TY - JOUR
T1 - Efficacy of venetoclax in relapsed chronic lymphocytic leukemia is influenced by disease and response variables
AU - Roberts, Andrew W.
AU - Ma, Shuo
AU - Kipps, Thomas J.
AU - Coutre, Steven E.
AU - Davids, Matthew S.
AU - Eichhorst, Barbara
AU - Hallek, Michael
AU - Byrd, John C.
AU - Humphrey, Kathryn
AU - Zhou, Lang
AU - Chyla, Brenda
AU - Nielsen, Jacqueline
AU - Potluri, Jalaja
AU - Kim, Su Young
AU - Verdugo, Maria
AU - Stilgenbauer, Stephan
AU - Wierda, William G.
AU - Seymour, John F.
N1 - Publisher Copyright:
© 2019 by The American Society of Hematology.
PY - 2019/7/11
Y1 - 2019/7/11
N2 - To define the efficacy of venetoclax with extended follow-up and identify clinical or biological treatment effect modifiers, updated data for previously treated patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) enrolled in 4 earlyphase trials were pooled. Rates of response, complete remission (CR/CRi), and undetectable minimal residual disease (U-MRD) were analyzed for all patients (n 5 436) and for those patients who were planned to receive 400 mg/day monotherapy (n 5 347). Univariate and multiple regression analyses were performed to identify the pretreatment factors associated with response rates and duration of response (DoR). Objective responses were documented in 75% of all patients, including 22% CR/CRi. Overall, 27% and 16% of the patients achieved U-MRD in blood and marrow, respectively. Estimated median progression-free survival (PFS), DoR, and time to progression were 30.2, 38.4, and 36.9 months, respectively. Similar efficacy outcomes were observed within the 400 mg/day monotherapy subset. For those who achieved CR/CRi, the 3-year PFS estimate was 83%. DoR was superior for patients achieving CR/CRi or U-MRD in landmark analyses. In multiple regression analyses, bulky lymphadenopathy (5 cm) and refractoriness to B-cell receptor inhibitor (BCRi) therapy were significantly associated with lower CR rate and shorter DoR. Fewer prior therapies were associated with higher CR rate, but not DoR. Chromosome 17p deletion and/or TP53 mutation and NOTCH1 mutation were consistently associated with shorter DoR, but not probability of response. Thus, both pretreatment factors and depth of response correlated with DoR with venetoclax. Patients without bulky lymphadenopathy, BCRi-refractory CLL, or an adverse mutation profile had the most durable benefit.
AB - To define the efficacy of venetoclax with extended follow-up and identify clinical or biological treatment effect modifiers, updated data for previously treated patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) enrolled in 4 earlyphase trials were pooled. Rates of response, complete remission (CR/CRi), and undetectable minimal residual disease (U-MRD) were analyzed for all patients (n 5 436) and for those patients who were planned to receive 400 mg/day monotherapy (n 5 347). Univariate and multiple regression analyses were performed to identify the pretreatment factors associated with response rates and duration of response (DoR). Objective responses were documented in 75% of all patients, including 22% CR/CRi. Overall, 27% and 16% of the patients achieved U-MRD in blood and marrow, respectively. Estimated median progression-free survival (PFS), DoR, and time to progression were 30.2, 38.4, and 36.9 months, respectively. Similar efficacy outcomes were observed within the 400 mg/day monotherapy subset. For those who achieved CR/CRi, the 3-year PFS estimate was 83%. DoR was superior for patients achieving CR/CRi or U-MRD in landmark analyses. In multiple regression analyses, bulky lymphadenopathy (5 cm) and refractoriness to B-cell receptor inhibitor (BCRi) therapy were significantly associated with lower CR rate and shorter DoR. Fewer prior therapies were associated with higher CR rate, but not DoR. Chromosome 17p deletion and/or TP53 mutation and NOTCH1 mutation were consistently associated with shorter DoR, but not probability of response. Thus, both pretreatment factors and depth of response correlated with DoR with venetoclax. Patients without bulky lymphadenopathy, BCRi-refractory CLL, or an adverse mutation profile had the most durable benefit.
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U2 - 10.1182/blood.2018882555
DO - 10.1182/blood.2018882555
M3 - Article
C2 - 31023700
AN - SCOPUS:85069798812
SN - 0006-4971
VL - 134
SP - 111
EP - 122
JO - Blood
JF - Blood
IS - 2
ER -