Comparing BTK Inhibitors in CLL Treatment

EP: 1.Case Presentation: A 67-Year-Old Man with Chronic Lymphocytic Leukemia

EP: 2.Testing and Risk Stratification in CLL

EP: 3.First-Line Therapy Options in CLL

EP: 4.Chronic Lymphocytic Leukemia: RESONATE-2 Trial

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EP: 5.Comparing BTK Inhibitors in CLL Treatment

EP: 6.Treatment Approaches for High-Risk Chronic Lymphocytic Leukemia

EP: 7.The Future of Chronic Lymphocytic Leukemia Treatment

John Allan, MD: Currently, one question that comes up on everyone's mind is, “how do you differentiate between the two currently FDA-approved BTK inhibitors for CLL in the frontline setting, those being ibrutinib and acalabrutinib?” There are some features that are very different between the two. In a frontline setting, they've not been tested head-to-head to understand these differences in younger patient populations and less pretreated patients. BTK inhibitors have classic effects of side effects. Those class effects are namely bleeding, hypertension, atrial fibrillation, arthralgias, potential skin rash, and diarrhea. Those are the big class effects that we look for and tell our patients about. Ibrutinib was first in class, it is a good drug. It does have some off-target effects against the kinome. Acalabrutinib was designed to be a more selective BTK inhibitor with less off-target effects and therefore, this hypothesis that it might be a better tolerated agent was put out there, and eventually tested in a head-to-head study in the ELEVATE TN study [ELEVATE TN: Phase 3 Study of Acalabrutinib Combined with Obinutuzumab (O) or Alone Vs O Plus Chlorambucil (Clb) in Patients (Pts) with Treatment-Naive Chronic Lymphocytic Leukemia (CLL)].

These drugs are approved both in relapsed refractory and frontline settings plus or minus anti-CD20. The BTK and Resonate-2 are the ibrutinib-based studies that put them on the map, and each respective frontline or relapsed state. The ASCEND [ASCEND: Phase 3, Randomized Trial of Acalabrutinib Versus Idelalisib Plus Rituximab or Bendamustine Plus Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia] and the ELEVATE TN study put an acalabrutinib respectively into those two places. The ASCEND study was an acalabrutinib versus idelalisib-rituximab or bendamustin-rituximab, favoring an acalabrutinib in terms of progression free survival as well as toxicity profile, and that was in relapsed refractory setting. The ELEVATE TN study was an interesting study because it was a three-arm study of acalabrutinib-obinutuzumab versus acalabrutinib monotherapy versus chlorambucil-obinutuzumab. The acalabrutinib arms beat the chlorambucil-based arms. What we saw was that for the first time, maybe there could be benefit of anti-CD20 therapy.

To this though, was not power to necessarily show a statistically significant difference. With that said, there's a modest 9% difference at the four-year follow-up, favoring the acalabrutinib-obinutuzumab arm. What's interesting is that it's mostly in the lowest risk patients; the highest risk patients don't seem to benefit as much by the addition of the anti-CD20. The number needed to treat is relatively high though it can be given.

It can, in the era of COVID-19, potentially add on to toxicity and detrimental toxicity that we don't want regarding B-cell depletion, etcetera. I think a lot of studies have shown Rituximab not to add much of ibrutinib. I think most people are comfortable utilizing monotherapy BTK inhibitors and in general, that's how I use the drugs because the anti-CD20 can complicate the regimen. It's not clear who it is that's necessarily going to benefit, and you do have to treat a lot of people in order to find that small number of patients that are going to do better than if you just gave them the monotherapy.

There is one head-to-head clinical trial in the relapsed setting ELEVATE-RR [ELEVATE-RR (NCT02477696) Study of Acalabrutinib (ACP-196) Versus Ibrutinib in Previously Treated Subjects With High Risk CLL], which was looking at high-risk patients. Del17p, del11q and were randomized in relapse setting and randomized by ibrutinib or acalabrutinib. This study has finally read out over the summer with showing a primary end point of noninferiority of the acalabrutinib compared to ibrutinib. In terms of progression-free survival, with a median in this very high-risk patient population, close to 55% of patients had a del17p in this study, with a median PFS of a little over 30 months.

The secondary end points were looking at toxicity differences and ultimately showed that acalabrutinib had an AFib [atrial fibrillation] rate of 9.6% versus 16% and also showed lower rates of hypertension, arthralgias, and bleeding, and some of these other end points. It was not able to meet its specified secondary end points beyond the atrial fibrillation, which were infections is and Richter's transformation [Richter'ssyndromeorRS] because it stopped finding significance in those specific hierarchical statistical analyses end point. Acalabrutinib met its primary point of noninferiority compared to ibrutinib and a lower rate of atrial fibrillation of 9.6% versus 16%. So those things come into play when you think about using these drugs.

For this case specifically, the fact that the patient is on an acid-suppressing agent makes acalabrutinib not an ideal drug. It is probably a little less recognized relative contraindication to utilize acalabrutinib in the presence of PPIs and acid-suppressing medications. You have to modify. H2 blockers are generally not used with proton pump inhibitors, and it's discouraged as the absorption of the drug is based on an acidic environment. These little nuances help differentiate between the drugs that you want to use. Ibrutinib is once a day and acalabrutinib is twice a day. If you have patients that have issues with those types of twice-a-day dosing, again, it may not be the best ideal drug for that patient. Those are the things I think about when I'm deciding between these two FDA-approved agents and things that should be taken into consideration as you are looking to utilize these drugs for your patients.

Transcript Edited for Clarity

Initial Presentation

• A 67-year-old man presented to PCP with complaints of fatigue and night sweats
• PMH: patient takes OTC antiacid tablets a few times a week for a “sensitive” stomach
• PE: Enlarged mobile lymph nodes bilaterally (~1.5 cm), no palpable spleen or liver
• Laboratory findings:
• WBC; 102 X 109/L
• Lymphocytes; 79 X 109/L
• Hb; 11.4 g/dL
• Platelets; 180 X 109/L
• ANC; 1,900/mm3
• LDH 1470 U/L
• Cytogenetics; del(11q), IgVH-unmutated
• beta2M, 3.0 mg/L
• Rai Stage I

Treatment Plan

• Patient was started on ibrutinib