patient care perspectives

Optimizing the Approach to Treatment-Naive Chronic Lymphocytic Leukemia

by Matthew S. Davids, MD, MMSc

Overview

Given the growing number of treatment options for chronic lymphocytic leukemia (CLL), the selection of first-line therapy requires an in-depth conversation with patients.

Expert Commentary

Matthew S. Davids, MD, MMSc

Associate Professor of Medicine
Harvard Medical School
Director of Clinical Research, Division of Lymphoma
Dana-Farber Cancer Institute
Boston, MA

“The discussions usually center on whether to give a BTK inhibitor as a continuous therapy in the front line or to give the 1-year time-limited regimen of venetoclax plus obinutuzumab.”

Matthew S. Davids, MD, MMSc

One of the most significant changes in the approach to frontline CLL therapy over the last couple of years is the shrinking number of patients who are candidates for chemoimmunotherapy (CIT) as the optimal approach. I would estimate that CIT is the optimal approach to frontline CLL therapy in only approximately 10% of patients who require treatment. This small group would include those under 65 years of age who are fit and have mutated IGHV and do not have 17p deletion or TP53 mutation. The reason I still consider the FCR regimen (fludarabine, cyclophosphamide, and rituximab) for this group is because we have long-term follow-up data from the original trials suggesting that a significant percentage of patients with those characteristics is still in complete remission 15 years after receiving 6 months of FCR. However, for the majority of patients with CLL who do not fit these criteria, novel agent–based regimens are used, and there are a number of different options.

I have long conversations with my patients weighing the pros and cons of different approaches. The discussions usually center on whether to give a Bruton tyrosine kinase (BTK) inhibitor as a continuous therapy in the front line or to give the 1-year time-limited regimen of venetoclax plus obinutuzumab. Some patients have a strong preference for a time-limited therapy that enables them to achieve a durable remission without having to keep taking pills. For others who are already taking chronic medication, taking an extra pill or two every day may not be an issue and they are fine with taking a BTK inhibitor.

The COVID-19 pandemic has changed the dynamic because it is quite easy to start BTK inhibitors, whereas it is more intensive to start on the venetoclax-obinutuzumab regimen, which requires patients to come in for infusional therapy a few times during the first month and then once per month thereafter, along with additional visits to monitor for tumor lysis syndrome. Thus, the venetoclax-obinutuzumab regimen requires an investment in time and energy early on, and some patients are hesitant to interact with health care providers to that extent with COVID-19 in the environment. On the other hand, BTK inhibitors may not be the best choice for patients with CLL who have cardiovascular issues at baseline. Genetic testing for 17p deletion/TP53 mutations is also important to guide therapy, and recent data presented at the 62nd American Society of Hematology Annual Meeting and Exposition suggest that such testing is drastically underutilized. The presence of these mutations will allow us to avoid the use of CIT in cases where data demonstrate a decreased response. In general, I present both options (BTK inhibitor or venetoclax plus obinutuzumab) to my patients, and we have good data supporting either choice of therapy.

References

Burger JA. Treatment of chronic lymphocytic leukemia. N Engl J Med. 2020;383(5):460-473. doi:10.1056/NEJMra1908213

Chai-Adisaksopha C, Brown JR. FCR achieves long-term durable remissions in patients with IGHV-mutated CLL. Blood. 2017;130(21):2278-2282. doi:10.1182/blood-2017-07-731588

Fischer K, Al-Sawaf O, Bahlo J, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019;380(23):2225-2236. doi:10.1056.NEJMoa1815281

Mato AR, Barrientos JC, Sharman JP, et al. Real-world prognostic biomarker testing, treatment patterns and dosing among 1461 patients (pts) with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) from the informCLL prospective observational registry [abstract 547]. Abstract presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020. 

Shadman M, Stephens DM. Debate: what is optimal first-line therapy for chronic lymphocytic leukemia? J Natl Compr Canc Netw. 2020;18(7.5):993-997. doi:10.6004/jnccn.2020.5011

Shanafelt TD, Wang XV, Kay NE, et al. Ibrutinib-rituximab or chemoimmunotherapy for chronic lymphocytic leukemia. N Engl J Med. 2019;318(5):432-443. doi:10.1056/NEJMoa1817073

Woyach JA. Treatment-naive CLL: lessons from phase 2 and phase 3 clinical trials. Blood. 2019;134(21):1796-1801. doi:10.1182/blood.2019001321

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