Correspondence

Macrocytosis Due to Treatment with Sunitinib

N Engl J Med 2007; 357:1351-1352September 27, 2007

Article

To the Editor:

In their letter to the editor, Gillessen et al. (May 31 issue)1 report that sunitinib therapy induced macrocytosis related to cobalamin deficiency. We have made a similar observation.

Between October 2005 and March 2007, a total of 40 patients with metastatic renal-cell carcinoma (80% of whom were men; mean age, 59 years) who were receiving 50 mg of sunitinib daily were retrospectively studied for red-cell abnormalities. All patients had an increased mean corpuscular volume, and in 10 patients, the mean corpuscular volume was 105 μm³ (range, 100 to 124) (Figure 1Figure 1Increases in Mean Corpuscular Volume in 40 Patients during Treatment with Sunitinib.). Five of the 10 patients had anemia (mean hemoglobin level, 8.84 g per deciliter). The patients with macrocytosis had low levels of cobalamin (mean, 112 pmol per liter; normal level, >133) and folate (mean, 4.03 nmol per liter; normal level, >6.80). No thyroid dysfunction was noted. Two of the 10 patients received a diagnosis of gastritis, with a normal intrinsic factor level. Macrocytosis commonly develops in gastrointestinal stromal tumors treated with imatinib2 and in patients with metastatic renal-cell carcinoma treated with sunitinib.3 Both drugs target c-kit, and sunitinib-induced macrocytosis seems to develop by means of a c-kit–related mechanism.

Bertrand Billemont, M.D.
Hassane Izzedine, M.D., Ph.D.
Olivier Rixe, M.D., Ph.D.
Hôpital Pitié–Salpêtrière, 75013 Paris, France
hassan.izzedine@psl.aphp.fr

3 References

1. 1

   Gillessen S, Graf L, Korte W, Cerny T. Macrocytosis and cobalamin deficiency in patients treated with sunitinib. N Engl J Med 2007;356:2330-2331
   Full Text | Web of Science | Medline

2. 2

   Aliberti S, Grignani G, Allione P, et al. Erythrocyte macrocytosis is a rather common, apparently uneventful yet unexplained finding in GIST imatinib (I) chronic therapy. J Clin Oncol 2005;23:Suppl:16S-16S
   

3. 3

   Khasawneh MF, Unnithan J, Choueiri T, et al. Macrocytosis in patients with metastatic renal cell carcinoma (mRCC) treated with tyrosine kinase inhibitors (TKI's). J Clin Oncol 2007;25:Suppl:18S-18S
   

Author/Editor Response

With regard to the comments of Billemont et al.: both imatinib and sunitinib target c-kit. In a mouse model, interference with the c-kit pathway leads to an increased volume of erythrocytes.1 Imatinib therapy induces macrocytosis that is independent of the level of cobalamin2,3; the mode of action is unclear.

Our patients had elevated homocysteine, normal folate, and decreased cobalamin and holotranscobalamin levels, all of which are compatible with a cellular cobalamin deficiency. The decreased holotranscobalamin level indicates a reduced supply of cellular cobalamin. Cobalamin deficiency can develop through reduced uptake, reduced release from stores, or increased consumption. Since no association of a tyrosine kinase interacting with cobalamin metabolism has been identified, to our knowledge, the mechanism of action remains to be elucidated.

Lukas Graf, M.D.
Silke Gillessen, M.D.
Wolfgang Korte, M.D.
Cantonal Hospital, 9007 St. Gallen, Switzerland
lukas.graf@ikch.ch

3 References

1. 1

   Rajaraman S, Davis WS, Mahakali-Zama A, Evans HK, Russel LB, Bedell MA. An allelic series of mutations in the kit ligand gene of mice. II. Effects of ethylnitrosourea-induced Kitl point mutations on survival and peripheral blood cells of kitl^Steel mice. Genetics 2002;162:341-353
   Web of Science | Medline

2. 2

   Aliberti S, Grignani G, Allione P, et al. Erythrocyte macrocytosis is a rather common, apparently uneventful yet unexplained finding in GIST imatinib (I) chronic therapy. J Clin Oncol 2005;23:Suppl:16S-16S
   

3. 3

   Meunier V, Bastuji-Garin S, Orrico M, et al. Imatinib-induced macrocytosis correlates to cytogenetic response in chronic myeloid leukaemia. Presented at the 7th Congress of the European Hematology Association, Florence, Italy, June 6–9, 2002.
   

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   Dale R Shepard, Jorge A Garcia. (2009) Toxicity associated with the long-term use of targeted therapies in patients with advanced renal cell carcinoma. Expert Review of Anticancer Therapy 9:6, 795-805
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   Brian I. Rini, Toni K. Choueiri, Paul Elson, Mohamad K. Khasawneh, Claudiu Cotta, Jaya Unnithan, Laura Wood, Tarek Mekhail, Jorge Garcia, Robert Dreicer, Ronald M. Bukowski. (2008) Sunitinib-induced macrocytosis in patients with metastatic renal cell carcinoma. Cancer 113:6, 1309-1314
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