Improving Outcomes in CLL With a Prognostic Approach

New York—By preemptively looking for patients with chronic lymphocytic leukemia (CLL) who are most likely to not respond to therapy with Bruton's tyrosine kinase (BTK) inhibitors in the long-term, or who will develop Richter’s transformation, clinicians can improve outcomes in this population.

This was the main topic of a presentation by Richard Furman, MD, Director of the CLL Research Center at Weill Cornell Medicine, New York, at the 2018 Lymphoma & Myeloma congress.

“What I really hope to show all of you is what I think is really the unmet medical need—what we really need to do next to help our patients, and what hopefully will be the final thing that we need to do to help our patients,” Dr Furman said at the start of his talk.

Outcomes Still Need Improvement

“It looks like, if you look at the historical data, we’re actually having an improvement in our outcomes for CLL patients in that they’re living longer,” Dr Furman told attendees. However, this is not the case.

Citing data from European studies dating from 1970 to 1998, he attributed the gradual increase in survival to earlier diagnosis, and by extension, earlier stage of disease at diagnosis.

Referring to 2010 as a “very good cutoff” for when we started to have novel agents become available for the treatment of CLL, Dr Furman expressed hope for a real improvement in survival for these patients, as well as a normal life expectancy at some point in the future.

According to him, the next frontier for achieving these goals is in non-chemotherapeutic approaches.

“We have our novel agents, which really include BCR-associated kinase inhibitors and BCL-2 Inhibitors, and we really have an array of them coming up,” he said.

Predicting a Lack of Treatment Response

Dr Furman then shifted gears to discussing what he described as being the most important question, “Who are those that will not have long-term disease control with BTK inhibition, and can we identify these patients ahead of time?”

There are 2 types of BTK inhibition failures. The first one involves patients with CLL who respond to treatment and then have disease progression. There are specific mutations involved, but according to Dr Furman they don’t develop as a result of therapy but likely pre-exist because of abnormalities in the CLL clone. The second type of failure is when CLL converts to Richter’s transformation; novel agents do not work on Richter’s transformation.

Prognostic Factors to Consider

Citing studies demonstrating variables associated with discontinuation of ibrutinib therapy in this patient population, Dr Furman pointed out that the main factors associated with progressed disease or Richter’s transformation are genomic.

Certain traits are also more common in patients who have CLL progression, including having 17p deletion or complex karyotype, and being aged <65 years.

In addition, the use of interphase fluorescence in situ hybridization has been shown to be a very significant predictor of outcomes with ibrutinib, particularly in the relapsed/refractory setting.

Data show that the median time to Richter’s transformation is an average of 1.8 years, which is very short, and approximately 50% of patients have Richter’s transformation before therapy.

“What this all speaks to is probably what’s one of the most important take-home messages, that Richter’s transformation is really the biology of the CLL, and not necessarily something treatment-related,” he told attendees. “It’s really something inherent in the CLL cells.”

In particular, data show that patients with the NOTCH1 mutation at diagnosis have an increased tendency to develop Richter’s transformation. Because this mutation shows up at diagnosis in roughly 10% of the population, Dr Furman posits that looking out for NOTCH1 at the point of presentation can off the bat help to determine 5% of patients who will develop this syndrome.

Thus, it is feasible to determine ahead of time which patients will develop resistance and treat them differently, either with earlier treatment initiation before mutations occur or with combination therapy that would allow you to knock down multiple pathways and prevent resistance.—Hina Khaliq