Drug resistance factors in acute myeloid leukemia: a comparative analysis

Abstract

To compare the clinical relevance of drug resistance factors in de novo acute myeloid leukemia (AML), we determined their relationship to both response to induction chemotherapy and survival of the patients in univariate as well as multivariate analyses. The drug resistance factors immunocytochemically studied in 111 patients at the time of diagnosis included the lung resistance protein (LRP), P-glycoprotein (P-gp), multidrug resistance protein (MRP1) and bcl-2. In the univariate analyses, age (P = 0.005), karyotype (P = 0.03), LRP (P = 0.003), P-gp (P = 0.02) and bcl-2 (P = 0.03) predicted for response to induction chemotherapy, whereas MRP1 had no predictive value. Age (P = 0.05), karyotype (P = 0.05) and LRP (P = 0.03) retained their predictive value in the multivariate logistic regression analyses. With regard to overall survival, age (P = 0.008), karyotype (P = 0.006), LRP (P = 0.001) and P-gp (P = 0.01) were of prognostic value in the univariate Cox regression analyses but only age (P = 0.01), karyotype (P = 0.02) and LRP (P = 0.01) retained their prognostic significance in the multivariate analyses. A risk score based on the number of independent prognostic factors allowed division of patients into four groups with different outcome. In these groups, the complete remission rates were 93%, 75%, 47% and 33%, respectively, and median overall survival was 2.4, 1.2, 0.6 and 0.2 years, respectively. Thus, several drug resistance factors did predict outcome in the univariate analyses but LRP was the only drug resistance factor with independent predictive and prognostic significance. The proposed risk score might be useful for risk-adapted treatment in the future. Leukemia (2000) 14, 68-76.

Relapse in childhood acute lymphoblastic leukemia is associated with a decrease of the Bax/Bcl-2 ratio and loss of spontaneous caspase-3 processing in vivo

“…Clinical resistance to therapy is also associated with an increased expression of Mcl-1 in adult ALL 15 and Bcl-2 expression in acute myeloid leukemia. 16 In contrast, a recent report showed that increased expression of the proapoptotic Bax in childhood ALL at diagnosis is associated with an increased risk of relapse. 17 The mechanisms by which p53 promotes apoptosis are not fully understood.…”

Diffuse large B-cell lymphomas with plasmablastic/plasmacytoid features are associated with TP53 deletions and poor clinical outcome

“…35 On the other hand, there is currently no information on specific cytogenetic abnormalities in PB/PC-F. 36 In anthracyclin-resistant disease, multidrug resistance genes might also play a role. 37 Of note, 'activated B-like' DLBCLs defined by microarray screening also have a poor prognosis. 10,11 Since PB/PC-F relapses early and seems to be refractory to PSCT, these patients might be candidates for alternative treatment strategies like allogeneic bone marrow transplantation or additional B-cell antibody therapy.…”

Bax expression correlates with cellular drug sensitivity to doxorubicin, cyclophosphamide and chlorambucil but not fludarabine, cladribine or corticosteroids in B cell chronic lymphocytic leukemia

“…4 High expression of Bcl-2, an anti-apoptotic protein, can be associated with drug resistance in hematological malignancies. 4,11,[36][37][38][39][40][41][42][43][44][45][46][47] Thus, even the lower expression of Bcl-2 in some samples could provide an optimal anti-apoptotic effect. The role of Bcl-2 as a prognostic indicator remains controversial and it has therefore been suggested that Bcl-2 should be evaluated in parallel with other apoptotic markers.…”