Expert Reviews Sequencing Strategies for Explosion of New CLL Treatment Options


While the treatment landscape for chronic lymphocytic leukemia has expanded with an explosion of new therapeutic options, physicians are plagued with questions about sequencing therapies for those who progress following therapy in the first-line setting, and little data exists to guide optimal therapy selection, according to Anthony Mato, MD.

Anthony Mato, MD

Anthony Mato, MD

While the treatment landscape for chronic lymphocytic leukemia (CLL) has expanded with an explosion of new therapeutic options, physicians are plagued with questions about sequencing therapies for those who progress following therapy in the first-line setting, and little data exists to guide optimal therapy selection, according to Anthony Mato, MD.

Since 2013, the FDA has approved 6 new drugs and combinations, resulting in 720 unique sequences of novel therapies, Mato said during a presentation at the 38th Annual CFS® virtual conference.1 “It’s really been an exciting time,” said Mato, director of the CLL Program/Leukemia Service at Memorial Sloan Kettering Cancer in New York, New York. “However, as we have more and more choices available to patients, new challenges are emerging on how to best sequence these therapies and how to manage patients who fail all of these molecules.”

After patients progress on frontline therapy, choices in the second line depend on which upfront therapy they received, reasons for discontinuation, and the levels of evidence available to evaluate options, Mato said. “There’s no comparative frontline data available for novel agent versus novel agent.”

The choices fall into 3 categories: Bruton tyrosine kinase (BTK) inhibitors, the BCL-2 inhibitor venetoclax (Venclexta), or a PI3K inhibitor such as idelalisib (Zydelig), Mato said.1

In a real-world study, Mato and colleagues compared sequencing outcomes for 683 patients treated in either the BTK inhibitor ibrutinib (Imbruvica), idelalisib, or venetoclax. In terms of kinase inhibitor (KI) selection, the results showed that those treated with ibrutinib achieved a longer progression-free survival (PFS) than those who had idelalisib in the frontline setting (HR, 2.8; CI, 1.3-6.3; P = .01) and in the relapsed/refractory (R/R) setting (HR, 2.8; CI, 1.9-4.1; P < .001). Patients who progressed after KI therapy had better outcomes with another KI or with venetoclax than they did with chemoimmunotherapy. The data also suggest that venetoclax may be more effective than idelalisib after ibrutinib failure.2

Therapy choices in the R/R setting were explored in the phase 3 ASCEND trial (NCT02970318), which randomized patients between the BTK inhibitor acalabrutinib (Calquence) and either idelalisib plus rituximab (Rituxan; IdR) or bendamustine plus rituximab (BR), which Mato said is not commonly prescribed in the United States. The findings show that median PFS was not reached for acalabrutinib compared with 15.8 months with IdR (HR, 0.29; 95% CI, 0.18-0.46; P < .001).3

“The take-home from this study was that they found the exact same thing that our real-word study had found 2 years earlier,” Mato said. “BTK was better not only from the perspective of PFS but was also better from the perspective of tolerability and discontinuation rates.”

For patients who received chemotherapy or chemoimmunotherapy in the frontline setting, there are no randomized data to guide R/R therapy choices and no trials are planned, Mato said. The results of an analysis of patients who received either ibrutinib or venetoclax with or without a CD20-targeting agent as the first-line novel therapy after relapse showed a significant PFS advantage favoring venetoclax (HR, 0.29; 95% Cl, 0.10-0.92; P = .036).4

“In all circumstances when clinical acceptable, the data support using a BTK inhibitor or venetoclax before a PI3K inhibitor,” Mato said. He added that there are no definitive data to support this conclusion but findings from real-world analyses are “intriguing.”

When it comes to evaluating R/R options for patients who have received a BTK inhibitor or venetoclax in the frontline setting, Mato said considerations should include prior therapies, resistance, and intolerance. Data on sequencing therapies after BTK inhibitors, which are increasingly being administered in the frontline and R/R settings, are available mostly from retrospective studies but also “a growing list of clinical trials.”

In a patients who received ibrutinib as frontline therapy, the overall discontinuation rate in the real-world setting was 24% (94 events in 391 patients), compared with the initial rate of 12.5% (17 events in 135 patients) in patients 65 years or older with treatment-naïve CLL or small lymphocytic leukemia enrolled in the phase 3 RESONATE-2 trial (NCT01722487). In all, 59.5% of patients said they discontinued therapy due to adverse events (AEs).5

After a 5-year follow-up, the discontinuation rate from patients treated with first-line ibrutinib in RESONATE-2 rose to 41%, with AEs most commonly cited for stopping therapy, according to data published in the New England Journal of Medicine.6 Mato said other studies have shown similar rates of discontinuation due to AEs or progression of disease because of CLL or Richter transformation.

After discontinuation of ibrutinib or idelalisib, Mato said, there is no role for sequencing chemoimmunotherapy and that venetoclax appears more effective than an alternative KI especially in the setting of ibrutinib resistance; however, there may be a role for switching agents in the BTK class in the case of KI intolerance.

For patients who start with venetoclax as their first novel agent, BTK inhibitors produce high overall response rates and durable remissions among patients who have not previously received a BTK-targeting agent, Mato said. He said follow-up data from the phase 3 MURANO trial (NCT02005471) indicate a response rate of nearly 100% for patients who received ibrutinib after venetoclax. The response rate was 55% among a small number of patients (6 of 11) who were retreated with venetoclax following prior therapy with that agent.7

Moving forward, Mato said, therapy choices will become even more complex as new strategies are introduced. “In all of these situations, you should be considering a clinical trial as the best option available for patients. In addition, as we have the emergence of cellular therapies, we should think about use of CAR T [chimeric antigen-receptor T-cell therapy] for patients who fail at least 2 novel agent based–therapies and/or the reemergence of allogeneic stem cell transplantation as we have more and more patients who are being treated with all of the available novel classes of patients and who no longer have standard-of-care options.”


  1. Mato AR. Choosing first-line therapy for CLL. Presented at: 38th Annual CFS®. November 4-6, 2020.
  2. Mato AR, Hill BT, Lamanna N, et al. Optimal sequencing of ibrutinib, idelalisib, and venetoclax in chronic lymphocytic leukemia: results from a multicenter study of 683 patients. Ann Oncol. 2017;28(5):1050-1056. doi:10.1093/annonc/mdx031
  3. Ghia P, Pluta A, nWach M, et al. ASCEND phase 3 study of acalabrutinib vs investigator’s choice of rituximab plus idelalisib (IDR) or bendamustine (BR) in patients with relapsed/refractory (r/r) chronic lymphocytic leukemia (CLL). Presented at: European Hematology Association Annual Meeting; June 13-16, 2019; Amsterdam, Netherlands. Abstract LBA2606. Accessed November 4, 2020.
  4. Eyre TA, Lamanna N, Roeker LE, et al. Comparative analysis of targeted novel therapies in relapsed, refractory chronic lymphocytic leukaemia. Haematologica. Published online February 20, 2020. doi:10.3324/haematol.2019.241539
  5. Mato AR, Roeker LE, Allan JN, et al. Outcomes of front-line ibrutinib treated CLL patients excluded from landmark clinical trial. Am J Hematol. 2018;93(11):1394-1401. doi:10.1002/ajh.25261
  6. Burger J. Treatment of chronic lymphocytic leukemia. N Engl J Med. 2020;383(5):460-473. doi:10.1056/NEJMra1908213
  7. Seymour JF, Kipps TJ, Eichhorst BF, et al. Four-year analysis of Murano study confirms sustained benefit of time-limited venetoclax-rituximab (VenR) in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Blood. 2019;134(suppl 1):355. doi:10.1182/blood-2019-123930
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