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P-glycoprotein 170 expression and function as an adverse independent prognostic factor in childhood acute
F Casale1, V D'Angelo, R Addeo
1Pediatric Oncology Service, Pediatric Department, II University of Naples, 80138 Napoli, Italy. fiorina.casale@unina2.it
Insights
Multidrug resistance (MDR) protein expression in childhood acute lymphoblastic leukemia (ALL) is linked to poorer outcomes. MDR1 positivity independently predicts adverse prognosis, highlighting its role as a potential biomarker for treatment response.
Area of Science:
- Pediatric Oncology
- Hematology
- Molecular Biology
Background:
- Multidrug resistance (MDR) is a significant challenge in treating childhood acute lymphoblastic leukemia (ALL).
- P-glycoprotein 170 (MDR1), a key cellular drug efflux pump, is implicated as a major contributor to MDR.
Purpose of the Study:
- To investigate the prognostic significance of MDR1 expression and function in newly diagnosed childhood ALL.
- To evaluate the impact of MDR1 on achieving complete remission (CR) and patient outcomes.
Main Methods:
- Retrospective analysis of 85 children with ALL treated with AIEOP ALL 91-95 protocols.
- MDR1 protein expression assessed via immunocytochemistry (ICC) and flow cytometry (FC).
- MDR1 functional activity evaluated using a rhodamine (Rhd)-123 efflux test, with and without verapamil.
Main Results:
- At diagnosis, 47% of patients expressed significant MDR1 protein levels.
- Complete remission (CR) was achieved in 90.6% of patients; all patients failing CR were MDR1 positive.
- 10-year event-free survival (EFS) was significantly higher in MDR1-negative (67.5%) versus MDR1-positive (36.8%) patients (p=0.001).
- Multivariate analysis confirmed MDR1 expression as an independent adverse prognostic factor for EFS.
Conclusions:
- MDR1 expression in childhood ALL is an independent adverse prognostic factor impacting patient outcomes.
- MDR1 may serve as a valuable biological marker for predicting treatment response in pediatric ALL.
- MDR1 functional activity also predicted response, though only in univariate analysis.
Abstract:
Little is known about the prognostic role of multidrug resistance (MDR) in newly diagnosed childhood acute lymphoblastic leukemia (ALL). P-glycoprotein 170 (MDR1), a cellular drug efflux pump, is thought to be one of the major causes of MDR. The aim of this retrospective study was to evaluate in 85 children with ALL the impact of the MDR1 product of the mdr-1 gene on the achievement of complete remission (CR) and outcome. MDR1 protein expression was performed by immunocytochemistry (ICC), and flow cytometry (FC). MDR1 functional activity was performed by a rhodamine (Rhd)-123 efflux test with or without verapamil. All patients enrolled in our study were treated with AIEOP ALL 91-95 protocols. At diagnosis, 40 patients (47%) expressed MDR1 protein at significant levels, and 45 (53%) were MDR1 negative. Forty-three of the latter patients were also negative for MDR1 function, while 34/40 (85%) patients MDR1 positive preserved the function. Rhd-123 efflux was inhibited by the MDR modulator verapamil in 12/40 (30%) patients. After induction treatment, CR was achieved in 77/85 children (90.6%). All patients who did not achieve CR were MDR1 positive. Twenty-nine patients relapsed, 17 (58.6%) of whom were MDR1 positive. The 10-year overall survival (OS) rate, and disease-free survival (DFS) for MDR1 negative patients compared to MDR1 positive patients were 75.7% versus 54.8%, and 67.5% versus 46%, respectively. The 10-year event-free survival (EFS) rate was significantly higher (67.5% versus 36.8%) in the MDR1 negative group compared with the MDR1 positive population (p=0.001). Multivariate analysis showed that only EFS was independent of age, WBC count, immunophenotype, FAB subtype and prednisone response (p=0.019). Our results, derived from a monocentric study, demonstrate that MDR1 expression in childhood ALL is an independent adverse prognostic factor on outcome, and could be a useful biological marker of response in these patients. Moreover, MDR1 function was also a predictor of response, but only in univariate analysis.
