Results of a phase 2 study investigating the use of ibrutinib/venetoclax combination therapy in the setting of relapsed/refractory chronic lymphocytic leukemia (R/R CLL) showed that approximately one-half and one-third of patients achieved eradication of minimal residual disease (MRD) in the peripheral blood and bone marrow, respectively. The findings from this study were published in the Journal of Clinical Oncology. 1

While some patients with R/R CLL have disease characterized by an indolent course and may not require treatment, others experience aggressive disease and an associated reduction in life expectancy despite the receipt of treatment.

Although remission is achieved in the majority of patients with CLL receiving rituximab-based chemoimmunotherapy, treatment complications are common, and the disease returns in most of these patients.

Use of the antiproliferative Bruton tyrosine kinase inhibitor, ibrutinib, approved by the US Food and Drug Administration (FDA) for both treatment-naive and previously treated adult patients with CLL,2 has been associated with improved overall survival (OS) in this setting, although few patients experience complete disease eradication. Consequently, many patients receive long-term ibrutinib therapy, although the adverse effects of this treatment, including hypertension and atrial fibrillation, may necessitate early treatment termination.

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The FDA has also approved the Bcl-2 inhibitor, venetoclax, a proapoptotic agent, for adult patients with CLL.3 Notably, in addition to improvement in OS, approximately 15% of patients with CLL enrolled in studies evaluating single-agent venetoclax have been reported to have experienced eradication of MRD, thereby raising the possibility of treatment discontinuation in a subset of patients.

The single-arm, phase 2 CLARITY (ISRCTN13751862) study was therefore designed to evaluate the hypothesis that the combination of ibrutinib and venetoclax would act synergistically to increase the proportion of patients with R/R CLL achieving an MRD-negative remission. The primary end point of the study was the proportion of patients experiencing less than 1 CLL cell in 10,000 leukocytes (MRD4) in both peripheral blood and bone marrow after 12 months of treatment.

Of the 53 patients enrolled in the study, the mean age was 64 years and the median number of prior treatment was 1, with 22%, 20%, and 75% having disease characterized by del(17p), del(11q) without del(17p), and wild-type IGVH genes, respectively.

Regarding the primary study end point, 53% and 36% of patients achieved MRD4 in the peripheral blood and bone marrow, respectively, following 12 months of study treatment (ie, ibrutinib [420 mg/day] starting on day 1/week 1; venetoclax [titrated from 20 to 400 mg/day] starting day 1/week 9 for most patients). At a median follow-up of 21.1 months, only 1 patient had experienced progressive disease, and no patient deaths had occurred.

Ibrutinib/venetoclax combination therapy was well tolerated in most patients. One patient experienced grade 3 biochemical tumor lysis syndrome, with grade 4 adverse events limited to neutropenia (10 individuals), thrombocytopenia (7 individuals), and pneumonitis (1 individual). All of these adverse events resolved with appropriate management, and did not result in removal of patients from the study. Ibrutinib was interrupted in 8 patients for a median of 6 days, and venetoclax was interrupted in 23 patients for a median of 8 days and the dose was reduced in 11 patients for a median of 15 days, mostly due to diarrhea and neutropenia.

“We have demonstrated promising efficacy that indicates potent synergy between ibrutinib and venetoclax for inducing MRD-negative responses with manageable adverse effects. The observation that a significant proportion of patients experience MRD-negative remission indicates that this combination can be given for a limited period and then stopped after patients achieve a deep remission. This observation is critical before taking the MRD-guided approach into larger phase 3 trials. Whether the combination leads to permanent disease eradication in a subset of these patients remains to be seen,” the study authors noted in conclusion.

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