BCL-2, BTK Inhibitors Can Be Considered for R/R CLL

Alexey Danilov, MD, PhD, associate director, Toni Stephenson Lymphoma Center, professor, Department of Hematology & Hematopoietic Cell Transplantation, City of Hope Comprehensive Cancer Center, Duarte, CA, reviewed the case of 71-year-old patient with chronic lymphocytic leukemia (CLL) and the treatment options for this particular scenario.

Targeted Oncology™: What do the National Comprehensive Cancer Network guidelines say is the best treatment regimen for relapsed CLL?

DANILOV: For relapsed/refractory therapy, for deletion 17p [del(17p)], we have several options including acalabrutinib [Calquence], ibrutinib [Imbruvica], venetoclax [Venclexta], duvelisib [Copiktra], and idelalisib [Zydelig].¹

Please describe data supporting ibrutinib for the relapsed/refractory setting.

The RESONATE trial [NCT01578707] was not specific for del(17p). Those patients were randomized to ibrutinib or ofatumumab [Truxima]; RESONATE is an older trial. It was stratified by presence or absence or del(17p).²

This is the trial which led to the initial approval of ibrutinib in patients with relapsed/refractory CLL.3 At the 6-year follow-up, the majority of patients were still progression free.²

[This was] the first trial that showed that there was no difference in patients with mutated versus unmutated IGHV. And patients with del(17p) did reasonably well, with median progression- free survival [PFS] of 40 months, which is better than any other chemotherapy that was used before. There was an improvement in overall survival [OS] on this study, which occurred early.

The adverse events [AEs] were [those] typically associated with ibrutinib. Over time there’s increasing incidence of hypertension, particularly after 1 to 2 years. Infections and neutropenia decrease with time, but hypertension is one of the AEs that persists. The majority of cases of atrial fibrillation occur during the first year, but then you still see some [cases] beyond, at 2 to 3 years.

Which other drugs are relevant in this space?

There’s a study [NCT01889186] of venetoclax monotherapy in the relapsed/refractory del(17p) CLL population. It was a singlearm study and patients received daily oral single agent venetoclax with a ramp-up schedule and continued on 400 mg per day.⁴

The median PFS was 27.2 months; this was lower than what we see with ibrutinib for this patient category. They achieved some minimal residual disease in the blood at 30%, but it’s lower than in previously untreated patients. There was a high response rate and 20% complete remission but remember that those are patients with del(17p), which is always difficult to treat. The common toxicities were hematologic-related.

Are there other trials looking at venetoclax in this patient population?

The MURANO study [NCT02005471] with venetoclax evaluated 389 patients. I believe about 20% of them had del(17p) and they were randomized to venetoclax and rituximab or bendamustine [Bendeka] and rituximab. The primary end point was PFS.⁵

The update from the 2019 American Society of Hematology [ASH] Annual Meeting [showed] a separation of Kaplan-Meier curves with improved OS [in MURANO]. The PFS curves continued to [separate] well. And this is particularly true in patients with del(17p), who did not have such great response to bendamustine and rituximab. Patients with mutated TP53 derived significant benefit from novel therapy.

For the secondary end points, there was a high overall response rate by independent review committee of 92.3% with a high complete response [CR] rate [of 8.2% in the venetoclax arm, versus 72.3% and a CR of 3.6% in the bendamustine arm]. CR is much higher when it’s determined by an investigator, at 26.8%, because it tends to be a little bit more lenient with patients’ lymph nodes. There were higher rates of minimal residual disease at 83.5% with venetoclax compared with 23.1% with bendamustine.

The typical toxicities included [rates of] 60% neutropenia [and] 5% thrombocytopenia, but the frequency of pneumonia and febrile neutropenia was low with venetoclax and rituximab despite higher rates of overall neutropenias. There was no hypotension in contrast to BTK [Bruton tyrosine kinase] inhibitors.

What was the role of the ASCEND trial (NCT02970318) for patients with relapsed/refractory disease?

The ASCEND study [has] the most decent data…presented in relapsed/refractory CLL, so this is what introduced acalabrutinib in relapsed CLL. About 300 patients [were] randomized to acalabrutinib or bendamustine and rituximab or idelalisib and rituximab.⁶

This was the first large randomized study that was compared with novel regimens. Everything else was comparing novel agents to chemotherapy. Here, there was investigator choice where physicians could choose whether they used bendamustine and rituximab or idelalisib and rituximab. The primary end point was PFS.

This trial showed significant separation of Kaplan-Meier curves, and it didn’t matter whether patients received bendamustine or idelalisib—acalabrutinib still performed better [median PFS not reached for acalabrutinib vs 16.5 months with idelalisib or bendamustine; HR, 0.31; 95% CI, 0.20-0.49; P <.0001].

The high-risk genetic subgroups included not just del(17p) but also patients with del(11q) and unmutated IGHV. There were significant benefits in those groups of patients. Patients with TP53 mutations benefited when they received acalabrutinib.

The most common AE was something we haven’t mentioned so far: headache. It seems to be much more common with acalabrutinib. The reasons for that are still unknown, but most of the AEs were mild. When you look at the idelalisib and rituximab combination, which the majority of patients in the control arm received, there was 45% neutropenia and 47% diarrhea, so it was a pretty toxic regimen. This included 24% diarrhea of grade 3 or more, so that’s significant.

Overall, acalabrutinib was well tolerated. Discontinuation rates for idelalisib and rituximab were around 40% to 50% due to AEs, so that’s one of the problems.

Are there data to support use of a certain therapy for this patient who previously received a BTK inhibitor?

So, if she started on a BTK inhibitor and 3 to 4 years later she is progressing with del(17p), [venetoclax is an option, but] the problem is that the MURANO study did not enroll any BTK-refractory patients.⁵

Outside of venetoclax, there are only retrospective data [for patients who previously received a BTK inhibitor]. There is retrospective data with PI3K inhibitors, which do not seem to perform [well] in that setting if patients progress on BTK inhibitors. There are data with chemotherapy, which is even worse, so the best data so far [are] with venetoclax.

The other body of data is with CAR T cells. In patients who are double refractory, [those] data [are] still immature, the follow-up is still short, and it’s experimental. So this is the patient population who we should be thinking about [for] clinical trials because the data [are] so sparse.

Do you see an increase of Richter syndrome in a patient who progresses on a BTK inhibitor?

It was initially suspected, but that’s because the earlier data from clinical trials [concerned] patients who received 8 to 10 chemotherapy regimens before they went on ibrutinib. So they already were at a particularly high risk for Richter transformation. It seems that we still don’t know with the newer data when patients are started on a BTK inhibitor upfront; but so far, the data seem to pan out, [indicating] that there’s not a high risk of Richter [syndrome]. This is still something which is not entirely clear, but [there’s] probably not [a high risk].

What would if venetoclax was used as a frontline regimen?

This is a data-free area. There are some data that suggest that re-treating with venetoclax is effective; it’s limited so far. There are also limited data that BTK inhibitors work in patients who progress on venetoclax, but none of this is formal.

_References

_{1. NCCN. Clinical Practice Guidelines in Oncology. Chronic lymphocytic leukemia/small lymphocytic lymphoma, version 1.2021. Accessed November 4, 2020. https://bit.ly/2I5F0HI}

_{2. Byrd JC, Hillmen P, O’Brien S, et al. Long-term follow-up of the RESONATE phase 3 trial of ibrutinib vs ofatumumab. Blood. 2019;133(19):2031-2042. doi:10.1182/blood-2018-08-870238}

_{3. U.S. FDA Approves IMBRUVICA (ibrutinib) for first-line treatment of chronic lymphocytic leukemia. News release. Johnson & Johnson; March 4, 2016. Accessed June 25, 2020. https://bit.ly/2TXLifa}

_{4. Stilgenbauer S, Eichhorst B, Schetelig J, et al. Venetoclax for patients with chronic lymphocytic leukemia with 17p deletion: results from the full population of a phase II pivotal trial. J Clin Oncol. 2018;36(19):1973-1980. doi:10.1200/JCO.2017.76.6840}

_{5. 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}

_{6. Ghia P, Pluta A, Wach M, et al. ASCEND: Phase III, randomized trial of acalabrutinib versus idelalisib plus rituximab or bendamustine plus rituximab in relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol. Published online May 27, 2020. doi:10.1200/JCO.19.03355}