New NCCN Guidelines for CLL/SLL Include Second-Generation BTK Inhibitors

June 2023, Vol 14, No 3 - Online Only

In a session during the 2023 National Comprehensive Cancer Network (NCCN) Annual Conference, Deborah M. Stephens, DO, Director, Chronic Lymphocytic Leukemia and Lymphoma Program, Huntsman Cancer Institute, University of Utah, Salt Lake City, provided important updates to treatment recommendations for patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), and identified key factors for selecting frontline and subsequent therapies, including immunoglobulin heavy chain variable (IGHV) gene status, 17p deletion (del17p)/TP53 mutation status, age, patient comorbidities, and resistance mutations.

Frontline Therapy

Frontline therapy options in the NCCN Clinical Practice Guidelines: CLL/SLL (Version 2.2023) are a Bruton tyrosine kinase (BTK) inhibitor plus or minus an anti-CD20 monoclonal antibody, venetoclax (Venclexta) plus an anti-CD20 monoclonal antibody, or chemoimmunotherapy, she said. The preferred regimens are acalabrutinib (Calquence) with or without obinutuzumab (Gazyva), venetoclax with or without obinutuzumab, or zanubrutinib (Brukinsa).1

Deborah M. Stephens, DO

For patients with CLL/SLL who require frontline therapy by International Workshop on Chronic Lymphocytic Leukemia criteria, enrollment in a clinical trial should be considered, Dr Stephens noted. “The reason being is that we still haven’t cured CLL outside the setting of allogeneic stem cell transplantation, for which most patients are not a candidate,” she said.

If a clinical trial is not available, “I check their IGHV status,” Dr Stephens went on to say. “If a patient has a mutated copy of this gene, the next step would be looking at their FISH [fluorescence in situ hybridization] results. If they have deletion 13q only and are aged <65 years, these are the only patients for whom I consider an FCR [fludarabine, cyclophosphamide, and rituximab {Rituxan}] regimen in this current era.”

Dr Stephens said that for patients with an unmutated copy of IGHV, with del17p or TP53, a good approach is to move them toward second-generation BTK inhibitors (eg, acalabrutinib, zanubrutinib). “For anyone else, you can consider their comorbidities,” she added.

For patients who have uncontrolled atrial fibrillation (AF) or who require anticoagulation, venetoclax plus obinutuzumab is a favored option secondary to the side effects of bleeding and AF observed with the BTK inhibitors. For patients with poor creatinine clearance, a second-generation BTK inhibitor is a better option, because these individuals are not negatively affected by poor kidney function. A BTK inhibitor should also be considered for patients with extensive infections, except aspergillosis, given evidence for immune reconstitution with BTK inhibitors, Dr Stephens added.

The CLL13 study showed no benefit to adding ibrutinib (Imbruvica) to venetoclax plus obinutuzumab regarding minimal residual disease (MRD) for fit patients with treatment-naïve CLL. This outcome is not surprising, Dr Stephens said, because venetoclax plus obinutuzumab is the “workhorse” in this regimen that drives the deep remission (undetectable MRD status). Venetoclax plus obinutuzumab, with or without ibrutinib, improved progression-free survival (PFS) over chemoimmunotherapy in CLL13. Ongoing trials (A041702 and CLL17) are comparing combination regimens involving ibrutinib, venetoclax, and obinutuzumab.

The GLOW study found that ibrutinib plus venetoclax improved PFS compared with obinutuzumab plus chlorambucil (an “antiquated” control arm, according to Dr Stephens) for patients with treatment-naïve CLL aged >65 years. The 3-month ibrutinib lead-in to the ibrutinib plus venetoclax arm limits the risk for tumor lysis syndrome with venetoclax and allows for patients to avoid hospital admission for their venetoclax ramp-up, she explained. Also, evidence suggests that patients on this regimen can respond to ibrutinib following relapse.

“It’s unclear at this point which population might benefit the most from this combination therapy,” Dr Stephens said.

Subsequent Therapies

When selecting subsequent therapies for patients with CLL/SLL, key factors to consider include the frontline therapy used, comorbidities, and resistance mutations. Venetoclax plus or minus anti-CD20 monoclonal antibodies or an alternate BTK inhibitor are the primary options for patients without a del17p/TP53 mutation. Enrollment in a clinical trial, if available, is recommended. Previous treatment is “one of the most important factors you need to use when deciding on the next line of therapy,” Dr Stephens said. She went on to discuss the algorithm she uses for subsequent treatment.

In cases with no previous BTK inhibitor or venetoclax treatment, comorbidities must be considered:

  • With uncontrolled AF or need for anticoagulation, Dr Stephens favors venetoclax plus obinutuzumab.
  • With reduced creatinine clearance or an inability to monitor for tumor lysis syndrome, or with del17p or TP53 mutation, consider acalabrutinib or zanubrutinib.
  • If the patient received venetoclax up front, options in the next line are acalabrutinib or zanubrutinib, or if >12 months since remission on venetoclax, consider retreatment with venetoclax plus obinutuzumab.
  • With previous BTK inhibitor and a BTK inhibitor resistance mutation, consider venetoclax plus obinutuzumab; without a resistance mutation, acalabrutinib or zanubrutinib is favored.
  • For patients who have received both a BTK inhibitor and venetoclax, clinical trial enrollment is favored.

In the ALPINE study comparing zanubrutinib with ibrutinib in patients with relapsed/refractory CLL, overall response rate and 24-month PFS were significantly better in the zanubrutinib arm. Zanubrutinib was also associated with a significantly lower rate of AF, a similar rate of hypertension, and numerically fewer major bleeding events and events leading to discontinuation compared with ibrutinib. Although the rate of neutropenia was higher with zanubrutinib, it was associated with a lower rate of grade ≥3 infections, Dr Stephens said.


  1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. Version 2.2023. January 25, 2023. Accessed April 18, 2023.

Related Articles