P-Glycoprotein Is Related to the Achievement of Complete Remission but Not to Disease-Free Survival in Adult Acute Lymphoblastic Leukemia: A Prospective Analysis in the JALSG-ALL97 Study.
Authors: Takeshita Akihiro , Ohnishi Kazunori , Miyazaki Yasushi , Jnnai Itsuro , Miyawaki Shuichi , Takahashi Masatomo , Murakami Toru , Inoue Nobumasa , Tanaka Junji , Asou Norio , Kobayashi Yukio , Ueda Ryuzo , Ohno Ryuzo 
Published: October 2019

In a part of the prospective multicenter study of the Japan Adult Leukemia Study Group (JALSG-ALL97), we studied the amount and function of three important multidrug resistant (MDR) proteins: P-glycoprotein (P-gp), multidrug resistance associated protein (MRP) and lung resistance related protein (LRP), in the leukemia cells of adult acute lymphobastic leukemia (ALL) at the diagnosis. We related the results with patients’ biological and clinical features and their treatment outcome. From May 1997 to December 2001, newly diagnosed patients with de novo ALL except B-ALL were registered and received an induction therapy including cyclophosphamide (1200 mg/m2, d1), daunorubicin (45 mg/m2, d1-3), vincristine (1.3 mg/m2, d1, 8, 15, 22), L-asparaginase (3000 U/m2, d1, 9, 11, 13, 16, 18, 20) and predonisolone (60mg/m2, d1-14). Patients achieving complete remission (CR) received 8 courses of consolidation/intensification therapy followed by maintenance therapy. Median age was 38 years old. Out of 175 patients tested, 169 were evaluable. The amount and function of the MDR proteins were analyzed in CD45-gated leukemia cells by flow cytometry. After incubating with biotinylated MRK16 (IgG2a (Fab’)), anti-MRP or anti-LRP antibodies, cells were post-stained with SA-RED670. The function of P-gp and MRP was determined by Rhodamin-123 (Rh-123) accumulation with PSC833 and carcein-AM efflux with probenecid, respectively. Factors to predict CR were age, performance status (PS), chromosome, pretreatment WBC count, CD25 expression and the function of P-gp in univariative analyses. Logistic regression analysis shows that favorable prognostic factors for the achievement of CR were PS (Ps=0) and the lower (<9%) function of P-gp (p=0.013 and 0.010, respectively). Factors predict of disease free survival (DFS) were pretreatment WBC count, LDH value, chromosome (non Ph) and lack of CD25 expression in univariative analyses. Cox’s proportional hazard analysis shows that chromosome and CD25 were favorable for longer DFS (p=0.040 and 0.001, respectively). Neither the amount nor function of P-gp related to longer DFS. There was no significant relationship between the amount of other MDR proteins and DFS.

The clinical importance of MDR proteins has been discussed in the treatment acute leukemias. We prospectively analyzed them in patients receiving the same treatment. Our study demonstrates that the function of P-gp in de novo ALL is one of the independent unfavorable factors for CR. However, it did not change the survival rates in the treatment of ALL with combination chemotherapy. Other MDR proteins relate to neither CR rate nor survival. We have also investigated these proteins in AML (Blood 102, 605a). The MDR proteins in the treatment of ALL are possibly less important as compared to those of AML.