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We reviewed the frequency and prognostic significance of FLT3 (fms-like tyrosine kinase receptor-3) and NPM (nucleophosmin) gene mutations and WT1 (Wilms' tumor) and BAALC (brain and acute leukemia, cytoplasmic) gene expression in 100 consecutive patients with intermediate and poor cytogenetic risk de novo acute myeloid leukemia (AML) receiving conventional anthracycline-AraC based therapy. We observed a strict relationship between unfavorable karyotype and BAALC >1000 ( p == 0.0001). Multivariate analysis of 81 patients with intermediate karyotype revealed that younger age ( p == 0.00009), NPM gene mutation ( p == 0.002), and WT1 >75th percentile (>2365) ( p == 0.003) were independent, positive factors for complete remission (CR). WT1 expression above 2365 was correlated also to longer event-free survival (EFS) and overall survival (OS) in the same subset of patients ( p == 0.003 and p == 0.02, respectively); the same finding occurred in younger patients with AML with intermediate karyotype ( p == 0.008 and p == 0.01, respectively). In patients with intermediate karyotype, FLT3 internal tandem duplication (ITD) negatively affected EFS (EFS at 30 months: 30%% vs. 6%% in FLT3-ITD negative and FLT3 positive patients, respectively; p == 0.01) and OS (OS at 30 months: 38%% vs. 20%%, p == 0.03). The positive prognostic value of high WT1 expression does not have a clear explanation; it may be implicated either with WT1 anti-oncogenic function, or with the stimulating effect of WT1 oncogene on the leukemic cellular cycle, possibly associated with an enhanced response to chemotherapy. [ABSTRACT FROM AUTHOR]

The aim of this study was to elucidate the relationship between clonal and normal haematopoiesis in chronic myelogenous leukemia (CML). Thirteen female patients who reached complete cytogenetic response (CCR) after Imatinib® treatment were studied. Although all the study patients exhibited a polyclonal pattern of X inactivation, p210 BCR/ABL transcript remained detectable in all cases by nested RT-PCR. This study also demonstrated the presence of p190 transcript in nine out of 13 study patients. A longer follow-up analysis is needed to clarify the prognostic value of these results. The recent observation that clonal cytogenetic abnormalities may occur in CML patients in polyclonal remission after imatinib suggests that a neoplastic stem cell lacking BCR/ABL rearrangement may acquire further cytogenetic alterations other than Philadelphia chromosome. [ABSTRACT FROM AUTHOR]

Documents the efficacy of combining fludarabine with other treatment regimens as first line therapy in patients with either post myelodysplastic syndrome or therapy related acute myeloid leukemia. Rate of complete remission; Overall response rate; Patient tolerance; Median time to granulocyte recovery.

Abstract: We report the occurrence of a BCR-JAK2 fusion gene in a case of acute myeloid leukemia (AML) resulting from a t(9;22)(p24;q11) translocation as the sole cytogenetic abnormality. The BCR-JAK2 fusion gene has the same breakpoint in BCR as is found in the BCR/ABL p210. The chimeric gene is the result of a reciprocal translocation between chromosomes 9 and 22, which implies a double break on chromosome 9; this has allowed generating an in-frame fusion transcript. Previously, BCR-JAK2 rearrangement was observed in a single case with atypical chronic myelogenous leukemia (CML), but in that case the breakpoint in the BCR was different. [Copyright &y& Elsevier]

Abstract: Chromosomal translocations involving the 12q14 band are rarely detected in hematological disorders, and are usually correlated with HMGA2 gene expression. HMGA2 is highly expressed during embryonic cell growth and differentiation, and regulates transcription and chromatin organization, but is rarely detectable in adult tissues. We describe a case of polycythemia vera with a t(12;21)(q14;q22). The 12q14 breakpoint was characterized by fluorescence in situ hybridization analysis using the bacterial artificial chromosome RP11-366L20 containing 3′ sequences of the HMGA2 gene. Qualitative and quantitative polymerase chain reaction showed the presence of high levels of HMGA2 gene expression, which were temporarily reduced with hydroxyurea therapy. The present case confirms that involvement of the 12q14 band may be associated with HMGA2 overexpression in chronic Philadelphia chromosome–negative myeloproliferative disease, regardless of the partner chromosome involved in the translocation. Such overexpression may contribute to the pathogenesis of the disease, which otherwise of itself shows a favorable and stable course. [Copyright &y& Elsevier]

The majority of splenic marginal zone lymphoma (SMZL) patients experience an indolent clinical course; however, some cases transform to a high-grade lymphoma. Cytogenetic analyses have shown that chromosome 7 is the most frequently altered chromosome and, in some cases, 7q deletion has been found as a single aberration, suggesting its association with the development of SMZL. We studied one patient showing clinical features of SMZL with an aggressive course. Immunophenotypic, conventional and molecular cytogenetic techniques were applied to support the diagnosis. The immunophenotype of peripheral blood mononuclear cells showed the presence of 90% B-lymphocytes. Cytogenetic analysis indicated the presence of a stem-line lacking normal chromosomes 7, but showing a der(7) and a ring, and a side-line with additional aberrations: t(2;22), add(8). Fluorescence in situ hybridization analysis revealed a loss of the 7q32 region. Nonclonal rearrangements involving chromosome 7 were also detected. Chromosome 7 rearrangements were studied to investigate their evolution during the development of the pathology. We have shown that in this patient both chromosomes 7 underwent different rearrangements leading to a loss of the 7q32 region and that the ring chromosome originated from chromosome 7 and was associated with a t(7;7) (p22;q31). We conclude that not only the 7q deletion but also the proneness of chromosome 7 to rearrange might have played a role in the progression of this SMZL. [Copyright &y& Elsevier]

Introduction: Normal immature hematopoietic progenitors are relatively well preserved in most patients newly diagnosed with chronic myeloid leukemia, but tend to decline rapidly with time. Such exhaustion could reflect a suppressive e3ect of the Philadelphia positive clone expansion and/or be induced by Interferon-α treatment. Patients and methods: A total of 51 CML patients were classified into three groups. Newly diagnosed untreated patients were group A (n = 30). Of the 21 treated individuals with Interferon-α, for at least 12 months, 15 showed no cytogenetic response (group B) while six showed persisting major/complete response (group C). Patients belonging to groups A and B were mobilized with chemotherapy plus G-CSF while patients of group C received a short course of G-CSF only. Results: Patients responding to IFN-α (group C) showed comparable numbers of bone marrow Ph[SUP-] long-term culture initiating cells to those of newly diagnosed individuals (group A): 8.5 (<1 - 65)/10[SUP6] MNC vs 10.5 (<1 - 30), while non-responders had markedly lower numbers: <1 (<1 - 5). The amount of Ph[SUP-] LTC-IC collected was significantly lower in patients of group B 1.8 (0 - 325) × 10[SUP2]/kg than in patients of either group A 31.3 (0 - 952) × 10[SUP2]/kg (P<0.002) or group C 109 (8 - 259) × 10[SUP2]/kg (P<0.01). Interestingly, five patients of group B who had 100% h[SUP+] metaphases, but Ph[SUP-] progenitors in their bone marrow, mobilized normal amounts of Ph[SUP-] progenitors. Conclusion: These findings suggest that the decline of normal hematopoietic progenitors, currently observed in the majority of CML patients, is not induced by IFN-α treatment, but it is likely due to the expanding leukemic clone. They also indicate that normal hematopoietic reservoir is consistently preserved in patients given IFN-α early after diagnosis and achieving a stable cytogenetic response. [ABSTRACT FROM AUTHOR]

Abstract: The cytogenetic studies and molecular evaluation of a Philadelphia chromosome negative chronic myelogenous leukemia patient with trisomy 21 (100% metaphases) and trisomy 9 (50% metaphases) at diagnosis are described. Fluorescence in situ hybridization revealed an atypical location of the BCR/ABL fusion signal on 9q, which was duplicated in cells with trisomy 9 simulating a double Ph. The patient was successfully treated with Glivec (also known as Gleevec; Novartis, Basel, Switzerland) and achieved complete hematological and cytogenetic response as well as a reduction of BCR/ABL transcripts detected by real-time quantitative PCR. [Copyright &y& Elsevier]