Purpose: Complete response (CR) to induction chemotherapy is observed in approximately 60% of patients with newly diagnosed non- M3 AML. However, no methods exist to predict with high accuracy at the individual patient level the response to standard AML induction therapy. Experimental Design: We applied single cell network profiling (SCNP) using flow cytometry, a tool that allows a comprehensive functional assessment of intracellular signaling pathways in heterogeneous tissues, to two training cohorts of AML samples (N = 34 and 88) to predict the likelihood of response to induction chemotherapy. Results: In the first study, univariate analysis identified multiple signaling "nodes" (readouts of modulated intracellular signaling proteins) that correlated with response (i.e. AUCROC ≥0.66; p ≤ 0.05) at a level greater than age. After accounting for age, similar findings were observed in the second study. For patients < 60 years old, CR was associated with the presence of intact apoptotic pathways. In patients ≥ 60 years old, non-response (NR) was associated with FLT3 ligand mediated increase in phospho (p)-Akt and p-Erk. Results were independent of cytogenetics, FLT3 mutational status and of diagnosis of secondary AML. Conclusions: These data emphasize the value of quantitatively measuring single cell networks (SCNs) under modulated conditions as a basis for the development of tests highly predictive for response to induction chemotherapy. The SCNP provides information distinct from other known prognostic factors such as age, secondary AML, cytogenetics and molecular alterations and is potentially combinable with the latter to improve clinical decision-making. Independent validation studies are warranted.
- Received January 13, 2010.
- Revision received April 29, 2010.
- Accepted May 19, 2010.