Abstract
Combining venetoclax, a selective BCL2 inhibitor, with low-dose navitoclax, a BCL-XL/ BCL2 inhibitor, may allow targeting of both BCL2 and BCL-XL without dose-limiting thrombocytopenia associated with navitoclax monotherapy. The safety and preliminary efficacy of venetoclax with low-dose navitoclax and chemotherapy was assessed in this phase I dose-escalation study (NCT03181126) in pediatric and adult patients with relapsed/refractory (R/R) acute lymphoblastic leukemia or lymphoblastic lymphoma. Forty-seven patients received treatment. A recommended phase II dose of 50 mg navitoclax for adults and 25 mg for patients <45 kg with 400 mg adult-equivalent venetoclax was identified. Delayed hematopoietic recovery was the primary safety finding. The complete remission rate was 60%, including responses in patients who had previously received hematopoietic cell transplantation or immunotherapy. Thirteen patients (28%) proceeded to transplantation or CAR T-cell therapy on study. Venetoclax with navitoclax and chemotherapy was well tolerated and had promising efficacy in this heavily pretreated patient population.
| Original language | English |
|---|---|
| Pages (from-to) | 1440-1453 |
| Number of pages | 14 |
| Journal | Cancer Discovery |
| Volume | 11 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - Jun 2021 |
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In: Cancer Discovery, Vol. 11, No. 6, 06.2021, p. 1440-1453.
Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Venetoclax and navitoclax in combination with chemotherapy in patients with relapsed or refractory acute lymphoblastic leukemia and lymphoblastic lymphoma
AU - Pullarkat, Vinod A.
AU - Lacayo, Norman J.
AU - Jabbour, Elias
AU - Rubnitz, Jeffrey E.
AU - Bajel, Ashish
AU - Laetsch, Theodore W.
AU - Leonard, Jessica
AU - Colace, Susan I.
AU - Khaw, Seong Lin
AU - Fleming, Shaun A.
AU - Mattison, Ryan J.
AU - Norris, Robin
AU - Opferman, Joseph T.
AU - Roberts, Kathryn G.
AU - Zhao, Yaqi
AU - Qu, Chunxu
AU - Badawi, Mohamed
AU - Schmidt, Michelle
AU - Tong, Bo
AU - Pesko, John C.
AU - Sun, Yan
AU - Ross, Jeremy A.
AU - Vishwamitra, Deeksha
AU - Rosenwinkel, Lindsey
AU - Kim, Su Young
AU - Jacobson, Amanda
AU - Mullighan, Charles G.
AU - Alexander, Thomas B.
AU - Stock, Wendy
N1 - Funding Information: V.A. Pullarkat reports other support from AbbVie during the conduct of the study; personal fees from AbbVie outside the submitted work. E. Jabbour reports grants, personal fees, and nonfinancial support from AbbVie, Adaptive Biotechnologies, Amgen, Pfizer, and Funding Information: Takeda, personal fees and nonfinancial support from BMS, and grants and personal fees from Genentech during the conduct of the study. J.E. Rubnitz reports grants from AbbVie during the conduct of the study. A. Bajel reports personal fees from AbbVie, Amgen, Pfizer, Novartis, Astellas, and Amgen outside the submitted work. T.W. Laetsch reports nonfinancial support from AbbVie during the conduct of the study; grants and personal fees from Bayer and Novartis, personal fees from Cellectis, Deciphera, Jumo Health, Y-mAbs Therapeutics, and grants from Pfizer outside the submitted work. J. Leonard reports other support from AbbVie, Takeda, Pfizer, and Adaptive Biotechnologies and grants from Amgen outside the submitted work. S. Khaw reports other support from Amgen, Novartis, AbbVie, Bristol-Myers Squibb, and Jazz Pharmaceuticals outside the submitted work; and recipient of a share in royalty payments paid to the Walter and Eliza Hall Institute of Medical Research. S.A. Fleming reports grants and personal fees from Amgen, personal fees from Servier, Celgene, and BMS outside the submitted work. R. Norris reports travel support from Merck outside the submitted work. J.T. Opfer-man reports other support from AbbVie and grants from NIH/NCI during the conduct of the study; grants from NIH/NHLBI outside the submitted work. C. Qu reports grants from AbbVie during the conduct of the study. J.A. Ross reports being an employee of AbbVie; may hold stock or other options. D. Vishwamitra reports other support from AbbVie during the conduct of the study. L. Rosenwinkel reports being an AbbVie employee. S. Kim reports personal fees from AbbVie during the conduct of the study; personal fees from AbbVie outside the submitted work; and is an employee of AbbVie and owns AbbVie stock. A. Jacobson is a previous employee of AbbVie and may hold stock. C.G. Mullighan reports grants from AbbVie during the conduct of the study; personal fees from Illumina, grants and personal fees from Pfizer, and grants and other support from Amgen outside the submitted work. T.B. Alexander reports other support from AbbVie during the conduct of the study. W. Stock reports other support from AbbVie during the conduct of the study; other support from AbbVie outside the submitted work. No disclosures were reported by the other authors. Publisher Copyright: © 2021, American Association for Cancer Research Inc.. All rights reserved.
PY - 2021/6
Y1 - 2021/6
N2 - Combining venetoclax, a selective BCL2 inhibitor, with low-dose navitoclax, a BCL-XL/ BCL2 inhibitor, may allow targeting of both BCL2 and BCL-XL without dose-limiting thrombocytopenia associated with navitoclax monotherapy. The safety and preliminary efficacy of venetoclax with low-dose navitoclax and chemotherapy was assessed in this phase I dose-escalation study (NCT03181126) in pediatric and adult patients with relapsed/refractory (R/R) acute lymphoblastic leukemia or lymphoblastic lymphoma. Forty-seven patients received treatment. A recommended phase II dose of 50 mg navitoclax for adults and 25 mg for patients <45 kg with 400 mg adult-equivalent venetoclax was identified. Delayed hematopoietic recovery was the primary safety finding. The complete remission rate was 60%, including responses in patients who had previously received hematopoietic cell transplantation or immunotherapy. Thirteen patients (28%) proceeded to transplantation or CAR T-cell therapy on study. Venetoclax with navitoclax and chemotherapy was well tolerated and had promising efficacy in this heavily pretreated patient population.
AB - Combining venetoclax, a selective BCL2 inhibitor, with low-dose navitoclax, a BCL-XL/ BCL2 inhibitor, may allow targeting of both BCL2 and BCL-XL without dose-limiting thrombocytopenia associated with navitoclax monotherapy. The safety and preliminary efficacy of venetoclax with low-dose navitoclax and chemotherapy was assessed in this phase I dose-escalation study (NCT03181126) in pediatric and adult patients with relapsed/refractory (R/R) acute lymphoblastic leukemia or lymphoblastic lymphoma. Forty-seven patients received treatment. A recommended phase II dose of 50 mg navitoclax for adults and 25 mg for patients <45 kg with 400 mg adult-equivalent venetoclax was identified. Delayed hematopoietic recovery was the primary safety finding. The complete remission rate was 60%, including responses in patients who had previously received hematopoietic cell transplantation or immunotherapy. Thirteen patients (28%) proceeded to transplantation or CAR T-cell therapy on study. Venetoclax with navitoclax and chemotherapy was well tolerated and had promising efficacy in this heavily pretreated patient population.
UR - https://www.scopus.com/pages/publications/85107711731
U2 - 10.1158/2159-8290.CD-20-1465
DO - 10.1158/2159-8290.CD-20-1465
M3 - Article
C2 - 33593877
AN - SCOPUS:85107711731
SN - 2159-8274
VL - 11
SP - 1440
EP - 1453
JO - Cancer Discovery
JF - Cancer Discovery
IS - 6
ER -