CLL Treatment Further Refined With Venetoclax Data Updates

Jennifer R. Brown, MD, PhD

The introduction of venetoclax (Venclexta) into the treatment paradigm of chronic lymphocytic leukemia (CLL) has led to options for time-limited therapy in a space that has been dominated by continuous therapeutic agents.

At the American Association for Cancer Research Virtual Meeting: Advances in Malignant Lymphoma, Jennifer R. Brown, MD, PhD, discussed the emergence of venetoclax and its promise as a standard therapy in the current and future landscape of CLL.¹

“Venetoclax has marked activity in CLL, including TP53-abberant disease, and achieves deep remissions with undetectable MRD [minimal residual disease],” said Brown, who is the director of the Center for Chronic Lymphocytic Leukemia at Dana-Farber Cancer Institute and a professor of medicine at Harvard Medical School, both in Boston. “Therapy now focuses on time-limited combination with anti-CD20 antibodies, and in that case, the primary predictor of PFS [progression-free survival] is MRD status.”

Early investigation into BCL-2 inhibition demonstrated efficacy against relapsed or refractory CLL, but toxicity rates were a concern with early agents such as navitoclax.²

“It’s hard to target BCL-2 without targeting BCL-xL because there are only 4 amino acid residues that differ within their BH3-binding grooves,” Brown said. “Venetoclax was reverse engineered to selectively inhibit BCL-2 in relation to BCL-xL.”

In an early study, 3 patients with relapsed or refractory CLL who were treated with a single dose of venetoclax, then known as ABT-199, demonstrated reduced tumor burden, but tumor lysis was also observed within 24 hours. These data supported the agent’s selective pharmacological inhibition of BCL-2 and the trial was redesigned so that venetoclax was administered at a slower rate over the ramp-up phase.³

“The first effort of doing this ramp up was still too quick…and still led to death due to tumor lysis,” Brown said. “The ultimate schedule that was selected was a weekly dose [for preventing tumor lysis].” Optimal dosing ramp-up for venetoclax involves 20 mg of the drug at week 1 that is eventually increased up to 500 mg at week 5, she continued.

According to Brown, risk stratification studies were also performed to determine factors predisposing patients to tumor lysis. “As we might expect, risk was dependent on nodal mass and lymphocyte count.” Determining these factors meant that patients who were assessed as being from a lower-risk group required less monitoring than those of a higher-risk group.

In a phase 1 dose-escalation study (NCT01328626), responses were noted at a rate of 79% in 116 patients and were independent of TP53 status. However, certain adverse prognostic factors such as deletion 17p (del[17p]) did lead to shorter PFS.⁴

Another important advance in the evolution of venetoclax development came when it was found to be effective post progression in patients who previously received ibrutinib (Imbruvica), with 65% of patients having an overall response in a cohort of patients with a median of 4 prior therapies.⁵

Importantly, the combination of venetoclax and rituximab (Rituxan) induced an overall response rate of 86% in patients with relapsed or refractory CLL in a phase 1b trial (NCT01682616).⁶

“In this study, the idea of time-limited therapy was piloted, and patients achieving undetectable MRD [minimal residual disease] or deep remissions could stop,” Brown said. “This served as the basis for the first randomized trial, MURANO [NCT02005471].”

Pivotal Data

In 2018, the FDA approved venetoclax for use in patients with previously treated CLL based on the results of the phase 3 MURANO trial, which demonstrated the efficacy of venetoclax plus rituximab versus bendamustine/rituximab (BR) in terms of superior PFS (HR, 0.19; 95% CI, 0.13-0.28; P < .0001).^7,8 The regimen administered to patients on the trial included 2 years of venetoclax with rituximab for the first 6 months versus BR for 6 months.

“Predictors of disease progression included MRD status, del(17p), or TP53-mutation status,” Brown said. “In fact, those patients with high MRD who relapsed early after discontinuation already had high and increasing levels of MRD prior to discontinuation, raising the possibility that they already had intrinsic resistance and discontinuation may not have necessarily affected their relapse.”

The MURANO investigators recently reported that high genomic complexity, defined as having 5 or more karyotypic changes, was linked to high rates of MRD positivity at the end of therapy as well as shorter PFS, Brown noted. The effects on PFS were also applicable to those patients treated in the BR control arm.¹

Another exploratory analysis showed that mutations in BRAF and BIRC3 were enriched in patients with high MRD, whereas patients with low MRD were more likely to have mutations in TP53, NOTCH1, IKZF3, and XPO1. Interestingly, there was no correlation evident between BCL-2 family member expression and MRD status at the end of treatment with the venetoclax combination.¹

Data supporting the approval of venetoclax in the frontline setting were based on the phase 3 CLL14 trial (NCT02242942) and led to further questions regarding time-limited therapy. In this trial, the experimental arm of venetoclax plus obinutuzumab (Gazyva) had superior PFS versus obinutuzumab/chlorambucil (HR, 0.33; 95% CI, 0.22-0.51; P < .0001).⁹

“In landmark analysis, MRD was [found to be] extremely predictive of progression-free survival in this context,” Brown said. “This may suggest that patients [with a high-risk karyotype] may require continuous therapy or it may be associated with a lower likelihood of achieving undetectable MRD.” Although she admitted more information is needed, Brown expressed concerns regarding time-limited therapy in patients with unmutated IGHV status and TP53 mutations.

Resistance to Venetoclax

Resistance is mostly understood in the context of continuous venetoclax therapy. Patients with early relapse are highly enriched for Richter transformation and CLL that is highly proliferative. Genomic changes associated with early relapse are also seen in those with karyotypic complexity, loss of CDKN2A/B, and NOTCH1 and BTG1 mutations.¹

On the other hand, patients with relapse later on in their disease tend to have progressive CLL with common mechanisms of resistance of BCL-2 mutations, MCL-1 (1q) amplifications, increased oxidative phosphorylation, and overexpression of BCL-xL.

The resistance mutation Gly101Val was first described in 2018 and was identified in 7 of 15 venetoclax-treated patients (46%) at progression on continuous therapy, but not at study entry.10 A subsequent report found that 10 of 11 patients with this mutation had a median of 3 additional BCL-2 mutations developing over a median of 3 years of therapy.¹¹

“The hope is that time-limited therapy with venetoclax may decrease the incidence of these mutations,” Brown said.

Overcoming Resistance

Besides time-limited therapy, Brown said combining other agents with venetoclax may hold promise in the treatment of CLL. One such strategy includes adding venetoclax to ibrutinib

A phase 2 study of the combination showed that after 18 cycles of venetoclax, 69% of patients had undetectable MRD in the bone marrow. “Many of these studies are showing plateaus in the extension of undetectable MRD at about the 70% to 80% level,” Brown said. “We’re seeing about 30% of these patients who are not able to eradicate MRD.” This gap in responses leads to critical research questions about those cells and why they remain resistant to therapy and if there are other ways to eradicate disease.¹²

Another Bruton tyrosine kinase inhibitor, acalabrutinib (Calquence) is also being explored with venetoclax therapy in a phase 2 trial with an end point of undetectable MRD. Early data look promising, with 65% of patients having undetectable MRD in either the blood or bone marrow at cycle 8.¹³ The results of this trial will be further updated at the 2020 American Society for Hematology Annual Meeting, Brown said.

Results of the phase 2 CRC043 trial (NCT03054896) that looked at venetoclax with dose-adjusted R-EPOCH (rituximab plus etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) in patients with Richter transformation demonstrated a median PFS of 16.3 months and complete response rate of 65%.¹⁴

_References:

_{1, Jennifer R. Brown. Targeting BCL-2 with venetoclax. Presented at: American Association for Cancer Research Virtual Meeting: Advances in Malignant Lymphoma; August 17-19, 2020.}

_{2. Roberts AW, Seymour JF, Brown JR, et al. Substantial susceptibility of chronic lymphocytic leukemia to BCL2 inhibition: results of a phase I study of navitoclax in patients with relapsed or refractory disease. J Clin Oncol. 2012;30(5):488-496. doi:10.1200/JCO.2011.34.7898}

_{3. Souers AJ, Leverson JD, Boghaert ER, et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med. 2013;19(2):202-208. doi:10.1038/nm.3048}

_{4. Roberts AW, Davids MS, Pagel JM, et al. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374(4):311322. doi:10.1056/NEJMoa1513257}

_{5. Jones JA, Mato AR, Wierda WG, et al. Venetoclax for chronic lymphocytic leukaemia progressing after ibrutinib: an interim analysis of a multicentre, open-label, phase 2 trial. Lancet Oncol. 2018;19(1):65-75. doi:10.1016/ S1470-2045(17)30909-9}

_{6. Brander DM, Seymour JF, Ma S, et al. Durability of responses on continuous therapy and following drug cessation in deep responders with venetoclax and rituximab. Blood. 2018;132(suppl 1):183. doi:10.1182/ blood-2018-183}

_{7. Seymour JF, Kipps TJ, Eichhorst B, et al. Venetoclax-rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2018;378(12):1107-1120. doi:10.1056/NEJMoa1713976}

_{8. FDA approves venetoclax for CLL or SLL, with or without 17 p deletion, after one prior therapy. FDA. June 8, 2018. Accessed September 24, 2020. https://bit.ly/3mR1gF9}

_{9. FDA approves venetoclax for CLL and SLL. FDA. May 15, 2019. Accessed September 24, 2020. https://bit.ly/3kD5vT4}

_{10. Blombery P, Anderson MA, Gong JN, et al. Acquisition of the recurrent Gly101Val mutation in BCL2 confers resistance to venetoclax in patients with progressive chronic lymphocytic leukemia. Cancer Discov. 2019;9(3):342-353. doi:10.1158/2159-8290.CD-18-1119}

_{11. Blombery P, Thompson ER, Nguyen T, et al. Multiple BCL2 mutations co-occurring with Gly101Val emerge in chronic lymphocytic leukemia progression on venetoclax. Blood. 2020;135(10):773-777. doi:10.1182/ blood.2019004205}

_{12. Jain N, Keating M, Thompson P, et al. Ibrutinib and venetoclax for f irst-line treatment of CLL. N Engl J Med. 2019;380(22):2095-2103. doi:10.1056/NEJMoa1900574}

_{13. Lampson BL, Tyekucheva S, Crombie JL, et al. Preliminary safety and efficacy results from a phase 2 study of acalabrutinib, venetoclax and obinutuzumab in patients with previously untreated chronic lymphocytic leukemia (CLL). Blood. 2019;134(suppl 1):32. doi:10.1182/ blood-2019-127506}

_{14. Davids MS, Rogers KA, Tyekucheva S, et al. A multicenter phase II study of venetoclax plus dose-adjusted R-EPOCH (VR-EPOCH) for Richter’s syndrome. J Clin Oncol. 2020;38(suppl 15):8004. doi:10.1200. JCO/2020.38.15_suppl.8004}