Targeting vascular endothelial growth factor for relapsed and refractory adult acute myelogenous leukemias

Therapy with sequential 1-β -D-arabinofuranosylcytosine, mitoxantrone, and bevacizumab

Judith E. Karp, Ivana Gojo, Roberto Pili, Christopher D. Gocke, Jacqueline Greer, Chuanfa Guo, David Qian, Lawrence Morris, Michael Tidwell, Helen Chen, James Zwiebel

Research output: Contribution to journalArticle

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Abstract

Purpose: Vascular endothelial growth factor (VEGF) promotes acute myelogenous leukemia (AML) cell growth and survival and may contribute to drug resistance, bevacizumab, an anti-VEGF monoclonal antibody, exhibits clinical activity against diverse malignancies when administered with cytotoxic chemotherapy. We conducted a Phase II clinical trial of bevacizumab administered after chemotherapy to adults with refractory or relapsed AML, using a timed sequential therapy (TST) approach. Experimental Design: bevacizumab 10 mg/kg was administered on day 8 after 1-β -D-arabinofuranosylcytosine 2 g/m2/72 h beginning day 1 and mitoxantrone 40 mg/m2 beginning day 4. In vivo laboratory correlates included AML cell VEGF receptor-1 (FLT-1) expression, marrow microvessel density, and free serum VEGF before and during TST with bevacizumab. Results: Forty-eight adults received induction therapy. Myelosuppression occurred in all of the patients similar to other TST regimens. Toxicities were decreased ejection fraction (6%), cerebrovascular bleed (4%), and mortality of 15%. Overall response was 23 of 48 (48%), with complete response (CR) in 16 (33%). Eighteen (14 CR and 4 partial response) underwent one consolidation cycle and 5 (3 CR and 2 partial response) underwent allogeneic transplant. Median overall and disease-free survivals for CR patients were 16.2 months (64%, 1 year) and 7 months (35%, 1 year). Marrow blasts demonstrated FLT-1 staining before bevacizumab and marked decrease in microvessel density after bevacizumab. VEGF was detected in pretreatment serum in 67% of patients tested, increased by day 8 in 52%, and decreased in 93% (67% undetectable) 2 h after bevacizumab. Conclusions: In this single arm study, cytotoxic chemotherapy followed by bevacizumab yields a favorable CR rate and duration in adults with AML that is resistant to traditional treatment approaches. The clearance of marrow blasts in some patients after bevacizumab suggests that VEGF neutralization might result directly in leukemic cell death. The potential biological and clinical activity of bevacizumab in AML warrants additional clinical and laboratory study.

Original languageEnglish (US)
Pages (from-to)3577-3585
Number of pages9
JournalClinical Cancer Research
Volume10
Issue number11
DOIs
StatePublished - Jun 1 2004
Externally publishedYes

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Mitoxantrone
Cytarabine
Acute Myeloid Leukemia
Vascular Endothelial Growth Factor A
Therapeutics
Bone Marrow
Microvessels
Drug Therapy
Bevacizumab
Vascular Endothelial Growth Factor Receptor-1
Phase II Clinical Trials
Serum
Drug Resistance
Disease-Free Survival
Cell Survival
Arm
Cell Death
Research Design
Monoclonal Antibodies
Staining and Labeling

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Targeting vascular endothelial growth factor for relapsed and refractory adult acute myelogenous leukemias : Therapy with sequential 1-β -D-arabinofuranosylcytosine, mitoxantrone, and bevacizumab. / Karp, Judith E.; Gojo, Ivana; Pili, Roberto; Gocke, Christopher D.; Greer, Jacqueline; Guo, Chuanfa; Qian, David; Morris, Lawrence; Tidwell, Michael; Chen, Helen; Zwiebel, James.

In: Clinical Cancer Research, Vol. 10, No. 11, 01.06.2004, p. 3577-3585.

Research output: Contribution to journalArticle

Karp, Judith E. ; Gojo, Ivana ; Pili, Roberto ; Gocke, Christopher D. ; Greer, Jacqueline ; Guo, Chuanfa ; Qian, David ; Morris, Lawrence ; Tidwell, Michael ; Chen, Helen ; Zwiebel, James. / Targeting vascular endothelial growth factor for relapsed and refractory adult acute myelogenous leukemias : Therapy with sequential 1-β -D-arabinofuranosylcytosine, mitoxantrone, and bevacizumab. In: Clinical Cancer Research. 2004 ; Vol. 10, No. 11. pp. 3577-3585.
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abstract = "Purpose: Vascular endothelial growth factor (VEGF) promotes acute myelogenous leukemia (AML) cell growth and survival and may contribute to drug resistance, bevacizumab, an anti-VEGF monoclonal antibody, exhibits clinical activity against diverse malignancies when administered with cytotoxic chemotherapy. We conducted a Phase II clinical trial of bevacizumab administered after chemotherapy to adults with refractory or relapsed AML, using a timed sequential therapy (TST) approach. Experimental Design: bevacizumab 10 mg/kg was administered on day 8 after 1-β -D-arabinofuranosylcytosine 2 g/m2/72 h beginning day 1 and mitoxantrone 40 mg/m2 beginning day 4. In vivo laboratory correlates included AML cell VEGF receptor-1 (FLT-1) expression, marrow microvessel density, and free serum VEGF before and during TST with bevacizumab. Results: Forty-eight adults received induction therapy. Myelosuppression occurred in all of the patients similar to other TST regimens. Toxicities were decreased ejection fraction (6{\%}), cerebrovascular bleed (4{\%}), and mortality of 15{\%}. Overall response was 23 of 48 (48{\%}), with complete response (CR) in 16 (33{\%}). Eighteen (14 CR and 4 partial response) underwent one consolidation cycle and 5 (3 CR and 2 partial response) underwent allogeneic transplant. Median overall and disease-free survivals for CR patients were 16.2 months (64{\%}, 1 year) and 7 months (35{\%}, 1 year). Marrow blasts demonstrated FLT-1 staining before bevacizumab and marked decrease in microvessel density after bevacizumab. VEGF was detected in pretreatment serum in 67{\%} of patients tested, increased by day 8 in 52{\%}, and decreased in 93{\%} (67{\%} undetectable) 2 h after bevacizumab. Conclusions: In this single arm study, cytotoxic chemotherapy followed by bevacizumab yields a favorable CR rate and duration in adults with AML that is resistant to traditional treatment approaches. The clearance of marrow blasts in some patients after bevacizumab suggests that VEGF neutralization might result directly in leukemic cell death. The potential biological and clinical activity of bevacizumab in AML warrants additional clinical and laboratory study.",
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T1 - Targeting vascular endothelial growth factor for relapsed and refractory adult acute myelogenous leukemias

T2 - Therapy with sequential 1-β -D-arabinofuranosylcytosine, mitoxantrone, and bevacizumab

AU - Karp, Judith E.

AU - Gojo, Ivana

AU - Pili, Roberto

AU - Gocke, Christopher D.

AU - Greer, Jacqueline

AU - Guo, Chuanfa

AU - Qian, David

AU - Morris, Lawrence

AU - Tidwell, Michael

AU - Chen, Helen

AU - Zwiebel, James

PY - 2004/6/1

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N2 - Purpose: Vascular endothelial growth factor (VEGF) promotes acute myelogenous leukemia (AML) cell growth and survival and may contribute to drug resistance, bevacizumab, an anti-VEGF monoclonal antibody, exhibits clinical activity against diverse malignancies when administered with cytotoxic chemotherapy. We conducted a Phase II clinical trial of bevacizumab administered after chemotherapy to adults with refractory or relapsed AML, using a timed sequential therapy (TST) approach. Experimental Design: bevacizumab 10 mg/kg was administered on day 8 after 1-β -D-arabinofuranosylcytosine 2 g/m2/72 h beginning day 1 and mitoxantrone 40 mg/m2 beginning day 4. In vivo laboratory correlates included AML cell VEGF receptor-1 (FLT-1) expression, marrow microvessel density, and free serum VEGF before and during TST with bevacizumab. Results: Forty-eight adults received induction therapy. Myelosuppression occurred in all of the patients similar to other TST regimens. Toxicities were decreased ejection fraction (6%), cerebrovascular bleed (4%), and mortality of 15%. Overall response was 23 of 48 (48%), with complete response (CR) in 16 (33%). Eighteen (14 CR and 4 partial response) underwent one consolidation cycle and 5 (3 CR and 2 partial response) underwent allogeneic transplant. Median overall and disease-free survivals for CR patients were 16.2 months (64%, 1 year) and 7 months (35%, 1 year). Marrow blasts demonstrated FLT-1 staining before bevacizumab and marked decrease in microvessel density after bevacizumab. VEGF was detected in pretreatment serum in 67% of patients tested, increased by day 8 in 52%, and decreased in 93% (67% undetectable) 2 h after bevacizumab. Conclusions: In this single arm study, cytotoxic chemotherapy followed by bevacizumab yields a favorable CR rate and duration in adults with AML that is resistant to traditional treatment approaches. The clearance of marrow blasts in some patients after bevacizumab suggests that VEGF neutralization might result directly in leukemic cell death. The potential biological and clinical activity of bevacizumab in AML warrants additional clinical and laboratory study.

AB - Purpose: Vascular endothelial growth factor (VEGF) promotes acute myelogenous leukemia (AML) cell growth and survival and may contribute to drug resistance, bevacizumab, an anti-VEGF monoclonal antibody, exhibits clinical activity against diverse malignancies when administered with cytotoxic chemotherapy. We conducted a Phase II clinical trial of bevacizumab administered after chemotherapy to adults with refractory or relapsed AML, using a timed sequential therapy (TST) approach. Experimental Design: bevacizumab 10 mg/kg was administered on day 8 after 1-β -D-arabinofuranosylcytosine 2 g/m2/72 h beginning day 1 and mitoxantrone 40 mg/m2 beginning day 4. In vivo laboratory correlates included AML cell VEGF receptor-1 (FLT-1) expression, marrow microvessel density, and free serum VEGF before and during TST with bevacizumab. Results: Forty-eight adults received induction therapy. Myelosuppression occurred in all of the patients similar to other TST regimens. Toxicities were decreased ejection fraction (6%), cerebrovascular bleed (4%), and mortality of 15%. Overall response was 23 of 48 (48%), with complete response (CR) in 16 (33%). Eighteen (14 CR and 4 partial response) underwent one consolidation cycle and 5 (3 CR and 2 partial response) underwent allogeneic transplant. Median overall and disease-free survivals for CR patients were 16.2 months (64%, 1 year) and 7 months (35%, 1 year). Marrow blasts demonstrated FLT-1 staining before bevacizumab and marked decrease in microvessel density after bevacizumab. VEGF was detected in pretreatment serum in 67% of patients tested, increased by day 8 in 52%, and decreased in 93% (67% undetectable) 2 h after bevacizumab. Conclusions: In this single arm study, cytotoxic chemotherapy followed by bevacizumab yields a favorable CR rate and duration in adults with AML that is resistant to traditional treatment approaches. The clearance of marrow blasts in some patients after bevacizumab suggests that VEGF neutralization might result directly in leukemic cell death. The potential biological and clinical activity of bevacizumab in AML warrants additional clinical and laboratory study.

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