Acalabrutinib-Based Regimens Demonstrate Long-Term Benefits Among Higher-Risk Patients With CLL

Matthew Davids, MD, Dana-Farber Cancer Institute, Boston, Massachusetts, discusses results from a pooled analysis of 5 clinical trials of acalabrutinib as monotherapy or in combination with obinutuzumab (ACE-CL-001, ACE-CL-003, ELEVATE-TN, ELEVATE-RR, and ASCEND) among patients with higher-risk chronic lymphocytic leukemia (CLL) in treatment-naive or relapsed/refractory (R/R) cohorts.

“Overall, our results do confirm the long-term benefit of acalabrutinib-based regimens in CLL in higher-risk patients. I think this is a great option for our patients regardless of line of therapy in CLL,” concluded Dr Davids.

Transcript:

Hello, I'm Dr. Matthew Davids, the Clinical Research Director in the Division of Lymphoma at Dana-Farber Cancer Institute and an Associate Professor of Medicine at Harvard Medical School in Boston. I'll be summarizing our recent publication looking at acalabrutinib-based regimens in frontline or relapsed/refractory higher-risk chronic lymphocytic leukemia (CLL).

This is the pooled analysis of 5 clinical trials. The inspiration for developing this work was that typically high-risk patients are a relative minority, especially in the frontline treatment setting in CLL. There are several different studies that do include these patients, but in any [singular] study, it's hard to draw any larger conclusions.

Our goal was to pool together data from 5 different clinical trials to generate a larger data set that we could use to look in a more detailed way at the long-term outcomes with acalabrutinib-based therapy. In total, we had 808 patients. This included a mix of patients with treatment-naive CLL (320) and patients with relapsed/refractory CLL (488).

These patients had a mix of different prognostic markers. In this study, we defined higher-risk CLL as either TP53 aberration, which can be deletion 17 by fluorescence in situ hybridization (FISH) or somatic mutation in TP53, unmutated immunoglobulin heavy chain variable region (IGHV), or complex karyotype defined as 3 or more cytogenetic abnormalities. The follow-up in the study is relatively long at close to 5 years in the treatment-naive group and about 3.5, almost 4 years in the relapsed/refractory group.

Across the different groups, the overall response rates were quite high in the 90 to 95% range, regardless of which of the different genetic factors were examined. Probably the most valuable aspect in my opinion is the progression-free survival (PFS) and overall survival (OS) analyses in this study. Let's start with the treatment-naive cohort.

In this group, the patients with TP53 aberration did have a slightly shorter PFS than those without, in the range of about 76 to 78% versus more like 85 to 90% in the patients without this high-risk abnormality. However, there were no differences in overall survival based on these different genetic factors in the treatment-naive group. In the relapsed/refractory group, the PFS rates were shorter, as we would expect.

At 36 months, the PFS rate was 54% in those patients with high genetic risk, TP53 aberration, which was a little bit shorter than the 65% with unmutated IGH, and 56 % in patients with complex karyotype. One of the more striking findings of the study is that patients with this high-risk TP53 aberration did have a shorter overall survival in this relapse setting, 73% at 3 years compared to 82% in the patients with unmutated IGHV. We also looked at the safety profile of acalabrutinib across these different cohorts and it was quite similar to what’s been reported previously. There were no differences in the safety profile based on the different genetic markers.

Overall, we concluded that the PFS and OS rates are high with acalabrutinib-based regimens in this higher-risk CLL population, both in the frontline and the relapsed/refractory setting. The safety profile also appears to be similar to what we’ve previously seen in other studies. Overall, I think our results do confirm the long-term benefit of acalabrutinib-based regimens in CLL in higher-risk patients. I think this is a great option for our patients regardless of line of therapy in CLL. Thank you.

Source:

Davids M, Sharman J, Ghia P, et al. Acalabrutinib-based regimens in frontline or relapsed/refractory higher-risk CLL: Pooled analysis of 5 clinical trials. Blood Adv. Published online June 26, 2024. doi: 10.1182/bloodadvances.2023011307