Expert Answers: What's the Best Frontline Treatment for Chronic Lymphocytic Leukemia

According to William G. Wierda, M.D., Ph.D., it might be best to have multiple frontline standard therapies for patients with chronic lymphocytic leukemia (CLL), as opposed to one standard frontline therapy. There is currently debate over which option is best: Imbruvica (ibrutinib) or chemoimmunotherapy with fludarabine, cyclophosphamide and Rituxan (rituximab) (FCR)

“To give everybody the same treatment these days is probably not critically thinking about what we are trying to achieve and acknowledging the fact that there are probably subgroups that benefit more than others with specific types of treatment,” said Wierda, medical director of the Leukemia Center at The University of Texas MD Anderson Cancer Center. “This is a topic where we need to have a good discussion with our patients and get back from them which approach they would like, because there are pros and cons to both.”

What are the biggest questions regarding the frontline management of CLL?

In an interview with CURE, Wierda discussed which groups of patients may benefit from Imbruvica versus chemoimmunotherapy and clinical trials that may provide further clarification. Recently the RESONATE-2 trial evaluated frontline therapy for patients over 65 receiving treatment with either chlorambucil or Imbruvica. That trial showed an improvement in progression-free survival as well as overall survival for patients that received Imbruvica as their first therapy.

Are there any subgroups of CLL where the ideal frontline therapy is more clear?

The question here is now how do we manage patients in the first-line setting? Does the RESONATE trial support giving everyone frontline Imbruvica therapy? The FDA gave approval to Imbruvica in this setting, not only limited to patients over 65 — the patients treated on this trial — but to all patients. These are areas of debate where there are not clear data that support one way over another.For me, the only absolute in the frontline setting is that patients who have a 17p deletion — a very small percentage of patients, about 5 percent to 8 percent — should go on Imbruvica therapy. They should not get chemotherapy or chemoimmunotherapy because their disease does not respond to that, and we are only doing them harm by giving them first-line chemotherapy. Everyone who has a 17p deletion, going on either first-line or salvage therapy, should get Imbruvica.

The other subgroup that has clearer data is the young, fit patients who have a mutated immunoglobulin heavy chain variable gene. We’ve done long-term follow-up on our FCR experience, and this has been confirmed by the German CLL group, that patients who have a mutated V gene benefit the most by the FCR frontline chemoimmunotherapy. About half to two-thirds of them will be progression free beyond two years of treatment. This is a more than 10-year treatment-free interval; these are patients who are potentially cured with FCR in the frontline setting. For me those data support giving FCR in the frontline setting to the young, fit patients who have a mutated V gene. We are working on strategies to minimize chemotherapy exposure and working towards achieving the same effects that we can with six cycles of FCR with our clinical trials. That is the other group for me where the data clearly support how they should be managed.

Are there any studies on the horizon that may further clarify which subgroups of patients should receive which frontline therapy?

For elderly patients and younger patients who have an unmutated V gene, I think a lot of what goes into choosing the first line of therapy depends on what the clinician needs to achieve in terms of the treatment and what the patient would also like in terms of management. In the RESONATE-2 trial, the comparator arm was chlorambucil, which I don’t think any of us currently involved in clinical trials in CLL agree is an appropriate control arm because it is an ineffective treatment. We have had several clinical trials that have shown improvements in outcome over chlorambucil with the addition of a CD20 antibody.

We have a clinical trial now at MD Anderson open for young, fit patients with mutated V gene to receive Imbruvica, fludarabine, cyclophosphamide and obinutuzumab with just three cycles of chemotherapy. The primary endpoint of that trial is MRD-negative complete remission after three months of treatment. We have some other trials for the unmutated and the elderly that focus more on achieving a good complete remission, which is MRD-negative, so that we can have some consideration about a treatment-free interval. In that way, we may be able to improve on the outcomes that we have with Imbruvica monotherapy.