|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Journal of Clinical Oncology, Vol 26, No 21 (July 20), 2008: pp. 3645-3646 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2008.17.0357
Erlotinib in a Patient With Acute Myelogenous Leukemia and Concomitant Non–Small-Cell Lung CancerDepartment of Medical Oncology, University of Messina, Messina, Italy In August 2007, a 64-year-old male smoker presented with a 1-month history of progressively worsening dyspnea; peripheral blood leukocyte count was 4.1 x 109/L with 7% neutrophils, 2% band, 39% lymphocytes and 52% myeloblasts (Fig 1); hemoglobin of 8.9g/dL; and a platelet count of 61 x 109/L. Bone marrow biopsy revealed 81% myeloperoxidase-positive blasts, while the immunophenotype was 81% CD34, 75% HLA-DR, 21% CD13, 8% CD33, 0% CD10, 6% CD19, 2% CD3% and 3% CD25 by flow cytometry, consistent with acute myelogenous leukemia (AML) -M1; the cytogenetics were normal. A body computed tomography scan showed a 3 x 3.7 cm mass in the left lower lobe of the lung (Fig 2). A core-needle biopsy obtained from the lung was consistent with a moderately differentiated adenocarcinoma. Positron emission tomography scanning revealed an uptake in the lung mass and mediastinum confirming the diagnosis of stage IIIA of non–small-cell lung cancer (NSCLC). To assess the epidermal growth factor receptor's (EGFR) mutational status, a complementary DNA sequencing from core-needle biopsy of the lung was performed, and a leucine-to-arginine substitution at amino acid 858 (L858R) was identified. Given the patient's poor performance status, no AML therapy was initiated, and he was prescribed oral erlotinib 150 mg daily. After two weeks of erlotinib therapy, routine blood examinations revealed a significant reduction of circulating blasts (10%), while leukocyte count was 3.7 x 109/L. A repeat bone marrow biopsy revealed manifested biochemical hallmarks of apoptosis as determined by terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate-biotin nick-end labeling assay, which has been shown to be a sensitive and specific method for detecting apoptosis in histologic sections1 (Fig 3). EGFR was undetectable on myeloblasts. After 3 months of erlotinib therapy, the patient had normal complete blood counts and no circulating blasts. A new chest computed tomography scan showed that the mass in the left lung had nearly completely resolved itself (Fig 4). Seven months after starting the treatment, he remains clinically well on erlotinib without any chest related symptons except for a grade 1 skin rash. A repeat bone marrow biopsy was mildly hypocellular with maturing trilineage hematopoiesis, less than 2% myeloblasts and normal cytogenetics.
EGFR is a receptor tyrosine kinase of the ErbB receptor family that is abnormally activated in many epithelial tumors. The aberrant activation leads to enhanced proliferation which provides a strong rationale to target this receptor family. Somatic mutations in the EGFR have been detected in patients with NSCLC and are associated with sensitivity to treatment with gefitinib or erlotinib which are adenosine triphosphate–competitive inhibitors of the receptor's tyrosine kinase.2-3 EGFR mutations occur mainly in the first four exons of the gene encoding tyrosine kinase domain (18-21) and are clustered around the ATP-binding pocket of the enzyme. Approximately 90% of EGFR mutations are missense mutations resulting in leucine to arginine substitution at codon 858 (L858R) in exon 21 and small exon 19 in-frame deletions. Other mutations occur at lower frequency at codon 719, resulting in the substitution of glycine to cysteine, alanine, or serine (G7 19X), and in exon 20 as in-frame insertion mutations.4 Unfortunately, despite the presence of activating EGFR mutations in their tumors, patients can fail to respond to tyrosine kinase, and also those with an initial dramatic response develop acquired drug resistance after variable periods of time due to additional genetic lesions.5 A recent study revealed the capacity of gefitinib to induce differentiation in 3 AML cell lines (U937, HL60, and Kasumi-1), all of which lack expression of the EGFR, thus unraveling an interesting off-target effect of a compound that was believed to specifically act on EGFR-expressing cells.6 On the basis of this report Boehrer et al7 studied the effects of the EGFR inhibitor erlotinib on EGFR-negative AML and myelodysplastic syndrome (MDS) cells in vitro and ex vivo. This study pointed out that erlotinib has an antineoplastic activity on MDS and AML cells that includes a strong proapoptotic effect in the erlotinib-sensitive AML cell line KG-1, as in vivo observed by us in this case report. Furthermore, one patient with both MDS and NSCLC manifested hematologic improvement after treatment with erlotinib. Finally, noteworthy, a recently published case report provides further clinical evidence for the therapeutic efficacy of erlotinib in EGFR–negative myeloid malignancies.8 The case of our patient points out the importance of the presence of L858R mutation within the kinase domain of EGFR as a predictive factor in determining the response to erlotinib, even if the most relevant aspect of our case is the unexpected antineoplastic activity of erlotinib on AML cells. This off-target effect could be explained by the inhibitory effects on JAK2,7 even if undoubtedly the lethal response to erlotinib is dictated by a poorly understood cellular context. In conclusion, our case report suggests that erlotinib could also be a potential therapeutic strategy for selected patients with AML. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest.
REFERENCES
1. Gavrieli Y, Sherman Y, Ben-Sasson SA: Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J Cell Biol 119:493-501, 1992 2. Sequist LV, Bell DW, Lynch TJ, et al: Molecular predictors of response to epidermal growth factor receptor antagonists in non–small-cell lung cancer. J Clin Oncol 25:587-595, 2007 3. Pao W, Miller VA: Epidermal growth factor receptor mutations, small-molecule kinase inhibitors, and non–small-cell lung cancer: Current knowledge and future directions. J Clin Oncol 23:2556-2568, 2005 4. Rosell R, Taron M, Sanchez JJ, et al: Setting the benchmark for tailoring treatment with EGFR tyrosine kinase inhibitors. Future Oncol 3:277-283, 2007[CrossRef][Medline] 5. Engelman JA, Zejnullahu K, Mitsudomi T, et al: MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 316:1039-1043, 2007 6. Stegmaier K, Corsello SM, Ross KN, et al: Gefitinib induces myeloid differentiation of acute myeloid leukemia. Blood 106:2841-2848, 2005 7. 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 8. 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
Related Correspondence
This article has been cited by other articles:
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
