scholarly journals MDR1 gene–related clonal selection and P-glycoprotein function and expression in relapsed or refractory acute myeloid leukemia

Blood ◽  
2001 ◽  
Vol 97 (11) ◽  
pp. 3605-3611 ◽  
Author(s):  
Marry M. van den Heuvel-Eibrink ◽  
Erik A. C. Wiemer ◽  
Marjan J. de Boevere ◽  
Bronno van der Holt ◽  
Paula J. M. Vossebeld ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Genetic Polymorphism ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Clonal Selection ◽  
Survival Rates ◽  
Mdr1 Gene ◽  
Allelic Variants ◽  
P Glycoprotein ◽  
Acute Myeloid

The expression of P-glycoprotein (P-gp), encoded by theMDR1 gene, is an independent adverse prognostic factor for response and survival in de novo acute myeloid leukemia (AML). Little is known about MDR1 expression during the development of disease. The present study investigated whether MDR1 gene– related clonal selection occurs in the development from diagnosis to relapsed AML, using a genetic polymorphism of the MDR1 gene at position 2677. Expression and function of P-gp were studied using monoclonal antibodies MRK16 and UIC2 and the Rhodamine 123 retention assay with or without PSC 833. No difference was found in the levels of P-gp function and expression between diagnosis and relapse in purified paired blast samples from 30 patients with AML. Thirteen patients were homozygous for the genetic polymorphism ofMDR1 (n = 7 for guanine, n = 6 for thymidine), whereas 17 patients were heterozygous (GT). In the heterozygous patients, no selective loss of one allele was observed at relapse. Homozygosity for the MDR1 gene (GG or TT) was associated with shorter relapse-free intervals (P = .002) and poor survival rates (P = .02), compared with heterozygous patients. No difference was found in P-gp expression or function in patients with AML with either of the allelic variants of the MDR1 gene. It was concluded that P-gp function or expression is not upregulated at relapse/refractory disease and expression of one of the allelic variants is not associated with altered P-gp expression or function in AML, consistent with the fact that MDR1 gene–related clonal selection does not occur when AML evolves to recurrent disease.

Clinical relevance of P-glycoprotein expression in de novo acute myeloid leukemia

Blood ◽  
1996 ◽  
Vol 87 (5) ◽  
pp. 1997-2004 ◽  
Author(s):  
G Del Poeta ◽  
R Stasi ◽  
G Aronica ◽  
A Venditti ◽  
MC Cox ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Survival Rates ◽  
Disease Free Survival ◽  
Normal Karyotype ◽  
Free Survival ◽  
Negative Phenotype ◽  
Acute Myeloid

Abstract Cytofluorimetric detection of the multidrug resistance (MDR)-associated membrane protein (P-170) was performed at the time of diagnosis in 158 patients with acute myeloid leukemia using the C219 monoclonal antibody (MoAb). In 108 of these cases the JSB1 MoAb was also tested. An improved histogram subtraction analysis, based on curve fitting and statistical test was applied to distinguish antigen-positive from antigen-negative cells. A marker was considered positive when more than 20% of the cells were stained. At onset, P-170 was detected in 43% of cases with C219 and in 73% of cases with JSB1. There was a strict correlation between C219 and JSB1 positivity, as all C219+ cases were also positive for JSB1 MoAb (P < .001). No relationship was found between sex, age, organomegaly, and MDR phenotype. Significant correlation was found between CD7 and both C219 and JSB1 expression (P < .001 and .001, respectively). C219-negative phenotype was more often associated with a normal karyotype (24 of 55 with P = .030). Rhodamine 123 (Rh123) staining and flow cytometry analysis showed a significantly decreased mean fluorescence in 51 C219+ and 38 JSB1+ patients compared to 42 MDR negative ones (P < .001). The rate of first complete remission (CR) differed both between C219+ and C219- cases and between JSB+ and JSB- ones (30.9% v 71.1% and 35.4% v 93.1%, respectively, P < .001). Of the 21 C219+ patients who had yielded a first CR, 19 (90.4%) relapsed, compared with 28 of 64 (43.7%) C219- patients (P < .001). Of the 28 JSB1+ patients in first CR, 17 (60.7%) relapsed relative to 8 (29.6%) of 27 JSBI- ones (P = .021). A higher rate of relapses among MDR+ compared with MDR- patients was observed both for C219 and JSB1 MoAbs taken separately (C219 80% v 44%; JSB1 52% v 27%), with no relationship to age. The survival rates (Kaplan-Meyer method) were significantly shorter both in C219+ patients and in JSB1+ cases (P < .001). Disease-free survival curves followed this same trend. The combination (C219- JSB1+) identified a subset of patients with an intermediate outcome compared to C219 positive cases. The prognostic value of both markers (C219 and JSB1) was confirmed in multivariate analysis. These results suggest that the assessment of MDR phenotype by flow cytometry may be an important predictor of treatment outcome.

P-Glycoprotein Expression in De Novo Acute Myeloid Leukemia

1997 ◽  
Vol 27 (3-4) ◽  
pp. 257-274 ◽  
Author(s):  
Giovanni Del Poeta ◽  
Adriano Venditti ◽  
Germano Aronica ◽  
Roberto Stasi ◽  
Maria Cristina Cox ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
P Glycoprotein ◽  
Acute Myeloid

scholarly journals Clinical relevance of P-glycoprotein expression in de novo acute myeloid leukemia

Blood ◽  
1996 ◽  
Vol 87 (5) ◽  
pp. 1997-2004 ◽  
Author(s):  
G Del Poeta ◽  
R Stasi ◽  
G Aronica ◽  
A Venditti ◽  
MC Cox ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Survival Rates ◽  
Disease Free Survival ◽  
Normal Karyotype ◽  
Free Survival ◽  
Negative Phenotype ◽  
Acute Myeloid

Cytofluorimetric detection of the multidrug resistance (MDR)-associated membrane protein (P-170) was performed at the time of diagnosis in 158 patients with acute myeloid leukemia using the C219 monoclonal antibody (MoAb). In 108 of these cases the JSB1 MoAb was also tested. An improved histogram subtraction analysis, based on curve fitting and statistical test was applied to distinguish antigen-positive from antigen-negative cells. A marker was considered positive when more than 20% of the cells were stained. At onset, P-170 was detected in 43% of cases with C219 and in 73% of cases with JSB1. There was a strict correlation between C219 and JSB1 positivity, as all C219+ cases were also positive for JSB1 MoAb (P < .001). No relationship was found between sex, age, organomegaly, and MDR phenotype. Significant correlation was found between CD7 and both C219 and JSB1 expression (P < .001 and .001, respectively). C219-negative phenotype was more often associated with a normal karyotype (24 of 55 with P = .030). Rhodamine 123 (Rh123) staining and flow cytometry analysis showed a significantly decreased mean fluorescence in 51 C219+ and 38 JSB1+ patients compared to 42 MDR negative ones (P < .001). The rate of first complete remission (CR) differed both between C219+ and C219- cases and between JSB+ and JSB- ones (30.9% v 71.1% and 35.4% v 93.1%, respectively, P < .001). Of the 21 C219+ patients who had yielded a first CR, 19 (90.4%) relapsed, compared with 28 of 64 (43.7%) C219- patients (P < .001). Of the 28 JSB1+ patients in first CR, 17 (60.7%) relapsed relative to 8 (29.6%) of 27 JSBI- ones (P = .021). A higher rate of relapses among MDR+ compared with MDR- patients was observed both for C219 and JSB1 MoAbs taken separately (C219 80% v 44%; JSB1 52% v 27%), with no relationship to age. The survival rates (Kaplan-Meyer method) were significantly shorter both in C219+ patients and in JSB1+ cases (P < .001). Disease-free survival curves followed this same trend. The combination (C219- JSB1+) identified a subset of patients with an intermediate outcome compared to C219 positive cases. The prognostic value of both markers (C219 and JSB1) was confirmed in multivariate analysis. These results suggest that the assessment of MDR phenotype by flow cytometry may be an important predictor of treatment outcome.

The comparative effectiveness of glasdegib in combination with low-dose cytarabine versus azacitidine by bone marrow blasts counts among patients with newly-diagnosed acute myeloid leukemia who are ineligible for intensive chemotherapy.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e19512-e19512
Author(s):  
Sophie van Beekhuizen ◽  
Yannan Hu ◽  
Ana Gezin ◽  
Bart Heeg ◽  
Timothy Bell ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Meta Analysis ◽  
Survival Rates ◽  
Open Label ◽  
Treatment Comparison ◽  
Treatment Comparisons ◽  
Acute Myeloid

e19512 Background: Acute myeloid leukemia (AML) is an orphan disease with one of the lowest five-year survival rates among myeloid malignancies. Recently, a randomized, open label study among previously untreated, chemotherapy-ineligible AML patients demonstrated improved overall survival (OS) among patients treated with glasdegib (GLAS) + LDAC compared with LDAC alone. Two trials of AZA vs. conventional care regimens report data by bone marrow blast (BMB) counts: one with 20-30% and the other with >30%. In the absence of head-to-head comparisons, this study aims to perform the indirect treatment comparison between GLAS+LDAC and AZA by BMB counts. Methods: As there were potential imbalances between the GLAS and AZA trials and within the AZA trial arms in the baseline characteristics (e.g. poor cytogenetics% and de novo%), simulated treatment comparisons (STCs) for GLAS+LDAC vs. LDAC were performed to derive robust estimation by adjusting for the imbalances in the baseline effect modifiers. Afterwards, the classical network meta-analysis (NMA) was conducted. To derive the hazard ratio (HR) of GLAS+LDAC vs. AZA, three NMAs were conducted in each BMB group. Each NMA used a different HR of GLAS+LDAC vs. LDAC: 1) an unadjusted HR (classical NMA), 2) an STC adjusted HR adjusting for potential imbalances between the trials, and 3) an STC adjusted HR additionally accounting for potential imbalances between arms within the AZA trial. Results: In the 20-30% BMB group (N = 30), the OS HRs of GLAS+LDAC vs. AZA resulting from the three respective NMAs were as follows: 1) 0.46 [95% confidence interval: 0.10-2.14], 2) 0.31 [0.06-1.69], and 3) 0.36 [0.06-2.15]. In the > 30% BMB group (N = 80), the HRs were 1) 0.69 [0.39-1.20], 2) 0.48 [0.23-0.97], and 3) 0.48 [0.24-1.00]. All the HRs suggest that patients with GLAS+LDAC have a survival advantage over patients with AZA. Conclusions: Both the classical NMAs and the NMAs based on the STC adjusted HRs correcting for the potential imbalances at baseline suggest that GLAS+LDAC may be preferred over AZA as a treatment option for previously untreated chemotherapy-ineligible AML patients regardless of BMB counts. [Table: see text]

Increase in the Incidence of Secondary Acute Myeloid Leukemia (2-AML): A Single Institution Experience Over 20 Years.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1498-1498
Author(s):  
Elias Jabbour ◽  
Hagop M Kantarjian ◽  
Sherry Pierce ◽  
Guillermo Garcia-Manero ◽  
Jorge Cortes ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Median Survival ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Survival Rates ◽  
Primary Cancer ◽  
Chromosome 11 ◽  
Secondary Acute Myeloid Leukemia ◽  
Acute Myeloid ◽  
Clonal Abnormalities

Abstract Secondary acute myeloid leukemia (2-AML) is a distinctive clinical syndrome occurring after primary malignancy treated or not with chemotherapy (CT), radiotherapy (RT), surgery, or a multimodality strategy. We analyzed the data on 2898 consecutive patients (pts) with AML (WHO criteria) referred to our institution between 1985 and 2005, including 1642 males and 1256 females. The median age was 58 years (range, 13–89 years) for pts with de novo AML (1-AML) (n=2198) and 66 years (range, 18–89 years) for those with 2-AML (n=700). 171 pts (18%) were treated for 2-AML between 1985 and 1994 versus 529 patients (27%) treated between 1995 and 2005 (p&lt;0.001). The predominant primary malignancies included lymphoma (18%), breast (16%), and prostate (13%). Pts had been administered various cytotoxic chemotherapy agents (185 pts, 26%) and RT (102 pts, 15%); 182 (26%) had undergone both modalities, and 231 pts (33%) had undergone surgery alone. At diagnosis, 181 (26%) pts with 2-AML had diploid cytogenetics versus 845 (38%) pts with 1-AML (p&lt;0.001). 252 (32%) pts with 2-AML had clonal abnormalities involving chromosomes 5 and 7 versus 383 (17%) pts with 1-AML (p&lt;0.001), and 49 (7%) pts with 2-AML had 11q abnormalities versus 73 (3%) with 1-AML (p&lt;0.001). Pts undergoing CT/RT had a worse cytogenetic risk profile compared to those undergoing surgery alone with more clonal abnormalities involving chromosomes 5 and 7 (36% versus 24%; p=0.002) and chromosome 11 (10% versus 2%; p&lt;0.001), and less diploid karyotype (19% versus 39%; p&lt;0.001). Median survival time after diagnosis of 2-AML was 6 months with 2- and 5-year survival rates of 18% and 11%, respectively. The median survival for pts treated with surgery alone for the primary cancer was 8 months versus 5 months for those receiving CT/RT (p=0.007); their 2- and 5-year survival rates were 22% and 14% and 16% and 9%, respectively. The median survival for pts treated for their primary cancer between 1985 and 1994 was 4 months versus 6 months for those treated after 1994 (p=0.089); their 2-year and 5-year survival rates were 16% and 9% and 19% and 12%, respectively. In conclusion, the incidence of 2-AML is increasing; patients receiving CT/RT had worse cytogenetic profiles and clinical outcomes than those receiving surgical treatment alone. There remains to be seen whether increased use of targeted therapies as prime modality of therapy in primary cancers will be associated with a decreased risk of 2-AML.

scholarly journals Predictive value for treatment outcome in acute myeloid leukemia of cellular daunorubicin accumulation and P-glycoprotein expression simultaneously determined by flow cytometry

Blood ◽  
1995 ◽  
Vol 85 (8) ◽  
pp. 2147-2153 ◽  
Author(s):  
A Guerci ◽  
JL Merlin ◽  
N Missoum ◽  
L Feldmann ◽  
S Marchal ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Glycoprotein P ◽  
Double Labeling ◽  
P Glycoprotein ◽  
De Novo Aml ◽  
Acute Myeloid

To evaluate the clinical relevance of multidrug resistance (MDR) phenotype, the intracellular daunorubicin accumulation (IDA) and P-glycoprotein (P-gp) expression were investigated in 87 adult patients with acute leukemia: 69 patients with de novo acute myeloid leukemia (AML), 10 with AML at relapse, and eight with secondary leukemia to myelodysplastic syndromes (MDS-AML). IDA and P-gp expression were determined by double-labeling flow cytometry analysis. Of 87 patients, 36 expressed P-gp (41%). P-gp expression was more frequently observed in AML at relapse and MDS-AML as compared with de novo AML (P = .0001). P-gp expression was significantly associated with CD34 expression (P = .0003) and chromosome 7 abnormalities (P = .027). A significantly reduced IDA was observed in P-gp+ as compared with P-gp- patients (P = .0007). Of the 87 patients, 51 achieved complete remission (CR). A reduced IDA was observed in patients in failure as compared with patients in CR (22% +/- 17% v 42% +/- 21%; P = 10(-4). Twelve of 36 P-gp+ patients as compared with 40 of 51 P-gp- patients achieved CR (33% v 78%; P = 10(-4). The prognostic value of IDA and P-gp expression was confirmed in multivariate analysis. These data suggest that the determination of IDA and P-gp expression may be useful in designing therapy for patients with AML.

Pediatric Therapy-Related Myelodysplastic Syndrome/Acute Myeloid Leukemia: The M. D. Anderson Cancer Center Experience

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5068-5068
Author(s):  
Dolly G Aguilera ◽  
Christos Vaklavas ◽  
Apostolia-Maria Tsimberidou ◽  
Sijin Wen ◽  
L. Jeffrey Medeiros ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myelodysplastic Syndrome ◽  
Myeloid Leukemia ◽  
Poor Prognosis ◽  
De Novo ◽  
Survival Rates ◽  
Latency Period ◽  
Cancer Center ◽  
Time Interval ◽  
Acute Myeloid

Abstract Background: Therapy-related myelodysplastic syndrome/acute myeloid leukemia (t-MDS/AML) is a long-term complication of pediatric cancer and it carries a poor prognosis. Patients and Methods: We retrospectively studied pediatric t-MDS/AML patients treated at M. D. Anderson from 1975 to 2007. We also compared these patients to pediatric patients with de novo MDS/AML during this time interval. Results: Among 2589 children with cancer treated at M. D. Anderson, we identified 22 (0.85%) patients with t-MDS/AML and 141 (5.4%) patients with de novo MDS/AML. Patients with t-MDS/AML had a median age of 14 years (range, 3–20). There was a male and Hispanic predominance. The most common primary malignancies were osteosarcoma and Hodgkin lymphoma. The median latency period was 4.1 years. Fourteen patients received AML-type chemotherapy, 5 underwent allogeneic stem cell transplantation (SCT) as induction therapy, and 3 received supportive care. Fourteen patients underwent SCT as induction (n=5), post-remission (n=5), or salvage therapy (n=4). Their respective 2-year survival rates were 20%, 40%, and 25% (p= 0.85). Patients with de novo AML were younger (p=0.001), and had higher rates of CR (p=0.03), and survival (p&lt;0.0001). Independent factors predicting shorter survival were poor/intermediate-risk cytogenetics (p=0.01), lower hemoglobin level (p=0.0001), and t-MDS/AML (vs. de novo) (p=0.003). Conclusion: Childhood t-MDS/AML has a poor prognosis. Although patients benefited from AML-type induction chemotherapy followed by SCT as post-remission therapy, effective therapies are needed.

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