Venetoclax and navitoclax in Combination with Chemotherapy in Patients with Relapsed or Refractory Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma

被引：206

作者：

Pullarkat, Vinod A. ^{[1
]}

Lacayo, Norman J. ^{[2
]}

Jabbour, Elias ^{[3
]}

Rubnitz, Jeffrey E. ^{[4
,5
]}

Bajel, Ashish ^{[6
,7
]}

Laetsch, Theodore W. ^{[8
,9
]}

Leonard, Jessica ^{[10
]}

Colace, Susan, I ^{[11
]}

Khaw, Seong Lin ^{[12
]}

Fleming, Shaun A. ^{[13
,14
]}

Mattison, Ryan J. ^{[15
]}

Norris, Robin ^{[16
]}

Opferman, Joseph T. ^{[17
]}

Roberts, Kathryn G. ^{[18
]}

Zhao, Yaqi ^{[18
]}

Qu, Chunxu ^{[18
]}

Badawi, Mohamed ^{[19
]}

Schmidt, Michelle ^{[19
]}

Tong, Bo ^{[19
]}

Pesko, John C. ^{[19
]}

Sun, Yan ^{[19
]}

Ross, Jeremy A. ^{[19
]}

Vishwamitra, Deeksha ^{[19
]}

Rosenwinkel, Lindsey ^{[19
]}

Kim, Su Young ^{[19
]}

Jacobson, Amanda ^{[19
]}

Mullighan, Charles G. ^{[18
]}

Alexander, Thomas B. ^{[20
]}

Stock, Wendy ^{[21
]}

机构：

[1] City Hope Natl Med Ctr, Dept Hematol & Hematopoiet Cell Transplantat, 1500 East Duarte Rd, Duarte, CA 91010 USA

[2] Stanford Univ, Dept Pediat Hematol Oncol, Palo Alto, CA 94304 USA

[3] Univ Texas MD Anderson Canc Ctr, Dept Leukemia, Div Canc Med, Houston, TX 77030 USA

[4] St Jude Childrens Res Hosp, Dept Oncol, 332 N Lauderdale St, Memphis, TN 38105 USA

[5] Univ Tennessee, Ctr Hlth Sci, Dept Pediat, Memphis, TN 38163 USA

[6] Royal Melbourne Hosp, Clin Haematol, Melbourne, Vic, Australia

[7] Peter MacCallum Canc Ctr, Melbourne, Vic, Australia

[8] Univ Texas Southwestern Med Ctr Dallas, Dept Pediat, Childrens Hlth, Dallas, TX 75390 USA

[9] Univ Penn, Div Oncol, Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA

[10] Oregon Hlth & Sci Univ, Dept Hematol Med Oncol, Portland, OR USA

[11] Nationwide Childrens Hosp, Pediat Hematol & Oncol, Columbus, OH USA

[12] Royal Childrens Hosp, Parkville, Vic, Australia

[13] Monash Univ, Alfred Hosp, Dept Hematol, Melbourne, Vic, Australia

[14] Monash Univ, Australian Ctr Blood Dis, Melbourne, Vic, Australia

[15] Univ Wisconsin, Carbone Canc Ctr, Madison, WI USA

[16] Cincinnati Childrens Hosp Med Ctr, Dept Pediat, Cincinnati, OH 45229 USA

[17] St Jude Childrens Res Hosp, Dept Cell & Mol Biol, 332 N Lauderdale St, Memphis, TN 38105 USA

[18] St Jude Childrens Res Hosp, Dept Pathol, Memphis, TN 38105 USA

[19] AbbVie Inc, N Chicago, IL USA

[20] Univ N Carolina, Dept Pediat, Chapel Hill, NC 27515 USA

[21] Univ Chicago Med, Chicago, IL USA

来源：

CANCER DISCOVERY | 2021年 / 11卷 / 06期

关键词：

BH3 MIMETIC ABT-263; LYMPHOCYTIC-LEUKEMIA; BCL-2; DEPENDENCE; IN-VITRO; CELL; SENSITIVITY; INHIBITOR; CHILDREN; ADULTS; PHARMACOKINETICS;

D O I：

10.1158/2159-8290.CD-20-1465

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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. SIGNIFICANCE: In this phase I study, venetoclax with low-dose navitoclax and chemotherapy was well tolerated and had promising efficacy in patients with relapsed/refractory acute lymphoblastic leukemia or lymphoblastic lymphoma. Responses were observed in patients across histologic and genomic subtypes and in those who failed available therapies including stem cell transplant.

引用

页码：1440 / 1453

页数：14

共 50 条

[1] Prognostic Factors and Outcomes of Adult Lymphoblastic Lymphoma in the United States [J].

Abd El-Fattah, Mohamed .

CLINICAL LYMPHOMA MYELOMA & LEUKEMIA, 2017, 17 (08) :498-+

[2] Mcl-1 is a potential therapeutic target in multiple types of cancer [J].

Akgul, C. .

CELLULAR AND MOLECULAR LIFE SCIENCES, 2009, 66 (08) :1326-1336

[3] BH3 Inhibitor Sensitivity and Bcl-2 Dependence in Primary Acute Lymphoblastic Leukemia Cells [J].

Alford, Sarah E. ;

Kotharil, Anisha ;

Loeff, Floris C. ;

Eichhorn, Joshua M. ;

Sakurikar, Nandini ;

Goselink, Henriette M. ;

Saylors, Robert L. ;

Jedema, Inge ;

Falkenburg, J. H. Frederik ;

Chambers, Timothy C. .

CANCER RESEARCH, 2015, 75 (07) :1366-1375

[4]

[Anonymous], FusionCatcher-a tool for finding somatic fusion genes in paired-end RNA-sequencing data, DOI [DOI 10.1101/011650, 10.1101/011650]

[5] Near-optimal probabilistic RNA-seq quantification (vol 34, pg 525, 2016) [J].

Bray, Nicolas L. ;

Pimentel, Harold ;

Melsted, Pall ;

Pachter, Lior .

NATURE BIOTECHNOLOGY, 2016, 34 (08) :888-888

[6] Poor Outcome for Children and Adolescents With Progressive Disease or Relapse of Lymphoblastic Lymphoma: A Report From the Berlin-Frankfurt-Muenster Group [J].

Burkhardt, Birgit ;

Reiter, Alfred ;

Landmann, Eva ;

Lang, Peter ;

Lassay, Lisa ;

Dickerhoff, Roswitha ;

Lakomek, Max ;

Henze, Guenter ;

von Stackelberg, Arend .

JOURNAL OF CLINICAL ONCOLOGY, 2009, 27 (20) :3363-3369

[7] Recommendations for Initial Evaluation, Staging, and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification [J].

Cheson, Bruce D. ;

Fisher, Richard I. ;

Barrington, Sally F. ;

Cavalli, Franco ;

Schwartz, Lawrence H. ;

Zucca, Emanuele ;

Lister, T. Andrew .

JOURNAL OF CLINICAL ONCOLOGY, 2014, 32 (27) :3059-+

[8] Maturation Stage of T-cell Acute Lymphoblastic Leukemia Determines BCL-2 versus BCL-XL Dependence and Sensitivity to ABT-199 [J].

Chonghaile, Triona Ni ;

Roderick, Justine E. ;

Glenfield, Cian ;

Ryan, Jeremy ;

Sallan, Stephen E. ;

Silverman, Lewis B. ;

Loh, Mignon L. ;

Hunger, Stephen P. ;

Wood, Brent ;

DeAngelo, Daniel J. ;

Stone, Richard ;

Harris, Marian ;

Gutierrez, Alejandro ;

Kelliher, Michelle A. ;

Letai, Anthony .

CANCER DISCOVERY, 2014, 4 (09) :1074-1087

[9] Incidence of asparaginase-related hepatotoxicity, pancreatitis, and thrombotic events in adults with acute lymphoblastic leukemia treated with a pediatric-inspired regimen [J].

Christ, Trevor N. ;

Stock, Wendy ;

Knoebel, Randall W. .

JOURNAL OF ONCOLOGY PHARMACY PRACTICE, 2018, 24 (04) :299-308

[10] Early T-cell precursor leukaemia: a subtype of very high-risk acute lymphoblastic leukaemia [J].

Coustan-Smith, Elaine ;

Mullighan, Charles G. ;

Onciu, Mihaela ;

Behm, Frederick G. ;

Raimondi, Susana C. ;

Pei, Deqing ;

Cheng, Cheng ;

Su, Xiaoping ;

Rubnitz, Jeffrey E. ;

Basso, Giuseppe ;

Biondi, Andrea ;

Pui, Ching-Hon ;

Downing, James R. ;

Campana, Dario .

LANCET ONCOLOGY, 2009, 10 (02) :147-156

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