Aplastic anemia evolving into overt myelodysplastic ...

Cancer Genetics and Cytogenetics 137 (2002) 91–94

Aplastic anemia evolving into overt myelodysplastic syndrome/acute myeloid leukemia with t(3;5)(p25;q31) Eri Kawataa, Junya Kuroda, Shinya Kimuraa,b, Yuri Kamitsujia, Yutaka Kobayashia,*, Toshikazu Yoshikawa a

First Department of Internal Medicine, Kyoto Prefectural University of Medicine, 465 Kajii Kamigyo-ku, Kyoto, 602 Japan b Department of Transfusion Medicine, Kyoto University Hospital, 54 Kawahara Shogoin, Sakyo-Ku, Kyoto, 606 Japan Received 23 January 2002; accepted in revised form 21 February 2002

Abstract

Advances in the treatment of aplastic anemia (AA) have led to the long-term survival of nontransplanted AA patients; however, the issue of subsequent hematological clonal disorders has been raised as some AA patients treated with immunosuppressive therapy or granulocyte-colony stimulating factor (G-CSF) went on to develop myelodysplastic syndromes (MDS) and/or acute myeloid leukemia (AML) with the frequent presentation of monosomy 7. We report a case of AA progressing to overt MDS/AML following 11 years of treatment that included immunosuppressive therapy and G-CSF. The patient’s MDS/AML proved refractory to therapy including myeloablative treatment with allogenic peripheral blood stem cell transplantation. Earlier reports and the present case strongly suggest that there is no recurrent chromosomal aberration other than monosomy 7 in cases of AA that progress to MDS/AML. To our knowledge, ours is the first reported case of a t(3;5)(p25;q31) among AA patients that have progressed to MDS/AML. © 2002 Elsevier Science Inc. All rights reserved.

1. Introduction

2. Case report

Aplastic anemia (AA) is characterized by severe pancytopenia due to bone marrow aplasia. In the absence of hematopoietic stem cell transplantation, its prognosis is poor [1]. Advances in immunosuppressive and cytokine therapy have improved the long-term survival of nontransplanted AA patients [2,3] and the issue of late complications such as relapse or subsequent hematological clonal disorders must now be addressed [3,4]. Among AA patients who received immunosuppressive therapy or granulocyte-colony stimulating factor (G-CSF), 20–30% developed secondary hematological clonal disorders such as paroxysmal nocturnal hematuria, myelodysplastic syndromes (MDS), or acute myeloid leukemia (AML) [3–6]. Monosomy 7 was frequently observed in these cases, however, its etiological role has not been clarified [4,7] and there is little information on possible other associated chromosomal aberrations. We report what, to our knowledge, is the first case of AA evolving into MDS/AML with a t(3;5)(p25;q31) but no monosomy 7.

A 26-year-old Japanese woman was admitted to our hospital with pancytopenia in May 1989. She was diagnosed as having AA with a normal karyotype. Until 1991, a partial response was elicited with therapy that included the administration of glucocorticosteroids, anabolic steroids, and G-CSF. From June 1991 until April 2000, she received cyclosporin A (CsA) and was in complete remission; however, in April 2000, 11 years after the diagnosis of AA, she was hospitalized with progressive pancytopenia. Hematological analysis on admission showed 2.5 109/L leukocytes (3.2–8.5 109/L), 6.2 g/dL hemoglobin (10.8–16.9 g/dL), and 19.0 109/L platelets (104–348 109/L). Peripheral leukocytes contained 2.0% abnormal blastic cells. Bone marrow aspiration revealed dysplasia with double nuclei or hyperlobulation in the granulocyte series, and micromegakaryocytes. The abnormal blasts constituted 19.8% of all nucleated marrow cells (ANC). Chromosomal analysis by G-banding showed 46,XX,4,del(9)(q?),mar [1]/46,XX[6] and she was diagnosed as MDS, refractory anemia with excess of blasts, according to French–American–British (FAB) classification [8]. Based on findings of the Japan Adult Leukemia Study Group AML-87 [9], systemic chemotherapy was performed. While her disease returned to refractory anemia, pancytopenia

* Corresponding author. Tel.: 81-75-251-5505; fax: 81-75-252-3721. E-mail address: [email protected] (Y. Kobayashi).

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Fig. 1. (A) Chromosomal analysis by G-banding at the time of leukemic progression, showing a karyotype of 46,XX,t(3;5)(p25;q31) in all analyzed metaphase spreads [20/20]. (B) Spectral karyotyping at leukemic progression.

with marrow hypoplasia persisted. At that time, G-banding revealed a karyotype of 46,XX,add(1)(p13),add(17)(q25)[1]/ 46,XX,add(1)(p13)[1]/46,XX[18]. She received myeloablative therapy with allogeneic peripheral blood stem cell transplantation (allo-PBSCT) from an HLA-matched sibling donor in September 2000; however, MDS reappeared on day 90. At that time, no bone marrow specimen was available for chromosomal analysis. Nonmyeloablative treatment with allo-PBSCT from the same sibling donor was performed on day 100; however, the disease persisted with the following complex karyotypic aberrations: 46,X,add(X)(p11),add(3)(p25),add(5)(q31),10,add(16) (q12),add(20)(q11),mar[1]/46,XX,add(3)(p25),add(5)(q31), add(11)(p11),add(17)(q21)[1]/46,XX[18]. After 1 month, in February 2001, the patient manifested

acute leukemia. The leukemic cells, 68.8% of ANC, were negative for myeloperoxidase. Immunophenotypically, the leukemic cells were positive for CD13, 33, 34, and HLA-DR, and negative for CD3, 7, 19, 20, and 56. A diagnosis of AML (M0) was made according to FAB classification [10]. G-banding and spectral karyotyping showed chromosomal aberration 46,XX, t(3;5)(p25;q31) in all analyzed metaphase spreads [20/20] (Fig. 1). The patient died in March 2001, on the 174th day after the first allo-PBSCT (74 days after the second PBSCT). 3. Discussion Our patient demonstrated hematological clonal evolution following 11 years of treatment (1989–2000), which included


the administration of CsA and G-CSF. She had received immunosuppressive therapy, G-CSF, and allo-PBSCT from an HLA-matched sibling. Differences in the outcomes of AA cases treated with immunosuppressive therapy and bone marrow transplantation were not clearly recognized at the time of her diagnosis in 1989 [2]. Hematopoietic stem cell transplantation is now recommended as the first-line of therapy in patients with severe AA who have HLA-matched sibling donors because their long-term outcomes have been found to be superior to the outcomes of AA patients treated with immunosuppressive therapy [1,3]. There are several reasons for the different outcomes produced by the different therapeutic approaches, and late complications such as the development hematological disorders have gained attention [3–7]. Although the factors leading to the development of hematological clonal disease remain to be identified, monosomy 7 is thought to be the most common cytogenetic characteristic in MDS/AML arising from AA [7,11]. In our case, cytogenetic analysis confirmed the absence of monosomy 7; the presence of t(3;5)(p25;q31) was identified at the time of leukemic progression. Although many cases with AA evolving into MDS/AML have been evaluated with respect to monosomy 7 [7,11], the possibility of other chromosomal aberrations has rarely been discussed. Based on our search of the literature and the findings made in our case, we suspect that the possibility of chromosomal aberrations other than monosomy 7 is slim. To our knowledge, ours is the first case of t(3;5) (p25;q31) in association with AA evolving into MDS/AML, and this translocation has not been described previously in association with hematological malignancies. The RAF1 gene is located on 3p25 and translocations involving 3p25 have been identified in several cancers such as parotid gland tumors [12] and renal cell carcinoma [13]. Wang et al. [14] reported that active RAF-1 improved BCL-2– mediated resistance to apoptosis, whereas a kinase-inactive RAF-1 mutant abrogated apoptotic suppression by BCL-2. In addition, deregulated apoptosis by increased BCL-2 expression in CD34 marrow cells of MDS is reportedly associated with progression in MDS and AML secondary to MDS [15]. Deletions and translocations at 5q31 are also suspected to associate with the development of AML and MDS. Interleukin-3, -4, -5, and -12, interferon regulatory factor, and granulocyte-macrophage CSF coding regions are located on 5q31 [16–18]. More importantly, several candidate tumor suppressor genes such as CDC25, HSPA9, EGR1 [19], 5qNCA [20], PURA [21], and GRAF [22] are known to locate on 5q31, and both PURA and GRAF may be implicated in the development of MDS and progression to AML [21,22]. These considerations suggest a possible association between t(3;5)(p25;q31) and the clonal evolution of CD34 leukemic cells in our patient. References [1] Kojima S, Horibe K, Inaba J, Yoshimi A, Takahashi Y, Kudo K, Kato K, Matsuyama T. Long-term outcome of acquired aplastic anemia in

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