Professor Peter Hillmen, MD, he leads the Experimental Haematology section in LICAP and the Translational Haematology Research group. He is a Professor of Experimental Haematology and Honorary Consultant Haematologist at Leeds Teaching Hospitals NHS Trust at University of Leeds. In this audio, he speaks about the EHA 2022 Abstract – The Combination Of Ibrutinib Plus Venetoclax Results In A High Rate Of Mrd Negativity In Previously Untreated Cll: The Results Of The Planned Interim Analysis Of The Phase III Ncri FLAIR Trial.
History
Ibrutinib (I) and venetoclax (V) both enhance CLL outcomes. I rarely eliminates measurable residual disease (MRD), whereas V (alone or in combination with anti-CD20) can eliminate MRD, allowing for time-limited therapy. Small studies imply that I and V work together, as I+V resulted in MRD negative in many patients (pts).
Targets
The major goal was to compare the rates of MRD eradication between I and I+V. Secondary goals included IWCLL overall response rate (ORR), complete response rate (CR), and safety.
Methodology
FLAIR (ISRCTN01844152), a phase III, randomized, controlled trial for previously untreated CLL that meets IWCLL criteria and requires therapy. Pts over 75 years old or with a 17p del of more than 20% were excluded. FLAIR was updated in July 2017 to include two additional arms, I monotherapy and I+V. I was prescribed 420mg each day. For I+V, V was added after two months of I, with the dose gradually increasing to 400mg/day over five weeks. MRD established the duration of therapy (DOT), with treatment lasting up to 6 years. MRD was measured centrally using flow cytometry, and MRD negativity was defined as 1 CLL cell in 10,000 leucocytes (IWCLL criteria). MRD was measured in peripheral blood (PB) and bone marrow (BM) at 9 months, 12 months, and subsequently 6 months. When PB was MRD negative, this was repeated three months later, and then three months later in both PB and BM. If both PB and BM were negative, the time to MRD negativity was computed (treatment start to first MRD negative PB), and the DOT was double that. The earliest therapy may be discontinued was two years after randomization. When 50% of points in the I and I+V arms had reached 2 years post-randomization, a formal interim analysis was done, and a p-value of 0.005 was statistically significant.
Outcomes
523 points were assigned to I or I+V. We present an interim analysis of the first 274 points (I [n=138] and I+V [n=136]) reached two years after randomization from 83 UK centers between 13/07/17 and 15/03/19. 72.3 percent were male, the median age was 63 years (34.3 percent were over 65 years old), and 40.9 percent were Binet C. IGHV was available for 256 (93.4 percent) patients, with 48.2 percent IGHV unmutated (98 percent homology to germline), 45.3 percent IGHV mutated, and 9.1 percent Subset 2. Hierarchical FISH testing found 16.1% 11q del, 19% trisomy 12, 21.9 percent normal, and 36.9% 13q del, with 6.2 percent failing. For all variables, the arms were well-balanced. MRD negative was reached in BM in 89/136 (65.4 percent) and PB in 97/136 (71.3 percent) within 24 months in the I+V arm compared to no points in the I arm (p0.0001). Within 24 months, MRD negative for I+V in BM was 51/64 (79.7%) for IGHV unmutated and 31/55 (56.4%) for IGHV mutated. At 9 months, 49/136 (36%) I+V patients were MRD negative in BM and 56/136 (41.2%) negative in PB, compared to 0/138 with I (p0.0001). ORR at 9 months in 120/136 (88.2%) I+V points and 119/138 (86.2%) I points (p=0.6157). At 9 months, CR was found in 81/136 (59.6%) of I+V cases and 11/138 (8%) of I cases (p0.0001). At any time, the I+V CR was 93.4 percent. At 24 months, 54/136 (39.7 percent) of the patients ceased I+V because they met the MRD stopping criterion.
Implication
Ibrutinib with venetoclax is a safe and effective combination that results in a high rate of MRD negative in blood (71.9%) and marrow (65.4%) in the first two years of treatment.