|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Originally published as JCO Early Release 10.1200/JCO.2008.20.7167 on February 2 2009 © 2009 American Society of Clinical Oncology.
In ReplyGeorgetown Dermatology, Washington, DC The correspondence item of van der Veldt et al presents much interest regarding the cellular regulation mechanisms of erythropoietic homeostasis. The unique 4-weeks-on, 2-weeks-off administration schedule of sunitinib allows a direct observation of the biologic effects of this drug on the tumor and various organ systems. This schedule was recommended by the regulatory authorities to allow recovery from bone marrow toxicities. The reported cyclic variations in hemoglobin (HgB) that parallel the administration of sunitinib reinforce our previous observations.1 It is the merit of van der Veldt et al to have conducted a large enough analysis to show statistical significance for the increase in HgB. I agree with the fact that cyclic administration of sunitinib is the cause of the observed phenomenon. In fact, other biologic processes pertaining to different organ systems share similar effects. Cyclic elevations in thyroid-stimulating hormone2 and a decrease in blood glucose level were both seen at the end of the 4-week-on periods of sunitinib.3 The mechanism of HgB increase and the exact nature of its cyclical pattern are still to be deciphered. An increased hepatic synthesis of erythropoietin (EPO) was shown to occur in response to vascular endothelial growth factor (VEGF) inhibition, and was postulated to play a role in the erythrocytosis produced by anti-VEGF medications.1 It is therefore relevant to note that markers of VEGF-system activation parallel HgB levels throughout the 6-week treatment cycle periodicity.4 Thus, at the end of sunitinib on cycles, serum vascular endothelial growth factor (sVEGF) increases approximately three-fold compared with baseline, and in most patients, sVEGF receptor 2 (sVEGFR2) and sVEGFR3 decrease by approximately 30%.5 Conversely, no cyclicity is observed with drugs which maintain steady plasma levels and/or constant intracellular effects, such as sorafenib and SU5416. An aspect brought into discussion by van der Veldt et al concerns the relatively rapid shifts in HgB during the 2-week intercycle periods off sunitinib, which prompted the commentary that volume shifts need to be taken into consideration to explain the rapidity of these changes. EPO drive and other alterations in the tyrosine kinase and phosphatase balance represent, in my opinion, the dominant mechanism of HgB cyclicity. An increase of 14 units per liter (U/L) in EPO from baseline, as described by van der Veldt et al, is similar to the elevations of 13 U/L seen in pulmonary disorders when compared with reference values. On the contrary, relative polycythemia, which is associated with an average increase in HgB of 3.5 g/dL, only manifests an increase in serum EPO of 1 U/L. This resemblance of serum EPO levels in sunitinib-induced erythrocytosis to the values classically associated with pulmonary hypoxemia points to an etiology similar to the hypoxia-driven mechanism, rather than volume contraction as in relative (stress) polycythemia. In addition, we have not observed discernable variations in serum albumin or sodium concentrations during the treatment with sunitinib. Furthermore, at least two reports6,7 confirmed a true polycythemic effect of multiple tyrosine kinase inhibitors by finding an increased red cell mass. I therefore believe that the polycythemic effect of tyrosine kinase inhibitors is exerted mainly by their influence on the kinase-regulating machinery, although an effect on the circulating volume may also play a lesser role. The 1 mmol/L (1.6 g/dL) decrease in HgB observed by van der Veldt et al during the 2 weeks off sunitinib is largely explained by the absence of EPO stimulation. Thus, in chronic hemodialysis patients dosed with EPO every 2 weeks, average HgB deviations of +1.8 g/dL and –0.9 g/dL have been seen outside of target HgB levels (11 to 12 g/dL). Furthermore, the majority of patients treated every 2 weeks experienced greater than 1 g/dL HgB decreases between dosing.8 In a transgenic murine model expressing human EPO receptor, a 10% decrease in hematocrit was seen after 2 weeks of discontinuing EPO.9 In addition, EPO withdrawal after 4 weeks of continuous stimulation by sunitinib may result in what is known to be a selective loss of new erythrocytes (necrocytolysis). A strong pro-erythropoietic mechanism needs to take place to produce erythrocytosis, as up- and downregulation of erythropoiesis may function in a tightly regulated equilibrium.1 Downregulation of erythropoiesis by sunitinib can result in anemia and may involve inhibition of Flt3, a stimulator of erythrocyte formation, and Kit, which stimulates committed erythroid progenitors towards proliferation and differentiation. In addition to blocking VEGF signaling, possible pro-erythropoietic mechanisms of sunitinib may involve the inhibition of DAPK2 kinase, a new erythroid-restricted putative negative regulator of erythropoiesis (dissociation constant, 150 nmol/L),10 and mitogen-activated protein kinase/extracellular (MEK) inhibition, which restores EPO signaling for late erythroblast development (dissociation constant, 110 to 130 nmol/L).11 In summary, the report of van der Veldt et al reveals an important aspect of hematopoietic dysregulation during treatment with sunitinib, consisting of 6-week cyclic variations in HgB. A different biphasic long-term response (4 to 6 months) was also observed.1 It consists of an ascending phase of HgB, followed by a plateau and a subsequent decrease of HgB. This pattern of response probably reflects the development of tolerance. The 4-weeks-on, 2-weeks-off schedule of sunitinib, although probably not therapeutically superior to the continuous dosing, teaches important lessons on the regulation of biologic processes by tyrosine kinase blockage. AUTHOR'S 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 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. Mannavola D, Coco P, Vannucchi G, et al: A novel tyrosine-kinase selective inhibitor, sunitinib, induces transient hypothyroidism by blocking iodine uptake. J Clin Endocrinol Metab 92:3531–3534, 2007. 3. Billemont B, Medioni J, Taillade L, et al: Blood glucose levels in patients with metastatic renal cell carcinoma treated with sunitinib. Br J Cancer 99:1380–1382, 2008.[CrossRef][Medline] 4. 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] 5. Deprimo SE, Friece C, Huang X, et al: Effect of treatment with sunitinib malate, a multitargeted tyrosine kinase inhibitor, on circulating plasma levels of VEGF, soluble VEGF receptors 2 and 3, and soluble KIT in patients with metastatic breast cancer. J Clin Oncol 24:22s; 2006 (suppl) abstr 578. 6. Alexandre I, Billemont B, Meric J-B, et al: Axitinib induces paradoxical erythropoietin synthesis in metastatic renal cell carcinoma. J Clin Oncol 3:472–473, 2009. 7. 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. 8. Nurko S, Spirko R, Law A, et al: Dosing intervals and hemoglobin control in patients with chronic kidney disease and anemia treated with epoetin alfa or darbepoetin alfa: A retrospective cohort study. Clin Ther 29:2010–2021, 2007.[CrossRef][Medline] 9. Liu Z, Stoll VS, Devries PJ, et al: A potent erythropoietin-mimicking human antibody interacts through a novel binding site. Blood 110:2408–2413, 2007. 10. Wojchowski DM, Menon MP, Sathyanarayana P, et al: Erythropoietin-dependent erythropoiesis: New insights and questions. Blood Cells Mol Dis 36:232–238, 2006.[CrossRef][Medline] 11. Menon MP, Fang J, Wojchowski DM: Core erythropoietin receptor signals for late erythroblast development. Blood 107:2662–2672, 2006.
Related Article
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
