Choosing Between Venetoclax or BTK Inhibitors in Frontline CLL

Javier Pinilla-Ibarz, MD, PhD

Head of Lymphoma Section

Department of Malignant Hematology

Moffitt Cancer Center

University of South Florida

CASE SUMMARY:

A 71-year-old woman reported symptoms of weight loss and increasing fatigue. She had a medical history of hypertension controlled with medication and takes over-the-counter proton pump inhibitor (PPI) tablets as needed for a “sensitive” stomach​. A physical examination revealed she had axillary lymphadenopathy. Her spleen was palpable and about 4 cm below costal margin. She was ill-appearing and continued only limited daily activity​.

Laboratory results​ showed a white blood cell count of 47,000, 76% lymphocytes, hemoglobin 8.7 g/dL, platelet count 115,000/mm3, absolute neutrophil count of 3,600/mm3, lactate dehydrogenase level of 250 U/L, and β2-microglobulin of 4.3 µg/L​. Flow cytometry showed she was CD5 positive, CD20 positive (dim), and CD23 positive with kappa restricted monoclonal B-cell population.

Fluorescence in situ hybridization assay discovered a deletion 11q mutation, but she was negative for a 11;14 translocation​ mutation. She was IGHV unmutated​. A bone marrow biopsy showed diffuse marrow infiltration by chronic lymphocytic leukemia (90%-95%)​.

DISCUSSION QUESTIONS:

• What treatment would you select and what factors influence your recommendation for this patient?
• What are the data and recommendations to guide therapy? ​

RICARDO PARRONDO, MD: I would choose acalabrutinib [Calquence] for her. She didn’t have any comorbidities that would preclude use of acalabrutinib. Hypertension is less with acalabrutinib than with ibrutinib [Imbruvica], and it’s controlled with medications.¹ She has unmutated IGHV. That’s what I would choose, and I usually do not give a CD20 antibody with Bruton’s tyrosine kinase [BTK] inhibitors. I know there are data that they inhibit each other a little bit. So, I think that ibrutinib inhibits the antibody-dependent cellular cytotoxicity [ADCC] or the BTK inhibitor inhibits the ADCC by the CD20 antibody.

JAVIER PINILLA-IBARZ, MD, PHD: I think that as Dr Parrondo mentioned, there are the in vitro data showing that ibrutinib, through [inhibiting] inducible T-cell kinase, could really diminish the effect of the monoclonal antibody.² However, the ALLIANCE A041202 trial [NCT01886872] didn’t show any advance of the reduction.³ We don’t know for sure [if this is an issue with] acalabrutinib, and I agree with Dr Parrondo. If I am going to use it, I use single agent because this potential issue still isn’t clear how clinically translated it could be, but it's definitely something to discuss.

MARINELY CRUZ-AMY, MD: I chose ibrutinib, maybe because I’m more comfortable with it. I’ve seen that patients tolerate it well. This patient doesn’t have any comorbidities that would worry me. [I would consider] her age but it all depends on the [ECOG] performance status of the patient.

PINILLA-IBARZ: I think it’s another very good alternative. I agree with [Dr Parrondo] that theoretically, [acalabrutinib] has less hypertension. We know that acalabrutinib is contraindicated [for PPI], but the question is why this patient is taking PPI.¹ And there is no doubt, Dr Cruz-Amy, you have good previous experience with ibrutinib, which is something fundamental when we choose medications, in my opinion.

TALHA BADAR, MD: In my experience giving BTK inhibitors in elderly patients, even if they don’t have comorbidities, it could be challenging in terms of infection risk and cardiovascular issues such as atrial fibrillation. Since this patient doesn’t have a 3p deletion or 17p deletion, I would go for a fixed duration therapy in that situation. Venetoclax [Venclexta] and CD20 inhibitor is an option. If you achieve minimal residual disease negativity, you can give a fixed duration therapy and then stop, but if you start ibrutinib, it’s not ending. You have to continue for a lifetime, until the disease develops growth effects or stops responding.

ERIC RISHE, MD: I would choose acalabrutinib. I was thinking about adding obinutuzumab [Gazyva] with it. I’m impressed with the flattening of the [Kaplan-Meier] curves we’re seeing with that combination.⁴ And it looks like patients are having long-term progression-free survival [PFS] on that combination. I think it’s an easy choice. I’m happy to give acalabrutinib.

RUBY DEVERAS, MD: I chose venetoclax and anti-CD20, but I’m afraid to give anti-CD20 in light of the pandemic. We’ve had lots of patients end very badly after they’ve gotten rituximab [Rituxan] and they’ve died, and I think it’s because of the rituximab. It’s not clear if I would choose that at the moment, just because…this pandemic. If the pandemic is ending, then maybe we could go back to selecting the [those] choices.

Going back to that, I’m not sure what the right choice is; the 3 choices seem wonderful. It comes back to my preference and my experience in using venetoclax and anti-CD20 antibodies.

PINILLA-IBARZ: I think you bring up an excellent point that we discuss very often about how the pandemic is modifying our current trends of therapies, and as you just pointed out, how our CLL population is very prone to get COVID-19. Unfortunately, as you have experienced, we have lost several patients after monoclonal antibodies because there is no real immunity for at least 18 months after the last dose of monoclonal antibody, so those patients may be at high risk.

GERARD CHAAYA, MD: I chose acalabrutinib. But in real life, I discuss the options with the patient, including BTK inhibitor versus venetoclax, just because of the duration of the treatment. I am a fan of the stop date, because I don’t like to keep treatment going. But it’s something I discuss with the patient. If the patient wants to have a stop date, I will go with the venetoclax plus obinutuzumab. But if a patient does not want to stop, or they have no preference, I will go with acalabrutinib.

PINILLA-IBARZ: How do you manage the PPI [issue], [given that it is associated with] around 40% to 45% reduction of efficacy?⁵ We know that PPI like this patient was taking will reduce the absorption of acalabrutinib, so how you will manage this patient?

CHAAYA: I can switch them to an anti-H2 antagonist.

PINILLA-IBARZ: Yes, I think that is a good point. What we have done many times, when we believe that acalabrutinib is the right thing, we try to understand the reason the patient is taking the PPI.

EIDER MORENO-CORTES, MD: I have chosen acalabrutinib. And also, there’s a good point about the PPI. I think it’s good to know what the patient is taking…so you can do a good patient education, and you can put the patient on acalabrutinib. Also, the acalabrutinib combination with the second-generation anti-CD20 has good results. It has even better results than acalabrutinib with chlorambucil. So, the patient will benefit from that.

PINILLA-IBARZ: You will choose the monoclonal antibody plus acalabrutinib, is that what you will favor in this case?

MORENO-CORTES: Yes. Just because of the hypertension, I’ll go over acalabrutinib instead of ibrutinib. Maybe it’s not that high, but it will be better to have more control over the other risks that the patient has.

_References:

_{1. NCCN. Clinical Practice Guidelines in Oncology. chronic lymphocytic leukemia/small lymphocytic leukemia, version 2.2022. Accessed February 11, 2022. https://bit.ly/35VbY9J}

_{2. Dubovsky JA, Beckwith KA, Natarajan G, et al. Ibrutinib is an irreversible molecular inhibitor of ITK driving a Th1-selective pressure in T lymphocytes. Blood (2013) 122 (15): 2539–2549. doi: 10.1182/blood-2013-06-507947}

_{3. Woyach JA, Ruppert AS, Heerema NA, et al. Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. N Engl J Med. 2018;379(26):2517-2528. doi:10.1056/NEJMoa1812836}

_{4. 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}

_{5. Acalabrutinib (Calquence). Prescribing Information. AstraZeneca; 2019. Accessed February 11, 2022. https://bit.ly/3gFmJzm}