Congenital acute leukemia with initial indolent presentation-A case report

Cytometry Part B (Clinical Cytometry) 80B:130–133 (2011)

Brief Communication: Case Report

Congenital Acute Leukemia with Initial Indolent Presentation—A Case Report Lydia Campos,1* Nathalie Nadal,1 Pascale Flandrin-Gresta,1 Christian Vasselon,1 Carmen Aanei,1 Claire Berger,2 and Jean Louis Stephan2 1

Laboratoire d’He´matologie, Hoˆpital Nord, Centre Hospitalier Universitaire, Saint Etienne, France Service d’Oncologie Pe´diatrique, Institut de Cance´rologie de la Loire, Saint Priest en Jarez, France

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Background: Congenital acute leukemia is a rare event, presenting usually as an aggressive disease with a poor prognosis. A differential diagnosis is the transient myeloproliferative disorder observed in Down syndrome. We describe the case of an apparently healthy newborn male child presenting with normal peripheral blood (PB) counts but with a blast population on differentials. The child’s condition and the blast population remained unchanged during the first year of life. Methods: Bone marrow and PB were morphologically analyzed. Multiparametric flow cytometry was performed at the time of diagnosis and repeated at 1 year. These studies were completed by cytogenetic and molecular analyses. Results: Bone marrow contained 40% of undifferentiated blasts. Multiparametric flow cytometry showed low expression of CD38, HLA-DR, and CD33 markers. All other markers were negative. Constitutional and blast cell karyotypes were normal. Fluorescence in situ hybridization analysis showed no rearrangement. Molecular studies were negative. The blast percentage remained stable during several months. After 1 year, the PB counts showed thrombocytopenia, with an increase of blast cells exhibiting the same phenotype. Clinically, an enlarged spleen was found. The child did not respond to chemotherapy and only partially to gemtuzumab ozogamicin. A cord blood cell transplantation was finally performed. With a follow-up of 12 months, the child is doing well. Conclusions: To our knowledge, this is the first case of congenital acute leukemia with initially indolent course in a newborn without Down syndrome. This observation emphasizes the importance of a careful follow-up. VC 2010 International Clinical Cytometry Society Key terms: congenital acute leukemia; transient myeloproliferative disorder; cord blood transplantation

How to cite this article: Campos L, Nadal N, Flandrin-Gresta P, Vasselon C, Aanei C, Berger C, Stephan JL. Congenital acute leukemia with initial indolent presentation—A case report. Cytometry Part B 2011; 80B: 130–133.

Although acute leukemia is the most common malignancy in childhood, congenital acute leukemia (CAL), manifesting within the first weeks of life, is a rare disease. Its frequency is less than 1% of all pediatric leukemias. Acute leukemia is derived from an abnormal immature hematopoietic precursor cell that has the capacity to expand and, nevertheless, shows characteristics of limited differentiation. Thus, acute myeloid leukemias (AMLs) retain many of the molecular and cellular phenotypic characteristics of their normal hematopoietic counterparts. CAL is a rare event, and, even though a few cases with spontaneous remission have been described (1), the prognosis is generally very poor. The literature on

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CAL is rather limited, most publications being single case reports. Bresters et al. (1), reviewed 117 CAL cases and showed that they differ from leukemia in older children because they are more often of the myeloid lineage and have a worse prognosis. Moreover, congenital acute lymphoblastic leukemia (ALL) constitutes a clinically and *Correspondence to: Lydia Campos, Laboratoire d’He´matologie, Hoˆpital Nord, Centre Hospitalier Universitaire, 42055 Saint Etienne, France. E-mail: [email protected] Received 9 June 2010; Revision 29 September 2010; Accepted 30 September 2010 Published online 2 December 2010 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/cyto.b.20578

CONGENITAL ACUTE LEUKEMIA WITH INITIAL INDOLENT PRESENTATION

biologically distinct entity from ALL diagnosed in older children (2). Van der Linden et al. (3) recently reported on a series of 30 patients with congenital ALL uniformly treated. They concluded that congenital ALL should be treated in a curative intent. However, the poor outcome makes it appropriate to test newer approaches to achieve higher remission rates and longer disease-free survival. Extensive investigations are needed to distinguish between congenital AML and transient myeloproliferative disorder (TMD). TMD is a leukemia-like syndrome described in 10% of newborns with Down syndrome (DS). Leukocytosis and thrombocytopenia are common. TMD blasts typically express platelet-specific surface markers. It remains a poorly understood entity, and the frequency might be underestimated because it can occur in asymptomatic neonates and because blood counts are not routinely performed in newborns with DS (4). This condition resolves without treatment in most cases within 3–6 months after birth. However, 20–30% of these children subsequently develop acute megakaryoblastic leukemia usually in the first 4 years of life. The differential diagnosis with CAL can be a real challenge because TMD has been described in a few non-DS infants with clonal trisomy 21 limited to hematopoietic lineage (5). To our knowledge, we present the first case of congenital acute undifferentiated leukemia in a full-term male newborn without DS. A fortuitous peripheral blood count (PBC) revealed a white blood cell count of 25
109 L1 (normal between 7 and 26
109 L1) with 17% blasts, a platelet count of 135
109 L1 (n ¼ 150–400), and a hemoglobin level of 185 g/L (n ¼ 160–200). Physical examination showed no particularities. The bone marrow (BM) aspiration revealed 40% large blasts with high nucleo-cytoplasmic ratio, which were morphologically undifferentiated. Particularly, no features of megakaryoblastic differentiation were observed. Cytochemical stains (myeloperoxidase and esterases) were negative in blast cells. Nonblast cells were morphologically normal. Multiparametric flow cytometry was performed on erythrocyte-lysed whole BM at the time of the diagnosis (Fig. 1). Using a CD45 gating strategy the blast gate represented 22% of cells. Blast cells were CD34 and CD123 (IL3RA, membrane low affinity receptor)-positive. A minor subset (10–15%) of blasts expressed the following surface markers: HLA-DR, CD33low, CD65low, CD38low, and CD4low. Other immaturity-related antigens (CD117 and CD133) were lacking. Lineage markers such as CD2, CD3, CD5, and CD7 for T-lymphoid lineage, CD19, CD22, and CD20 for B-lymphoid lineage, CD11b, CD13, CD15, CD16, and MPO for granulocytic lineage, CD14, CD36, and CD64, for monocytic lineage, and CD61 for megakaryocytic lineage were negative. CD56 (N-CAM) was also negative. Cytogenetic analyses showed a normal male karyotype (46,XY) in all 40 metaphases. Fluorescence in situ hybridization analyses using MLL split signal and LSI ETO/AML probes showed no rearrangement at bands

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11q23, 8q22, and 21q22. The molecular analyses by real-time polymerase chain reaction to test for BCR-ABL, AML/ETO, CBFB/MYH11 fusion genes, and FLT3-ITD and NPM1 mutations were negative. At this time, the child was not treated because he had no clinical manifestations. A follow-up was instituted, and repeated blood counts and BM examinations were performed. After 4 months, the blast count decreased in peripheral blood to 5% and remained stable over the next 6 months. At 1 year of age, the child presented with splenomegaly. PBC showed thrombocytopenia (40
109 L1) and 5% blasts. The BM aspiration revealed the presence of 29% blasts. Immunophenotypic studies showed blast cells expressing the same markers as found at birth. In addition, CD41 and CD42 were assessed and were negative. Cytogenetic and molecular analyses were still normal. The patient was treated with cytarabine, mitoxantrone, and amsacrine according to the standard AML protocol, ELAM 02. Remission was not obtained after two induction courses. At day 40, BM phenotyping showed the persistence of 14% CD45dim cells and 2.5% blast cells exhibiting the phenotype described at diagnosis. A rescue treatment was started with gemtuzumab ozogamicin (chaliceamycin-conjugated anti-CD33 monoclonal antibody) and cytarabine. Cytological complete remission finally occurred, but immunophenotypic studies showed the persistence of 1.2% blasts. The child underwent allogeneic cord blood cell transplantation. With a follow-up of 12 months, the child is well and with no evidence of disease, as seen by flow cytometry analysis. The course of this disease is rather unusual. Typically, CAL presents as an aggressive disorder manifesting within the first 4 weeks of life and with a high leukemic cell load. However, a limited number of spontaneous remissions have been described (1). In our case, physical symptoms did not appear before 1 year of age, and the diagnosis would not have been done at birth if a PBC had not been performed. The possibility of TMD was, therefore, raised, but the diagnosis was ruled out because the infant presented neither constitutional trisomy 21 nor acquired trisomy 21 in the blast cells. In addition, megakaryocytic markers were negative and blasts never disappeared. This case was difficult to diagnose because immunophenotyping did not show a lineage assignment. Although two myeloid markers were weakly positive (CD33 and CD65), this case was considered myeloidnegative (score < 2 based on the system of the European Group for the Immunological Characterization of Leukemias) (6). Morphological aspect and lack of CD56 also ruled out dendritic cell leukemia. An aberrant CD13 CD33þ pattern and a variable expression of CD34 are frequently encountered in AML with minimal maturation (7). Venditti et al. (8) compared the immunophenotypic and karyotypic features of 25 cases of minimally differentiated acute myeloid (AML-M0) with those of 247 cases, including all other French-American-British subtypes. AML-M0 expressed more frequently low levels

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FIG. 1. FCM acquisition was performed with a Canto II cytometer, and the data analysis with Diva software 6.2.1. CD45-side scatter (SSC) gating is displayed. Gating is based on the expression of CD45 in combination with the SSC (left) (a), which allows a clear separation of CD45þlow cells (orange) and pathological blasts (black) from lymphocytes (green), lymphoid precursors (turquoise), monocytes (blue), and granulocytes (pink). The pathological blast gate (b–n) was drawn around the CD34þ CD4þlow cells cluster. Blast gate shows the following markers: CD34variable, HLA-DR, CD33low, CD65low, CD38low, and CD4low. HPC, hematopoietic precursor cells; Ly, lymphocytes, Mo, monocytes.

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CONGENITAL ACUTE LEUKEMIA WITH INITIAL INDOLENT PRESENTATION

of CD4. The CD2, CD5, CD10, and CD19 markers were similarly expressed in all AML types. This observation emphasizes that CAL is not always associated with aggressive presentation. Postponing treatment in the absence of clinical symptoms may give time to differentiate leukemoid reaction or TMD from CAL, or even to observe a spontaneous remission. In this setting, a careful monitoring for disease progression, including flow cytometry analysis, is mandatory. LITERATURE CITED 1. Bresters D, Reus ACW, Veerman AJP, Van Wering ER, Van Der DoesVan Den Berg A, Kaspers GJL. Congenital leukemia: The Dutch experience and review of the literature. Br J Haematol 2002;117:513– 524. 2. Sande JE, Arceci RJ, Lampkin BC. Congenital and neonatal leukaemia. Semin Perinatol 1999;23:274–285. 3. Van der Linden MH, Valsecchi MG, De Lorenzo P, Mo¨ricke A, Janka G, Leblanc TM, Felice M, Biondi A, Campbell M, Hann I, Rubnitz JE,

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