What are some of the most common challenges in CLL treatment?

Selecting the optimal treatment strategy requires careful evaluation of the patient’s characteristics—comorbidities, age, fitness, impairment of any organ function, prior lines of therapies—and the tumor’s prognostic markers such as high-risk cytogenetics and IGHV mutational status. For example, a patient who has a CLL diagnosis with a 17p deletion should not be treated with chemoimmunotherapy, as these regimens will expose the patient to undue toxicity.

The only regimens that will work for these patients are the novel agents (ibrutinib, acalabrutinib, venetoclax). Given the aggressiveness of the disease with a 17p deletion, many CLL investigators would recommend continuous daily dosing rather than a fixed duration regimen given the concern for potential early relapse.


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Most patients with a CLL diagnosis in the US are now being treated with targeted agents. These novel agents have proven to be superior against chemoimmunotherapy in randomized clinical trials. Although these drugs are much better tolerated overall when compared to chemotherapy, they have particular toxicity profiles that require a tailored treatment approach.9 We want patients to be able to tolerate these regimens without drug holds, discontinuations, or dose modifications.

There are no randomized head-to-head clinical trials testing a BTK inhibitor vs venetoclax, so any treatment decision needs to take into consideration that BTK inhibitors are given continuously until progression of disease or tolerability issues occur, whereas venetoclax is given as a fixed-duration treatment strategy in combination with a monoclonal antibody.

What are the most notable recent developments in treatment strategies for CLL?

There is no doubt that the novel agents have changed the treatment paradigm and the life expectancy of our patients with a CLL diagnosis. Despite these advances, patients may develop toxicities from the use of these drugs. The recently presented data at ASCO 2021 and EHA 2021 show that the more selective second-generation BTK inhibitor acalabrutinib showed noninferiority to ibrutinib with identical median progression-free survival. Acalabrutinib had less cardiovascular toxicities, which could still occur over time, but with less frequency and severity.10

Researchers investigating the second-generation BTK inhibitor zanubrutinib presented early data from their phase 3 trial, but these data are not yet fully mature—the initial data are promising, but longer follow-up is needed to draw solid conclusions.11 These presentations did not answer the question of which second-generation BTK inhibitor to select, and there are no ongoing studies addressing this question at this time.

What are the most pressing remaining research needs in this area?

We are currently evaluating the role of combination treatment strategies to see if we can obtain deeper remissions that may afford the opportunity of treatment-free remissions, particularly in younger patients. We know from imatinib real-world experience that compliance with a drug that needs to be taken indefinitely decreases over time.

Combination treatment strategies may not be the right option for everyone, as they may result in more toxicities. The recently presented CAPTIVATE and GLOW trials (investigating a combination of ibrutinib and venetoclax as first-line therapy) demonstrated a higher incidence of severe toxicities in the older patient cohort.12,13

Another important area of research is identifying novel agents that will be effective in patients whose tumors have developed mechanisms of resistance – for example, BTK mutations or PLCg mutations. Novel agents in the pipeline, such as CAR-T cell therapy and reversible BTK inhibitor, are showing promising activity in patients despite the presence of these mutations.

Disclosures: Dr Barrientos disclosed several industry relationships in her paper cited below.8 Please refer to the original reference for a full list of disclosures.

References

  1. American Cancer Society. Key statistics for chronic lymphocytic leukemia. American Cancer Society website. Updated January 21, 2021. Accessed July 2, 2021. https://www.cancer.org/cancer/chronic-lymphocytic-leukemia/about/key-statistics.html
  2. Shadman M, Goodrich A. Improving outcomes for patients with chronic lymphocytic leukemiaJ Adv Pract Oncol. 2020;11(3):312-315. doi:10.6004/jadpro.2020.11.3.19
  3. Thompson MC, Mato AR. Treatment of relapsed chronic lymphocytic leukemia after venetoclax. Hematology Am Soc Hematol Educ Program. 2020;2020(1):18-23. doi:10.1182/hematology.2020000160
  4. Wang Y, Ding W. Richter transformation of chronic lymphocytic leukemia in the era of novel agents. Clin Adv Hematol Oncol. 2020;18(6):348-357. doi:10.1182/asheducation-2018.1.256
  5. Mato AR, Shah NN, Jurczak W, et al. Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): a phase 1/2 study. Lancet. 2021;397(10277):892-901. doi:10.1016/S0140-6736(21)00224-5
  6. Loxo Oncology at Lilly. Programs: Pirtobrutinib (LOXO-305). Loxo Oncology website. Accessed July 2, 2021. https://www.loxooncology.com/pipeline/loxo-305
  7. Loxo Oncology at Lilly announces publication of pirtobrutinib (LOXO-305) phase 1/2 data in The Lancet. Indianapolis, IN: PRNewswire; March 5, 2021.
  8. Sternberg A. IND for CD20-targeted CAR T-cell therapy is accepted by FDA for R/R CLL. Cancer Network. Published online May 11, 2021.
  9. Brander D, Islam P, Barrientos JC. Tailored treatment strategies for chronic lymphocytic leukemia in a rapidly changing era. Am Soc Clin Oncol Educ Book. 2019;39:487-498. doi:10.1200/EDBK_238735
  10. Byrd JC, Hillmen P, Ghia P, et al. First results of a head-to-head trial of acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia. J Clin Oncol. 2021;39:15 suppl;7500. doi:10.1200/JCO.2021.39.15_suppl.7500
  11. Hillmen P, Eichhorst B, Brown JR, et al. First interim analysis of ALPINE study: Results of a phase 3 randomized study of zanubrutinib vs ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma. Presented at: European Hematology Association 2021 Virtual Congress; June 2021; Abstract LB1900.
  12. CAPTIVATE study shows an IMBRUVICA® (ibrutinib) plus VENCLEXTA®/VENCLYXTO® (venetoclax) chemotherapy-free combination has potential to provide remission after fixed-duration treatment for chronic lymphocytic leukemia (CLL). North Chicago, IL: Abbvie; June 7, 2021.
  13. IMBRUVICA® (ibrutinib) plus VENCLEXTA®/VENCLYXTO® (venetoclax) combination shows superior progression-free survival compared to chlorambucil plus obinutuzumab in first-line chronic lymphocytic leukemia (CLL) phase 3 GLOW study. North Chicago, IL: Abbvie; June 12, 2021.