Nivolumab + Ibrutinib Active in Relapsed/Refractory CLL and Richter Transformation
The combination of nivolumab and ibrutinib is active in patients with relapsed/refractory chronic lymphocytic leukemia.
SAN DIEGO – The combination of nivolumab and ibrutinib is active in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) and Richter transformation, according to preliminary findings presented at the American Society of Hematology (ASH) 58th Annual Meeting and Exposition.1
"Understanding of the BCR signaling pathway and the development of BCL2 inhibitors revolutionized CLL treatment, but the majority of responses are partial and those with del(17p) and Richter transformation continue to have poor outcomes," said Nitin Jain, MD, of the department of leukemia at The University of Texas MD Anderson Cancer Center in Houston, Texas.
Increased PD-1 receptors have been found on T cells and increased PD-L1 and PD-L2 receptors have been observed on CLL cells. A preclinical study demonstrated that PD-L1 inhibition and ibrutinib have synergistic activity in a mouse lymphoma model.
Researchers postulated that immune dysregulation in CLL is a result of overexpression of checkpoint receptors by T cells and respective ligands on CLL cells.
To determine whether checkpoint inhibition would result in correction of immune dysregulation and an anti-leukemia effect, researchers developed a phase 2 clinical trial to assess the activity and tolerability of nivolumab plus ibrutinib in patients with CLL and those with Richter transformation.
For the study (ClinicalTrials.gov Identifier: NCT02420912), investigators have enrolled 5 patients with relapsed/refractory CLL and 5 patients with Richter transformation (cohort 1) and 3 patients with CLL who had been on ibrutinib for at least 9 months with persistent disease.
Patients in cohort 1 received nivolumab every 2 weeks for 1 cycle, with nivolumab every 2 weeks plus ibrutinib daily for cycle 2 onwards. Those in cohort 2 continued ibrutinib with added nivolumab from course 1.
In cohort 1, 4 patients with CLL achieved a response, including 1 complete response and 3 partial responses. Of the 5 with Richter transformation, 2 achieved complete responses for Richter transformation and partial responses for CLL, and 1 had a partial response.
The 3 patients in cohort 2 had stable disease. In all 3 patients of cohort 2, researchers observed a reduction in the lymphocytic infiltrate in the marrow, but no patient achieved a complete remission or complete remission with incomplete bone marrow recovery.
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No patients discontinued therapy due to adverse events, and there were no grade 3 or worse immune-related adverse events."We observed encouraging activity in the Richter transformation cohort and modest activity in CLL patients," Dr Jain concluded. "A study evaluating combined checkpoint blockade with ipilimumab, nivolumab, and ibrutinib is being planned."
- Jain N, Basu S, Thompson PA, et al. Nivolumab combined with ibrutinib for CLL and Richter transformation: A phase II trial. Paper presented at: American Society of Hematology (ASH) 58th Annual Meeting and Exposition; December 3-6, 2016; San Diego, CA.