Role of Chemotherapy in CLL Shifts as Novel Agents Transform Clinical Practice

William G. Wierda, MD, PhD

With several new agents recently approved for treating chronic lymphocytic leukemia (CLL), the role of chemotherapy in the management of the disease is in a state of flux. William G. Wierda, MD, PhD, says oncologists are now focused on delaying chemotherapy as long as possible and controlling the disease instead with the new targeted treatments.

Eventually, the hope is to treat patients without ever having to administer chemotherapy, according to Wierda, a professor in the Department of Leukemia, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center.

In an interview with OncLive, Wierda discusses the changing role of chemotherapy in the management of CLL and the integration of novel agents into clinical practice.

OncLive: What is the current status of the use of chemotherapy in CLL?

Dr Wierda: We are transitioning into an era where chemotherapy is delayed as long as possible, in preference to using small molecule inhibitors that can control the disease for an extended period of time. That way, patients may ultimately be spared of ever getting chemotherapy, though there will likely be some that eventually will need it.

What is the current standard use of chemotherapy in the frontline CLL setting?

In terms of frontline, chemotherapy is still the standard of care, except for patients who are untreated and have a 17p deletion. It is those patients for which ibrutinib is the frontline choice of treatment.

For younger, fit patients who can tolerate chemoimmunotherapy, fludarabine/cyclophosphamide/rituximab (FCR) is favored over bendamustine/rituximab (BR). However, some data suggest FCR has a higher cost of myelosuppression and perhaps infection. Progression-free survival (PFS) is improved with FCR, so for the younger, fit patients this treatment is the standard of care.

For patients who are frail, have comorbidities, or are over 65, chlorambucil plus obinutuzumab is the standard frontline therapy. This is based on a randomized trial , which showed obinituzumab was superior to rituximab in terms of efficacy. The chlorambucil plus obinutuzumab combination is preferred over chlorambucil and rituximab, as well as chlorambucil monotherapy.

Also, there is some data for chlorambucil plus ofatumumab, which showed improvements in outcomes compared to chlorambucil monotherapy. However, chlorambucil plus obinutuzumab showed improvements in overall survival (OS) compared to chlorambucil, while chlorambucil plus ofatumumab did not. The ofatumumab and chlorambucil combination was superior in terms of PFS compared to chlorambucil, but not in terms of OS. That survival advantage with obinutuzumab is what leads me to recommend that combination as the standard first-line therapy for the elderly population. For salvage patients, both ibrutinib and idelalisib are approved. Those would be considered standard treatment for previously treated patients.

Are there patients with CLL who should not be treated with small molecule inhibitors?

There is data generated by MD Anderson and a German CLL study group that showed there is a subgroup of patients eligible for chemoimmunotherapy and who do exceptionally well with it, which may cure some of them. These are patients who have a mutated V gene.

When treated with chemoimmunotherapy, particularly FCR, roughly two-thirds of that subgroup will have PFS beyond 10 years. I think that is an important feature. For some patients, chemoimmunotherapy may be the ideal option. Initially, further strategies may not be directed at eliminating chemotherapy for that subgroup, but instead may be directed at reducing the amount of necessary cycles or the exposure to required chemotherapy, in order to get similar effects.

What results do you expect to see from the RESONATE-2 trial, which examines frontline ibrutinib versus chlorambucil in newly diagnosed elderly patients with CLL?

I expect the initial reports to show improved outcomes for patients with ibrutinib over chlorambucil. Because of the crossover, it may be a long time before we see OS differences because you can salvage the patients with ibrutinib after they receive chlorambucil. They will likely do very well based on what we know from the RESONATE-1 trial. I expect to see improved PFS in terms of toxicities and tolerability.

Are there any secondary mutations that occur with ibrutinib that oncologists should be aware of?

We haven’t had many patients with ibrutinib resistance. Some patients who develop ibrutinib resistance have Richter’s transformation (RT) as the clinical picture for their resistance. This is about 30% to 40% of those patients. In terms of genetic changes or mutations that develop in those patients with RT, it is not as much of a significant issue. Those patients will need to move to an aggressive treatment for RT or a clinical trial.

Some patients just have resistance without RT, and some will discontinue treatment because of tolerability, toxicity, or infection. Possible causes include mutation in Bruton’s tyrosine kinase, or a downstream molecule PLC gamma, which renders resistance to ibrutinib, has occurred. Those are important for clinical research and collecting data, but in terms of the standard clinical use of the drug, I don’t think there is a need to adjust treatment or monitor for mutations based on that. I do think it is important to look for it for research purposes.

What do you see as the future for CLL treatment?

These newer agents are active and effective at controlling the disease. Our work is not yet done because many patients have a partial remission with these newer agents, and there is still a level of disease even at the best response. The future is figuring out how to get rid of the rest of CLL, how to get patients off treatment so they can have a treatment-free period, and how to reestablish the immune system so they don’t have these complications still occurring in the era of small molecule inhibitors. Our work is not done, but there is a lot of exciting stuff happening.