SAN DIEGO — In untreated chronic lymphocytic leukemia (CLL), patients who received ibrutinib plus venetoclax for a duration determined by disease characteristics rather than a fixed schedule had significantly better progression-free and overall survival compared with conventional chemoimmunotherapy, a new phase 3 analysis shows.
The targeted therapy combination was also associated with better progression-free survival among patients with CLL with worse prognostic features, including immunoglobulin heavy chain variable (IGHV) unmutated disease and cytogenetic abnormalities, such as the 11q deletion, trisomy 12, and 13q deletion.
Personalizing treatment duration of ibrutinib-venetoclax, as determined by measurable residual disease (MRD), allowed more than half of patients assigned to the combination therapy to stop therapy by 3 years because they had achieved MRD negativity, reported Peter Hillmen, MBChB, PhD, from the Leeds Institute of Medical Research at St James's University Hospital in Leeds, United Kingdom.
The shorter course of therapy could help to ameliorate toxicities and lower the risk for the development of drug-resistant disease, he said.
"This is the first trial to show that an MRD-guided approach with treatment beyond [MRD] negativity has a significant advantage over chemoimmunotherapy, both in terms of [progression-free] and overall survival. Over 90% of patients achieve an MRD-negative in this combination in the peripheral blood," said Hillmen in a media briefing prior to his presentation of the data in an oral abstract session here at the American Society of Hematology (ASH) annual meeting.
The study results were also published online in The New England Journal of Medicine to coincide with the presentation.
Adaptive Trial
The FLAIR study is a phase 3 open-label platform trial that initially compared ibrutinib-rituximab with fludarabine-cyclophosphamide-rituximab (FCR) in patients with untreated CLL. However, in 2017 the trial was adapted to include both an ibrutinib monotherapy and an ibrutinib-venetoclax arm with therapy duration determined by MRD.
At ASH 2023, Hillmen presented data from an interim analysis of 523 patients comparing ibrutinib-venetoclax with FCR.
In the ibrutinib-venetoclax group, patients received oral ibrutinib 420 mg daily, with venetoclax added after 2 months, beginning with a 20-mg dose ramped up to 400 mg in a weekly dose-escalation schedule. The combination could be given for 2-6 years, depending on MRD responses. FCR was delivered in up to six cycles of 28 days each. Two thirds of patients assigned to FCR completed all six cycles.
After a median follow-up of 43.7 months, 12 patients (4.6%) randomly assigned to ibrutinib-venetoclax had disease progression or died compared with 75 patients (28.5%) assigned to FCR. The estimated 3-year progression-free survival with ibrutinib-venetoclax was 97.2%, compared with 76.8% with FCR, translating into a hazard ratio (HR) for progression or death with the targeted therapy combination of 0.13 (P <.001).
Among patients with unmutated IGHV, the combination led to improved progression-free survival compared with FCR (hazard ratio [HR] for progression or death, 0.07); for patients with mutated IGHV, however, the combination did not improve progression-free survival (HR, 0.54; 95% CI, 0.21-1.38).
In all, eight patients (3.5%) assigned to ibrutinib-venetoclax and 23 assigned to FCR (9.5%) died.
The 3-year overall survival rates were 98% in the targeted therapy group vs 93% in the FCR group (HR for progression or death, 0.31).
At 2 years, 52.4% of patients assigned to ibrutinib-venetoclax had undetectable MRD in bone marrow compared with 49.8% with FCR. At 5 years, the respective percentages for MRD in bone marrow were 65.9% vs 49.8% and 92.7% vs 67.9% for MRD in peripheral blood.
The safety analysis showed higher rates of blood and lymphatic system disorders with FCR, whereas cardiac, metabolic/nutrition disorders, and eye disorders occurred more frequent with ibrutinib-venetoclax.
A total of 24 secondary cancers were diagnosed in 17 patients randomly assigned to ibrutinib-venetoclax and 45 secondary cancers among 34 patients randomly assigned to FCR. One patient assigned to ibrutinib-venetoclax developed myelodysplastic syndrome/acute myeloid leukemia (AML), as did eight patients assigned to FCR. One patient in the ibrutinib-venetoclax arm and four patients in the FCR arm had Richter's transformation.
The incidence rate for other cancers was 2.6 per 100 person-years with ibrutinib-venetoclax compared with 5.4 per 100 person-years with FCR.
The most frequently occurring cancers in each arm were basal cell or squamous cell carcinomas. The incidence of myelodysplastic syndromes, AML lymphoma, and prostate/urologic cancers was higher among patients on FCR.
This research "unequivocally shows the superiority of targeted therapy over traditional cytotoxic chemotherapy," commented briefing moderator Mikkael A. Sekeres, MD, from the University of Miami Miller School of Medicine.
The ibrutinib-venetoclax combination has the potential to reduce the incidence of myelodysplastic syndromes secondary to CLL therapy, Sekeres suggested.
"As someone who specializes in leukemia and myelodysplastic syndromes, I have the feeling I won't be seeing these CLL patients in my clinic — years after being treated for CLL — much longer," he said.
In an interview with Medscape Medical News, Lee Greenberger, PhD, said that "I think that duration-adapted therapy is a great story. Using MRD negativity is a perfectly justified way, I think, to go about a new combination that's going to be really potent for CLL patients and probably give them many years of treatment and then to get off the drug, because ultimately the goal is to get cures."
This combination, though highly efficacious, is unlikely to be curative; however, because even when MRD is undetectable, "it will come back," said Greenberger, chief scientific officer for the Leukemia & Lymphoma Society.
Greenberger added that MRD testing of bone marrow, which provides a more detailed picture of MRD status than testing of peripheral blood, is feasible in academic medical centers but may be a barrier to MRD-adapted therapy in community oncology practices.
The FLAIR study is supported by grants from Cancer Research UK, Janssen, Pharmacyclics, and AbbVie. Hillmen disclosed employment and equity participation with Apellis Pharmaceuticals. Sekeres disclosed board activities for Geron, Novartis, and Bristol-Myers Squibb and owner of stock options Kurome. Greenberger reported no relevant financial disclosures.
Neil Osterweil, an award-winning medical journalist, is a long-standing and frequent contributor to Medscape.
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