Emerging Therapies in Immune Thrombocytopenia

Immune thrombocytopenia (ITP) is an acquired bleeding disorder with a heterogeneous and incompletely understood pathophysiology. The complex interplay of abnormalities, including immune dysregulation, antiplatelet autoantibodies, defects in cellular immunity, and altered platelet production, result in often profound thrombocytopenia and variable bleeding symptoms.¹  For decades, treatment options were limited to corticosteroids and splenectomy, followed by the plasma-derived treatments. However, as understanding of ITP disease biology improves, an expanded treatment repertoire is emerging.

Current State of ITP Treatment

Broadly, two categories of agents are available for the treatment of ITP: 1) those that rapidly and transiently interfere with the process of platelet destruction for management of acute bleeding or bleeding risk (front-line therapies), and 2) those with potential to provide a more durable improvement in the platelet count (second-line therapies). Corticosteroids, intravenous immunoglobulin (IVIG), and anti-D immune globulin remain the mainstay of front-line treatment of acute bleeding symptoms in both adults and children. Although corticosteroids remain the most commonly used ITP therapy, controversy still exists surrounding selection of agent, dosing, and duration of therapy. Several groups have investigated whether dexamethasone could be superior to prednisone in primary ITP.^2-4  Dexamethasone has a significantly increased anti-inflammatory effect compared to prednisone, and laboratory data suggest that dexamethasone more effectively modulates the T cell abnormalities seen in ITP.⁵  However, given the increased potency of dexamethasone, the adverse effect profile may be less favorable. A recent meta-analysis analyzed nine randomized trials comparing various steroid regimens and found that while the initial response rate may be higher in adult patients treated with dexamethasone, the durable response rates were not significantly different.⁶  The authors proposed consideration of dexamethasone instead of prednisone in adults if more rapid improvement in platelet count was desired.⁶  For treatment with prednisone, it is generally accepted that shorter courses are preferable to chronic therapy.

Choice of Second-Line Therapy

What to do next? The approach to the management of patients who fail front-line treatment or have persistent or chronic ITP has evolved dramatically since the publication of two pivotal clinical practice guidelines for the management of ITP. Both the ASH 2011 evidence-based practice guideline for ITP⁷  and the 2010 international consensus report on the investigation and management of primary ITP developed by an international working group⁸  address three classes of second-line therapies: splenectomy, rituximab, and the thrombopoietin receptor agonists (TPO-RA). While there were adequate data for the efficacy and safety of splenectomy and rituximab, both sets of guidelines were published relatively shortly after the 2008 U.S. Food and Drug Administration (FDA) approval of two TPO-RA therapies, romiplostim and eltrombopag. Due to a relative lack of data, their use was recommended only in patients who were refractory to splenectomy and other therapies. In the years since the publication of these guidelines, abundant data on the efficacy and safety of the TPO-RA have become available; as such, these treatments are being used earlier and more frequently in the disease course in both adults and children.^9,10  Increasing use of rituximab and the TPO-RA agents is leading to overall reduced rates of splenectomy, especially in young children and older adults, who are considered to have the highest risk of complications after splenectomy.¹¹  Future studies are likely to clarify the role of TPO-RA in earlier phases of ITP treatment.

TPO-RA Efficacy and Safety Data, and a New TPO-RA

Data on long-term use of romiplostim and eltrombopag are available in both adults and children.^12-15  These studies generally show that response can be maintained and that the agents are safe for long-term use, with no additional safety signals or rates of adverse events than previously reported. Although these agents were not designed to be used with curative intent, a small number of patients have gone into extended remission after treatment with a TPO-RA,^16,17  prompting additional research into the biology of the effect of TPO-RA on the bone marrow.

Avatrombopag is a newer, nonpeptide thrombopoietin receptor agonist that has been in ongoing clinical trials since its development in 2008.¹⁸  This drug is orally bioavailable and does not have the divalent cation interactions limiting timing of meals or potential for hepatotoxicity seen with eltrombopag therapy; it may eventually provide another alternative for patients who are good candidates for TPO-RA therapy. Data from a phase III, randomized, double-blind, placebo-controlled study of avatrombopag in adults with chronic ITP was presented at the 2017 ASH Annual Meeting.¹⁹ 

Novel Approaches and New Therapies

Despite the increasing use of TPO-RA, many patients remain refractory to available treatments. Current research is focused on combining therapies to address multiple mechanisms of disease simultaneously. Additionally, as our understanding of the complex pathophysiology of ITP improves, novel therapies targeting alternative pathways are becoming available.

Combination Treatment

Several studies have evaluated the combination of agents targeting different aspects of the disease biology, with the goal of inducing durable remission.³  The combination of dexamethasone and rituximab has been evaluated in multiple trials and has been shown to provide superior results to either drug as monotherapy in some patients,^20-22  and the possibility to revert lymphocyte subset abnormalities commonly seen in active disease.²³  The addition of cyclosporine to rituximab and dexamethasone has also been evaluated in small adult studies and has provided enduring remission in a subset of treated patients, without substantial reported toxicity.²⁴ 

Recombinant human TPO (rhTPO) is available outside the United States and was recently evaluated in combination with dexamethasone compared to dexamethasone monotherapy in newly diagnosed adults. The authors report higher day-14 and six-month overall response and complete response rates in patients who received the combination therapy.²⁵ 

Fostamatinib

Fostamatinib is an orally bioavailable spleen tyrosine kinase (SYK) inhibitor that received FDA approval for the treatment of chronic ITP in adults in April 2018.^26,27  SYK signaling is a critical step in phagocytosis of Fc receptor–bound, antibody-coated platelets, and blockade with fostamatinib has shown favorable results in two parallel phase III randomized, double-blind, placebo-controlled clinical trials in adults with persistent or chronic ITP. Forty-three percent of patients in this refractory cohort demonstrated a response to fostamatinib after failure of other treamtents including rituximab, TPO-RA, and/or splenectomy, compared to 14 percent of patients on the placebo arm. Median time to response was 15 days. The safety profile has been generally favorable in adults, with gastrointestinal adverse effects and hypertension being most common, but not dose limiting.²⁶  Fostamatinib is not in clinical trials for pediatric ITP due to potential effects on cartilage.

Rozanolixizumab

Another novel agent is rozanolixizumab, an antineonatal Fc receptor (FcRn) recycling agent that decreases circulating pathologic IgG by blocking FcRn, the receptor primarily responsible for recycling IgG and prolonging its half-life. Studies in murine autoimmune disease demonstrated favorable results.^28-30  Based on preliminary data in humans showing the effect of this agent on reducing circulating IgG,³¹  investigators began evaluating the effect of this agent in ITP and other autoimmune diseases. The interim analysis of an ongoing phase II multiple-dose study of rozanolixizumab in adult ITP was presented at the 2017 ASH Annual Meeting.³²  Rozanolixizumab is administered subcutaneously, and in this dose-escalation study, 4 mg and 7 mg doses were well tolerated, with 30 percent of treated patients achieving an improvement in the platelet count.

Other Agents

Monoclonal antibodies targeting various pathways are the subject of ongoing research as potential therapeutic options for ITP, including agents that interfere with the interaction of CD154 and CD40. This is a critical step in the development of autoreactive T cell populations. The clinical development of these agents has been limited by an increased frequency of thrombosis in early clinical trials. Therapies that interfere with Fc receptor binding via different mechanisms than the recently approved fostamatinib are also in development. An additional agent targeting the FcRn/IgG interaction is also being investigated.³³  Other thrombopoietin agonists and cytoprotective agents with the potential to augment platelet production are in various stages of development.³⁴ 

Summary

ITP is an extraordinarily complex and heterogeneous disease. The highly variable response rates to agents targeting different mechanisms of immune dysregulation suggest that individual patients may have different disease biology predominating. Improved understanding of ITP pathophysiology is leading to the availability of new treatment options for even the most refractory patients. Ongoing research may eventually offer insight into individual patient disease biology and lead to possible future targeted therapeutic approaches. In combination with an expanding number of available treatment options with favorable safety profiles, targeted therapy may eventually become possible in ITP, hopefully resulting in improved response rates and less toxicity.