  • febrile neutropenia (40%)
  • hypokalemia (22%)
  • neutropenia (22%)
  • anemia (18%)

Dr. Lacayo pointed out that 58% of patients had grade 3/4 AEs related to venetoclax and 42% had grade 3/4 AEs related to navitoclax.

During the study, 4 patients (9%) discontinued treatment due to AEs, and 1 patient died due to a treatment-related AE (intestinal ischemia). Seven patients (16%) experienced a dose-limiting toxicity (the study’s primary endpoint), including 4 cases of delayed count recovery, 1 case of drug-induced liver injury; 1 case of intestinal ischemia; and 1 case of increased blood bilirubin.

In terms of efficacy, preliminary results show that, of the 45 patients enrolled, 22 (49%) experienced a CR, CR with incomplete marrow recovery (CRi), or a CR with incomplete platelet recovery (CRp). Another 4 patients (9%) had a partial response, for an overall response rate of 58%. Responses occurred within a median of 1.2 months (range = 0.2-3.5), and the median duration of response was 9.1 months (range = 1.9-11.5). In addition, 11 patients were able to proceed to CAR T-cell therapy or hematopoietic cell transplantation.

Dr. Lacayo noted that 12 responders were considered measurable residual disease (MRD)–negative, also highlighting that, of 11 pediatric patients enrolled, 6 (55%) had a CR/CRi/CRp and 5 achieved MRD negativity.

The findings of this early-phase study are limited by the small patient population, as well as the open-label and non-randomized design. An expansion cohort is enrolling patients to explore a 21-day dosing schedule of venetoclax plus navitoclax 50 mg to mitigate prolonged count recovery, which was a dose-limiting toxicity reported in the present study, Dr. Lacayo concluded.

Study authors report relationships with AbbVie, which sponsored the trial.


Lacayo NJ, Pullarkat VA, Stock W, et al. Safety and efficacy of venetoclax in combination with navitoclax in adult and pediatric relapsed/refractory acute lymphoblastic leukemia and lymphoblastic lymphoma. Abstract #285. Presented at the 2019 ASH Annual Meeting, December 8, 2019; Orlando, FL.