Recap: Noninferiority Comparison of Acalabrutinib and Ibrutinib for Previously Treated CLL


Michael R. Bishop, MD, and Bruce B. Bank, MD, review results from the ELEVATE-RR noninferiority trial on acalabrutinib versus ibrutinib in CLL, and discuss the clinical implications of the findings.

For years, ibrutinib (Imbruvica) was the foremost standard-of-care Bruton tyrosine kinase (BTK) inhibitor for the treatment of patients with previously treated chronic lymphocytic leukemia (CLL), following its approval in 2014 based on results of the phase 3 RESONATE trial (NCT01578707).1 Following on its heels was the second-generation agent acalabrutinib (Calquence),2 opening a debate over whether or not one agent was superior to the other in the treatment of relapsed/refractory CLL.

Recently, Michael R. Bishop, MD, director of The David and Etta Jonas Center for Cellular Therapy at University of Chicago Medicine and a member of the Lymphoma Program at the University of Chicago, sat down for a discussion with Bruce B. Bank, MD, of Northwest Oncology and Hematology in Rolling Meadows, Illinois, to discuss a head-to-head phase 3 study of ibrutinib vs acalabrutinib in patients with previously treated CLL. The event was an installment of the CancerNetwork® Between The Lines series, and it focused on results published in the Journal of Clinical Oncology in July 2021.3

Overview of CLL

The conversation began with the experts discussing the characteristics of a typical patient presenting to their respective practices.

“A typical patient [in my practice has] normal complete blood count results
except for a slightly elevated white blood cell count, maybe in the range of 15 to 20 [× 109/L], and an automated differential that will show a slight preponderance of lymphocytes,” Bank said.

Bishop noted that physicians often ask him about optimal timing of treatment initiation for patients with CLL.

“I’ve always found this to be a very vexing question,” Bank said. “What I find is that you know some patients [need to] start therapy, and then you know [some] patients don’t need therapy. Then, there are quite a few patients in the gray zone.”

Patients who clearly need to begin therapy, Bank continued, include those showing signs of hemolytic anemia, significant autoimmune cytopenias, or bone marrow failure, as well as those who have symptomatic lymphadenopathy or abdominal organomegaly. But one “vexing” situation might occur when a patient does not feel ill but has an elevated white blood cell count of 150 to 200 × 109/L, and both the patient and their referring physician are anxious to begin treatment. Symptomatic anemia and generalized fatigue are other markers.

“We have data to back up that some patients develop fatigue even without much lymphadenopathy or cytopenia,” said Bishop. “It’s always difficult to figure out, because these are usually older patients who have a half-dozen other possible reasons for being fatigued. If I don’t find any other good reason, I think that’s a possible reason to initiate treatment.”

Next, Bishop asked Bank about his preferences in treatment modalities.

“When you do treat, what is your go-to therapy, or does it depend upon the patient and what the roles of Bruton tyrosine kinase inhibitors are in your clinical practice?” Bishop asked.

The treatment depends on the patient, Bank responded. Patients with “aggressive” disease, which Bank specified meant those with a high symptom burden including cytopenias and lymphadenopathy, may receive R-CHOP (rituximab [Rituxan], cyclophosphamide, doxorubicin, vincristine, and prednisone) therapy if they have PET avidity in the lymph nodes.

“For the more common presentation of a patient who requires treatment, BTK inhibitors are the best way to start,” Bank said.

Acalabrutinib vs Ibrutinib

In an open-label phase 3 noninferiority trial (NCT02477696) with results published by John C. Byrd, MD, of the University of Cincinnati College of Medicine, and colleagues, 533 patients with previously treated CLL and centrally confirmed deletion 17p or 11q were randomly assigned to receive either acalabrutinib (n = 268) at a dose of 100 mg twice daily or ibrutinib (n = 265) at a dose of 420 mg once daily. The main outcome was independent review committee–assessed noninferiority of progression-free survival (PFS).

At a median follow-up of 40.9 months, the median PFS was 38.4 months in both the acalabrutinib (95% CI, 33.0-38.6) and ibrutinib (95% CI, 33.0-41.6) arms (HR, 1.00; 95% CI, 0.79-1.27).

“When we looked at the number of events and follow-up, we saw strikingly similar results in terms of median PFS,” Bishop said, adding that investigator-
assessed outcomes were “nearly identical” to those determined by the independent review committee.

Neither arm reached median overall survival, with slightly more deaths
reported in the ibrutinib group (27.5%) vs the acalabrutinib group (23.5%; HR, 0.82; 95% CI, 0.59-1.15).

Patients assigned to acalabrutinib experienced fewer instances of atrial fibrillation or atrial flutter of any grade (9.4% vs 16.0%; P = .02), according to the investigators. Both groups experienced similar rates of grade 3 or higher infections at 30.8% for acalabrutinib vs 30.0% for ibrutinib. Fewer patients assigned to acalabrutinib discontinued treatment in response to adverse events (AEs) compared with the ibrutinib group, at 14.7% vs 21.3%, respectively. Further, cardiac events of any grade leading to discontinuation occurred in 0.8% (n = 2) of patients in the acalabrutinib group compared with 4.2% (n = 11) in the ibrutinib group. The groups showed similar rates of infection, with 82 patients (30.8%) in the acalabrutinib group and 79 patients (30.0%) in the ibrutinib group experiencing grade 3 or higher events.

The investigators wrote that 17 patients (6.4%) died of AEs in the acalabrutinib group compared with 25 (9.5%) in the ibrutinib group.

“I didn’t necessarily have any reason to believe that acalabrutinib was inferior or better than ibrutinib, because we do see target specificity play a role in that in other situations,” said Bank. “But I understand that for this trial, the real thrust was to try to minimize AEs and toxicities.”

In response to Bishop’s question about his go-to BTK inhibitor in practice, Bank replied, “Right now, it’s acalabrutinib.”

Bishop next asked Bank whether he had seen AEs like those in the study during his clinical practice, specifically regarding arthralgias, which occurred in 15.8% of patients on acalabrutinib and 22.8% on ibrutinib, and upper respiratory infections at rates of 26.7% and 24.7%, respectively.

“Yes, although I must confess that I have not been sensitive to arthralgias as an AE until now,” Bank said. “My experience is that a lot of patients complain of arthralgias. I tend to think it has something to do with being older and having degenerative disease. [However, I have not] seen many upper respiratory infections in my patients.”

Near the end of the discussion, Bishop asked Bank what he felt was his biggest takeaway from the study.

“It’s the [rates of] atrial fibrillation,” Bank said. “I have quite a few patients on acalabrutinib now and none of them has developed atrial fibrillation. To me, that has always been the main takeaway, and I don’t have any question in my mind that it’s a superior drug to ibrutinib, even though ibrutinib paved the way for this class of drugs.”

The discussion ended with Bishop asking Bank about unmet needs in CLL.

“In my opinion, many trials for CLL are guilty of focusing on data that [strictly emphasize] molecular complete remission vs clinically relevant complete remission [CR],” said Bank. “The unmet need is to be able to use the criteria from bone marrow studies. [In other words], if [those trials measure success by] strict molecular remission to guide further therapy, can we stop therapy for those patients?”

Furthermore, Bank said there was the possibility of a cure for CLL. He
recalled one patient he began seeing nearly
25 years ago who today is disease free.

“Most people in academics to whom I’ve spoken agree that a small percent of patients may be curable,” Bank concluded. “I would like to know what those criteria [for calling a patient ‘cured’] are. Just as with my patients, these patients who have been on ibrutinib now for 5 years and are in CR, I’d like to know whether we could stop the ibrutinib.”


  1. Imbruvica (ibrutinib) receives regular approval by U.S. FDA in chronic lymphocytic leukemia (CLL) and CLL patients with del 17p. News release. Johnson & Johnson; July 28, 2014. Accessed May 18, 2022.
  2. Project Orbis: FDA approves acalabrutinib for CLL and SLL. FDA. November 21, 2019. Accessed May 18, 2022.
  3. 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
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