Questions With BTK Inhibitors and Anti-CD20 Combos Require Further Study in CLL

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Farrukh Awan, MD, discusses the rationale for combining BTK inhibitors with CD20-directed monoclonal antibodies in CLL, sequencing challenges, and remaining questions in the chronic lymphocytic leukemia.

Farrukh Awan, MD

BTK inhibitors, such as ibrutinib (Imbruvica) and acalabrutinib (Calquence), have dramatically changed the treatment landscape of chronic lymphocytic leukemia (CLL), said Farrukh Awan, MD. However, the utility of these agents in combination with CD20-directed monoclonal antibodies, such as obinutuzumab (Gazyva), has yet to be fully fleshed out.

In January 2019, the combination of ibrutinib and obinutuzumab became the first non-chemotherapy regimen to receive FDA approval as frontline therapy for patients with CLL. The approval was based on data from the phase III iLLUMINATE (PCYC-1130) trial, which showed a 77% reduction in the risk of progression or death with the combination compared with obinutuzumab plus chlorambucil (HR, 0.23; 95% CI, 0.15-0.37; P <.0001).1

Additionally, in November 2019, acalabrutinib received regulatory approval for the treatment of patients with CLL or small lymphocytic lymphoma. The approval was partially based on data from the phase III ELEVATE-TN trial.

Data from the trial, which were updated at the 2019 ASH Annual Meeting, demonstrated a 90% reduction in risk of progression or death with acalabrutinib/obinutuzumab versus obinutuzumab/chlorambucil in treatment-naïve patients with CLL (HR, 0.10; 95% CI, 0.06-0.17; P <.0001).2

In an interview during the 2020 OncLive® State of the Science Summit on Hematologic Malignancies, Awan, associate professor, Department of Internal Medicine, Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, discussed the rationale for combining BTK inhibitors with CD20-directed monoclonal antibodies in CLL, sequencing challenges, and remaining questions in the space.

OncLive: How are you deciding whether to give a patient a BTK inhibitor alone or in combination with a CD20-directed antibody?

We don't know what patient population [is best suited] for this approach. I have a discussion with all of my patients who I am contemplating starting on a BTK inhibitor and who are not enrolled on a clinical trial.

During that discussion, the first question I think about is, "What benefit could that patient derive from the addition of a CD20-directed antibody [to a BTK inhibitor]?"

Early data showed us that outcomes were not necessarily better with ibrutinib in combination with rituximab (Rituxan) versus ibrutinib alone. Instead, they were fairly similar. We automatically assumed that adding a CD20-directed antibody [to a BTK inhibitor] would elicit longer remissions for patients.

Conversely, in the CLL11 trial, obinutuzumab outperformed rituximab. As such, combination strategies with obinutuzumab made sense, at least as [part of] a clinical trial. There are emerging data that suggest a trend toward improved outcomes with the combination of obinutuzumab and acalabrutinib, and possibly with ibrutinib; however, we don't yet have the right trials to answer that specific question.

When would you utilize the combination of BTK inhibitor and a CD20-directed antibody?

I feel it is a very individualized decision. If the patient has high-risk features or if they may want to eventually stop therapy, I have a discussion with them about starting a CD20-directed antibody. That [regimen] allows patients the opportunity to achieve minimal residual disease (MRD)-negativity. I would be more confident about stopping therapy with the expectation that the patient's remission will be sustained for an extended period of time [with the combination].

[I would also consider this combination] for patients with high-risk disease features, such as 17p deletion. Those patients tend to do poorly compared with patients who do not harbor these abnormalities. Though, outcomes have improved significantly across that population of patients.

How do you sequence these agents?

Every trial seems to have done it in a different way. I feel that the risk of tumor lysis syndrome with acalabrutinib or ibrutinib in combination with a CD20-directed antibody, specifically obinutuzumab, is not that high.

However, obinutuzumab can cause significant infusion reactions, particularly during the first dose. Starting the patient on the BTK inhibitor a few days prior to starting them on obinutuzumab can substantially mitigate these infusion reactions as demonstrated in multiple studies. That is a tempting reason to start the BTK inhibitor therapy first and then follow it with the CD20-directed antibody.

Other studies are currently evaluating the timing of the CD20-directed antibody. Moreover, some data from Britain suggest that if we start the CD20-directed antibody later, patients may achieve deeper remissions.

Currently, we don't know what the best approach is, but that question is being actively addressed in multiple clinical trials. Hopefully, those data will lead to better answers in the future.

Do you think triplet or quadruplet regimens have a role in CLL, or will doublets remain the standard?

This is an extremely important question that is being addressed in multiple clinical trials. Can we combine 3 drugs and eventually stop treatment once a certain defined endpoint is met? For example, [the triplet] could be given in a time-limited fashion for 18 months. Perhaps patients could stop treatment after achieving MRD-negativity.

The triplet of acalabrutinib, venetoclax (Venclexta), and obinutuzumab is an example of a combination being explored in a clinical trial currently. Other trials from the cooperative groups in the United States are looking at others with similar endpoints.

The ultimate question is, "What does a patient gain from a 3-drug combination versus a 2-drug combination?" Yes, they will likely achieve a deeper remission, but would it allow them to stop therapy? If so, that would be a perfectly rational reason to use the triplet.

There are a number of other questions in this space regarding what would happen to patients long-term. What happens with the disease kinetics should the patient relapse? How would we then sequence therapy?

Additionally, a subset of patients receiving doublet regimens indefinitely will develop resistance to that treatment. This is especially true in the case of BTK inhibitors. Those patients have to be salvaged with BCL-2 inhibitors.

Alternatively, if we give all 3 agents upfront, what do we do if the patient relapses? The argument becomes that the therapy [should not be] stopped due to resistance, but rather because it was planned to be stopped. In theory, the 3 drugs should still work because the patient's disease is slowly coming back.

Of course, there are other trials combining different agents in an effort to answer these questions. It is an exciting problem to have because patient outcomes have improved significantly.


  1. Moreno C, Greil R, Demirkan F, et al. Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in first-line treatment of chronic lymphocytic leukemia (iLLUMINATE): a multicenter, randomized, open-label, phase 3 trial. Lancet Oncol. 2019;20(1):43-56. doi: 10.1016/S1470-2045(18)30788-5
  2. Sharman JP, Banerji V, Fogliatto LM, et al. ELEVATE-TN: phase 3 study of acalabrutinib combined with obinutuzumab (o) or alone vs o plus chlorambucil (clb) in patients (pts) with treatment-naïve chronic lymphocytic leukemia (CLL). Blood. 2019;134(suppl_1):31. doi: 10.1182/blood-2019-128404