Over the last decade, there have been numerous developments and changes in treatment practices for the management of patients with immune thrombocytopenia (ITP). This article is an update of the International Consensus Report published in 2010. A critical review was performed to identify all relevant articles published between 2009 and 2018. An expert panel screened, reviewed, and graded the studies and formulated the updated consensus recommendations based on the new data. The final document provides consensus recommendations on the diagnosis and management of ITP in adults, during pregnancy, and in children, as well as quality-of-life considerations.

IMPORTANCEMost patients with hepatocellular carcinoma (HCC) are diagnosed with advanced disease not eligible for potentially curative therapies; therefore, new treatment options are needed. Combining nivolumab with ipilimumab may improve clinical outcomes compared with nivolumab monotherapy. OBJECTIVE To assess efficacy and safety of nivolumab plus ipilimumab in patients with advanced HCC who were previously treated with sorafenib. DESIGN, SETTING, AND PARTICIPANTSCheckMate 040 is a multicenter, open-label, multicohort, phase 1/2 study. In the nivolumab plus ipilimumab cohort, patients were randomized between January 4 and September 26, 2016. Treatment group information was blinded after randomization. Median follow-up was 30.7 months. Data cutoff for this analysis was January 2019. Patients were recruited at 31 centers in 10 countries/territories in Asia, Europe, and North America. Eligible patients had advanced HCC (with/without hepatitis B or C) previously treated with sorafenib. A total of 148 patients were randomized (50 to arm A and 49 each to arms B and C).INTERVENTIONS Patients were randomized 1:1:1 to either nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, administered every 3 weeks (4 doses), followed by nivolumab 240 mg every 2 weeks (arm A); nivolumab 3 mg/kg plus ipilimumab 1 mg/kg, administered every 3 weeks (4 doses), followed by nivolumab 240 mg every 2 weeks (arm B); or nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks (arm C). MAIN OUTCOMES AND MEASURESCoprimary end points were safety, tolerability, and objective response rate. Duration of response was also measured (investigator assessed with the Response Evaluation Criteria in Solid Tumors v1.1). RESULTSOf 148 total participants, 120 were male (81%). Median (IQR) age was 60 (52.5-66.5). At data cutoff (January 2019), the median follow-up was 30.7 months (IQR, 29.9-34.7). Investigator-assessed objective response rate was 32% (95% CI, 20%-47%) in arm A, 27% (95% CI, 15%-41%) in arm B, and 29% (95% CI, 17%-43%) in arm C. Median (range) duration of response was not reached (8.3-33.7+) in arm A and was 15.2 months (4.2-29.9+) in arm B and 21.7 months (2.8-32.7+) in arm C. Any-grade treatment-related adverse events were reported in 46 of 49 patients (94%) in arm A, 35 of 49 patients (71%) in arm B, and 38 of 48 patients (79%) in arm C; there was 1 treatment-related death (arm A; grade 5 pneumonitis). CONCLUSIONS AND RELEVANCEIn this randomized clinical trial, nivolumab plus ipilimumab had manageable safety, promising objective response rate, and durable responses. The arm A regimen (4 doses nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks then nivolumab 240 mg every 2 weeks) received accelerated approval in the US based on the results of this study.

Immune thrombocytopenia (ITP) is a common bleeding disorder caused primarily by autoantibodies against platelet GPIIbIIIa and/or the GPIb complex. Current theory suggests that antibody-mediated platelet destruction occurs in the spleen, via macrophages through Fc–FcγR interactions. However, we and others have demonstrated that anti-GPIbα (but not GPIIbIIIa)-mediated ITP is often refractory to therapies targeting FcγR pathways. Here, we generate mouse anti-mouse monoclonal antibodies (mAbs) that recognize GPIbα and GPIIbIIIa of different species. Utilizing these unique mAbs and human ITP plasma, we find that anti-GPIbα, but not anti-GPIIbIIIa antibodies, induces Fc-independent platelet activation, sialidase neuraminidase-1 translocation and desialylation. This leads to platelet clearance in the liver via hepatocyte Ashwell–Morell receptors, which is fundamentally different from the classical Fc–FcγR-dependent macrophage phagocytosis. Importantly, sialidase inhibitors ameliorate anti-GPIbα-mediated thrombocytopenia in mice. These findings shed light on Fc-independent cytopenias, designating desialylation as a potential diagnostic biomarker and therapeutic target in the treatment of refractory ITP.

Key Points• HD-DXM is a preferred strategy to conventional prednisone as first-line management of newly diagnosed adult primary ITP.This study compared the efficacy and safety of high-dose dexamethasone (HD-DXM) and conventional prednisone (PDN) on the largest cohort to date as first-line strategies for newly diagnosed adult primary immune thrombocytopenia (ITP). Patients enrolled were randomized to receive DXM 40 mg/d for 4 days (n 5 95, nonresponders received an additional 4-day course of DXM) or prednisone 1.0 mg/kg daily for 4 weeks and then tapered (n 5 97). One or 2 courses of HD-DXM resulted in a higher incidence of overall initial response (82.1% vs 67.4%, P 5 .044) and complete response (50.5% vs 26.8%, P 5 .001) compared with prednisone. Time to response was shorter in the HD-DXM arm (P < .001), and a baseline bleeding score ‡8 was associated with a decreased likelihood of initial response. Sustained response was achieved by 40.0% of patients in the HD-DXM arm and 41.2% in the PDN arm (P 5 .884). Initial complete response was a positive indicator of sustained response, whereas presence of antiplatelet autoantibodies was a negative indicator. HD-DXM was generally tolerated better. We concluded that HD-DXM could be a preferred corticosteroid strategy for first-line management of adult primary ITP. This study is registered at www.clinicaltrials.gov as #NCT01356511. (Blood. 2016;127(3):296-302)

Immune thrombocytopenia (ITP) is the most common acquired thrombocytopenia after chemotherapy-induced thrombocytopenia. Existing guidelines describe the management and treatment of most patients who, overall, do well, even if they present with chronic disease, and they are usually not at a high risk for bleeding; however, a small percentage of patients is refractory and difficult to manage. Patients classified as refractory have a diagnosis that is not really ITP or have disease that is difficult to manage. ITP is a diagnosis of exclusion; no specific tests exist to confirm the diagnosis. Response to treatment is the only affirmative confirmation of diagnosis. However, refractory patients do not respond to front-line or other treatments; thus, no confirmation of diagnosis exists. The first section of this review carefully evaluates the diagnostic considerations in patients with refractory ITP. The second section describes combination treatment for refractory cases of ITP. The reported combinations are divided into the era before thrombopoietin (TPO) and rituximab and the current era. Current therapy appears to have increased effectiveness. However, the definition of refractory, if it includes insufficient response to TPO agents, describes a group with more severe and difficult-to-treat disease. The biology of refractory ITP is largely unexplored and includes oligoclonality, lymphocyte pumps, and other possibilities. Newer treatments, especially rapamycin, fostamatinib, FcRn, and BTK inhibitors, may be useful components of future therapy given their mechanisms of action; however, TPO agents, notwithstanding failure as monotherapy, appear to be critical components. In summary, refractory ITP is a complicated entity in which a precise specific diagnosis is as important as the development of effective combination treatments.