Fertility and Gonadal Function After Treatment of Early Unfavorable Hodgkin Lymphoma (HL): An Analysis of the German Hodgkin Study Group (GHSG)

Two cycles of BEACOPP_escalated followed by two cycles of ABVD (“2+2”) improves the primary outcome in early unfavorable HL patients as shown in the GHSG HD14 trial. Compared to 4xABVD, this benefit might be compromised by more gonadal toxicity in women and men. We thus analyzed gonadal function and fertility of survivors in the HD14 trial.

Women between 18–40 years and men between 18–50 years at diagnosis in ongoing remission at least one year after therapy, treated with either 4xABVD (arm A) or “2+2” (arm B), were included. In women, different hormone parameters (follicle-stimulating hormone (FSH), Anti-Muellerian-Hormone (AMH)) as well as menopausal symptoms, prophylactic measures to preserve fertility, concurrent hormonal treatment, menstrual cycle, pregnancies, and offspring were evaluated. In men, serum levels of FSH, testosterone, and inhibin B were determined as well as symptoms of hypogonadism (aging males symptom scale, AMS) and children after therapy.

From a total of 579 women addressed, 331 participated in the present study (57%) and 263 per-protocol treated patients qualified for the comparison of treatment arms (A: 137, B: 126; mean time from end of therapy 42 and 43 months, respectively). The rates of regular menstrual cycle after treatment (A: 87%, B: 83%) and time to recovery (≤12 months) were not different. FSH and AMH, reflecting ovarian reserve, were significantly better in arm A and AMH levels were also low after 4xABVD in women >30 years. In contrast, pregnancies after therapy favored arm B (A: 15%, B: 26%, p=0.043) and motherhood rates were equivalent to the German normal population in both arms. A multivariate analysis revealed prophylactic use of GnRH-analogues as highly relevant and significant prognostic factor for preservation of fertility (OR=12.87, p=0.001). Severe menopausal symptoms were reported frequently in women ≥30 years (A: 21%, B: 25%). From a total of 592 men addressed, 322 participated in the present study (54%) and 235 per-protocol treated patients qualified for the comparison of treatment arms (A: 111, B: 124; mean time from end of therapy 43 and 45 months, respectively). Levels of FSH (A: 4.3 U/l, B: 7.7 U/l, p<0.001) and inhibin B (A: 140.7 ng/l, B: 46.9 ng/l, p<0.001) were significantly better in arm A and children after therapy were also more frequently reported after treatment with 4xABVD (A: 12%, B: 5%, p=0.075). However, levels of testosterone and symptoms of hypogonadism were not different between treatment arms. In addition, symptoms of hypogonadism were equivalent as compared to the reference population.

With focus on hormonal markers, results of the present study demonstrate higher gonadal toxicity in women and men after the “2+2” regimen compared to 4xABVD. Accordingly, in men, more children after 4xABVD are reported. In women, fertility is not compromised within the evaluated observation time, especially when GnRH-analogues were used.

No relevant conflicts of interest to declare.