Japanese Journal of Clinical Oncology 30:310-312 (2000)
© 2000 Foundation for Promotion of Cancer Research
Essential Thrombocythemia Transformed to Acute Myelogenous Leukemia with t(3;17)(p24; q12), del(5)(q13q34) After Treatment with Carboquone and Hydroxyurea
1Department of Hematology, Jichi Medical School, Tochigi and 2Division of Hematology, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
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ABSTRACT |
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In 1991, a 52-year-old woman was diagnosed as having essential thrombocythemia (ET). She was doing well with continuous medication with carboquone (CQ) and subsequently hydroxyurea (HU). However, substantial leukocytosis with leukemic blast cells, anemia and thrombocytopenia developed in 1996. Analysis of peripheral blood showed 4.4 x 103/µl white blood cells with 82% of leukemic blast cells. These blasts showed negative staining with myeloperoxidase by immunostaining, but the myeloperoxidase was positive by electron microscopic analysis. Cytogenetic analysis of bone marrow cells revealed a t(3;17)(p24; q12), del(5)(q13q34). On the basis of these findings, the leukemic blast cells were classified as acute myelogenous leukemia (AML: M0) in the FAB classification. The causative agent, CQ and HU in secondary leukemia from ET and chromosomal abnormality related to ET blastic crisis (BC) are discussed.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONCASE REPORTDISCUSSIONAcknowledgmentsREFERENCES |
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Essential thrombocythemia (ET) is an uncommon disorder characterized by a marked increase in the number of platelets. ET is one of the myeloproliferative disorders (MPD) which include polycythemia vera (PV), chronic myelocytic leukemia (CML) and myelofibrosis (1,2). Unlike CML, however, there is no cytogenetic or molecular abnormality that definitively establishes its diagnosis. Rather, the diagnosis of ET is made when a patient has an elevated platelet count, an increased number of megakaryocytes in the bone marrow, no identifiable underlying abnormality known to cause thrombocytosis and the absence of findings suggestive of a different MPD (3). The main clinical features of ET are thrombotic or hemorrhagic episodes due to the increased number of functionally abnormal platelets. ET may transform into AML, especially following therapy with alkylating agents or radioactive phosphorus. Recently, Sterkers et al. reported that a high proportion of AML and MDS occurring in ET patients treated with HU (alone or possibly followed by pipobroman) have morphological, cytogenetic and molecular characteristics of the 17p-syndrome (4). Here, we report a case of ET that transformed into AML: M0 with a t(3;17)(p24; q12), del(5)(q13q34) after treatment with CQ and HU.
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CASE REPORT |
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TOPABSTRACTINTRODUCTIONCASE REPORTDISCUSSIONAcknowledgmentsREFERENCES |
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In November 1991, a 52-year-old woman was diagnosed as having ET, with an elevated platelet count of 152 x 104/µl and hyperplasia of megakaryocytes as determined by bone marrow aspiration, according to the criteria of the Polycythemia Vera Study Group (5). At this point, chromosomal analysis revealed no abnormalities. The platelet number was controlled at around 50 x 104/µl. She was treated with CQ (1 mg daily) for 12 months and HU (1000 mg daily) for 36 months and then showed the development of severe thrombocytopenia. In the course of the treatment, 1–2% blast cells were observed in the peripheral blood, but no laboratory findings suggestive of leukemic transformation such as leukocytosis or thrombocytopenia were noted. In 1996, the platelet number decreased and anemia developed gradually along with leukocytosis. Hematological findings revealed Hb 6.6 g/dl, WBC 4.4 x 103/µl (82% blast cells) and platelet count 7.2 x 104/µl. Bone marrow aspiration revealed an elevation in the number of blast cells (Fig. 1) and biopsy specimens showed substantial myelofibrosis. Cytochemical analyses showed that the blast cells were negative for myeloperoxidase, Sudan Black B and esterase double stains. Myeloperoxidase was positive according to the results of electron microscopic analysis. Immunophenotypical analysis revealed positivity for CD13, CD33 and HLA-DR, but negativity for CD41. Cytogenetic analysis of bone marrow cells revealed t(3;17)(p24; q12), del(5)(q13q34). A diagnosis of transformation into AML M0 from ET with myelofibrosis was made. Combination chemotherapy with Ara-C (100 mg/m2 per day for 7 days) and aclarubicin (14 mg/m2 per day for 7 days) was performed. After this chemotherapy, bone marrow aspiration showed that there had been no improvement in blast cell infiltration and chromosome abnormality. At 2 months after the chemotherapy, bone marrow aspiration showed that the number of blast cells had decreased to 43% of ANC, but chromosome abnormalities t(3;17)(p24; q12), del(5)(q13q34) were observed in 92.9% (26/28) of analyzable cells. Subsequently, WBC was controlled by HU or AraC. However, in July 1998, she died from myeloblastoma of the palate and medulla spinalis.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONCASE REPORTDISCUSSIONAcknowledgmentsREFERENCES |
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ET is a clonal disorder of multipotent hematopoietic stem cells, with abnormalities involving all three hematopoietic lineages, especially the megakaryocytic lineage (6). Hemorrhage and/or thrombosis are the main clinical manifestations. The clinical course of ET is usually long and the frequency of blastic transformation in ET is very low compared with that in CML, idiopathic myelofibrosis and polycythemia vera. The incidence of progression to blastic crisis in patients with ET was reported to be about 5% (1). Radioactive phosphorus (32P) and cytoreductive agents such as busulfan and HU, which have been used in the treatment of ET, are thought to play a causative role in the pathogenesis of leukemic transformation (2). HU is a non-alkylating myelosuppressive agent that inhibits DNA synthesis by inhibition of ribonucleoside diphosphate reductase but also inhibits DNA repair (7). The leukemogenic potential of HU has been mainly studied in cases of PV. In cases of PV treated with HU alone, the incidence of progression to AML had initially been reported to be only 1–3% in two cohorts of
100 cases followed over a median of 5 years (8,9). Furthermore, leukemic transformation of ET is also influenced by the alkylating agent CQ (10,11). Here, we report a case of ET that terminated with a blastic transformation (M0) after using CQ and HU accompanied by the chromosomal abnormality t(3;17)(p24; q12), del(5)(q13q34). Sterkers et al. reviewed cases of AML and MDS occurring in 357 cases of ET diagnosed from 1970 to 1991 and monitored until August 1996 (4). Seventeen cases of AML and MDS were observed, mostly in the patients treated exclusively or predominantly with HU. Seven of these patients had 17p deletions and other characteristics of the 17p-syndrome (4). They also reported that there is a strong correlation between 17p deletion, resulting from unbalanced translocations between 17p and another chromosome or less often from monosomy 17 or isochromosome(17q), typical dysgranulopoiesis combining pseudo Pelger Hüet hypolobulation and small vacuoles in neutrophils and p53 mutation (12,13). The use of 32P or melphalan followed by HU was not associated with an increased incidence of acute leukemia. The use of HU probably also increases the leukemic risk of other cytoreductive treatments given in cases of ET. Since a period of about 5 years was required for leukemic transformation in the present case, the possibility of the transformation being a spontaneous process cannot be excluded. However, during the treatment of this case, 1–2% blast cells appeared in peripheral blood, suggesting MDS preceding leukemic transformation. Since therapy-related leukemia is often preceded by MDS (14), this case is suspected to have been secondary leukemia caused by HU. Recent studies have suggested the involvement of p53 gene mutation on chromosome 17 in blastic crisis (BC) of ET (4,15), while other studies have also suggested an association with chromosome 21 aberration (16). The cause of BC of ET is still unknown, but several factors appear to be involved. In the present case, an adequate amount of samples could not be obtained and examination according to cell lines could not be performed. However, since the G-CSF gene as cell growth factor is located on the 17q arm, the involvement of cytokines in BC of ET is also suspected. To our knowledge, there has been no report of the involvement of 17q in secondary leukemia followed by HU. Sterkers et al. encouraged the publication of all cases of AML and MDS occurring during the course of ET treated with HU, with special emphasis on their morphological and cytogenetic characteristics (4).
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Acknowledgments |
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TOPABSTRACTINTRODUCTIONCASE REPORTDISCUSSIONAcknowledgmentsREFERENCES |
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We thank Ayumi Yamazaki and Makiko Nakamura for their expert technical assistance.
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FOOTNOTES |
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+ For reprints and all correspondence: Shigehiko Imagawa, Division of Hematology, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan. E-mail: simagawa@md.tsukuba.ac.jp Abbreviations: ET, essential thrombocythemia; CQ, carboquone; HU, hydroxyurea; AML, acute myelogenous leukemia; BC, blastic crisis; MPD, myeloproliferative disorders; PV, polycythemia vera; CML, chronic myelocytic leukemia
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REFERENCES |
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Received March 14, 2000; accepted May 8, 2000.
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