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NCCN Revamps Treatment Preferences in CLL/SLL

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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 some known 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 not intolerant to ibrutinib can continue treatment until disease progression
  • Grade 3 or higher AF events require reduction of ibrutinib dose, discontinuation, or use of anticoagulation
  • The optimal anticoagulants for ibrutinib-related AF are not clear
  • Patients must be monitored closely for drug-drug interactions with direct oral anticoagulants and CYP3A4-inhibitor antiarrhythmic drugs

Acalabrutinib with or without obinutuzumab is among category 1 recommended preferred first-line therapy options for all patients, including those in high-risk subgroups such as del(11q) or del(17p)/TP53 mutation and unmutated IGHV.

Data from the ELEVATE-TN trial demonstrated a PFS benefit for acalabrutinib with or without obinutuzumab in patients with del(17p)/TP53 mutation, but only 14% of patients in the trial harbored the del(17p) mutation.

Currently, acalabrutinib with or without obinutuzumab, zanubrutinib, and venetoclax + obinutuzumab are included as preferred regimens for first-line therapy for patients with

untreated del(17p) CLL. That advice has a category 1 recommendation. In addition, Ibrutinib now has a category 1 recommendation as another recommended but not preferred regimen.

The NCCN said venetoclax plus obinutuzumab is an effective fixed-duration chemotherapy-free first-line treatment option for all patients, including those with del(17p)/TP53 mutation.

For CLL/SLL with del(17p)/TP53 mutation

  • 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.
  • Ofatumumab (Kesimpta) was removed as an option for second-line and subsequent therapy.
  • Acalabrutinib (Calquence) with or without obinutuzumab (Gazyva), venetoclax (Venclexta) with obinutuzumab, and zanubrutinib remain preferred regimens in first-line therapy.
  • Acalabrutinib, venetoclax plus rituximab, venetoclax, and zanubrutinib are preferred second-line and subsequent therapy regimens.

For CLL/SLL 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.

Key Takeaways

  • Zanubrutinib is now one of the preferred options for patients with CLL/SLL, both frontline, and second-line
  • For second-line, acalabrutinib, zanubrutinib, and venetoclax with rituximab are now the preferred options
  • 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 therapy 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: https://www.nccn.org/patientresources/patient-resources/guidelines-for-patients/guidelines-for-patients-details?patientGuidelineId=6

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