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Originally published as JCO Early Release 10.1200/JCO.2008.19.5685 on November 10 2008 © 2008 American Society of Clinical Oncology.
Paradoxical Clinical Effects of Epidermal Growth Factor Receptor–Tyrosine Kinase Inhibitors for Acute Myelogenous Leukemia
Department of Respiratory Medicine, Okayama University Hospital, Okayama, Japan
Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan
Department of Respiratory Medicine, Okayama University Hospital, Okayama, Japan To the Editor: We read with great interest the article by Pitini et al1 in which they reported that erlotinib, an epidermal growth factor receptor–tyrosine kinase inhibitor (EGFR-TKI), was effective for combined EGFR-negative acute myelogenous leukemia (AML) –M1 and EGFR mutation–positive non–small-cell lung cancer (NSCLC). Another patient who had both AML-M1 and NSCLC also benefited substantially from the erlotinib treatment.2 These results are supported by in vitro studies in which TKIs have antiproliferative effects against AML.3,4 Contrary to their exciting case presentation, we and others previously observed the emergence of AML-M3 during long-term treatment with gefitinib (250 mg/d), another TKI, in four patients with NSCLC.5,6 We find these paradoxical clinical results rather interesting. There are several possible explanations for the results. First, some cytotoxic drugs or radiotherapy that the patient had undergone before the gefitinib treatment, rather than the gefitinib itself, might have been a risk factor for leukemogenesis in our patients. The greater the improvement in patient survival (the actual interval between the initial treatment and the emergence of AML-M3, which was 35, 48, and 69 months in our three patients), the more frequently we might observe secondary malignancies. In addition, each case was diagnosed at an early stage of AML-M3 with mild to moderate cytopenia and no disseminated intravascular coagulation, and leukemic cells could be detected only in the bone marrow in two of the three patients. Based on these clinical features, we postulate that in our three patients, gefitinib suppressed the proliferation of leukemic cells to an extent, obscuring the diagnosis of AML-M3, despite the need for further relevant investigations. As another explanation for the paradoxical findings, TKIs might have different leukemogenic effects among the subtypes of AML. We consider further research is required to clarify whether TKIs might induce especially the BCR-ABL fusion gene, the genetic cause of AML-M3.7 We agree with the conclusion of Pitini et al.1 that TKIs are a potential therapeutic strategy for AML. From this perspective, they shed light on an exciting aspect of EGFR-TKIs that needs to be evaluated in future preclinical and clinical evaluations. In addition, worldwide epidemiological research might clarify the association between long-term TKI treatment and the rare events that we have noted.5 AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The authors indicated no potential conflicts of interest. NOTES published online ahead of print at www.jco.org on November 10, 2008. REFERENCES
1. Pitini V, Arrigo C, Altavilla G: Erlotinib in a patient with acute myelogenous leukemia and concomitant non–small-cell lung cancer. J Clin Oncol 26:3645-3646, 2008 2. Chan G, Pilichowska M: Complete remission in a patient with acute myelogenous leukemia treated with erlotinib for non–small-cell lung cancer. Blood 110:1079-1080, 2007 3. Stegmaier K, Corsello SM, Ross KN, et al: Gefitinib induces myeloid differentiation of acute myeloid leukemia. Blood 106:2841-2848, 2005 4. Boehrer S, Adès L, Braun T, et al: Erlotinib exhibits antineoplastic off-target effects in AML and MDS: A preclinical study. Blood 111:2170-2180, 2008 5. Uchida A, Matsuo K, Tanimoto M: APL during gefitinib treatment for non–small-cell lung cancer. N Engl J Med 352:842-843, 2005 6. Ennishi D, Sezaki N, Senoo T, et al: A case of acute promyelocytic leukemia during gefitinib treatment. Int J Hematol 84:284-285, 2006[CrossRef][Medline] 7. Cortes J, Kantarjian H: New targeted approaches in chronic myeloid leukemia. J Clin Oncol 23:6316-6324, 2005
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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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