Ibrutinib is superior to chlorambucil in elderly patients with treatment-naïve chronic lymphocytic leukemia

Phase III data demonstrate that treatment with single-agent ibrutinib is superior to chlorambucil in terms of progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and event-free survival (EFS) in treatment-naïve, older patients with chronic lymphocytic leukemia (CLL), or small lymphocytic lymphoma (SLL). In fact, the study showed that ibrutinib is associated with an 84% reduction in the risk of death. Moreover, the safety profile of ibrutinib was acceptable.

CLL and SLL primarily affect older patients who often have other chronic diseases or conditions. As a result, these patients are often not fit enough to be treated with the standard first-line CLL treatment regimen consisting of fludarabine, chlorambucil and rituximab (FCR). In this population of patients, chlorambucil monotherapy is often used as first-line therapy, but the efficacy of this regimen is limited.

In a study reported by Byrd et al. earlier this year, ibrutinib, a first-in-class, oral, Bruton’s tyrosine kinase (BTK) inhibitor that targets B-cell malignancies, showed high activity in treatment-naïve patients aged ≥65 years, with an ORR of 84% and a 30-month PFS rate of 96%. The presented randomized phase III study sought to evaluate the efficacy and safety of ibrutinib in newly diagnosed, previously untreated, older patients with CLL/SLL. Investigators randomized 269 patients with a median age of 73 years to receive either continuous daily doses of ibrutinib (420 mg daily until progression) or chlorambucil (0.5 mg/kg, up to a maximum of 0.8 mg/kg, on days 1 and 15 of a 28-day cycle for up to 12 cycles). The baseline patient characteristics were well balanced between the 2 arms. In total, 45% of patients had an advanced Rai stage, 20% harbored a del(11q), and 69% had comorbidities at baseline including a CIRS score >6, a reduced creatinine clearance, or an ECOG performance status of 2.

With a median follow-up of 18.4 months, ibrutinib significantly prolonged the PFS as compared to chlorambucil (median not reached versus 15.0 months; HR [95%CI]: 0.09 [0.04-0.17], p < 0.0001). For patients who received ibrutinib, the 18-month PFS rate was 93.9% compared to 44.8% in patients treated with chlorambucil. This PFS was consistent in all investigated subgroups, including patients aged 70 years or older, patients with a del(11q), and patients with an unmutated IGHV status.

In addition to this, ibrutinib significantly prolonged the OS as compared to chlorambucil (median not reached for both arms; HR [95%CI]: 0.16 [0.05-0.56], p = 0.0010). Patients who received ibrutinib achieved a 24-month OS rate of 97.8% versus 85.3% in patients treated with chlorambucil. The median EFS was also prolonged with ibrutinib (not reached versus 12 months; HR [95%CI]: 0.17 [0.10-0.26]; p < 0.0001). The ORR was 86.0% with ibrutinib (complete response [CR], or a CR with incomplete bone marrow recovery [CRi] in 4.4%) compared to 35.3% with chlorambucil (1.5% CR/CRi). Finally, the rates of sustained hematologic improvements were significantly higher with ibrutinib than with chlorambucil. This was also the case in patients with baseline anemia (84% versus 45%; P < 0.0001) or thrombocytopenia (77% versus 43%; p=0.0054). The safety profile of ibrutinib was in line with what was reported earlier for this drug. No new, unexpected safety signals were reported.

In conclusion, single-agent ibrutinib was superior to chlorambucil in terms of PFS, OS, ORR, EFS and hematologic improvement in treatment-naïve older CLL/SLL patients. These results underscore that targeted therapy is effective in patients with previously untreated CLL/SLL and identify ibrutinib as an excellent first-line treatment option for this population.


Tedeschi A, Barr P, 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-2TM). Presented at Ash 2015; Abstract #495.

Speaker Alessandra Tedeschi


Alessandra Tedeschi, MD,
Hematologist, Ospedaliera Niguarda Cà Granda, Milano, Italy


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