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Purpose: Evaluate the impact of BAALC (brain and acute leukemia, cytoplasmic), a gene whose expression has been associated with adverse outcome in acute myeloid leukemia (AML) with normal cytogenetics, and FLT3 internal tandem duplication (ITD) mutations as independent prognostic factors in a larger study., Patients and Methods: BAALC expression was determined by real-time reverse transcriptase polymerase chain reaction in pretreatment blood samples of 307 adults

Multi drug resistance (MDR) is a major obstacle for cancer therapy. The three major candidates accounting for the development of MDR in acute myeloid leukaemia (AML) are multi drug resistance gene (MDR1), multi drug resistance-related protein gene (MRP1) and lung resistance protein gene (LRP). So far, the differential impact of resistance gene expression on treatment outcome in AML is not clear. Therefore, we examined MDR1, MRP1 and LRP gene expression at diagnosis in 331 adult AML patients in the context of other known prognostic factors, such as age, disease status, cytogenetics and FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication mutational status. Median observation time was longer than 5 years [64.1 months (40.0-87.6)]. MDR1 expression proved to be an independent prognostic factor for outcome of induction therapy (P <0.001) and overall survival (P=0.02), whereas MRP1 expression was an independent predictor for disease-free survival (P=0.01) in the multivariate analysis. This prognostic impact of both resistance genes was also found in patients with intermediate risk cytogenetics. LRP expression, however, had no impact on treatment outcome in AML. Our study shows that resistance gene expression should be considered together with age, cytogenetics and FLT3 mutational status for risk-adapted treatment strategies in AML in the future.

Acute myeloid leukaemia (AML) carrying t(8;21) has an overall favourable prognosis. However, relapse occurs and the impact of multidrug resistance gene (MDR1) expression on recurring disease in this group of patients is not known. We determined quantifiable MDR1 expression in the bone marrow of 28 AML patients with t(8;21) by a validated real-time polymerase chain reaction assay. Using MDR1 expression, white blood cell count and CD56 expression at diagnosis we observed complete concordance of predicted and observed relapses. A calculated logit out of these three variables was a strong independent prognostic factor for overall (P = 0.007) and disease-free survival (P = 0.002).

Background: Chromosomal abnormalities are one of the most important prognostic factors in acute myeloid leukemia (AML). However, only a limited number of patients have such informative chromosomal abnormalities. The prognostic value of immunophenotyping in this disease is still unclear., Methods: Seven hundred and eighty-three newly diagnosed AML patients treated in the German SHG-AML trials in 1991 and 1996 were analyzed with a panel of 33 antibodies. Expression was correlated to overall survival, complete remission-rate, and complete remission duration, and tested in a multivariate analysis including other clinical and biological markers., Results: With a median follow-up of 4.3 years, patients with AML blasts negative for CD9, CD11b, CD13, CD34, and CD41, or positive for CD15, CD33, CD38, CD64, and MPO had superior overall survival. This effect was associated with a significantly higher complete remission rate (CD13, CD34, CD41, and CD64) or a longer complete remission duration (CD9, CD11b, and CD64). Cox-regression analysis, including cytogenetic, morphologic, and biologic parameters showed CD9, CD13, CD34, and CD64 as independent factors for overall survival. These markers were used for a prognostic score. Patients were pooled in three groups with highly significant differences of overall survival. The prognostic relevance of this score was confirmed in patients with normal karyotype and/or in younger patients

Background and Objectives: Treatment outcome in elderly patients with acute myeloid leukemia (AML) is still disappointing. However, some trials showed that increasing the dosage of anthracyclines within induction therapy improved treatment outcome substantially. We, therefore, tried to escalate induction therapy further in a group of young elderly AML patients., Design and Methods: In a multicenter trial 33 patients aged 61-65 years with de novo or secondary AML were treated with double induction therapy including high dose mitoxantrone, etoposide and ara-C (MAV) in the first course and m-amsacrine together with high dose ara-C (MAMAC) in the second course. Treatment results were compared to those in 39 AML patients older than 65 years receiving conventional double induction therapy including daunorubicin and ara-C (DA I and DA II) within the same time period., Results: Compared to results achieved with conventional induction therapy, intensified double induction therapy did not significantly improve CR rates, overall or disease-free survival. Hematologic toxicity was not different between the two groups, but non-hematologic toxicity was significantly higher with MAV/MAMAC. This was mainly due to gastro-intestinal or liver toxicity. The rate of early mortality (death within the first 12 weeks) was 42% in the group receiving intensified therapy and 18% in that given conventional induction therapy (p=0.04)., Interpretation and Conclusion: Intensification of double induction therapy using high dose mitoxantrone and high dose ara-C in AML patients aged 61-65 years did not lead to improved treatment outcome and conferred an unacceptable early death rate due to high non-hematologic toxicity. Risk-adapted or alternative treatment strategies are needed to improve treatment outcome in these young elderly AML patients.

Background and Objectives: Cytogenetics and mdr1 expression are established prognostic factors for treatment outcome in adult acute myeloid leukemia (AML). The association, however, between specific cytogenetic aberrations and mdr1 expression has not yet been examined in a large cohort of patients., Design and Methods: We therefore looked for mdr1 gene expression at diagnosis within specific cytogenetic aberrations in 331 previously untreated adult patients with de novo or secondary AML (not including t(15;17)) entered into the German SHG AML96 treatment trial., Results: The proportion of mdr1 positive blast probes was significantly higher in patients with aberrant karyotypes than in those with normal karyotypes (39% vs. 15%; p<0.001). Looking at specific cytogenetic aberrations significantly more mdr1 positive AML patients were found within t(8;21), +8, +21, del(7q), del(5q), -7, abn(3q) and multiple aberrations. In contrast, no patient with inv(16) was positive for mdr1. Only 26% of mdr1 positive patients with aberrant karyotypes achieved complete remission (CR) whereas 54% of the mdr1 negative counterparts did so (p=0.002). Furthermore, within abn(11q), +21, +22, -5 or abn(3q) no mdr1 positive patient reached CR, whereas the mdr1 negative counterparts had CR rates comparable to the CR rate of patients with a normal karyotype. This was most impressive in mdr1 negative patients with multiple aberrations achieving a CR rate of 63% (p=0.019). In the multivariate analysis age, disease status and mdr1 expression were the strongest independent predictors for induction treatment failure., Interpretation and Conclusions: The correlation described here between mdr1 gene expression and some cytogenetic aberrations might explain the prognostic divergence of such cytogenetic aberrations in different AML treatment trials due to the amount of mdr-drugs used within the protocols.