Venetoclax consolidation in high-risk CLL treated with ibrutinib for ≥1 year achieves a high rate of undetectable MRD

• Published in: Leukemia 2023-07, Vol.37 (7), p.1444-1453
• Main Authors: Thompson, Philip A., Keating, Michael J., Ferrajoli, Alessandra, Jain, Nitin, Peterson, Christine B., Garg, Naveen, Wang, Sa A., Jorgensen, Jeffrey L., Kadia, Tapan M., Bose, Prithviraj, Pemmaraju, Naveen, Short, Nicholas J., Wierda, William G.
• Format: Article
• Language: English
• Subjects: 692/308/153; 692/308/2779/109/1941; 692/699/1541/1990/283/1895; Adenine - therapeutic use; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Bone marrow; Bridged Bicyclo Compounds, Heterocyclic; Cancer; Cancer Research; Chronic lymphocytic leukemia; Critical Care Medicine; Flow cytometry; Gene deletion; Hematology; Humans; Inhibitor drugs; Intensive; Internal Medicine; Karyotypes; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell - genetics; Medicine; Medicine & Public Health; Mutation; Neoplasm, Residual - etiology; Oncology; Peripheral blood; Remission; Remission (Medicine); β2 Microglobulin
• ISSN: 0887-6924; 1476-5551; 1476-5551
• DOI: 10.1038/s41375-023-01901-4

Patients receiving ibrutinib for CLL rarely achieve undetectable measurable residual disease (U-MRD), necessitating indefinite therapy, with cumulative risks of treatment discontinuation due to progression or adverse events. This study added venetoclax to ibrutinib for up to 2 years, in patients who had received ibrutinib for ≥12 months (mo) and had ≥1 high risk feature ( TP53 mutation and/or deletion, ATM deletion, complex karyotype or persistently elevated β 2 -microglobulin). The primary endpoint was U-MRD with 10 –4 sensitivity (U-MRD4) in bone marrow (BM) at 12mo. Forty-five patients were treated. On intention-to-treat analysis, 23/42 (55%) patients improved their response to CR (2 pts were in MRD + CR at venetoclax initiation). U-MRD4 at 12mo was 57%. 32/45 (71%) had U-MRD at the completion of venetoclax: 22/32 stopped ibrutinib; 10 continued ibrutinib. At a median of 41 months from venetoclax initiation, 5/45 patients have progressed; none have died from CLL or Richter Transformation. In 32 patients with BM U-MRD4, peripheral blood (PB) MRD4 was analyzed every 6 months; 10/32 have had PB MRD re-emergence at a median of 13 months post-venetoclax. In summary, the addition of venetoclax in patients treated with ≥12mo of ibrutinib achieved high rate of BM U-MRD4 and may achieve durable treatment-free remission.