Phase I data showed that combining venetoclax and navitoclax plus chemotherapy demonstrated encouraging responses and tolerability in patients with relapsed/refractory acute lymphoblastic leukemia or lymphoblastic lymphoma.
Andrew Hantel, MD
Phase I data showed that combining the BCL-2 inhibitor venetoclax (Venclexta) and the investigational small molecule inhibitor navitoclax (ABT-263) plus chemotherapy demonstrated encouraging responses and tolerability in patients with relapsed/refractory acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LL).
In the small study, which was presented at the 2018 SOHO Annual Meeting, the regimen was found to induce an objective response rate of 66.7% in adults with relapsed/refractory ALL or lymphoblastic lymphoma LL.1 Five of 9 patients had a complete response (CR) and 1 patient had a partial response (PR).
Additionally, 4 patients with CR had B-cell ALL and 1 patient had T-cell disease. Two patients with CR had no detectable minimal residual disease (MRD).
“Based on preliminary data from 9 patients, the combination appears efficacious in patients with relapsed/refractory ALL who have had multiple lines of therapy, including transplantation and CAR T-cell therapy,” said first author Andrew Hantel, MD, a hematology/oncology fellow at the University of Chicago Medicine.
Venetoclax is a highly-selective BCL-2 inhibitor and navitoclax is an investigational, orally bioavailable small molecule inhibitor of BCL-2, BCL-XL, and BCL-W. investigators hypothesized that venetoclax in combination with low-dose navitoclax could improve efficacy while minimizing dose-limiting toxicities previously observed with standard-dose navitoclax monotherapy. In results published in 2010, navitoclax was associated dose-limiting bronchitis, pleural effusion, increase in aminotransferases, thrombocytopenia, and arrhythmia in patients with relapsed/refractory lymphoid malignancies.2
To assess the combination for safety and efficacy, investigators enrolled patients aged ≥4 years and weighing ≥20 kg into the open-label, dose-escalation study (NCT03181126) at 15 academic centers in the United States. Patients received daily oral venetoclax at a weight-adjusted dose of 200 mg equivalent on day 1 and onwards and 400 mg-equivalent thereafter. Starting on day 3, patients weighing ≥45 kg received daily navitoclax at 25 mg, 50 mg, 100 mg while those <45 kg received 25 mg or 50 mg. Treatment continued for 2 cycles.
Investigators could administer chemotherapy (1250 IU/m2 of peg-asparaginase on days 9 and 22; 1.5 mg/m2 of weekly vincristine; 20 mg/m2 of divided, twice-daily dexamethasone) at their discretion. Patients with ALL were assessed at days 8, 36, and 57, while patients with LL were assessed at days 36 and 85.
The median patient age was 29 years (range, 19-45), and 8 patients were male. All patients had received prior therapy and 2 had received more than 5 previous treatments. Two patients had undergone prior stem cell transplant. Five patients had pre-B—ALL, 2 had early T-cell precursor ALL, and 2 had medullary T-cell ALL.
Patients have been on the study for 0.6 to 5.8 months as of the June 1, 2018, data cutoff. Three patients, 1 with PR and 2 with stable disease, have not reached the day assessment. Among the 7 responders, 3 remain on treatment.
There were no grade 4 adverse events (AEs) recorded in the study. There was 1 (11%) incidence each of grade 3 nausea and vomiting, and 2 (22%) each of grade 3 pain and back pain. Most AEs were grade 1, most often muscle spasms (44%).
Two deaths have been observed, 1 due to progression and the other was due to an AE unrelated to the study drug.
“The combination of venetoclax and navitoclax with chemotherapy is well tolerated without any unexpected adverse events,” Hantel said. “The most common adverse events leading to treatment interruption were nausea and vomiting. The only dose-limiting toxicity was due to prolonged myelosuppression.”
In June, the FDA granted a standard approval to venetoclax for the treatment of patients with chronic lymphocytic leukemia or small lymphocytic lymphoma, with or without 17p deletion, following at least 1 prior therapy. The BCL-2 inhibitor is now also approved for use in combination with rituximab (Rituxan) in the same patient population.
The approval is based on the phase III MURANO trial, in which the median progression-free survival at a median follow-up of 23 months was not reached with venetoclax plus rituximab compared with 18.1 months (95% CI, 15.8-22.3) with bendamustine plus rituximab (HR, 0.19; 95% CI, 0.13-0.28; P <.0001). The overall response rate was 92% versus 72%, respectively.3