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NCCN Revamps Treatment Preferences in CLL / SLL

In science and medicine, information is constantly changing and may become out-of-date as new data emerge. All articles and interviews are informational only, should never be considered medical advice, and should never be acted on without review with your health care team.

Updated on January 31, 2023

In guidelines released in August 2022, the National Comprehensive Cancer Network (NCCN) moved zanubrutinib (Brukinsa) into the “preferred regimens” category for patients with CLL / SLL.

The NCCN gave zanubrutinib a “category 1” recommendation, meaning that the recommendation is based on “high-level evidence.” Previously, Bruton’s tyrosine kinase (BTK) inhibitor had level 2A support, the second strongest recommendation.

The NCCN categorizes its recommendations based on levels of evidence. For example, a category 1 recommendation is based on “uniform NCCN consensus” based on “high-level evidence,” while a category 2A recommendation is based on “lower-level evidence” with “uniform consensus,” and 2B indicates “lower-level evidence” with “NCCN consensus.”

At the same time, the network moved ibrutinib (Imbruvica), long the standard of care, to “other recommended regimens.” The NCCN made the move based on the agent’s toxicity profile. Ibrutinib is generally well tolerated and induces rapid and durable responses, but the agent has a higher incidence of some side effects, the most serious of which are atrial fibrillation (AF) and bleeding.

  • The NCCN recommends a baseline assessment of cardiac function before initiating ibrutinib.
  • Patients who are tolerating ibrutinib can continue treatment until disease progression.

For CLL / SLL with and without del(17p)/TP53 mutation first-line

  • Ibrutinib moved from “preferred regimens” to “other recommended regimens” based on toxicity. The NCCN recommends a cardiac assessment before initiating ibrutinib.
  • Ibrutinib plus venetoclax was added as an “other recommended regimens” though a lower category (2B) recommendation.
  • Acalabrutinib (Calquence) with or without obinutuzumab (Gazyva), venetoclax (Venclexta) with obinutuzumab, and zanubrutinib remain preferred regimens in first-line therapy.

For CLL / SLL with and without del(17p)/TP53 mutation in second-line and subsequent therapy

  • Ibrutinib moved from “Preferred Regimens” to “Other Recommended Regimens” based on toxicity. The NCCN recommends a cardiac assessment before initiating ibrutinib.
  • Zanubrutinib, acalabrutinib, and venetoclax plus rituximab remain preferred regimens.
  • Ofatumumab (Kesimpta) was removed as an option.

Key Takeaways

  • For front-line, acalabrutinib, zanubrutinib, and venetoclax with obinutuzumab are now the preferred options.
  • For second-line and subsequent therapy, acalabrutinib, zanubrutinib, and venetoclax with rituximab are now the preferred options.
  • Ofatuzumab is no longer recommended. It is very rarely used so this is not an issue for most patients.
  • Acalabrutinib and zanubrutinib are both effective options to consider for patients with intolerance to ibrutinib.
  • There is still a role for ibrutinib based on its long track record, and there is no need to change therapies if one is doing well.
  • Optimal sequencing of therapies needs further clarification.

See the full guidelines at NCCN Clinical Practice Guidelines in Oncology: Chronic Lymphocytic Leukemia/Small Lymphocytic Leukemia. Version 1.2023.

You can find the patient friendly version that CLL Society has helped with in the past at:

There are now several effective therapy available for CLL patients at all stages of therapy. They include ibrutinib, acalabrutinib, zanubrutinib, venetoclax and of course clinical trials. More options are in the pipeline. Please keep in mind that NCCN guidelines, are just that, guidelines, and each CLL / SLL patient in consultation with their healthcare team, should make their own decision about their best choice of therapy based on their particular circumstances.

Braxton Cole has more than 20 years of experience as a journalist, including over a decade covering hematology/oncology for various outlets.