The Bottom Line:
Fixed duration combination therapy of obinutuzumab, ibrutinib, and venetoclax with treatment adjustment based on clinical response and results of measurable residual disease testing shows high efficacy and safety for the front-line treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL / SLL) patients with del (17p) or TP53 mutation offering exciting hope for what has been an unmet need for this group of patients with high-risk disease.
Who Performed the Research and Where Was it Presented:
Dr. Stephan Stilgenbauer and Dr. Henriette Huber from the Department of Internal Medicine, Städtisches Klinikum Karlsruhe and University Hospital Ulm, Germany, and colleagues presented the results of the CLL2-GIVe trial at the American Society for Hematology (ASH) Annual Meeting in December 2022.
CLL / SLL is a heterogenous disorder ranging from indolent to aggressive disease. The loss of function of the tumor protein 53 gene (TP53), which resides on chromosome 17, either through a mutation of TP53 or through (del)17p, which is the actual loss of part of the chromosome containing the gene is associated with more difficult to treat disease and portends a less favorable prognosis.
Over the past decade, chemoimmunotherapy regimens have proven ineffective for managing patients with loss of function of TP53. Improved outcomes have been found with the newer agents, ibrutinib, a Bruton tyrosine kinase inhibitor, venetoclax, a B-cell lymphoma-2 (BCL-2) inhibitor, and obinutuzumab, an anti-C20 antibody. However, success with each agent alone has been limited. Therefore, the CLL2-GIVe trial used ibrutinib, venetoclax, and obinutuzumab, each with a distinctly different mechanism of action, together for time-limited and response-adapted therapy as initial treatment to see if improved outcomes for this subgroup of high-risk patients can be obtained.
Following the presentation at ASH, Dr. Brian Koffman interviewed Dr. Stephan Stilgenbauer, Professor of Medicine and Medical Director of the Comprehensive Cancer Center at Ulm University, Germany, to gain further insights into this research.
Methods and Participants:
- Previously untreated CLL / SLL patients with del(17p) and/or TP53 mutation were enrolled in this open-label, phase 2 trial conducted at 8 locations in Germany.
- A combination of obinutuzumab, venetoclax, and ibrutinib was administered during the trial’s first 6, 28-day cycles, followed by venetoclax and ibrutinib administration during the next 6, 28-day cycles.
- Testing for minimal residual disease (MRD) to 10-4 in peripheral blood was done at the end of cycles 9 and 12. Final restaging was completed at the beginning of cycle 15, including MRD testing in the peripheral blood and bone marrow.
- For those patients not reaching undetectable MRD and complete response (CR) at the end of cycles 9 and 12, ibrutinib was administered for cycles 13-36, each lasting 28 days.
- 41 patients were enrolled from September 2016-August 2018, with the last patient reaching the end of the study in January 2022.
- At cycle 15, a CR rate of 58.5% and a partial remission (PR) rate of 41.5% were achieved.
- At cycles 9 and 12, 87.8%% of patients achieved undetectable MRD in the peripheral blood. At cycle 15, 78% of patients had undetectable MRD in the peripheral blood and 65.9% in the bone marrow. At cycle 36, 43.9% of patients had undetectable MRD in the peripheral blood, 29.3% had detectable MRD, and 26.8% analysis was not performed.
- At 36 months, the overall survival (OS) was 92.6%, and the progression-free survival (PFS) was 79.9%. Neither the median OS nor PFS had been reached at this point.
- The most frequent severe treatment-emergent side effects were low white blood cell count, low platelet count, and infections. The most frequent low-grade events were gastrointestinal disorders. Atrial fibrillation occurred in 14.6% of patients.
The response-adapted, fixed-duration, early-phase CLL2-GIVe drug trial demonstrated significant efficacy and safety of obinutuzumab, venetoclax, and ibrutinib combination therapy for the front-line treatment of high-risk CLL / SLL patients and warrants further study in phase 3 drug trials.
The combination of obinutuzumab, venetoclax, and ibrutinib is potent, but the question remains what the best combination is? Which drugs for which patients? Are two or three drugs best? Is sequencing better than combinations? We are starting to get some answers for some populations in trials such as ASH 2022: Dr. Matthew Davids on the Contribution of Obinutuzumab to Acalabrutinib Therapy in Patients with Chronic Lymphocytic Leukemia or Small Lymphocytic Leukemia (CLL / SLL), though likely some important answers will be a long way off. Because many treatments offer durable responses, it could take years to identify the best clinical pathways.
Links and Resources:
You can watch the interview with Dr. Stephan Stilgenbauer here:
You can read the actual ASH abstract here:
We share in this journey together,
Kim Davidson, MD
CLL patient and physician