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What’s New Regarding Frontline Combination Regimens in CLL

Ian W. Flinn, MD, PhD

Director, Lymphoma Research Program
Sarah Cannon Research Institute
Nashville, Tennessee

Ian W. Flinn, MD, PhD, has disclosed that he has received consulting fees from AbbVie, Seattle Genetics, TG Therapeutics, and Verastem Oncology and funds for research support paid to his institution from AbbVie, Acerta, Agios, ArQule, AstraZeneca, BeiGene, Calithera, Celgene, Constellation, Curis, Forma, Forty Seven, Genentech, Gilead Sciences, Incyte, Infinity, Janssen, Juno, Karyopharm, Kite, Merck, MorphoSys, Novartis, Pfizer, Pharmacyclics, Portola, Roche, Seattle Genetics, Takeda, Teva, TG Therapeutics, Trillium, Unum, and Verastem Oncology.

View ClinicalThoughts from this Author

Released: May 3, 2019

Frontline treatment options for patients with newly diagnosed chronic lymphocytic leukemia (CLL) continue to expand at a rapid pace. In this commentary, I will share insights on important new data on frontline combination regimens in CLL and how we might interpret these data for clinical practice now and in the future.

Ibrutinib in Frontline Combination Regimens
Data from 3 important phase III trials in frontline CLL were presented at the 2018 ASH annual meeting:

  • ECOG-E1912 compared ibrutinib plus rituximab to fludarabine/cyclophosphamide/rituximab (FCR) in 529 patients with untreated CLL aged 70 years or younger
  • ALLIANCE A041202 compared ibrutinib alone with ibrutinib plus rituximab and with bendamustine plus rituximab (BR) in 547 patients with untreated CLL aged 65 years or older
  • The iLLUMINATE trial compared obinutuzumab plus ibrutinib with obinutuzumab plus chlorambucil in 229 patients with untreated CLL aged 65 years or older or younger than 65 years of age with comorbidities 

If one assesses the results of these trials together, it is clear that ibrutinib—either alone or in combination with an anti-CD20 antibody—substantially improves outcomes for patients with previously untreated CLL in terms of PFS compared with current standards of care. In all 3 trials, the PFS benefit was most profound among patients with adverse prognostic factors, although patients with good-risk cytogenetics also benefited from ibrutinib. 

Of importance, the ALLIANCE trial had both an ibrutinib monotherapy arm as well as an arm with ibrutinib plus rituximab and suggested that there was no additional benefit of adding rituximab to ibrutinib vs ibrutinib alone. Based on these data, I do not think there is an advantage to adding rituximab to ibrutinib; using ibrutinib as a single agent in frontline CLL is a reasonable approach instead of the ibrutinib/rituximab combination.

The outstanding question now is whether the addition of obinutuzumab—widely regarded as a superior anti‑CD20 antibody—improves outcomes over ibrutinib alone. The iLLUMINATE trial did not explicitly address that question. Rather, it demonstrated that the combination of ibrutinib and obinutuzumab was superior to obinutuzumab plus chlorambucil. It is difficult to tease out how much of the efficacy was due to ibrutinib alone or the combination with obinutuzumab. Either approach is reasonable in an older patient population, but I suspect many clinicians would elect to use primarily single‑agent ibrutinib in the frontline setting.

The ongoing phase III ELEVATE-TN trial will help clarify the role of obinutuzumab in the frontline setting in combination with a BTK inhibitor. This trial is assessing the second-generation BTK inhibitor acalabrutinib as a single agent vs combination with obinutuzumab vs obinutuzumab plus chlorambucil in frontline CLL. A phase Ib/II trial of the acalabrutinib/obinutuzumab combination showed high response rates in both frontline and relapse populations.

The bigger question involves the comparison of acalabrutinib vs ibrutinib: Which is the superior BTK inhibitor? There is an ongoing head-to-head trial in the relapsed setting. Acalabrutinib certainly has a different adverse event (AE) profile from ibrutinib. I think most assume that if efficacy is superior and the AE profile is superior in the relapsed setting, the same will be true in the frontline setting.

Venetoclax in Frontline Combination Regimens
There are multiple ongoing trials testing venetoclax combined with other agents in frontline CLL. Our group just published data from a phase IB trial showing that venetoclax plus obinutuzumab resulted in profound MRD negativity as frontline treatment of CLL. ORR was 100%, and the vast majority (91%) of patients became MRD negative in peripheral blood. ORR and MRD negativity rates did not seem to vary according to cytogenetic subgroup in this trial; high‑risk patients did just as well as the low‑risk patient population.

MRD negativity is important because it might allow patients to discontinue treatment after approximately 1 year. In comparison, current ibrutinib-based regimens do not seem to result in profound MRD negativity. As a result, patients remain on these regimens as long as they are tolerating them and are not experiencing AEs.

In the phase III CLL14 trial, the German CLL Study Group investigated venetoclax plus obinutuzumab vs obinutuzumab plus chlorambucil in patients with previously untreated CLL. A hint to the results of this trial came from a press release announcing an improvement in PFS. I expect CLL14 will confirm the data that our group just published showing deep MRD‑negative remissions with time‑limited therapy. These results are going to be important for clinical practice and may further change our treatment paradigms, although the CLL14 study population is similar to iLLUMINATE, which enrolled only older or unfit patients.

Other Frontline Combination Regimens
To come full circle, I should mention that there were several presentations at ASH 2018 looking at the combinations of ibrutinib/venetoclax or ibrutinib/venetoclax/obinutuzumab as frontline therapy in CLL. These smaller, limited studies showed that these combinations led to high ORR and deep remissions with MRD negativity, but we do not know which regimen is optimal. We will have to see how the data mature.

An important trial that will help clarify many outstanding questions regarding targeted therapy combinations in frontline CLL and may suggest new paradigms for the future is the ongoing phase III CLL13 study. This trial is comparing standard chemoimmunotherapy with FCR or BR to 3 separate venetoclax-based regimens: venetoclax plus rituximab, venetoclax plus obinutuzumab, or triple therapy with venetoclax plus ibrutinib and obinutuzumab. This trial will explore whether targeted therapy combination approaches can supplant chemoimmunotherapy as well as compare various doublet or triplet combinations using venetoclax. When using combinations, one must also be sensitive to the potential for AEs and cost. It does not make sense to prescribe these extremely expensive regimens unless there is a clear advantage. Hence, I think CLL13 will yield very important results.

In addition, the phase II CAPTIVATE study is assessing the combination of venetoclax and ibrutinib in the frontline setting and includes 2 different cohorts. One of the cohorts is assessing MRD-guided discontinuation, ie, whether a time‑limited approach with this combination makes sense. The other cohort is assessing fixed-duration therapy with the same combination.

Frontline Treatment Recommendations
When making recommendations on frontline treatment for CLL today, I would recommend ibrutinib alone or in combination with obinutuzumab for most patients. The exception would be for those patients with a contraindication to ibrutinib. I tend to mostly use single-agent ibrutinib; there are not many patients for whom I would use the combination with obinutuzumab. If I were to use combination therapy, it would be with older or less fit patients based on the evidence from the iLLUMINATE trial. Unfortunately, I do not think we have enough information to know if one approach is better than the other. Data from some of the ongoing trials will shed more light on this question.

When treating patients who are not ideal candidates for ibrutinib—for example, they are on anticoagulation therapy, have heart problems, are intolerant to ibrutinib—I would recommend a combination of obinutuzumab and venetoclax if insurance is not an issue. In my practice, I have moved away from FCR and BR and now recommend obinutuzumab/venetoclax for these patients. I suspect that more patients will be switched over to frontline venetoclax combinations once we start to see results from some of the ongoing trials. Hopefully in the future, using one of these combination therapies with venetoclax, which allows patients to come off treatment, will become a real possibility.

Your Thoughts?
How do you approach frontline therapy for patients with CLL? I encourage you to answer the polling question and post your thoughts in the comments box. For more expert insight on the treatment of CLL, check out this interactive decision support tool to see how 5 experts would proceed for your cases. The tool is currently being updated, so check back here to explore the new version soon.

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