Mechanisms of Chemotherapy-Resistance in Elderly AML Patients: An Immunohistochemical and Molecular Study with Therapeutic and Prognostic Implications
JT Bunning, HM Kantarjian, LJ Medeiros, M Nguyen, S Konoplev, C Bueso-Ramos. MD Anderson Cancer Center, Houston, TX
Background: Acute myelogenous leukemia (AML) in elderly patients (≥65 years) is an aggressive disease with a dismal prognosis. Sapacitabine (SAPA), a nucleoside analog inhibitor (NAI), is being investigated in AML therapy. To determine whether abnormalities in nucleoside metabolism or the nucleotide excision repair (NER) pathway contribute to a poor response to SAPA therapy, we evaluated expression levels of proteins associated with the proper functioning of NAIs in AML patients.
Design: The study group is 16 patients older than 65 years with newly diagnosed AML. All subjects were treated with SAPA only. The patients were stratified into 2 subgroups based on overall survival (OS). The rapid progression group (RP, n = 7) consisted of patients with OS less than 6 months (median = 2 mo., range 1-4). The long survivor group (LS, n = 9) consisted of patients with OS longer than 12 months (median = 15.5 mo., range 12-22). Poor-risk cytogenetic features were evenly distributed between the subgroups. Fixed, paraffin-embedded bone marrow biopsy sections were assessed by immunohistochemistry (IHC) using antibodies specific for human equilibrative nucleoside transporter-1 (hENT1, an NAI membrane transport protein), deoxycytidine kinase (dCK, an NAI prodrug activation enzyme), cytidine deaminase (CDA, an NAI prodrug inhibitor), and the excision repair cross-complementation group 1 protein (ERCC1, a NER enzyme). We validated IHC results by quantitative RT-PCR using gene-specific primers to dCK and CDA.
Results: There were no significant differences in age, performance status, serum LDH, blast percentages, or cytogenetic abnormalities between the two groups. Blasts from patients in the RP group showed mean positivity rates of 12% for dCK (0–29%), 14% for CDA (2–27%), 23% for hENT-1 (5–50%), and 46% for ERCC-1 (11–98%). Patients from the LS group demonstrated significantly higher levels of dCK (43%, 17 – 82; P=0.001), CDA (41%, 16–70; P=0.002), hENT-1 (23%, 32–77; P=0.002), and ERCC-1 (71%, 46–98; P=0.04) when compared to the RP group. Quantitative RT-PCR results confirmed these findings.
Conclusions: A subset of elderly AML patients have low (<30% positivity) levels of dCK, CDA, and hENT proteins. These patients have a very poor prognosis compared to AML patients with higher protein levels. Decreased levels of these critical proteins may alter the pharmacokinetic properties of NAIs and render them less efficacious in the treatement of AML.
Tuesday, March 23, 2010 11:15 AM
Platform Session: Section B, Tuesday Morning