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PubMed2003

AML with 11q23/MLL abnormalities as defined by the WHO classification: incidence, partner chromosomes, FAB subtype, age distribution, and prognostic impact in an unselected series of 1897 cytogenetically analyzed AML cases.

Acute myeloid leukemia (AML) cases with 11q23 abnormalities involving the MLL gene comprise one category of recurring genetic abnormalities in the WHO classification. In an unselected series of 1897 AML cases, 54 patients with an 11q23/MLL rearrangement were identified, resulting in an incidence of 2.8%. The incidence of AML with MLL rearrangement was significantly higher in therapy-related AML (t-AML) than in de novo AML (9.4% vs 2.6%, P <.0001). The frequency of MLL rearrangements was significantly higher in patients younger than 60 years (5.3% vs 0.8%, P <.0001). While the incidence of MLL rearrangements in AML M4, M5a, and M5b was 4.7%, 33.3%, and 15.9%, respectively, it was found in only 0.9% of all other French-American-British (FAB) subtypes (P <.0001). Compared with AML with intermediate karyotype, AML with 11q23/MLL rearrangement had a worse outcome, which was rather comparable with AML with unfavorable karyotype. Compared with t-AML, the median overall survival (OS) of de novo AML with MLL rearrangement was significantly better (2.5 vs 10 months, P =.0143). No significant differences in median OS were observed between cases with t(9;11) compared with all other MLL rearrangements (10.0 vs 8.9 months, P =.36). In conclusion, the category AML with 11q23/MLL abnormalities accounts for 2.8% of unselected AML, is closely associated with monocytic differentiation, and has a dismal prognosis. (

Adolescent↗

PubMed1993

Characterization of acute myeloid leukemia (AML) coexpressing lymphoid markers: different biologic features between T-cell antigen positive and B-cell antigen positive AML.

The clinical and biologic characteristics of acute myeloid leukemia (AML) with coexpression of lymphoid-associated antigens (Lym+ AML) were studied from 39 cases who represented 24% of 161 newly diagnosed de novo AML. Twenty-seven cases (16.8%) were positive for the expression of T-cell markers (T+ AML) and 12 (7.5%) for B-cell markers (B+ AML). Chromosomal abnormalities t(9;22)(q34;q11) and t/del(11)(q23), which were considered to be associated with acute leukemia coexpressing markers of more than one cell lineage, were detected in five and in four patients, respectively. There was no prognostic significance of B-cell or T-cell antigen expression in AML. Of 12 T+ AML cases in which cells were available for gene analysis, all showed germline configuration of immunoglobulin heavy chain and T-cell receptor beta chain genes, while seven of nine B+ AML showed rearrangements of either or both of the genes. Double labeling of the cells with myeloperoxidase and lymphoid markers demonstrated that individual blasts in all the five T+ AML tested were simultaneously expressing myeloperoxidase activity and CD7; however, most blasts in the three B+ AML studied expressed either myeloperoxidase activity or CD10, but not both. In eight of the nine T+ AML tested, the T-cell antigen-positive leukemic blasts were significantly decreased to less than 10%, after in vitro culture with the differentiation-inducing agent phorbol ester. B-cell markers remained positive (> or = 20%) on the cells in the two B+ AML who had the same study. These findings suggested that T+ AML and B+ AML might have different biologic features. Further studies on more patients are needed to clarify this point.

Acute Disease↗

PubMed1995

Morphological comparison of dysplastic changes between de novo acute myeloid leukemia (AML) with trilineage myelodysplasia and AML developed from de novo myelodysplastic syndromes.

To elucidate the clinical and morphological differences between de novo acute myeloid leukemia (AML) with trilineage myelodysplasia (AML/TMDS) and AML developed from de novo myelodysplastic syndrome (MDS), we analyzed 12 and 13 cases, respectively. The median age of AML/TMDS patients was lower, but not significantly so, than the median age of patients with AML from MDS (45 vs 55 years). Platelet counts and the percentage of peripheral blasts were significantly higher in the patients with AML/TMDS than in the patients with AML from MDS (p < 0.05 and p < 0.01, respectively). Four patients with AML from MDS could not be classified into FAB subtypes. Eight patients (67%) with AML/TMDS achieved complete remission (CR). Nine with AML from MDS were treated with less intensive regimens; none of these patients achieved CR. In the comparison of dysplastic changes in both groups, the rate of pseudo-Pelger anomaly was significantly higher in the patients with AML from MDS (p < 0.001), and micromegakaryocytes and multinuclear erythroblasts were also more frequent in the patients with AML from MDS than in those with AML/TMDS (p < 0.05). The overall survival curves showed that the 12 patients with TMDS had a significantly better survival than the 13 patients with AML from MDS (p < 0.01). Our findings suggest that AML/TMDS is a subtype of de novo AML and is different from AML from MDS. Further study is required to determine the biological differences between AML with TMDS and AML transformed from MDS.

Adolescent↗

PubMed1997

Increased circulating colony-stimulating factor-1 (CSF-1) in SJL/J mice with radiation-induced acute myeloid leukemia (AML) is associated with autocrine regulation of AML cells by CSF-1.

The SJL/J mouse strain has a high spontaneous incidence of a B-cell neoplasm, reticulum cell neoplasm type B (RCN B). In addition, following irradiation, 10% to 30% of these mice develop acute myelomonocytic leukemia (radiation-induced acute myeloid leukemia [RI-AML]), an incidence that can be increased to 50% by treatment of the mice with corticosteroids after irradiation. The role played by the mononuclear phagocyte growth factor, colony-stimulating factor-1 (CSF-1), in the development of RI-AML in SJL/J mice was investigated. Mice dying of RI-AML, but not those dying of RCN B or without disease, possessed elevated concentrations of circulating CSF-1. In addition, in mice developing RI-AML with a more prolonged latency, circulating CSF-1 concentrations were increased before overt expression of RI-AML. First-passage tumors from 14 different RI-AMLs all contained high concentrations of CSF-1, and six of six different first- or second-passage tumors expressed the CSF-1 receptor (CSF-1 R). Furthermore, in vitro colony formation by first- or second-passage tumor cells from 20 of 20 different RI-AMLs was blocked by neutralizing anti-CSF-1 antibody, and four of four of these tumors were inhibited by anti-CSF-1R antibody. The results of these antibody neutralization studies, coupled with the observation of elevated circulating CSF-1 in mice developing RI-AML, show an autocrine role for CSF-1 in RI-AML development in SJL/J mice. Southern blot analysis of tumor DNA from six of six of these tumors failed to reveal any rearrangements in the genes for CSF-1 or the CSF-1R. Studies in humans have shown that patients with AML possess elevated levels of circulating CSF-1 and that AML cells can express CSF-1 and the CSF-1R. Thus, RI-AML in the SJL/J mouse appears to be a useful model for human AML.

Acute Disease↗

PubMed2000

New strategies in the treatment of acute myelogenous leukemia: mobilization and transplantation of autologous peripheral blood stem cells in adult patients.

During the last decade high-dose Ara-C (HIDAC; single doses of 3 g/m(2)) and autologous stem cell transplantation have been increasingly used as postremission therapy in adult acute myelogenous leukemia (AML). Controlled clinical trials have demonstrated a long-term disease-free survival of 40%-50% for patients treated with at least two courses of HIDAC. Other studies have demonstrated that postremission autologous bone marrow transplantation results in a disease-free survival equal to or better than conventional chemotherapy. However, autotransplantation with mobilized peripheral blood stem cells (PBSC) would now be preferred instead of autologous bone marrow, due to the shorter hematopoietic reconstitution period. The results reviewed in the present article suggest that HIDAC and autologous PBSC transplantation can be combined in the postremission treatment of adult AML, and this combination therapy may also reduce minimal residual disease and the risk of posttransplant relapse. From the available studies it cannot be concluded whether graft purging further reduces the relapse risk. However, the possible advantage of combination therapy with repeated courses of HIDAC and autologous PBSC transplantation needs to be demonstrated in prospective clinical trials before it can be recommended as a part of the routine treatment in AML.

Adult↗

PubMed2003

Characteristics of t(8;21) acute myeloid leukemia (AML) with additional chromosomal abnormality: concomitant trisomy 4 may constitute a distinctive subtype of t(8;21) AML.

t(8;21)(q22;q22) is the most frequently observed karyotypic abnormality associated with acute myeloid leukemia (AML), especially in FAB M2. Clinically, this type of AML often shows eosinophilia and has a high complete remission rate with conventional chemotherapy. t(8;21) AML is also frequently associated with additional karyotypic aberrations, such as a loss of the sex chromosome; however, it is unclear whether these aberrations change the biological and clinical characteristics of t(8;21) AML. To investigate this issue, 94 patients with t(8;21) AML were categorized according to their additional karyotypic aberrations, which were detected in more than three cases, and then morphologic features, phenotypes, expression of cytokine receptors, and clinical features were compared to t(8;21) AML without other additional aberrant karyotypes. t(8;21) AML with loss of the sex chromosome and abnormality of chromosome 9 were found in 27 cases (29.3%) and 10 cases (10.6%), respectively; however, no differences were observed from the t(8;21) AML without other additional karyotypes in terms of morphological and phenotypic features. There was also no significant difference in the clinical outcome among these three groups. On the other hand, trisomy 4 was found in three cases (3.2%) and these cells showed low expressions of CD19 (P=0.06) and IL-7 receptor (P=0.05), and high expressions of CD33 (P=0.13), CD18 (P=0.03), and CD56 (P=0.03) when compared to t(8;21) AML without additional karyotypes. Moreover, all three t(8;21) AML cases with trisomy 4 did not show eosinophilia in their bone marrow and died within 2.4 years. These observations suggest that additional karyotypic aberration, t(8;21) with trisomy 4 is rare, but it may constitute a distinctive subtype of t(8;21) AML.

Adolescent↗

PubMed1988

Phenotyping of acute myelocytic leukemia (AML) progenitors: an approach for tracing minimal numbers of AML cells among normal bone marrow.

Previous studies have shown that the phenotypes of progenitors of human AML (AML-CFU) are variable, reflecting arrests at different stages of maturation. We were interested to seek discrepancies between the surface properties of AML precursors and normal bone marrow colony formers in order to detect minimal numbers of AML cells among normal bone marrow cells in remission bone marrow. Therefore, we selected two surface markers, the MoAb CD34, reactive with blast cells, and Vim-2, a surface marker reactive with mature myeloid cells, and determined the antigen density of these markers (relative fluorescence intensity using fluorescence-activated cell sorting) for normal marrow and AML progenitors. While these markers defined an identical phenotype (CD34++/Vim-2-/+) for a broad spectrum of normal progenitors, i.e., CFU-GEMM, BFU-e, day 15 CFU-GM, and day 7 CFU-GM, referred to as the "normal" progenitor phenotype, AML progenitors frequently exhibited different phenotypes. In 12 of 20 cases the phenotypes of the majority of AML progenitors were discrepant from the normal surface profile, i.e., according to one marker in 8 cases (CD34-/+/Vim-2-/+ or CD34++/Vim-2++) and two markers in 4 cases (CD34-/+/Vim-2++). Since these data indicate that AML and normal progenitors were frequently distinguishable, we then determined the potential utility of these phenotypic dissimilarities for detection of minimal disease. Artificial mixtures of normal bone marrow and minimal numbers (0.1-1%) of AML cells were prepared. Based upon the phenotypic discrepancies, AML metaphases were successfully demonstrated in these mixtures following cell sorting and culture. Thus, it appears that minimal numbers of AML mitoses can be identified with an approximate 10(-2) to 10(-3) sensitivity by taking advantage of differential coexpression of surface antigens.

Antibodies, Monoclonal↗

PubMed1993

Comparison between immunogenotypic findings in de novo AML and AML post MDS.

We compared immunogenotypic findings in 73 patients with de novo acute myeloid leukemia (AML) and 30 patients with AML developed in myelodysplastic syndrome (AML post MDS) to determine the biological difference between these hematopoietic neoplasias. Lymphoid-associated antigens were detected in 13 patients with de novo AML, four of whom exhibited rearrangement of the immunoglobulin heavy-chain (IgH) gene. T-cell receptor (TCR) gene rearrangements were detected in 10 patients with de novo AML who did not have lymphoid-associated antigens, none of whom carried rearranged IgH. This group included two AML patients with trilineage dysplasia. Neither lymphoid markers nor IgH rearrangement was detected in any of the 30 patients with AML post-MDS; TCR rearrangements were detected in eight out of 30 patients, TCR-beta rearrangements in six out of 30, and TCR-delta rearrangements in five out of 30. The TCR rearrangement without rearranged IgH in some AML post MDS patients might not be due to a common recombinase activity, and this alteration may link to genomic instability. Some patients with de novo AML also showed this pattern, suggesting a close biologic association between AML post MDS and some patients with de novo AML.

Adult↗

PubMed2001

Down-regulation of catalase gene expression in the doxorubicin-resistant AML subline AML-2/DX100.

A major obstacle to successful cancer chemotherapy is the development of multidrug resistance (MDR). The previous study revealed that a doxorubicin-resistant AML subline (AML-2/DX100) overexpressed an MDR-associated protein (MRP) but not P-glycoprotein. The AML-2/DX100 also showed various levels of resistance to daunorubicin and vincristine but was paradoxically sensitive to hydrogen peroxide (5-fold), t-butyl hydroperoxide (3-fold), and paraquat (2-fold) when compared to the drug-sensitive parental AML-2 cells (AML-2/WT). We compared the activities of antioxidant enzymes to detoxify reactive oxygen species (ROS), including superoxide dismutases, glutathione S-transferase, catalase, glutathione reductase, glutathione peroxidase, and glucose-6-phosphate dehydrogenase in both AML-2/WT and AML-2/DX100. Interestingly, of these antioxidant enzymes, catalase activity of AML-2/DX100 decreased significantly to about one-third that of AML-2/WT (P < 0.000005). The decreased activity of catalase was due to reduced expression of the catalase gene; confirmed by Western blot and reverse transcription-polymerase chain reaction (RT-PCR) analyses. The decreased activity of catalase was maintained even in the absence of doxorubicin for 3 months as well as by the treatment of probenecid, an MRP inhibitor. In addition, there was no difference in catalase activity between HL-60 and another MRP-overexpressing subline HL-60/Adr. Taken together, the paradoxical increase in the sensitivity of an MRP-overexpressing AML-2/DX100 in response to peroxides and paraquat is due to the down-regulation of catalase gene expression, which totally independent of overexpression of MRP. It is therefore possible that decreased catalase activity could be exploited as an Achilles' heel in resistant cells such as this.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1998

Biphasic expression of CD4 in acute myelocytic leukemia (AML) cells: AML of monocyte origin and hematopoietic precursor cell origin.

In 227 of 495 (45.9%) Japanese adult patients with acute myelocytic leukemia (AML), leukemic cells expressed CD4. Incidence of CD4 expression in each FAB subtype was as follows: M1 37.4%, M2 33.7%, M3 35.4%, M4 65.0%, and M5 78.3%. The typical expression pattern of myelomonocytic differentiation antigens and cytokine receptors in CD4+ AML was CD34lowCD33high CD11bhighGM-CSFRhigh. AML cases with 11q23 abnormalities and with inv(16) were frequently CD4-positive. These data collectively indicate that CD4 expression in AML cells is associated with monocytic characteristics. However, CD4+CD34high AML cases appear to have unique immature characteristics including low expression of myelomonocytic differentiation antigens (ie CD33 and CD11b), and accumulation of chromosome abnormalities (ie t(8;21) in CD4lowCD34high AML and chromosome 7 abnormalities in CD4highCD34high AML). We speculate that these leukemia subsets originate from CD4+ hematopoietic precursor cells, therefore then should be considered separately from most of the CD4+ AML as represented by CD34lowCD33high CD11bhighGM-CSFRhigh. Overall survival of patients with CD4+ AML in our series was worse than that of those with CD4 AML (P = 0.0202).

Adult↗

PubMed2004

Early deaths and treatment-related mortality in children undergoing therapy for acute myeloid leukemia: analysis of the multicenter clinical trials AML-BFM 93 and AML-BFM 98.

PURPOSE: The rates of early death (ED) and treatment-related mortality (TRM) are unacceptably high in children undergoing intensive chemotherapy for acute myeloid leukemia (AML). Better strategies of supportive care might help to improve overall survival in these children. PATIENTS AND METHODS: In a retrospective study, we analyzed incidence, clinical features, and risk factors for lethal complications of 901 children enrolled onto the multicenter trials Acute Myeloid Leukemia-Berlin-Frankfurt-Muenster (AML-BFM) 93 and AML-BFM 98. RESULTS: One hundred four patients (11.5%) enrolled onto the clinical trials AML-BFM 93 and AML-BFM 98 died shortly after diagnosis or as a result of treatment-related complications. Thirty-two patients (3.5%) died before (six patients) or during (26 patients) the first 14 days of treatment, mainly as a result of bleeding or leukostasis. Low performance status, hyperleukocytosis, and French-American-British type M5 were the main risk factors for a lethal event before day 15. After day 15, the predominant causes of death were complications caused by infections, particularly bacterial and fungal infections. The incidence of lethal infections was highest during induction therapy and decreased thereafter. When comparing both clinical trials, significantly fewer patients died within the first 6 weeks in AML-BFM 98 than in AML-BFM 93 (14 [3.5%] of 430 patients v 35 [7.4%] of 471 patients; P = .01). CONCLUSION: To reduce the high incidence of ED and TRM in children with AML, early diagnosis and adequate treatment of complications are needed. Children with AML should be treated in specialized pediatric cancer centers only. Prophylactic and therapeutic regimens for better treatment management of bleeding disorders and infectious complications have to be assessed in future trials to ultimately improve overall survival in children with AML.

Adolescent↗

PubMed2002

Comparison between pediatric acute myeloid leukemia (AML) and adult AML in VEGF and KDR (VEGF-R2) protein levels.

We reported previously that high levels of vascular endothelial growth factor (VEGF) were associated with shorter survival in adult acute myeloid leukemia (AML) patients. In this study, cellular VEGF and its receptor, VEGF-R2 (kinase domain receptor (KDR)), were analyzed in 45 pediatric AML patients using Western blot and solid-phase radioimmunoassay (RIA). Cellular VEGF levels were significantly lower in pediatric AML compared to adult AML patients. In contrast, there was no significant difference in VEGF-R2 levels between adult and pediatric AML. Higher VEGF and VEGF-R2 levels in pediatric AML patients correlated with higher white blood cell (WBC). Unlike in adults, VEGF and VEGF-R2 levels in pediatric AML patients did not correlate with survival. This data suggest that the role of VEGF and its receptor VEGF-R2 in pediatrics AML may be different from that in adult AML.

Acute Disease↗

PubMed2000

Trisomy 10 in acute myeloid leukemia. Three additional cases from the database of the Japan Adult Leukemia Study Group (JALSG) AML-92 and AML-95.

To clarify the clinical and hematologic features of a rare numerical chromosome abnormality, we searched for trisomy 10 in acute myelogenous leukemias (AMLs) using the database of the Japan Adult Leukemia Study Group (JALSG) AML 92 and 95. Among the sequentially registered patients of JALSG-AML 92 (655 patients) and JALSG-AML 95 (531 patients), chromosome results were obtained in 1,074 patients (90.6%), and we found 3 patients with trisomy 10 as a sole abnormality. The first patient had an AML-M1 morphology with CD7 antigen; the patient obtained complete remission (CR) with the first course of chemotherapy. The second patient had an AML-M1 morphology without expressing CD7 antigen; this patient obtained CR, but relapsed 3 months later, and underwent allogeneic bone marrow transplantation. He suffered from chronic graft-versus-host disease and expired 38 months after the AML diagnosis. The third patient had AML-M0 with CD7 positivity. He obtained CR; however, brain abscess and cerebral hemorrhage occurred. In the literature, the mean age of patients with trisomy 10 AML is 57.8 years, the gender ratio is M/F = 1.5, and the frequency of M0/M1/M2 is 85.7%. A high incidence (81. 8%) of CD7 expression of leukemia cells is notable. About 73% of patients survived for greater than 12 months.

Adult↗

PubMed2003

Flt3-mediated signaling in human acute myelogenous leukemia (AML) blasts: a functional characterization of Flt3-ligand effects in AML cell populations with and without genetic Flt3 abnormalities.

BACKGROUND AND OBJECTIVES: Intracellular signaling initiated via Flt3 seems important in both leukemogenesis and chemosensitivity in acute myelogenous leukemia (AML). Flt3 is activated by binding of its natural Flt3-ligand (Flt3-L), but Flt3 genes with internal tandem duplications (Flt3-ITD) or Asp(D)-835 point mutations encode molecules with constitutive activation. The aim of this study was to compare functional effects of exogenous Flt3-L on AML blast populations with and without genetic Flt3 abnormalities. DESIGN AND METHODS: Native AML blasts were derived from 64 consecutive patients with high blast counts in peripheral blood, and in vitro models were used to characterize the Flt3-L effects. RESULTS: The Flt3 protein levels showed a similar wide variation between AML blast populations with and without genetic Flt3 abnormalities. Flt3-L was an autocrine growth factor only for 2 patients. Flt3-ITD+ AML cells had lower responsiveness to exogenous cytokines than cell populations without Flt3 abnormalities, but exogenous Flt3-L increased blast proliferation both for patients without Flt3 abnormalities and patients with Flt3-ITD as well as D835 mutations. This enhancement was observed even in the presence of other exogenous cytokines and included clonogenic AML progenitors. Flt3-L inhibited proliferation only for 1 patient, but had divergent effects on AML blast cytokine release. Flt3-L affected AML blast differentiation (inhibition of erythroid colonies, increased neutrophil granulation) only in a minority of patients, whereas it had an anti-apoptotic effect for a larger subset of patients. INTERPRETATION AND CONCLUSIONS: Intracellular signaling initiated by Flt3 ligation modulates the functional phenotype for native human AML blasts both with and without genetic Flt3 abnormalities.

Adult↗

PubMed1996

Irradiated B7-1 transduced primary acute myelogenous leukemia (AML) cells can be used as therapeutic vaccines in murine AML.

Recent studies have shown that tumor cells genetically modified by transduction of B7-1, a natural ligand for the T-cell costimulatory molecules CD28 and CTLA-4, are rejected in syngeneic hosts. In these reports, transformed cell lines and drug-selected cells have been used for vaccinations. To determine the effectiveness of B7-1-transduced primary acute myelogenous leukemia (AML) cells on the induction of antitumor immunity, we have studied a murine AML model in which primary AML cells were retrovirally transduced with the murine B7-1 cDNA. A defective retroviral producer clone expressing B7-1 and secreting a high titer of virus was used for infection of AML cells. Unselected transduced AML cells, expressing a high level of B7-1, were used for in vivo vaccinations. Our results show that one intravenous (IV) injection of irradiated B7-1-positive (B7-1+) AML cells can provide long-lasting (5 to 6 months) systemic immunity against subsequent challenge with wild-type AML cells. Furthermore, one exposure to irradiated B7-1+ AML cells results in rejection of leukemia by leukemic mice when the vaccination occurs in the early stages of the disease. The antileukemia immunity is CD8+ T-cell-dependent and B7/CD28-mediated, since in vivo treatment of mice with anti-CD8 monoclonal antibody or CTLA-4 Ig leads to abrogation of the specific antileukemia immune response. These results emphasize that B7-1 vaccines may have therapeutic usefulness for patients with AML.

Animals↗

PubMed2005

Long-term results in children with AML: NOPHO-AML Study Group--report of three consecutive trials.

In all, 447 children with acute myeloid leukaemia (AML) have been treated on three consecutive NOPHO studies from July 1984 to December 2001. NOPHO-AML 84 was of moderate intensity with an induction of three courses of cytarabine, 6-thioguanine and doxorubicin followed by four consolidation courses with high-dose cytarabine. The 5-year event-free survival (EFS), disease free survival (DFS) and overall survival (OS) were 29, 37 and 38%. NOPHO-AML 88 was of high intensity with the addition of etoposide and mitoxantrone in selected courses during induction and consolidation. The interval between the induction courses should be as short as possible, that is, time intensity was introduced. The 5-year EFS, DFS and OS were 41, 48 and 46%. In NOPHO-AML 93, the treatment was stratified according to response to first induction course. The protocol utilised the same induction blocks as NOPHO-AML 88, but after the first block, children with a hypoplastic, nonleukaemic bone marrow were allowed to recover before the second block. Consolidation was identical with NOPHO-AML 88. The 5-year EFS, DFS and OS in NOPHO-AML 93 were 48, 52 and 65%. The new NOPHO-AML protocol has been based on experiences from previous protocols with stratification of patients with regard to in vivo response and specific cytogenetic aberrations.

Acute Disease↗

PubMed2000

Screening for MLL tandem duplication in 387 unselected patients with AML identify a prognostically unfavorable subset of AML.

Partial tandem duplications of the MLL gene have been associated with trisomy 11 in acute myeloid leukemia (AML) and recently, have also been reported for karyotypically normal AML. In order to test the incidence and prognostic importance of this molecular marker, we have analyzed eight cases of AML with trisomy 11 and 387 unselected consecutive cases with AML for partial duplications of the MLL gene. Patients with normal karyotypes and those with various chromosome aberrations were included. De novo as well as secondary leukemias including all FAB subtypes were analyzed. Performing a one-step RT-PCR with 35 cycles using an exon 9 forward primer and an exon 3 reverse primer partial tandem duplications of the MLL gene were demonstrated in 3/8 (37.5%) patients with trisomy 11. In addition, 13/387 (3.4%) of unselected cases revealed a tandem duplication. Ten of these 13 cases were cytogenetically normal, the other three cases had < or =2 additional chromosomal alterations. Sequencing of the RT-PCR products of all 16 positive cases revealed fusions of MLL exon 9/exon 3 (e9/e3) (six cases), e10/e3 (three cases), e11/e3 (four cases) or combinations of differentially spliced e10/e3 and e11/e3 (three cases) transcripts. The duplications were confirmed by genomic long range PCR and Southern blot hybridization. Twelve cases with the MLL duplication were de novo myeloid leukemia, one was a secondary AML after MDS, three were therapy-related AML (t-AML). Of the 16 MLL-duplication positive cases, seven were classified as FAB M2, two as M1, five as M4, one as M0, one as M5b. The mean age was 62.3 years for patients with MLL duplication vs 50.3 years for the control group. Of 15 adult patients, 12 received treatment. Of these, three were nonresponders, five had early relapse (< or =6 months), four relapsed between 7 and 12 months. Median survival and relapse-free interval of the MLL duplication positive group was significantly worse than those of an age-matched karyotypically normal control group. In conclusion, MLL tandem duplications (1) are less common than previously reported; (2) are preferentially observed in AML with normal karyotypes, but can also be found in the presence of chromosome alterations; (3) are not strongly associated with an FAB subtype; (4) were not observed with the prognostically favorable t(8;21), inv(16), and t(15;17), other recurrent translocations, or in complex karyotypes; and (5) identifies a subgroup of patients with an unfavorable prognosis.

Aged↗

PubMed2006

Treatment for myeloid leukaemia of Down syndrome: population-based experience in the UK and results from the Medical Research Council AML 10 and AML 12 trials.

Down syndrome (DS) children are at an increased risk of developing myelodysplasia and acute myeloid leukaemia (AML). We retrospectively analysed the population-based data on 81 children with myeloid leukaemia of Down syndrome (ML-DS) from the UK National Registry of Childhood Tumours and experience in the Medical Research Council (MRC) AML 10 and AML 12 trials, which enrolled 46 children with ML-DS from 1988 to 2002. Eight per cent of UK children with AML had DS, but DS children comprised only 5% of children registered in MRC trials. The unique clinical characteristics of ML-DS were confirmed. Overall survival (OS) of ML-DS at 5 years increased from 47% in UK children diagnosed from 1988 to 1995 to 75% in children diagnosed from 1996 to 2002. OS for DS children registered in AML 10 and AML 12 was 74% in 5 years and improved from AML 10 to AML 12 (56% vs. 83%) There was no significant difference in OS between DS and non-DS children (OS: 74% vs. 62%, P = 0.4) in the trials, but this result masked a significant increase in early death amongst DS children, with a significant reduction in mortality later on. Relapse was significantly reduced (3% vs. 39%, P = 0.0003), leading to the improved disease-free survival (83% vs. 56%, P = 0.02). Given the increased number of early treatment-related deaths, future treatment protocols should aim to reduce chemotherapy dosage or intensity whilst maintaining low rates of resistant and recurrent disease.

Adolescent↗