Not So Benign
Immune Thrombocytopenia: New and Emerging Therapies for a Challenging “Benign” Hematologic Disease

Immune thrombocytopenia (ITP) is a disease characterized by the autoimmune-mediated destruction of platelets and impaired platelet production, which puts patients at increased risk of bleeding and decreased quality of life, with potential for morbidity and mortality.¹  Most patients requiring treatment for ITP respond to first-line treatment with corticosteroids, but few of them experience sustained remission.²  Prolonged corticosteroid use is associated with unacceptable adverse effects, and even relatively low doses of corticosteroid (prednisone 5 mg equivalent) substantially increases infection risk.³  Current guideline-recommended second-line treatment options include rituximab, thrombopoietin receptor agonists (TPO-RAs), or splenectomy.¹  These treatments are not always effective and have important toxicities of their own. Some patients are also refractory to multiple treatments, creating an ongoing need for further effective ITP therapies.^4,5  This review will discuss some of the most promising therapies that have recently become available or are currently in the clinical trials pipeline.

Although TPO-RAs are not a new treatment for ITP, they were a paradigm-shifting non-immunomodulatory ITP treatment. These agents are highly effective, with overall response rates of approximately 75% and durable responses in about 65% of patients, with some (10-30%) of patients able to discontinue treatment with ongoing responses.²  Avatrombopag is a newer orally administered TPO-RA that appears similarly efficacious to eltrombopag (based on the results of a phase III placebo-controlled randomized controlled trial [RCT]), without the latter’s inconvenient food and drug interactions or the need to monitor liver enzymes.⁶  Therefore, avatrombopag represents an important addition to the ITP therapeutic armamentarium, and is approved for this indication in the U.S., European Union, and Canada.

Autoantibody-opsonized platelets are phagocytosed by macrophages in a process mediated by FcyR and spleen tyrosine kinase (Syk), which is inhibited by the small molecule fostamatinib.⁴  Two parallel phase III RCTs demonstrated an overall response rate of 43% and a stable response rate of 18% in patients who had not responded adequately to previous therapies, with a median time to response of 15 days.⁷  Important toxicities of fostamatinib include diarrhea and hypertension.⁸  While clearly not a solution for everyone, the high-quality evidence demonstrating its efficacy in treatment-refractory patients led to the U.S. Food and Drug Administration’s approval of fostamatinib for patients with insufficient response to at least one prior ITP therapy.

Following a similar logic to that applied for fostamatinib, researchers have explored the role of Bruton tyrosine kinase (BTK) downstream in the FcyR transduction pathway as a therapeutic target in ITP.^4.5  Rilzabrutinib is an oral, highly selective BTK inhibitor, allowing for treatment of autoimmunity without the obviously problematic platelet-inhibitory effects of less-selective BTK inhibitors such as ibrutinib.⁵  A phase I/II trial of rilzabrutinib in patients with heavily pretreated ITP showed a response rate of 40%, with responders experiencing durable responses.⁹  Responses were also relatively rapid, with a median time to response (defined as reaching a platelet count of at least 50 × 10⁹/L) of 11.5 days. The most common adverse effects were diarrhea (32%) and nausea (30%), with no reported bleeding or thrombotic events grade 2 or higher, infections, hepatic toxicity, or cardiac arrhythmias.⁹  A phase III RCT of rilzabrutinib in patients age 12 years and older with persistent or chronic ITP is now underway (LUNA 3, NCT04562766).

The neonatal Fc receptor (FcRn) has a crucial role in the recycling of immunoglobulin G (IgG), rescuing IgG from degradation in lysosomes, meaning that FcRn inhibition could shorten the half-life of IgG – a potential therapeutic target in diseases with humoral autoimmunity.⁵  Efgartigimod is a human IgG1 Fc fragment that binds FcRn with high affinity, preventing IgG recycling and reducing serum IgG concentrations (including autoantibodies).^5,10  A recently published phase III placebo-controlled RCT of efgartigimod for persistent or chronic ITP reported a sustained platelet response (defined as platelet count above 50 × 10⁹/L in at least four of the last six weeks) in 22% of efgartigimod-treated patients versus 5% in placebo-treated patients.¹⁰  The primary reported adverse events were headache, hematuria, and petechiae, but these occurred at similar frequency in the treatment and placebo groups. Notably, no increased risk of infection was observed.¹⁰ 

The complement system is not completely understood, but it is thought to be implicated in the pathogenesis of ITP for at least some patients.⁴  Sutimlimab is an anti-C1s IgG4 antibody that selectively inhibits the classical complement pathway.¹¹  A phase I study of sutimlimab in patients with chronic refractory ITP (defined as a platelet count lower than 30 × 10⁹/L and inadequate response to at least 2 ITP therapies) was published in 2023.¹¹  Of 12 patients treated, 42% had a response (platelet count greater than 50 × 10⁹/L), with four patients (33%) having a platelet count response for more than 70% of study visits. Migraine was the only treatment-related adverse event observed (n=1).

B-cell depletion in the form of the anti-CD20 monoclonal antibody rituximab has a long-established role in the treatment of ITP. However, rituximab does not target long-lived plasma cells in the spleen and bone marrow, which can continue to produce antiplatelet autoantibodies.⁵  These cells can be effectively targeted by anti-CD38 monoclonal antibodies such as daratumumab, which is now under active study in ITP. The investigation is still in its early days, however, with the evidence base consisting primarily of case reports and the ongoing phase II dose-escalation DART study (NCT04703621).⁵ 

A deepening understanding of the pathophysiologic underpinnings of ITP has led to an expanding toolkit of therapeutic options. As is the case for many malignant hematologic disorders, the challenge for the ITP clinician is now shifting from one of a paucity of evidence-based therapies to one of appropriate therapy selection and sequencing. Careful consideration of mechanism of action, potential toxicities, patient values and preferences, and, of course, cost will inform these decisions. While much work remains, there is undoubtedly ample cause for optimism for patients living with ITP.

Dr. Scott has received funding from Amgen (speaker honorarium) and Recordati (conference travel support).

The author wishes to acknowledge Dr. Michelle Sholzberg for providing thoughtful suggestions as to therapies to focus on in this piece.