Venetoclax plus navitoclax in R/R ALL and lymphoblastic lymphoma

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Published: 3 Jul 2020
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Dr Elias Jabbour - MD Anderson Cancer Center, Houston, USA

Dr Elias Jabbour speaks to ecancer in an online interview for the virtual EHA 2020 meeting.

He outlines the rationale behind this phase I dose-escalation study, which assessed the safety and efficacy of venetoclax plus navitoclax and chemotherapy, for the treatment of relapsed/refractory (R/R) acute lymphoblastic leukaemia (ALL) and lymphoblastic lymphoma (LL) in adult and paediatric patients.

Dr Jabbour details the methods and results of the study, which found that this combination is well-tolerated and shows promising clinical efficacy in heavily pretreated patients.


I presented at the EHA meeting an abstract on the combination of venetoclax and navitoclax in patients with relapsed/refractory ALL. The unmet need is that patients with ALL when they relapse the outcome is really poor and that is more significant in adult patients where their survival at best is 7 months. We know that in some lines, this ALL, some lines rely on BCL-2 pathways which means the cells are not dying. There is data showing that inhibition of BCL-2 and B6L [?] can be of benefit. When we combine them together we can have synergistic activity. It will allow us to use a lower dose of navitoclax because by itself navitoclax, being a BCL-2/B6L inhibitor it can cause thrombocytopenia. So the combination will provide two benefits – one is the synergistic activity, the second it will allow us to reduce the dose of navitoclax and thus improve on the rate of thrombocytopenia.

So we designed this study for paediatric and adult patients who failed prior therapies. Then the regimen at the beginning was given with venetoclax and navitoclax. From day nine and onward we can add chemotherapy. Down the road the protocol was amended and chemotherapy was permitted to be added from day one.

We enrolled 47 patients who failed multiple things, including CAR T-cells, blinatumomab and inotuzumab. In this heavily pre-treated population we did see good response rates, a 60% response rate, and more than half of the responders achieved an MRD negativity which is good. The toxicity profile was manageable and the dose recommended for the phase II was 50mg/day of navitoclax on a 21 day dose schedule for people who are 45kg and above and 25mg for patients who are less than 45kg of weight, 21 day schedule.

Right now we are moving into the expansion phase where we are combining venetoclax navitoclax plus chemotherapy from day one and we’re giving a 21 day dose schedule therefore we give a break, allowing the count to recover. 
In this study the median overall survival was 7.8 months with a better outcome in B-cell compared to T-cell ALL. When we did RNA sequencing on this patient profiling we did see an activity across the board. There will be actually profiling as well, showing that T-cells are more reliant on BCL-2 pathways where the B-cells can be under B6L and BCL-2.

So these results in a patient population, heavily pre-treated, are significant and warrant further evaluation of these compounds in ALL.