P‐glycoprotein expression on acute myeloid leukaemia blast cells at diagnosis predicts response to chemotherapy and survival

Abstract

P-glycoprotein (Pgp) expression, which is associated with the multi-drug resistance (MDR) phenotype, has been reported to be a useful predictor of treatment outcome in acute leukaemia. We have examined the expression of Pgp on acute myeloid leukaemia (AML) cells in 54 newly diagnosed patients, using a novel streptavidin-biotin complex (ABC) technique. 55% of patients at diagnosis were positive for Pgp with JSB-1, a monoclonal antibody that binds to an internal epitope of Pgp. All patients received intensive induction chemotherapy. Post-remission treatment consisted of further chemotherapy +/- bone marrow transplantation. Complete remission (CR) rates were significantly lower in the Pgp positive group than in the Pgp negative group (60% v 92%; P = 0.02). The overall survival for Pgp-positive patients was significantly shorter (329 v 534d, P = 0.004), disease-free survival was also reduced but the difference was not statistically significant (median 277 v 522d, P = 0.16). In this study CD34 expression was not predictive of response to chemotherapy nor was it associated with Pgp expression. Our results confirm the prognostic value of Pgp expression in AML at diagnosis and we suggest that Pgp could be a useful therapeutic target for reversing multi-drug resistance. Furthermore, our simple and sensitive method of detecting Pgp should enable widespread testing to be performed.

P‐glycoprotein (PGP) and lung resistance‐related protein (LRP) expression and function in leukaemic blast cells

“…The role of PGP in the determination of clinical multidrug resistance in leukaemia is more uncertain (Haber, 1992). However, this problem is of particular interest as (1) the MDR caused by PGP involves several first-line drugs used in leukaemic chemotherapy, such as vinca alkaloids, anthracyclines and epipodophyllotoxins (Tsuruo, 1988); (2) in cell lines showing mdr-1 gene amplification, a wide range of drugs can block PGP function and restore drug sensitivity (Ford et al, 1990); (3) in leukaemia, many authors have already reported that PGP over-expression is frequent and can predict lower remission rates and a higher frequency of relapse (Campos et al, 1992a;Michieli et al, 1992;Ino et al, 1994;Wood et al, 1994;Zöchbauer et al, 1994).…”

Acute lymphoblastic leukemia with maturation–a new entity with clinical significance

“…25,26 However, several authors have already reported that Pgp overexpression is associated with lower remission rates and poor prognosis. 6 A simple and sensitive method to detect Pgp in tumor cells is provided by immunohistochemical staining with monoclonal antibody. 6 Nuclear chromatin pattern has been reported to be changed in drug-selected human MDR cells and not in other MDR cells without drug selection.…”

“…6 A simple and sensitive method to detect Pgp in tumor cells is provided by immunohistochemical staining with monoclonal antibody. 6 Nuclear chromatin pattern has been reported to be changed in drug-selected human MDR cells and not in other MDR cells without drug selection. 27 However, the ALLm patients in this study were not exposed to any chemotherapeutic drugs before and no ALLm cases showed Pgp expression before induction chemotherapy by immunohistochemistry.…”

“…Recently, multidrug resistance (MDR) caused by the P-glycoprotein (Pgp) has been documented in acute leukemias. [5][6][7] We have experienced 19 cases of ALL where leukemic cells showed morphological maturation beyond prolymphocytes. However, the clinical significance of morphologic maturation of the leukemic cells in ALL has not been evaluated and what makes the leukemic cells morphologically mature is not clear.…”

True

“…4,5 Although immunohistochemistry is a morphological means with inherent limitations concerning quantitative evaluation, many semiquantitative immunohistochemical studies provided evidence for the prognostic value of P-gp for patients' survival or a disease-free interval and corroboration has come from investigations measuring mRNA expression. [7][8][9][10] This speaks of some validity of immunohistochemistry in general. Nevertheless, the considerable inter-and intralaboratory variations presented at the American and French workshops hamper a reliable clinical routine application.…”