Minimal Residual Disease–Driven Treatment Intensification With Sequential Addition of Ibrutinib to Venetoclax in Relapsed/Refractory CLL
abstract
This abstract is available on the publisher's site.
Access this abstract nowUndetectable MRD (uMRD) is achievable in patients with CLL with the BCL2-inhibitor venetoclax alone or combined with the BTK-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 endpoint of the study was proportion of uMRD4 with venetoclax+/-ibrutinib. Secondary endpoints were ORR, PR, CR, PFS, DOR, OS, 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% unmutated IGHV) started venetoclax. ORR with venetoclax was 36/38(95%) (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) of combined treatment, 16/19 (84%) 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 PFS was not reached; 10 patients progressed (4 restarted venetoclax, 3 without treatment need, 2 developed Richter transformation, 1 dropped-out). 7/32 patients (22%) remain uMRD4 after 3 years of follow-up. Neutropenia was the most frequent G3-4 adverse event, no grade 5 events occurred on study. This sequential MRD-guided approach led to uMRD4 in 33/38 patients (87%) with venetoclax monotherapy or combined with ibrutinib., delivering treatment combination only in a fraction, and ultimately identifying the few patients benefiting from continuous therapy. Clinical trial number: NCT04754035.
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MINIMAL RESIDUAL DISEASE-DRIVEN TREATMENT INTENSIFICATION WITH SEQUENTIAL ADDITION OF IBRUTINIB TO VENETOCLAX IN R/R CLL
Blood 2022 Aug 03;[EPub Ahead of Print], L Scarfo, S Heltai, E Albi, E Scarano, L Schiattone, L Farina, R Moia, M Deodato, A Ferrario, M Motta, G Reda, R Sancetta, M Coscia, P Rivela, L Laurenti, M Varettoni, E Perotta, A Capasso, P Ranghetti, M Colia, P GhiaFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
In the era of oral chemotherapy targeting B-cell signaling, the outcomes of patients with CLL have improved. It is, therefore, essential for newer studies to balance the risk between toxicity and benefit while maintaining the quality of life. The present study by Scarfo et al is a phase II multicenter study in patients with relapsed/refractory CLL that aimed to assess minimal residual disease (MRD) eradication (at the level of <10-4) with single-agent venetoclax, with the addition of a second agent (ibrutinib) for patients who do not achieve this endpoint. For those who achieved undetectable MRD, therapy could be discontinued. The study demonstrated that single-agent venetoclax can achieve undetectable MRD in approximately 45% of patients after 11 cycles (28 days) of therapy. For those who did not achieve undetectable MRD, the addition of ibrutinib resulted in an additional 40% of patients achieving undetectable MRD after a median of 7 months of combination therapy. This sequential approach is logical and avoids exposing all patients to combination therapy. However, a key question remains — whether undetectable MRD is truly the right endpoint moving forward. In the present study, the majority of patients experienced MRD relapse (78%) but most did not experience clinical progression requiring therapy. Although it is tempting to combine oral agents, both in the front-line and relapsed/refractory settings, improved long-term outcomes for patients with standard-risk disease (ie, the majority of patients) have yet to be demonstrated over a single-agent strategy. Longer follow-up and randomized studies comparing this strategy with a single-agent strategy (eg, ibrutinib or venetoclax) with or without anti-CD20 therapy will be needed to answer whether achieving undetectable MRD will translate to improved survival and/or quality of life.