BEACOPP de-escalation may reduce ovarian insufficiency in women with Hodgkin lymphoma

De-escalating the BEACOPP_escalated* regimen through a PET-driven strategy may reduce the risk of acute premature ovarian insufficiency (POI) in women with newly diagnosed advanced Hodgkin lymphoma (HL), subanalysis results of the phase III AHL2011 trial have shown.

“[T]he introduction of multi-agent therapies [has led to the] improvement in survival rates of patients with cancer … [Y]oung patients afflicted with HL now have a 95-percent chance of survival after 5 years,” said Dr Isabelle Demeestere from the Université Libre de Bruxelles in Brussels, Belgium, who presented the findings at ESHRE Virtual 2020.

However, increasing the intensity of such regimens entails an increased risk of toxicity, she underscored. “Chemo-induced ovarian damage is a major concern for young patients treated for advanced HL … In BEACOPP, cyclophosphamide and procarbazine [are introduced. These] are highly gonadotoxic,” she said, citing evidence showing a heightened risk of premature menopause with both agents. [Rev Bras Hematol Hemoter 2012;34:48-53] “[ABVD** is] less gonadotoxic,” she added.

A new therapeutic strategy

The team sought to evaluate the advantages of a de-escalated over the standard six-cycle BEACOPP_escalated regimen in terms of acute POI (characterized by high FSH*** [>25 IU/L] and low AMH^# levels [<0.16 ng/mL]) risk reduction in women aged <45 years old from the AHL2011 cohort.

Of the 252 young women (mean age 26.8 years) enrolled, 146 were randomized 1:1 to the standard or the study arm (two initial BEACOPP_escalated cycles). A subsequent PET scan determined the succeeding steps for the study arm – a negative scan signalled a shift to four ABVD cycles, while a positive scan required resumption of the remaining four cycles of the standard regimen. [ESHRE 2020, abstract O-035]

At 3 years, the study vs the standard arm had fewer women with high FSH (<10 percent vs >40 percent) and low AMH levels (<20 percent vs 60 percent). These suggest that fewer women on the de-escalated BEACOPP_escalated regimen had POI, noted Demeestere.

Both standard and study arms had a similar number of women conceiving after treatment (n=29 vs 30, respectively). However, there was a higher spontaneous pregnancy rate in the study vs the standard arm (n=27 vs 21). Though nonsignificant, the fertility advantage of the study regimen should be explored further, highlighted Demeestere.

While both regimens did influence ovarian function, the fraction of women exhibiting characteristics of acute POI in the study arm reflect the edge of the de-escalated BEACOPP_escalated over the standard regimen in this setting, noted Demeestere.

“It is important to note that only one patient in the study arm had to continue the BEACOPP_escalated regimen. [The rest] shifted to ABVD because of the negative PET scan after two BEACOPP_escalated cycles,” she stressed. This indicates that the PET-driven strategy played a crucial role in achieving the results, as it facilitated the use of a less gonadotoxic regimen, eventually mitigating the detrimental gonadotoxic effects of the standard BEACOPP_escalated regimen. [Lancet Oncol 2019;20:202-215]

Cancer societies should inform young women with HL about the gonadotoxicity of the treatment regimens available, noted Demeestere. “[Women should be referred] to fertility clinics for fertility preservation if they have a middle/high risk of POI after treatment … [The findings] should encourage us to be involved in oncologic trials to evaluate reproductive outcomes and provide accurate prospective data for fertility preservation counselling.”