BTK Inhibition in CLL: An Embarrassment of Riches

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Chronic lymphocytic leukemia (CLL) is a B-cell lymphoproliferative disorder defined by a specific phenotype and the presence of more than 5,000 clonal B cells in the peripheral blood.1 In the absence of this number of circulating cells, its soft-tissue/bone-marrow counterpart is semantically referred to as small lymphocytic lymphoma.1 It is a disorder with a median age at diagnosis in the late 60s to early 70s. Though a proportion of individuals with this disorder may never need therapy, many will at some time require treatment to minimize disease burden or place the illness into clinical remission.

Gregory Bociek, MD, MSc

Gregory Bociek, MD, MSc

It can be argued that medicine has always been “personalized” from the standpoint of choosing a treatment that is most palatable to and most likely to benefit a particular individual patient. Advances in understanding the biology of CLL have come from decades of research on molecular/genetic drivers of the illness and how they predict responses to therapy. Prognostic factors such as the presence of somatic hypermutation of the variable region of the immunoglobulin heavy chain locus (IGHV mutation)2 and the use of fluorescence in situ hybridization cytogenetics3 helped identify some of the sources of wide heterogeneity seen in CLL, but before the dawn of targeted agents, they did less to assist in the choice of the somewhat limited available therapies.

A Host of Targeted Agents

The plethora of targeted agents we now have before us could be considered an embarrassment of riches relative to 20 years ago. One can make an argument that therapeutic choices for CLL are actually becoming less personalized because increasingly what is “good for the goose” may in fact also be “good for the gander.”

Ibrutinib is an orally bioavailable small molecule that was the first Bruton’s tyrosine kinase (BTK) inhibitor to secure U.S. Food and Drug Administration regulatory approval for B-cell malignancies—specifically, relapsed or refractory mantle cell lymphoma—in 2013,4 followed shortly thereafter by a similar designation/approval for CLL in 2014 based on a phase Ib/II trial in 85 patients.5 Nonrandomized trials began to demonstrate that targeted agents such as ibrutinib could, to some extent, overcome the poor prognostic variables associated with the inferior outcomes seen with chemoimmunotherapy regimens in those populations.6,7 The maturing randomized trials for targeted agents in both the upfront and relapsed settings have consistently demonstrated improved outcomes over chemoimmunotherapy regimens.8-10

The most clinically important toxicities/limitations of BTK as a target include the propensity to increase the risk of bleeding, the development of atrial arrhythmia, and hypertension.11 The demonstration that second-generation BTK agents appear to have fewer off-target kinase effects (eg, EGFR, TEC) gave investigators a hypothetical reason to hope that these newer agents might be associated with less toxicity; thus, there was a need for randomized trials with specified efficacy and toxicity endpoints to determine the degree to which these issues were clinically relevant. Acalabrutinib has demonstrated high response rates and tolerability in patients with CLL intolerant to ibrutinib, with 64% of patients not experiencing a recurrence of the adverse events they had with ibrutinib.12

ELEVATE-RR Trial: BTK Inhibitors Face Off

As reported by Byrd et al in the Journal of Clinical Oncology—and summarized in this issue of The ASCO Post—the ELEVATE-RR trial is the first randomized trial comparing acalabrutinib and ibrutinib as single agents in the relapsed/refractory setting.13 The trial was designed to demonstrate whether or not the purported greater degree of BTK selectivity with acalabrutinib could be translated into meaningful clinical endpoints—specifically, noninferior efficacy and improved tolerability.

Eligible subjects were aged 18 or older, had previously treated CLL, required therapy by International Workshop on CLL criteria, and had an appropriate Eastern Cooperative Oncology Group (ECOG) performance status plus high-risk genetics, such as del(17p) and/or del(11q), confirmed by central testing. Patients with significant cardiac disease, a concomitant need for warfarin or its equivalent, prior use of BTK/BCL2 inhibitors, or the need for a proton pump inhibitor were excluded. The trial was conducted as a multicenter open-label noninferiority study. Subjects were randomly assigned 1:1 to receive ibrutinib or acalabrutinib at label doses. Randomization was stratified by the presence of del(17p), ECOG performance status, and number of prior therapies. Study therapy was continued until disease progression or unacceptable toxicity.

The sample size provided 80% power to detect (by independent review committee) a prespecified noninferiority margin equating to a hazard ratio (HR) of 1.4 for the primary endpoint of progression-free survival, with a one-sided 0.025 significance level. Secondary endpoints were the incidence rates of atrial fibrillation, ≥ grade 3 infections, Richter’s transformation, and overall survival.

At a median follow-up of 40.9 months, the prespecified criterion of noninferiority was met: median progression-free survival was 38.4 months with acalabrutinib vs 38.4 months with ibrutinib (HR = 1.00, 95% confidence interval = 0.79–1.27), with 41% of those treated with ibrutinib and 46% of those given acalabrutinib remaining on therapy at data cutoff. Progression-free survival was comparable among all prognostic groups, and the median overall survival had not been reached at the time of data analysis.


The CHA2DS2-VASc score (essentially a modification of the older CHADS2 score) calculates stroke risk for patients with atrial fibrillation by assessing the following factors:

  • Age
  • Sex
  • Congestive heart failure history
  • Hypertension history
  • History of stroke, transient ischemic attack, thromboembolism
  • Vascular disease history (prior myocardial infarction, peripheral artery disease, or aortic plaque)
  • Diabetes history

With respect to safety, patients randomly assigned to ibrutinib reported/experienced more grade ³ 3 diarrhea (4.9% vs 1.1%) and hypertension (8.7% vs 4.1%). Considering any-grade toxicities, ibrutinib was associated with more diarrhea, arthralgias, reported contusions, atrial fibrillation, urinary tract infections, muscle spasms, and dyspepsia than acalabrutinib. There were no significant differences in the frequency of ≥ grade 3 infections or Richter’s transformation. Treatment discontinuation for adverse events occurred in 21% of subjects receiving ibrutinib and 15% of those receiving acalabrutinib. A similar duration of exposure was seen in each group, so this would not likely have confounded safety or efficacy outcomes.

Clinical Importance of Study Findings

The results of this trial are important for two reasons. First, at a minimum, the demonstration of noninferiority reasonably diminishes the uncertainty of efficacy differences. Second, the paradigm of indefinite therapy lends importance to both the cumulative incidence and chronicity/management of the expectable toxicities.

The choice of atrial fibrillation as a prespecified secondary endpoint reflects the recognized clinical importance of this toxicity, as most patients requiring these therapies will likely have CHA2DS2-VASc scores of 2 or greater—generally requiring anticoagulation at the onset of atrial fibrillation with the attendant risk of already being on a BTK inhibitor (see sidebar).

The twice-daily vs once-daily dosing might be considered a minor nuisance by some patients, and the gastric pH absorption sensitivity of acalabrutinib means that concurrent use of a proton pump inhibitor is not recommended with acalabrutinib. Both agents require dosing considerations in the setting of concurrent use with CYP3A inhibitors or inducers.

Another second-generation BTK inhibitor, zanubrutinib, has similarly been associated with a reduced incidence of toxicity in a randomized trial comparing it with ibrutinib in Waldenström’s macroglobulinemia.14 Ibrutinib certainly still affords us some continued comfort in the longevity of results and the convenience of once-a-day dosing. However, noninferiority in progression-free survival and improvement in some measures of tolerability make acalabrutinib another choice of therapy, as we continue to move the needle. 

DISCLOSURE: Dr. Bociek has served as a consultant or advisor for and is -employed by Innate Pharma.

Dr. Bociek is affiliated with the Division of Oncology and Hematology, University of Nebraska Medical Center, Omaha.


1. Hallek M, et al: IWCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood 131:2745-2760, 2018.

2. Hamblin TJ, et al: Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood 94:1848-1854, 1999.

3. Döhner H, et al: Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med 343:1910-1916, 2000.

4. Wang ML, et al: Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med 369:507-516, 2013.

5. Byrd JC, et al: Targeting BTK with ibrutinib in relapsed/refractory chronic lymphocytic leukemia. N Engl J Med 369:32-42, 2013.

6. Farooqui MZH, et al: Ibrutinib for previously untreated and relapsed or refractory chronic lymphocytic leukemia with TP53 aberrations. Lancet Oncol 16:169-176, 2015.

7. O’Brien S, et al: Ibrutinib for patients with relapsed or refractory chronic lymphocytic leukemia with 17p deletion (RESONATE-17). Lancet Oncol 17:1409-1418, 2016.

8. Woyach JA, et al: Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. N Engl J Med 379:2517-2528, 2018.

9. Shanafelt TD, et al: Ibrutinib-rituximab or chemoimmunotherapy for chronic lymphocytic leukemia. N Engl J Med 381:432-443, 2019.

10. Seymour JF, et al: Venetoclax-rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med 378:1107-1120, 2018.

11. Byrd JC, et al: Three-year follow-up of treatment-naive and previously treated patients with CLL and SLL receiving single-agent ibrutinib. Blood 125:2497-2506, 2015.

12. Awan FT, et al: Acalabrutinib monotherapy in patients with chronic lymphocytic leukemia who are intolerant to ibrutinib. Blood Adv 3:1553-1562, 2019.

13. Byrd JC, et al: Acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia. J Clin Oncol. July 26, 2021 (early release online).

14. Tam CS, et al: A randomized phase 3 trial of zanubrutinib vs ibrutinib in symptomatic Waldenström macroglobulinemia: The ASPEN study. Blood 136:2038-2050, 2020.

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