Researchers Examine Acquired Mutations Linked to Ibrutinib Resistance in CLL

Danielle Bucco

Jennifer A. Woyach, MD

Jennifer A. Woyach, MD

Ibrutinib (Imbruvica) has shifted the treatment paradigm in chronic lymphocytic leukemia (CLL); however, some patients relapse after receiving the BTK inhibitor and experience rapid disease progression.
In a recent study, researchers at The Ohio State University Comprehensive Cancer Center (OSUCCC) examined acquired mutations in BTK and PLCG2 that cause resistance to ibrutinib and identified risk factors associated with ibrutinib resistance.
“We showed that there are certain baseline characteristics that are independently associated with risk of progression on ibrutinib. For CLL progression, those included complex karyotypes, the presence of del(17)(p13.1), and age less than 65,” lead researcher, Jennifer A. Woyach, MD, said in an interview with OncLive.
Woyach sees an opportunity for earlier intervention in patients who are likely to become resistant to ibrutinib.
“When patients do develop these mutations, they are going to relapse and hopefully by detecting them early, there might be an opportunity for intervention,” said Woyach, an associate professor at OSUCCC.
The research by Woyach and her her colleagues involved 308 patients enrolled at OSUCCC into 4 Institutional Review Board­–approved sequential trials of ibrutinib in patients with CLL. There were 237 patients treated with single-agent ibrutinib on 3 trials, with the remaining 71 patients treated with ibrutinib in combination with ofatumumab (Arzerra).
The time to discontinuation of therapy was measured from the first date of treatment until the off-study date. Transformation and CLL progression were the variables most strongly associated with discontinuing ibrutinib therapy. Another reason for discontinuation included severe toxicity.
Overall, patients had a median of 3 prior therapies, with 8 patients, all 65 years or older, having no prior therapies. With a median follow-up time of 3.4 years, 136 patients (44%) remain on therapy, 14 patients (4.5%) have received transplantation or therapy elsewhere, and 158 patients (51%) have discontinued ibrutinib with the median time to discontinuation being 98 days. Discontinuation for adverse reasons other than transformation or CLL progression tended to reach a plateau after 3 years. The median survival time from discontinuation was 3.9 months for patients with transformation and 22.7 months for patients with CLL progression.
Of the 158 patients who discontinued ibrutinib, 83 patients (52.5%) discontinued as a result of disease progression and the remaining 75 patients (24%) discontinued due to adverse events. Thirty-one of these patients received infection, 21 patients dying within 30 days. For the patients with fatal infections, 12 had pneumonia, 7 had unspecified sepsis, and 2 had Pseudomonas bacteremia.
Transformation tended to occur within the first 2 years of therapy, whereas CLL progressions tended to occur later, with an estimated cumulative incidence of CLL progression of 0.7% at 1 year, which increased to an estimated 19.1% at 4 years.
Complex karyotype at baseline was the variable that was most strongly associated with risk for transformation, with the next strongest variable being MYC abnormalities but it did not reach statistical significance. Complex karyotype at baseline, fluorescent in situ hybridization (del[17][p13.1]), and age less than 56 years were independently associated with risk for CLL progression.
The risk for CLL progression was lower for patients aged more than 65 years without complex karyotype or del(17)(p13.1). The estimated cumulative incidence for progression at 4 years was 44%.
There were 46 patients with progressive CLL who had samples at relapse available for deep sequencing by Ion Torrent Platform from Life Technologies. Of these patients, 40 (87%) had mutations in BTK and/or PLCG2 at the time of clinical relapse. Thirty-one patients had BTK C481 alone, 3 patients had PLCG2 alone, and 6 patients had mutations in both BTK and PLCG2.

Variant allele frequency was varied and generally correlated with the presence of disease progression in the peripheral blood versus primarily nodal relapse. There were 7 patients with variant allele frequency of less than 10%. Of the 7 patients, all but 1 had disease progression only in the lymph nodes, with low lymphocyte count in the peripheral blood.
For 20 patients with BTK and PLCG2 mutations that were analyzed, relapse was detected incidentally in 2 patients, by bone marrow biopsy in 1 patient, by increasing lymphocytosis alone in 4 patients, by lymph node enlargement alone in 8 patients, and by both lymphocytosis and enlarging nodes in 5 patients. 

Eight patients have experienced clinical relapse, and all 8 patients had BTKC481S mutations with expansion of the clone before relapse. In an additional 8 patients, BTKC481S mutations of greater than 1% allelic frequency were detected. Seven patients have had increasing circulation CLL cells in the peripheral blood by flow cytometry, and all have had expansion of the resistant clones. Of these 7 patients, 4 had an increase of lymph node size, but have not yet met criteria for clinical relapse. There have been no early signs of progression in patients with BTKC481S clones.
“We could detect those mutations an average of 9.3 months before clinical progression. I think that this is a very important part because if we have this very long time period between, what we call molecular progression and clinical progression, it might be a time that we can actually do something, such as adding another drug to ibrutinib,” said Woyach.
Woyach JH, Ruppert AS, Guinn D, et al. BTKC481S-mediated resistance to ibrutinib in chronic lymphocytic leukemia [published online February 13, 2017]. J Clin. Oncol. doi:10.1200/JCO.2016.70.2282.

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