Treatment of MDS with Excess Blasts by Bevacizumab Is Well Tolerated and Is Associated with a Decrease of VEGF Plasma Level.

AML and MDS are associated with increased in BM vascularity and increased levels of various angiogenic factors including VEGF, which is implicated in the proliferation and survival of leukemic cells and whose autocrine production may contributes to leukemia self-renewal and resistance to apoptotic and maturation stimuli (Kerbauy DB, 2007). Higher VEGF plasma levels have been observed in MDS with excess blasts (Brunner B, 2002). The humanized MoAb against VEGF, Bevacizumab (BEV) has proved an effective treatment targeting VEGF.

The GFM conducted a multicentric phase II trial testing the efficacy and tolerance of BEV in MDS with excess of marrow blasts and the impact of BEV on angiogenesis (ClinicalTrials.gov Identifier: NCT00565656). BEV was administered at 5 mg/kg IV every 2 weeks for 12 weeks. Patients with no response could receive, in the absence of major toxicities, 4 additional cycles with dose escalation of BEV to 10 mg/kg every 2 weeks.

20 patients (pts) were included of whom 17 were currently evaluable for efficacy: 14M/3F, median age 70 years (62–84), RAEB-1 (8), RAEB-2 (9), IPSS INT-1 (6), INT-2 (9), and high (2).

No patient stopped treatment before week 12 because of side effects and no treatment related SAE was reported. Preliminary results on haematological adverse events have shown mild toxicity. Four pts with grade 0–2 neutropenia and 3 pts with grade 0–2 anemia have progressed in a grade 3–4 during treatment.

One of 17 evaluable pts was responder (RBC transfusion independence in a pt requiring 2 RBC concentrates/month), during 2 months.

Bone marrow microvessel density, VEGF plasma level, VEGF mRNA expression, HIF-1a expression were determined before the treatment to characterise angiogenesis in the pts included and after treatment to evaluate the impact of Bevacizumab on this angiogenesis. Median plasma VEGF was 56.6 pg/ml (range: 13.2–151.7 pg/ml) at inclusion. After 12 weeks of treatment VEGF plasma level was significantly decreased to 30.4 pg/ml (range: 13.9–53.1 pg/ml). This decrease was observed in all pts and has been confirmed for bone marrow VEGF mRNA in the first analysed patients (n=4) by RTQPCR. Further results of this study will be presented.

In our study, BEV was well tolerated but had limited efficacy. On the other hand, in colorectal cancer, BEV alone has limited efficacy and mainly plays a therapeutic role by enhancing the efficacy of chemotherapy. The in vivo decrease of plasma VEGF with BEV in this study, and its limited toxicity, suggest that it could be associated in higher risk with agents having different mechanisms of action, especially hypomethylating agents, to produce synergistic effects while maintaining tolerable safety profiles.

Brunner B et al. Blood levels of angiogenin and vascular endothelial growth factor are elevated in myelodysplastic syndromes and in acute myeloid leukemia. J Hematother Stem Cell Res. 2002 Feb;11(1):119–25

Dias S et al. Autocrine stimulation of VEGFR-2 activates human leukemic cell growth and migration. J Clin Invest. 2000 Aug;106(4):511–21.

Kerbauy DB, Deeg HJ. Apoptosis and antiapoptotic mechanisms in the progression of myelodysplastic syndrome. Exp Hematol. 2007 Nov;35(11):1739–46.

No relevant conflicts of interest to declare.