Ibrutinib Leads to Better Overall and Progression-Free Survival Than Chlorambucil in Older Patients with CLL/SLL

Chronic lymphocytic leukemia (CLL) is a disease of older adults, many of whom have other medical problems in addition to their cancer. Chlorambucil is a standard first-line therapy for older patients with CLL or those with co-existing conditions.

Ibrutinib, a first-in-class oral Bruton’s tyrosine kinase inhibitor, is approved for the treatment of patients with CLL who have received at least one prior therapy. In the phase III RESONATE trial, single-agent ibrutinib prolonged overall survival (OS) compared with ofatumumab in older patients with previously treated CLL.

To further examine whether single-agent ibrutinib has a role as initial treatment in CLL patients, Jan A. Burger, MD, PhD, from the University of Texas MD Anderson Cancer Center, and colleagues conducted the phase III, international, open-label, randomized RESONATE-2 trial, which compared treatment with ibrutinib versus chlorambucil in older patients with previously untreated CLL or small lymphocytic lymphoma (SLL).

A total of 269 patients 65 years old or older (median age = 73 years) were included in the study and randomized to receive:

  • Ibrutinib: 420 mg once daily (n=135)
  • Chlorambucil: 0.5 mg/kg of body weight on days 1 and 15 of each 28-day cycle and increased to 0.8 mg/kg if there was no toxicity (n=132)

Eligibility criteria included patients aged 65 years or older, who had previously untreated CLL or SLL, with an Eastern Cooperative Oncology Group performance status score of <2, an absolute neutrophil count of ≥1,000 cells/mm3, a platelet count of ≥50,000/mm3, and adequate liver and kidney function. Patients were ineligible if they had chromosome 17p13.1 deletion.

Patients were treated until disease progression, unacceptable toxicity, or an observed lack of efficacy and were followed for a median of 18.4 months starting in March 2013. Eighty-seven percent of patients taking ibrutinib were still receiving treatment at the time of analysis.

The rate of progression-free survival (PFS) at 18 months, the study’s primary endpoint, was significantly higher in patients treated with ibrutinib than with chlorambucil: 90 percent versus 52 percent (p<0.001). At the time of last follow-up, the overall PFS had not been reached for ibrutinib and was 18.9 months for chlorambucil. The response rate (assessed by an independent review committee) was 86 percent in the ibrutinib cohort and 35 percent in the chlorambucil cohort (p<0.001).

The relative risk of progression or death was 84 percent lower for patients receiving ibrutinib compared with chlorambucil (hazard ratio [HR] = 0.16; 95% CI 0.09-0.28; p<0.001).
In addition, ibrutinib significantly prolonged OS. At 24 months, the estimated survival rate was 98 percent in the ibrutinib cohort and 85 percent in the chlorambucil group, with a relative risk of death that was 84 percent lower for those treated with ibrutinib (HR=0.16; 95% CI 0.05-0.56; p=0.001). At the latest time of follow-up, the OS had not been reached in either cohort.

“Furthermore, ibrutinib-treated patients had a restoration of bone marrow function, with a significantly higher rate of sustained improvement in hematologic variables,” Dr. Burger and colleagues added. “This finding has particular clinical relevance because bone marrow failure is a common cause of complications in patients with CLL, with anemia and thrombocytopenia being frequent indications for initiating treatment in this population.”

Three patients in the ibrutinib group died during follow-up, compared with 17 in the chlorambucil group. The most common adverse events (AEs) in the ibrutinib and chlorambucil cohorts included:

  • Diarrhea: 42% vs. 17%, respectively
  • Fatigue: 30% vs. 38%
  • Cough: 22% vs. 15%
  • Nausea: 22% vs. 39%
  • Peripheral edema: 19% vs. 9%
  • Dry eye: 17% vs. 5%
  • Arthralgia: 16% vs. 7%
  • Neutropenia: 16% vs. 23%
  • Vomiting: 13% vs. 20%

“Treatment exposure and AE follow-up was nearly 2.5 times as long with ibrutinib as with chlorambucil,” the authors wrote. Nine percent of patients in the ibrutinib cohort discontinued treatment due to AEs, compared with 23 percent in the chlorambucil group.

“Compared with chlorambucil, a standard cytotoxic chemotherapy, ibrutinib was associated with significantly longer progression-free survival and overall survival and with higher rates of response and improvement in hematologic variables among patients with previously untreated CLL or small lymphocytic lymphoma,” the authors concluded.

The median PFS with chlorambucil (18.9 months) observed in this study appears to be generally longer than that reported in previous trials with chlorambucil in previously untreated patients. “The relatively strong performance of chlorambucil in the current study may have been influenced, in part, by a generally longer exposure to involving previously untreated patients with CLL or by the exclusion of patients with chromosome 17p13.1 deletion,” the authors wrote, noting one possible limitation.

“Better results with ibrutinib might be obtained when it is used as first-line treatment rather than for later relapses or in patients with refractory disease,” Dr. Burger and colleagues reported, since chlorambucil-treated patients with disease progression who were allowed to cross over to ibrutinib treatment experienced prolonged OS.

Chlorambucil may be considered by some as a suboptimal comparison group, which is a limitation of the study. In addition, some patients could have tolerated a more aggressive therapy.


Burger JA, Tedeschi A, Barr PM, et al. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015;373:2425-37.