Commentary

Article

Acalabrutinib Yields Long-Term Efficacy in a Pooled Analysis of Higher-Risk CLL

Author(s):

Treatment with acalabrutinib-based regimens led to long-term benefits in patients with higher-risk CLL, across all lines of therapy.

Matthew S. Davids, MD, MMSc

Matthew S. Davids, MD, MMSc

Treatment with acalabrutinib (Calquence)–based regimens led to long-term efficacy in patients with chronic lymphocytic leukemia (CLL) with higher-risk genomic features, regardless of line of therapy, according to findings from a pooled analysis of 5 prospective clinical trials, which was published in Blood Advances.1

At a median follow-up of 59.1 months, 51.3% of patients with treatment-naive higher-risk CLL (n = 320) remained on treatment at the last follow-up. For patients in the 17p deletions/TP53 mutations, unmutated immunoglobulin heavy chain variable region genes (uIGHV), and complex karyotype subgroups, the median progression-free survival (PFS) and overall survival (OS) were both not reached (NR), respectively.

At a median follow-up of 44.3 months in patients with relapsed/refractory higher-risk CLL (n = 488), 26.8% of patients remained on treatment at the last follow-up. In the 17p deletions/TP53 mutations, uIGHV, and complex karyotype patient subgroups, the median PFS was 38.6 months, 46.9 months, and 38.6 months, respectively, and the median OS was 60.6 months, NR, and NR, respectively.

“Most clinical trials in CLL only include a limited number of patients with high-risk genetic markers such as del(17p) and/or TP53 mutation,” Matthew S. Davids, MD, MMSc, said to OncLive®. “Our study pools together data from 5 trials and demonstrates that continuous treatment with acalabrutinib provides durable response in these high-risk patients whether used as initial therapy or in the setting of relapsed disease, with excellent tolerability for most patients.”

Davids is an attending physician and the director of Clinical Research in the Division of Lymphoma, as well as the associate director of the CLL Center, at Dana-Farber Cancer Institute, and an associate professor of medicine at Harvard Medical School, both of which are located in Boston, Massachusetts.

Because patients with CLL who possess high-risk genomic features have gad historically inferior outcomes, there was an unmet medical need to be addressed in this patient population.2 However, targeted therapies, such as the second-generation BTK inhibitor acalabrutinib, have demonstrated efficacy for patients with these high-risk features in clinical trials.1

This pooled analysis included data from 5 clinical trials evaluating acalabrutinib alone or in combination with obinutuzumab in 808 patients with CLL with higher-risk genomic features, defined as 17p deletions/TP53mutations, uIGHV, and complex karyotype with at least 3 chromosomal abnormalities. In this analysis, patients were stratified by prior treatment status. The treatment-naive portion of the analysis included data from the treatment-naive cohorts of the phase 1/2 ACE-CL-001 (NCT02029443) and phase 3 ACE-CL-003 (NCT02296918) trials, as well as data from the phase 3 ELEVATE-TN trial (NCT02475681). The relapsed/refractory portion of the analysis included data from patients who had received at least 1 prior therapy for CLL in the ACE-CL-001, ACE-CL-003, phase 3 ELEVATE-RR (NCT02477696), and phase 3 ASCEND (NCT02970318) trials.

Across the 5 trials, all patients received acalabrutinib at 100 mg twice daily until progressive disease (PD) or unacceptable toxicity, except for some patients in ACE-CL-001 and ACE-CL-003 who initially received the agent at 200 mg once daily. Patients in the ACE-CL-003 trial and the acalabrutinib/obinutuzumab (Gazyva) arm of the ELEVATE-TN trial also received 6 cycles of obinutuzumab at a schedule of 100 mg on day 1, 900 mg on day 2, and 1000 mg on days 8 and 15 of cycle 2, followed by 1000 mg on day 1 of cycles 3 through 7. This pooled analysis excluded data from treatment arms of these trials in which patients received interventions other than acalabrutinib monotherapy or acalabrutinib plus obinutuzumab.

In the treatment-naive cohort of this analysis (n = 475), 20%, 90%, 25%, and 15% of patients had 17p deletions/TP53 mutations, uIGHV, complex karyotype overall, and complex karyotype without 17p deletions/TP53 mutations, respectively. In the relapsed/refractory cohort, these respective values were 45%, 87%, 33%, and 14%. In the higher-risk subgroup, baseline genetic status was generally similar between the treatment-naive and relapsed/refractory cohorts. However, as expected, there were relatively lower proportions of patients with 17p deletions/TP53 mutations and complex karyotype in the treatment-naive cohort compared with the relapsed/refractory cohort. Baseline characteristics between the higher-risk and lower-risk subgroups were generally similar in both cohorts; however, in the relapsed/refractory cohort, the median number of prior therapies was higher in the higher-risk subgroup than in the lower-risk subgroup.

In the treatment-naive cohort, the most common reason for treatment discontinuation was treatment-emergent adverse effects (TEAEs; 13.8%); additionally, 8.1% of patients discontinued treatment because of disease progression. In the relapsed/refractory cohort, the most common reason for treatment discontinuation was disease progression (30.5%), and 16.6% of patients discontinued treatment because of TEAEs.

In the patients with treatment-naive, lower-risk CLL, the median follow-up was 61.0 months. In this cohort, the most common reason for treatment discontinuation after following study closure was TEAEs (14.8%). In the patients with relapsed/refractory, lower-risk disease, the median follow-up was 48.6 months. In this cohort, the most common reasons for treatment discontinuation after study closure were disease progression and TEAEs (19.6% each).

In the treatment-naive cohort, the respective overall response rates (ORRs) in the higher-risk and lower-risk patient subgroups were 95.0% and 92.3%. Investigators observed no statistically significant difference in PFS between the lower-risk and higher-risk subgroups or between the lower-risk patients and patients with uIGHV, complex karyotype, or complex karyotype without 17p deletions/TP53 mutations. However, the median PFS was significantly shorter in patients with 17p deletions/TP53 mutations compared with lower-risk patients. Moreover, no statistically significant OS differences were observed between the lower-risk and higher-risk subgroups or between the lower-risk patients and patients with 17p deletions/TP53 mutations.

The ORR for treatment-naive patients with 17p deletions/TP53 mutations was 90.6%, including a 23.4% complete response (CR) rate. In this patient subgroup, the median PFS was NR, and the 48-month PFS rate was 76.9%. The median PFS was significantly shorter in patients with 17p deletions/TP53 mutations than in those without these alterations (HR, 2.02; 95% CI, 1.20-3.26; P = .0046). The 48-month OS rate was 88.6%. Investigators observed no statistically significant OS difference in patients with vs without 17p deletions/TP53mutations (HR, 1.75; 95% CI, 0.83-3.36; P = .1099).

The ORR for treatment-naive patients with uIGHV was 95.8%, including a 19.9% CR rate. In this patient subgroup, the median PFS was NR, and the 48-month PFS rate was 85.6%. No statistically significant PFS difference was observed in treatment-naive patients with uIGHV vs mutated IGHV (mIGHV; HR, 1.44; 95% CI, 0.93-2.28; P = .1086). The 48-month OS rate was 93.5%. Investigators observed no statistically significant OS difference in patients with uIGHV vs mIGHV (HR, 0.89; 95% CI, 0.51-1.58; P = .6804).

The ORR for treatment-naive patients with complex karyotype was 91.1%, including a 19.0% CR rate. In this overall patient subgroup, the median PFS was NR, and the 48-month PFS rate was 84.1%. In the subset of patients with complex karyotype without 17p deletions/TP53 mutations, the 48-month PFS rate was 92.7%. No statistically significant PFS difference was observed in treatment-naive patients with vs without complex karyotype (HR, 1.45; 95% CI, 0.85-2.35; P = .1487). The 48-month OS rate was 90.6%. Investigators observed no statistically significant OS difference in patients with vs without complex karyotype (HR, 1.50; 95% CI, 0.73-2.83; P = .2325).

In the relapsed/refractory cohort, the respective ORRs in the higher-risk and lower-risk patient subgroups were 87.2% and 84.9%. The median PFS was significantly shorter in the higher-risk subgroup vs the lower-risk subgroup, as well as in the patients with 17p deletions/TP53 mutations, uIGHV, or complex karyotype vs the lower-risk subgroup. However, no significant PFS difference emerged between the lower-risk patients compared with the patients with complex karyotype without 17p deletions/TP53 mutations. Moreover, the median OS was significantly shorter in the higher-risk subgroup and the subgroup of patients with 17p deletions/TP53 mutations vs lower-risk patients.

The ORR for relapsed/refractory patients with 17p deletions/TP53 mutations was 86.0%, including a 5.1% CR rate. In this patient subgroup, the 36-month PFS rate was 54.4%. Like in the treatment-naive cohort, the median PFS was significantly shorter in relapsed/refractory patients with 17p deletions/TP53 mutations than in those without these alterations (HR, 2.34; 95% CI, 1.81-3.03; P < .0001). The 36-month OS rate was 72.5%. In patients with 17p deletions/TP53 mutations, the median OS was significantly shorter than in those without 17p deletions/TP53 mutations (HR, 2.84; 95% CI, 1.98-4.12; P < .0001).

The ORR for relapsed/refractory patients with uIGHV was 87.3%, including a 7.8% CR rate. In this patient subgroup, the 36-month PFS rate was 64.6%. The median PFS was significantly shorter in relapsed/refractory patients with uIGHV than in those with mIGHV (HR, 1.71; 95% CI, 1.25-2.37; P = .0009). The 36-month OS rate was 82.0%. Like in the treatment-naive cohort, there was no statistically significant OS difference in patients with uIGHV vs mIGHV (HR, 1.22; 95% CI, 0.81-1.88; P = .3549).

The ORR for relapsed/refractory patients with complex karyotype was 83.6%, including a 10.3% CR rate. In this overall patient subgroup, the 36-month PFS rate was 55.7%. In the subset of patients with complex karyotype without 17p deletions/TP53 mutations, the 36-month PFS rate was 68.4%. The median PFS was significantly shorter in relapsed/refractory patients with vs without complex karyotype (HR, 1.74; 95% CI, 1.31-2.29; P < .0001). The 36-month OS rate was 77.4%. The OS was significantly shorter in patients with vs without complex karyotype (HR, 1.51; 95% CI, 1.02-2.21; P = .0339).

In a multivariable analysis of the treatment-naive patient cohort, the combined presence of 17p deletions/TP53mutations, uIGHV, and complex karyotype was significantly associated with a shorter median PFS. However, none of the 3 genomic features were significantly associated with a shorter median OS.

In a multivariable analysis of the relapsed/refractory patient cohort, the combined presence of 17p deletions/TP53 mutations and uIGHV, as well as the presence of all 3 genomic features, were significantly associated with a shorter median PFS. Furthermore, the presence of 17p deletions/TP53 mutations alone, 17p deletions/TP53 mutations combined with uIGHV, or the presence of all 3 genomic features, was significantly associated with a shorter median OS.

In both the treatment-naive and relapsed/refractory cohorts, patients with higher-risk disease received a median of 1 subsequent line of therapy. In the treatment-naive cohort, the most common subsequent therapies consisted of either chemotherapy-based and/or immunotherapy-based treatment (4.7%), as well as targeted therapies (2.8%). In the relapsed/refractory cohort, the most common subsequent therapies were targeted therapies (14.3%) and chemotherapy- and/or immunotherapy-based treatment (7.2%).

The safety profile of acalabrutinib-based therapy was consistent with the known safety profile of the agent in a broader CLL population across these higher-risk patient populations. In the treatment-naive and relapsed/refractory patient cohorts, the respective median durations of treatment exposure were 59.3 months and 39.1 months. Across the entire study population, 70.3% of patients experienced at least 1 TEAE of grader 3 or higher. The most common grade 3 or higher TEAEs recorded include neutropenia, pneumonia, anemia, thrombocytopenia, and hypertension, which were seen in 19.3%, 9.5%, 8.4%, 6.2%, and 5.4% of patients, respectively. Any-grade TEAEs leading to treatment discontinuation occurred in 16.5% of patients, the most common of which were pneumonia (0.9%) and thrombocytopenia (0.6%). The most common AEs of clinical interest were infections (any-grade, 78.3%; grade ≥ 3, 28.5%) and neutropenia (23.9%; 22.3%). Furthermore, investigators observed atrial fibrillation/flutter (any-grade, 7.4%; grade ≥ 3, 2.6%) and hemorrhage (45.7%; 4.2%). The safety profile of acalabrutinib-based therapy in the lower-risk subgroup was similar to that in the higher-risk subgroup in the treatment-naive and relapsed/refractory cohorts.

In the treatment-naive cohort, deaths occurred in 10.6% of patients; the most common cause of death was AEs (5.9%). In the relapsed/refractory cohort, deaths occurred in 23.4% of patients, most commonly due to AEs (11.7%). In the treatment-naive and relapsed/refractory cohorts, the most common cause of death from an AE per system organ class was infections and infestations, at 2.2% and 5.7%, respectively. The most common infection and infestation event in the treatment-naive and relapsed/refractory cohorts was COVID-19 (0.9%) and pneumonia (1.6%), respectively. Death due to PD occurred in 0.9% and 6.8% of patients in the treatment-naive and relapsed/refractory cohorts, respectively. Death from Richter transformation was uncommon, occurring in 1 and 6 patients in the treatment-naive and relapsed/refractory cohorts, respectively.

“Our data continue to support the approach of continuous acalabrutinib as a highly effective and well tolerated option for treating a broad population of patients with CLL, particularly those with higher-risk genetic features,” the authors concluded. “However, treatment optimization in patients with 17p deletions/TP53 mutations is still an urgent unmet need, particularly in the relapsed/refractory setting.”

References

  1. Davids MS, Sharman JP, 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 April 19, 2024. doi:10.1182/bloodadvances.2023011307
  2. Hallek M, Cheson BD, Catovsky D, et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood. 2018;131(25):2745-2760. doi:10.1182/blood-2017-09-806398
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