Warburg-Effect Driven Lactic Acidosis Is Associated with Early Death in Patients with Lymphoma

Introduction: Lactic acidosis is a medical emergency and in most cases results from an imbalance between tissue oxygenation and oxygen demand (Type A). However, Type B lactic acidosis occurs in the absence of a recognizable impairment in tissue oxygenation and is commonly associated with toxin ingestion, sepsis, thiamine deficiency, and less commonly, malignancy.

The capacity of shifting glucose metabolism to anaerobic pathway despite the presence of adequate oxygen, enhancing the rate of glucose uptake, accelerated glycolysis and hence producing more lactate, is a well-defined phenomenon in malignant cell metabolism, and is called the Warburg Effect (WE) or aerobic glycolysis.

A systemic rise in lactate and lactic acidosis has been reported in hematologic malignancies and is thought to occur as a consequence of both increased production of lactate- reflecting high malignancy burden, and impaired lactate turnover or elimination by liver or kidney.

Few case reports or series have demonstrated a possible correlation between early death (ED) and elevated lactate in patients with hematologic malignancy.

We aim to systematically characterize the incidence and clinical impact of Warburg-driven lactic acidosis on early outcome of patients with lymphoma.

Methods: A retrospective study of consecutive patients admitted to the haemato-oncology department in a large tertiary medical center between the years 2013-2022 with a documented lactate level during the first week of admission. Patients with hematologic diseases other than lymphoma were excluded. Medical records of patients with elevated lactate were reviewed for a recognizable cause for elevated lactate, or none (assigned as the WE group). ED was defined as death of any cause within 4 weeks of admission.

Results: Out of 1259 patients reviewed, 318 patients presented with elevated lactate during the first week of admission, of whom 216 patients were excluded because of underlying hematological malignancy other than lymphoma. Of the remaining 102 patients with lymphoma and elevated lactate, 58 patients fulfilled the criteria for WE and 44 patients had their high lactate level attributed to infectious (n=31), or non-infectious causes (concomitant metformin use n=9 or other n=4).

Median age in patients with WE was 63 years (range 25-86) and 60% (n=35) were males. 72% had aggressive lymphoma. Diffuse Large B cell Lymphoma was the most frequent type (n=31) followed by T cell Lymphoma (n=8) and Hodgkin’s lymphoma (n=6). Most patients had advanced disease (Stage III-IV in 82%). The median maximal lactate level was 31.5 mg/dL (range 20-114; upper limit of normal -20 mg/dL).

ED was documented in 26% (n=15) of patients with WE. 36% (n=21) died during the index admission and 60-day mortality was 43%. Lymphoma-related complications were the main cause of death (n=21) followed by infections (n=13).

Higher lactate level was associated with worse survival with a median survival of 46 days for those with lactate levels >= 25mg/dL, compared to 862 days for patients with above normal lactate but lower than 25mg/dL. (P=0.01).

Earlier initiation of chemotherapy was associated with a trend toward better outcome. Chemotherapy was initiated at an average of 5.5 days after first elevated lactate in surviving patients (range (-)4-30), vs 9.05 days after first elevated lactate in pts. that did not survive (range 0-25) (P=0.13). Thiamin therapy (n=13) was not associated with better outcome, and dextrose infusion (n=12) portended worse outcome and reduced survival (p=0.01).

AST/ALT ratio emerged as significant predictor of survival in patients with WE. A median survival of 862 days and 50 days was demonstrated in patients with an AST/ALT of <1 and >1, respectively. (P=0.03)

Considering all causes of elevated lactate (n=102), the median survival of patients with elevated lactate attributed to WE (n=58) was 159 days, and only 25 days in patients with elevated lactate as a consequence of non-WE causes (n=42; 19 days for infection, 8 days for hypotensive crisis or hypoxia. (P<0.001)

Conclusion: To the best of our knowledge, this study represents the largest systematic review of lactatemia and WE in patients with lymphoma, indicating that Warburg-driven lactic acidosis is a marker of ‘acute cancer’ and is associated with a high mortality. Early recognition of this high-risk clinical scenario is of utmost importance, and prompt initiation of anti-lymphoma therapy may improve outcomes.