Myelodysplastic syndrome with clonal cytogenetic abnormalities followed by fatal erythroid leukemia after 14 years of exposure to hydroxyurea for sickle cell anemia
Authors: Cédric Aumont, Françoise Driss, Thierry Lazure, Véronique Picard, Rita Creidy, Stéphane De Botton, Véronique Saada, Olivier Lambotte, Chrystèle Bilhou‐Nabera, Gérard Tertian, Jean‐Marie Michot
Journal: American Journal of Hematology (2015)

Here, we report on a 49-year-old male patient suffering from sickle cell anemia who experienced 14 years of cumulative exposure to hydroxyurea (HU), then developed myelodysplastic syndrome with a complex karyotype including a chromosome 17p deletion, followed by acute erythroid leukemia. HU is an approved treatment for severe sickle cell disease (SCD), due to its efficacy in preventing vaso-occlusive crisis 1. HU induces an inhibitory effect on hemoglobin S polymerization by increasing the synthesis of fetal hemoglobin. HU also reduces the expression or activity of several adhesion molecules on red blood cells and endothelial cells, thus improving blood flow in the microcirculation 2. The main adverse hematologic effect of HU is usually mild myelosuppression. Regarding the hematologic side effects of HU exposure, no case of malignancy was reported in large series of SCD patients 3-5. Very few cases of myelodysplastic syndrome or acute leukemia after HU in patients suffering from SCD have been reported 6-9. We report here a 49 year-old male SCD patient who experienced 14 years of exposure to HU and developed myelodysplastic syndrome followed by acute erythroid leukemia. A male patient, born in 1962, had severe SS SCD that was complicated by many episodes of vaso-occlusive crisis, bilateral hip necrosis requiring hip replacement, retinopathy, pulmonary infections and digestive salmonellosis, biliary lithiasis, ischemic stroke in 2003, and chronic RBC transfusion-induced iron overload. HU was initiated in 1991, stopped from 1993 to 1996 because of noncompliance and reintroduced in 1997. The duration of cumulative exposure to HU was 14 years, at a daily dose ranging from 1.0 to 1.5 g. He was admitted in May 2009 for severe macrocytic nonregenerative anemia (hemoglobin 4.7 g/dL, mean corpuscular volume 137 fL, reticulocytes 25.109/L) but white blood cell and platelet counts were normal. Blood smears showed Howell-Jolly bodies and poikilocytosis. Folic acid and vitamin B12 levels were in the normal ranges, and human parvovirus B19 serology was negative. Bone marrow aspiration showed dysmyelopoiesis in three cell lineages with no excess blasts (Fig. 1). In 2/20 metaphases, conventional cytogenetic analysis identified a hypodiploid clone with monosomy 20 and structural abnormalities involving the long arm of one chromosome 5, the short arm of one chromosome 17 and the long arm of the second chromosome 17. Fluorescence In Situ Hybridization (FISH) analysis confirmed a monoallelic deletion of the EGR1 gene (5q31) (Vysis LSI EGR1/D5S23, D5S721 dual color probe, Abbott France) and of the TP53 gene (17p13.1) (Vysis LSI p53/LSI ATM Multi-color Probe, Abbott France). HU was stopped and the patient received red blood cell transfusions. Two years later, he was readmitted for an aggressive clinical course with severe bone pains and hypercalcemia. Blood analysis showed: hemoglobin 8.1 g/dl, reticulocytes 35 109/l, leukocytes 6.5 109/l, platelets 177 109/l, and erythroblastosis at 66% (4.3 109/l). Bone marrow (BM) aspiration was difficult. Cytological examination of the BM smears revealed poor cellularity and infiltration by large cells with regular nuclei, a nucleo-cytoplasmic ratio of 0.7, beaded and multinucleated chromatin consistent with undifferentiated blast cells. A BM biopsy unveiled massive necrosis and infiltration by large tumor cells associated with severe reticulin fibrosis. Tumor cell staining was positive for EMA, CD99, CD117, Glut1, Glycophorin, and E-cadherin (Fig. 2). Lymphoid, granulocytic, monocytic, and megakaryoblastic markers were negative. Other markers tested ruled out metastasis from sarcoma, carcinoma, melanoma, or myeloma. Cytogenetic analysis displayed a highly complex BM karyotype including the 17p deletion and a probable del(5)(q13;q33) deletion. These results were consistent with the diagnosis of pure erythroid leukemia (FAB-M6 acute myeloid leukemia) arising from myelodysplastic syndrome. Despite induction chemotherapy with cytosine arabinoside and etoposide, the patient died three weeks later as a result of disease progression with central nervous system involvement. Bone marrow aspiration at the diagnosis of myelodysplastic syndrome. May-Grünwald Giemsa staining (×100) showing myelodysplastic features: (a) dyserythropoiesis, karyorrhexis, (b) dyserythropoiesis, laminated cytoplasm, (c) dysmegakaryopoiesis, hypolobulated nucleus, and (d) dysmegakaryopoiesis, binucleated megakaryocyte. Bone marrow analysis at diagnosis of acute leukemic myeloid. (a) Marrow aspiration with immature erythroblasts. (b) Bone marrow biopsy showing large abnormal erythroid precursors with hematein eosin saffron staining (×500). (c) Bone marrow biopsy specimen: strongly positive glycophorin staining (×640) in 100% of tumor cells. (d) Bone marrow biopsy specimen: positive E-Cadherin staining (×500) in more than 50% of tumor cells. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] The relationship between very long-term exposure to HU and leukemia is under debate. In the two prolonged largest series of patients with SCD treated with HU with a median follow-up of 8 years, no case of myelodysplasia or acute myeloid leukemia was reported 3, 4. However, the leukemogenic potential of HU over the very long term (i.e., after 10 to 15 years of exposure) remains unknown. The question must be addressed because HU is widely used in young children with severe SCD and the duration of treatment is indefinite. Our case shares similarities with that reported by Baz et al. 6 in terms of the duration of exposure to HU and the karyotype abnormalities involving chromosome 17p. Deletion of whole chromosome 17 or its short arm is associated with HU treatment in patients with myelodysplastic syndromes or acute leukemia secondary to myeloproliferative disorders 10, 11. As HU is an antineoplastic agent that inhibits DNA synthesis through the inhibition of ribonucleoside diphosphate reductase, it may promote an accumulation of acquired DNA mutations and eventually leukemogenic transformation. This leukemogenic risk could theoretically increase with the duration of drug exposure. The index of DNA damage in peripheral blood leukocytes from HU-treated patients with SCD was higher than in controls and was influenced by the duration and mean dose of HU treatment but also by the HbS genotype 12. The leukemogenic risk of HU was suggested in patients with myeloproliferative diseases although these patients are exposed to leukemic transformation due to the intrinsic genetic instability of the disease 13, 14. Otherwise, the risk of cancer in patients with SCD not treated with HU could be related to additional factors 15, 16. The current risk-benefit balance is in favor of using HU therapy in severe SCD 3, 5. Despite the favorable safety profile of HU, the very long-term adverse effect of HU administered to young patients and continued for decades remains to be determined. Patients who received HU for more than 10 years should be carefully followed up for hematologic abnormalities. JMM, GT, and CA drafted the manuscript; VS, VP, TL, CA, and RC performed the hematological and immunological analysis; CBN performed the cytogenetic analysis; GT, VS, SDB, OL, and FD participated in the critical analysis of the results; all authors have approved the manuscript. Cédric Aumont,1 Françoise Driss,2 Thierry Lazure,3 Véronique Picard,1 Rita Creidy,1 Stéphane De Botton,4,5 Véronique Saada,6 Olivier Lambotte,2,5 Chrystèle Bilhou-Nabera,1 Gérard Tertian,1,5 and Jean-Marie Michot2,4* 1Service D'hématologie Biologique, Assistance Publique-Hôpitaux De Paris, Hôpital Universitaire Bicêtre, Le Kremlin Bicêtre Cedex, France; 2Service De Médecine Interne Et Immunologie Clinique, Assistance Publique-Hôpitaux De Paris, Hôpital Universitaire Bicêtre, Le Kremlin Bicêtre Cedex, France; 3Service D'anatomie Pathologique, Assistance Publique-Hôpitaux De Paris, Hôpital Universitaire Bicêtre, Le Kremlin Bicêtre, Cedex, France; 4Service D'hématologie, Gustave Roussy, Villejuif Cedex, France; 5Université Paris Sud 11, Le Kremlin-Bicêtre, Cedex, France; 6Laboratoire D'hématologie, Gustave, Roussy, Villejuif Cedex, France