In Practice: Challenges in Treating Patients With Relapsed or Refractory CLL

Jacqueline Claudia Barrientos, MD

Jacqueline Claudia Barrientos, MD, is an assistant professor at Hofstra North Shore-LIJ School of Medicine, New York.

Q: What are the standard treatments for patients with relapsed or refractory chronic lymphocytic leukemia (R/R CLL), and on what basis do you choose between them?

A: Today, a combination purine analog with a monoclonal antibody, such as fludarabine + cyclophosphamide + rituximab, is the standard of care for treatment-naïve patients with CLL who are young and fit. Unfortunately, most patients with CLL are elderly with multiple comorbidities and are not able to tolerate such intensive regimens. If a patient achieved a long period of remission after the initial treatment (eg, 6 years or more) it would be reasonable to consider using the same chemoimmunotherapy that was used the first time. Most physicians 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. The monoclonal antibody ofatumumab is also used as single agent, since the drug has activity in fludarabine-refractory and alemtuzumab-refractory patients. Most recently, the Bruton’s tyrosine kinase inhibitor ibrutinib has been approved for the treatment of relapsed CLL as monotherapy. Ibrutinib has excellent activity in relapsed or refractory disease, including in high-risk patients, such as those with the dreaded 17p deletion. The drug is well tolerated even in patients with multiple comorbidities. Most importantly, ibrutinib has significant clinical activity in patients who have failed multiple prior regimens, and it is demonstrating durable remissions.¹

John C. Byrd, MD, on Resistance to Ibrutinib

Byrd is a professor at The Ohio State University Comprehensive Cancer Center.

Q: What outcome measures are the most useful for assessing treatment response in patients with R/R CLL?

A: 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 rate 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.

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

A: The best single agent available that has shown excellent activity in patients with 17p deletion is ibrutinib. Data presented at this year’s ASCO meeting showed that median progression-free survival (PFS) for this particular cohort of patients was 28 months,¹and this is the best remission duration that I have seen for any agent, approved or in clinical trials. Other new agents in clinical trials are showing activity in this hard-to-treat population (such as idelalisib and ABT-199), but the data for these agents are still maturing.

Q: 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?

A: The beauty of the new targeted agents is that they are showing excellent responses with minimal toxicities. With the advent of these drugs in clinical trials, we are able to use these new agents in patients that, 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 transfusion support, secondary malignancies). The development of these new targeted agents is opening the possibility of prolonging the natural history of the disease as more people are going to be able to get therapy.

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

A: 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 a treatment option approved by the US Food and Drug Administration (FDA). Idelalisib in combination with rituximab phase III data²were so overwhelmingly positive that FDA granted idelalisib a Breakthrough Therapy Designation for relapsed CLL. Another targeted agent was recently approved, obinutuzumab in combination with chlorambucil, for treatment-naïve patients with CLL. Based on the superiority of the combination to single-agent chlorambucil or to rituximab and chlorambucil,³it is reasonable to expect that the combination of obinutuzumab, with more effective drugs than chlorambucil, may lead to longer remission durations.

Q: Do you have any specific advice for community oncologists about the use of targeted therapies for R/R CLL?

References

A: 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 realize that these drugs are very patient friendly and easy to use. 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.

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) Abstract 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): Abstract 7012.
3. Goede V, Fischer K, Busch R, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions.N Engl J Med. 2014;370(12):1101-1110.

Financial Interest Statement

Jacqueline Claudia Barrientos, MD, receives research support from AbbVie, Gilead, and Pharmacyclics to conduct clinical trials. She has served on the advisory board for Gilead and Pharmacyclics.