Paul J. Hampel, MD, a hematologist/oncologist at Mayo Clinic, Rochester, Minnesota, underscored the complexity of this arm of the adaptive FLAIR trial, which compared measurable residual disease (MRD)-directed ibrutinib plus venetoclax with standard, fixed-duration, FCR (fludarabine, cyclophosphamide, and rituximab) chemoimmunotherapy in patients with previously untreated chronic lymphocytic leukemia (CLL). In essence, he said, “this arm used the time it took for the treatment to achieve undetectable MRD in an individual patient to guide that person’s length of treatment.” According to Dr. Hampel, accomplishing this personalized approach at a large scale (96 UK centers and more than 500 patients in a phase III trial) and in a randomized fashion “deserves praise itself.”
As Dr. Hampel noted, both progression-free survival and overall survival at 3 years favored the combination of ibrutinib and venetoclax, “with survival benefits most clear in the patients with unmutated IGHV disease.”
“On the other hand, although the data trend toward favoring ibrutinib plus venetoclax in patients with IGHV-mutated disease, this was not statistically significant,” he continued. “For patients requiring CLL-directed treatment with low-risk disease (no TP53 aberration and mutated IGHV), a fixed duration of venetoclax plus obinutuzumab (as demonstrated in the CLL14 study1 against chlorambucil plus obinutuzumab and more recently against FCR or BR chemoimmunotherapy arms in CLL132) may be a simpler and adequate approach.”
Paul J. Hampel, MD
Regulatory Approvals and Practice Guidelines
“These results are impressive and exciting for patients and clinicians, especially delivered in a large, randomized trial such as this,” said Dr. Hampel. He added that based on data from the GLOW study,3 ibrutinib plus venetoclax was approved in August 2022 by the European Commission in fixed-duration format. No Bruton’s tyrosine kinase (BTK) inhibitor–plus-venetoclax combination (whether fixed-duration or MRD-driven) has been approved by the U.S. Food and Drug Administration yet, but ibrutinib plus venetoclax is listed (as a category 2B recommendation) in the National Comprehensive Cancer Network® Clinical Practice Guidelines in Oncology, version 1.2024.
Dr. Hampel also discussed the potential effect of TP53 disruption on treatment selection. In the FLAIR trials, patients with more than 20% del(17p) cells were excluded, and the outcomes in those with less than 20% del(17p) were not reported.
“The results in patients with CLL with some form of TP53 disruption in either the ibrutinib monotherapy (not presented at ASH 2023) or ibrutinib-plus-venetoclax arms of FLAIR will be anticipated results,” said Dr. Hampel, who noted the disparity in the 5-year progression-free survival rate between patients with del(17p) or mutated TP53, as reported in different studies: the CAPTIVATE study had a 54-month progression-free survival rate of 45%,4 whereas the MDACC study showed a 5-year progression-free survival rate of 86%.5
The duration of combination therapy in these studies was highlighted as a potential reason for this difference. According to Dr. Hampel, the median duration of treatment in the FLAIR trial, which was just over 2 years, more closely approximates the duration of therapy seen in the smaller MDACC study.
“The use of a BTK inhibitor plus a BCL2 inhibitor vs continuous, indefinite BTK inhibition for this high-risk group of patients with TP53 aberrations…remains a question relevant to and facing clinicians and patients now,” Dr. Hampel concluded.
DISCLOSURE: Dr. Hampel reported no conflicts of interest.
REFERENCES
1. Al-Sawaf O, Zhang C, Jin HY, et al: Transcriptomic profiles and 5-year results from the randomized CLL14 study of venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab in chronic lymphocytic leukemia. Nat Commun 14:2147, 2023.
2. Eichhorst B, Niemann CU, Kater AP, et al: First-line venetoclax combinations in chronic lymphocytic leukemia. N Engl J Med 388:1739-1754, 2023.
3. Kater AP, Owen C, Moreno C, et al: Fixed-duration ibrutinib-venetoclax in patients with chronic lymphocytic leukemia and comorbidities. NEJM Evid. May 13, 2022 (early release online).
4. Ghia P, Wierda WG, Barr PM, et al: Relapse after first-line fixed duration ibrutinib + venetoclax: High response rates to ibrutinib retreatment and absence of BTK mutations in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma with up to 5 years of follow-up in the phase 2 CAPTIVATE study. 2023 ASH Annual Meeting & Exposition. Abstract 633. Presented December 10, 2023.
5. Jain N, Keating MJ, Thompson PA, et al: Combined ibrutinib and venetoclax for first-line treatment of patients with chronic lymphocytic leukemia: 5-year follow-up data. 2023 ASH Annual Meeting & Exposition. Abstract 4635. Presented December 11, 2023.
