BTK Inhibitors Represent the Preferred Frontline Regimen in CLL


The majority of patients with newly diagnosed chronic lymphocytic leukemia have better outcomes with BTK inhibitors compared with standard chemoimmunotherapy, making them the logical choice for frontline therapy.

Susan O’Brien, MD

Susan O’Brien, MD

The majority of patients with newly diagnosed chronic lymphocytic leukemia (CLL) have better outcomes with BTK inhibitors compared with standard chemoimmunotherapy, making them the logical choice for frontline therapy, explained Susan O’Brien, MD, in a virtual debate-style presentation during the 2021 Pan Pacific Lymphoma Conference.1

The first study results that support this stance came from the phase 3 RESONATE-2 trial (NCT01722487), which compared ibrutinib (Imbruvica) with chlorambucil in patients aged 65 years or older with treatment-naïve disease. With the longest follow-up of any BTK inhibitor trial in CLL, now out to 7 years, the results showed that the median progression-free survival (PFS) had not been reached with ibrutinib. Moreover, at 6.5 years, 61% of patients on ibrutinib were progression free and alive vs 9% of patients on chlorambucil.2

“Very importantly, the patients with 11q deletion [del(11q)] appear to be doing somewhat better [with ibrutinib vs chlorambucil] and they’re certainly not looking like a high-risk group. Additionally, there’s no difference in outcome by mutation status still with 7 years of follow-up,” said O’Brien, the associate director for Clinical Research in the Chao Family Comprehensive Cancer Center and the medical director of the Sue and Ralph Stern Center for Cancer Clinical Trials and Research at UC Irvine Health, in the debate-style presentation during the conference.

Even the highest-risk patients with TP53 aberrations appear to derive significant benefit with ibrutinib, said O’Brien, who cited data from a pooled analysis that reflected a 4-year PFS rate of 79%.3

“Venetoclax [Venclexta] is nowhere near as good [as ibrutinib] in this population,” O’Brien, who is also a professor in the Divison of Hematology/Oncology of the Department of Medicine at UC Irvine Health, added during the debate-style presentation.

Patients with del(11q) represent another historically high-risk group. However, these patients too experience benefit with frontline ibrutinib, said O’Brien, who called attention to an integrated analysis of more than 1,000 patients that showed that those with del(11q) experienced a 42-month PFS rate of 70% vs 65% in those without del(11q) (P =.02).4

“Not only is del(11q) not unfavorable anymore, but it’s actually favorable with ibrutinib,” said O’Brien. “[TP53 and del(11q)] are two high-risk subsets that are not really high risk anymore [with BTK inhibitors], which is important.”

The phase 3 ELEVATE-TN trial (NCT02475681) is another example of why BTK inhibitors should be used up front, explained O’Brien. The study randomized patients to acalabrutinib (Calquence) alone, acalabrutinib plus obinutuzumab (Gazyva), or obinutuzumab plus chlorambucil.

The 4-year PFS rate was 78% with acalabrutinib monotherapy, 87% with acalabrutinib plus obinutuzumab, and 25% with obinutuzumab plus chlorambucil.5 Among patients with 17p deletion del(17p) and/or mutated TP53, the 4-year PFS rates were 76%, 75%, and 18%, respectively. Among patients with unmutated IGHV, the 4-year PFS rates were 77%, 86%, and 4%, respectively.

Acknowledging that chemoimmunotherapy is not the only alternative to BTK inhibitors, O’Brien turned her attention to the phase 3 CLL14 trial (NCT02242942), which compared venetoclax plus obinutuzumab with chlorambucil plus obinutuzumab.

Although time-limited therapy has garnered significant interest as an alternative to continuous treatment with BTK inhibitors, O’Brien explained that she is not as convinced that it’s such a home run, particularly in terms of efficacy.

According to updated results of the CLL14 trial, the 4-year PFS rate was 74.0% with venetoclax/obinutuzumab vs 35.4% with chlorambucil/obinutuzumab (HR, 0.33; 95% CI, 0.25-0.45; P < .0001).6

Although O’Brien said that the overall PFS looks “pretty good” at 4 years, when broken by TP53 and IGHV status, it becomes apparent that patients with TP53 aberrations and unmutated IGHV perform significantly worse with venetoclax/obinutuzumab than the same populations on BTK inhibitors, explained O’Brien.

In CLL14, patients with TP53 aberrations and unmutated IGHV experienced a median PFS of 49.0 months and 57.3 months, respectively.

“The 4-year PFS for del(17p) on ibrutinib is 79%, which is a heck of a lot better than what [we’re seeing with venetoclax/obinutuzumab],” said O’Brien.

Moreover, although patients with unmutated IGHV did “pretty well” with venetoclax/obinutuzumab at 4 years, the same population on acalabrutinib/obinutuzumab experienced a 4-year PFS rate of 86%.

“Patients who are treated with venetoclax/obinutuzumab have a shorter PFS if they are [IGHV] unmutated, which includes most del(11q) patients, and an even shorter PFS if they have a p53 aberration,” said O’Brien.

In conclusion, O’Brien stated, “the vast majority of patients with CLL who need therapy will have better outcomes with a BTK inhibitor.”


  1. O’Brien S. Should BTKi be the preferred frontline regimen in CLL? Of course! Presented at: 2021 Pan Pacific Lymphoma Conference; August 9-13, 2021; Big Island, HI.
  2. Barr PM, Owen C, Robak T, et al. Up to seven years of follow-up in the RESONATE-2 study of first-line ibrutinib treatment for patients with chronic lymphocytic leukemia. J Clin Oncol. 2021;39(suppl 15):7523. doi:10.1200/JCO.2021.39.15_suppl.7523
  3. Ahn IE, Shanafelt T, Wiestner A, et al. Long-term efficacy of first-line (1L) ibrutinib (Ibr) treatment after 4 years of follow-up in patients (pts) with TP53 aberrant chronic lymphocytic leukemia (CLL): a pooled analysis of 4 trials. Presented at: 25th Annual International Congress on Hematologic Malignancies; February 24-27, 2021; virtual. Abstract 9.
  4. Kipps TJ, Fraser G, Coutre SE, et al. Long-term studies assessing outcomes of ibrutinib therapy in patients with del(11q) chronic lymphocytic leukemia. Clin Lymphoma Myeloma Leuk. 2019;19(11):715-722.e6. doi:10.1016/j.clml.2019.07.004
  5. Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib ± obinutuzumab versus obinutuzumab + chlorambucil in treatment-naïve chronic lymphocytic leukemia: Elevate-TN four-year follow up. J Clin Oncol. 2021;39(suppl 15):7509. doi:10.1200/JCO.2021.39.15_suppl.7509
  6. Al-Sawaf O, Zhang C, Robrecht S, et al. Venetoclax-obinutuzumab for previously untreated chronic lymphocytic leukemia: 4-year follow-up analysis of the randomized CLL14 study. Presented at: European Hematology Association 2021 Virtual Congress; June 9-17, 2021. Abstract S146.
Related Videos
Tycel Phillips, MD
Ajai Chari, MD
Alexey Danilov, MD, PhD
Hayder Saeed, MD
Jeremy L. Ramdial, MD, assistant professor, Department of Stem Cell Transplantation and Cellular Therapy, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center
Alexandra Gomez Arteaga, MD, Weill Cornell Medicine/New York-Presbyterian Hospital
Rahul Banerjee, MD, FACP, assistant professor, Clinical Research Division, Fred Hutchinson Cancer Center; assistant professor, Division of Hematology and Oncology, University of Washington
Alice Bertaina, MD, PhD
Jeffery Auletta, MD, The Ohio State University College of Medicine
Betty Hamilton, MD, Cleveland Clinic