Preliminary findings from an observational multicenter study suggest that temporary off-label use of thrombopoietin receptor agonists (TPO-RAs) for the treatment of severe and/or refractory immune thrombocytopenia (ITP) during pregnancy is safe for the mother and neonate and may be effective when administered before delivery. The study findings were published in Blood by Marc Michel, MD, of the Hôpitaux de Paris in France, and coauthors.
Safety outcomes associated with TPO-RAs when administered during pregnancy have not been systematically studied, Dr. Michel and researchers noted. Currently available TPO-RAs for adult ITP, of which eltrombopag and romiplostim were the first to be FDA approved, are generally not recommended for use during pregnancy, and these medications may cross the placenta.
To examine both the safety and efficacy of off-label use of TPO-RAs during pregnancy, study authors conducted a retrospective study of 15 pregnant adult women with primary or secondary ITP who had been treated with eltrombopag (n=8) or romiplostim (n=7) for at least 1 week during their pregnancy. Only patients with at least 1-month follow-up data after TPO-RA initiation were included in the analysis.
The study included a total of 17 pregnancies and 18 neonates. Ten women presented with pre-existing chronic ITP with a mean duration of 9.3±3.2 years. Another 2 patients had secondary ITP, 1 patient had persistent ITP at the onset of pregnancy, and 4 patients had ITP diagnosed during pregnancy.
Prior to the initiation of TPO-RA, patients had received a median of 3 prior therapies (range = 2-7), including 5 women who had splenectomy. TPO-RAs used during pregnancy included:
- eltrombopag (n=8) with a mean maximal daily dose of 60 mg±24.4 (median = 50 mg [range = 25-100])
- romiplostim (n=7) with a mean maximal weekly dose of 7.28 μg/kg±2.97 (median = 7 μg/kg [range = 3-10])
The women in this analysis had a median duration of TPO-RA exposure during pregnancy of 4.4 weeks (range = 1-39 weeks).
Symptomatic ITP was reported in 13 of 17 pregnancies (76%) at the time of TPO-RA initiation. Four women had chronic ITP and were on TPO-RA therapy when they became pregnant, and 3 women with symptomatic ITP started TPO-RA early in their third trimesters.
Six women experienced mucosal bleeding, and 1 had life-threatening gastrointestinal bleeding at the start of TPO-RA. Platelet count was ≤20×109/L in 10 (58%) pregnancies.
No serious adverse events or clinically symptomatic thromboembolic events were reported, but 2 patients treated with off-label TPO-RA reported mild headache, the investigators wrote. While 1 patient was positive for lupus anticoagulant, anti-cardiolipin, and anti-β2-glycoprotein I antibodies, none of the patients required thromboprophylaxis.
In addition, there were no reports of fetal loss. Five pregnancies (29%) resulted in pre-term delivery (i.e., 34-38 weeks of gestation); 11 of the 17 women had vaginal delivery, and 6 had a C-section delivery.
Thrombocytopenia was observed in 6 out of the 14 neonates for whom platelet counts were available at birth. Thrombocytosis with a platelet count of 558×109/L was observed in 1 baby.
Two neonates had severe birth defects, including 1 case of chromosomal aneuploidy and 1 case of pulmonary artery stenosis, which led to 1 death and 1 grade 1 intraventricular hemorrhage. According to the investigators, these events were not directly related to or attributable to TPO-RA treatment.
Three-quarters of patients (n=10) responded to treatment with TPO-RA, which included 6 complete responses and 4 partial responses. Responses mostly occurred in women who were receiving concomitant ITP medication, including corticosteroids. None of the women who presented with longstanding chronic ITP responded to treatment.
“Based on these preliminary findings, temporary off-label use of a TPO-RA for severe or refractory ITP during pregnancy seems safe for both mother and neonate,” the authors concluded, “and is likely to be helpful especially prior to delivery.”
Limitations of this study include its retrospective design, the small number of patients, and the possible underestimation of placental thrombosis, the researchers noted.
To address the limitations inherent in this study and to further identify the safety of TPO-RAs in this population, the researchers wrote that “a prospective international registry is needed to monitor whether, with a more widespread use of these treatments in the future, any maternal or neonatal complications may emerge, especially in the neonatal and postneonatal period.”
The authors report relationships with Novartis, which manufactures eltrombopag, and Amgen, which manufactures romiplostim.
Michel M, Ruggeri M, Gonzalez-Lopez TJ, et al. Use of thrombopoietin receptor agonists for immune thrombocytopenia in pregnancy: results from a multicenter study. Blood. 2020 August 19. [Epub ahead of print]