Part 2: Venetoclax and PI3K Inhibition for Relapsed/Refractory CLL

Danielle Brander, MD

Assistant Professor of Medicine

Duke Cancer Institute

Durham, NC

Targeted Oncology™: How is venetoclax (Venclexta) used in CLL?

BRANDER: Venetoclax/rituximab [Rituxan] in the relapsed/refractory setting was compared 1:1 with BR [bendamustine/rituximab] [in the randomized MURANO trial (NCT02005471)]. Patients with del(17p) were allowed [and made up] about 25% of patients in each arm. The study was done at a time without the availability of targeted agents in this setting. The other difference from the use in the front line is the venetoclax/rituximab was given as a fixed-duration therapy for 2 years.¹

The primary end point was progression-free survival [PFS], which at the 4-year follow-up was significantly different [HR, 0.19; 95% CI, 0.13-0.28; P < .0001]. This is notable because these are patients with relapsed/refractory CLL and del(17p) who stopped therapy at the end of 2 years. The difference at 2 years for the PFS rate [is 75.5% for venetoclax/rituximab and 68% for BR]. The difference in overall survival was also significant in this group [HR, 0.41; P < .0001]. That’s despite the fact some of those patients could get novel therapy after the BR. Like we saw with other agents, this held true across disease status, even in high-risk patients.

In addition, secondary end points looked at overall response rates and particularly the MRD [minimal residual disease] rates, which for relapsed/refractory patients are

going to be lower than in the front line. Still, very impressive for undetectable MRD at the level of 10^-4.

They’ve now published some follow-up looking at MRD at the end of therapy and how that predicts progressive disease or becoming low-level MRD positive,² [and whether that provides] a window to restart therapy before they have fully progressive disease.

What are the safety concerns with venetoclax?

The treatment-emergent AEs are similar to those seen in the front line. You can still see high rates of neutropenia. Patients in studies of venetoclax were allowed to receive growth factor support, and if that can help patients to stay [on therapy], especially during the dose ramp-up, I do use growth factor support. Tumor lysis syndrome risk with the ramp-up dose was also relatively low here.

Can you briefly discuss the use of PI3K inhibitors?

Idelalisib [Zydelig] and duvelisib [Copiktra] are both approved for relapsed/refractory CLL and SLL [small lymphocytic lymphoma] after 2 lines of therapy based on randomized studies.^3,4 The comparator [arms in both trials] were antibody alone, with about a year and a half of follow-up data. The overall response rates are promising for PI3K inhibitors. What has often prohibited their use is that incorporation for many of us [involves] encountering AEs, many [of which are] thought to be immune mediated.

_REFERENCES

_{1. Seymour JF, Kipps TJ, Eichorst BF, et al. Venetoclax plus rituximab is superior to bendamustine plus rituximab in patients with relapsed/ refractory chronic lymphocytic leukemia - results from pre-planned interim analysis of the randomized phase 3 MURANO study. Blood. 2017;130(suppl 1):LBA-2. doi:10.1182/blood.V130.Suppl_1.LBA-2.LBA-2}

_{2. Kater AP, Seymour JF, Hillmen P, et al. Fixed duration of venetoclax-rituximab in relapsed/refractory chronic lymphocytic leukemia eradicates minimal residual disease and prolongs survival: post-treatment follow-up of the MURANO phase III study. J Clin Oncol. 2019;37(4):269-277. doi:10.1200/JCO.18.01580}

_{3. U.S. Food and Drug Administration approves Gilead’s Zydelig (idelalisib) for relapsed chronic lymphocytic leukemia, follicular lymphoma and small lymphocytic lymphoma. News release. Gilead Sciences Inc. July 23, 2014. Accessed November 16, 2021. https://bit.ly/31q2Y7T}

_{4. Duvelisib (Copiktra, Verastem, Inc.) for adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). FDA. September 24, 2018. Accessed November 16, 2021. https://bit.ly/3aWlJTy}