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Originally published as JCO Early Release 10.1200/JCO.2008.20.2366 on December 15 2008 © 2009 American Society of Clinical Oncology.
In Reply
Georgetown University, Division of Hematology and Oncology, Washington, DC
Department of Hematology/Oncology, Saint Francis Hospital and Medical Center, Hartford, CT An important observation is made by Alexandre et al, who in their letter describe an incidence of erythrocytosis during treatment with axitinib in a patient with metastatic renal cell carcinoma. Their letter documents an increased serum erythropoietin (EPO) level that is different from the EPO level at the upper limit of normal in our patient cohort.1 The onset of erythrocytosis 5 weeks into the vascular endothelial growth factor receptor (VEGFR) blockade, and the absence of other secondary causes of polycythemia are similar to our findings. This difference in EPO concentrations could represent the end result of different erythropoietic mechanisms, explained, at least in part, by the distinct pharmacologic profiles of the drugs involved. In addition, Alexandre et al elegantly confirm the true polycythemic effect of VEGF inhibition by isotopic measurement of red cell mass, and the repeated need for phlebotomy. The leading physiologic mechanism of erythropoiesis, which is represented by EPO signaling, is being modulated in mice and primates by VEGF, which induces an increased production of hepatic erythropoietin.2 Thus, in preclinical models, an increased VEGF level resulted in an increased hematocrit ranging from 60% to 75%. The demonstration of the principle "VEGF inhibitors make blood" prompted Fischer et al3 to remark in 2006 that paradoxically, no clinical reports of erythrocytosis had been presented, despite many thousands of patients being treated with VEGFR inhibitors. Three publications now confirm the clinical development of erythrocytosis with tyrosine kinase inhibitors (TKIs) in humans (Alexandre et al),1,4 which appears to rely on mechanisms similar to the ones established in animal models. As demonstrated in primates, an increase in serum VEGF is also seen in humans with the use of VEGFR blockers, through a physiologic rebound mechanism. Therefore, the occurrence of erythrocytosis relies, at least in part, on the resulting increased hepatic synthesis of EPO. However, not all patients display increased EPO levels. Although the patient described by Alexandre et al exhibited an increased serum EPO (46 mU/mL; normal, 5 to 25), the EPO levels in our patients were either within normal limits or only slightly above the upper limit of normal (7.6 to 36 mU/mL).1 Richard et al4 report no significant EPO variations from baseline, with all values in the low to normal range (1.9, 2.6, and 8.0 mU/mL). Such differences, which occur in the presence of similar elevations of the hematocrit, point toward the existence of an EPO-independent mechanism for erythrocytosis in some patients. The basis for this phenomenon may reside in different pharmacologic potencies of the VEGFR inhibitors reported to induce erythrocytosis. Thus, axitinib is a potent VEGF TKI (concentration that inhibits 50% [IC50] for VEGFR-1, VEGFR-2, and VEGFR-3 of 0.1, 0.2, and 0.3 nmol, respectively), with less activity for other tyrosine kinases. On the contrary, a broader spectrum of inhibition with relatively less anti-VEGFR potency is exerted by sunitinib (corresponding IC50 of 10, 10, and 10 nmol, respectively), sorafenib (IC50 of 26, 90, and 20 nmol, respectively), and semaxanib (IC50 of 100, 100, and 100 nmol, respectively).5,6 As a result, the plasma levels of VEGF are higher with axitinib—a 4.4-fold variation from pretreatment levels was recorded7—compared with sunitinib (2.8-fold variation)8 and semaxanib (1.2-fold variation).9 Therefore, higher production of EPO is expected to occur with axitinib as a result of higher circulating VEGF levels, which is consistent with the increased EPO level of 46 mU/mL observed by Alexandre et al. This value is in fact close to the serum EPO value encountered in secondary polycythemias (average value, 47 mU/mL), which further points toward a similar effector mechanism involving some of the hypoxia-induced pathways. Conversely, the polycythemic effect seen with agents like sunitinib, sorafenib, and semaxanib may rely more on other alternative pathways that stimulate erythropoiesis, rather than on the production of EPO. Such EPO-independent erythropoiesis would result from the interference of the broad-spectrum TKIs sunitinib, sorafenib, and semaxanib with other kinases and phosphatases involved in hematopoiesis. The variation in time of plasma VEGF, expressed as a ratio to baseline, appears to parallel the time course of observed erythrocytosis. Thus, Deprimo et al10 demonstrated that plasma VEGF levels increase from the start of treatment with sunitinib, and reach levels two times higher than normal at 4 weeks of treatment. The VEGF levels reach maximum value in the next 12 to 16 weeks, with a subsequent decline. Accordingly, the clinical evolution of polycythemia in all seven patients closely overlapped this time course; a graphic representation of the hematocrit during the course of treatment is available.1,4 In summary, a different spectrum of tyrosine kinase inhibition may explain the EPO-dependent and EPO-independent pathways of erythropoiesis during therapy with multiple TKIs. A better understanding of this phenomenon may result in an in-depth characterization of the mechanisms underlying the erythrocytosis of myeloproliferative disorders, and in the development of newer treatments to stimulate red cell production. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Doru T. Alexandrescu, Bayer (C) Stock Ownership: None Honoraria: Doru T. Alexandrescu, Bayer Research Funding: None Expert Testimony: None Other Remuneration: None NOTES published online ahead of print at www.jco.org on December 15, 2008 REFERENCES
1. Alexandrescu DT, McClure R, Farzanmehr H, et al: Secondary erythrocytosis produced by the tyrosine kinase inhibitors sunitinib and sorafenib. J Clin Oncol 26:4047-4048, 2008 2. Tam BY, Wei K, Rudge JS, et al: VEGF modulates erythropoiesis through regulation of adult hepatic erythropoietin synthesis. Nat Med 12:793-800, 2006[CrossRef][Medline] 3. Fischer C, Carmeliet P, Conway EM: VEGF inhibitors make blood. Nat Med 12:732-734, 2006[CrossRef][Medline] 4. Richard S, Croisille L, Yvart J, et al: Paradoxical secondary polycythemia in von Hippel-Lindau patients treated with anti-vascular endothelial growth factor receptor therapy. Blood 99:3851-3853, 2002 5. Sonpavde G, Hutson TE, Rini BI: Axitinib for renal cell carcinoma. Expert Opin Investig Drugs 17:741-748, 2008[CrossRef][Medline] 6. Fiedler W, Mesters R, Tinnefeld H, et al: A phase 2 clinical study of SU5416 in patients with refractory acute myeloid leukemia. Blood 102:2763-2767, 2003 7. Giles FJ, Bellamy WT, Estrov Z, et al: The anti-angiogenesis agent, AG-013736, has minimal activity in elderly patients with poor prognosis acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Leuk Res 30:801-811, 2006[CrossRef][Medline] 8. Rini BI, Michaelson MD, Rosenberg JE, et al: Antitumor activity and biomarker analysis of sunitinib in patients with bevacizumab-refractory metastatic renal cell carcinoma. J Clin Oncol 26:3743-3748, 2008 9. Heymach JV, Desai J, Manola J, et al: Phase II study of the antiangiogenic agent SU5416 in patients with advanced soft tissue sarcomas. Clin Cancer Res 10:5732-5740, 2004 10. Deprimo SE, Bello CL, Smeraglia J, et al: Circulating protein biomarkers of pharmacodynamic activity of sunitinib in patients with metastatic renal cell carcinoma: Modulation of VEGF and VEGF-related proteins. J Transl Med 5:32, 2007[CrossRef][Medline]
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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