AT ASH 2016

SAN DIEGO (FRONTLINE MEDICAL NEWS) – More than 90% of the first patients with previously untreated chronic lymphocytic leukemia who received ibrutinib in an early study are alive and without disease progression 5 years later, investigators reported.

Among 31 treatment-naive patients with chronic lymphocytic leukemia/small lymphocytic leukemia (CLL/SLL) who were started on the Bruton’s tyrosine kinase inhibitor ibrutinib (Imbruvica) in the phase Ib/II PCYC-1102/1103 study , the 5-year progression-free survival (PFS) rate was 92%, with the median PFS not reached. Estimated 5-year overall survival (OS) among these patients was also 92%, with the median not reached, Susan O’Brien, MD, of the University of California, Irvine, reported at the annual meeting of the American Society of Hematology.

The 5-year PFS rate for patients with relapsed/refractory disease who had received a median of four prior lines of therapy before starting on single-agent ibrutinib was 43%, with a median PFS of 52 months. In this group, the overall survival (OS) rate was 57%, with the median not reached.

“At 5 years of follow-up, there are very durable responses in treatment-naive and relapsed refractory patients. You saw that, in the treatment-naive group, there is, in fact, only one patient who has progressed so far,” Dr. O’Brien said.

In a separate study, investigators from the phase III RESONATE-2 trial reported updated safety and efficacy data showing that in first-line therapy for patients aged 65 years and older with CLL/SLL with active disease, ibrutinib was associated with significantly better PFS at 24 months, compared with chlorambucil.

In this study by Dr. O’Brien and colleagues, 31 patients with previously untreated CLL/SLL and 101 patients with relapsed/refractory disease (progression or no objective response within 24 months of starting on chemoimmunotherapy) were treated with oral ibrutinib once daily at doses of 420 mg or 840 mg until disease progression or unacceptable toxicity.

After 5 years of follow-up, 20 of the 31 treatment-naive patients (65%) and 30 of the 101 relapsed/refractory patients (30%) remained on ibrutinib therapy. The primary reasons for discontinuation among relapsed/refractory patients included progressive disease in 33%, adverse events in 21%, and investigator decision in 11%.

Best response rates in treatment-naive patients were 87% (29% complete response, 55% partial response, 3% partial response-L) and 89% in relapsed/refractory patients (10%, 76%, and 3%, respectively).

An analysis of survival by IGHV (immunoglobulin heavy chain variable) mutational status in patients with relapsed/refractory disease showed a 53% 5-year PFS rate among patients with mutated IGHV and a median PFS of 63 months, compared with 38% and 43 months for patients with unmutated IGHV. Respective 5-year overall survival rates were 66% (median OS, 63 months) and 55% (median not reached).

In an analysis of survival outcomes by chromosomal abnormalities detected by FISH (fluorescent in situ hybridization) among patients with relapsed/refractory disease, median PFS and OS rates were highest among patients with the 13q deletion, at 91% for both PFS and OS, compared with 80% for each in patients with trisomy 12, 33% and 61% for patients with deletion 11q, and 19% and 32% for patients with deletion 17p. In patients with no chromosomal abnormalities, the 5-year PFS rate was 66% (median not reached), and the 5-year OS rate was 83% (median not reached).

Among patients with complex karyotype, 90% of whom had relapsed refractory disease, the 5-year PFS rate was 36% (median 33 months), and the OS rate was 46% (median 57 months). In contrast, respective PFS and OS rates for patients without complex karyotype were 69% and 84%, with the median not reached in either survival category.

In multivariate analysis, only deletion 17p was identified as a significant predictor of PFS and OS.

Grade 3 or greater treatment-emergent adverse events occurred mostly frequently in the first year of therapy and declined thereafter. The most common grade 3 or greater events were hypertension, (26% of all patients), pneumonia (22%), neutropenia (17%), and atrial fibrillation (9%).

Paul M. Barr, MD, of the University of Rochester presented updated data from RESONATE-2 , comparing ibrutinib with chlorambucil in patients 65 and older with newly diagnosed, active CLL/SLL.

At a median follow-up of 29 months, the rates of 2-year PFS were 89% for patients treated with ibrutinib (median PFS not reached) vs. 34% for chlorambucil (median PFS 15 months). This translated into a hazard ratio for ibrutinib of 0.121 (P less than .0001). The benefit of ibrutinib occurred without regard to IGHV status, and ibrutinib continues to demonstrate an OS benefit over chlorambucil with longer follow-up and crossover. Overall survival at 24 months was 95% for patients treated with ibrutinib (included 55 patients who were crossed over from chlorambucil) vs. 84% for patients treated with chlorambucil only.

“The depth of the responses has improved over time, now with 18% of patients achieving a CR with ibrutinib, and lastly, ibrutinib remains tolerable in this elderly population, with 79% of patients that are continuing on therapy,” Dr. Barr said.

Both studies were funded by Pharmacyclics. Dr. Barr and Dr. O’Brien disclosed serving as consultants to the company, and Dr. O’Brien further disclosed honoraria and research funding from Pharmacyclics.