Cyclosporine-Romiplostim-IVIG Combination Therapy In Patients With Severe Immune Thrombocytopenia (ITP)
Authors: Gudbrandsdottir Sif , Leven Emily , Imahiyerobo Allison , Lee Soo , Bussel James B. 
Published: October 2019

Abstract

Introduction
In patients with ITP, a small proportion of children and adults are very unresponsive to treatment, do not respond to single agents, and may benefit from combination therapy with 1st and/or 2nd line agents. Studies have investigated combinations of 2nd-line immunosuppressive agents in patients with severe ITP, but none have been well validated because of small patient populations. Also, combinations of ≥ 2 chemotherapy agents increase concern regarding side effects. In this retrospective study, safety and efficacy of combination therapy with romiplostim, cyclosporine A (CSA) and IVIG were investigated. Romiplostim, a thrombopoietin receptor agonist (TPO-RA), stimulates platelet production, CSA inhibits T cell activation, and IVIG blocks antibody-mediated platelet destruction. Thus, 2 forms of platelet destruction as well as impaired production were simultaneously targeted with agents whose toxicity is non-overlapping

Methods
Adult and pediatric severe ITP patients treated with CSA-romiplostim-IVIG therapy at the Weill Cornell Medical College were included. 13/14 patients had been unresponsive to monotherapy with TPO-RA. Romiplostim was injected weekly in individually adjusted doses; CSA was taken at sub-transplant doses (100-200 ng/ml) to minimize toxicity; and IVIG was infused as needed. Primary outcome was platelet counts consistently ≥30,000. Secondary outcomes were reduction in dose or frequency of IVIG and/or reduction of romiplostim dose.

Results
14 severe ITP patients (4 children) received the CSA-romiplostim-IVIG regimen for median 5 months (range 1-22 mos) (Table). Ten patients (71%) including 2 children met the primary outcome criteria and were responders (Figure). 2 responders no longer required IVIG; 3 more had less need for it. 1 responder discontinued romiplostim due to stable platelet counts; another 4 reduced their dose. 5 responders discontinued combination therapy: 1 due to sustained response (22 months); 1 due to pregnancy (6 months); 1 entered a clinical trial (5 months); 1 due to side effects of CSA (3 months); 1 died (5 months) from pre-existing cardiac disease. 2 responders received short courses of danazol: 1 during the first 2 weeks of combination therapy and 1 after 12 months when a bone marrow biopsy revealed fibrosis and romiplostim was discontinued. Adverse effects of CSA (headache, abdominal pain, diarrhea and peripheral neuropathy) were reported in 6 responders and 2 non-responders; 1 non-responder had worsened hypertension, which resolved upon discontinuation of CSA. 5 additional patients received mycophenolate mofetil (MMF) instead of CSA with TPO-RA and IVIG; 4 responded.

Conclusion
There has been increasing focus on T cells in ITP in the past few years. CSA inhibits T-cell activation, so the efficacy of CSA in combination with IVIG and stimulation of platelet production supports both the hypothesis that activated T cells contribute to unresponsiveness in ITP and that targeting different aspects of the pathophysiology of ITP may be highly effective. Reported responses of CSA monotherapy in ITP are 17/22 adults and 16/31 children with a relapse rate of 36%. Reported adults had received doses of CSA to maintain serum levels of 200-400 ng/mL and had failed only 1-4 treatments; none had received TPO-RA. In contrast, our responders had failed 5-8 treatments, failed TPO-RA, and apparently had lesser toxicity because of lower doses of CSA.
CSA can optimally be used in combination with romiplostim and IVIG to manage patients with severe ITP; however, CSA toxicity requires monitoring and potentially adjustment of therapy. Studies are planned to further investigate the use of romiplostim and IVIG in combination with CSA and other T-cell agents such as MMF or sirolimus.

Disclosures:
Gudbrandsdottir: Amgen: Research Funding; GlaxoSmithKline: Research Funding. Bussel:Amgen: Family owns stock Other, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Cangene: Research Funding; Genzyme: Research Funding; GlaxoSmithKline: Family owns stock, Family owns stock Other, Membership on an entity’s Board of Directors or advisory committees, Research Funding; IgG of America: Research Funding; Immunomedics: Research Funding; Ligand: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Eisai: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Shionogi: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Sysmex: Research Funding; Symphogen: Membership on an entity’s Board of Directors or advisory committees.