Originally published as JCO Early Release 10.1200/JCO.2008.19.6204 on November 10 2008

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In Reply

Vincenzo Pitini, Carmela Arrigo, Giuseppe Altavilla

Department of Medical Oncology, University of Messina, Messina, Italy

We thank Hotta et al for their interesting comments about our article.¹ Regarding their first point, we agree to the question as to whether tyrosine kinase inhibitors might induce the reciprocal chromosome translocation t(15;17) (q22;q11-12), the genetic cause of acute myeloid leukemia (AML) –M3; it is not known whether cytotoxic drugs or radiotherapy rather than the gefitinib itself was a risk factor for leukemogenesis, even if an experimental study has demonstrated that gefitinib induces myeloid differentiation of AML.² Furthermore, gefitinib has been used to treat more than 10,000 patients with locally advanced or metastatic non–small-cell lung cancer with no reported deleterious effects on normal hematopoiesis. The suggestion that gefitinib suppressed the proliferation of leukemic cells to an extent, obscuring the diagnosis of AML-M3, is intriguing. At the genetic level, acute promyelocytic leukemia is characterized by a unique reciprocal chromosome translocation leading to a fusion between the promyelocytic (PML) gene on chromosome 15 and the retinoic acid receptor alpha (RARA) gene on chromosome 17. Based on the PML breakpoint location, the PML/RARA transcript subtypes bcr1, bcr2, and bcr3 (short type) may be formed. Interesting FLT3 receptor mutations including point mutations in the tyrosine kinase II domain have been detected at high frequency in acute promyelocytic leukemia, and these mutations have been associated with higher WBC count at presentation and with the short type PML/RARA fusion.³ Unfortunately, in the four reported patients with non–small-cell lung cancer and AML-M3,^4,5 the PML breakpoint location has not been formed, so no definitive conclusions can be drawn whether gefitinib suppressed the proliferation of leukemic cells.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) 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[Free Full Text]

2. Stegmaier K, Corsello SM, Ross KN, et al: Gefitinib induces myeloid differentiation of acute myeloid leukemia. Blood 106:2841-2848, 2005[Abstract/Free Full Text]

3. Lo-Coco F, Ammatuna E, Montesinos P, et al: Acute promyelocytic leukemia: Recent advances in diagnosis and management. Semin Oncol 35:401-409, 2008[CrossRef][Medline]

4. Uchida A, Matsuo K, Tanimoto M: APL during gefitinib treatment for non–small-cell lung cancer. N Engl J Med 352:842-843, 2005

5. 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]

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