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Venetoclax + navitoclax promising for R/R ALL or LL

Presented By
Prof. Elias Jabbour , University of Texas MS Anderson Cancer Centre, USA
EHA 2020
Phase 1
Venetoclax + navitoclax was well-tolerated without unexpected toxicity and with promising preliminary efficacy in heavily pre-treated patients with relapsed or refractory acute lymphoblastic leukaemia or lymphoblastic lymphoma (R/R B- and T-ALL or LL).

Prof. Elias Jabbour (University of Texas MS Anderson Cancer Centre, USA) presented the phase 1, multicentre, open-label, dose-escalation study [1], addressing the unmet need for new treatment options in R/R ALL and LL. The investigators hypothesised that BCL2 inhibitor venetoclax in combination with low-dose navitoclax (a BCL-XL inhibitor) could improve efficacy while minimising dose-limiting toxicities known to occur with standard-dose navitoclax monotherapy.

Patients (n=47, median age 29 years, median number of prior therapies was 4) received 400 mg venetoclax (weight-adjusted equivalent) daily, together with daily oral navitoclax at 25, 50, 100 mg for patients ≥45 kg, or 25, 50 mg for patients <45 kg. Dose-limiting toxicities were observed in 7 patients: neutropenia (25 mg); neutropenia and drug-induced liver injury (50 mg); ischaemic bowel, hyper bilirubinaemia, pancytopenia, and delayed count recovery (100 mg).

The recommended dose for phase 2 navitoclax (in combination with 400 mg venetoclax) was determined to be 50 mg for patients ≥45 kg or 25 mg for patients <45 kg. The most common grade 3/4 adverse events (AEs) were febrile neutropenia (39%), neutropenia (26%), and hypokalaemia (24%). Non-haematologic grade 3/4 treatment-emergent AEs related to venetoclax or navitoclax included vomiting (n=3), increased ALT (n=2), and sepsis (n=2). One death due to intestinal ischaemia was attributed to the study drug combination.

Complete response with or without incomplete haematological recovery (CR/CRi) was achieved by 25 (54%) patients with 15 (33%) achieving undetectable minimal residual disease (MRD). Median overall survival (OS) was 9.7 months for B-cell ALL patients and 6.6 months for T-cell ALL patients. A total of 11 (24%) patients went on to stem cell transplant or CAR-T. In a subgroup analysis, paediatric patients had similar results; CR/CRi was 58%, 50% had undetectable MRD, and median OS was 9.7 months. Similar CR rates were observed across additional subgroups (see Figure).

Figure: CR rate for all assessed subgroups [1]

ALL, acute lymphoblastic leukaemia; BM, bone marrow; CAR-T, chimeric antigen receptor T; CR, complete response; CR rate, CR + CRi + CRp; LL, lymphoblastic lymphoma.
*5 ALL patients had BM blasts <5% at baseline and are included in the total study population. Of these 5 patients, 4 remained CR after treatment and achieved uMRD.

In conclusion, venetoclax + navitoclax with chemotherapy is well-tolerated, and efficacy is promising in heavily pre-treated patients (including those with prior blinatumomab, inotuzumab, or CAR-T) with suggestive high rates of CR/CRi.

    1. Jabbour E, et al. Venetoclax and navitoclax in relapsed or refractory acute lymphoblastic leukemia and lymphoblastic lymphoma. EHA25 Virtual, 11-21 June 2020, Abstract S116.

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