Venetoclax in combination with navitoclax and chemotherapy showed manageable safety and promising efficacy in heavily pretreated pediatric patients with acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LL), according to findings from an open-label, multi-center, phase 1 study being presented by Jeffrey E. Rubnitz, MD, Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, at the virtual 62nd American Society of Hematology Annual Meeting and Exposition. 

"Improved therapeutic strategies for patients with relapsed/refractory acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LL) remain an unmet need. Venetoclax and navitoclax have shown synergistic antileukemic effects in ALL preclinical models, suggesting dependence on BCL-2 family members," wrote Dr Rubnitz and colleagues.

Eligible pediatric patients (aged, 4-18 years; weight, ≥20 kg) with relapsed/refractory ALL and LL were enrolled in the study. Patients received 400mg of venetoclax (weight-adjusted equivalent) daily, and navitoclax at 3 dose levels (25, 50, 100 mg) daily for patients ≥45 kg and 2 dose levels (25, 50 mg) for patients weighing <45 kg. Bayesian optimal interval design guided dose escalation decisions. A discontinuous dosing schedule, 21 days on and 7 days off, of venetoclax with 50 mg navitoclax (25 mg for patients weighing <45 kg) was assessed by a safety expansion cohort. 

Patients had the option to receive chemotherapy (PEG-asparaginase, vincristine, and dexamethasone) at the investigator's discretion.

The primary outcome measures were safety assessments and pharmacokinetics, while secondary included efficacy assessments. The exploratory biomarker assessments included the evaluation of minimal residual disease (MRD). 

Of the 18 patients enrolled (12 in dose-escalation; 6 in safety expansion), 13 patients had B-ALL, 3 had T-ALL, and 2 had LL. The median age was 10 years (range, 6–16 years), 56% of pts were male, and the median number of prior therapies was 2 (range, 1–6). In the dose-escalation phase, 6 patients received 25mg of navitoclax, and 6 received 50 mg. 

The median duration of the study was 10.4 months, 10 pediatric patients (56%) achieved a complete response (CR)/CR incomplete recovery (CRi)/CR without platelet recovery (CRp), while 7 patients (39%) achieved undetectable MRD. Eight patients (44%) proceeded to transplantation (n=5) or CAR T-cell therapy (n=3; cells harvested before the start of the study. The median overall survival was 11.4 months (95% CI, 2.9 months–not estimable).

All patients experienced treatment-emergent adverse events (TEAEs), the most common being febrile neutropenia (50%), vomiting (44%), hyperglycemia (39%), and hypokalemia (39%). 89%  of patients experienced TEAEs of grade 3/4, with febrile neutropenia (50%), neutropenia (33%), thrombocytopenia (33%), and anemia (28%) being the most common.

Alanine aminotransferase increase (n = 2) and vomiting (n = 2) were the only TEAEs related to venetoclax and navitoclax. 2 pediatric patients experienced dose-limiting toxicities (DLTs), DLTs included delayed count recovery (25 mg navitoclax) and sepsis (50 mg navitoclax, occurred after database lock). No grade 5 TEAEs occurred, nor did any pediatric patient experience tumor lysis syndrome. 8 pediatric patients (44%) died from disease progression.

"Venetoclax with navitoclax and chemotherapy was well tolerated and had promising efficacy in heavily pretreated pediatric patients with ALL and LL," explained Dr Rubnitz et al. 

"Given that there were four DLTs with 100 mg navitoclax without evidence of increased efficacy, the recommended Phase 2 dose for adult and pediatric patients is 400 mg venetoclax with 50 mg navitoclax for patients weighing ≥45 kg and 25 mg Nav for patients weighing <45 kg," they concluded.—Alexandra Graziano

Jeffrey E. Rubnitz, Thomas B. Alexander, Theodore W. Laetsch, et al. Venetoclax and Navitoclax in Pediatric Patients with Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma. Presented at: the 62nd ASH Annual Meeting and Exposition; December 5-8, 2020; virtual. Abstract 466.