Incidence Of Acute Leukemia Research Articles

Spatial variations of childhood acute leukaemia in France, 1990–2006

Childhood acute leukaemia (AL) accounts for a third of childhood cancers. Analysing the spatial distribution of the incidence of AL and its lymphoblastic and myeloblastic subtypes may contribute to the identification of risk factors. This national registry-based study aimed to evaluate global spatial heterogeneity in the incidence rates of AL and to detect clusters in France over the period 1990-2006 on the 'living-zone' scale. Between 1990 and 2006, 7675 cases of AL were registered in the National Registry of Childhood Haematopoietic malignancies. Their spatial distribution in the 1895 'living zone' was first evaluated with two tests for global spatial heterogeneity (Potthoff-Witthinghill and Rogerson's tests) and then with the SaTScan and FleXScan methods, which aim to locate spatial and space-time clusters. Over 1990-2006, no spatial heterogeneity of AL or its subtypes was evidenced. In addition, none of the most likely clusters identified with SaTScan and FleXScan over the whole period was significant, and the systematic search for space-time clusters yielded nonsignificant results. However, when three subperiods were considered, five statistically significant nonoverlapping spatial clusters were identified. This study did not find evidence of any global spatial heterogeneity of AL incidence rates in France over the period 1990-2006. Although no significant spatial cluster was detected over the whole period, the study identified a few significant spatial clusters in specific periods. Even though the significance levels of those clusters do not strongly support the existence of local risk factors, the clusters may still reflect a slight impact of shared risk factors, including background environmental exposures, which require further investigation.

Profil étiologique des pancytopénies chez l’adulte à Marrakech (Maroc)

This retrospective study evaluated the frequency of different causes of pancytopenia in all adult patients with pancytopenia presenting to the Department of Haematology of Mohamed VI Hospital, Marrakesh from 1 January 2008 to 31 December 2010. A total of 118 cases of pancytopenia were found (average of 39 cases per year). The mean age of patients was 52 years (range 18-82 years) and 52.5% were male. The main clinical signs were pallor (100%), asthenia (100%) and fever (30.5%). Mean haemoglobin was 6.5 g/dL (range 2.9-9.2 g/dL), mean white blood cell count was 2360/mm3 (range 840-3360/mm3) and platelet count 66 000/mm3 (range 3000-123 000/mm3). Bone marrow aspiration was performed in 112 patients; megaloblastosis was found in 32.2% and marrow blasts in 23.7%. Anaemia due to vitamin B12 deficiency (32.2%), acute leukaemia (23.7%) and aplastic anaemia (15.2%) were the main causes of pancytopenia. Given the incidence of acute leukemia among our cases, patients presenting with pancytopenia require urgent diagnosis and treatment.

Childhood leukemia around French nuclear power plants—The geocap study, 2002–2007

The aim of this work is to study the risk of childhood acute leukemia (AL) around French nuclear power plants (NPPs). The nationwide Geocap case-control study included the 2,753 cases diagnosed in mainland France over 2002-2007 and 30,000 contemporaneous population controls. The last addresses were geocoded and located around the 19 NPPs. The study used distance to NPPs and a dose-based geographic zoning (DBGZ), based on the estimated dose to bone marrow related to NPP gaseous discharges. An odds ratio (OR) of 1.9 [1.0-3.3], based on 14 cases, was evidenced for children living within 5 km of NPPs compared to those living 20 km or further away, and a very similar association was observed in the concomitant incidence study (standardized incidence ratio (SIR)=1.9 [1.0-3.2]). These results were similar for all the 5-year-age groups. They persisted after stratification for several contextual characteristics of the municipalities of residence. Conversely, using the DBGZ resulted in OR and SIR close to one in all of the dose categories. There was no increase in AL incidence over 1990-2001 and over the entire 1990-2007 period. The results suggest a possible excess risk of AL in the close vicinity of French NPPs in 2002-2007. The absence of any association with the DBGZ may indicate that the association is not explained by NPP gaseous discharges. Overall, the findings call for investigation for potential risk factors related to the vicinity of NPP and collaborative analysis of multisite studies conducted in various countries.

Acute leukemia incidence and patient survival among children and adults in the United States, 2001-2007

AbstractSince 2001, the World Health Organization classification for hematopoietic and lymphoid neoplasms has provided a framework for defining acute leukemia (AL) subtypes, although few population-based studies have assessed incidence patterns and patient survival accordingly. We assessed AL incidence rates (IRs), IR ratios (IRRs), and relative survival in the United States (2001-2007) in one of the first population-based, comprehensive assessments. Most subtypes of acute myeloid leukemia (AML) and acute lymphoblastic leukemia/lymphoma (ALL/L) predominated among males, from twice higher incidence of T-cell ALL/L among males than among females (IRR = 2.20) to nearly equal IRs of acute promyelocytic leukemia (APL; IRR = 1.08). Compared with non-Hispanic whites, Hispanics had significantly higher incidence of B-cell ALL/L (IRR = 1.64) and APL (IRR = 1.28); blacks had lower IRs of nearly all AL subtypes. All ALL/L but only some AML subtypes were associated with a bimodal age pattern. Among AML subtypes, survival was highest for APL and AML with inv(16). B-cell ALL/L had more favorable survival than T-cell ALL/L among the young; the converse occurred at older ages. Limitations of cancer registry data must be acknowledged, but the distinct AL incidence and survival patterns based on the World Health Organization classification support biologic diversity that should facilitate etiologic discovery, prognostication, and treatment advances.

High incidence of acute leukemia in the proximity of some industrial facilities in El Bierzo, northwestern Spain

To estimate the incidence of acute leukemia (AL) in El Bierzo (BZ) and to carry out a cross-association analysis in order to suggest some etiological clues. We registered all new AL cases diagnosed 2000-2005. Annual standardized incidence rate (SIR) was calculated by the direct method. A cross-association analysis was performed by non-parametric methods and we checked the potential interaction between putative etiological factors by calculating Chi-square-for-trend. SIR was 5.1 cases per 100 000, surpassing the Spanish, European and world average figures and heterogeneous throughout the region. We detected a negative correlation between acute myeloblastic leukemia (AML) SIR in every municipality and both the air distance to the nearest thermoelectric power plant (TPP) (Rho = -0.409; p = 0.01) and to the point of maximum density of the high-power lines (HPL) network (Rho = -0.329; p = 0.04). Accordingly, SIR was higher in the municipalities situated < 7.5 km away from TPP (9.58 vs. 1.72; p = 0.004) or < 10 km away from HPL (3.90 vs. 3.19; p = 0.045). A positive relation between both factors was observed (Chi-square-for-trend = 9.209; p = 0.006). SIR of AL in BZ is higher than the Spanish average and that of most countries in the world. Residing near TPP or HPL confers a higher risk of AML, with synergistic effect between both factors.

Acute leukemia incidence and patient survival among children and adults in the United States, 2001-2007

Acute leukemia incidence and patient survival among children and adults in the United States, 2001-2007

Immunophenotypic characterization of acute leukemia at a public oncology reference center in Maranhão, northeastern Brazil.

The incidence of acute leukemia (AL) subtypes varies according to geographical distribution. The aim here was to determine the incidence of morphological and immunophenotypic AL subtypes in the state of Maranhão, Brazil, and to correlate the expression of aberrant phenotypes in children with acute lymphoblastic leukemia (ALL) with prognostic factors. Single prospective cohort study at a public oncology reference center in Maranhão. Seventy AL cases were diagnosed between September 2008 and January 2010. For the diagnosis, complete blood cell counts, myelograms (at diagnosis and at the end of the induction phase), cytochemical analysis and immunophenotyping were performed. Among adult patients (n = 22), the incidence of AL types was: ALL (22.7%) and acute myeloid leukemia (AML) (77.3%). The subtype AML M0 occurred most frequently (29.4%). In children (n = 48), the types were: AML (18.7%), most frequently subtype AML M4 (33.4%); biphenotypic acute leukemia (BAL) (4.2%); and ALL (77.1%), including the subtypes B-ALL (72.9%) and T-ALL (27.1%). Among the children with ALL, there were no statistically significant differences between patients with and without aberrant phenotypes, in relation to hematological parameters and treatment response. This work demonstrates that the frequencies of AML M0 cases among adults and T-ALL cases among children in Maranhão were high. This suggests that there may be differences in AML subtype incidence, as seen with ALL subtypes, in different regions of Brazil. No association was found between the expression of aberrant phenotypes and prognostic factors, in children with ALL.

Hiatus in Infant Acute Leukemia Incidence rates in Belarus: Adaptation-to-Low-Dose-Radiation Phenomenon?

Abstract 507The question of whether child acute leukemia (ChAL) incidence has changed as a result of Chernobyl is of great scientific and public interest. Our initial report (Nature, 1993) showed no increase in the incidence rates (IR) of ChAL in Belarus in the whole group of children (0–14 y.o.) 5 years (1986 – 1991) after accident. This data were confirmed in several European countries. As concerns infant’s AL (0–1 y.o.), Petridou et al. reported 2.6 times increase of AL in Greek infants, exposed in utero to Chernobyl radiation. No significant difference in IR was found among children aged 1 – 4 y.o. or older. All epidemiological data concerning separate analysis of infant (0–1 y.o.) ChL was concentrated on the first decade after Chernobyl and no any systematic data is available after 1996. Since 1979 the occurrence of leukemia has been documented accurately through the Registry of Blood diseases. The patients had to be inhabitants of Belarus and were grouped by age at diagnosis. AL diagnostic accuracy was confirmed by the international experts. Rates were standardized directly to the standard world population. We present the age-cohort-period analyses of IR trends of ChAL from 1979 to 2006 in Belarus. It comprised 1077 ChAL cases (0–4 y.o.). Number of cases and equivalent doses of whole body radiation exposure was tabulated by age at diagnosis and period of observation (seven pre-accident years, 1979–1985) and post-accident 7-year periods: 1986–1992, 1993–1999 and 2000–2006.During first 7 years after the accident (1986–1992) the IR of infant AL (0–1 y.o.) increased significantly – from 49 (IR=4.33) before Chernobyl to 67 cases (IR=6.36) in 1986–1992 (RR=1.47; p=0.04). Older age group (1–4 y.o.) did not show any increase in ChAL rates. Following 7-years period (1993–1999) revealed the statistically significant decrease of incidence of infant leukemia: from 49 (IR=4.33) before Chernobyl to 16 cases (IR=2.29) in 1993–1999 years (RR=0.53; p=0.024). Surprisingly, during the next 7 years (2000–2006) we found a further decrease of the incidence of infant leukemia with only 3 cases (IR=0.47) in 7 years. It is highly significant when compared with 49 cases (IR=4.33) before Chernobyl (p= 0.0000053, RR=0.11) and 67 cases (IR=6.36) appeared during first 7 years following Chernobyl accident (p < 0.0000001, RR=0.04). As concerns the older group (1–4 y.o.) we did not find any decrease of IR into the second (1993–1999) and third (2000–2006) 7-year periods.Actually we are working on the next time period (2007–2010) and new upgraded data will be presented.Long-term analysis of incidence of post-Chernobyl childhood acute leukemia permitted to discover the biphasic dynamics of infant's AL incidence rate. Significant increase into the first 7-year period followed by dramatic decrease between year +8 and year + 21. From radiological point of view it is relatively simpler to explain the increase into the first 7 years, because ionizing radiation is one of the few exposures for which the casual relationship with childhood leukemia has been established. Much more difficult to explain following after decrease in incidence rate of infant leukemia in Belarus. Can we speculate about the “adaptation-to-radiation” mechanisms? Over the past decades the growing body of data from cell cultures, experimental animals and humans suggests that low-dose ionizing radiation may have some beneficial (hormetic or adoptive) effect. Several epidemiological studies (India, China, Japan, USA) of a long-term low dose environmental irradiation are in favor of the hypothesis of radiation hormesis or adaptation. The carcinogenic effects of low dose radiation exposure may be restricted to children exposed in utero or in early infancy (0-12 months) during the first years after explosion. Following after dramatic decrease of IRs of infant leukemia might be explained by the developing of adaptive response to chronic low dose ionizing radiation exposure. The presented data may be one of the first clinical evidence concerning human ability of adaptation to long-term low dose radiation. Disclosures:No relevant conflicts of interest to declare.

Acute lymphoblastic leukaemia in children with Down syndrome: an updated review

Down syndrome (DS) is the most common chromosomal abnormality in children and also carries a marked increased incidence of acute leukaemia. Current therapy for acute lymphoblastic leukaemia (ALL) in children with DS offers similar treatment outcome as compared to children without DS. However, in general, there is increased morbidity associated with chemotherapy in children with DS. In recent years, a better understanding of the biology of ALL has led to the elucidation of differences in DS ALL vs non-DS ALL. Further research in these differences may provide a more targeted therapy for DS ALL, with the hopes of continuing good therapeutic outcome while decreasing the toxicities seen in these patients. This review provides an update on the current treatment outcomes and the biological differences seen in DS ALL.

Childhood acute leukemias are frequent in Mexico City: descriptive epidemiology

BackgroundWorldwide, acute leukemia is the most common type of childhood cancer. It is particularly common in the Hispanic populations residing in the United States, Costa Rica, and Mexico City. The objective of this study was to determine the incidence of acute leukemia in children who were diagnosed and treated in public hospitals in Mexico City.MethodsIncluded in this study were those children, under 15 years of age and residents of Mexico City, who were diagnosed in 2006 and 2007 with leukemia, as determined by using the International Classification of Childhood Cancer. The average annual incidence rates (AAIR), and the standardized average annual incidence rates (SAAIR) per million children were calculated. We calculated crude, age- and sex-specific incidence rates and adjusted for age by the direct method with the world population as standard. We determined if there were a correlation between the incidence of acute leukemias in the various boroughs of Mexico City and either the number of agricultural hectares, the average number of persons per household, or the municipal human development index for Mexico (used as a reference of socio-economic level).ResultsAlthough a total of 610 new cases of leukemia were registered during 2006-2007, only 228 fit the criteria for inclusion in this study. The overall SAAIR was 57.6 per million children (95% CI, 46.9-68.3); acute lymphoblastic leukemia (ALL) was the most frequent type of leukemia, constituting 85.1% of the cases (SAAIR: 49.5 per million), followed by acute myeloblastic leukemia at 12.3% (SAAIR: 6.9 per million), and chronic myeloid leukemia at 1.7% (SAAIR: 0.9 per million). The 1-4 years age group had the highest SAAIR for ALL (77.7 per million). For cases of ALL, 73.2% had precursor B-cell immunophenotype (SAAIR: 35.8 per million) and 12.4% had T-cell immunophenotype (SAAIR 6.3 per million). The peak ages for ALL were 2-6 years and 8-10 years. More than half the children (58.8%) were classified as high risk. There was a positive correlation between the average number of persons per household and the incidence of the pre-B immunophenotype (Pearson's r, 0.789; P = 0.02).ConclusionsThe frequency of ALL in Mexico City is among the highest in the world, similar to those found for Hispanics in the United States and in Costa Rica.

Mutations in ANKRD26 are responsible for a frequent form of inherited thrombocytopenia: analysis of 78 patients from 21 families

AbstractUntil recently, thrombocytopenia 2 (THC2) was considered an exceedingly rare form of autosomal dominant thrombocytopenia and only 2 families were known. However, we recently identified mutations in the 5′-untranslated region of the ANKRD26 gene in 9 THC2 families. Here we report on 12 additional pedigrees with ANKRD26 mutations, 6 of which are new. Because THC2 affected 21 of the 210 families in our database, it has to be considered one of the less rare forms of inherited thrombocytopenia. Analysis of all 21 families with ANKRD26 mutations identified to date revealed that thrombocytopenia and bleeding tendency were usually mild. Nearly all patients had no platelet macrocytosis, and this characteristic distinguishes THC2 from most other forms of inherited thrombocytopenia. In the majority of cases, platelets were deficient in glycoprotein Ia and α-granules, whereas in vitro platelet aggregation was normal. Bone marrow examination and serum thrombopoietin levels suggested that thrombocytopenia was derived from dysmegakaryopoiesis. Unexplained high values of hemoglobin and leukocytes were observed in a few cases. An unexpected finding that warrants further investigation was a high incidence of acute leukemia. Given the scarcity of distinctive characteristics, the ANKRD26-related thrombocytopenia has to be taken into consideration in the differential diagnosis of isolated thrombocytopenias.

Childhood leukemia incidence in Brazil according to different geographical regions

Resource-rich countries tend to have a higher incidence of childhood acute lymphoblastic leukemia (ALL), whereas lower rates are seen in more deprived countries. This study describes the incidence of childhood acute leukemia in Brazil, an upper middle-income country, based on data from 16 population-based cancer registries (PBCRs). Data were examined from 16 PBCRs in Brazilian cities located in five geographical regions during the period from 1997 to 2004. Incidence rates were analyzed according to gender, age, and type of leukemia. The Wilcoxon test was performed to evaluate for gender-age based difference between by leukemia type. The median age-adjusted incidence rate (AAIR) of leukemia in children aged 0-14 years old was 53.3 per million. A different AAIR was found regarding ALL and myeloproliferative disorders (MPD) that ranged from 24.8 to 76.84 per 1,000,000 children. Manaus, although located in a poor area of Brazil, exhibited the highest AAIR (56.6 per million) of ALL. Goiania had the highest AAIR (24.5 per million) of MPD. The median age-specific incidence rate (ASIR) for the 16 Brazilian PBCRs demonstrated a marked peak in incidence of ALL at age 3 years old, in both genders. This population-based study of childhood leukemia demonstrates that substantial regional differences exist regarding the incidence of acute leukemia in Brazil, which warrants further ecological study.

Myelodisplastic Syndrome with Trysomy 21 IN A Patient with Constitutional Submicroscopic 21Q22 Deletion.

Abstract 4831 IntroductionPrevious studies showed that chromosomal and genomic aberrations leading to activation of oncogenes or haploisufficiency of tumor suppressor genes are well-known pathogenic mechanisms in cancer. Additional copies of chromosme 21 are frequently found in Myelodisplastic Syndrome (MDS) and in Acute Myeloid Leukemia (AML); the presence of these chromosomal abnormalities and the high incidence of acute leukemias in subjects with constitutional trisomy 21, suggest that genes on chromosome 21, including RUNX1/AML1, play a particular role in leukemogenesis and hematopoiesis. We describe a patient with syndromic trombocytopenia ( average platelet count= 70000/mm3), psychomothor delay, microcephaly and low stature, that developed a progressive anemia and became transfusion-dependent at seventeen years of age. Materials and methodsCytogenetic analysis was performed on bone marrow cells and on peripheral blood lymphocytes, with standard techniques and evaluated with Giemsa-trypsin-Giemsa banding according to International System for Human Cytogenetic Nomenclature (ISCN 2005). Fluorescent In Situ Hybridization (FISH) experiments was performed on bone marrow samples with LSI AML1/ETO Dual Color, Dual Fusion Translocation and, at the same time, the High-resolution oligo array-CGH (Agilent Human Genome CGH Microarray 44B) was performed on the DNA of the patient. ResultsThe bone marrow cells showed marked dysplastic morphology and the following abnormal karyotype: 46,XX[14]/47,XX,+21[6]; the peripheral blood karyotype was normal. The High-resolution oligo array-CGH demonstrated a constitutional de novo microdeletion of one chromosome 21. The interstitial deletion was found to be approximately 4,4Mb (Megabases), extending from 32,29 Mb to 36,51 Mb on band 21q22.11-12, involving MRAP, IFNAR2, IFNGRR2, KCNE2, KCNE1 and RUNX1 genes. The FISH performed on bone marrow cells, revealed two orange signals representing normal copies of ETO and one green signal for AML1 in 60% interphase cells and two orange signals and two green signals in the remaining 40% cells. The first pattern of signals, for AML1, is related to cells with karyotype 46,XX, while the second pattern of signals is related to cells with karyotype 47,XX,+21. These results indicate that in the myelodisplastic clone the third chromosome 21 are not deleted on band 21q22. ConclusionThree cases were recently published of syndromic thrombocytopenia with 21q22 constitutional deletion, including RUNX1, and variable degree of dysmorphic features and mental delay. One of the three patients developed LMA at the age of six years. Our results further support the fundamental role, in the pathogenetic mechanism of syndromic trombocytopenia and MDS/AML, of the numerical abnormalities of chromosome 21 associated with submicroscopic rearrangement of RUNX1 and other dosage-sensitive unknown genes on chromosome 21. DisclosuresNo relevant conflicts of interest to declare.

Evaluation of childhood acute leukemia incidence and underreporting in Brazil by capture–recapture methodology

Background: Population-based cancer registries (PBCR) are important in cancer epidemiology as they provide the basis for monitoring cancer incidence. Childhood acute lymphoblastic leukemia (ALL) is said to have lower incidence in developing countries, which has implications for its pathogenesis, but there are few studies concerning the completeness of cancer registries in developing countries. This study analyzes the number of cases and incidence of childhood acute lymphoblastic leukemia in three different cities in Brazil and estimates underreporting cases and possible PBCR failures. Methods: We evaluated the completeness of PBCR and the incidence rates of childhood ALL from three different Brazilian cities using the two-source capture–recapture method. The sources used were a population-based registry and databases from a diagnosis reference laboratory in 2001 and the Chapman's formula was used to calculate the estimates. Results: The estimated incidence was 5.76, 6.32 and 5.48 per 100,000 inhabitants for Salvador, Recife and Belo Horizonte, respectively. The estimated completeness of childhood ALL in PBCRs was 15.5%, 35.4% and 29.2%, respectively, for Salvador, Recife and Belo Horizonte. Conclusions: There was a high estimated underreporting of childhood leukemia cases in some Brazilian cities. The relationship between information systems and the capture–recapture method application improved epidemiological estimates. Childhood acute lymphoblastic leukemia incidence rates are similar to those of developed countries.

FP39-WE-05 High incidence of acute leukaemia in multiple sclerosis patients treated with mitoxantrone: a retrospective multicentre Italian study

FP39-WE-05 High incidence of acute leukaemia in multiple sclerosis patients treated with mitoxantrone: a retrospective multicentre Italian study

Geographical variations in the incidence of childhood acute leukaemia in France over the period 1990–2004

Spatial variations in childhood acute leukaemia (AL) incidence rates were investigated by département, in mainland France, over the period 1990-2004. This is the first spatial study of this incidence to cover a 15-year period. French National Registry of Childhood Haematological Malignancies data and population counts by type of leukaemia (AL, acute lymphoblastic leukaemia, acute myeloblastic leukaemia), time period (1990-2004, 1990-1994, 1995-1999 and 2000-2004), sex, and age group (0-14, 0-4, 5-9 and 10-14 years of age) were considered. The overall homogeneity of the relative risks of leukaemia was tested, as well as comparison to 1 of each relative risk by the exact Poisson test. To give a more stable estimate of the underlying relative risk pattern than that provided by the local standardized incidence ratios (SIRs), Bayesian hierarchical models using four different spatial priors have been produced: the parametric BYM and CAR models, and two semiparametric models. Very slight overall heterogeneity was observed on the whole AL data set (SIR overdispersion 18.6%, P=0.10). Irrespective of the model, the ranges of the smoothed SIRs exhibited considerable shrinkage relative to the ranges of the local SIRs. The associated maps were slightly heterogeneous; the smoothed SIRs of overall acute lymphoblastic leukaemia of the south-west départements were slightly higher than those of the north-east. The results, however, did not remain stable when investigated by leukaemia type, time period, sex or age group. No spatial heterogeneity of childhood AL incidence on the département scale was observed but that does not exclude spatial heterogeneity on other scales.

In vivo expansion of cells expressing acquired CSF3R mutations in patients with severe congenital neutropenia

AbstractSevere congenital neutropenia (CN) is a rare bone marrow failure syndrome with a high incidence of acute leukemia. In previous studies, we could show that point mutations in the gene for the granulocyte colony-stimulating factor (G-CSF) receptor CSF3R are a highly predictive marker for leukemic development in CN patients. To find out at which stage of hematopoietic development these mutations emerge and how they are propagated during hematopoietic differentiation, we analyzed single cells of different hematopoietic subpopulations from CN patients with CSF3R mutations. We found that CSF3R mutations are not restricted to the myeloid compartment but are also detectable in lymphoid cells, although at a much lower percentage. From our observations, we conclude that CSF3R mutations are acquired in multipotent hematopoietic progenitor cells in CN patients and that they are clonally expanded in myeloid cells expressing the G-CSF receptor due to the growth advantage mediated by the CSF3R mutation.

Transformation of aplastic anemia to acute myeloid leukemia in a Chinese adult after 16 years

Aplastic anemia (AA) is a potentially life-threatening failure of hemopoiesis defined as pancytopenia and an empty bone marrow. It is a more common disease in Asia than in the west with the annual incidence in china of 7.4 per million in contrasts to 2.34 per million in Europe and Israel (1 2). Clonal hematopoiesis has been related to AA, including paroxysmal nocturnal hemoglobinuria (PNH), myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) (3). The true incidence of acute leukemia after AA in China is not known but appears to be rare. Here, we report a case of aplastic anemia evolving into acute myeloid leukemia (AML) after 16 years.

Enhancment of SCA1 Positive Hematopoietic Progenitors in Polycythemic Mice Inhibits Leukemogenesis

PV is a myeloproliferative disease, displaying a pronounced increase in the number of erythroid cells. Despite this increase, PV patients exhibit a lower incidence of acute leukemia and in particular erythroleukemia compared to its related disorder CML. In this study we induced erythroleukemia in a mouse model of familiar polycythemia, carrying a truncated form of the human erythropoietin-receptor (Epo-R). Previous studies have shown that these mice develop a disease similar to patients with familiar polycythemia, from whom this gain-of-function receptor was isolated and introduced as transgene. We show that the progression of erythroleukemia induced by Friend virus is significantly delayed in this genetic mouse model of polycythemia. These mice exhibit a massive enrichment of Sca1+/cKit− progenitors and mature immune cells compared to normal mice. Co-transplantation experiments revealed that Sca1+/cKit− progenitors inhibit the robust tumorigenic potential of Sca1−/cKit+ erythroleukemic cells.In order to determine the mechanism of erythroleukemia inhibition, we established cell lines from Sca1+/cKit− cell populations and demonstrated a similar anti-leukemic inhibition in vivo. These cells also express cell surface markers for early B-cells (B220) and macrophages (Mac1), and are able to undergo differentiation into macrophages and dendritic cells following treatment with GM-CSF and IL4. We have shown that these cells also secrete factors that inhibit proliferation of erythroleukemic cells in culture, such as Nitric Oxide (NO). Accordingly, an NO inhibitor can suppress the inhibitory effect of the Sca-1+/cKit−/B220+/Mac1+ cells. To further demonstrate the importance of these leukemic inhibitory cells, we induced a polycythemia in normal mice through administration of Epo. Epo administration delayed the development of Friend virus-induced erythroleukemia and significantly increased the number of leukemic inhibitory Sca1+ cells. Our study also demonstrates a significant increase in the number of leukemic inhibitory cells with anti-proliferative effects in response to Epo and granulocyte macrophage-colony stimulating factor (GM-CSF) stimulation. We therefore propose that administration of Epo and GM-CSF in combination with NO agonistic drugs, as well as the identification of novel drugs that can induce the inhibitory Sca-1+/cKit−/B220+/Mac1+ cells, may lead to improved therapies for the treatment of myelodysplastic syndrome. Together, our results identify Sca-1+/cKit−/B220+/Mac1+ cells as potent cellular inhibitors of leukemia and unravel a potentially novel therapeutic approach.

Essential Thrombocythemia in Young Individuals: Frequency and Risk Factors for Vascular Events and Evolution to Myelofibrosis in 126 Patients.

Vascular events and evolution to either myelofibrosis (MF) and acute leukemia (AL) are the main causes of morbidity and mortality in individuals with essential thrombocythemia (ET). However, the frequency of these complications in young ET patients is not well known. The objective of the present study was to assess the frequency of vascular events and the incidence of MF and AL in young patients with ET and to identify the factors associated with the development of such complications. In 126 subjects diagnosed with ET at a median age of 31 years (range: 5–40), overall survival and probability of survival free of either thrombosis, bleeding, MF, AL, and polycythemia vera (PV) were analyzed by the Kaplan-Meier method, followed by the log-rank test. With a median follow-up of eleven years (range: 4–25) three patients have died, being the probability of survival 98% at ten years. A total of 31 thrombotic events were registered in 25 patients; thrombosis-free survival (TFS) was 84% at ten years. Tobacco use was the only factor associated with an increased thrombotic risk, since TFS at 10 years was 72% in smokers versus 90% in non-smokers (p=0.03). Severe hemorrhagic complications were observed in 11 patients, and the estimated probability of bleeding-free survival was 92% at ten years. Evolution to MF was seen in 6 patients, four of whom had never received treatment for ET. MF-free survival was 97% at 10 years, with the risk being higher in patients showing an increased reticulin network in the bone marrow biopsy performed at diagnosis of ET (p=0.005). Transformation to AL was registered in one patient. JAK2 was mutated in 33 out of the 87 assessable patients (38%) and the mutation was associated with higher Hb values at diagnosis (p = 0.001). ET evolved into PV in five patients, being the probability of evolution into PV of 15% in JAK2 V617F positive patients versus 0% in JAK2 V617F negative patients (p=0.01). In conclusion, severe vascular complications are not infrequent in young subjects with ET, whereas transformation to MF or AL is a rare event.