Venetoclax and navitoclax in combination with chemotherapy in patients with relapsed or refractory acute lymphoblastic leukemia and lymphoblastic lymphoma

Vinod A. Pullarkat; Norman J. Lacayo; Elias Jabbour; Jeffrey E. Rubnitz; Ashish Bajel; Theodore W. Laetsch; Jessica Leonard; Susan I. Colace; Seong Lin Khaw; Shaun A. Fleming; Ryan J. Mattison; Robin Norris; Joseph T. Opferman; Kathryn G. Roberts; Yaqi Zhao; Chunxu Qu; Mohamed Badawi; Michelle Schmidt; Bo Tong; John C. Pesko; Yan Sun; Jeremy A. Ross; Deeksha Vishwamitra; Lindsey Rosenwinkel; Su Young Kim; Amanda Jacobson; Charles G. Mullighan; Thomas B. Alexander; Wendy Stock

doi:10.1158/2159-8290.CD-20-1465

Venetoclax and navitoclax in combination with chemotherapy in patients with relapsed or refractory acute lymphoblastic leukemia and lymphoblastic lymphoma

Vinod A. Pullarkat, Norman J. Lacayo, Elias Jabbour, Jeffrey E. Rubnitz, Ashish Bajel, Theodore W. Laetsch, Jessica Leonard, Susan I. Colace, Seong Lin Khaw, Shaun A. Fleming, Ryan J. Mattison, Robin Norris, Joseph T. Opferman, Kathryn G. Roberts, Yaqi Zhao, Chunxu Qu, Mohamed Badawi, Michelle Schmidt, Bo Tong, John C. PeskoYan Sun, Jeremy A. Ross, Deeksha Vishwamitra, Lindsey Rosenwinkel, Su Young Kim, Amanda Jacobson, Charles G. Mullighan, Thomas B. Alexander, Wendy Stock

Research output: Contribution to journal › Article › peer-review

141 Scopus citations

Abstract

Combining venetoclax, a selective BCL2 inhibitor, with low-dose navitoclax, a BCL-X_L/ BCL2 inhibitor, may allow targeting of both BCL2 and BCL-X_L 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 (US)
Pages (from-to)	1440-1453
Number of pages	14
Journal	Cancer discovery
Volume	11
Issue number	6
DOIs	https://doi.org/10.1158/2159-8290.CD-20-1465
State	Published - 2021

ASJC Scopus subject areas

Oncology

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Pullarkat, V. A., Lacayo, N. J., Jabbour, E., Rubnitz, J. E., Bajel, A., Laetsch, T. W., Leonard, J., Colace, S. I., Khaw, S. L., Fleming, S. A., Mattison, R. J., Norris, R., Opferman, J. T., Roberts, K. G., Zhao, Y., Qu, C., Badawi, M., Schmidt, M., Tong, B., ... Stock, W. (2021). Venetoclax and navitoclax in combination with chemotherapy in patients with relapsed or refractory acute lymphoblastic leukemia and lymphoblastic lymphoma. Cancer discovery, 11(6), 1440-1453. https://doi.org/10.1158/2159-8290.CD-20-1465

Pullarkat, VA, Lacayo, NJ, Jabbour, E, Rubnitz, JE, Bajel, A, Laetsch, TW, Leonard, J, Colace, SI, Khaw, SL, Fleming, SA, Mattison, RJ, Norris, R, Opferman, JT, Roberts, KG, Zhao, Y, Qu, C, Badawi, M, Schmidt, M, Tong, B, Pesko, JC, Sun, Y, Ross, JA, Vishwamitra, D, Rosenwinkel, L, Kim, SY, Jacobson, A, Mullighan, CG, Alexander, TB & Stock, W 2021, 'Venetoclax and navitoclax in combination with chemotherapy in patients with relapsed or refractory acute lymphoblastic leukemia and lymphoblastic lymphoma', Cancer discovery, vol. 11, no. 6, pp. 1440-1453. https://doi.org/10.1158/2159-8290.CD-20-1465

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title = "Venetoclax and navitoclax in combination with chemotherapy in patients with relapsed or refractory acute lymphoblastic leukemia and lymphoblastic lymphoma",

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.",

author = "Pullarkat, {Vinod A.} and Lacayo, {Norman J.} and Elias Jabbour and Rubnitz, {Jeffrey E.} and Ashish Bajel and Laetsch, {Theodore W.} and Jessica Leonard and Colace, {Susan I.} and Khaw, {Seong Lin} and Fleming, {Shaun A.} and Mattison, {Ryan J.} and Robin Norris and Opferman, {Joseph T.} and Roberts, {Kathryn G.} and Yaqi Zhao and Chunxu Qu and Mohamed Badawi and Michelle Schmidt and Bo Tong and Pesko, {John C.} and Yan Sun and Ross, {Jeremy A.} and Deeksha Vishwamitra and Lindsey Rosenwinkel and Kim, {Su Young} and Amanda Jacobson and Mullighan, {Charles G.} and Alexander, {Thomas B.} and Wendy Stock",

year = "2021",

doi = "10.1158/2159-8290.CD-20-1465",

language = "English (US)",

volume = "11",

pages = "1440--1453",

journal = "Cancer discovery",

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publisher = "American Association for Cancer Research Inc.",

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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

PY - 2021

Y1 - 2021

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.

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AN - SCOPUS:85107711731

SN - 2159-8274

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JO - Cancer discovery

JF - Cancer discovery

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ER -

Venetoclax and navitoclax in combination with chemotherapy in patients with relapsed or refractory acute lymphoblastic leukemia and lymphoblastic lymphoma

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