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Answers to Frequently Asked Questions on State-of-the-Art Management of CLL

Jeremy S. Abramson, MD, MMSc

Associate Professor
Department of Medicine
Harvard Medical School
Director, Center for Lymphoma
Massachusetts General Hospital
Boston, Massachusetts


Jeremy S. Abramson, MD, MMSc, has disclosed that he has received consulting fees from AstraZeneca, BeiGene, Bluebird Bio, Celgene/Bristol-Myers Squibb, Epizyme, Genentech, Genmab, Incyte, Kite, and Kymera.


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Anthony Mato, MD, MSCE

Associate Professor
Division of Leukemia
Memorial Sloan Kettering Cancer Center
New York, New York


Anthony Mato, MD, MSCE, has disclosed that he has received funds for research support from AbbVie, Acerta/AstraZeneca, Adaptive, DTRM BioPharma, Johnson & Johnson, Loxo Oncology, Pharmacyclics, Regeneron, Sunesis, and TG Therapeutics and has received consulting fees from AbbVie, Acerta/AstraZeneca, Adaptive, Celgene, DTRM BioPharma, Johnson & Johnson, Pharmacyclics, Sunesis, TG Therapeutics, and Verastem.


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Released: June 30, 2021

In this commentary, Jeremy S. Abramson, MD, MMSc, and Anthony Mato, MD, MSCE, answer questions on the management of chronic lymphocytic leukemia (CLL) that were submitted by an audience of healthcare professionals during a recent live Clinical Care Options (CCO) webinar.

What is your general perspective on using measurable residual disease (MRD) in clinical practice for the management of patients with CLL?

Jeremy S. Abramson, MD, MMSc:
We currently lack good evidence indicating that we should monitor MRD and change therapy accordingly. In the CLL14 study, all patients stopped therapy at 1 year regardless of MRD status. We now know that those who were MRD detectable at the end of treatment—which was a minority in the venetoclax plus obinutuzumab arm—have a higher likelihood of subsequently progressing. Of course, those patients may respond very well to treatment when next indicated.

In my practice, I check MRD at the end of treatment. If MRD is detectable, I counsel the patient that treatment was discontinued for all patients in the CLL14 study treatment, and although we currently lack study data, I offer the option of continuing therapy if insurance will provide coverage. Once patients are in remission, I do not monitor MRD for disease recurrence, preferring to follow patients clinically by examination and with blood counts and only resume therapy if they meet clinical or blood count criteria.

What blood counts would you use for guiding when to initiate treatment in an otherwise asymptomatic 70‑year‑old patient who is developing anemia and/or thrombocytopenia?

Jeremy S. Abramson, MD, MMSc:
Patients can be asymptomatic with modest cytopenias for a long time, so I prefer to assess kinetics rather than relying on any single laboratory value alone.

If a patient’s platelet count has steadily declined to below 75,000/µL, we discuss when starting treatment would make sense for them if they are otherwise completely asymptomatic. I consider treatment mandatory once the count is below 50,000/µL.

For hemoglobin levels, once they are below 10 g/dL, I have a similar discussion about when to start treatment, with treatment becoming mandatory if the levels continue to drop or if the patient becomes symptomatic.

What is our current understanding of using zanubrutinib for CLL treatment?

Anthony Mato, MD, MSCE:
Zanubrutinib is a next-generation Bruton tyrosine kinase (BTK) inhibitor under investigation in the setting of CLL. It is very well tolerated and has been studied in some unique populations. Of note, frontline therapy with zanubrutinib was associated with excellent efficacy in 109 patients with del(17p) enrolled on the phase III SEQUOIA study. It remains somewhat uncertain how zanubrutinib will fit into the CLL treatment landscape, but interim data from the phase III AIPINE trial presented at European Hematology Association 2021 showed that zanubrutinib improved overall response rate vs ibrutinib with a lower rate of atrial fibrillation.

For me, agents such as acalabrutinib and zanubrutinib will distinguish themselves from ibrutinib by their safety profiles, the unique patient populations enrolled in the different trials, and the specific therapies with which they will be combined.

The ELEVATE-RR study compared acalabrutinib vs ibrutinib in a population that included patients with del(11q). What is your perspective on the significance of del(11q) in our current era of targeted therapy, and the inclusion of patients with del(11q) in that study?

Anthony Mato, MD, MSCE:
Although del(11q) was associated with poor outcomes with chemoimmunotherapy, long‑term data from populations treated with ibrutinib have revealed that del(11q) is not so adverse when the patient is treated with a BTK inhibitor. There have even been hints that patients with del(11q) may do better with BTK inhibitors than the general population.

Regarding the relevance of ELEVATE-RR, this is an older study with long follow-up, and at the time it was designed, there was still concern about del(11q) conferring high risk. Nowadays, I would not want to see another study of a novel agent that defines del(11q) as high risk. I think that novel agents have largely overcome this issue with del(11q).

Guidelines recommend both acalabrutinib and ibrutinib as options for CLL treatment. What factors do you consider when choosing between these 2 options?

Jeremy S. Abramson, MD, MMSc:
For the average patient, we choose based on efficacy and safety, first and foremost. The ELEVATE-RR data in the relapsed/refractory setting are quite interesting. Compared with ibrutinib, acalabrutinib appears to be associated with less toxicity overall—including events such as any‑grade atrial fibrillation and bleeding, but also arthralgias and myalgias, which can be really troublesome for patients. In general, I prefer acalabrutinib over ibrutinib in most cases, with a few caveats.

First, if a patient is on a proton pump inhibitor such as omeprazole, that has a drug–drug interaction with acalabrutinib. If the patient cannot stop the medication or switch to an H2 blocker, then I would prefer ibrutinib. Second, if a patient is experiencing intolerance to acalabrutinib, then they can switch to ibrutinib. Third, I would consider ibrutinib in patients with del(17p) because we have the longest follow-up data showing long‑term durability of remission with ibrutinib in this population; we currently lack long-term data for acalabrutinib among these patients. Finally, I prefer ibrutinib when I see those rare cases of CLL with central nervous system (CNS) disease. We have much better evidence for CNS penetration with ibrutinib and a little more data on ibrutinib activity in CNS lymphoproliferative disorders.

Anthony Mato, MD, MSCE:
I think both BTK inhibitors remain reasonable options because both have great efficacy data. There is less cardiovascular toxicity with acalabrutinib, which is a major factor. But differences in discontinuation and toxicity rates have not yet translated into an observable difference in efficacy, so both are great options. As I mentioned earlier, selection really depends on how each agent has been studied—the patient populations, combinations, and so forth.

How might allogeneic stem cell transplant fit into our CLL treatment options?

Anthony Mato, MD, MSCE:
We do not have much data on allogeneic transplant in novel agent–treated patients—perhaps a few case series and some data from MD Anderson Cancer Center. Our group reported on a multicenter experience with allogeneic transplant in a couple of novel agent–treated patients. The sparse data appear similarly good for allogeneic transplant following either novel agents or chemoimmunotherapy.

Our take-home message was that you should only begin to consider allogeneic transplant or another cellular therapy after failing 2 novel agents. I consider allogeneic transplant to be a reasonable option in that setting and we will certainly gain more data and experience with this approach as more and more patients progress with available novel agents.

Do you recommend antifungal, viral, and/or Pneumocystis carinii pneumonia (PCP) prophylaxis in your patients?

Jeremy S. Abramson, MD, MMSc:
I do not routinely recommend antifungal prophylaxis. The exceptions are when patients have prolonged neutropenias and/or severe lymphopenia from extensive prior therapies, which we do not see as much with targeted therapies.

Regarding viral and PCP prophylaxis, patients with CLL are immunocompromised and at increased risk for shingles and pneumocystis. I typically have my patients on antiviral prophylaxis in the relapsed/refractory setting, and if they are lymphopenic, I consider pneumocystis prophylaxis as well.

In previously untreated patients, I typically do not use prophylaxis, but I am vigilant about infection even though the incidence of opportunistic infections with initial therapy is quite low.

Given that the phosphoinositide 3-kinase (PI3K) inhibitors idelalisib and duvelisib are approved by the FDA for CLL and we are anticipating approval of umbralisib for CLL, can you give your perspective on where PI3K inhibitors fit into CLL treatment algorithms?

Anthony Mato, MD, MSCE:
Depending on whether you have used 2 BTK inhibitors in the setting of intolerance and then retreatment, I could see using the currently approved PI3K inhibitors in the third or fourth line. My major concerns with this drug class are, first, the very high rate of discontinuation due to adverse events. Second, these agents have not been studied in a modern patient population previously treated with standard therapies (ie, ibrutinib, acalabrutinib, or venetoclax). We need prospective trial data with this class of therapy in patients who have had prior BTK inhibitors before these agents can become more of a treatment mainstay. Umbralisib may be approved in the front line with ublituximab and that could potentially change our thinking, but I would not sequence the currently approved PI3K inhibitors before a BTK inhibitor or venetoclax.

More Information on CLL Management and BTK Inhibitors

More on the expert management of CLL and small lymphocytic lymphoma on the CCO website! Remember to download the Downloadable Slidesets associated with the live webinar for this program.

Click here to use CCO’s Interactive Decision Support Tool: Expert Guidance for the Treatment of CLL to receive management recommendations from a panel of 5 experts for a wide variety of patient presentations.

Click here to use CCO’s An Interactive Algorithm Tool: Assessment and Management of BTK Inhibitor Adverse Events to receive management recommendations from a panel of 5 experts for a wide variety of patient presentations.

Your Thoughts?
What are your thoughts and questions on the management of patients with CLL using newer targeted therapies? Please answer the polling question and join the conversation by posting a comment in the discussion section.

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