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Dr. Paolo Ghia, at the European Hematology Association (EHA) 2021 virtual annual meeting, presented the results of seven years of follow-up of treatment-naïve chronic lymphocytic leukemia patients treated with ibrutinib, a once-daily Bruton’s tyrosine kinase inhibitor. The RESONATE-2 trial, and many others before and since, changed everything for CLL patients. Today, ibrutinib is still the only targeted therapy proven to have both a significant progression-free survival (PFS) and overall survival (OS) benefit in phase 3 studies compared with established chemoimmunotherapy regimens in previously untreated CLL patients.
The phase 3 RESONATE-2 study enrolled patients with previously untreated CLL/SLL who were ≥65 years and without del(17p) (N=269). Patients were randomly assigned in 1:1 to receive either once-daily single-agent ibrutinib (420 mg) until disease progression or unacceptable toxicity (n=136), or chlorambucil (0.5–0.8 mg/kg) for up to 12 cycles (n=133). To give a sense of how much progress has been made, there is no way this trial could be conducted today, as randomizing patients to chlorambucil would be unethical as it is a clearly inferior option. Bluntly, even at the time of the trial, it was not a strong comparator, but there weren’t many good choices for the researchers or for the patients before the 2014 approval of ibrutinib. The reassuring long-term outcomes, including PFS, OS, overall response rate (ORR), and safety of the ibrutinib, is what’s important and why these results matter to CLL patients. That ibrutinib is better than chlorambucil needs no more proof.
- PFS benefit was sustained for patients treated with ibrutinib versus chlorambucil (hazard ratio [HR] 0.160). That means that those randomized to ibrutinib were 94% less likely to progress.
- At 6.5 years, 61% of patients treated with ibrutinib vs 9% of patients treated with chlorambucil remained progression-free.
- Ibrutinib treatment resulted in an OS rate of 78% at 6.5 years.
- The ORR for ibrutinib-treated patients was 92%, and the complete response rate rose to 34% at the time of data collection.
- As to adverse events (AEs) or side effects, rates remained low for grade ≥3 (grade ≥3 AEs are serious) hypertension (year 5–6: 5%, n=4; year 6–7: 4%, n=3), and grade ≥3 atrial fibrillation with only one more patient in both year 5–6 and year 6–7.
- There were no major bleeding events in years 5–7.
- Grade ≥3, or serious AEs leading to dose reductions, were observed in only one patient in year 5–6 and one more in year 6–7.
- For the 31 patients who had dose reductions due to AEs over the 8 years of the trial, 22 had resolution or improvement of the AE.
- Progressive disease was the primary reason for discontinuations in year 5–6 (5%, n=4) and year 6–7 (6%, n=4).
- AEs of any grade leading to discontinuations were observed in only 2 patients in year 5–6 and none in year 6–7.
- With up to 7 years of follow-up, 47% of patients remain on single agent ibrutinib.
With extended long-term follow-up from RESONATE-2, first-line treatment with ibrutinib demonstrated sustained PFS and OS benefit for patients. Almost half the patients were still on ibrutinib after 7 years, but that means more than half had stopped due to disease progression or drug intolerance. Responses continued to deepen over time with over a third reaching a CR. Serious AEs of interest were rare in the last few years of the study as were discontinuations and dose reductions due to AEs. It does seem that if patients can tolerate ibrutinib for the first few years, AEs are rare, and when they occur, they can be managed with dose reduction. What is most encouraging is that no new problems were observed in the later years. Ibrutinib was the first oral targeted agent in CLL and now has an impressive long term safety record.
Here is the link to the EHA 2021 abstract.
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Stay strong. We are all in this together.
Brian Koffman MDCM (retired) MS Ed
Co-Founder, Executive VP and Chief Medical Officer
CLL Society, Inc.