New Strategies Emerge for Managing CLL Patients in Community Settings

Jacqueline Claudia Barrientos, MD

Physician, CLL Research and Treatment Program

North Shore-LIJ Cancer Institute

New Hyde Park, NY

The treatment landscape for patients with chronic lymphocytic leukemia (CLL) is rapidly changing, with the emergence of four new therapeutic options for this malignancy in recent months.

In November 2013, the FDA approved obinutuzumab (Gazyva) in combination with chlorambucil for patients with previously untreated CLL. Earlier this year, ibrutinib (Imbruvica) was approved for patients who have had at least one prior therapy, and more recently gained an indication for therapy in patients with 17p deletion (including treatment-naïve patients).

In addition, ofatumumab (Arzerra) in combination with chlorambucil gained an indication for patients with previously untreated CLL who are not candidates for fludarabine-based therapy. And most recently, idelalisib (Zydelig) in combination with rituximab was approved for patients with relapsed CLL for whom rituximab alone would be considered appropriate therapy due to other existing medical conditions.

Jacqueline Claudia Barrientos, MD, has conducted research into emerging CLL compounds and is a practicing physician at North Shore—LIJ Cancer Institute in New Hyde Park, New York, a component of the North Shore–LIJ Health System. She discussed some of the considerations confronting oncology specialists treating patients with CLL in light of the new options available.

OncologyLive: What are the standard treatments for patients with relapsed or refractory CLL, and on what basis do you choose between them?

Barrientos: Today, the standard of care for initial therapy in young and fit CLL patients is a combination with a purine analog and a monoclonal antibody, such as fludarabine + cyclophosphamide + rituximab (also known as FCR). Unfortunately, most patients with CLL are elderly with multiple comorbidities and are not able to tolerate such intensive regimens.

If a patient achieves a long period of remission after the initial treatment (eg, 4 years or more), it would be reasonable to consider using the same chemoimmunotherapy used previously. However, most physicians often choose a different regimen, such as bendamustine + rituximab (BR), which has been shown to have good activity in relapsed disease with a good safety profile, because it is a “gentler combination” that is easier to tolerate. The monoclonal antibody ofatumumab is also used as a single-agent therapy in relapsed disease, since the drug has been shown to have activity in fludarabine-refractory and alemtuzumab-refractory patients. The choice of therapy depends on the patient’s comorbidities and preference. Alemtuzumab used to be an option for relapsed CLL, but its use has fallen out of favor due to increased risk of infections (like cytomegalovirus reactivation).

The Bruton tyrosine kinase inhibitor ibrutinib was recently approved as monotherapy for the treatment of relapsed CLL and in patients with 17p deletion. Ibrutinib has excellent activity in relapsed or refractory disease, including among patients with high-risk disease, such as those with the dreaded 17p deletion. The drug is well tolerated even in patients with multiple comorbidities with minimal toxicities that include diarrhea, fatigue, and infection. Most importantly, ibrutinib has significant clinical activity in patients who have failed multiple prior regimens, and the drug is showing durable remissions never before seen in this cohort of patients with multiple prior lines of therapy.¹

What outcome measures are the most useful for assessing treatment response in patients with relapsed/refractory CLL?

Ideally, the best regimen to choose is the one where the patient will have the best response for the longest period of time with the lowest level of toxicities. Even though chemoimmunotherapeutic approaches have been the standard treatment options for patients with relapsed disease, the recent approval of new targeted agents (that are better tolerated with excellent responses and long remission durations) will likely lead to many patients living longer.

How do patients’ status with regard to genetic risk factors, such as del(17p13.1), affect the choice of treatment?

The best single agent available for patients with 17p deletion is ibrutinib. Data presented at this year’s American Society of Clinical Oncology meeting showed that median progression-free survival for this particular patient population was 28 months,¹ and this is the best remission duration that I have seen for any agent, approved or in clinical trials.

Other new agents in clinical trials with promising clinical activity in this hard-to-treat population are idelalisib and ABT-199, but the data for these agents are still evolving. Both drugs are currently being tested in clinical trials developed specifically to test the activity and remission duration in patients with a 17p deletion.

What is the potential for newer kinase-targeting agents, such as Bcl 2 inhibitors or B-cell receptor—signaling inhibitors, to address the shortcomings of current agents?

The beauty of the new targeted agents is that they are showing excellent responses with minimal toxicities compared with traditional chemotherapeutic agents. With the advent of these new drugs in clinical trials, we are able to use these agents in patients who, due to multiple comorbidities or impaired renal clearance, were not candidates for cytotoxic chemotherapies.

So far, these targeted drugs are showing excellent responses in difficult-to-treat patients without the short- or long-term toxicities traditionally associated with chemotherapy (ie, prolonged neutropenias leading to infections, anemia requiring transfusions, secondary malignancies). The development of these new targeted agents is opening the possibility of prolonging the lives of people since more will be able to undergo therapy.

The new Bcl-2 inhibitor ABT-199 is not yet approved for use by the FDA, but early results from phase I trials (monotherapy and in combination with rituximab) are showing very promising activity in patients with fludarabine-refractory disease and with 17p deletion.

Since this drug does not target the B-cell receptor signaling pathway, it is reasonable to postulate that you could use this drug to salvage patients that become refractory to ibrutinib or idelalisib. The other interesting idea would be to test this new drug ABT-199 in combination with ibrutinib or idelalisib to see if it can help patients achieve a deeper response (complete remissions or minimal residual disease negativity). These are very exciting times for patients and researchers as we test and determine the optimal use and sequence of these new agents.

Are there any other novel agents or combination therapies that you think hold particular promise?

With the advent of the B-cell receptor inhibitors (eg, ibrutinib and idelalisib) into clinical trials, a whole new treatment paradigm started to take place and the idea of targeting a pathway became a reality.

The data presented for ibrutinib were so remarkable that the drug was approved based on phase II data, and the recently presented data on the phase III trial confirmed the dramatic responses and efficacy of the drug compared with ofatumumab, a treatment option previously approved by the FDA for use as monotherapy in relapsed patients. Ibrutinib recently gained full approval for use in relapsed disease and also gained approval for therapy in patients with a 17p deletion, regardless of whether patients had received prior therapy.

Idelalisib in combination with rituximab phase III data² were so overwhelmingly positive that the FDA granted idelalisib approval for relapsed CLL when used in combination with rituximab in patients who would be able to tolerate rituximab therapy due to coexisting medical conditions.

Targeted agents recently approved for “frontline therapy” in combination with chlorambucil are obinutuzumab and ofatumumab, both monoclonal antibodies with minimal side effects, except for possible infusion reactions. Both monoclonal antibodies target CD20, a marker present only in B cells.

In both trials, patients who were too frail to tolerate stronger chemotherapy were able to achieve a response with long remission duration. Now the next logical step would be to test these monoclonal antibodies in combination with the newly approved targeted agents as we feel that their activity may be superior to chlorambucil, which was the drug used for the combination that led to the approval of both drugs for upfront therapy.^3,4

Do you have any specific advice for community oncologists about the use of targeted therapies for relapsed/refractory CLL?

We are living in an amazing time with a future full of promise for better, safer drugs to treat CLL. As with everything, there is a learning curve, but as community oncologists get more experience with these newly approved (or about to be approved) agents, they will find that these drugs are very patient friendly and easy to use as long as proper monitoring and patient education is done.

At the end of the day, we all have seen how chemotherapy can cripple the patient’s quality of life or interfere with his or her activities of daily living. The new targeted agents are offering a new way to keep the disease in remission, while minimally interfering with the quality of life of our patients.

References

1. O'Brien SM, Furman RR, Coutre SE, et al. Independent evaluation of ibrutinib efficacy 3 years post-initiation of monotherapy in patients with chronic lymphocytic leukemia/small lymphocytic leukemia including deletion 17p disease. J Clin Oncol. 2014;32:5s(suppl; abstr 7014).
2. Coutre SE, Furman RR, Sharman JP, et al. Second interim analysis of a phase 3 study evaluating idelalisib and rituximab for relapsed CLL. J Clin Oncol. 2014;32:5s(suppl; abstr 7012).
3. Goede V, Fischer K, Busch R, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions [published online January 8, 2014]. N Engl J Med. 2014;370(12):1101-1110.
4. Hillmen P, Robak T, Janssens A, et al. Ofatumumab + chlorambucil versus chlorambucil alone in patients with untreated chronic lymphocytic leukemia (CLL): results of the phase III study Complement 1 (OMB110911). Blood. 2013;122(21). Abstract 528.