Acute lymphoblastic leukemia (ALL) is the most common malignancy of childhood. While frontline therapy is highly effective, 10-20% of children with ALL will relapse, and outcomes for those with relapsed or refractory ALL (collectively, rALL) or lymphoblastic lymphoma (LLy) remain poor. Prognosis is particularly unfavorable in patients with early relapses (<36 months from diagnosis), and those with T-ALL/LLy.

Many high-risk subsets of ALL are sensitive to the oral BCL-2 inhibitor venetoclax in vitro. However, some ALL subtypes are resistant to venetoclax while retaining sensitivity to the BCL-2/ BCL-xL inhibitor navitoclax. Notably, many T-ALL are more sensitive to navitoclax than venetoclax.

The recommended phase 2 dose (RP2D) of venetoclax and navitoclax in combination with 3-drug reinduction chemotherapy (vincristine, asparaginase, and dexamethasone) has been established. This combination showed acceptable tolerability and promising activity, with 6 of 12 treated children achieving minimal residual disease (MRD)-negative remission in prior studies.

To further evaluate this approach, we conducted a multicenter phase I/II trial (NCT03194932) of venetoclax (240mg/m2/day, max 400mg) and navitoclax (25mg [20 to <45kg] or 50mg [≥45kg]) in combination with 3-drug reinduction chemotherapy in children and young adults with rALL/LLy (block 1). Patients who tolerated block 1 therapy could receive block 2 therapy, which included 2 discrete rolling-6 phase 1 arms: arm A, containing high-dose cytarabine, dexamethasone, asparaginase, venetoclax, and navitoclax; and arm B, combining blinatumomab and venetoclax. Patients with T-ALL or ABL-class fusions also received dasatinib in all blocks. Following completion of the phase 1 portion, two dose expansion cohorts were enrolled. The primary outcome for block 1 was MRD-negative remission on day 29, assessed via flow cytometry. The primary outcomes for blocks 2a and 2b were the RP2Ds. The study was approved by the institutional review boards of participating institutions and consent/ assent was obtained in accordance with the Declaration of Helsinki.

The primary cohort enrolled 29 patients; Exploratory cohorts enrolled 6 patients: 3 did not receive asparaginase due to prior toxicities, 2 had isolated extramedullary relapse, and 1 was 22 years old at study entry. Following block 1 therapy, complete remissions with or without full hematological recovery occurred in 19 (65%) patients in the primary cohort and 3 patients in the exploratory cohorts. MRD-negative remissions occurred in 16 (55%) patients in the primary cohort and 3 patients in the exploratory cohorts; this rate was higher than the historical MRD-negative rate of 28% (p<0.01). Within the primary cohort, MRD-negative remissions were seen in 4/5 B-ALL with late first relapse, in 5/9 B-ALL with early first relapse, in 6/11 B-ALL beyond first relapse, and in 1/4 T-ALL. Responses were observed across genetic subgroups and were associated with greater in vitro asparaginase sensitivity (p=0.025), with a trend toward association with in vitro navitoclax sensitivity (p=0.055).

Serious infections during block 1 included: 1 fatal meningitis, 1 fatal sepsis, and 6 patients with grade 4 infections. Grade 4 tumor lysis syndrome (TLS) attributed to venetoclax occurred in a patient with early relapsed B-ALL, and grade 3 TLS occurred in 1 additional early B-ALL relapse and 1 patient with T-ALL.

No patient treated in the phase 1 portion of block 2A experienced a dose limiting toxicity (DLT, defined as a grade 4/5 non-hematological adverse event [AE]) and the RP2D was cytarabine 3g/m2/dose q12h x4 in combination with 7 days of venetoclax and navitoclax. Similarly, there were no DLTs (grade 3-5 non-hematological AE) in the phase 1 portion of block 2B; the RP2D was venetoclax 240mg/m2 (max 400mg) days 8-28 combined with a 28-day blinatumomab cycle.

The study was closed when the navitoclax development ended. Together, these data suggest combination therapy with venetoclax and navitoclax is active in rALL/LLy. Response rates were higher than published data using either conventional 4-drug reinduction or venetoclax without navitoclax in similar populations. Life-threatening or fatal infections affected 23% of patients during block 1. Novel combinations, including BCL-xL inhibition with high-dose cytarabine and venetoclax combined with immunotherapy, were well tolerated. Further evaluation of BH3 inhibition in rALL/LLy is warranted.

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2025
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