Acalabrutinib With or Without Obinutuzumab Improved Survival for Previously Untreated CLL

The combination of acalabrutinib, with or without obinutuzumab, produced a strong survival benefit for patients with treatment-naïve chronic lymphocytic leukemia over treatment with ibrutinib or venetoclax plus obinutuzumab.

Compared with ibrutinib (Imbruvica) or venetoclax (Venclexta) plus obinutuzumab, a significant efficacy benefit was seen with acalabrutinib (Calquence), with or without obinutuzumab (Gazyva), for patients with treatment-naïve chronic lymphocytic leukemia (CLL), according to findings presented during the 63rd ASH Annual Meeting and Exposition.1

Matthew S. Davids, MD, MS, director of clinical research for the Division of Lymphoma with Dana Farber Cancer Institute and an associate professor of medicine at Harvard Medical School, presented the findings from a matching-adjusted indirect treatment comparison (MAIC).

“Both acalabrutinib-containing regimens were associated with a favorable safety profile compared with ibrutinib and venetoclax plus obinutuzumab in patients with treatment-naive CLL. Acalabrutinib plus obinutuzumab is also associated with a significant efficacy benefit compared with ibrutinib and venetoclax plus obinutuzumab,” said Davids. “Our findings provide insight into comparisons of acalabrutinib-based therapy with fixed-duration venetoclax plus obinutuzumab while we await data from the prospective phase 3 MAJIC trial [NCT05057494].”

Compared with ibrutinib, acalabrutinib monotherapy was associated with differences in PFS (HR, 0.83; 95% CI, 0.50-1.37; P = .454) and OS (HR, 0.69, 95% CI 0.37-1.29; = .247) that were numerically superior but not statistically significant. Investigators did not observe significant differences in PFS (HR, 0.96; 95% CI 0.56-1.65; P =.883) or OS (HR, 0.99; 95% CI 0.51-1.91; = .974) for acalabrutinib monotherapy vs venetoclax/obinutuzumab.

When comparing acalabrutinib/obinutuzumab vs ibrutinib, investigators did observe significant differences favoring the combination in PFS (HR, 0.48; 95% CI 0.27-0.88; = .017) and OS (HR, 0.41; 95% CI, 0.18-0.91; P ­= .029). Similarly, there were statically significant differences in PFS (HR, 0.38; 95% CI, 0.20-0.73; = .004) and OS (HR, 0.43; 95% CI 0.19-0.99; = .047) favoring acalabrutinib/obinutuzumab vs venetoclax/obinutuzumab.

Findings from the phase 3 ELEVATE-RR trial (NCT02477696) published online in July 2021 showed that acalabrutinib was noninferior to ibrutinib for progression-free survival (PFS) while inducing fewer cardiovascular adverse events (AEs).2 However, that trial did not include treatment-naïve patients. At ASH, Davids presented results based on findings from an earlier MAIC in treatment-naïve patients with CLL which demonstrated that acalabrutinib-based therapy had a favorable safety profile compared with other targeted therapies without compromising efficacy.3

“Compared with the previous MAIC, our analysis includes a longer duration of follow-up and a larger effective sample size, which provided sufficient power to test for significance in some of the comparisons,” he said.

Median follow-up duration increased from 28 months to 47 months for acalabrutinib with or without obinutuzumab, from 29 months to 38 months for ibrutinib, and from 29 months to 40 months for venetoclax/obinutuzumab.

Investigators used an unanchored MAIC methodology, and weighted independent patient data for the acalabrutinib-containing arms to match the aggregate baseline characteristics for the ibrutinib and venetoclax/obinutuzumab arms. Davids and his colleagues selected matching variables based on the literature, clinical judgment, and demonstrated statistically significant association with PFS, overall survival (OS), and grade 3 or higher AEs.

Individual patient data for the acalabrutinib/obinutuzumab arm from the ELEVATE-TN trial (47 months median follow-up) were weighted to match the aggregate baseline characteristics of the and the venetoclax/obinutuzumab arm from the CLL-14 trial (NCT02242942) and the ibrutinib monotherapy arm of the ALLIANCE trial (NCT03737981). Data from the ibrutinib plus rituximab (Rituxan) arm of ALLIANCE was not included because this treatment is not approved for CLL.

After matching to ibrutinib, 154 patients were assigned to acalabrutinib monotherapy and 146 were assigned to acalabrutinib/obinutuzumab. After matching venetoclax/obinutuzumab, 96 patients were assigned 96 acalabrutinib monotherapy and 104 acalabrutinib/obinutuzumab.

Compared with ibrutinib, Davids said there were statistically significant differences favoring the acalabrutinib arms for grade 3 or higher in rates for atrial fibrillation, hypertension, decreased neutrophil count, and decreased platelet count.

Compared with venetoclax/obinutuzumab, patients treated acalabrutinib monotherapy had significantly lower rates of febrile neutropenia (0.3% vs 5.2%), infusion-related reactions (0.0% vs 9.0%), leukopenia (0.0% vs 2.4%), neutropenia (9.0% vs 52.8%), nonmelanoma skin cancer (0.4% vs 8.0%), secondary primary malignancies excluding nonmelanoma skin cancer (3.0% vs 9.0%), and thrombocytopenia (2.2% vs 13.7%). Patients treated with the acalabrutinib combination had significantly lower rates of infusion-related reaction (1.4% vs 9.0%), leukopenia (0.2% vs 2.4%), neutropenia (29.1% vs 52.8%), and nonmelanoma skin cancer (1.3% vs 8.0%).

Davids cautioned that investigators could only adjust MAIC analysis for observed or published baseline characteristics across trials, so unadjusted cross-trial population differences may cause residual bias. Furthermore, the acalabrutinib and acalabrutinib/obinutuzumab are treat-to-progression regimens while venetoclax/obinutuzumab is a fixed-duration therapy. As a result, investigators could not account for differences in median duration of treatment. Finally, Davids and colleagues included relevant prognostic factors, but not all factors, to conserve the effective sample size.


  1. Davids MS, Mato A, Hum J, et al. Matching-adjusted indirect treatment comparison (MAIC) of acalabrutinib alone or in combination with obinutuzumab versus ibrutinib or venetoclax plus obinutuzumab in patients with treatment-naïve chronic lymphocytic leukemia. Presented at: 2021 ASH Annual Meeting; December 9-14, 2021; Atlanta, GA. Abstract 2633.
  2. Byrd JC, Hillmen P, Ghia P, et al. Acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia: results of the first randomized phase III trial. J Clin Oncol. 2021;39(31):3441-3452. doi: 10.1200/JCO.21.01210
  3. Davids MS, Telford C, Abhyankar S, et al. Matching-adjusted indirect comparisons of safety and efficacy of acalabrutinib versus other targeted therapies in patients with treatment-naïve chronic lymphocytic leukemia. Leuk Lymphoma. 2021;62(10):2342-2351. doi: 10.1080/10428194.2021.1913144