CLL Landscape to Change Dramatically Over Next Decade

Gina Columbus @ginacolumbusonc
Published Online: Monday, Nov 21, 2016

Jose Leis, MD

Jose Leis, MD

Standard treatment approaches for patients with chronic lymphocytic leukemia (CLL) will continue to include fludarabine, cyclophosphamide, and rituximab (FCR) and allogeneic stem cell transplantation.

However, recent approvals of novel agents and ongoing developments of combination regimens are advancing the field into a realm of new, improved, and individualized possibilities for patients, explains Jose Leis, MD.

One clinical opportunity is a phase II study of ibrutinib (Imbruvica)—which was first approved as a treatment for patients with previously treated CLL in September 2014 and later as a frontline therapy in March 2016—plus venetoclax (Venclexta) in patients with relapsed/refractory disease or high-risk untreated patients (NCT02756897). Venetoclax was approved by the FDA in April 2016 in pretreated patients who have a 17p deletion (del[17p]).

Leis lectured on this shifting landscape of CLL during the 2016 OncLive State of the Science Summit on the Treatment of Hematologic Malignancies.

“To be aware of your patient and really understand them is really going to be pivotal to what therapy you recommend for that patient,” said Leis. “It’s very clear that 1 medication—1 therapy—does not fit all.”

In an interview, Leis, a professor of Medicine and head of the Chronic Lymphocytic Leukemia Program at Mayo Clinic, spoke on the current state of the disease and pivotal clinical trial findings in CLL to be presented at the 2016 ASH Annual Meeting. Additionally, he provided insight into the potential of chimeric antigen receptor (CAR) T-cell therapies in CLL and how the treatment paradigm will look in the coming years.

OncLive: How have we seen the field of CLL evolve?

Leis: The world of CLL therapy has just really dramatically changed in the last 20 years. I got interested in CLL because my father-in-law called while I was a young faculty member at Harvard and told me he had been diagnosed with CLL. In 1995, we didn’t know about prognostic factors; we didn’t really know anything about the clinical course of aggressive CLL. Unfortunately, within 3 years, he passed from his disease.

What we knew at that time really didn’t tell us what the basis of the disease was. The first major advance was that our understanding that cytogenetics made a difference. In a German study published in The New England Journal of Medicine in 2000, it showed that it’s really not 1 disease; it’s a broad spectrum of B-cell aggressiveness from the 17p deletion patients who literally have 6 months before they progress to needing treatment, to 13q deletion (del[13q]) patients who will go for a decade before they might progress. There is also the finding about the mutational status in immunoglobulin genes. That’s going to be a really important thing in the next 20 years.

The big advances started with the combination of chemoimmunotherapy, the FCR regimen by Dr. Michael Keating of The University of Texas MD Anderson Cancer Center in the early 2000s. That really improved the responses and the complete remission rates.

The second thing that really happened in the late 2000s was the understanding that the B-cell–receptor pathway plays a major role. Once that became known, then targeted therapies could be developed. We went from chlorambucil as single therapy, lymphoma-type regimens with fludarabine and purine analogs, and then combination therapy. In the 2010s, the era has become that of targeted therapies.

What is the state of the disease now?

It is depending on each individual patient. The University of Texas MD Anderson Cancer Center group and the Germans who collaborated on this mutational status study are playing a major role. Twenty percent to 40% and more of patients treated with FCR who had the mutated subtype immunoglobulin genes had favorable cytogenetics. At a 13-year follow-up, they don’t have any evidence of disease.

Therefore, MRD status is playing a role here. However, the important thing is that, potentially, chemoimmunotherapy can cure some patients. That is really very different than we used to think—that nobody could be cured. For favorable-risk patients who are young and fit, FCR may cure a subset of those patients.

For the high-risk patients, you need targeted therapies, which have been nothing but phenomenal. The response rates seen with single agents have been at more than 80%. Results with ibrutinib have been dramatic in the high-risk 17p deletion patients. It looks like upfront therapy with ibrutinib is better than in the relapsed/refractory setting; we know that patients with 17p deletion who have had other therapies will relapse at a median of 28 months. However, that has been much better with upfront therapy.




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Online CME Activities
TitleExpiration DateCME Credits
Cancer Summaries and Commentaries™: Update From Orlando: Advances in Myeloproliferative NeoplasmsJan 29, 20172.0
Cancer Summaries and Commentaries™: Update from Orlando: Advances in Non-Hodgkin LymphomaJan 29, 20171.5
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