Cyclosporine-Romiplostim-IVIG Combination Therapy in Refractory ITP
Authors: Leven Emily , Miller Allison , Cooper Brittany , Bussel James B 
Published: October 2019

Abstract
Abstract 1095

Introduction:
Refractory ITP can be very difficult to treat and may not respond to a single agent. Even the thrombopoeitic agents (TPO-A) and IVIG, which have response rates of 60–90%, are at the lower end of this range in the worst cases. Therefore combination therapy may be required. Previous studies using small numbers of patients have suggested CHOP (Figueroa,NEJM,1993); danazol and azathioprine[aza](Boruchov, Blood, 2007);3 low dose immunosuppressives (cyclosporine[CSA]-mycophenalate[MMF]-aza)(Arnold, Blood, 2010); and alemtuzumab-rituximab (Gómez-Almaguer, Blood, 2010). The latter 2 combinations tend to have overlapping mechanisms of effect; none of the 4 have been widely validated.

Methods:
Patients with very difficult ITP were selected for combination treatment utilizing 3 different mechanisms: CSA, a T cell modulating agent; weekly injections of romiplostim [Nplate], a TPO-A; and as-needed IVIG. CSA was administered at sub-transplant doses aiming for 100–200 ng/ml to minimize toxicity. This retrospective study sought to analyze the treatment effect of the addition of CSA to IVIG and TPO-A in patients unresponsive to the latter agents. Patients were responders if they had higher platelet counts, required less frequent IVIG infusions, and/or used a lower dose or frequency of romiplostim while taking CSA.

Results:
Nine patients with chronic ITP were treated with this CSA, romiplostim, and IVIG combination including 6 females and 7 patients who had undergone splenectomy. The average patient age was 41 yrs. Patients had received an average of 7.667 prior treatments for ITP and 8/9 patients were non-responders to TPO-A. Seven of 9 patients (4 females, 3 males) were responders. Two responding patients tapered to lower romiplostim doses, and 1 more completely discontinued romiplostim. Four required no IVIG after starting CSA and 1 patient required a single IVIG treatment 3 weeks into CSA treatment; the other 2 responding patients reduced their frequency and/or dose of IVIG therapy. All 7 responders achieved a platelet count ≥ 50 x103/uL and 6/7 ≥ 100 x103/uL. These 6 had > 50% of platelet counts ≥ 50 x103/uL. Four of 7 had > 50% of their counts ≥ 100 x103/uL. The 2 non-responders were both female and splenectomized. They continued to need rescue IVIG at similar intervals to those before CSA treatment; CSA was discontinued after 3–4 months.
Of the 9 patients on the study, 6 experienced headaches (4 responders) and 4 patients experienced abdominal discomfort. One responder discontinued CSA therapy after 12 weeks due to toxicity, which included headaches, increased irritability and worsening of preexisting molluscum contagiosum. There was not a clinically significant elevation of blood pressure in any responder; however, 1 non-responder with pre- existing treated hypertension had a clinically significant increase in blood pressure, which resolved upon discontinuation of the medication. None of the patients developed renal dysfunction or de novo infection while on combination therapy.

Conclusions:
These results suggest that cyclosporine can be used as part of an effective combination with romiplostim and IVIG to manage patients with difficult ITP. The 3 agents were chosen to target different mechanisms of disease pathobiology: FcR “blockade” (IVIG), stimulation of platelet production (TPO-A) and inhibition of T cell activation (CSA). The efficacy of added CSA suggests that activated T cells contribute to refractoriness in difficult ITP. Future research would aim to identify patients in whom activated T cells play an important role and which T-cell agent, eg CSA, MMF or sirolimus, might be indicated in which patients.

Disclosures:
Bussel: Amgen: Family owns Amgen stock Other, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cangene: Research Funding; GlaxoSmithKline: Family owns GSK stock, Family owns GSK stock Other, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: 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; Portola: Consultancy. Off Label Use: The use of romiplostim in pediatric patients was examined in this study.