NCCN Session Offers Considerations for Frontline, Second-line Treatment Choices in CLL


An April 1 session at the 2023 National Comprehensive Cancer Network (NCCN) on updates in CLL/SLL featured results on the ALPINE study, which led to the January 2023 approval of zanubrutinib in the frontline setting.

The ALPINE trial, which examined frontline use of the second-generation Bruton tyrosine kinase (BTK) inhibitor zanubrutinib (Brukinsa) in chronic lymphocytic leukemia and small lymphocytic leukemia (CLL/SLL), was the highlight of the 2022 American Society of Hematology Annual Meeting & Exposition in New Orleans, Louisiana.1 So, it’s little surprise that an April 1 session at the 2023 National Comprehensive Cancer Network (NCCN) on updates in CLL/SLL featured these results, which led to the January 2023 approval of zanubrutinib in this setting.2

However, as Deborah M. Stephens, DO, assistant professor at the Huntsman Cancer Institute at the University of Utah explained, that doesn’t mean choices for treating newly diagnosed CLL are always straightforward. There are many considerations, including a patient’s age, whether the person has atrial fibrillation, other comorbidities, and whether a clinical trial is available.



Is a second-generation BTK inhibitor the best choice if it means indefinite use? Is the time-limited combination of venetoclax, a B-cell lymphoma-2 inhibitor, with obinutuzumab, a better option, for younger patients who may want to stop therapy at some point? Does the patient live close to the cancer center, making monitoring easy?

Always, Stephens said, physicians should ask, “Is there a great clinical trial available for these patients? If the answer is yes, I enrolled them—the reason being because we still haven’t cured chronic lymphocytic leukemia outside the setting of an allogeneic stem cell transplant,” and most patients are not candidates for this option.

If no trial is available, Stephens starts by checking immunoglobulin variable (IGHV) heavy chain status. “If there is a mutated copy of this gene, the next step would be looking at their FSH [follicle-stimulating hormone] results,” she said.

Then, for frontline therapy, it’s a matter of identifying characteristics and comorbidities:

  • For those with deletion 13Q disorder only who are younger than 65 years, Stephens will consider the combination of fludarabine, cyclophosphamide, and rituximab (FCR).
  • If deletion 17p or TP53 are present, second-generation BTK inhibitors, acalabrutinib or zanubrutinib, are preferred.
  • If the patient has uncontrolled atrial fibrillation—a condition that can be aggravated by BTK inhibitors—then the combination of venetoclax and obinutuzumab is in order.
  • For those with poor creatinine clearance—or without easy access to a lab facility—the second generation BTK inhibitors are the best choice, “because [they] are not really impacted by poor kidney function,” Stephens said.

The BTK inhibitor drug class might also be considered “for folks who have extensive infections, as there is evidence of immune reconstitution after being on BTK inhibitors,” she said.

Data on combinations. Stephens reviewed data from the CLL13 study, known as GAIA,3 performed by the German CLL group, which examined 4 study arms: the first taking FCR or bendamustine and rituximab for 6 months, the second taking venetoclax and rituximab for 12 months, the third taking venetoclax and obinutuzumab for 12 months, and the fourth taking a triplet of venetoclax, obinutuzumab and ibrutinib for 12 months, with the option to extend ibrutinib to 36 months.Patients with deletion 17p were excluded.

There have been some interesting takeaways, she said.

It appears the patients taking obinutuzumab are more likely than those taking rituximab to achieve undetectable minimal residual disease. “It really just adds to the growing number of studies that show that obinutuzumab is a better antibody for patients who have CLL as compared [with] rituximab, so that was a little bit of a surprising result,” she said.

Also, the early returns don’t show much benefit from adding ibrutinib to venetoclax and obinutuzumab, and no more patients are being added to that arm of the study. “However, this regimen is continued longer,” she said, “so this is something to watch…A big question will be if the toxicity of adding ibrutinib outweighs any efficacy benefit.”

The GLOW study recently reported on treatment-naïve CLL patients 65 years or older who were given obinutuzumab and chlorambucil vs fixed-duration ibrutinib and venetoclax.4 Although the second combination produced superior progression-free survival, Stephens suggested that a future combination would use second-generation BTK inhibitors. “I would hope that any future studies involving this combination would not be considered for patients with CLL because we have so many better drugs now.”

What comes next? Stephens noted the conundrum clinicians face if the most current therapies are used in a frontline setting: what happens when patients relapse?

It does appear that going first with time-limited therapy may limit the pressure on long-term use of BTK inhibitors, she said. Combinations that involved ibrutinib and showed toxicity may see different results with the second-generation BTK inhibitors. “There are multiple studies ongoing,” she said.

Insurance coverage may be a question mark, however.

“If any of you have prescribed these medications, you know that both [acalabrutinib and zanubrutinib] are very expensive medications. And so, I don't know how the authorization process is going to work,” she said. “Hopefully, the [pharmaceutical] companies are far ahead of us and have already figured something out. But it's unclear at this point which population might benefit the most from this combination therapy.”

Analyses of subgroups may follow, but as of now, “There’s still not evidence of a functional cure. And what do I mean by a functional cure?”

If long-term data, including that for FCR, show patients diagnosed in their 70s live for up to 15 years and possibly longer, “I think that is a functional cure.”

These data do not yet exist, Stephens said.

When patients relapse, a clinical trial is again the best option. Clinicians should review the prior treatment history, especially to see if BTK inhibitors or venetoclax were used in the frontline setting. And obinutuzumab should be considered in a second-line setting. “Admittedly, this regimen has not been studied in phase 3 study in the second-line setting,” Stephens said.

The MURANO study paired venetoclax and rituximab in second line,5 and many payers will look to that data—but Stephens emphasized how many studies now show the superiority of obinutuzumab to rituximab.

Clinicians should return to many of the same questions they asked with first-line therapy: what are the comorbidities? Can patients travel for monitoring? If a deletion 17p or TP53 mutation is present, she said, “I lean toward the second-generation BTK inhibitors,” she said.

“Or if it's been more than 12 months of remission, maybe you can give venetoclax and obinutuzumab again,” Stephens said, based on emerging data. “It’s not a hard and fast rule.”

As more studies are released, recommendations may be refined. The ELEVATE RR study showed non-inferiority for acalabrutinib,6 while data from ALPINE showed superiority of zanubrutinib over ibrutinib in a head-to-head trial across multiple lines of care.1 And data from the BRUIN study presented during ASH shows that a third-generation BTK inhibitor, pirtobrutinib—already approved in mantle cell lymphoma, may offer efficacy in CLL with the least toxicity yet.7


1. Brown JR, Eichhorst B, Hillmen P, Jurczak W et al, for the ALPINE investigators. Zanubrutinib or ibrutinib in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2023;388(4):319-332. doi: 10.1056/NEJMoa2211582

2. FDA approves zanubrutinib for chronic lymphocytic leukemia or small lymphocytic lymphoma. News release. FDA newsroom. January 19, 2023. Accessed April 12, 2023.

3. Eichhorst B, Niemann C, Kater A, et al. Time-limited venetoclax-obinutuzumab +/- ibrutinib is superior to chemoimmunotherapy in frontline chronic lymphocytic leukemia (CLL): PFS co-primary endpoint of the randomized phase 3 GAIA/CLL13 trial. Presented at EHA 2022; June 9-12, 2022. Abstract LB2365.

4. Kater AP, Owen C, Moreno C, et al, for the GLOW investigators. Fixed-duration ibrutinib-venetoclax in patients with chronic lymphocytic leukemia and comorbidities. NEJM Evid. 2022;1(7): DOI: 10.1056/EVIDoa2200006

5. Kater AP, Wu JQ, Kipps T, et al. Venetoclax plus rituximab in relapsed chronic lymphocytic leukemia: 4-year results and evaluation of impact of genomic complexity and gene mutations form the MURANO phase III study. J Clin Oncol. 2020;38(34):4042-4054. doi: 10.1200/JCO.20.00948.

6. Wolska-Washer A, Robak T. Acalabrutinib: a bruton tyrosine kinase inhibitor for the treatment of chronic lymphocytic leukemia. Expert Rev Hematol. 2022;15(3):183-194. doi: 10.1080/17474086.2022.2054800.

7. Mato AR, Woyach JA, Brown JR, et al. Efficacy of pirtobrutinib in covalent BTK-inhibitor pretreated relapsed/refractory CLL/SLL: additional patients and extended follow-up from the phase 1 / 2 BRUIN study. Presented at: 64th American Society of Hematology Annual Meeting and Exposition; New Orleans, Louisiana; December 10-13, 2022. Abstract 961.

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