Updated Treatment Guidelines for CLL/SLL

By Dustin Samples - Last Updated: April 6, 2023

On Saturday, April 1, at the 2023 National Comprehensive Cancer Network (NCCN) Annual Meeting in Orlando, Florida, Deborah Stephens, DO, of the Huntsman Cancer Institute, University of Utah, presented an update on the NCCN guidelines for chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL).

In the talk, Dr. Stephens reviewed the current treatment options and available evidence on sequencing therapy and gave examples of individualized treatment plans. She presented algorithms for decision-making on first-, second-, and third-line treatments. Notably, she placed heavy emphasis on enrolling all patients, regardless of first diagnosis or relapsed/refractory (R/R) status, in clinical trials if available. “The reason being is because we still haven’t cured [CLL] outside the setting of [an] allogenic stem cell transplant, which most patients are actually not a candidate [for],” she told the presentation attendees.

Options for front- and second-line therapies are largely similar. The 3 current options include:

  1. Bruton Tyrosine Kinase (BTK) inhibitors with or without anti-CD20 monoclonal antibody (mAb),
  2. Venetoclax (ven) with anti-CD20 mAb, or
  3. Immunotherapy.

What differed were the algorithms used for first treatment versus treatment for R/R CLL. Dr. Stephens presented detailed algorithms for each scenario and cited the relevant clinical trial results for each treatment decision.

First-line Treatment Algorithm

Patients should be enrolled in a clinical trial if available. If no clinical trial is available, check the immunoglobulin heavy chain gene (IgHV) mutation status.

  1. If IgHV is mutated, check fluorescence in situ hybridization (FISH) results. Discuss chemotherapy using 6 cycles of cyclophosphamide, fludarabine, and rituximab (FCR) if the patient is <65 years old and has deletion 13q (del13q+).
  2. If IgHV is unmutated and the patient has deletion 17p (del17p+) or TP53 mutations, treat with second-generation BTK inhibitors, including acalabrutinib (acal) or zanubrutinib (zanu).
  3. If no or other types of deletions are detected and the patient has comorbidities such as uncontrolled atrial fibrillation (afib), requires anticoagulative therapy, or strongly prefers time-limited therapy, treat with ven and obinutuzumab (obin) for 12 months.
  4. If the patient has poor creatinine clearance (ClCr < 30ml/min) or an inability to monitor for tumor lysis syndrome (TLS), treat with acal or zanu.

Second-line Treatment Algorithm

First, enroll the patient in a clinical trial if available. If no clinical trial is available, review the patient’s first-line treatment.

  1. Consider comorbidities if the patient has no prior treatment history with BTK inhibitors or ven. Treat the patient with ven + obin for 24 months if they have uncontrolled afib and/or require anticoagulants. Treat them with acal or zanu if they have poor CrCL, del17p or TP53 mutations, or TLS is unmonitorable.
  2. If the patient has no prior treatment with ven, was treated with acal or zanu, or has been in remission for >12 months, retreat them with ven and add obin (24 months).
  3. Determine whether BKT inhibitor resistance mutations are present if the patient had prior treatment with BKT inhibitors. If they are present, treat the patient with ven + obin for 24 months. If they are not present, treat them with acal and zanu.
  4. If the patient underwent prior treatment with BKT inhibitors and ven, re-check for available clinical trials as this type of patient has the shortest survival period. If clinical trials are unavailable, refer the patient for CAR-T cell therapy or stem cell transplant.

Resistance to BTK inhibitors

Finally, Dr. Stephens discussed what to do if patients develop resistance to BTK inhibitors. Resistance typically occurs after 2-3 years of BTK inhibitor therapy. Patients begin to develop a mutation in the cysteine at position 481 (C481S). This mutation indicates that covalent bonds no longer exist between the BTK protein and drug molecules. The implication is that bonding occurs sometimes, but the bonds are loose. This situation is precarious as patients will relapse quickly if BTK inhibitor therapy is discontinued (remember that some bonds are still forming, so there is still some efficacy).

According to Dr. Stephens, the emerging treatment for this situation is pirtobrutinib (pirt), which has minimal toxicity and does not require C481 binding. In the BRUIN phase 1/2 study of 261 heavily pretreated patients, the overall response rate to pirt was nearly 70%, and progression-free survival was independent of BTK mutation status. However, despite being approved for R/R mantle cell lymphoma, pirt is not yet approved for CLL, and trials are ongoing.


Stephens D. NCCN Guidelines® update: chronic lymphocytic leukemia/small lymphocytic lymphoma. Presented at the 2023 National Comprehensive Cancer Network Annual Meeting, Orlando, Florida, March 31-April 2, 2003.

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