Ibrutinib (Imbruvica) significantly reduced the risk for disease progression or death compared with standard treatment with chlorambucil (Leukeran) in older (aged ≥65 years) treatment-naïve patients with chronic lymphocytic leukemia (CLL). Ibrutinib achieved a 91% reduction in the risk for disease progression and an 84% reduction in the risk for death compared with chlorambucil.
“This population is frequently frail and undertreated. Chlorambucil has been the standard of care. No other regimen has improved survival in the elderly,” said lead investigator Alessandra Tedeschi, MD, Azienda Ospedaliera Niguarda Ca’ Granda, Milan, Italy, who presented these results at ASH 2015.
These results of the RESONATE-2 trial suggest that ibrutinib could become a new standard of care for this group of patients, who typically cannot tolerate the chemotherapy regimens used in younger patients.
Ibrutinib is a first-in-class oral inhibitor of Bruton’s tyrosine kinase and is FDA approved for patients with CLL who have received >1 previous therapies and for patients with the 17p deletion (del 17p). These results are expected to lead to an expanded indication for ibrutinib for the upfront treatment of elderly patients.
RESONATE-2 is the first phase 3 clinical trial of a direct comparison of ibrutinib and chemotherapy in this older population. The study enrolled 269 patients with CLL aged ≥65 years. All patients were not considered candidates for fludarabine (Fludara) plus cyclophosphamide and rituximab (Rituxan), which is used in younger patients. The exclusion criteria included del 17p and receiving warfarin. The median patient age was 73 years; 70% of the patients were aged >70 years. Overall, 43 patients crossed over to ibrutinib over the course of the trial.
Ibrutinib significantly prolonged progression-free survival (PFS); at a median of 18.4 months of follow-up, the median PFS was not reached in the ibrutinib group and was 18.9 months in the chlorambucil group (P <.001).
Ibrutinib significantly prolonged overall survival (OS), with an estimated OS of 98% at 24 months versus 85% with chlorambucil (P = .001). The overall response rate was also significantly superior with ibrutinib versus chlorambucil (86% vs 35%, respectively).
The most common adverse events associated with ibrutinib were diarrhea, fatigue, cough, and nausea. The most common adverse events associated with chlorambucil included nausea, fatigue, neutropenia, and vomiting.
Grade 3 hypertension was reported in 14% of patients receiving ibrutinib. Hypertension was treated with antihypertensive medications, and no dose reduction or treatment discontinuation were needed. Atrial fibrillation was 6% with ibrutinib; 2 of these patients discontinued treatment, and no dose modifications were needed for the other 4 patients.
Adverse events leading to treatment discontinuation were reported in 9% of patients with ibrutinib and in 23% of those who received chlorambucil. During the 18.4 months of follow-up, 3 deaths were reported in the ibrutinib arm and 17 deaths in the chlorambucil arm. No deaths were reported in patients who progressed with ibrutinib during follow-up.