Targeting vascular endothelial growth factor for relapsed and refractory adult acute myelogenous leukemias: therapy with sequential 1-beta-d-arabinofuranosylcytosine, mitoxantrone, and bevacizumab.
OBJECTIVE
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.


METHODS
bevacizumab 10 mg/kg was administered on day 8 after 1-beta-d-arabinofuranosylcytosine 2 g/m(2)/72 h beginning day 1 and mitoxantrone 40 mg/m(2) 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.
Karp
Judith E
JE
University of Maryland Greenebaum Cancer Center, Baltimore, Maryland, USA. jkarp2@jhmi.edu
Gojo
Ivana
I
Pili
Roberto
R
Gocke
Christopher D
CD
Greer
Jacqueline
J
Guo
Chuanfa
C
Qian
David
D
Morris
Lawrence
L
Tidwell
Michael
M
Chen
Helen
H
Zwiebel
James
J
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D000068258:Bevacizumab; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003561:Cytarabine / Q000627:therapeutic use*; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism*; D008297:Male; D008833:Microcirculation; D008875:Middle Aged; D008942:Mitoxantrone / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000737:chemistry; D012008:Recurrence; D013997:Time Factors; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000097:blood / Q000737:chemistry / Q000378:metabolism*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; D003561:Cytarabine; D000068258:Bevacizumab; D008942:Mitoxantrone; D040281:Vascular Endothelial Growth Factor Receptor-1