Does arsenic trioxide impact fertility?

Arsenic trioxide (ATO) is highly effective in patients with relapsed or refractory acute promyelocytic leukemia (APL) [1]. ATO as a first-line agent in induction and consolidation, either alone or in combination with all-trans retinoic acid (ATRA), with or without cytotoxic chemotherapy, has taken on new prominence, and is emerging as a highly curative therapeutic strategy. The cure of any malignancy, particularly acute leukemia, without chemotherapy would usher in a new era of cancer therapy and represent an unprecedented shift in treatment paradigms. This new era has arrived. A growing body of literature demonstrates the feasibility and efficacy of ATO, usually given with ATRA, in the treatment of patients with newly diagnosed APL. Completed and ongoing clinical studies minimize or eliminate chemotherapy from treatment regimens [2–4]. However, novel treatments bring potential unintended toxicities. One of these, impaired fertility in both men and women, has long been associated with cytotoxic chemotherapy. This issue is particularly relevant to patients with APL since they are more likely than patients with other subtypes of acute myeloid leukemia to present during their childbearing years. By incorporating ATO and minimizing or completely eliminating chemotherapy, are we trading a non-chemotherapy treatment approach for impaired patient fertility? Will an ATO-inclusive regimen lead to increased birth defects in the offspring of those patients who successfully deliver?

In this issue of the journal, Gupta and colleagues provide some preliminary observations [5]. In their report, six of 43 patients with APL treated with ATO subsequently went on to successfully reproduce. The cumulative doses of ATO administered to these patients ranged from 280 mg to 1330 mg. All six patients successfully conceived and delivered without the use of additional reproductive technologies, with a range of 6 months to 7 years between ATO completion and first successful pregnancy. In this small series, there was no correlation between the dose of ATO and time to first pregnancy.

Although the authors inform us about the six patients who received ATO and successfully conceived, we are not told whether other patients attempted to conceive and were unsuccessful, or whether yet others had miscarriages or stillbirths. A murine model of arsenic toxicity, seeking to replicate environmental exposure to arsenic from drinking water, demonstrated a dose–response relationship between increased doses of arsenic (0 ppm to 75 ppm), decreased mouse fecundity and increased miscarriage rate. When examined histologically, the placentas of mice exposed to the highest concentrations of arsenic showed changes consistent with defective placental vasculogenesis [6]. In humans the data are mixed. Some studies suggest an increased risk of adverse pregnancy outcomes, while other studies show no effect on fertility [7,8]. The fertility changes induced by arsenic exposure are not limited to females. Li and colleagues demonstrated an inverse relationship between the amount of arsenic in human seminal plasma and sperm concentration and motility in a population of Chinese men [9]. In addition, prior studies have attempted to show relationships between low levels of constant arsenic exposure from groundwater and fertility.

The conclusions we can draw from the small case series reported here are that some patients exposed to curative doses of ATO for the treatment of APL can conceive and carry a pregnancy to term. The data provided by Gupta and colleagues are a first step toward integrating larger scale, prospective, correlative studies of fertility and pregnancy outcome into clinical trials which employ ATO and ATRA, without chemotherapy, in induction and consolidation. These correlative studies will allow investigation of the relationship between ATO and fertility without confounding factors such as concomitant administration of chemotherapy and age at conception. As most new clinical trials will incorporate ATRA and ATO in combination, and ATRA itself is a well-known teratogen, it will be important to elucidate the contribution of each agent to fertility. Ideally, a well designed clinical trial that uses ATO will incorporate measurements of sperm quality, sex hormone levels and menstrual cycles before, during and after treatment, and would take into account the ability to successfully reproduce, time to conception, miscarriage rate and incidence of birth defects. It would also measure the health quality, intellect, behavioral achievement and social achievement among the offspring of ATO-treated patients. These large prospective studies will identify the long-term cost, if any, incurred by curing patients with APL using ATO-based regimens. In fact, it may be that prospective trials will show that fertility after ATO-based therapy for APL is more robust, since fewer patients will be exposed to conventional cytotoxic chemotherapy.

Potential conflict of interest

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