Evolution Anticipated in First-Line Treatment for CLL, Indolent Lymphomas

Elizabeth Leick and Gina Columbus
Published Online: Tuesday, Jan 03, 2017

Andrew D. Zelenetz, MD, PhD

Andrew D. Zelenetz, MD, PhD

Novel therapies are being investigated in 2 areas of hematologic malignancies, but the first-line setting is where the brunt of research needs to be conducted, explains Andrew D. Zelenetz, MD, PhD.

For patients with indolent lymphoma or chronic lymphocytic leukemia (CLL), the optimal frontline choice does not exactly exist, he says. While treatment options have evolved and improved over time, researchers are still debating between bendamustine- or CHOP-based regimens for follicular lymphoma, for example. And while chemoimmunotherapy remains a standard frontline approach for younger, fit patients with CLL, it’s not as clear as to what is best for the older patient population.

Zelenetz, the medical director of Quality Informatics at Memorial Sloan Kettering Cancer Center, spoke on indolent lymphoma and CLL treatment during the 2016 OncLive® State of the Science Summit on Hematologic Malignancies. In an interview during the meeting, he discussed how the field has evolved over the last several years to include more effective treatments, and the work being done to determine optimal first-line therapies in both spaces.

OncLive: Can you provide an overview of your presentation?

Zelenetz: When you are diagnosed with follicular lymphoma, your expected survival is inferior to the age match general population, but not by very much. The median survivals in this disease have changed from 8 to 10 years 25 years ago, to 16 to 20 years as a median survival today.

We know that first-line therapy is important. First-line therapy can result in long progression-free survival (PFS). We’re still struggling to find the optimal first-line therapy, whether it’s bendamustine-based, or CHOP or CVP; the answer is not crystal clear.

One of the interesting things we saw from the 2016 ASH Annual Meeting is what’s called the GALLIUM trial, which is bendamustine plus CHOP or CVP combined with rituximab (Rituxan) or obinutuzumab (Gazyva). This was a head-to-head comparison of rituximab versus obinutuzumab in indolent lymphoma. The follicular lymphoma cohort was spoken about at the presentation, while the non-follicular indolent cohort wasn’t. It actually met its endpoint. The statistical plan was looking for an improvement (with obinutuzumab)—a hazard ratio of 0.74. The hazard ratio is 0.66. That corresponds to a 50% increase in the PFS.

People think that not much has been accomplished because the curves don’t look that different, but the curves can’t look that different. A 50% increase in PFS is going to correlate to about a 10-year survival after first-line therapy. That’s pretty impressive, and it’s going to be hard to beat. We have a large, randomized study comparing rituximab and lenalidomide (Revlimid) with rituximab chemotherapy, but it’s going to be hard to beat a median PFS of 10 years with chemoimmunotherapy.

What about the CLL landscape?

In the CLL world, we are still struggling with first-line therapy. There’s a group of patients, particularly young, fit patients with mutated immunoglobulin genes, who have a 10-year PFS in the range of 70%. They’re probably cured. There are very few events in that group of patients. From that group, which is a very small group, we can define a standard of care, which is FCR (fludarabine, cyclophosphamide, and rituximab).

However, for the older patient or the fit patient who does not have a mutated immunoglobulin gene, chemoimmunotherapy works, but will fail. Findings from the RESONATE-2 trial suggest that you can give ibrutinib (Imbruvica). However, the problem with ibrutinib is it’s going to be far too expensive in the United States, let alone the rest of the world. This is the economic challenge of introducing new drugs early in the treatment paradigm. We know ibrutinib works really well after chemoimmunotherapy. In the selected patient, ibrutinib should be used. We now have idelalisib (Zydelig) and venetoclax (Venclexta), so we have other options in the relapsed refractory setting.

There are a couple of the emerging things from the 2016 ASH Annual Meeting in the relapse setting for indolent lymphoma. Ibrutinib looks okay in marginal zone lymphoma, but positively awful in follicular lymphoma. Again, this is pointing out that all indolent lymphomas are not created equal; these are different diseases.




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