Conference Coverage

Studies need to address best follow-on therapy to ibrutinib in CLL


Reporting AT LYMPHOMA & MYELOMA 2017

NEW YORK – Clinical trials are needed to determine the best follow-on therapies when patients discontinue the ibrutinib due to adverse events or disease progression, according to a leading expert on chronic lymphocytic leukemia (CLL).

Anthony Mato, MD, MSCE, from the Abramson Cancer Center at the University of Pennsylvania in Philadelphia, discussed how real-world experience with the use of ibrutinib (Imbruvica) can fill the gaps in knowledge left by clinical trials and point to the need for further study.
“Regulatory bodies around the world are more and more interested in what’s going on in the clinic, and there is a question about whether or not the experiences for patients that we take care of might actually answer some important questions that aren’t easily answered in the context of clinical research,” he said at the annual Lymphoma & Myeloma International Congress on Hematologic Malignancies here.

“Are the experiences in practice with novel agents similar to experiences from clinical trials? I think that’s very important,” he added.
Other important questions that real-world experience may help to answer include whether it’s possible to refine adverse event profiles and reasons for ibrutinib discontinuation, what therapies should be prescribed after ibrutinib, and what is the optimal sequencing of therapies for CLL.
For example, in the RESONATE-2 trial, an open-label, international phase 3 study comparing ibrutinib with chlorambucil in previously untreated patients 65 and older, ibrutinib was found to be superior to chlorambucil in terms of progression-free survival (PFS), overall survival (OS), response rate, and improvements in hematologic variables.

However, this trial excluded patients with the deleterious chromosome 17p deletion (del17p) and included only patients 65 and older, a population that does not necessarily reflect clinical experience.
To get a better sense of how ibrutinib is used to treat CLL in the front-line setting Dr. Mato and colleagues conducted a retrospective cohort study of 391 patients treated in 19 US and international academic and community centers.

The median age of the sample was 68 years, but 41% of the patients were younger than 65. In all, 62% were male, and 80% had Rai stage 2 or greater disease. Genetic analyses showed that 30% of the patients were positive for del17p, and 17% had both del17p and the 11q deletion (del11q). Mutations in TP53 were seen in 20% of patients, 23% had a complex karyotype, and 67% had an unmutated immuglobulin heavy chain variable region (IGHV). Only 57 patients (14.5%) were classified as genetically low risk.

Anthony Mato, MD, MSCE

Additionally, only 79 of the 391 patients had complete data for CLL International Prognostic Index (CLL-IPI) scoring, “which goes, I think, to show how often this is actually being tested and utilized in clinical practice,” Dr. Mato said.

Off-label use of ibrutinib in combination therapy was given to 16% of patients, most commonly with an anti-CD20 inhibitor such as rituximab.
In all, 17% of patients required permanent dose reductions; and 42% had a dose interruption, with a median hiatus of 12 days.
Grade 3 or 4 adverse events were uncommon, but more than 20% of patients experienced arthralgias or myalgias of any kind, about 19% reported fatigue, 18% had dermatologic toxicities, 18% reported bruising, 17% had diarrhea or colitis and 15% had infections.
The toxicities seen in RESONATE-2 were somewhat similar, but generally occurred in higher frequencies in the trial than in real-world practice.
Dr. Mato and colleagues found that at a median of 12 months of follow-up, 24% of patients had discontinued ibrutinib. In contrast, in RESONATE-2, after 18 months of follow-up, 13% of patients had discontinued the drug.

The most common reasons for discontinuation in clinical practice were for toxicities (59.5% of 94 discontinuations) including atrial fibrillation in 20% of the patients who discontinued, arthralgias/myalgias and skin toxicities in 14.5% each, and bleeding in 9.1%.
Other reasons for discontinuation included Richter’s transformation in 9.6%, doctor or patient preference in 7.4%, and deaths that were not secondary to CLL progression in 3.2%.

“We also tried to get a sense of whether or not cost was a factor for patients, and in this series and the relapsed refractory setting, 1% or less of patients discontinued due to financial issues,” Dr. Mato said.

Outcomes in the real word were quite good, he noted, with an overall response rate (ORR) of 81.7%, which included 17.4% complete responses (CR), Neither median PFS nor OS have been reached and the respective PFS and OS at 12 months were 92% and 95%. The respective PFS and OS rates for patients with del17p were 87% and 89%. An analysis of predictors of survival showed that only the presence of del17p was associated with inferior PFS (odds ratio 1.91, P = .035)

Dr. Mato noted that there was no clear standard treatment approach for patients who discontinued ibrutinib or for whom ibrutinib did not work. The top three second-line approaches used included an anti-CD20 agent combined with chlorambucil, venetoclax (Venclexta), or a different kinase inhibitor. Chemoimmunotherapy with either fludarabine, cyclophosphamide, and rituximab or bendamustine and rituximab was given to only 5 patients as a second line therapy.

Dr. Mato disclosed serving as a consultant for AbbVie, AstraZeneca, Janssen/Pharmacyclics, and TG Therapeutics.

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