December 11, 2023
By Mark L. Fuerst
Ibrutinib plus venetoclax significantly improved responses, progression-free survival (PFS), and overall survival (OS) compared to standard chemoimmunotherapy in fit patients with previously untreated chronic lymphocytic leukemia (CLL). Among patients with newly diagnosed CLL who were treated with the two targeted agents and whose duration of treatment was determined by high-sensitivity testing for residual cancer cells in the blood, 97.2 percent were free of cancer progression and 2 percent had died at 3 years. In comparison, PFS for patients receiving the standard of care was 76.8 percent with a death rate of 7 percent.
“These results appear better than those seen in any previous Phase III trial in CLL,” said lead author Peter Hillmen, MB ChB, PhD, Professor of the University of Leeds in the United Kingdom, at a press briefing at the 2023 American Society of Hematology annual meeting (Abstract 631). “They show that targeted therapy, with high-sensitivity testing used to individualize the duration of treatment, is a more effective approach than current standard therapy and represents a new gold standard for previously untreated CLL.” The study was published simultaneously in the New England Journal of Medicine.
Ibrutinib, an irreversible BTK inhibitor, and venetoclax, a BCL-2 inhibitor, target two key pathophysiological pathways in CLL and appear to be synergistic. In earlier trials, together they showed results in high proportions of measurable residual disease (MRD) negativity.
FLAIR, a large UK Phase III, multicenter, randomized, controlled, open, parallel group trial for untreated CLL, compared the combination of the novel treatments against the standard of care, a regimen of fludarabine, cyclophosphamide, and rituximab (FCR). A total of 523 patients with untreated CLL (71.3% male, median age 62) were randomly assigned to receive FCR or ibrutinib and venetoclax. Patients with more than 20 percent 17p deleted cells were excluded. FLAIR was adapted in 2017 to add two arms—ibrutinib alone and ibrutinib and venetoclax compared to FCR.
In the ibrutinib and venetoclax group after 2 months of ibrutinib, venetoclax was added with a 4-week dose escalation to 400 mg/day and then ibrutinib + venetoclax was given for up to 6 years with duration of ibrutinib and venetoclax defined by MRD. Peripheral blood MRD was assessed at 12 months and then 6 monthly and, if negative, was repeated at 3 months and 6 months in both the peripheral blood and bone marrow. If all tests were MRD-negative, the patient was treated for twice the duration of time from the start of ibrutinib and venetoclax treatment to the first MRD-negative test.
“Patients’ duration of treatment was determined by how quickly they responded,” said Hillmen. Duration of treatment ranged from 2-6 years.
At a median 43.7 months follow-up, patients treated with FCR were approximately 8 times as likely to have disease progression compared with patients who received ibrutinib and venetoclax. There were 87 progressions—75 in FCR patients and 12 in ibrutinib and venetoclax patients. This finding was consistent regardless of patient gender, age, or disease stage. Moreover, patients with a worse prognosis appeared to do particularly well.
At 3 years, 2.8 percent of patients had progressed on ibrutinib and venetoclax compared to 23.2 percent on FCR. There have been 34 deaths (25 FCR and 9 ibrutinib and venetoclax) resulting in improved OS for ibrutinib and venetoclax versus FCR with a hazard ratio of 0.31. “This is the first time a combination of these drugs has shown an OS advantage,” said Hillmen.
At 9 months (3 months post-FCR) 48.3 percent of FCR patients became MRD-negative in bone marrow compared to 41.5 percent for ibrutinib and venetoclax. However, with continued ibrutinib and venetoclax, more patients became MRD-negative; 90.6 percent of patients achieved peripheral blood MRD-negativity at up to 5 years of ibrutinib and venetoclax and 88 percent of these were bone marrow MRD-negative 6 months after their first peripheral blood MRD-negativity result. At 9 months a higher proportion achieved complete response and overall response for ibrutinib and venetoclax. This difference was greater for best response at any time.
Ibrutinib plus venetoclax was well-tolerated with no unexpected toxicities. Serious adverse events (SAEs) were reported in 252 (51.3%) patients (129 FCR vs. 123 ibrutinib and venetoclax). Notable SAEs included infections (18.8% of FCR patients vs. 22.2% for ibrutinib and venetoclax); blood and lymphatic (31% vs. 5%); and cardiac (0.4% vs. 10.7%). Four patients had sudden or cardiac deaths—two in each treatment group. The incidence of other cancers per 100 patient-years was greater for FCR (5.4) than ibrutinib and venetoclax (2.6). There were seven cases of MDS/AML with FCR and one with ibrutinib and venetoclax.
“More patients achieve an MRD-negative remission with ibrutinib plus venetoclax than FCR,” Hillmen noted. “The majority of ibrutinib plus venetoclax patients achieved the MRD stopping criteria. PFS was better in IGHV unmutated, 11q deleted, Trisomy 12 and 13q deleted CLL, among other subgroups. The excellent results seen with ibrutinib plus venetoclax indicate that directing the duration of therapy according to individual MRD response maximizes outcomes.”
Mark L. Fuerst is a contributing writer.