Minimal residual disease–driven treatment intensification with sequential addition of ibrutinib to venetoclax in R/R CLL

• Published in: Blood Vol. 140; no. 22; pp. 2348 - 2357
• Main Authors: Scarfò, Lydia, Heltai, Silvia, Albi, Elisa, Scarano, Eloise, Schiattone, Luana, Farina, Lucia, Moia, Riccardo, Deodato, Marina, Ferrario, Andrea, Motta, Marina, Reda, Gianluigi, Sancetta, Rosaria, Coscia, Marta, Rivela, Paolo, Laurenti, Luca, Varettoni, Marzia, Perotta, Eleonora, Capasso, Antonella, Ranghetti, Pamela, Colia, Maria, Ghia, Paolo
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.12.2022
• Subjects: Antineoplastic Combined Chemotherapy Protocols - adverse effects; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Neoplasm, Residual - drug therapy; Pyrazoles - adverse effects; Pyrimidines - therapeutic use
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood.2022016901

•A sequential MRD-guided addition of ibrutinib to venetoclax led to uMRD in 33 (87%) of 38 patients with relapsed/refractory CLL.•This MRD-driven strategy allowed identical depth of response to be reached in each patient with an individualized time-limited approach. [Display omitted] Undetectable measurable residual disease (uMRD) is achievable in patients with chronic lymphocytic leukemia (CLL) with the BCL2-inhibitor venetoclax alone or combined with the Bruton’s tyrosine kinase inhibitor ibrutinib. This phase 2, multicenter, MRD-driven study was designed to discontinue treatment upon reaching uMRD4 (<10−4) in patients with relapsed/refractory CLL receiving venetoclax monotherapy or after the addition of ibrutinib. Primary end point of the study was proportion of uMRD4 with venetoclax ± ibrutinib. Secondary end points were overall response rate, partial response, complete response, progression-free survival, duration of response, overall survival, and safety of venetoclax ± ibrutinib. Patients with uMRD4 at Cycle 12 Day 1 discontinued venetoclax. MRD+ patients added ibrutinib and continued both drugs up to Cycle 24 Day 28/uMRD4/progression/toxicity. After Cycle 24 Day 28, MRD+ patients continued ibrutinib. Thirty-eight patients (29% with TP53 aberrations; 79% with unmutated IGHV) started venetoclax. Overall response rate with venetoclax was 36 (95%) of 38 patients (20 complete; 16 partial response). Seventeen patients (45%) with uMRD4 at Cycle 12 Day 1 discontinued venetoclax. Nineteen (55%) MRD+ subjects added ibrutinib. After a median of 7 months (range, 3-10 months) of combined treatment, 16 (84%) of 19 achieved uMRD4, thus stopping both drugs. Two MRD+ patients at Cycle 24 Day 28 continued ibrutinib until progression/toxicity. After a median follow-up of 36.5 months, median progression-free survival was not reached; 10 patients progressed (4 restarted venetoclax, 3 without treatment need, 2 developed Richter transformation, and 1 dropped out). Seven (22%) of 32 patients remain uMRD4 after 3 years of follow-up. Neutropenia was the most frequent grade 3 to 4 adverse event; no grade 5 events occurred on study. This sequential MRD-guided approach led to uMRD4 in 33 (87%) of 38 patients, with venetoclax monotherapy or combined with ibrutinib, delivering treatment combination only in a fraction, and ultimately identifying the few patients benefiting from continuous therapy. This trial was registered at www.clinicaltrials.gov as # NCT04754035. Combining Bruton tyrosine kinase inhibitors with the BCL2 inhibitor venetoclax increases efficacy in patients with relapsed chronic lymphocytic leukemia but with increased toxicity and cost. Scarfò and colleagues report on the prospective IMPROVE trial evaluating a minimal residual disease (MRD)-driven approach to individualized treatment, commencing with venetoclax and only adding ibrutinib if MRD persists while discontinuing all therapy after a fixed duration if MRD is undetectable. These phase 2 data provide proof-of-concept and encourage randomized trials to define the optimal ways to combine these drugs.