Efficacy and Safety of a Combination of Thrombopoietin Receptor Agonist with an Immunosuppressant Therapy for the Management of Multirefractory Adult ITP: Results from a Retrospective, Multicenter, Observational Study

Introduction Multirefractory adult ITP, defined as no response to splenectomy, rituximab, and thrombopoietin receptor agonists (TPO-Ra), is associated with high morbidity and mortality. In a previous study, we have shown that combining an immunosuppressant therapy with one TPO-Ra could be a promising therapeutic strategy for managing patients with multirefractory ITP. Objective The aim of this study was to assess the efficacy and safety of such combination in multirefractory ITP on a larger series of patients. Patients and methods We conducted a retrospective, multicenter, observational study in France. Adult patients treated by a combination of a TPO-Ra with an immunosuppressant therapy (i.e., mycophenolate mofetil, azathioprine, ciclosporin, everolimus, or cyclophosphamide) for chronic (> 12 months) or persistent (> 3 months) multirefractory ITP, were included through the national reference center for adult immune cytopenia (CERECAI) network. Multirefractory ITP was defined as disease not responding to rituximab, to splenectomy (or contraindication to splenectomy), and to the 2 TPO-Ras licensed in France (romiplostim and eltrombopag) administered at the maximal approved dose. Clinical and biological data were retrospectively collected using a standardized form. Complete response (CR) was defined by a platelet count >100 x109/L and response (R) by a platelet count between 30-100 x109/L with at least a 2-fold increase from baseline, according to the international recommendations. Results Thirty-one patients (65% female, median age 57 years [range 23 - 82]) were included. Five (16%) of them had secondary ITP (Evans syndrome (n=2), systemic lupus (n=1) with antiphospholipid syndrome (APS), primary APS (n=1), and Waldenstrom macroglobulinemia (n=1). Four patients had a monoclonal gammopathy of undetermined significance, and 11 (35%) had antinuclear antibodies (titer >1/160) without definite clinical autoimmune disease. All patients had previously received corticosteroids and 16/31 (52%) were corticosteroid-refractory. Previous treatments lines also included intravenous immunoglobulin (28/31, 90%) and at least one immunosuppressant therapy (16/31, 52%). Splenectomy was performed in 25 patients (81%), and not performed in the remaining 6 patients because of advanced age and comorbidities (n=3), underlying APS (n=2), or patient refusal (n=1). At the time of treatment combination initiation, median ITP duration was 57 months [3 - 393], with 28/31 (90%) chronic ITP and 3/31 (10%) persistent ITP. Bleeding symptoms were present in 23 patients (74%) and the median platelet count was 10 x109/L [range 1 - 35]. The combination regiment included eltrombopag (n=18) or romiplostim (n=13), associated with either mycophenolate mofetil (n=15), azathioprine (n=12), cyclophosphamide (n=2), ciclosporine (n=1), or everolimus (n=1). Median duration of combination therapy was 12 months [range 1 - 103]. Nineteen patients (61%) had no therapeutic intervention other than the combined treatment, while 10 patients were also given corticosteroids (either short course of high dose steroids [n=5], or on a long-term at low dose [n=5]), and/or hydroxychloroquine (n=5). Overall, 81% of patients (25/31) achieved at least a R, including 19/31 (61%) CR. Among responders, the median time to response was 30 days [range 7 - 270], and the median duration of the response was 12 months [4 - 55]. Response rates were similar in patients who did not receive concomitant corticosteroids (59% CR, 12% R), and in patients that were previously exposed to immunosuppressant therapy given alone (63% CR, 25% R). Regarding safety, 13/31 (42%) patients experienced at least one adverse event potentially related to treatment, including 7 severe adverse events. Three patients without APS but who were splenectomized had a thromboembolic event, including 3 deep vein thrombosis/pulmonary embolism, and 1 cerebral venous thrombosis; Three patients had an infection (one cholecystitis, one herpes zoster, and one dental abscess). After a median follow-up of 18 months [6-103], one patient died (from a previously diagnosed adenocarcinoma). Conclusion In summary, these data show that most of the patients managed for multirefractory ITP may benefit from the combination of TPOra with an immunosuppressant therapy by achieving a durable response. The safety profile of this combination in this population seems acceptable. Disclosures Moulis: Novartis SAS: Membership on an entity's Board of Directors or advisory committees, Other: meeting attendance grant, Research Funding; Amgen: Other: meeting attendance grant; Grifols: Research Funding. Michel:Bioverativ: Consultancy; Rigel: Consultancy; Alexion Pharmaceuticals: Consultancy. Godeau:LFB: Honoraria; Amgen: Research Funding; Amgen: Honoraria; Novartis: Honoraria. Mahevas:GSK: Research Funding. OffLabel Disclosure: Some immunosuppressant drugs were given off-label for adult ITP.