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PubMed1999

Studies on treatment of acute promyelocytic leukemia with arsenic trioxide: remission induction, follow-up, and molecular monitoring in 11 newly diagnosed and 47 relapsed acute promyelocytic leukemia patients.

Fifty-eight acute promyelocytic leukemia (APL) patients (11 newly diagnosed and 47 relapsed) were studied for arsenic trioxide (As2O3) treatment. Clinical complete remission (CR) was obtained in 8 of 11 (72.7%) newly diagnosed cases. However, As2O3 treatment resulted in hepatic toxicity in 7 cases including 2 deaths, in contrast to the mild liver dysfunction in one third of the relapsed patients. Forty of forty-seven (85.1%) relapsed patients achieved CR. Two of three nonresponders showed clonal evolution at relapse, with disappearance of t(15;17) and PML-RARalpha fusion gene in 1 and shift to a dominant AML-1-ETO population in another, suggesting a correlation between PML-RARalpha expression and therapeutic response. In a follow-up of 33 relapsed cases over 7 to 48 months, the estimated disease-free survival (DFS) rates for 1 and 2 years were 63.6% and 41.6%, respectively, and the actual median DFS was 17 months. Patients with white blood cell (WBC) count below 10 x 10(9)/L at relapse had better survival than those with WBC count over 10 x 10(9)/L (P =.038). The duration of As2O3-induced CR was related to postremission therapy, because there was only 2 of 11 relapses in patients treated with As2O3 combined with chemotherapy, compared with 12 of 18 relapses with As2O3 alone (P =.01). Reverse transcription polymerase chain reaction (RT-PCR) analysis in both newly diagnosed and relapsed groups showed long-term use of As2O3 could lead to a molecular remission in some patients. We thus recommend that ATRA be used as first choice for remission induction in newly diagnosed APL cases, whereas As2O3 can be either used as a rescue for relapsed cases or included into multidrug consolidation/maintenance clinical trials.

Adult↗
PubMed1999

Treatment of adult myelodysplastic syndromes.

Patients with myelodysplastic syndromes (MDS) suffer from pancytopenia and are at substantial risk for progression to acute myeloid leukemia. The principal pathogenetic features of MDS are clonal evolution, ineffective hematopoiesis (apoptosis), and reduced cellular maturation. T-cell-mediated myelosupression may add to disease development in some patients. The disease is progressive and, for the majority of patients, the aim of treatment will be to improve blood values and quality of life. A minority of patients could be cured by allogeneic bone marrow transplantation, which results in an overall disease-free survival of about 40%. The value of autologous stem-cell transplantation is currently being investigated in clinical trials; this treatment may be found to be beneficial for some MDS patients. High-dose chemotherapy may lead to significant improvement and complete remission in about 50% of treated patients, but remission duration is usually short. Low-dose chemotherapy may also be used to improve peripheral blood values. Several new low-dose treatments are being tested at present. Growth factors can be used to improve both ineffective hematopoiesis and cytopenia. The value of treatment with growth factors alone for granulocytopoiesis is uncertain, whereas treatment for impaired erythropoiesis using erythropoietin alone or erythropoietin in combination with other growth factors seems more promising. Subgroups of MDS in which T-cell-mediated myelosuppression are present may respond favorably to cyclosporin A or antithymoglobulin. Antiapoptotic agents such as amifostine may improve blood values in some patients with MDS, but the value of this treatment is not yet clear. Increasing pathogenetic knowledge and better use of predictive models have resulted in some progress in MDS treatment. In the future, more effective treatments may result from further insights into the biology of the disease, the discovery of new therapeutic approaches, and the search for better ways to use existing therapeutic options.

Adult↗
PubMed2000

Analysis of expressed immunoglobulin heavy chain genes in familial B-CLL.

In this study, we wished to determine whether familial chronic lymphocytic leukemia of B-cell phenotype (CLL) shares with sporadic B-CLL the same immunoglobulin (Ig) heavy chain variable region (VH) gene usage and occurrence of somatic mutation, to gain insight into the pathogenetic relatedness of these epidemiologically distinct forms of CLL. We therefore analyzed the expressed Ig heavy chain genes in 23 cases (11 families) of familial CLL, and compared these results with data previously reported for sporadic CLL. In addition, we assessed the relationship of the occurrence of somatic mutation to several clinical and phenotypic features. The distribution of V genes among these cases was similar to that observed in sporadic CLL: VH3 > VH1 > VH4. Thirteen of the 23 cases (57%) showed germ line VH gene sequences, whereas somatic mutations were detected in 10 cases (43%). The average mutation frequency of these latter 10 cases of was 6.7% (ranging from 1.7% to 8.8%), and evidence of antigen selection was noted in 6. Intraclonal variation, followed by clonal evolution and the appearance of a second clone over a 20-year period was observed in 1 case, suggesting that mutations can continue to accumulate after neoplastic transformation. The presence of somatic mutations correlated with age at presentation, low white blood cell (WBC) count, and low fluorescence intensity of surface CD5, and the potential significance of these relationships is discussed. Our data indicate that familial and sporadic B-CLL display a similar pattern of immunoglobulin gene usage and frequency of somatic mutation, and are consistent with a common ontogeny and immunogenetic origin for these 2 epidemiologically distinct forms of CLL. (Blood. 2000;95:1413-1419)

Adult↗
PubMed2000

Antilymphocyte globulin, cyclosporine, prednisolone, and granulocyte colony-stimulating factor for severe aplastic anemia: an update of the GITMO/EBMT study on 100 patients. European Group for Blood and Marrow Transplantation (EBMT) Working Party on Severe Aplastic Anemia and the Gruppo Italiano Trapianti di Midolio Osseo (GITMO).

One hundred consecutive patients with severe aplastic anemia (SAA) received horse antilymphocyte globulin (ALG), cyclosporin A (CyA), 6-methylprednisolone (6Mpred), and granulocyte colony-stimulating factor (G-CSF) as first-line therapy. The median age was 16 years (range, 1-72 years) and median neutrophil count was 0.2 x 10(9)/L (range, 0-0.5 x 10(9)/L). Trilineage hematologic recovery (at a median interval of 96 days from treatment) was seen in 77 patients (48 complete, 29 partial) after 1 (n = 50) or more courses of ALG (n = 27). Of the 23 nonresponders, 11 patients died at a median interval of 83 days (range, 16-1132 days), 6 were considered treatment failures and underwent transplantation, and 6 were pancytopenic. Cytogenetic abnormalities were seen in 11% of patients, clonal hematologic disease in 8%, and relapse of marrow aplasia in 9%. The actuarial survival at 5 years was 87% (median follow-up 1424 days): 76% versus 98% for patients with neutrophil counts less than versus greater than 0.2 x 10(9)/L (P =.001) and 88% versus 87% for patients aged less than versus more than 16 years (P =.8). The actuarial probability of discontinuing CyA was 38%. Patients who did not achieve a white blood cell (WBC) count of 5 x 10(9)/L during G-CSF treatment have a low probability of responding (37%) and a high mortality rate (42%). This update confirms a high probability for SAA patients of becoming transfusion independent and of surviving after treatment with ALG, CyA, 6Mpred, and G-CSF, with a significant effect of neutrophil counts on outcome. Problems still remain, such as absent or incomplete responses, clonal evolution, relapse of the original disease, and cyclosporine dependence. Early transplantation, also from alternative donors, may be warranted in patients with poor WBC response to G-CSF. (Blood. 2000;95:1931-1934)

Adolescent↗
PubMed2000

Variable heavy chain gene analysis of follicular lymphomas: correlation between heavy chain isotype expression and somatic mutation load.

The expansion of follicular lymphomas (FLs) resembles, both morphologically and functionally, normal germinal center B-cell growth. The tumor cells proliferate in networks of follicular dendritic cells and are believed to be capable of somatic hypermutation and isotype switching. To investigate the relation between somatic mutation and heavy chain isotype expression, we analyzed the variable heavy (V(H)) chain genes of 30 FL samples of different isotypes. The V(H) genes of the FLs were heavily mutated (29.3 mutations on average). In addition, isotype-switched lymphomas contained more somatic mutations than immunoglobulin M-positive lymphomas (33.8 mutations per V(H) gene versus 23.0, respectively). In all but one of the FLs, the ratios of replacement versus silent mutations in the framework regions were low, independent of the absolute number of somatic mutations and the level of intraclonal variation. Analysis of relapse samples of 4 FLs showed no obvious increase in somatic mutation load in most FLs and a decrease in intraclonal variation in time. In 3 of 4 cases, we obtained evidence for selection of certain subclones, rather than clonal evolution. Our findings question if intraclonal variation is always a reflection of ongoing somatic hypermutation. This may have implications for the concept of antigen-driven lymphomagenesis. (Blood. 2000;95:2922-2929)

Adult↗
PubMed2000

The role of methylation in CML.

Methylation of the proximal promoter of the ABL1 oncogene is common epigenetic alteration associated with clinical progression of chronic myeloid leukemia (CML). In presented study we queried whether both the Ph'-associated and normal ABL1 alleles undergo methylation; what may be the proportion of hematopoietic progenitors bearing methylated ABL1 promoters in chronic versus acute phase disease; whether methylation affects the promoter uniformly or in patches with discrete clinical relevance; and, finally whether methylation of ABL1 reflects a generalized process or is gene-specific. To address these issues, the technique of methylation-specific PCR and bisulfite-sequencing was adapted to study the regulatory regions of ABL1 and other genes. In cell lines established from CML blast crisis, which only carry a single ABL1 allele nested within the BCR-ABL fusion gene, ABL1 promoters were universally methylated. In clinical samples from patients at advanced stages of the disease, both methylated and unmethylated promoter alleles were detectable. In colonies derived from single hematopoietic progenitors methylated and unmethylated promoter alleles were revealed as well. ABL1 methylation was was noted in the vast majority of colonies from blast crisis, but not chronic-phase CML. It was shown finally that ABL1 methylation does not reflect a generalized process and may be unique among DNA repair/genotoxic stress response genes. These data suggest that specific methylation of the Ph'-associated ABL1 allele accompanies clonal evolution in CML.

Alleles↗
PubMed2000

High frequency of clonally related tumors in cases of multiple synchronous lung cancers as revealed by molecular diagnosis.

In patients with multiple synchronous lung tumors, discrimination of multicentric lung cancers from intrapulmonary metastasis is important for treatment decision, but this is sometimes difficult. The aim of this study was to retrospectively distinguish multicentric lung cancers from intrapulmonary metastases in 14 such cases by loss of heterozygosity (LOH) and p53 mutational status. DNA was extracted from microdissected tumor cells in paraffin-embedded archival tissue, and 3p14.2, 3p21, 3p25, 9p21, and 18q21.1 were investigated for LOH. Exons 5-8 of the p53 gene were examined for mutations by the PCR, followed by single-strand conformation polymorphism analysis and DNA sequencing. For cases with the same LOH pattern, we calculated a clonality index, the probability of the given LOH pattern when these tumors were hypothesized to be independent in origin. Eleven of 14 cases (79%) were thus diagnosed as having pulmonary metastasis and only one case as having genuinely multicentric lung cancers. Two cases presented difficulty in diagnosis. In several cases, the LOH patterns conflicted with p53 mutation patterns, suggesting that clonal evolution is directly affected by certain genetic changes. The combination of p53 with LOH helped increase both the sensitivity and specificity of the assay.

Adult↗
PubMed2001

Detection of trisomy 8 in philadelphia chromosome-positive CML patients using conventional cytogenetic and interphase fluorescence in situ hybridization techniques and its relation to c-myc involvement.

Trisomy 8 (+8) is a common clonal evolution marker for progression in chronic myelogenous leukemia. The relationship of +8 to various stages of t(9;22) leukemias is not firmly established. To explore this association we examined bone marrow (BM) cells from 10 Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML) patients in different stages of the disease, using conventional cytogenetic technique(CCT) and interphase fluorescence in situ hybridization (FISH). FISH detection of chromosome 8 was accomplished using the D8Z2 (Oncor) probe specific for the centrometric region of chromosome 8. Five hundred interphase nuclei were counted for each patient. Three of the 10 patients were selected for detection of c-myc gene locus located in the 8q24.2-24.3 region using the L

Adult↗
PubMed2001

FISH monitoring of 100 courses of human leukemias: the cytogenetic viewpoint.

Interphase fluorescence in situ hybridization (I-FISH) analyses were performed from 2 up to 13 times along the course of 100 human leukemias (36 chronic myeloid leukemias, 38 acute myeloblastic leukemias, 17 acute lymphoblastic leukemias, and 9 additional hematopoietic neoplasias) in order to control clonality, evolution, and disappearance of the basic cytogenetic changes. The relevance of these data to confirm clinical remission or to detect minimal residual disease and/or relapse was evaluated. Fifty-four patients were monitored following hematopoietic stem cell transplantation, and 46 cases after chemotherapy. Various chromosome or aberration specific DNA probes were applied for follow-up in the time frame of 1 month up to 13 years. From the cytogenetic point of view, the aim was to determine the power of resolution of the I-FISH technique in the detection of clinically significant changes in the course of disease and its usefulness in daily routine cyto-genetics as compared with classical cytogenetics. In addition, reliability standards of the various DNA probes should be established. In 75 patients with remissions during the entire period of I-FISH monitoring no conspicuous signal constitution was detected. Of 25 relapses or progresses of disease, which were clinically confirmed, 22 were reliably detected by I-FISH, in only 1 case I-FISH monitoring failed to detect the aberrant clone. In 2 patients conventional karyotype analysis confirmed the relapse by detecting complex chromosomal aberrations, but specific probes for I-FISH confirmation were not available. These data suggest that I-FISH analyses in the follow-up of leukemias is a simple and in most cases sufficiently sensitive and highly reliable way of monitoring the outcome of therapy. It may well serve to close the gap between conventional karyotyping and the highly sensitive molecular techniques.

Adolescent↗
PubMed2002

Translocation t(2;7)(p12;q21-22) with dysregulation of the CDK6 gene mapping to 7q21-22 in a non-Hodgkin's lymphoma with leukemia.

BACKGROUND AND OBJECTIVES: A female patient presented with splenomegaly and lymphocytosis with atypical lymphoid cell morphology. We identified t(2;7)(p12;q21) prompting studies of the translocation breakpoint and its consequences on protein expression to confirm or otherwise the recently reported involvement of CDK6 and IG k genes in the t(2;7) leading to over-expression of CDK6 protein. DESIGN AND METHODS: A variety of clinical and laboratory techniques including cell marker, cytogenetic and histologic studies were applied in order to establish the diagnosis. Fluorescence in situ hybridization (FISH) and Southern blotting were used for mapping the translocation breakpoint and Western blotting for assessing protein expression. RESULTS: Immunophenotyping showed the presence of a B-cell population with strong expression of FMC7, CD22, CD79b, CD5 and k restricted surface immunoglobulins. Based on morphology and immunophenotypic markers the diagnosis of B-cell non-Hodgkin's lymphoma was made. Karyotyping revealed a clone with t(2;7)(p12;q21-22). Evidence for clonal evolution with additional abnormalities including a deletion of the TP53 was present. We established by FISH and Southern blotting that the breakpoint on 7q21-22 fell in a region 66kb telomeric to the previously reported breakpoint for the t(2;7) and was the same as that observed in a t(7;21). CDK6 protein was over-expressed. The patient received alkylating agents and splenectomy and is alive but the lymphocytosis persists with evidence of disease progression. INTERPRETATIONS AND CONCLUSIONS: We have demonstrated that CDK6 expression is dysregulated even when the breakpoint on 7q21-22 is located 66kb upstream from the coding region. Interestingly, the precise assignment of the lymphoma type in our case was not possible even when the splenic histology was analyzed.

Aged↗
PubMed2002

Polymerase chain reaction-based clonality analysis in thyroid lymphoma.

A previous patho-epidemiological study indicated that thyroid lymphoma (TL) evolves among active lymphoid cells into chronic lymphocytic thyroiditis (CLTH), a thyroid-specific autoimmune disease. In this study, clonality of B-cells in the CLTH and TL lesions was analyzed using polymerase chain reaction (PCR)-based method on surgically resected samples from 10 cases of TL; 7 mucosa-associated lymphoid tissue (MALT) lymphoma and 3 diffuse large B-cell lymphoma (DLBCL). CLTH lesions coexisted in all the cases with MALT lymphoma, but not in the three DLBCL cases. In cases of MALT lymphoma, the lymphomatous and CLTH areas were separately microdissected from each section and analyzed for clonality. In the cases of DLBCL, the whole specimens were used for clonality analysis. CLTH lesions showed smear in 6 samples, two bands in one, and more than three (oligoclonal pattern) in 2. MALT lymphoma lesions showed single or two bands (monoclonal pattern) in 4, oligoclonal pattern in 4, and smear in one. DLBCL showed monoclonal pattern in two and oligoclonal pattern in one. One common band was present among two separate MALT lesions in one case, but no common bands were found in the remaining six cases. These findings suggested the clonal evolution of B-cell from polyclonal to monoclonal proliferation to take place in the continuum of lymphoproliferative lesions into autoimmune thyroiditis.

Aged↗
PubMed2002

Treatment of philadelphia chromosome-positive, accelerated-phase chronic myelogenous leukemia with imatinib mesylate.

PURPOSE: Imatinib mesylate, a specific Bcr-Abl tyrosine kinase inhibitor, has shown encouraging activity in chronic myelogenous leukemia (CML). EXPERIMENTAL DESIGN: We treated 237 patients (median age, 50 years; age range, 18-82 years) with Philadelphia chromosome (Ph)-positive accelerated-phase CML with oral imatinib mesylate at daily doses of 400 mg (26 patients) or 600 mg (211 patients) and evaluated response and survival characteristics in univariate and multivariate analyses. RESULTS: Among the 200 patients with accelerated-phase CML for whom follow-up was 3 months or more, rates of complete and partial hematological response were 80% and 10%. Cytogenetic responses were evident in 90 patients [45%; complete response in 47 patients (24%) and partial response (Ph 1-34%) in 21 patients (11%)]. The estimated 18-month survival rate was 73%. The estimated complete hematological response rate at 18 months was 68%; that for cytogenetic response was 82%. In multivariate analyses, a diagnosis-to-treatment interval of 3 years or more, splenomegaly, and peripheral blasts predicted poor major cytogenetic response; age >60 years, marrow basophilia, and clonal evolution predicted poor survival. The 600-mg drug dose was associated with better cytogenetic response and survival in univariate analysis (P < 0.01) but not in multivariate analysis. Landmark analysis showed that achieving a cytogenetic response at 3 months or a major cytogenetic response (Ph < 35%) at 6 months was associated with better long-term survival. Seven of 15 patients who were in a second chronic phase achieved major cytogenetic response. The incidence of severe nonhematological toxic effects was 23%; drug discontinuation for severe toxicity was needed in 3% of patients. CONCLUSIONS: Imatinib mesylate was active against Ph-positive, accelerated-phase CML, and the prognostic factors identified in this study could aid in tailoring treatment strategies to specific risk groups.

Adolescent↗
PubMed2002

Imatinib mesylate for Philadelphia chromosome-positive, chronic-phase myeloid leukemia after failure of interferon-alpha: follow-up results.

We treated 261 patients with Philadelphia chromosome (Ph)-positive chronic myeloid leukemia (CML) in chronic phase after failure of IFN-alpha with the Bcr-Abl tyrosine kinase inhibitor imatinib mesylate (400 mg/day given p.o.) and analyzed hematological and cytogenetic responses, long-term prognosis, factors associated with achievement of major cytogenetic response and survival, and comparative survival in similar patients treated with other regimens. Median patient age was 55 years; 34% were 60 years or older, and median chronic-phase duration was 33 months. Overall, 94% achieved a complete hematological response, and 71% had a cytogenetic response [major (Ph+ cells <35%) in 62% and complete in 45%]. At a median follow-up of 17 months, 241 patients (92%) were still taking imatinib mesylate; estimated 18-month freedom from progression and survival rates were 93 and 96%. Multivariate analysis of factors associated with major cytogenetic response identified long chronic phase, marrow basophilia, high percentage of Ph+ cells before therapy, and prior hematological resistance to IFN-alpha as being adverse factors. This model was used to generate good-, intermediate- and poor-risk subgroups who had estimated major cytogenetic response rates of 93, 53, and 34%, respectively. Univariate analysis in terms of survival identified leukocytosis, high percentages of peripheral and marrow blasts, marrow basophilia, and the presence of cytogenetic clonal evolution as being adverse factors. Achieving a cytogenetic response at 3 or 6 months of therapy was associated with prolonged survival. In a subset analysis, survival rates among 161 patients with Ph-positive CML after hematological or cytogenetic failure after IFN-alpha who had been treated with imatinib mesylate were better than those for similar patients treated previously with other regimens. In summary, imatinib mesylate is highly effective in chronic-phase CML after IFN-alpha failure. We identified pretreatment and treatment-associated factors that were associated with higher major cytogenetic response rates and with improved survival.

Benzamides↗
PubMed2002

Impact of DNA amplification on gene expression patterns in breast cancer.

Genetic changes underlie tumor progression and may lead to cancer-specific expression of critical genes. Over 1100 publications have described the use of comparative genomic hybridization (CGH) to analyze the pattern of copy number alterations in cancer, but very few of the genes affected are known. Here, we performed high-resolution CGH analysis on cDNA microarrays in breast cancer and directly compared copy number and mRNA expression levels of 13,824 genes to quantitate the impact of genomic changes on gene expression. We identified and mapped the boundaries of 24 independent amplicons, ranging in size from 0.2 to 12 Mb. Throughout the genome, both high- and low-level copy number changes had a substantial impact on gene expression, with 44% of the highly amplified genes showing overexpression and 10.5% of the highly overexpressed genes being amplified. Statistical analysis with random permutation tests identified 270 genes whose expression levels across 14 samples were systematically attributable to gene amplification. These included most previously described amplified genes in breast cancer and many novel targets for genomic alterations, including the HOXB7 gene, the presence of which in a novel amplicon at 17q21.3 was validated in 10.2% of primary breast cancers and associated with poor patient prognosis. In conclusion, CGH on cDNA microarrays revealed hundreds of novel genes whose overexpression is attributable to gene amplification. These genes may provide insights to the clonal evolution and progression of breast cancer and highlight promising therapeutic targets.

Breast Neoplasms↗
PubMed1976

G-banding analysis of complex aneuploidy in multiple myeloma bone marrow cells.

Chromosome studies with the banding technique have been performed in a considerable number of cases of myeloproliferative diseases, but technical difficulties have so far prevented detailed studies of chromosomal abnormalities in multiple myeloma. The karyotypes of bone marrow cells from two patients with multiple myeloma have been analyzed by a trypsin-Giemsa banding technique. Evidence is given for clonal evolution which in one patient has probably occurred by cell fusion and subsequent chromosome loss. Eight different marker chromosomes are characterized. Nonrandom chromosomal participation in the translocations and the existence of specific vulnerable points on chromosomes 1, 3, and 16 are suggested.

Aged↗
PubMed2002

[Helicobacter pylori and malignant diseases of the stomach].

The association between Helicobacter pylori infection and gastric malignancies, cancer and MALT lymphoma, has been suggested through several lines of evidence during the last decade. Although unresolved issues still cast doubts on the real weight of these association, in the sequence of events that leads to gastric cancer or lymphoma, Helicobacter pylori appears to play a prominent role in the very initial steps as causative agent of chronic gastritis. The subsequent events in the sequence--atrophy, intestinal metaplasia, dysplasia and cancer are multifactorial involving environmental agents, host response and characteristics of the bacterial strain itself. Recognition of the causal role of Helicobacter pylori infection in the cancer induction theoretically presents tools for its prevention. The ongoing studies will show in the future whether eradication or prevention of infection are followed by a reduction in risk of cancer. Lymphomas arising from gastric mucosa-associated lymphoid tissue (MALT) may be a clonal evolution starting from the infection. In low-grade gastric MALT lymphoma cure of the infection induces complete remission in the majority of patients. Longer follow-up investigations are necessary to determine if remissions indicate a cure of the disease.

Chronic Disease↗
PubMed2003

Multicenter prospective study of clonal complications in adult aplastic anemia patients following recombinant human granulocyte colony-stimulating factor (lenograstim) administration.

To elucidate the relationship between treatment with granulocyte colony-stimulating factor (G-CSF) and the development of chromosomal abnormalities and clonal evolution in adult aplastic anemia (AA) patients, we performed a prospective multicenter study. Of the 104 registered patients, 91 were found by the central review committee to have the diagnosis of AA. Of the 91 patients, 84 were determined to be evaluable in this study and were treated with regimens including G-CSF (lenograstim). A time-course study (at registration and 6 and 12 months after registration) of G-banded chromosomes, fluorescence in situ hybridization (FISH) analysis for monosomy 7, and morphological assessment of bone marrow was performed with these patients during the 1-year follow-up period. G-banding analysis demonstrated the development of cytogenetic abnormalities in 10 (16.1%) of the 62 evaluable patients. The most common aberration was monosomy 7. FISH analysis demonstrated monosomy 7 in 7 (10.4%) of the 67 evaluable patients. Evolution into myelodysplastic syndrome (MDS) was observed in 5 (7.7%) of the 65 patients who underwent morphological assessment of bone marrow. All patients who developed cytogenetic abnormalities or MDS received immunosuppressive agents and/or steroids with G-CSF. This study demonstrated that some adult AA patients exhibit evolution into MDS and development of chromosomal abnormalities such as monosomy 7. Although the incidence seems to be comparable with that found in previous studies, further long-term follow-up will be necessary to confirm the relationship between G-CSF and the development of chromosomal abnormalities and MDS.

Adolescent↗
PubMed2003

Immunophenotypic findings in acute myeloid leukemia with FLT3 internal tandem duplication.

BACKGROUND AND OBJECTIVES: The biological characteristics and the prognostic significance of the internal tandem duplication of the FLT3 (FLT3/ITD) were investigated in a series of de novo acute myeloid leukemia (AML) patients. One hundred and fifty-six adult patients with AML were included in the study. FLT3/ITD was detected in 41 (26%) patients (FLT3/ITD(+)). DESIGN AND METHODS: The main differences observed between the groups with and without FLT3/ITD: a higher leukocyte count, a raised percentage of a normal karyotype and a more frequent M5 FAB diagnosis in the FLT3/ITD(+) patients. As regards the immunophenotype characteristics the FLT3/ITD(+) group very often expressed monocytic markers (CD36 and CD11b) and less commonly immature markers (CD34 and CD117). A promyelocytic-like immunophenotype pattern was also detected in a minority of these patients(4/36). RESULTS: The FLT3/ITD(+) patients had a shorter overall survival, a shorter event-free survival and a higher probability of relapse. Minimal residual disease (MRD) was investigated in the FLT3/ITD(+) patients using flow cytometry. This technique had a sensitivity of 62% and a specificity of 83% in relapse prediction. Minimal residual disease analysis was hampered by the low number of patients with detectable aberrant immunophenotype. INTERPRETATION AND CONCLUSIONS: A high frequency of changes in the phenotype and/or genotype pattern between diagnosis and relapse was detected (5/6). FLT3/ITD is a frequent molecular lesion in de novo adult AML and seems to be associated with a monocytic differentiation, a high leukocyte count and a poor prognosis. Immunophenotype and genotype patterns observed at relapse suggest that the FLT3/ITD(+) blasts may be genetically unstable and prone to clonal evolution. FLT3/ITD may not be a suitable target for minimal residual disease studies.

Acute Disease↗