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Journal of Clinical Oncology, Vol 26, No 24 (August 20), 2008: pp. 4047-4048 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2008.18.3525
Secondary Erythrocytosis Produced by the Tyrosine Kinase Inhibitors Sunitinib and SorafenibGeorgetown University, Washington Cancer Institute, Washington, DC
Department of Pathology, Washington Hospital Center, Washington, DC
Mayo Clinic, Anatomic and Clinical Pathology and Hematology, Rochester, MN
Department of Hematology-Oncology, Group Health, Seattle, WA To the Editor: Rationally designed molecular antineoplastic targeted therapies have been developed and are in clinical use as a result of recent advancements in understanding cancer cell biology. When used for treatment of various cancers, the remarkable clinical efficacy of these compounds is followed by new and often puzzling adverse effects, and new problems do not cease to occur.1 Although individual variations and specific adverse effects may occur, the toxicities of currently used tyrosine kinase inhibitors (TKIs), of which sorafenib and sunitinib serve as prototypes, seem to represent class effects. Hematopoietic, cutaneous, cardiovascular, thyroid-related, and constitutional effects are being commonly encountered. A common disturbance of erythropoiesis during the use of sorafenib and sunitinib is the gradual development of anemia. With sunitinib, anemia developed in 26% of patients in second-line treatment for metastatic clear cell renal cell carcinoma (RCC; 20% grade 2, 4% grade 3, and 2% grade 4).2 Grade 3 to 4 anemia developed in 3% of patients during first- or second-line treatment of metastatic RCC during an expanded access study with sorafenib.3 We are reporting the occurrence of reversible erythrocytosis in five (23.8%) of 21 patients treated with the TKIs sorafenib and sunitinib for various metastatic cancers (RCC, melanoma, and hepatocellular carcinoma [HCC]). Patient 1 is an 87-year-old white female with metastatic melanoma to the lungs who underwent treatment with sorafenib 400 mg orally (PO) twice daily and dacarbazine 600 mg/m2 every 3 weeks. A minor response was noted after 12 weeks of treatment (Table 1). Patient 2 is a 52-year-old white female with advanced HCC, diffusely metastatic in the abdomen, who received sorafenib 400 mg PO twice daily. She experienced a gradual improvement of her liver function tests after 2 weeks of treatment. Patient 3 is a 47-year-old African American male with RCC of clear cell type who had multiple metastatic lesions in the lungs and was administered sunitinib 50 mg daily as first-line treatment. Minimal disease progression occurred after 8 weeks of treatment, followed by stabilization. Patient 4 is a 58-year-old white female with metastatic clear cell RCC to both lungs receiving treatment with sunitinib 50 mg PO daily for 4 out of every 6 weeks, with stabilization of the disease after 6 months of treatment. Patient 5 is a 65-year-old white male who developed mediastinal and chest wall masses after nephrectomy for left RCC. Treatment with sunitinib 50 mg daily was accompanied by stabilization of the disease.
Erythrocytosis developed with a relatively rapid onset over 1 to 2 weeks, reaching a peak at 4 to 9 weeks after the onset of TKI treatment. Although the increase in hemoglobin (Hb) seemed to occur predictably within this timeframe, development of tolerance was subsequently noted. Resolution of the erythrocytosis had a more variable course (Fig 1). The mean increase in Hb was 3.06 g/dL (from 12.34 to 15.40 g/dL, P = .002). Variations of erythropoietin (EPO) were seen in the opposite direction from Hb, but EPO was not suppressed below the normal range at any time. No clinical or biochemical signs of dehydration or stress erythrocytosis manifested in our patients. A thorough smoking history was negative for any exposures. The oxygen saturation was greater than 92% in all patients. No hematopoietic growth factors were used.
The occurrence of an elevated Hb/hematocrit in a temporal relationship with administration of treatment indicates that the probable cause is the therapy with TKIs and not a paraneoplastic effect. Although resumption of normal hematopoiesis after addressing cancer-related anemia through TKI treatment is a consideration, the high post-treatment values of Hb and the lack of pretreatment anemia in patients 1 and 5 make it unlikely. Furthermore, most patients had stable disease, making an improvement in anemia of chronic disease improbable. The mechanism of erythrocytosis with the TKIs sunitinib and sorafenib is not known. All patients tested negative for JAK2V617F, and no causation by volume contraction or stress erythrocytosis was identified. Although the serum EPO was not increased, a possible sensitization to its effects through tyrosine kinase inhibition is possible, although other mechanisms modulating the erythropoietic pathways may be involved. It is unclear why some patients react by developing erythrocytosis, while others develop anemia. We can hypothesize that the ratio between the vascular endothelial growth factor blockage, which induces rebound erythrocytosis by stimulating hypoxia-induced elements, and c-kit inhibition, which may cause anemia, might influence the erythropoietic balance. In summary, we are reporting a reversible erythrocytosis, which occurs in a subset of cancer patients treated with the TKIs sunitinib and sorafenib. This phenomenon was observed in a general population of patients treated for metastatic RCC, HCC, and melanoma. 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
REFERENCES 1. Porta C, Paglino C, Imarisio I, et al: Uncovering Pandora's vase: The growing problem of new toxicities from novel anticancer agents—The case of sorafenib and sunitinib. Clin Exp Med 7:127-134, 2007[CrossRef][Medline] 2. Motzer RJ, Rini BI, Bukowski RM, et al: Sunitinib in patients with metastatic renal cell carcinoma. JAMA 295:2516-2524, 2006 3. Knox JJ, Figlin RA, Stadler WM, et al: The Advanced Renal Cell Carcinoma Sorafenib (ARCCS) expanded access trial in North America: Safety and efficacy. J Clin Oncol 25:237s, 2007 (suppl, abstr 5011)
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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