<i>MDR1</i> and <i>MRP1</i> gene expression are independent predictors for treatment outcome in adult acute myeloid leukaemia

Schaich, Markus; Soucek, Silke; Thiede, Christian; Ehninger, Gerhard; Illmer, Thomas

doi:10.1111/j.1365-2141.2004.05319.x

Cited by 155 publications

(90 citation statements)

References 40 publications

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“…24 A German study found a positive correlation between the expression of another MDRrelated protein, MRP1, and resistance to FLT3 inhibitors. 25 The additive negative effect on DFS that we observed in ABCG2þ/FLT3þ patients could be explained by a regulatory role of FLT3 mutation on ABCG2. In fact, the constitutive activation of intracellular transcriptional pathways induced by mutated FLT3 may justify the expansion of the entire leukemia progenitor population (explaining the higher WBC count in mutated cases) and the activation of the antiapoptotic machinery in these cells.…”

Section: Discussionmentioning

confidence: 73%

Concomitant ABCG2 overexpression and FLT3‐ITD mutation identify a subset of acute myeloid leukemia patients at high risk of relapse

Tiribelli¹,

Geromin²,

Michelutti³

et al. 2010

Cancer

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BACKGROUND: ABCG2 protein overexpression and FLT3 internal tandem duplication (ITD) correlate with higher relapse rate and shorter disease-free survival (DFS) in acute myeloid leukemia (AML), but no data are available on the possible effect of concomitant presence of these 2 factors. METHODS: The authors analyzed the outcome of 166 cases of adult AML patients who were homogeneously treated with a fludarabine-based induction therapy. RESULTS: ABCG2 overexpression and FLT3-ITD were detected in 83 (50%) and 47 (28%) patients, respectively. A significant correlation was found between ABCG2 positivity and FLT3 mutation, with 33 (40%) ITD in 83 ABCG2-positive patients compared with 14 (17%) ITD in 83 ABCG2-negative patients (P ¼ .002). Complete remission (CR) after induction therapy was achieved in 95 (57%) patients. Neither ABCG2 overexpression nor FLT3-ITD had any impact on achievement of CR. Relapse occurred in 42 of 95 (44%) patients at a median time of 28 months. Time to relapse was shortened in patients overexpressing ABCG2 (P ¼ .0004). DFS was not affected by FLT3-ITD alone, but FLT3 mutation significantly worsened long-term outcome of ABCG2-positive patients. DFS at 1 and 3 years in patients with overexpression of both ABCG2 and FLT3-ITD was only 36% and 28%, respectively; in ABCG2-positive/FLT3-negative patients, DFS at 1 and 3 years was 65% and 48%, respectively; and in ABCG2-negative cases (regardless of FLT3 status), DFS at 1 and 3 years was greater than 85% and 75%. CONCLUSIONS: Concomitant overexpression of ABCG2 and FLT3-ITD is relatively frequent and identifies a subgroup of AML patients with a significantly worse prognosis. The possible interactions between these 2 prognostic factors need to be defined. Cancer 2011;117:2156-62.

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Section: Discussionmentioning

confidence: 73%

Concomitant ABCG2 overexpression and FLT3‐ITD mutation identify a subset of acute myeloid leukemia patients at high risk of relapse

Tiribelli¹,

Geromin²,

Michelutti³

et al. 2010

Cancer

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“…33). However, in our series, only 35% (9 of 26) of ITD+ patients were classified in the monocytic group and FAB M1 mostly (35). The strongest negative effect was found in the intermediate cytogenetic population, with respect to CR achievement, DFS, and OS.…”

Section: Discussionmentioning

confidence: 73%

Flt3 Internal Tandem Duplication and P-Glycoprotein Functionality in 171 Patients with Acute Myeloid Leukemia

Marzac

Teyssandier²,

Calendini³

et al. 2006

Clinical Cancer Research

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Purpose: Patients with adult acute myeloid leukemia (AML) with intermediate cytogenetics remain a heterogeneous group with highly variable individual prognoses. New molecular markers could help to refine cytogenetic stratification. Experimental Design: We assessed P-glycoprotein (Pgp) activity and Flt3 internal tandem duplication (ITD+) because of their known prognostic value and because they might lead to targeted therapy. We did a multivariate analysis on 171 patients with adult AML treated in the European Organization for Research and Treatment of Cancer protocols. Results: ITD+ and high Pgp activity (Pgp+) were found in 26 of 171 (15%) and 55 of 171 (32%) of all patients, respectively. ITD and Pgp activities were negative in 94 of 171 (55%, PgpÀITDÀ group), mutually exclusive in 73 of 171 (43%, PgpÀITD+ and Pgp+ITDÀ groups), and only 4 of 171 (2%, Pgp+ITD+ group) patients were positive for both. In multivariate analyses, Pgp+ITD+ (P < 0.0001) and age (P = 0.0022) were independent prognostic factors for the achievement of complete remission (CR). Overall survival (OS), CR achievement (P < 0.0001),WHO performance status (P = 0.0007), and Pgp+ITD+ status (P = 0.0014) were also independent prognostic factors. In 95 patients with intermediate cytogenetics, the CR rates of ITD+ patients were 40% versus 62% for ITDÀ (P = 0.099) and 41% versus 67% (P = 0.014) for Pgp+ versus PgpÀ patients. In the PgpÀITDÀ group (41 of 95), CR rates were 70 % versus 44% for others (P = 0.012), OS achieved 48% versus 16% (P < 0.0001) and disease-free survival was 56% versus 27% (P = 0.024), respectively. Furthermore, the OS curves of the intermediate cytogenetics-PgpÀITDÀ group were not significantly different from the favorable cytogenetic group. Conclusion: Flt3/ITD and Pgp activity are independent and additive prognostic factors which provide a powerful risk classification that can be routinely used to stratify the treatment of patients with intermediate cytogenetic AML. ITD+ and Pgp+ patients should be considered for targeted therapy.

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“…Recently published data of multi-drug-resistance gene expression showed negative influence on therapy response in complex aberrant patients. 37 Association of p53 deletion and MDR1 expression has been confirmed for CML, but not for AML. 38 An independent negative additive effect with decreased induction of apoptosis and increased cytostatica efflux can therefore be considered.…”

Section: Discussionmentioning

confidence: 90%

The prognostic impact of 17p (p53) deletion in 2272 adults with acute myeloid leukemia

et al. 2009

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Loss of p53Fa tumor suppressor gene located on the short arm of chromosome 17 (band 17p13.1)Fwas detected in 105 out of 2272 (5%) adult acute myeloid leukemia (AML) patients who took part in the Study Alliance Leukemia AML96 and AML2003 multi center trials. There were 85 patients with 17p (p53) deletion with multiple aberrations and 20 patients with a 17p (p53) deletion as single aberration or with only one additional chromosomal abnormality. None of the p53-deleted patients displayed additional low-risk aberrations, like t(8;21) or inv(16). Significant positive association between p53 deletion and other high-risk factors was identified for del(5q) (Po0.001), À5 (Po0.001) and À7 (Po0.05). The molecular risk factors FLT3-ITD and NPM1 mutation showed an inverse correlation to the p53 deletion in complex aberrant patients (Po0.001). The multivariate analysis revealed p53 deletion without multiple aberrations as an independent negative prognostic factor for disease-free survival (Po0.001), relapse risk (P ¼ 0.028) and overall survival (Po0.001). Thus, the single p53 deletion should be considered as a high-risk aberration for future risk-adapted treatment strategies in AML.

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MDR1 and MRP1 gene expression are independent predictors for treatment outcome in adult acute myeloid leukaemia

Cited by 155 publications

References 40 publications

Concomitant ABCG2 overexpression and FLT3‐ITD mutation identify a subset of acute myeloid leukemia patients at high risk of relapse

Concomitant ABCG2 overexpression and FLT3‐ITD mutation identify a subset of acute myeloid leukemia patients at high risk of relapse

Flt3 Internal Tandem Duplication and P-Glycoprotein Functionality in 171 Patients with Acute Myeloid Leukemia

The prognostic impact of 17p (p53) deletion in 2272 adults with acute myeloid leukemia

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