Med Oncol (2015) 32:382 DOI 10.1007/s12032-014-0382-0

LETTER TO THE EDITOR

Occurrence of BCR/ABL fusion gene in a patient with acute promyelocytic leukemia Li-juan Zhang • Yi-min Gan • Liang Yu

Received: 24 October 2014 / Accepted: 18 November 2014 / Published online: 27 November 2014 Ó Springer Science+Business Media New York 2014

Introduction Acute promyelocytic leukemia (APL) is a common malignant hematological tumor characterized by the t(15;17) chromosome translocation, which results in the fusion of the retinoic acid receptor alpha (RARa) gene on chromosome 17 and the PML gene on chromosome 15, with the expression of a PML–RARa fusion protein [1]. The BCR/ABL fusion gene, which is caused by the t(9;22) chromosome translocation, is mainly found in patients with chronic myeloid leukemia (CML). However, it is also the most common cytogenetic abnormality detected in adult acute lymphoblastic leukemia (about 30 %) and is also observed in a few acute myeloid leukemia (AML) patients. However, BCR/ABL is rarely found in APL. Here, we report the occurrence of both PML–RARa and BCR/ABL in a patient with primary APL.

Case report A 51-year-old woman was admitted to our hospital in July 2013 due to sore throat during half a month. Physical examination showed red throat, swollen bilateral tonsils, sternal tenderness, without purpura, lymphadenopathy or hepatosplenomegaly. Leukocytosis was observed, and complete blood count showed white blood cells 287.83 9 109/L, hemoglobin 74 g/L and platelets 116 9 109/L. The differential leukocyte counts showed that myeloblasts and

L. Zhang  Y. Gan  L. Yu (&) Department of Hematology, Huai’an First People’s Hospital, Nanjing Medical University, Huai’an 223300, Jiangsu Province, People’s Republic of China e-mail: [email protected]

promyelocytes account for 40 % of all cells. Clotting function demonstrated APTT 33.10 s, PT 18.40 s, FIB 1.66 g/L, D-dimer [20 lg/mL, 3P test negative and FDP positive. Urine red blood cell was positive (3?). Stool, liver and kidney function was normal. Chest X-ray, abdominal ultrasound and electrocardiogram showed no abnormalities. Bone marrow aspiration showed hypercellular marrow with 8.5 % myeloblasts and 43.5 % promyelocytes. The blasts were positive for myeloperoxidase. Flow cytometric analysis of bone marrow showed that the cells were positive for MPO, CD13, CD33 and CD34, but negative for HLA–DR. Chromosome analysis displayed 46, XX, t(9;22) (q34;q11) and t(15;17) (q22; q21) (Fig. 1). PCR showed amplicons for both PML/RARa and BCR/ABL. The fluorescence in situ hybridization (FISH) analysis on interphase/metaphase cells confirmed the presence of BCR/ABL (Fig. 2). Given the comprehensive information including clinical manifestation, morphology and immunophenotype, the patient was diagnosed as BCR/ABL-positive APL. According to the Chinese guideline for APL in 2011, the patient was treated with retinoic acid (ATRA) (20 mg bid, oral administration) in combination with DA regimen: daunorubicin (80 mg/d d2, d4, d6, i.v.) and cytosine arabinoside (250 mg/d d1–7, i.v.). One month later, the patient was in complete remission (CR). Thereafter, the patient entered the consolidation therapy phase, with the regimen of ATRA (20 mg bid) in combination with arsenic trioxide (10 mg/d), as well as imatinib (400 mg/d). After two cycles of consolidation therapy, the patient entered the maintenance treatment phase, with the regimen of imatinib (400 mg/d). In June 2014, the complete blood count showed white blood cells 8.4 9 109/L, hemoglobin 118 g/L, platelets 560 9 109/L and with bone marrow aspiration showing CR. However, PCR showed the presence of both PML/RARa and BCR/ ABL.

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Fig. 1 The arrow shows 22q, the so-called Philadelphia chromosome, where the BCR/ABL fusion gene is located

Fig. 2 Site-specific probe LSI ABL (9q34) on chromosome 9 is labeled in red, whereas LSI BCR (22q11) on chromosome 22 is labeled in green. FISH result shows two red, a green and a fusion signal, demonstrating formation of the BCR/ABL fusion gene

Discussion APL is a special subtype of AML and accounts for 20–30 % of AML. In addition to the t(15;17) chromosomal translocation, other chromosomal abnormalities have also been observed in 20–30 % of APL patients, such as ?8, ?10, ?4, ?7 and ider(17) t(15;17) [2–4]. Mutations in the BRCA2 gene have also been reported to predispose for APL development [5]. The patient we report here shows the t(15;17) (q22;q21) chromosomal translocation and the presence of a PML–RARa fusion gene, i.e., typical APL was diagnosed. In addition, BCR/ABL was detected both by PCR and FISH. Because BCR/ABL is the characteristic genetic change in CML, one possibility was that the patient had entered into blast crisis (APL transformation) of CML. However, the patient had no history of CML, was without splenomegaly, but with anemia at diagnosis. Bone marrow and peripheral blood showed a high proportion of promyelocytes, but

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normal eosinophils and basophils, i.e., the clinical diagnosis was BCR/ABL-positive APL. It was reported that BCR/ABL has been observed in only 0.9–3.0 % AML patients [6], but rarely founded in APL. Mao et al. [7] have reported a case of BCR/ABLpositive APL, but the patient died of multiple intracranial hemorrhages the day after being diagnosed. Sun et al. have diagnosed and treated another case of BCR/ABL-positive APL, with a more complex karyotype, 46, XY, t(9;22) (q34;q11), t(15;17) (q22;q21)/47, idem, ?8/46, idem and der(14) t(9;14) (q10;q10). However, bone marrow cytology and flow cytometric analysis demonstrated CR 2 months later. Moreover, in this report, quantitative PCR and FISH detected no PML–RARa or BCR/ABL in the bone marrow [8]. Currently, APL patients in our country have been treated according to the 2011 Chinese guidelines for APL, which recommend ATRA and anthracycline-based chemotherapy to induce remission. If the anthracycline cannot be tolerated, ATRA plus arsenic trioxide can be used instead. After the bone marrow showed evidence of CR, there were two courses of consolidation chemotherapy, followed by maintenance treatment based on ATRA and arsenic trioxide alternating therapy [9]. However, the treatment for BCR/ABL-positive APL is more difficult; there is no standard regimen. Sun et al. [8] have reported a patient who was in CR for 18 months after being treated with ATRA (20 mg tid) in combination with arsenic trioxide (10 mg/d) and imatinib (400 mg/d). After the patient acquired CR upon the induction chemotherapy (DA combined with ATRA), we adjusted the regimen to be comprised of ATRA, arsenic trioxide as well as imatinib because of the positive BCR/ABL. The main theoretical basis is as follows: Arsenic trioxide has multiple anti-tumor functions and has been extensively studied in hematological malignancies and solid tumors. It can decrease PML–RARa protein and induce APL cell apoptosis. Arsenic trioxide monotherapy for APL has achieved very satisfying results in China since 1992. Imatinib is a BCR/ABL signaling pathway inhibitor, which interacts with the ATP binding site of BCR/ABL, hence inhibiting the enzyme activity of the protein competitively. This blocks proliferation of tumor cells, thereby achieving targeted therapy for CML [10]. Through in vitro studies, it has been found that arsenic trioxide can induce BCR/ABL-positive cell apoptosis, enhance the pro-apoptotic activity of imatinib and down-regulate the BCR/ABL oncoprotein levels [11–13]. Du et al. [14] have demonstrated a treatment strategy, where combining arsenic trioxide with imatinib appears to induce markedly more cell apoptosis than imatinib alone for CML patients. Therefore, we adopted the consolidation therapy program of ATRA, arsenic trioxide and imatinib, as well as the maintenance

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therapy of imatinib. There were no significant drug side effects during the treatment courses. Up to date, the bone marrow remains in CR for 9 months, but yet without molecular remission, possibly due to the short treatment course, so further clinical observation is needed. BCR/ABL is an independent risk factor to predict the poor prognosis and early recurrence of acute leukemia. It has been reported that BCR/ABL-positive AML has a median survival time of 9 months [15]. However, the survival time of BCR/ABL-positive APL patients has not been reported. Maybe the allogeneic hematopoietic stem cell transplantation and the regimen based on arsenic trioxide and imatinib are the most promising strategies of treatment to cure the disease. The patient we report was treated with ATRA combined with DA regimen for the induction chemotherapy, followed by the consolidation therapy program including ATRA, arsenic trioxide and imatinib after the bone marrow acquired CR. Up to date, the patient remains in CR for 9 months, but the BCR/ABL is still positive. We do not know whether she can be cured by this regimen. Further study, as well as more patients, is needed to investigate the best treatment strategy for BCR/ ABL-positive APL. Acknowledgments This work was supported by the National Natural Science Foundation of China under Grant 81170489. We thank Professor C. I. Edvard Smith (from Karolinska Institutet in Sweden) for carefully reading and polishing the manuscript. Conflict of interest

None.

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ABL fusion gene in a patient with acute promyelocytic leukemia.

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