Reasons for Ibrutinib Discontinuation Linked With Length of CLL Survival

Patients with chronic lymphocytic leukemia (CLL) who discontinue treatment with the Bruton tyrosine kinase inhibitor ibrutinib due to disease progression or transformation had significantly worse survival compared with patients who discontinued therapy because of intolerance, according to the long-term results of a study published recently in Cancer.

“Ibrutinib has significantly improved outcomes for patients with CLL,” wrote Preetesh Jain, MBBS, MD, PhD, of the department of leukemia at the University of Texas MD Anderson Cancer Center, and colleagues. “Nevertheless, there continue to be challenges with this treatment, because most patients achieve partial remission as the best response, treatment is continuous and indefinite, and some patients must discontinue treatment because of resistance or intolerance/toxicity.”

Studies have shown that between 10% and 20% of patients who receive ibrutinib will ultimately discontinue therapy because of intolerance, progression or other causes. It is believed that survival is poor among those patients who discontinue therapy because of intolerance or disease progression.

In a previous study, Jain and colleagues reported that survival after ibrutinib was very short in patients who discontinued therapy because of transformation, and was shorter than 1.5 years in those who discontinued because of disease progression.

In this analysis, the researchers reported long-term outcomes of patients with CLL who discontinued ibrutinib. The researchers retrospectively analyzed data taken from 320 patients who received ibrutinib while on clinical trials between 2010 and 2015 at the University of Texas MD Anderson Cancer Center.

They found that a little less than one-third (28%) of patients discontinued ibrutinib after first-line or salvage therapy. The median time to discontinuation was 15 months overall, 19 months among treatment-naive patients and 14.5 months for patient with relapsed or refractory disease.

Among the reasons for discontinuation of ibrutinib were intolerance (32%), miscellaneous (31%), progression (21%), and Richter transformation (RT; 10%).

With a median follow-up of 38 months, 44% of patients were alive at last follow-up. Patients had a median post-ibrutinib survival of 20.6 months. Median survival varied according to reason for discontinuation: for intolerance, 33 months; for miscellaneous, 11 months; for progressive CLL, 16 months; and for transformation, 2 months. 

Those patients with progressive CLL had significantly better survival than those patient with transformation (hazard ratio, 6.7; P < .0003).

“As the use of ibrutinib treatment continues to increase in patients with CLL; it is essential to delineate the pattern of mutations and dynamics of clonal evolution in those patients who discontinue ibrutinib because of disease progression/transformation and to identify pathways for therapeutic targeting to improve the survival outcomes for these patients,” the researchers wrote. “The development of effective salvage strategies for patients who develop progression/RT while receiving ibrutinib therapy is of critical importance.”