Marie-Pierre Pages

Myelodysplasia and leukemia of Fanconi anemia are associated with a specific pattern of genomic abnormalities that includes cryptic RUNX1/AML1 lesions

Fanconi anemia (FA) is a genetic condition associated with bone marrow (BM) failure, myelodysplasia (MDS), and acute myeloid leukemia (AML). We studied 57 FA patients with hypoplastic or aplastic anemia (n = 20), MDS (n = 18), AML (n = 11), or no BM abnormality (n = 8). BM samples were analyzed by karyotype, high-density DNA arrays with respect to paired fibroblasts, and by selected oncogene sequencing. A specific pattern of chromosomal abnormalities was found in MDS/AML, which included 1q+ (44.8%), 3q+ (41.4%), -7/7q (17.2%), and 11q- (13.8%). Moreover, cryptic RUNX1/AML1 lesions (translocations, deletions, or mutations) were observed for the first time in FA (20.7%). Rare mutations of NRAS, FLT3-ITD, MLL-PTD, ERG amplification, and ZFP36L2-PRDM16 translocation, but no TP53, TET2, CBL, NPM1, and CEBPα mutations were found. Frequent homozygosity regions were related not to somatic copy-neutral loss of heterozygosity but to consanguinity, suggesting that homologous recombination is not a common progression mechanism in FA. Importantly, the RUNX1 and other chromosomal/genomic lesions were found at the MDS/AML stages, except for 1q+, which was found at all stages. These data have implications for staging and therapeutic managing in FA patients, and also to analyze the mechanisms of clonal evolution and oncogenesis in a background of genomic instability and BM failure.

t(5;14)/HOX11L2-positive T-cell acute lymphoblastic leukemia. A collaborative study of the Groupe Francais de Cytogenetique Hematologique (GFCH)

To accurately estimate the incidence of HOX11L2 expression, and determine the associated cytogenetic features, in T-cell acute lymphoblastic leukemia (T-ALL), the Groupe Français de Cytogénétique Hématologique (GFCH) carried out a retrospective study of both childhood and adult patients. In total, 364 patients were included (211 children ⩽15 years and 153 adults), and 67 (18.5%) [47 children (22.4%) and 20 adults (13.1%)] were shown to either harbor the t(5;14)q35;q32) translocation or express the HOX11L2 gene or both. Most of the common hematological parameters did not show significant differences within positive and negative populations, whereas the incidence of CD1a+/CD10+ and cytoplasmic CD3+ patients was significantly higher in positive than in negative children. Out of the 63 positive patients investigated by conventional cytogenetics, 32 exhibited normal karyotype, whereas the others 31 showed clonal chromosome abnormalities, which did not include classical T-ALL specific translocations. Involvement of the RANBP17/HOX11L2 locus was ascertained by fluorescence in situ hybridization in six variant or alternative (three-way translocation or cytogenetic partner other than 14q32) translocations out of the 223 patients. Our results also show that HOX11L2 expression essentially occurs as a result of a 5q35 rearrangement, but is not associated with another identified T-ALL specific recurrent genetic abnormality, such as SIL-TAL fusion or HOX11 expression.

Leukaemic presentation of small cell variant anaplastic large cell lymphoma: report of four cases

We report four cases of a rare subtype of CD30‐positive anaplastic large cell lymphoma (ALCL) with a predominant small cell component (small cell variant of ALCL) presenting with a leukaemic feature. Lymph node biopsy showed malignant cells of varying size with a predominant population of small to medium‐sized malignant cells associated with large anaplastic cells strongly positive for CD30 and epithelial membrane antigen (EMA). Both large and small cells were reactive with antibody ALK1, which recognizes the chimaeric NPM‐ALK protein associated with the t(2;5)(p23;q35). All patients presented with hyperleucocytosis with atypical small lymphocytes. Bone marrow involvement was detected on both aspirate and bone marrow trephine where scattered malignant cells were only demonstrated by immunostaining for CD30 and ALK protein. Atypical cells in peripheral blood, lymph node and skin biopsies showed a T or null cell phenotype. Cytogenetic analysis of blood, bone marrow and/or lymph node revealed the t(2;5)(p23;q35) characteristic of ALCL. The patients responded to chemotherapy but showed early relapse without abnormal cells in peripheral blood.

Acute Megakaryoblastic Leukaemia: A National Clinical and Biological Study of 53 Adult and Childhood Cases by the Groupe Français d'Hématologie Cellulaire (GFHC)

Since the WHO classification of haematological malignancies recommended the description of global entities, we performed a national M7-AML study to correlate morphological, immunological and cytogenetic features, and to find new clinically relevant M7 entities. This study is based on accurate morphological and immunological study to select pure megakaryoblastic proliferations and to eliminate megakaryocytic participation in haemopathies. We collected 53 cases: 23 adults and 30 children. We confirm the wide heterogeneity of adult M7. In adults, the cytogenetic abnormalities are frequently those of secondary leukaemia while a few patients have a previous history and morphological features of dyshaematopoiesis; their outcome is very poor. Among children, besides the well-known Down syndrome M7, we in particular, studied ten t(1;22) M7 and one OTT-MAL transcript positive case with normal karyotype presenting specific features. We were already aware of their younger age, female and tumoral presentation, but we also found a lower percentage of bone marrow blasts, sometimes without any megakaryoblastic bone marrow involvement, but always, with a dysmegakaryocytopoiesis associated with micromegakaryocytes. They are generally good responders to intensive AML chemotherapy with very long disease-free survivals (DFS). Accordingly, OTT-MAL transcript study, in infant M7 with normal karyotype, is recommended and we feel that this entity should be added to the WHO AML classification.

Wide diversity of PAX5 alterations in B-ALL: a Groupe Francophone de Cytogénétique Hématologique study

PAX5 is the main target of somatic mutations in acute B lymphoblastic leukemia (B-ALL). We analyzed 153 adult and child B-ALL harboring karyotypic abnormalities at chromosome 9p, to determine the frequency and the nature of PAX5 alterations. We found PAX5 internal rearrangements in 21% of the cases. To isolate fusion partners, we used classic and innovative techniques (rolling circle amplification-rapid amplification of cDNA ends) and single nucleotide polymorphism-comparative genomic hybridization arrays. Recurrent and novel fusion partners were identified, including NCoR1, DACH2, GOLGA6, and TAOK1 genes showing the high variability of the partners. We noted that half the fusion genes can give rise to truncated PAX5 proteins. Furthermore, malignant cells carrying PAX5 fusion genes displayed a simple karyotype. These data strongly suggest that PAX5 fusion genes are early players in leukemogenesis. In addition, PAX5 deletion was observed in 60% of B-ALL with 9p alterations. Contrary to cases with PAX5 fusions, deletions were associated with complex karyotypes and common recurrent translocations. This supports the hypothesis of the secondary nature of the deletion. Our data shed more light on the high variability of PAX5 alterations in B-ALL. Therefore, it is probable that gene fusions occur early, whereas deletions should be regarded as a late/secondary event.

Results of 58872 and 58921 trials in acute myeloblastic leukemia and relative value of chemotherapy vs allogeneic bone marrow transplantation in first complete remission: the EORTC Children Leukemia Group report.

The first EORTC (European Organization of Research and Treatment of Cancer) acute myeloblastic leukemia (AML) pilot study (58872) was conducted between January 1988 and December 1991. Out of 108 patients, 78% achieved complete remission (CR), and event-free survival (EFS) and survival rates (s.e., %) at 7 years were 40 (5) and 51% (6%), respectively. It indicated that mitoxantrone could be substituted for conventional anthracyclines in the treatment of childhood AML without inducing cardiotoxicity. The aim of the next EORTC 58921 trial was to compare the efficacy and toxicity of idarubicin vs mitoxantrone in initial chemotherapy courses, further therapy consisting of allogeneic bone marrow transplantation (alloBMT) in patients with an HLA-compatible sibling donor or chemotherapy in patients without a donor. Out of 177 patients, recruited between October 1992 and December 2002, 81% reached CR. Overall 7-year EFS and survival rates were 49 (4) and 62% (4%), respectively. Out of 145 patients who received the first intensification, 39 had a sibling donor. In patients with or without a donor, the 7-year disease-free survival (DFS) rate was 63 (8) and 57% (5%) and the 7-year survival rate was 78 (7) and 65% (5%), respectively. Patients with favorable, intermediate and unfavorable cytogenetic features had a 5-year EFS rate of 57, 45 and 45% and a 5-year survival rate of 89, 67 and 53%, respectively.

Low incidence of sepsis due to viridans streptococci in a ten-year retrospective study of pediatric acute myeloid leukemia

Infections remain an important cause of morbidity and mortality in children with acute myeloid leukemia (AML), and particularly viridans group streptococci (VGS) sepsis. The present study, conducted between 1993 and 2003 in children with AML, sought to assess the frequency and characteristics of infectious complications (ICs), the incidence of VGS sepsis, the interest of preventive decontamination, and a possible cytarabine dose‐effect on the occurrence of ICs.

Human herpesvirus 6 infection and transient acquired myelodysplasia in children

To demonstrate that primary human herpesvirus 6 (HHV‐6) infection in childhood can cause hematopoietic dysplasia that mimics a myelodysplastic syndrome (MDS) in severe cases.

Childhood near-tetraploid acute lymphoblastic leukemia: an EGIL study on 36 cases

Objectives:  Patients with near‐tetraploid (karyotype: 81 – 103 chromosomes) acute lymphoblastic leukemia (NT‐ALL) constitute about 1% of childhood ALL and data reported on them are limited and controversial. The aim of the study was to enlarge the knowledge on these rarely occurring ALL.

Thrombocytosis and toxocariasis: report of two pediatric cases.

We report two cases of visceral larva migrans (VLM) syndrome by Toxocara in children. The biological presentation was unusual and characterized by persistent secondary thrombocytosis (>1,000 × 109/L) mimicking an essential thrombocythemia and variable hypereosinophilia syndrome. Both children had non‐specific symptoms including abdominal pain, skin rash, and fever. The diagnosis was confirmed by serology. The children were treated with either thiabendazole or albendazole, resulting in normalization of eosinophil and platelet counts.