Acute lymphoblastic leukemia (ALL) is a potentially fatal disease treated with intensive multi-agent therapy. In Germany, treatment follows GMALL expert panel (German Multicenter Study Group on Adult ALL) recommendations using a “pediatric-inspired” approach, which includes pegylated asparaginase (PEG-asparaginase) among other classical therapeutic agents. Therapy-associated osteonecrosis has received increasing attention in adult patients. Osteonecrosis (ON) is a chronic, often quality-of-life-altering adverse event with substantial patient impact. A single-center real-world analysis revealed an ON incidence of 12% among 87 adult ALL patients treated between January 2017 and March 2024 at the University Medical Center Hamburg-Eppendorf, Germany (Klingler et al., Abstract PF387, EHA 2025). This study aims to enhance understanding of osteonecrosis by analyzing routinely collected laboratory parameters for characteristic changes in affected patients.

A total of 139,140 laboratory results were extracted from the dataset, including ALAT (17,036; alanine aminotransferase), ASAT (16,827; aspartate aminotransferase), GGT (7,282; gamma-glutamyl transferase), total bilirubin (16,881), lipase (4,895), albumin (12,743), serum glucose (15,784), triglycerides (4,507), total cholesterol (958), antithrombin (7,511), fibrinogen (Clauss method; 7,532), D-dimers (244), vitamin D (570), total calcium (15,570), inorganic phosphate (10,785), and bone-specific alkaline phosphatase (15). To further investigate the associations between laboratory abnormalities, the occurrence of osteonecrosis, and the impact of PEG-asparaginase, we limited our analysis to lab-defined toxicities that began within 30 days after PEG-asparaginase administration due to its duration of action. Within this interval, 60,267 of the aforementioned laboratory test results were available. Toxicities that persisted more than 90 days after administration were no longer considered to be associated to PEG-asparaginase.

Considering the frequency of adverse events after PEG-asparaginase administration, 39% of patients developed at least one episode of significant hypertriglyceridemia (CTCAE G3/G4; Common Terminology Criteria for Adverse Events). The proportion of patients who developed relevant hypertriglyceridemia was lower among those who did not develop osteonecrosis (nON;35%) compared to those who did (yON; 67%;p=0.054). The increased proportion of hypertriglyceridemia in yON patients was confirmed in the analysis of single PEG-asparaginase administrations (42% versus 25%;p<0.001). Hypercholesterolemia was generally rare (2.3%), with a lower incidence in nON patients (1.3%) than in yON patients (8.3%;p=0.3). Severe hyperbilirubinemia (CTCAE G3/G4) was present in 42% of yON patients and 17% of nON patients (p=0.12).

Out of a total of 397 PEG-asparaginase administrations, 305 (77%) were given to nON patients (N=75) and 92 (33%) to yON patients (N=12) with a median of 2 applications per patient (Min-Max:1-9). Severe hypoalbuminemia (CTCAE G3/G4) occurred significantly more often in nON patients (30%) than in yON patients (17%;p=0.018). No relevant differences were observed in the other laboratory parameters analyzed (ALAT, ASAT, bilirubin, lipase, glucose, and inorganic phosphate).

Hazard ratios for all parameters were calculated using clustered Cox proportional hazards modeling. An increased risk for osteonecrosis was observed in the presence of severe hypertriglyceridemia (HR=2.18;95% CI 0.98–4.83;p=0.05) and severe hypercholesterolemia CTCAE G3/G4 (HR=3.69;95% CI 1.17–11.65;p=0.03). Hypofibrinogenemia over 10 or more days was associated with a reduced risk of osteonecrosis (HR=0.40;95% CI 0.18–0.85;p=0.02), despite substitution when Fibrinogen was < 0,6 g/l. Brief (< 6 days) severe hypoalbuminemia was associated with an increased risk of osteonecrosis (HR=3.81;95% CI 1.21–12.00;p=0.02). No difference in risk was observed with respect to antithrombin levels.

The presented results on the impact of hypertriglyceridemia and hypercholesterolemia support the hypothesis that disturbances in lipid metabolism may promote the development of osteonecrosis. Furthermore, the results underscore the importance of plasma coagulation in the pathogenesis of osteonecrosis. To date, the influence of hypoalbuminemia on bone health has been less well investigated. These data can serve as a basis for future studies aiming to develop a risk score for predicting the occurrence of osteonecrosis.

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2025
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