Chlorambucil is considered a standard therapy for older patients with chronic lymphocytic leukemia (CLL) but, according to results from the RESONATE-2 trial presented at the 2015 ASH Annual Meeting, ibrutinib could take over as standard, first-line treatment in older patients with this disease. The recent randomized, open-label, phase III trial evaluated the safety and efficacy of single-agent ibrutinib compared with chlorambucil in treatment-naïve patients age ≥65 years who had CLL and/or small lymphocytic lymphoma (SLL).
“This is one of the first steps toward a chemotherapy-free regimen,” Alessandra Tedeschi, MD, of the Azienda Ospedale Niguarda Cà Granda in Milan, Italy, who presented the results, told ASH Clinical News. “A chemotherapy-free approach would be important for all patients, but particularly elderly patients who have many comorbidities.
Immunochemotherapy may be too toxic for this population, so it would be important for these patients to receive a chemotherapy-free approach as first-line treatment.”
Ibrutinib is currently approved by the U.S. FDA for use in patients with CLL who have received one or more prior therapies and for those with the deletion of the 17p13 chromosomal region (del17p) mutation.
A total of 269 patients were randomized 1:1 to receive:
- Ibrutinib 420 mg daily until progression
- Chlorambucil 0.5 mg/kg (up to maximum 0.8 mg/kg) on days 1 and 15 of a 28-day cycle for up to 12 cycles
Patients with del17p were excluded from the study.
Median patient age was 73 years, with 70 percent of patients ≥70 years old. Progression-free survival was the study’s primary endpoint; secondary endpoints included overall survival (OS), overall response rate (ORR), event-free survival, rate of hematologic improvement, and safety.
The median duration of treatment was 17.4 months with ibrutinib compared with 7.1 months with chlorambucil.
After a median follow-up of 18.4 months, the investigators found that ibrutinib significantly prolonged PFS compared with chlorambucil (median = not reached vs. 18.9 months; hazard ratio [HR] = 0.16; 95% CI 0.09-0.28; p<0.0001). Treatment with ibrutinib almost doubled the rate of PFS at 18 months (93.9% vs. 44.8%), and reduced the risk of disease progression or death by 91 percent compared with chlorambucil (HR=0.09; 95% CI 0.03-0.17; p<0.0001).
Similarly, the ORR rate among patients receiving ibrutinib was substantially higher than among those receiving chlorambucil (86% versus 35.3%).
Ibrutinib significantly prolonged OS compared with chlorambucil (median = not reached for either arm; HR=0.16; 95% CI 0.05-0.56), and more patients receiving ibrutinib were alive two years after starting therapy compared with the chlorambucil cohort (97.8% vs. 85.3%, respectively).
“We didn’t achieve a very high rate of complete remission, even though PFS was so high,” Dr. Tedeschi said, “suggesting that achieving a complete remission might not be necessary to prove the efficacy of these targeted drugs in CLL. Most interestingly, ibrutinib significantly improved bone marrow function.” This, she noted, is very important for older patients, for whom bone marrow failure is a common cause of death.
Over a median follow-up of 1.5 years, three patients receiving ibrutinib died during the study period, compared with 17 of those receiving chlorambucil.
The safety profile, the authors noted, was in line with that seen in other CLL trials. The most frequently reported adverse events (AEs) among ibrutinib-treated patients included: diarrhea, fatigue, cough, and nausea. In the chlorambucil-treated arm, however, the most common AEs included: nausea, fatigue, neutropenia, anemia, and vomiting.
Major hemorrhage occurred in 4 percent of the ibrutinib population (grade 2 in 1 patient; grade 3 in 4 patients; and grade 4 in 1 patient), and in two percent of the chlorambucil population. And, though hypertension was observed more frequently among the ibrutinib cohort, it was limited to grade 1-3 and was managed without modifying or discontinuing treatment.
AEs led to treatment discontinuation more frequently in the chlorambucil group compared with the ibrutinib cohort (23% vs. 9%, respectively); at the time of the analysis, 87 percent of patients receiving ibrutinib remained on therapy.
Tedeschi A, Barr PM, Robak T, et al. Results from the international, randomized phase 3 study of ibrutinib versus chlorambucil in patients 65 years and older with treatment-naïve CLL/SLL (RESONATE-2™). Abstract #495. Presented at the 2015 ASH Annual Meeting, December 7, 2015; Orlando, Florida.