Expert Expands on Treatment Choices in Patients With Genomic Aberrations in CLL

Jonathon B. Cohen, MD, MS

During a Targeted Oncology Case-Based Peer Perspective event, Jonathon B. Cohen, MD, MS, codirector, Lymphoma Program Medical Director, Infusion Services, associate professor, Department of Hematology and Medical Oncology, Emory University School of Medicine, Winship Cancer Institute of Emory, discussed therapeutic options for a 71-year-old patients with chronic lymphocytic leukemia (CLL) and a genomic aberration.

Targeted Oncology^TM: What are reasonable treatment options to consider in a patient with CLL?

COHEN: The National Comprehensive Cancer Network guidelines offer 6 treatment options for patients with del(17p).¹ As I tell my fellows when I work with them, if you ever see a list of preferred regimens with 6 options, that likely means that nobody really knows what the best option is.

The 1 option not listed in the guideline is chemotherapy, especially in the relapsed setting for patients with del(17p). I generally would not use chemotherapy.

The only exception to that might be a situation where we have a patient who’s young and for whom we’re thinking about moving on to something like an allogeneic transplant or some other definitive therapy. We might consider using chemotherapy for a cycle or 2. But otherwise, if you’re not going in that direction, that’s the 1 thing we do feel comfortable saying—that is, that chemotherapy is probably not the right option.

What were the outcomes for patients in the ASCEND trial?

The ASCEND trial [NCT02970318] compared acalabrutinib [Calquence] monotherapy [versus investigator's choice of] rituximab plus idelalisib [Zydelig] or bendamustine and rituximab [BR].² Patients were allowed to cross over from the conventional arm to acalabrutinib. The trial included patients with del(17p).

The PFS [progression-free survival] rate was updated at ASCO [American Society of Clinical Annual Meeting], demonstrating an 18-month PFS of 82% for acalabrutinib, which is quite good.³ In general, in the relapse setting, we don’t see the same response durations as we see in the treatment setting. For the BR or idelalisib-containing arm, the median PFS was around 16.5 months [95% CI, 14.0-17.1].

The response rates were comparable between these 2 arms. In most cases, especially during a first relapse, you’re not going to have patients who progress right on therapy. But you also are going to have a relatively low rate of complete response. It’s always important to have that discussion with patients early on.

Fortunately, however, the 18-month duration of response was 85% for acalabrutinib. So even though most of these patients achieved a partial response or less, less than 15% of [patients who] responded ultimately progressed within the first year and a half.

Looking specifically at PFS in the high-risk group, regardless of whether the patients had del(17p), those patients in the acalabrutinib arm did better than their counterparts. This was similarly observed in patients with IGHV mutation.

Although this is a relatively short follow-up, it is encouraging to see that even in this high-risk group of patients, this agent is highly active with durable remissions.

How did the subgroups fare in this trial?

Patients with del(17p), a TP53 mutation, or an IGHV mutation all did better in the acalabrutinib arm compared with the control arm. Similarly, looking at other demographics and baseline studies, acalabrutinib was favored.

What did the safety profile of acalabrutinib reveal?

Looking at the AEs [adverse effects] of clinical interest, across the board, there was a high rate of AEs. But the rate of grade 3 or higher AEs was lower in the acalabrutinib-treated patients compared with the idelalisib-treated patients. [Further], AEs were comparable with BR, although this was a smaller number of patients. As we saw previously, the rate of atrial fibrillation with acalabrutinib in a number of different studies appears to be lower than what’s been reported with ibrutinib, although you do continue to see some hemorrhage.

Overall, acalabrutinib was either equally or favorably compared with the other arms. It still is important to recognize that as well tolerated as this agent is, toxicity remains, some of which may be mild and not life-threatening but can certainly be annoying for patients. So these patients will still require ongoing monitoring and supportive care. Up to 15% of patients ultimately had to discontinue the drug because of AEs, although that is less than what we see, for example, with idelalisib.

How did ibrutinib (Imbruvica) fare when compared with chlorambucil?

Ibrutinib was compared with chlorambucil in the frontline setting in a randomized trial that also involved ofatumumab [Arzerra; NCT01578707].⁴ As a reminder, when these studies were first developed, there weren’t a lot of great options in the relapse setting for CLL. So there weren’t necessarily great comparator arms to choose from. But in this case, patients received ofatumumab, and they could potentially cross over to ibrutinib.

The patients had to have been previously treated and were stratified according to whether they were refractory to a purine analogue, such as fludarabine.

The outcomes show that patients in the ibrutinib arm significantly outperformed those in the ofatumumab arm. Results from a follow-up that was published last year show that the median PFS after 6 years of follow-up still has not been reached for the ibrutinib arm compared with ofatumumab.5 This signifies that ofatumumab is not a great drug. But typically you would still expect patients to have some duration of response with a CD20 antibody, and it speaks to the fact that these were beat-up patients, many of whom were refractory to other options.

How did patients with aberrations do in the ibrutinib arm?

For patients with high-risk features who were treated with ibrutinib, regardless of whether they had an IGHV [mutation], it did make a big difference. Similarly, if you had a del(17p), del(11q), or neither, outcomes were similar. Now, those who had del(17p) did worse than those who did not have del(11q) or del(17p).

How does venetoclax (Venclexta) compare with BR?

We can look to the MURANO trial [NCT02005471], which was a randomized trial of venetoclax and rituximab versus BR.⁶ This trial included patients who had had 1 to 3 prior lines of therapy. In addition, patients were stratified based on del(17p) status.

There was an improvement in PFS for those patients who received venetoclax versus those who received BR. The investigators also reported an improvement in overall survival that is statistically significant, although it was a fairly modest improvement. But what is impressive is that this was statistically significant early on.

In the subgroup analysis, I would emphasize that regardless of whether a patient had del(17p), the venetoclax-containing arm outperformed the BR arm. Many of these oral therapies are much more active in these high-risk patients compared with conventional chemotherapy.

The preplanned analysis that was published in the New England Journal of Medicine highlighted the improved overall response rate.⁷ There were also some improvements in the complete remission rate as well as minimal residual disease status.

A review of the AEs indicates that oncologists need to be aware of neutropenia. That is something that tends to continue throughout treatment. There was a relatively low rate of tumor lysis syndrome. I think that is because we’ve become good at identifying high-risk patients and managing [their care] appropriately. You do see that there’s Richter transformation in both arms, but it doesn’t appear to be significant.

_References:

_{1. NCCN. Clinical Practice Guidelines in Oncology. Chronic lymphocytic leukemia/small lymphocytic leukemia, version 4.2020. Accessed June 25, 2020. nccn.org/professionals/physician_gls/pdf/cll.pdf}

_{2. 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}

_{3. Ghia P, Pluta A, Wach M, et al. Acalabrutinib (Acala) versus idelalisib plus rituximab (IdR) or bendamustine plus rituximab (BR) in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL): ASCEND final results. J Clin Oncol. 2020;38 (suppl 15):8015. doi:10.1200/JCO.2020.38.15_suppl.8015}

_{4. Burger JA, Barr PM, Robak T, et al. Long-term efficacy and safety of firstline ibrutinib treatment for patients with CLL/SLL: 5 years of follow-up from the phase 3 RESONATE-2 study. Leukemia. 2020;34(3):787-798. doi:10.1038/s41375-019-0602-x}

_{5. 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}

_{6. Seymour JF, Kipps TJ, Eichhorst 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}

_{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}