Details of Different Therapies and Modalities Decide Treatment of CLL in the Second Line

Danielle Brander, MD

For the second-line treatment of patients with chronic lymphocytic leukemia, the armamentarium includes many therapies and strategies. Danielle Brander, MD, assistant professor of Medicine at Duke Cancer Institute, discussed how to select treatment for patients during a Targeted Oncology Case-Based Peer Perspectives event.

Targeted Oncology™: What are the guideline-recommended regimens to treat a patient with CLL such as this one?

BRANDER: The [National Comprehensive Cancer Network] guidelines for regimens in the relapsed/refractory setting include acalabrutinib [Calquence] and venetoclax [Venclexta], which are approved in all lines of therapy. In the relapsed/refractory setting, there’s also approval of duvelisib [Copiktra] and idelalisib [Zydelig], which are PI3K inhibitors.¹

What data support the use of ibrutinib (Imbruvica), which is another guideline-recommended agent for the treatment of this patient?

The data that led to the initial approval of ibrutinib was the RESONATE trial [NCT01578707]. [The trial] randomized patients 1:1 to either ibrutinib or the anti-CD20 antibody standard-of-care agent in the relapsed/refractory setting, ofatumumab. Patients were allowed to cross over on this study.²

There are now 6-year follow-up data [showing that the] median progression-free survival [PFS] for the ibrutinib arm was not reached but was short [8.1 months] for the ofatumumab alone [HR, 0.133; 95% CI, 0.099-0.178].

Markers [of prognosis] that would indicate inferior response to chemoimmunotherapy are either the patients with IGHV unmutated or del(17p) or del(11q), who are still having good responses. This is in the relapsed/refractory setting with novel agents.

The grade 3 or greater AEs [adverse effects] that you’ll see are infectious complications. Infections and neutropenia do get better in terms of incidence with [time]. But obviously, if they have to stop [treatment] in the first year, it’s still detrimental to them. One thing [to keep in mind when] monitoring patients is that time on therapy does increase risks for hypertension. Atrial fibrillation and bleeding remain a risk throughout treatment. Often, they first appear early on treatment.

What other Bruton tyrosine kinase (BTK) inhibitors would you consider for treatment of this patient?

The phase 3 ASCEND study [NCT02970318] was recently updated, presented, and published. In the relapsed/refractory [setting], it looked at acalabrutinib versus either choice of BR [bendamustine and rituximab] or idelalisib/rituximab. This was mostly done internationally, especially with approvals and availability at the time. The primary end point was PFS.³

The difference in PFS of acalabrutinib was not reached versus 16 months with either idelalisib/rituximab or BR [HR, 0.41; 95% CI, 0.20-0.49; P < .0001]. PFS by subgroup is as we’ve seen with [ibrutinib, with benefit in most patients].

Versus chemoimmunotherapy, there are less hematological toxicities. You will see more of other AEs like diarrhea [with chemoimmunotherapy and PI3K inhibitors], and these can be seen [at lower rates] with BTK inhibitors.

How is venetoclax used in this setting?

Venetoclax/rituximab in the relapsed/refractory setting was compared 1:1 with BR [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.⁴

The primary end point was PFS, which at the 4-year followup 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,5 [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 on 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. TLS [tumor lysis syndrome] risk with the ramp-up dose was also relatively low here.

Can you briefly discuss the use of PI3K inhibitors?

Idelalisib and duvelisib are both approved for relapsed/refractory CLL and SLL [small lymphocytic lymphoma] after 2 lines of therapy based on randomized studies.6,7 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.

_Reference:

_{1. NCCN. Clinical Practice Guidelines in Oncology. Chronic lymphocytic leukemia/small lymphocytic lymphoma, version 4.2020. Accessed December 20, 2019. https://bit.ly/3jemRoI}

_{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. Ghia P, Pluta A, Wach M, et al. ASCEND phase 3 study of acalabrutinib vs investigator’s choice of rituximab plus idelalisib (IDR) or bendamustine (BR) in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Abstract presented at: 24th European Hematology Association Congress; June 13-15, 2020; Amsterdam, Netherlands. Accessed August 26, 2020. https://bit.ly/2Eskpfj}

_{4. 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}

_{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. 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 August 25, 2020. https://bit.ly/31q2Y7T}

_{7. 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 August 25, 2020. https://bit.ly/3aWlJTy}