Emerging Treatments in CLL

Recent research suggests that B-cell receptor (BCR) activation may play a role in the pathogenesis of CLL, according to Dr Robak.

“In 2014, 2 novel agents targeting the BCR signaling pathway—ibrutinib and idelalisib—were approved for patients with 17p deletion and/or p53 mutations and in the relapsed situation because of high efficacy and a favorable toxicity,” Dr Robak said.

Ibrutinib is a Bruton’s tyrosine kinase (BTK) inhibitor; idelalisib is a phosphatidylinositol 3-kinase δ (PI3Kδ) inhibitor. Both are known to target the BCR cascade.

In 2016, ibrutinib was approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency for first-line use among patients with CLL based on data from the RESONATE-2 (ClinicalTrials.gov Identifier: NCT01722487) trial. Elderly patients were randomly assigned to either ibrutinib or traditional chemotherapy. Ibrutinib significantly prolonged progression-free survival, reducing the relative risk for progression or death by 84%.8 According to Dr Robak and colleagues, these results “represent a valuable milestone in identifying first-line treatment for elderly, less-fit patients.”

Study results supported the use of the PI3Kδ inhibitor, idelalisib, as a front-line treatment for older patients with CLL, though these studies also showed that idelalisib can lead to serious adverse events, including death attributed to infection.

Finally, drugs targeting BCL2, an anti-apoptotic protein implicated in the pathology of CLL, are being researched. In 2016, the FDA approved the BCL2 inhibitor venetoclax for patients with at least 1 prior course of therapy and del 17p deletions.9 Studies of venetoclax in the first-line, including among unfit or elderly patients, are underway.

Looking Forward

Although the role of these novel targeted agents in the first-line is unclear, in the next few years, targeted drugs should be used more commonly in the up-front setting, according to Dr Robak.

“Second-generation BTK inhibitors and the delta isoform of PI3Kδ inhibitors should be available, and combinations with venetoclax will probably be used in first line,” he said.

RELATED: Venetoclax Plus Rituximab Promising for Relapsed/Refractory CLL

Continued research is needed to determine which targeted agents should be used in young, fit patients and elderly unfit patients, and which regimens should be used first.

“Obviously, tailored therapy will be a standard, and patient age and comorbidities, in addition to cytogenetics, are very important,” Dr Robak said. 

References

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  2. Cancer Stat Facts: Chronic Lymphocytic Leukemia (CLL). National Cancer Institute website. https://seer.cancer.gov/statfacts/html/clyl.html. Accessed December, 2016.
  3. Hallek M, Fischer K, Fingerle-Rowson G, et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet. 2010;376(9747):1164-74. doi: 10.1016/S0140-6736(10)61381-5
  4. Strati P, Wierda W, Burger J, et al. Myelosuppression after frontline fludarabine, cyclophosphamide, and rituximab in patients with chronic lymphocytic leukemia: analysis of persistent and new-onset cytopenia. Cancer. 2013;119(21):3805-11. doi: 10.1002/cncr.28318
  5. Eichhorst B, Fink AM, Bahlo J, et al. First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): an international, open-label, randomised, phase 3, non-inferiority trial. Lancet Oncol. 2016;17(7):928-42. doi: 10.1016/S1470-2045(16)30051-1
  6. 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):528.
  7. 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):1101-10. doi: 10.1056/NEJMoa1313984
  8. Burger JA, Tedeschi A, Barr PM, et al. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015;373(25):2425-37. doi: 10.1056/NEJMoa1509388
  9. FDA approves new drug for chronic lymphocytic leukemia in patients with a specific chromosomal abnormality. U.S. Food and Drug Administration website. http://www.fda.gov/ NewsEvents/Newsroom/PressAnnouncements/ucm495253.htm. Published April 11, 2016. Accessed December, 2016.