Combination of ibrutinib plus venetoclax results in a high rate of MRD-negativity in previously untreated CLL

In the first-line treatment of patients with chronic lymphocytic leukaemia there is still a medical need for new, effective therapies that improve remission rates, reduce relapses and have few side effects. Results of a planned interim analysis of the phase III NCRI FLAIR trial indicate that ibrutinib plus venetoclax is an effective and well tolerated combination, resulting in a high rate of MRD negativity in blood and marrow in the first two years of treatment.

Ibrutinib (I) and venetoclax (V) improve outcome in chronic lymphocytic leukaemia (CLL). While ibrutinib rarely eradicates measurable residual disease (MRD), venetoclax (alone or with anti-CD20) can eradicate MRD permitting time-limited therapy. Small studies suggest synergy between I and V, as I+V results in MRD negativity in many patients. The NCRI FLAIR trial was initially designed to assess whether ibrutinib plus rituximab was superior to chemo-immunotherapy with fludarabine, cyclophosphamide and rituximab. However, the trial has an adaptive design and at the end of 2017, FLAIR was adapted to add two arms, I monotherapy as an additional control and I+V as an additional test arm. At EHA 2022, Prof. Hillmen presented an interim analysis of the comparison between I and I+V, when 50% of patients reach two years post-randomisation.

Study design

FLAIR is a phase III, randomised, controlled trial for previously untreated CLL requiring therapy by IWCLL criteria. Patients older than 75 years or with more than 20% 17p del were excluded. In the I monotherapy arm, I was given at 420mg/day. For the I+V arm, V was added after two months of I with dose escalation to 400 mg/day over 5 weeks. The duration of therapy (DOT) was defined by MRD with treatment for up to 6 years. MRD was assessed centrally by flow cytometry and MRD negativity was defined as < 1 CLL cell in 10,000 leucocytes (IWCLL criteria). MRD was assessed in peripheral blood (PB) and bone marrow (BM) at 9 months post randomisation, in PB at 12 months and then every 6 months. When PB was MRD negative, this was repeated after 3 months and then in both PB and BM 3 months later. If PB & BM were negative, the time to MRD negativity was calculated (treatment start to first MRD negative PB). The DOT was double the time it takes to reach MRD negativity (minimum two years, maximum 6 years). A formal interim analysis was performed when 50% of patients in I and I+V arms had reached 2 years post-randomisation and a p-value of <0.005 was statistically significant.

Results

In total, 523 patients were randomised to I or I+V and the first interim analysis reports on the first 274 patients reaching 2 years post-randomisation. Among them, 72.3% were male and the median age was 63 years, 40.9% had Binet stage C. There were slight imbalances in IGHV subset 2 (12.3% for I and 5.9% for I+V) and 13q deletions (41.3% for I and 32.4% for I+V).

The objective response rate at nine months post-randomisation was 86.2% in the I arm and 88.2% in the I+V arm. However, only 8.0% of patients in the I arm achieved a complete response, as compared to 59.6% in the I+V arm. At the two-year time-point, 65.4% and 71.3% of patients receiving I+V achieved MRD negativity in the BM and PB, respectively. As no patients in the I arm achieved MRD negativity in the PB or BM, penalised logistic regression models were fitted to enable finite parameter estimation. The odds ratio of becoming MRD negative in the bone marrow by 2 years post-randomisation were 454 (95%CI: 29.0-7122, p< 0.0001). The median time to MRD negativity in the I+V arm was 12 months for the PB and 19 months in the BM. In the I+V arm, 42.6% achieved MRD negativity after one year of treatment and thus stopped treatment at 24 months. MRD negativity for I+V in BM within 24 months was 79.7% for IGHV unmutated and 56.4% for IGHV mutated.

The most frequent any grade adverse events (AEs) within 12 months of randomisation differing between I+V and I were diarrhoea (52.6% I+V patients, 29.4% I), nausea (40.7% vs. 14%), anaemia (28.9% vs. 16.9%) and leukopenia (36.3% vs. 8.8%). Leukopenia was the only grade ≥ 3 serious AE (SAE) reported in > 10% of patients (27.4% I+V and 5.1% I). Laboratory tumour lysis syndrome (TLS) was reported in 6/136 (4.4%) of I+V patients and none with I. There were no cases of clinical TLS. Infectious SAEs were reported in 14.8% vs. 19.9% and cardiac SAEs in 11.9% vs. 8.1% of patients for I+V and I, respectively. In total,  9.4% of patients in the I arm and 13.2% of patients in the I+V arm discontinued ibrutinib early due to AEs.

Conclusion

Ibrutinib plus venetoclax resulted in 65.4% MRD-negative remissions in the marrow in the first two years of treatment, compared to none for ibrutinib monotherapy. Furthermore, the combination resulted in 59.6% complete responses after nine months, compared to only 8% for ibrutinib alone. Ibrutinib plus venetoclax was well tolerated with higher rates of cytopenias and diarrhoea.

Reference

Hillmen P, et al. 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. Presented at EHA 2022; Abstract S145.