Paper Details

ABSTRACT

Introduction: Fixed-duration acalabrutinib + venetoclax (AV) was superior to chemoimmunotherapy in patients (pts) with treatment (tx)-naive (TN) chronic lymphocytic leukemia (CLL) without del(17p) or TP53 mutation (TP53m) in the phase 3 AMPLIFY trial (NCT03836261), establishing it as a new standard of care option. Recently, CLL17 (NCT04608318) showed that a BTKi/BCL-2i combination (ibrutinib + V) had lower rates of undetectable minimal residual disease (uMRD) yet similar progression-free survival (PFS) vs V + obinutuzumab (VO). We report results from a prespecified interim analysis (IA) of MAJIC, which directly compares AV to VO in a broad pt population with TN CLL/small lymphocytic lymphoma (SLL), including pts with TP53 aberrations, with both regimens utilizing MRD-guided tx duration of either 1 or 2 y (1Y, 2Y).

Methods: MAJIC (NCT05057494) is an ongoing, randomized, open-label, global phase 3 trial in pts with TN CLL/SLL aged ≥18 y including pts with del(17p) and/or TP53m. Pts were randomized (stratified by del(17p)/TP53m status, IGHV status, and age ≥65 y) 1:1 to oral AV (A 100 mg BID cycles [C] 1–14 or 24; V 400 mg QD C3–14 or 24 with standard 5-wk dose ramp-up initiated C3 day [D] 1) or VO (oral V 400 mg QD C1–12 or 24 with standard 5-wk dose ramp-up initiated C1D22; intravenous O C1–6 by standard dosing). Tx was stopped after ~1Y of V (end C14 AV or C12 VO) for at least partial response (PR) and uMRD in peripheral blood (PB) at <10^-5 (uMRD5) by clonoSEQ; otherwise, V (VO arm) and AV continued through C24 (2Y). The IA was performed after all pts completed the required study tx. The event-driven primary endpoint analysis of PFS will be reported when mature. The descriptive secondary endpoint analyses include investigator-assessed overall response rate (ORR; defined as best overall response of complete response [CR]/PR) and CR rate, uMRD rate (PB by clonoSEQ) and safety. Response was based on 2018 iwCLL criteria and adverse events (AEs) were graded according to CTCAE v5.

Results: Among 607 randomized pts (AV, n=306; VO, n=301), baseline characteristics were well balanced. Median age was 66 y (55% ≥65 y; range 34–86 y), 66% were male, 10% had del(17p)/TP53m, and 61% had unmutated IGHV (uIGHV). Median tx duration was 22.1 mo (AV) and 11.5 mo (VO). Tx completion rates at 1Y due to meeting clinical response and uMRD criteria were 22.0% (AV) and 81.8% (VO).

ORRs were 91.2% for AV and 90.7% for VO; CR/CR with incomplete marrow recovery rates (CRRs) were 19.3% for AV and 23.3% for VO. In pts with del(17p)/TP53m, ORRs (CRRs) were 86.7% (26.7%) for AV and 92.9% (17.9%) for VO. With uIGHV, ORRs (CRRs) were 93.6% (19.3%) for AV and 90.2% (21.7%) for VO. uMRD5 (uMRD4) rates in AV vs VO were 23.5% (38.2%) vs 83.1% (87.0%) at 1Y and 38.2% (51.6%) vs 54.2% (69.1%) at 2Y. With del(17p)/TP53m, uMRD5 (uMRD4) rates were 20.0% (33.3%) for AV and 67.9% (82.1%) for VO at 1Y and 33.3% (40.0%) and 42.9% (57.1%) at 2Y. With uIGHV, uMRD5 (uMRD4) rates were 27.3% (45.5%) for AV and 82.6% (87.0%) for VO at 1Y and 43.3% (57.8%) and 54.9% (65.8%) at 2Y.

Among 601 treated pts (AV, n=305; VO, n=296), premature tx discontinuation occurred in 14.8% (AV) and 10.8% (VO), most commonly due to AEs (7.9% and 5.4%). Grade (G) 3+ AEs occurred in 55.7% (AV) and 67.6% (VO), most commonly neutropenia/decreased neutrophil count (33.1% and 46.3%) and thrombocytopenia/decreased platelet count (3.3% and 14.5%). Serious AEs occurred in 23.0% (AV) and 26.0% (VO). Any-G atrial fibrillation and ventricular arrhythmias were 2.6% and 0.7% (AV) and 1.7% and 0.3% (VO). G3+ cardiac events and hemorrhage were 1.6% and 1.6% (AV), and 2.4% and 0.7% (VO). G3+ infections were 8.2% (AV) and 10.5% (VO). Any-G tumor lysis syndrome were 0.7% (AV) and 2.0% (VO) and any-G infusion-related reaction in 54.4% (VO only).

Conclusion: This IA of MAJIC shows similar ORR/CRR for AV and VO in an all-comer CLL/SLL population. With VO, uMRD rates were higher at 1Y and most pts completed tx at that time, whereas uMRD rates with AV increased at 2Y. MRD-guided, all-oral AV offers an infusion-free, time-limited regimen, with an overall favorable safety profile and similar cardiac and infection AE rates as VO, despite longer tx duration for the majority of pts. Though longer follow-up and mature PFS are needed to appropriately compare these regimens, initial data suggest MRD-guided AV may offer an effective, safe, and convenient option for TN CLL/SLL, including pts with higher-risk genetics.