Combination of thrombopoietin receptor agonists, immunosuppressants and intravenous immunoglobulin as treatment of severe refractory immune thrombocytopenia in adults and children

Abstract

Primary immune thrombocytopenia (ITP) is characterized by immune-mediated peripheral platelet destruction and suboptimal platelet production in the bone marrow affecting both children and adults. The pathogenesis of ITP is not fully understood, but anti-platelet autoantibodies as well as autoreactive Th and Tc cells have been identified in ITP patients with active disease(Neunert et al., 2011; Zufferey et al., 2017; Neunert & Cooper, 2018). A small proportion of both children and adults do not respond to conventional first- or second-line treatments. Increasingly, splenectomy is not proposed, declined or contra-indicated. Some patients with severe ITP, before or after splenectomy, therefore may benefit from combination therapy (Miltiadous et al., 2020). In this retrospective study, we report safety and efficacy of combination therapy with thrombopoietin receptor agonists (TPO-RAs) romiplostim or eltrombopag; immunosuppressants ciclosporin A (CSA) or mycophenolate mofetil (MMF); and intravenous immunoglobulin G (IVIG). We identified adult and paediatric primary ITP patients, refractory (Rodeghiero et al., 2009) or not responding to previous therapies, treated with a combination of CSA or MMF, TPO-RAs and IVIG at Platelet Disorders Center, Weill Cornell Medicine in New York. All patients were unresponsive to monotherapy with TPO-RAs and/or IVIG. For TPO-RAs, romiplostim was administered weekly as a subcutaneous injection and eltrombopag daily, taken orally on an empty stomach. CSA was administered at 5 μg/kg/day aiming for serum concentrations of 100–200 ng/ml to minimize toxicity. MMF was administered as 500 or 1000 mg twice daily. IVIG 1 g/kg was administered to increase the platelet count when clinically needed. The number of prior medical treatments, splenectomy status, blood pressure and platelet counts at baseline were obtained from patient charts. The observation period extended from initiation of treatment to data collection, during which the variables above were recorded at weeks 1, 2, 3 and 4, and monthly as available. Patients were considered responders if platelet counts increased to >30 × 109/l and double the baseline after week 1. Patients who presented sporadic, but frequent platelet counts <30 × 109/l during the observation period were still considered responders, hence allowing for dose-adjustements and rescue IVIG. Secondary end-points were a reduction in dose or frequency of IVIG infusions and/or a lower dose of romiplostim or eltrombopag. Eighteen patients with chronic or persistent ITP treated with the combination therapy were identified, including six children and twelve adults, nine females and nine males; median age 40 years (1–77). Median duration of ITP was 6·5 years (range 3 months to 22 years). Patients had received a mean of 6·5 prior treatments for ITP (range: 3–14), eleven patients (all adults) were splenectomised at baseline and fourteen of the eighteen patients were non-responders to TPO-RA monotherapy. At the time of data collection, the patients had been on combination therapy for a median of five months (range: 1–22 months) (Table 1). Thirteen patients (six females, seven males) reached the primary end-point of an increased platelet count and were considered responders to therapy according to the predefined criteria (Fig 1). One responding patient was able to discontinue romiplostim while six others tapered to lower TPO-RA doses. Five responders no longer required IVIG after starting CSA/MMF + TPO-RA, while three others reduced IVIG frequency and/or dose. One patient (a two-year-old boy) was administered monthly IVIG infusions due to acquired hypogammaglobulinaemia after treatment with rituximab (Table 1). Two adult responders reported bleeding symptoms during combination treatment. The five non-responders included two female splenectomised adults and three non-splenectomised children. The two adults both had a transient increase in platelet counts, but values dropped to pretreatment levels after three weeks and three months, respectively. They continued to need rescue IVIG at similar intervals to those before CSA treatment and CSA was discontinued after three months. One child had a transient increase in platelet counts during the first two months, but values then dropped to pretreatment levels. One child had no effect on platelet counts, which continued to be <30 × 109/l; treatment was discontinued after four months. The third child was treated for one year with CSA + romiplostim + IVIG until he moved to another country; the lowest platelet count recorded in the observation period was 24 × 109/l. He did not meet the criteria for response as defined in this study, although he avoided bleeding with the combination regimen. Of the eighteen patients on the study, eleven (eight responders) experienced headaches and/or abdominal discomfort. One responder discontinued CSA therapy after 12 weeks due to toxicity, which included headaches, increased irritability and worsening of pre-existing molluscum contagiosum. One non-responder with pre-existing treated hypertension had a clinically significant increase in blood pressure, which resolved upon discontinuation of ciclosporin. Recently an increasing focus on the role of T cells in the pathogenesis of ITP has developed (Zufferey et al., 2017). CSA as single agent or in combination with prednisone has been recommended as second-line treatment of refractory ITP(Neunert et al., 2011; Neunert & Cooper, 2018)Romiplostim and eltrombopag have been validated as treatment of refractory ITP in large placebo-controlled trials reporting complete or partial response in most patients (Bussel et al., 2009; Wong et al., 2017; Ghanima et al., 2019). In this retrospective study, we evaluated combination therapy with CSA/MMF, TPO-RA and IVIG in eighteen patients with refractory ITP. The combination targetted three different mechanisms of disease pathobiology, as CSA and MMF inhibit T-cell activation, TPO-RAs stimulate platelet production, and IVIG blocks Fc receptors, thereby inhibiting auto-antibody-mediated platelet destruction. Toxicity was important but manageable. The study is limited by the relatively small number of patients, short observation periods, and platelet counts were not available for all patients at the predetermined time intervals. All patients were treated before fostamatinib became commercially available. If fostamatinib, which also blocks phagocytosis, can substitute for IVIG, the treatment would be facilitated by no longer needing IVIG management. Once treatment is established, if a response is seen, one or more agents can be tapered slowly. In this study, results suggest that CSA or MMF can be used as part of an effective combination therapy with TPO-RA and IVIG to manage patients with severe refractory ITP. The authors thank Brittany Cooper for her help with data administration. The study was designed by JB. Data was collected by EL, AI and CL. SG, EL and JB analysed the data and wrote the manuscript. Sif Gudbrandsdottir: has previously received research funding from Amgen and GlaxoSmithKline. James Bussel received research funding from Cangene, Genzyme, IgG of America, Immunomedics and Sysmex, is member of advisory boards and has received research funding from Amgen, GlaxoSmithKline, Ligand, Eisai, Shinogi and Symphogen.

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