Recent NCCN Update Moves Zanubrutinib Ahead of Ibrutinib in CLL/SLL Based on Toxicity Profile

The National Comprehensive Cancer Network recommendations come as the FDA weighs an indication in chronic lymphocytic leukemia/small lymphocytic leukemia (CLL/SLL) for zanubrutinib.

As drugmaker BeiGene awaits word from FDA on whether zanubrutinib will receive an additional indication in chronic lymphocytic leukemia/small lymphocytic leukemia (CLL/SLL), a key stakeholder has already weighed in with good news.

The National Comprehensive Cancer Network (NCCN) guidelines committee, which had previously included zanubrutinib in its recommendations, has placed the second-generation Bruton tyrosine kinase (BTK) inhibitor in higher rungs on the guidelines in several areas. Meanwhile, ibrutinib, a first-generation BTK inhibitor, has lost ground due to its toxicity profile.1

In June, BeiGene announced that FDA would postpone the target action date for a CLL/SLL indication for zanubrutinib until January 20, 2023. BeiGene had asked to include new data from the ALPINE trial that showed a superior overall response rate compared with ibrutinib. This was deemed a major amendment by FDA; since that time, presentations at the European Hematology Association from the ALPINE and SEQUOIA trials also showed superior quality of life for zanubrutinib.

Besides listing preferred and other recommended regimens, the NCCN committees put regimens in categories based on levels of evidence. 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.”

Among the key changes in its update, released August 30, 2022, the NCCN panel on CLL/SLL guidelines put notations on ibrutinib’s recommendation based on its toxicity profile. The first-generation BTK inhibitor is known to have “off target” cardiac effects.

Changes in CLL/SLL without del(17p)/TP53 mutation for first-line therapy include the following:

  • Ibrutinib was moved from “Preferred Regimens” to “Other Recommended Regimens.” A footnote states that the recommendation is based on toxicity profile, and “a baseline assessment of cardiac function should be done prior to initiation of ibrutinib. In patients with no intolerance ibrutinib can be continued until disease progression.”
  • Preferred regimens are zanubrutinib, which was moved from category 2A to category 1, and venetoclax with obinutuzumab, which moved from 2A to 1 for patients younger than age 65 without significant comorbidities.
  • Regimens removed were: chlorambucil, rituximab, and fludarabine with rituximab.

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

  • Regimens were reorganized into 2 categories: second-line or third-line therapy, and therapy for R/R disease after BTK inhibitor or venetoclax-based treatment.
  • In the first category, ibrutinib was moved from “Preferred Regimens" to “Other Recommended Regimens,” with the same footnote as in first-line therapy. It retains a category 1 recommendation.
  • Existing “Preferred Regimens” in the first category are the BTK inhibitors zanubrutinib and acalabrutinib (category 1), and the BCL-2 inhibitor venetoclax (category 1).
  • Also in the first category, several combinations were removed, most notably bendamustine, rituximab (BR), plus ibrutinib. However, BR remains an option in the second category.
  • In the first category, retreatment with venetoclax and obinutuzumab may be useful in certain circumstances.

Under recommendations for CLL/SLL with del(17p)/TP53 mutation:

  • In first-line therapy and second-line and subsequent therapy, ibrutinib was moved from “Preferred Regimens” to “Other Recommended Regimens,” with the same footnote regarding toxicity and cardiac assessment. It retains a category 1 recommendation.
  • Under “Other Recommended Regimens,” ibrutinib plus venetoclax was added as a category 2B recommendation.
  • In second-line and subsequent therapy, ofatumumab was removed.
  • In first-line therapy, the “Preferred Regimens” remain acalabrutinib with or without obinutuzumab, venetoclax with obinutuzumab, and zanubrutinib.
  • In second-line and subsequent therapy, “Preferred Regimens” are acalabrutinib (category 1), venetoclax plus rituximab (category 1), venetoclax, and zanubrutinib.

Zanubrutinib, sold as Brukinsa, is approved by FDA for adult patients with Waldenström’s macroglobulinemia, those with mantle cell lymphoma who have received at least one prior therapy, and R/R marginal zone lymphoma who have received at least one anti-CD20-based regimen.


National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Chronic Lymphocytic Leukemia/Small Lymphocytic Leukemia. Version 1.2023. Published August 30, 2022. Accessed September 7, 2022.