Sustained Efficacy and Safety of Ibrutinib in Relapsed/Refractory CLL

Long-term results from the international, open-label, randomized phase 3 trial comparing single-agent ibrutinib to ofatumumab in high-risk relapsed patients with chronic lymphocytic leukemia (CLL) (RESONATE; ClinicalTrials.gov Identifier: NCT01578707) showed sustained efficacy and safety of ibrutinib in these patients. The study was published online in Blood.¹

The majority of patients diagnosed with CLL experience disease relapse following initial treatment with chemoimmunotherapy. At a median follow-up of 9.4 months, previously reported results from the phase 3 RESONATE trial comparing ibrutinib with ofatumumab in patients with relapsed/refractory CLL or small lymphocytic lymphoma (SLL) who were considered inappropriate for purine analogue therapy showed that median progression-free survival (PFS) (P <.001) and overall survival (OS) (P =.005) were significantly longer for patients randomly assigned to the ibrutinib arm compared with the ofatumumab arm.²  

Pneumonia (7%), urinary tract infection (4%), and diarrhea (4%) were the most frequent grade 3 or higher nonhematologic adverse events for patients in the ibrutinib arm, and neutropenia (16%), followed by thrombocytopenia (6%) and anemia (5%) were the most common grade 3 or higher hematologic adverse events observed in this group.

Some of the key findings of long-term follow-up (ie, median follow-up of 44 months) for patients enrolled in the RESONATE trial include the following:

• Median PFS was not reached for patients receiving ibrutinib vs 8.1 months for those receiving ofatumumab
  • PFS remained significantly longer for ibrutinib vs ofatumumab (hazard ratio [HR]=0.133; 95% confidence interval [CI], 0.099-0.178; P <.0001)
  • 3-year PFS rate was 59% with ibrutinib vs 3% with ofatumumab
  • On multivariate analysis, more than 2 lines of therapy (P =.007) and elevated baseline beta-2 microglobulin levels (P =.044) were significantly associated with decreased PFS for patients receiving ibrutinib
• There was a continued trend for improved OS for patients assigned to the ibrutinib arm despite 68% of  patients assigned to the ofatumumab arm crossing over to ibrutinib
  • 3-year OS rates of 74% in the ibrutinib arm and 65% in the ofatumumab arm (irrespective of crossover)
  • Following censoring for crossover, OS was significantly longer for patients randomly assigned to the ibrutinib arm compared with those assigned to the ofatumumab arm (HR=0.591; 95% CI, 0.378-0.926; P =.0208)
• 91% of patients receiving ibrutinib experienced a response; and overall response increased over time
• The most common grade 3 or higher hematologic adverse events included neutropenia (23%), anemia (9%) and thrombocytopenia (8%). Pneumonia (17%), hypertension (8%), urinary tract infection (6%), atrial fibrillation (6%), and diarrhea (6%) were the most frequent grade 3 or higher nonhematologic adverse events occurring on long-term follow-up.

References

1. Byrd JC, Hillmen P, O’Brien S, et al. Long-term follow-up of the RESONATE™ phase 3 trial of ibrutinib versus ofatumumab [published online March 6, 2019]. Blood.  doi: 10.1182/blood-2018-08-870238
2. Byrd JC, Brown JR, O’Brien S, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371:213-223.