Potential Ibrutinib Resistance Mechanisms Identified in CLL

Jennifer Woyach, MD

Progression on treatment with ibrutinib in patients with chronic lymphocytic leukemia (CLL) was associated with pretreatment BCL6 abnormalities, acquired mutations in BTK and PLCG2, and complex karyotypes, according to a retrospective analysis of four studies published online in JAMA Oncology.

Of the 308 patients examined in the studies, 76 discontinued treatment: 31 (10.1%) as a result of disease progression and 45 (14.6%) from other causes, including adverse events and infection. Altogether, 18 patients treated with ibrutinib developed Richter’s transformation and 13 progressed with CLL. All patients with progressive disease harbored an acquired mutation in BTK and PLCG2, the researchers noted.

“These data enhance our understanding of how patients do on ibrutinib long-term and who is likely to relapse,” senior author Jennifer Woyach, MD, a hematologist at The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC - James), said in a statement. “We know that many patients will have very durable remissions with ibrutinib, and understanding which patients are at higher risk helps us select who might benefit from clinical trials investigating other new agents and combination therapies rather than starting ibrutinib treatment by itself.”

The clinical trials accrued patients from May 2010 until April 2014. Data were locked in June 2014, with a median follow-up of 20 months. Patients had received a median of 3 prior therapies, 80% had unmutated IGHV, 58% had a complex karyotype, 37% had 17p deletions, and 26% had an 11q deletion.

Richter’s transformation generally occurred early, with a cumulative incidence at 12 months of 4.5% (95% CI, 2.0%-7.0%). Median survival following Richter’s transformation was just 3.5 months (95% CI, 0.3-6.0). Sequencing on peripheral blood from 8 patients with Richter’s transformation revealed 2 with mutations in BTK. However, lymph node samples showed no mutations in BTK or PLCG2.

The cumulative incidence of CLL progression was 0.3% (95% CI, 0%-1.0%), with a median survival of 17.6 months (95% CI, 4.7-not reached). Deep sequencing of samples from 11 patients with progressive CLL using Ion Torrent revealed BTK or PLCG2 mutations in all. These mutations were not identified before treatment in any patient.

“Outcomes data show poor prognosis after discontinuation, especially for those patients with Richter's transformation. Patients with either progressive CLL or Richter's tend to require therapy quickly after ibrutinib is stopped, so having a plan in place for alternative therapy is necessary,” study author Kami Maddocks, MD, a hematologist at OSUCCC - James, said in a statement.

A multivariable analysis revealed an HR for the cumulative incidence of progression in patients with BCL6 abnormalities versus those without of 2.7 (95% CI, 1.25-5.85; P = .01). Additionally, for those with a complex karyotype versus those without the HR was 4.47 (95% CI, 1.50-13.34; P = .007).

"We have confirmed that specific gene mutations are seen in patients who relapse, which gives us an idea of other drugs that might be effective in these circumstances," said Woyach.

Of the 45 patients who discontinued therapy for reasons other than disease progression, 28 were due to infection and 8 because of other adverse events. Nine discontinued due to other events including progressive multifocal leukoencephalopathy (n = 1), medication noncompliance (n = 1), comorbid medical condition (n = 2), failure to thrive (n = 1), sudden cardiac death (n = 1), need for anticoagulation (n = 2), and cerebrovascular event (n = 1).

Therapy-limiting infections occurred early, with a median time to discontinuation of 102 days. Sixteen discontinuations due to infectious toxic effects occurred during the first 6 months of therapy, 7 within 6 to 12 months, and 5 beyond 12 months.

Risk factors for discontinuation included advanced age (HR for 10-year increase was 1.87; 95% CI, 1.33-2.64; P&thinsp;<&thinsp;.001) and multiple prior therapies, although the association between discontinuation risk and number of therapies was not statistically significant (HR = 1.09; 95% CI, 1.00-1.19; P&thinsp;=&thinsp;.054).

“This sub-segment of patients who relapse on ibrutinib remains a high research priority to identify new targets and new therapies, and we have multiple studies ongoing at the James to try to help these patients,” Maddocks said.

The FDA initially approved ibrutinib for patients with MCL who received at least one prior therapy in November 2013. Ibrutinib was then approved for patients with previously treated CLL in February 2014, which was followed by a full FDA approval and a new indication for high-risk patients with 17p deletions in July 2014.

The full approval for ibrutinib in CLL was based on data from the phase III RESONATE study. In this analysis, treatment with ibrutinib lowered the risk of progression by 75% in patients with CLL who harbored a 17p deletion and by 78% in the full population of the study when compared with ofatumumab. At 12 months, the OS rate was 90% for patients treated with ibrutinib compared with 81% in the ofatumumab group. The median OS was not reached for patients treated with ibrutinib (HR = 0.43; 95% CI, 0.24-0.79; P = .005).

Maddocks KJ, Ruppert AS, Lozanski G, et al. Etiology of ibrutinib therapy discontinuation and outcomes in patients with chronic lymphocytic leukemia. [published online February 26, 2015] Jama Oncology. doi: 10.1001/jamaoncol.2014.218.