Distinct Activities of Glycolytic Enzymes Identify Chronic Lymphocytic Leukemia Patients with a more Aggressive Course and Resistance to Chemo-Immunotherapy
Georg Gdynia,
Tadeusz Robak,
Jürgen Kopitz,
Anette Heller,
Svetlana Grekova,
Katarina Duglova,
Gloria Laukemper,
Monika Heinzel-Gutenbrunner,
Cornelius Gutenbrunner,
Wilfried Roth,
Anthony D. Ho,
Peter Schirmacher,
Michael Schmitt,
Peter Dreger,
Leopold Sellner
Affiliations
Georg Gdynia
Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
Tadeusz Robak
Medical University of Lodz, Copernicus Memorial Hospital, Lodz, Poland
Jürgen Kopitz
Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
Anette Heller
Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
Svetlana Grekova
Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
Katarina Duglova
Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
Gloria Laukemper
Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
Monika Heinzel-Gutenbrunner
Department of Child and Adolescent Psychiatry, University Hospital Marburg, Marburg, Germany
Cornelius Gutenbrunner
MH Statistical Consulting, Marburg, Germany
Wilfried Roth
Institute of Pathology, University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany
Anthony D. Ho
Department of Medicine V, University Hospital Heidelberg, Heidelberg, Germany
Peter Schirmacher
Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
Michael Schmitt
Department of Medicine V, University Hospital Heidelberg, Heidelberg, Germany; National Center for Tumor Diseases (NCT), German Cancer Consortium (DKTK), Heidelberg, Germany
Peter Dreger
Department of Medicine V, University Hospital Heidelberg, Heidelberg, Germany; National Center for Tumor Diseases (NCT), German Cancer Consortium (DKTK), Heidelberg, Germany
Leopold Sellner
Department of Medicine V, University Hospital Heidelberg, Heidelberg, Germany; National Center for Tumor Diseases (NCT), German Cancer Consortium (DKTK), Heidelberg, Germany; Corresponding author at: Department of Medicine V, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
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. Keywords: CLL, Metabolism, PK M2, LDH, High-risk
