EBioMedicine, 2018-06, Vol.32, p.125-133
A higher capacity to grow under hypoxic conditions can lead to a more aggressive behavior of tumor cells. Determining tumor activity under hypoxia may identify chronic lymphocytic leukemia (CLL) with aggressive clinical course and predict response to chemo-immunotherapy (CIT). A metabolic score was generated by determining pyruvate kinase and lactate dehydrogenase, key enzymes of glycolysis, ex vivo in primary CLL samples under normoxic and hypoxic conditions. This score was further correlated with clinical endpoints and response to CIT in 96 CLL patients. 45 patients were classified as metabolic high risk (HR), 51 as low risk (LR). Treatment-free survival (TFS) was significantly shorter in HR patients (median 394 vs 723 days, p = .021). 15 HR patients and 14 LR patients received CIT after sample acquisition. HR patients had a significantly shorter progression-free survival after treatment compared to LR patients (median 216 days vs not reached, p = .008). Multivariate analysis evaluating age, IGHV, TP53 deletion or mutation and 11q22–23 deletion besides the capacity of tumor cells to grow under severe hypoxic conditions identified the metabolic profile as the strongest independent risk factor for shorter TFS (hazard ratio 2.37, p = .011). The metabolic risk can provide prognostic and predictive information complementary to genetic biomarkers and identify patients who might benefit from alternative treatment approaches.
•The activity of distinct glycolytic enzymes can identify CLL patients with resistance to chemo-immunotherapy•The activity of distinct glycolytic enzymes can identify CLL patients who may benefit from specific pathway inhibitors•We provide a tool for the evaluation of specific glycolytic enzymes in primary CLL cells for clinical diagnostics
Adult ; Aged ; Aged, 80 and over ; Biomarkers, Tumor - genetics ; CLL ; Disease-Free Survival ; Female ; Glycolysis - genetics ; High-risk ; Humans ; Immunotherapy ; LDH ; Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy ; Leukemia, Lymphocytic, Chronic, B-Cell - genetics ; Leukemia, Lymphocytic, Chronic, B-Cell - immunology ; Leukemia, Lymphocytic, Chronic, B-Cell - pathology ; Male ; Metabolism ; Middle Aged ; Mutation ; PK M2 ; Prognosis ; Proportional Hazards Models ; Risk Factors ; Tumor Hypoxia - genetics ; Tumor Hypoxia - immunology
Permalink to record
https://www.ncbi.nlm.nih.gov/pubmed/29884457$$D View this record in MEDLINE/PubMed