Background/Purpose:

Gonadotoxicity is a known side effect of cyclophosphamide (CYC) therapy in childhood-onset systemic lupus erythematosus (cSLE).  Gonadotropin releasing hormone (GnRH) agonists, such as triptorelin, can induce complete ovarian suppression (COS), which makes ovaries resistant to CYC gonadotoxicity. The aims of this research are to determine (1) the dose of triptorelin sufficient for reliable COS in cSLE patients receiving CYC, and (2) the safety profile of triptorelin in cSLE.

Methods:

This double-blind, placebo-controlled, dose-escalation RCT (phase I/II) recruited cSLE patients from 7 international centers (NCT00124514).  All patients were female, aged ≤ 21 years and Tanner breast stage ≥ 2. They were randomized in a 4:1 fashion to receive either intramuscular triptorelin [µg/kg/dose: 25 (T1), 50 (T2), 75 (T3), 100 (T4)] or placebo every 4 weeks during CYC induction. The primary efficacy endpoint was the monthly dose of triptorelin that resulted in maintenance of COS which was defined a priorias (A) basal level of Follicle Stimulating Hormone (FSH) < 2 mIU/ml and of Luteinizing Hormone (LH) < 1 mIU/ml; or (B) FSH < 3 mIU/ml and of LH < 2 mIU/ml during GnRH Stimulation Testing (GAST). FSH and LH levels were drawn at the expected trough levels of triptorelin (27 days post administration). The triptorelin dose was escalated by 25% or at least 20 µg/kg until maintenance of COS was achieved (maximum=150 µg/kg/dose).  Adverse events (AE) were graded according to the National Cancer Institute Common Toxicity Criteria, Version 2.

Results:

Twenty-nine females were randomized (Placebo=6, T1= 9, T2=8, T3=5, T4=1). Of those who received triptorelin, 4 patients did not complete the study due to CYC discontinuation or withdrawal of consent. As expected, none of those in the placebo group achieved COS.  A dose of 75 and 110 µg/kg maintained COS in 75% and 90% of the patients, respectively.  There was no relationship between the triptorelin dose and the patients’ age, Tanner stage, global disease activity, renal and hepatic function. None of the patients in T3 and T4 arms needed dose escalation of triptorelin while the converse is true for majority of patients in T1 and T2. AE were mild and the most common were hot flashes (24%), headache (14%), and insomnia (10%). Serious AE included hospitalization due to dehydration (Placebo=1), worsening of SLE disease activity (Placebo=1), and cutaneous vasculitis (T3=1).

Conclusion:

This interim analysis supports that higher doses of triptorelin than previously suggested are needed for COS in adolescent females with cSLE who require CYC. Doses of intramuscular triptorelin at 110 µg/kg induce continuous COS between injections given every 28 days in almost all females, and thus likely provide ovarian protection.  These high doses of triptorelin appear well tolerated.

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« Back to 2013 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/phase-2-trial-on-triptorelin-for-ovary-protection-in-childhood-onset-systemic-lupus-erythematosus/