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Mantle cell lymphoma progression during ibrutinib treatment leads to poor outcomes
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Patients with mantle cell lymphoma who progressed on ibrutinib have poor outcomes and no effective therapies following ibrutinib treatment, according to results of a retrospective cohort study.
“The first key point is that we observed, fairly consistently in multiple international centers, that people with mantle cell lymphoma that progressed while receiving ibrutinib [Imbruvica, Pharmacyclics] tended to do poorly with post-ibrutinib therapies,” Peter Martin, MD, assistant professor of medicine at Weill Cornell Medicine and medical oncologist at NewYork-Presbyterian, told HemOnc Today. “We thought that this was important information both from a patient perspective and a physician perspective, since it might inform decisions, including timing of transplant, post-ibrutinib treatments, end-of-life care and clinical trial design.”
Peter Martin
Ibrutinib appears very effective in some patients with mantle cell lymphoma, garnering a 68% response rate and a median PFS of 13.9 months in a phase 2 trial. Further, long-term follow-up demonstrated 47% of patients were alive at 2 years and 31% remained progression free.
However, primary resistance to the enzyme inhibitor occurs in about 33% of all patients and acquired resistance is universal.
Because the mechanism for this resistance remains unclear and likely to be multifactorial, Martin colleagues sought to improve the understanding of patient outcomes and to identify risk factors associated with survival in this setting.
The investigators identified 114 patients (85 men; median age, 68 years; range, 46-85) with mantle cell lymphoma who were treated at 15 different academic centers in the U.S., U.K., Germany and Poland. Patients received single-agent ibrutinib on a clinical trial (n = 95) or were treated with commercially available ibrutinib (n = 19).
Patients had a median of three (range, 0-10) prior therapies.
Twenty-three percent of patients had a low mantle cell lymphoma international prognostic index (MIPI) score, whereas 31% had an intermediate score and 46% had a high score.
Of the 47 patients with available data prior to ibrutinib treatment, 34 (72.3%) had a Ki67 greater than 30. Of the 12 patients who had available data after ibrutinib treatment, 11 (91.7%) had a Ki67 greater than 30.
The median time on ibrutinib was 4.7 months (range, 0.7-43.6 months).
Median OS following ibrutinib cessation was 2.9 months (95% CI, 1.6-4.9). All patients experienced progressive disease.
Patient characteristics and risk factors were available for 104 patients at the time they stopped ibrutinib treatment. Thirty-one patients (29.8%) received no additional systemic therapy, whereas 73 patients (70.2%) received at least one additional course of treatment.
Patients commenced subsequent treatments an average of 0.3 months (range, 0-21.7 months; 95% CI, 0.2-0.5) after stopping ibrutinib. Median OS from the time of the start of subsequent therapy was 5.8 months (95% CI, 3.7-10.4).
Researchers conducted univariate Cox regression analyses to determine factors associated with OS following treatment with ibrutinib. Only MIPI prior to ibrutinib (HR = 1.81; 95% CI, 1.32-2.49) and duration of ibrutinib treatment (HR = 0.96; 95% CI, 0.93-1) appeared associated with OS.
Multivariate analyses that included MIPI prior to subsequent treatments and subsequent treatment with bendamustine (Treanda, Cephalon), cytarabine or lenalidomide (Revlimid, Celgene) revealed no significant associations with OS.
“I suspect that the factors that make mantle cell lymphoma more aggressive tend to migrate along with the factors that make it resistant to ibrutinib, and that these factors tend to be more common in people that start with more aggressive disease and have received multiple lines of therapy,” Martin said. “We will have an opportunity to pick apart these mysteries with more research looking at ibrutinib used in different combinations and in different lines of therapy.” – by Anthony SanFilippo
Disclosure: Martin reports consultant/advisory and speakers bureau roles with Acerta, Bayer, Celgene, Genentech, Gilead, Janssen and Novartis. The other researchers report consultant/advisory and speakers bureau roles with and research funding from AbbVie, Acerta, Celgene, Janssen, Kite Pharma, Pharmacyclics, Roche and Takeda.
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