Chemical structure of ibrutinib
Compiling results from four ibrutinib clinical trials in chronic lymphocytic leukemia (CLL) patients from a single institution, researchers have identified patient factors linked with discontinuation of ibrutinib therapy for reasons other than disease progression, including older age and greater number of prior treatments. The risk factors associated with disease progression on ibrutinib treatment include abnormalities in the BCL6 gene, as well as complex karyotype.
The results of the study were published in JAMA Oncology.
Ibrutinib is a Bruton’s tyrosine kinase (BTK) inhibitor approved by the US Food and Drug Administration for treatment of previously treated mantle cell lymphoma, as well as for CLL carrying a deletion in chromosome 17 (17p deletion) that is associated with poor outcomes.
It has been previously shown that resistance to ibrutinib can be mediated through mutations in BTK or PLCG2 in a small group of patients.
Jennifer A. Woyach, MD, of the Ohio State University Comprehensive Cancer Center, and colleagues analyzed 308 CLL patients-237 were treated with ibrutinib monotherapy in 3 clinical trials and 71 were part of a clinical trial combining ibrutinib with ofatumumab. Patients were mostly high-risk and had received a median of three prior therapies.
With a median follow-up of 20 months, 31 patients discontinued therapy due to disease progression and 232 remained on therapy. Forty-five patients discontinued therapy for reasons other than disease progression, including 28 who had an infection and 8 who had another adverse event. Discontinuation not due to relapse tended to occur early in treatment, before 24 months.
Age was the only significant independent risk factor for therapy discontinuation for a reason other than disease progression (P < .001). An increased number of previous therapies was also associated with non-relapse discontinuation but was not statistically significant (P = .054).
Patients who discontinued therapy for a reason other than relapse did poorly, with a median survival of 8 days after stopping the drug. However, 28 patients in this group had an infection and 16 of the 28 died the same day as stopping therapy. Of the patients who stopped therapy but did not have an infection, the median survival was 238 days; 7 of 17 patients had not died as of the last follow-up.
Of the 31 patients who discontinued therapy due to disease progression, 13 progressed with CLL, and 18 progressed with Richter’s transformation with most developing diffuse large B-cell lymphoma. The median survival was 3.5 months following Richter’s transformation and 17.6 months after CLL progression.
Factors that increased the risk of either progressive CLL or Richter’s transformation included an increased number of prior therapies (P = .03), BCL6 abnormalities (P < .001), MYC abnormalities (P = .01), presence of 17p deletion (P = .03), and complex karyotype (P = .003).
“These data confirm that ibrutinib is a drug capable of shifting the paradigm of therapy for relapsed disease. In our group of high-risk patients, the estimated cumulative incidence of disease progression at 18 months was only 8.9%,” stated the authors in their discussion.
The study showed that for the small proportion of patients with disease progression on therapy, progression was quick. “[This] points to a need for clinical trials to allow shorter washout periods for these patients,” wrote the authors. The authors advised that physicians may consider waiting until an alternative therapeutic plan can be formed before discontinuing ibrutinib therapy and to continue “ibrutinib therapy in combination with Richter’s transformation-directed therapy in select patients.”