Yucai Wang, MD, PhD, on Richter Transformation of CLL: Findings on Combination Therapy With an Immune Checkpoint Inhibitor

So, Richter's transformation is a rare but devastating complication of chronic lymphocytic leukemia or small lymphocytic lymphoma. The prognosis of this disease is poor without established standard of care treatments. Our institution did a phase two clinical trial investigating the efficacy of pembrolizumab in this disease. Previously, we have reported preliminary efficacy results of this trial. So in the first nine patients with Richter's transformation, we observed a response rate of 44%. In this updated analysis, we report updated efficacy data of single-agent pembrolizumab and the combination therapy with pembrolizumab and a BCR inhibitor. So in this trial, patients were first treated with single-agent pembrolizumab every three weeks for up to 12 months. Patients who only have stable disease after three cycles of treatment or those who progress at any time during this single-agent treatment phase can add a inhibitor of the B-cell receptor, either with a BTK inhibitor or a PI3K inhibitor. So in this updated analysis, we enrolled a total of 26 patients, nine in the initial cohort, as reported a number of years earlier, and 17 in an expansion cohort. Looking at the patient and the disease baseline characteristics, this is consistent with what you would observe in this patient population. To highlight, most of the patients had unmutated IgHV and about 40% of the patients had TP53 alterations. This is a heavily pretreated population with a median of three lines of prior therapy, with up to 11 lines of therapy for CIL and five lines of therapy for Richter's transformation. Over half of the patients were previously exposed to BTK inhibitor ibrutinib already, and the massive majority of those patients actually had disease progression on this agent. So again, a high-risk patient population, difficult to treat. So in this trial, we observed that with single-agent pembrolizumab treatment, the objective response rate was 23%, or six out of 26 responses. It was two CR and 4 PRs. What's interesting is that for the 16 patients who went on to receive a doublet therapy with pembrolizumab either in combination with ibrutinib or idelalisib, we saw a high response rate of over 60%. So again, these are patients who progressed through pembrolizumab, and most of the patients have been previously exposed to ibrutinib, so this 60% response rate is very encouraging. In terms of survival outcomes, in a single-agent phase they observed the median progression-free survival was three months, and the median progression-free survival in the doublet therapy phase was about eight months. In total, the median overall survival is about one year, and the overall survival rate at two years is 27%. So again, in this heavily pretreated population with high-risk disease features, this doublet therapy certainly looks very encouraging in inducing a response and to maintain that. So these data do suggest that a PD-L1 blockade in combination with a BCR inhibitor is efficacious in treating Richter's transformation and it warrants further exploration. We do have another ongoing trial examining the combination of PD-L1 blockade in combination with a BTK inhibitor and the venetoclax in this patient population, and we look forward to sharing those results in the future.