TY - JOUR
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
Y1 - 2004/6/1
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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U2 - 10.1158/1078-0432.CCR-03-0627
DO - 10.1158/1078-0432.CCR-03-0627
M3 - Article
C2 - 15173063
AN - SCOPUS:2542547507
SN - 1078-0432
VL - 10
SP - 3577
EP - 3585
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 11
ER -