The use of undetectable measurable residual disease (uMRD) to determine discontinuation of venetoclax or the addition of ibrutinib resulted in achievement of similar depth of response among patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL), according to the results of a phase 2 study published in Blood.

This multicenter, open-label, phase 2 IMPROVE study treated 38 patients with R/R CLL with venetoclax for 11 cycles. Patients who achieved uMRD4 (<10-4) at cycle 12, day 1 discontinued venetoclax, whereas patients who were MRD-positive initiated ibrutinib. At cycle 24, day 28, patients who achieved uMRD4 discontinued both venetoclax and ibrutinib, and MRD-positive patients continued with both drugs until progression or toxicity. The primary endpoint was uMRD4 and secondary endpoints included response, duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety.

At baseline, the median age was 64, and the majority of patients were Rai stage I-II. There were 79% of patients with unmutated IGHV, 29% with a TP53 mutation, 21% with del(17p), 28% with del(11q), and 27% with del(13q). The median number of prior therapies was 1 (range, 1-7), with most patients having received either fludarabine plus cyclophosphamide with or without rituximab or bendamustine plus rituximab.

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During the entirety of the study, 85% of patients achieved uMRD4. At cycle 12, day 1, 45% of patients achieved uMRD4 and 16 of these 17 patients discontinued venetoclax, whereas 55% were MRD-positive and added ibrutinib. Of the patients who added ibrutinib, 84% achieved uMRD4 within a median of 7 months. There were 2 patients who continued treatment with venetoclax and ibrutinib.

The median PFS was not reached after a median follow-up of 36.5 months and was estimated to be 74.5% at 36 months. There were 22% of patients who remained uMRD4 after 3 years and 10 patients who progressed. Of the patients who progressed, 4 restarted venetoclax, 3 did not need treatment, 2 developed Richter transformation, and 1 dropped out of the study.

Of the 33 patients who discontinued treatment due to achievement of uMRD4, 78% demonstrated MRD relapse within a median of 7 months. However, only 8 of these patients developed clinical progression.

There were no grade 4 adverse events (AEs), and the most common grade 3-4 AE was neutropenia. Other common AEs of any grade included cough, fever, diarrhea, and upper respiratory tract infection.

The authors concluded that “this MRD-driven strategy allowed identical depth of response to be reached in each patient with an individualized time-limited approach, preventing overtreatment…and identifying individuals who may benefit from continuous treatment.”

Disclosures: This study was supported by AbbVie. Please see the original reference for a full list of disclosures.


Scarfó L, Heltai S, Albi E, et al. Minimal residual disease–driven treatment intensification with sequential addition of ibrutinib to venetoclax in R/R CLL. Blood. 2022;140:2348-2357. doi: 10.1182/blood.2022016901