Differential ex vivo drug resistance profile in first and subsequent relapsed childhood acute myeloid leukemia in comparison to initial diagnosis

2012 ◽  
Vol 26 (2) ◽  
Author(s):  
Beata Kuryło-Rafińska ◽  
Beata Kołodziej ◽  
Małgorzata Kubicka ◽  
Mariusz Wysocki ◽  
Jan Styczyński
Keyword(s):  
Drug Resistance ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Ex Vivo ◽  
Initial Diagnosis ◽  
Resistance Profile ◽  
Drug Resistance Profile ◽  
Childhood Acute Myeloid Leukemia ◽  
Acute Myeloid

Prognostic Impact of Combined Ex Vivo Drug Resistance to Fludarabine, Treosulphan and Mitoxantrone in Childhood Acute Myeloid Leukemia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2780-2780
Author(s):  
Jan Styczynski ◽  
Mariusz Wysocki ◽  
Agnieszka Dluzniewska ◽  
Krzysztof Czyzewski ◽  
Robert Debski ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Prognostic Value ◽  
De Novo ◽  
Ex Vivo ◽  
Prognostic Significance ◽  
Resistance Profile ◽  
Drug Resistance Profile ◽  
Childhood Acute Myeloid Leukemia ◽  
Acute Myeloid

Abstract Combined ex vivo drug resistance profile to prednisolone, vincristine and L-asparaginase (PVA) has prognostic significance in childhood de novo ALL (Den Boer JCO 2003, Styczynski JCO 2004). So far, no data exist to support prognostic value of in vitro drug resistance profile in childhood acute myeloid leukemia (AML). The aim of this study was the analysis of prognostic value of ex vivo drug resistance profile in childhood AML. A total number of 90 children (46 male, 44 female) aged 0.1–17 yrs (median 10 yrs), with de novo AML were included into the study. All patients were recruited between 1999 and 2004 and were treated according to ANLL-98 protocol. Patients with early deaths were excluded from the study. Drug resistance profile was done by the MTT assay in one laboratory for 4–24 drugs. According to median cytotoxicity for each of tested drugs, all patients were scored as resistant or sensitive to this drug. Patients who received a HSC transplantation were censored at the time of transplantation. Drug resistance profile and other known prognostic parameters, were examined by Kaplan-Meier method and by multivariate analysis using the Cox regression proportional hazard model. Probability of overall survival was 0.57±0.05, p(LFS)=0.72±0.05, mean LFS 3.36 yrs (95%CI=2.95–3.77). Relapses occurred in 17/90 children; 40/90 children died during follow-up. Children who relapsed during follow-up showed median higher in vitro resistance of leukemic blasts to most of tested drugs, except for cytarabine, cladribine, vincristine, mercaptopurine and thioguanine. Better LFS was observed for patients with favourable cytogenetics (1.00 vs 0.74±0.09, p=0.055); early BM response by day 15 (0.76±0.07 vs 0.54±0.13, p=0.013); BM remission by day 28 of induction (0.74±0.07 vs 0.35±0.26, p=0.018); ex-vivo sensitive patients to cyclophosphamide (0.83±0.15 vs 0.65±0.09, p=0.12), doxorubicin (0.81±0.12 vs 0.64±0.09, p=0.18), epirubicin (0.72±0.13 vs 0.61±0.12, p=0.26), fludarabine (0.73±0.12 vs 0.62±0.11, p=0.22), mitoxantrone (0.77±0.12 vs 0.51±0.13, p=0.07), treosulphan (0.88±0.12 vs 0.62±0.11, p=0.29), etoposide (0.70±0.13 vs 0.63±0.09, p=0.4) and for patients with leukemic cells being sensitive to fludarabine, treosulphan and mitoxantrone ie. FTM score (0.73±0.12 vs 0.50±0.14, p=0.034). In multivariate analysis, two factors showed prognostic value: early BM response by day 15 (p=0.0021; HR=0.29, 95%CI=0.13–0.64) and combined ex vivo drug resistance profile to fludarabine, treosulphan and mitoxantrone (FTM score), p=0.0048; HR=0.38, 95%CI=0.19–0.77. Combined ex vivo drug resistance profile to fludarabine, treosulphan and mitoxantrone has prognostic significance in childhood acute myeloid leukaemia, however cytogenetics and early bone marrow response to therapy seems to have stronger prognostic value.

scholarly journals ABCA3 as a Possible Cause of Drug Resistance in Childhood Acute Myeloid Leukemia

2006 ◽  
Vol 12 (14) ◽  
pp. 4357-4363 ◽  
Author(s):  
Daniel Steinbach ◽  
Jean-Pierre Gillet ◽  
Axel Sauerbrey ◽  
Bernd Gruhn ◽  
Kristin Dawczynski ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Childhood Acute Myeloid Leukemia ◽  
Possible Cause ◽  
Acute Myeloid

scholarly journals Clinical Significance of ABCB1 in Acute Myeloid Leukemia: A Comprehensive Study

Cancers ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 1323 ◽  
Author(s):  
Boyer ◽  
Gonzales ◽  
Barthélémy ◽  
Marceau-Renaut ◽  
Peyrouze ◽  
...  
Keyword(s):  
Gene Expression ◽  
Drug Resistance ◽  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Myeloid Leukemia ◽  
Ex Vivo ◽  
Standard Chemotherapy ◽  
Poor Prognostic Factor ◽  
Transporter Family ◽  
Acute Myeloid

ABCB1 is a member of the ATP binding cassette transporter family and high ABCB1 activity is considered as a poor prognostic factor in acute myeloid leukemia (AML) treated with intensive chemotherapy, its direct relation with drug resistance remains unclear. We evaluated ABCB1 activity in relation with clinical parameters and treatment response to standard chemotherapy in 321 patients with de novo AML. We assessed multiple clinical relationships of ABCB1 activity—ex vivo drug resistance, gene expression, and the ABCB1 inhibitor quinine were evaluated. ABCB1 activity was observed in 58% of AML and was linked to low white blood cell count, high expression of CD34, absence of FLT3-ITD, and absence of mutant NPM1. Moreover, ABCB1 activity was associated with worse overall- and event-free survival. However, ABCB1 activity did not directly lead to ex vivo drug resistance to anthracyclines. We found that ABCB1 was highly correlated with gene expressions of BAALC, CD34, CD200, and CD7, indicating that ABCB1 expression maybe a passenger characteristic of high-risk AML. Furthermore, ABCB1 was inversely correlated to HOX cluster genes and CD33. Thus, low ABCB1 AML patients benefited specifically from anti-CD33 treatment by gemtuzumab ozogamicin in addition to standard chemotherapy. We showed prognostic importance of ABCB1 gene expression, protein expression, and activity. Furthermore, ABCB1 was not directly linked to drug resistance, ABCB1 inhibition did not improve outcome of high ABCB1 AML patients and thus high ABCB1 may represent a passenger characteristic of high-risk AML.

High Expression of MDR1 and BCRP1 in Leukemic Stem Cells Correlates with Reversible Drug Resistance Ex Vivo and Predicts Failure of Remission Induction Chemotherapy in Patients with Acute Myeloid Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3385-3385
Author(s):  
Maria M. Ho ◽  
Donna E. Hogge ◽  
Victor Ling
Keyword(s):  
Stem Cells ◽  
Drug Resistance ◽  
Acute Myeloid Leukemia ◽  
Abc Transporter ◽  
Abc Transporters ◽  
Myeloid Leukemia ◽  
Drug Sensitivity ◽  
Ex Vivo ◽  
Leukemic Stem Cells ◽  
Acute Myeloid

Abstract Although overexpression of members of the ATP-Binding-Cassette (ABC) transporter superfamily has been implicated in chemotherapy failure in acute myeloid leukemia (AML) in some studies, results have been conflicting. Previously we found no consistent difference in pre-treatment ABC transporter expression when comparing total blasts of 18 patients achieving complete remission (CR) and 13 patients who were refractory to induction chemotherapy (NR). However, among the CD34+CD38− AML cells (enriched for candidate “leukemic stem cells” which engraft in immunodeficient mice), as assessed by quantitative RT-PCR, elevated expression of MDR1 and/or BCRP1, two ABC transporters associated with drug resistance, was found in 8/10 NR patients as compared to 0/7 CR patients. No difference between CR and NR samples was observed in the more differentiated CD34+CD38+ or CD34− AML cells while none of the subpopulations showed a significant difference in MRP1 expression between CR and NR patient samples. To determine if this difference in gene expression was associated with altered functional activity of MDR1/BCRP1, the relative sensitivity of subpopulations of AML cells to induction of apoptosis following ex vivo treatment with daunorubicin with or without ABC inhibitors (PSC-833 and Verapamil) was assessed. All subpopulations of AML cells isolated from 2 CR patients showed similar drug sensitivity profiles (IC50 <0.04 μg/ml). In contrast, CD34+CD38− cells from 6 NR patients were more resistant to daunorubicin-induced apoptosis (p<0.05 for comparison of IC50s between CR and NR samples). ABC transporter inhibition in CD34+CD38− cells did not change daunorubicin sensitivity in CR samples, but increased drug sensitivity in a dose-dependent manner in NR samples, particularly in the CD34+CD38− fraction. This suggests a role for ABC transporters in sustaining a population of chemotherapy resistant leukemic stem cells which may allow survival of the malignant clone in patients following induction therapy. If the value of measuring MDR1/BCRP1 expression among these cells in predicting chemotherapy outcome is confirmed in a larger patient population, it may be possible to use such analysis to modify therapy for individual AML patients to overcome drug resistance.

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