Dr Anita Kumar with patient
In a biologically-related B-cell Non-Hodgkin lymphoma/leukemia called chronic lymphocytic leukemia (CLL), it is well-established that novel biologically-targeted therapies are more effective than standard chemotherapy in patients with TP53 mutation or deletion. Based on this previous positive research, we have specifically designed this new phase II clinical trial for mantle cell lymphoma (MCL) patients with TP53 mutation.
The BOVen clinical trial for TP53 mutant MCL will be testing the efficacy and safety of a chemotherapy-free combination of zanubrutinib, obinutuzumab, and venetoclax. There is preclinical and clinical evidence of synergy when BTK and BCL-2 inhibitors are combined and evidence of therapeutic activity in TP53 mutant MCL. The BOVen treatment program has already been tested in 39 CLL patients and the promising results were recently reported at ASCO 2020. The treatment program was found to be well-tolerated and associated with a rapid and high conversion rate to undetectable minimal residual disease.
Overall survival has improved for some MCL patients in recent years, however, patients who harbor a TP53 mutation, approximately 15-20 percent of newly diagnosed MCL patients, continue to have very poor outcomes. MCL patients with high risk features such as blastic, blastoid, or pleomorphic morphology and elevated proliferative index are more likely to have a TP53 mutation at initial presentation.
One of the reasons that overall survival has improved for younger, transplant-eligible patients is the development of intensive frontline treatment programs such as cytarabine-containing induction chemoimmunotherapy followed by high dose therapy and autologous stem cell rescue. However, data from the Nordic Lymphoma Group suggest that TP53 mutant MCL patients do not benefit from intensive immunochemotherapy in the frontline setting. This study examined the prognostic value of baseline genetic aberrations in 183 younger MCL patients treated on the Nordic MCL2 and MCL3 studies. The authors concluded that those with TP53 mutations appeared to have a phenotypically distinct and highly aggressive form of MCL, with poor or no response to regimens that include cytarabine, rituximab, and autologous stem cell transplantation. The OS for TP53 mutant patients, despite intensive upfront therapy, was less than 2 years. At the current time, there is clearly an unmet need for MCL patients with TP53 mutation as existing frontline chemoimmunotherapy programs are ineffective.
To identify eligible patients for this exciting clinical trial, next generation sequencing on a tumor sample at time of diagnosis can identify the presence of TP53 mutation. At MKS, patients with MCL can undergo genomic profiling on baseline tumor sample with MSK-IMPACT™, which stands for integrated mutation profiling of actionable cancer targets, including TP53 mutation.
Another novel MSK clinical trial is also currently recruiting patients with newly diagnosed mantle cell lymphoma who do not have a TP53 mutation. Eligible candidates are 65 years or older and/or have a TP53 deletion. Called SYMPATICO, it is also a chemo-free clinical trial that combines ibrutinib with venetoclax.
At MSK, we are committed to improving patient outcomes and minimizing the adverse effects of cancer treatment through evidence-based research.