International Journal of
HEMATOLOGY Letter to the Editor
Eosinophils Derived from Acute Promyelocytic Leukemia Cells after Arsenic Trioxide Treatment Kazuhito Yamamoto,a,b Nobuhiko Emi,a,c Tomohiro Kajiguchi,a Shunji Yamamori,d Yoshitaka Ono,e Tomoki Naoea a
Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan; b Department of Hematology and Cell Therapy, Aichi Cancer Center Hospital, Nagoya, Aichi, Japan; c Department of Hematology and Chemotherapy, Fujita Health University Hospital, Toyoake, Aichi, Japan; d Mitsubishi Kagaku Bio-Clinical Laboratory, Inc, Tokyo, Japan; eDepartment of Internal Medicine, Anjo Kosei Hospital, Anjo, Aichi, Japan Received November 28, 2006; received in revised form March 9, 2007; accepted March 16, 2007
Int J Hematol. 2007;85:456-457. doi: 10.1532/IJH97.06225 © 2007 The Japanese Society of Hematology
A 54-year-old Japanese woman was referred to our hospital in September 2003 because of a second relapse of acute promyelocytic leukemia (APL). The onset of APL had occurred in December 2001, and she had received treatment with all-trans retinoic acid (ATRA) and chemotherapy including cytarabine, daunorubicin, and mitoxantrone. Complete remission was obtained in 1 course, and consolidation therapy was finished in May 2002. The patient’s first relapse was diagnosed in September 2002. Therapy with ATRA alone was not effective, and chemotherapy with idarubicin, cytarabine, and etoposide produced the second remission. Three months after the last chemotherapy, however, pancytopenia had progressed, and a bone marrow smear demonstrated the second relapse of APL. On the patient’s admission to our hospital, a complete blood count showed a hemoglobin level of 11.8 g/dL, a white blood cell (WBC) count of 3.1 × 109/L with 10% blasts, and a platelet count of 31 × 109/L with mild coagulopathy. A relative APL cell count of 80% was confirmed by bone marrow aspiration. Therapy with arsenic trioxide (ATO) was started at a daily dose of 0.15 mg/kg after informed consent was obtained. The WBC count decreased to 8 × 109/L by day 8 and then increased to 34.8 × 109/L on day 23 without an increase in blasts or progression of the coagulopathy. The
WBC count decreased only with ATO therapy and returned to a normal count on day 30. Because an examination of a bone marrow aspirate on day 42 did not detect any apparent leukemic cells, ATO therapy was discontinued on day 41. The patient achieved complete hematologic remission on day 57. During induction therapy with ATO, significant amounts of eosinophils were detected in the peripheral blood (Figure 1A), and a 26% eosinophil count (WBC count, 2.3 × 109/L) was seen on day 40.A bone marrow smear on day 42 showed 6.7% eosinophil myelocytes, 11.8% eosinophil metamyelocytes, and 5.9% segmented eosinophils. The patient did not present any eosinophilia-related symptoms, such as fever, rash, or dyspnea. An increase in eosinophils was not observed in the first induction therapy with ATRA and chemotherapy or in consolidation therapy with ATO. Figure 1B shows May-Grünwald-Giemsa staining of a bone marrow smear sample (Figure 1B, left).The same smear was hybridized with SpectrumOrange Dual Color, Dual Fusion Translocation PML Probe (Vysis, Downers Grove, IL, USA) and SpectrumGreen Dual Color, Dual Fusion Translocation RARA Probe (Vysis) (Figure 1B, right). Eosinophils showed 1 orange dot for PML (thick arrow), 1 green dot for RARα (thin arrow), and 2 fusion dots (arrowheads), indicating that the eosinophils were derived from APL cells and differentiation had been induced by ATO. Ten percent of the eosinophils were positive for PML-RARα, and 5.5% of the myeloid series were positive on the same smear. This case report is the first to show that APL cells can differentiate into an eosinophilic line. Whereas ATRA induces APL cells toward terminal differentiation [1], the mechanism of action of ATO is induction of both differentiation and
Correspondence and reprint requests: Kazuhito Yamamoto, MD, Department of Hematology and Cell Therapy, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, Aichi 464-8681, Japan; 81-52-762-6111; fax: 81-52-764-2967 (e-mail:
[email protected]).
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into eosinophils [7] and giving rise to an eosinophilic subline, HL60 7.7 [8]. Our case provides direct evidence that APL originates from a precursor that can differentiate into both neutrophils and eosinophils and that APL cells can differentiate into an eosinophil lineage. Moreover, considering that this patient achieved complete remission, the appearance of eosinophils in the peripheral blood implies the success of differentiation therapy with ATO.
Figure 1. Fluorescent in situ hybridization analysis of eosinophils. A, Eosinophils in peripheral blood. May-Grünwald-Giemsa staining of a peripheral blood smear sample. B, Left, May-Grünwald-Giemsa staining of a bone marrow smear; right, the same smear was hybridized with SpectrumOrange Dual Color, Dual Fusion Translocation PML Probe (Vysis) and SpectrumGreen Dual Color, Dual Fusion Translocation RARA Probe (Vysis). Eosinophils showed 1 orange dot for PML (thick arrow), 1 green dot for RARα (thin arrow), and 2 fusion dots (arrowheads), indicating that eosinophils were derived from acute promyelocytic leukemia cells. apoptosis, depending on the ATO concentration [2,3]. The pharmacologic level of ATO (1 μM) causes apoptosis in NB4 cells, an APL cell line, in vitro [2]. APL patients treated with ATO present with so-called APL syndrome [4], suggesting that ATO induces differentiation of APL cells in vivo, even at pharmacologic concentrations. Differentiation of APL cells into an eosinophilic granulocytic line was suggested from the evidence of clinical observations and in vitro data. Clinically, there is a case report describing APL with dysplastic eosinophils [5]; in vitro, another report has described an APL line with the ability to differentiate in vitro into neutrophils and eosinophils, with the lineages dependent on the cytokines added [6]. The HL60 line was also capable of differentiating
References 1. Melnick A, Licht JD. Deconstructing a disease: RARα, its fusion partners, and their roles in the pathogenesis of acute promyelocytic leukemia. Blood. 1999;93:3167-3215. 2. Chen GQ, Shi XG, Tang W, et al. Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL), I: As2O3 exerts dose-dependent dual effects on APL cells. Blood. 1997;89: 3345-3353. 3. Kitamura K, Minami Y, Yamamoto K, et al. Involvement of CD95independent caspase 8 activation in arsenic trioxide-induced apoptosis. Leukemia. 2000;14:1743-1750. 4. Camacho LH, Soignet SL, Chanel S, et al. Leukocytosis and the retinoic acid syndrome in patients with acute promyelocytic leukemia treated with arsenic trioxide. J Clin Oncol. 2000;18: 2620-2625. 5. Ghosh K, Varma N, Dash S. Dysplastic eosinophils in three patients with acute promyelocytic leukaemia. Leuk Res. 1988;12:963-967. 6. Kishi K, Toba K, Azegami T, et al. Hematopoietic cytokine-dependent differentiation to eosinophils and neutrophils in a newly established acute promyelocytic leukemia cell line with t(15;17). Exp Hematol. 1998;26:135-142. 7. Metcalf D. Clonal analysis of the response of HL60 human myeloid leukemia cells to biological regulators. Leuk Res. 1983;7:117-132. 8. van Dijk TB, Caldenhoven E, Raaijmakers JA, Lammers JW, Koenderman L, de Groot RP. The role of transcription factor PU.1 in the activity of the intronic enhancer of the eosinophil-derived neurotoxin (RNS2) gene. Blood. 1998;91:2126-2132.
