Initial Treatment with Ibrutinib Increases Survival Compared to Chlorambucil in Older Patients with Chronic Lymphocytic Leukemia

EBM Focus - Volume 11, Issue 2

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Reference - RESONATE-2 trial (N Engl J Med 2015 Dec 17;373(25):2425) (level 1 [likely reliable] evidence)

  • Ibrutinib is currently recommended for the initial management of chronic lymphocytic leukemia (CLL) only in patients with chromosome 17p deletions.
  • Compared to chlorambucil, ibrutinib increased overall survival, progression-free survival, and overall response rates in older patients with previously untreated CLL or small lymphocytic lymphoma without chromosome 17p deletions.
  • Although the median treatment duration was longer with ibrutinib, it did not appear to increase adverse events and was associated with a lower rate of discontinuation due to adverse events.

Recommendations for the initial management of chronic lymphocytic leukemia (CLL) vary based on age, fitness, comorbidities, and chromosomal deletions (NCCN 2015 Mar). In patients without chromosome 11 or 17 deletions, chlorambucil alone is currently recommended for patients ≥ 70 years old and younger patients with comorbidities (NCCN 2015 Mar, Ann Oncol 2011 Sep;22 Suppl 6:vi50). Ibrutinib, a covalent inhibitor of Bruton tyrosine kinase, is recommended for initial management of patients with CLL and chromosome 17p deletions. In patients without 17p deletions, ibrutinib is currently approved only as a second-line therapy. To further assess the safety and efficacy of ibrutinib, a recent randomized trial compared ibrutinib 420 mg orally once daily vs. chlorambucil 0.5 mg/kg IV on days 1 and 15 of each 28 day cycle in 269 patients ≥ 65 years old with untreated CLL or small lymphocytic lymphoma without chromosome 17p deletions. Treatment continued until disease progression or the development of unacceptable toxic effects, and patients randomized to chlorambucil could receive a maximum of 12 cycles.

The median treatment duration was 17.4 months with ibrutinib vs. 7.1 months with chlorambucil and patients were followed for a median of 18.4 months. Comparing ibrutinib vs. chlorambucil, 24 month overall survival was 98% vs. 85% (p = 0.001) and 18-month progression free survival was 90% vs. 52% (p < 0.001). The overall response rate was 86% in the ibrutinib group vs. 35% in the chlorambucil group (p < 0.001, NNT 2). Ibrutinib was also associated with a lower rate of discontinuation due to adverse events and a significantly greater sustained improvement in hematological parameters. These results were consistent across subgroup analyses by age, sex, disease stage, performance status, chromosome 11q deletion, IGHV mutation, and presence of bulky disease. The most common adverse events associated with ibrutinib were diarrhea, fatigue, nausea, and cough, while nausea, fatigue, neutropenia, anemia, and vomiting were the most commonly reported with chlorambucil.

The results of this trial found that ibrutinib was not only more effective than chlorambucil, with higher survival and response rates in the ibrutinib group, but it was also better tolerated. The median treatment duration was much longer with ibrutinib and few patients discontinued treatment due to adverse events. In fact, at the time of the analysis 87% of patients randomized to ibrutinib were still receiving treatment, but only 40% of patients completed the maximum 12 cycles of chlorambucil. Even with the longer exposure time, ibrutinib did not appear to have a higher rate of adverse events.

This study also raises a few additional considerations for the treatment of CLL. First, new therapies including obinutuzumab plus chlorambucil and bendamustine plus rituximab are now available. A trial is currently underway comparing bendamustine plus rituximab vs. rituximab plus ibrutinib vs. ibrutinib alone (NCT01886872), and the results of that trial should provide further information on the comparative efficacy of ibrutinib in patients with untreated CLL. Second, longer follow-up is necessary to fully evaluate ibrutinib therapy. However, the overall results of this trial suggest that ibrutinib should be considered for the initial management of all older patients with CLL or small lymphocytic lymphoma, not just patients with chromosome 17p deletions.

For more information, see the Initial management of chronic lymphocytic leukemia (CLL) topic in DynaMed Plus. DynaMed users click here.