The analysis of the open-label FLAIR trial, published in The Lancet Oncology, tracked 771 patients with CLL for a median follow-up of 53 months (interquartile ratio, 41-61 months) and found that median progression-free survival was not reached with ibrutinib/rituximab versus 67 months with FCR (hazard ratio, 0.44, P < .0001).
“This paper is another confirmation to say that Bruton’s tyrosine kinase inhibitors are more powerful than even our strongest chemoimmunotherapy. That’s very reassuring,” said hematologist/oncologist Jan A. Burger, MD, PhD, of the University of Texas MD Anderson Cancer Center, Houston, in an interview. He did not take part in the analysis but is familiar with its findings.
There are caveats to the study. More patients in the ibrutinib/rituximab arm died of cardiac events, possibly reflecting a known risk of those drugs. And for unclear reasons, there was no difference in overall survival – a secondary endpoint – between the groups. The study authors speculate that this may be because some patients on FCR progressed and turned to effective second-line drugs.
Still, the findings are consistent with the landmark E1912 trial, the authors wrote, and adds “to a body of evidence that suggests that the use of ibrutinib-based regimens should be considered for patients with previously untreated CLL, especially those with IGHV-unmutated CLL.”
The study, partially funded by industry, was led by Peter Hillmen, PhD, of Leeds (England) Cancer Center.
According to Dr. Burger, FCR was the standard treatment for younger, fitter patients with CLL about 10-15 years ago. Then Bruton’s tyrosine kinase inhibitors such as ibrutinib entered the picture. But, as the new report notes, initial studies focused on older patients who weren’t considered fit enough to tolerate FCR.
The new study, like the E1912 trial, aimed to compare ibrutinib-rituximab versus FCR in younger, fitter patients.
From 2014 to 2018, researchers assigned 771 patients (median age, 62 years; IQR 56-67; 73% male; 95% White; 66% with World Health Organization performance status, 0) to FCR (n = 385) or ibrutinib/rituximab (n = 386).
Nearly three-quarters (74%) in the FCR group received six cycles of therapy, and 97% of those in the ibrutinib-rituximab group received six cycles of rituximab. Those in the ibrutinib-rituximab group also received daily doses of ibrutinib. Doses could be modified. The data cutoff was May 24, 2021.
Notably, there was no improvement in overall survival in the ibrutinib/rituximab group: 92.1% of patients lived 4 years versus 93.5% in the FCR group. This contrasts with an improvement in overall survival in the earlier E1912 study in the ibrutinib/rituximab group.
However, the study authors noted that overall survival in the FCR group is higher than in earlier studies, perhaps reflecting the wider availability of targeted therapy. The final study analysis will offer more insight into overall survival.
In an interview, hematologist David A. Bond, MD, of Ohio State University, Columbus, who is familiar with the study findings, said “the lack of an improvement in overall survival could be due to differences in available treatments at relapse, as the FLAIR study was conducted more recently than the prior E1912 study.” He added that “the younger ages in the E1912 study may have led to less risk for cardiovascular events or deaths for the patients treated with ibrutinib in the E1912 study.”
The previous E1912 trial showed a larger effect for ibrutinib/rituximab versus FCR on progression-free survival (HR, 0.37, P < .001 for E1912 and HR, 0.44, P< .0001 for the FLAIR trial). However, the study authors noted that FLAIR trial had older subjects (mean age, 62 vs 56.7 in the E1912 trial.)
As for grade 3 or 4 adverse events, leukopenia was most common in the FCR group (n = 203, 54%), compared with the ibrutinib/rituximab group (n = 55, 14%). Serious adverse events were reported in 205 (53%) of patients in the ibrutinib/rituximab group versus 203 (54%) patients in the FCR group.
All-cause infections, myelodysplastic syndrome, acute myeloid leukemia, Richter’s transformation, and other diagnosed cancers were rare but more common in the FCR group. Deaths from COVID-19 were the same at 3 in each group; 2 of 29 deaths in the FCR group and 3 of 30 deaths in the ibrutinib/rituximab group were considered to be likely linked to treatment.
Sudden unexplained or cardiac deaths were more common in the ibrutinib-rituximab group (n = 8, 2%) vs. the FCR group (n = 2, less than 1%).
Dr. Bond said “one of the takeaways for practicing hematologists from the FLAIR study is that cardiovascular complications and sudden cardiac death are clearly an issue for older patients with hypertension treated with ibrutinib. Patients should be monitored for signs or symptoms of cardiovascular disease and have close management of blood pressure.”
Dr. Burger also noted that cardiac problems are a known risk of ibrutinib. “Fortunately, we have second-generation Bruton’s tyrosine kinase inhibitors that could be chosen for patients when we are worried about side effects.”
He said that chemotherapy remains the preferred – or only – treatment in some parts of the world. And patients may prefer FCR to ibrutinib because of the latter drug’s side effects or a preference for therapy that doesn’t take as long.
The study was funded by Cancer Research UK and Janssen. The study authors reported relationships with companies such as Lilly, Janssen, AbbVie, AstraZeneca, BeiGene, Gilead, and many others. Dr. Burger reports financial support for clinical trials from Pharmacyclics, AstraZeneca, Biogen, and Janssen. Dr. Bond reported no disclosures.
