Bone Mineral Density in Hodgkin Lymphoma Patients Treated with Escalated Beacopp: Focus on Steroid Administration and Age-Related Effects

Background: Most Hodgkin lymphoma (HL) patients younger than 60 years are nowadays cured, especially those treated with front-line escalated BEACOPP (escBEACOPP), thus understanding long-term side effects is essential. Avascular joint necrosis (AVN) is a known side-effect of this regimen, possibly related to bone mineral density (BMD) loss. In order to reduce steroid-related side-effects, we reduced steroid exposure from the original 14 days to 7-8 days per escBEACOPP cycle without loss of efficacy and a trend towards reduced osteoarticular side effects. This study was performed to further investigate the impact of escBEACOPP and different steroid schedules on bone metabolism in patients with classical HL.

Methods: Previously untreated patients with classical HL receiving at least two cycles of escBEACOPP for early unfavorable (EU, stage I - II with at least one unfavorable prognostic factor as per GHSG criteria) or advanced stage disease (AS, stage IIB bulky – IV), and at least one evaluable PET-CT for BMD assessment were included. BMD was assessed using the Hounsfield unit (HU) scale on axial images of the L3 vertebra from PET-CT scans performed at baseline, post-treatment, or during follow-up when available. The threshold for normal BMD was set at 160 HU, with values between 100-159 HU considered osteopenia and below 100 HU as osteoporosis. BMD reduction of ≥15% and ≥25% from baseline to post-treatment were considered clinically relevant. Demographic, treatment, steroid administration, and side-effects data were obtained retrospectively from patient medical records. Data were analyzed using descriptive statistics, chi-square tests, Fisher's exact tests, repeated measures ANOVA, t-tests, and logistic regression analysis.

Results: The study cohort consisted of 177 patients (56.5% male, median age 31 years, all Caucasian). Seventy-four % had AS disease, of which 61% were stage IV. Sixty-two % received 6 cycles of escBEACOPP, 22% received 2 cycles of escBEACOPP + 2 cycles of ABVD, and 16% other combinations. BMD changed significantly across all time points (p<0.001). Baseline mean BMD was 204.71 (SD = 44.4), decreasing to 161.49 (SD = 43.84) post-treatment and 170.77 (SD = 49.45) at follow-up. Baseline BMD measurements showed normal BMD in 84.8% of patients, 13.6% had osteopenia, and 1.7% had osteoporosis. Post-treatment, the proportions were 50.6% normal, 42.9% osteopenia, and 6.5% osteoporosis. The median BMD reduction from baseline to post-treatment for 117 evaluable patients was 23%, with 64% of patients having a BMD reduction ≥15% and 45% ≥25%. During follow-up, the median BMD reduction from baseline for 44 evaluable patients was 18%, with 54% of patients having a reduction ≥15% and 22% ≥25%. Age (stratified by groups <30, 31-40, 41-50, 50+y) significantly influenced the risk of having osteopenia at baseline (OR 4.79, p<0.001). Age was also significantly associated with the risk of developing osteoporosis after treatment (p<0.001, OR 5.85). Stage IV disease was a significant predictor of BMD reduction of ≥15% (p = 0.01), whereas age, gender, baseline BMD, EU vs. AS, and number of BEACOPP cycles were not. Only age presented an increased risk of a more significant BMD decline by ≥25% (p=0.014, OR 1.85). The decrease in steroid dosing from 14 to 7-8 days of prednisone per cycle did not significantly impact BMD outcomes (p=0.404 for reduction≥15%; p=0.51 for ≥25%). There was no correlation between BMD dynamics and the development of clinically relevant osteoarticular events (13 pts, 7.23%). No pathological fractures were documented.

Conclusions: This study highlights a significant reduction in BMD in HL patients treated with escBEACOPP, with only minor recovery during follow-up. Despite efforts to reduce steroid-related bone loss by decreasing steroid exposure, no significant improvements were observed. The BMD reduction was more pronounced in older patients and in patients with stage IV disease, regardless of number of escBEACOPP cycles, suggesting that certain host and disease characteristics likely contribute to BMD loss in addition to therapy. Using routine PET-CT scans for BMD measurement in HU is feasible and easy to implement in everyday clinical practice. Abnormal results should trigger further work-up and DEXA confirmation. Long-term monitoring and intervention strategies, as well as development of less toxic regimens, are crucial for managing bone health in HL patients.