High MRD-Negative Rates Seen with Venetoclax in Patients With Relapsed/Refractory CLL

William G. Wierda, MD, PhD

Patients with relapsed/refractory chronic lymphoblastic leukemia (CLL) treated with single-agent venetoclax (Venclexta) attained high rates of minimal residual disease (MRD) negativity in peripheral blood and bone marrow, according to a pooled analysis of 2 clinical trials reported in a poster at the 2018 ASH Annual Meeting.

Overall, treatment with venetoclax led to undetectable MRD <10-4 (U-MRD4) or low MRD (L-MRD+; ≥10-4 to <10-2) status in peripheral blood samples from 90% (142/159) of evaluable patients. U-MRD4 status was observed across all International Workshop (iwCLL) response categories, including 77% of patients who achieved complete response or complete response with incomplete hematologic recovery (CR/CRi). Analysis of bone marrow results showed U-MRD4 or L-MRD+ in 84% of 75 evaluable patients, including 91% of patients with CR/CRi.

U-MRD4 in peripheral blood was associated with significantly better PFS compared with MRD+ (HR, 0.22; P <.001). Separate analyses showed improved PFS with U-MRD4 in peripheral blood versus L-MRD+ (HR 0.28, P = .0002) and versus high-MRD (H-MRD+; HR, 0.09; P <.001). L-MRD+ was associated with improved PFS compared with H-MRD+ (HR, 0.34; P = .003).

PFS at 24 months from the start of therapy was 89.9%, 71.9%, and 33.9% with peripheral blood U-MRD4, L-MRD+, and H-MRD+, respectively.

“Venetoclax monotherapy induced high rates of peripheral blood U-MRD4 and L-MRD+ in both complete response and partial response iwCLL categories,” lead investigator William Wierda, MD, of the University of Texas MD Anderson Cancer Center, and colleagues concluded. “In this dataset, peripheral blood and bone marrow MRD levels achieved with venetoclax were highly concordant. These results are in contrast to those found with immunochemotherapy, where the MRD in bone marrow is typically 1-log higher than in peripheral blood.

“Achievement of U-MRD4 in peripheral blood with venetoclax monotherapy administered to progression appears to be associated with longer progression-free survival (PFS) than MRD+. Increased sample size and longer follow-up are required to confirm this finding.”

Previous studies demonstrated that U-MRD4 and L-MRD+ in both peripheral blood and bone marrow correlated with PFS and overall survival in patients with newly diagnosed or relapsed CLL treated with immunochemotherapy. The prognostic significance of U-MRD4 in patients treated with targeted agents had not been well established, primarily because of low rates of U-MRD4 achieved with B-cell receptor pathway inhibitors, the investigators noted.

The multicompartmental nature of CLL and differing effects of therapies on the compartments could lead to different MRD levels in peripheral blood versus bone marrow. As a result, the relationship between effects in peripheral blood and bone marrow must be defined for each new treatment approach.

To examine MRD in patients with relapsed/refractory CLL treated with venetoclax, investigators reviewed findings from the phase II M14-032 (NCT02141282) and M13-982 (NCT01889186) clinical trials involving a total of 285 patients. Data on MRD status for peripheral blood and/or bone marrow were available for 161 patients.

Study objectives included determination of MRD status, concordance for MRD status between peripheral blood and bone marrow, and the prognostic significance of MRD levels achieved with venetoclax.

Overall, 82 of 159 (52%) patients with peripheral blood samples attained U-MRD4 with venetoclax. Across the iwCLL response categories, U-MRD4 was attained in 34 of 44 (77%) patients with CR/CRi, 43 of 99 (43%) with partial remission/nodular partial remission (PR/nPR), and 5 of 16 (31%) with stable disease. An additional 60 (38%) patients attained L-MRD+ with venetoclax: 9 (20%) who had CR/CRi, 45 (45%) with PR/nPR, and 6 (38%) with stable disease. Only 1 patient who achieved CR/CRi had H-MRD+, as compared with 11 (11%) patients who achieved PR/nPR, and 5 (31%) who had stable disease.

Analysis of data for the 75 patients with available bone marrow samples showed that 20 of 34 (59%) with CR/CRi attained U-MRD4, as did 6 of 37 (16%) with PR/nPR, and 1 of 4 patients with stable disease, resulting in an overall U-MRD4 rate of 36%. L-MRD+ was observed in 11 (32%) patients with CR/CRi, 23 (78%) in the PR/nPR response category, and 2 of 4 with stable disease. H-MRD+ was seen in 3 (9%) patients who achieved CR/CRi, 8 (22%) who had PR/nPR, and 1 patient with stable disease.

Analysis of 42 matched samples of peripheral blood and bone marrow showed concordance for U-MRD4 in 38 (91%). Matched bone marrow samples from 16 patients showed concordance for U-MRD4 in peripheral blood in 12 (75%). No patient with U-MRD4 in bone marrow had detectable MRD in peripheral blood.

Weirda WG, Roberts AW, Ghia P, et al. Minimal residual disease status with benetoclax monotherapy is associated with progression-free survival in chronic lymphocytic leukemia. Presented at: 2018 ASH Annual Meeting; Dec. 1-4, 2018; San Diego. Abstract 3134.

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