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Harvard Medical School
Attending Hematologist and Clinical Investigator
Division of Hematology Oncology
Massachusetts General Hospital
Hanny Al-Samkari, MD: consultant/advisor/speaker: Agios, Argenx, Dova/Sobi, Forma, Moderna, Novartis, Rigel; researcher (paid to his institution): Agios, Amgen, Dova/Sobi.
In the past 2 decades, immune thrombocytopenia (ITP) has evolved from a disease of the 3 S’s—steroids, splenectomy, and salvage therapy—to one with the availability of 4 FDA-approved drugs. Goals for management include resolving present bleeding events and reducing the risk of future bleeding episodes. When therapy is warranted, corticosteroids are a traditional first-line treatment. While platelet autoantibodies are important in ITP pathophysiology, it is increasingly recognized that ITP is much more than a disease of autoantibodies. Several aspects of the immune system and platelet production are dysregulated in patients with ITP, and newer therapies are targeting each of those mechanisms.
Therapy Options Following Corticosteroids
There are 4 FDA-approved options for ITP treatment—romiplostim, eltrombopag, avatrombopag, and fostamatinib—as well as a fifth alternative that is not approved by the FDA but has data from randomized trials supporting its use.
The 3 thrombopoietin receptor agonists (TPO-RAs)—romiplostim, eltrombopag, and avatrombopag—stimulate the production of platelets. Romiplostim and eltrombopag have been available for more than a decade and are alternatives for adults and children who have not responded well to corticosteroids. Romiplostim is administered subcutaneously once weekly, and eltrombopag is administered orally. Eltrombopag is usually taken without food or spaced from food or medications containing polyvalent cations. Avatrombopag is a newer oral TPO-RA indicated for adults with chronic ITP with insufficient response to previous treatment.
The spleen tyrosine kinase inhibitor—fostamatinib—functions as an immunomodulatory agent to reduce phagocytosis of platelets by the macrophages in the spleen. It is administered orally and does not appear to have the theoretical thrombosis risk associated with TPO-RA therapy. Post hoc analysis of the fostamatinib trial data has shown that it has greater efficacy when used earlier in the disease course.
The fifth alternative is rituximab, which targets CD20-positive B-cells and reduces antiplatelet antibodies. It has been used off label in ITP but has robust randomized trial level data to support its use. These agents provide a decent armamentarium, but more understanding of disease pathology provides opportunity for further drug development.
My colleagues and I have developed an Interactive Decision Support Tool (coming soon!) to provide education for healthcare professionals in making optimal choices for monitoring or treating patients with ITP. A series of questions allows healthcare professionals to select individual patient characteristics that are necessary to consider when making management choices. These characteristics include age, platelet count, presence of risk factors for bleeding, and/or current clinical manifestations. Based on the characteristics entered, the tool will display expert recommendations for the specific patient case.
Emerging Treatment Options
To target platelet autoantibodies, neonatal Fc receptor antagonists are being evaluated for ITP. These are new therapeutics that block the recycling of immunoglobulin G (IgG) antibodies, including the pathologic platelet autoantibodies that are IgG. They alter the recycling by reducing the half‑life of those antibodies from approximately 3 weeks to 1 week. Data from phase II studies with efgartigimod and rozanolixizumab demonstrated drops in platelet autoantibody levels with improvements in platelet counts.
Bruton tyrosine kinase (BTK) is a very common target in lymphoid malignancies, and there are BTK inhibitors approved to treat lymphoid malignancies. An issue with BTK inhibitors is that they reduce platelet function, which is not desirable in ITP. Rilzabrutinib is a BTK inhibitor that did not inhibit platelet aggregation or reduce platelet function in healthy volunteers. A phase I/II study evaluating rilzabrutinib in patients with relapsed/refractory ITP demonstrated a response rate of 40%, which is very encouraging for that patient population.
Complement‑directed agents that inhibit a branch of the immune system have not been investigated in treatment of ITP until now. Sutimlimab is an antibody that binds to the complement C1S protein and shuts down the classical complement pathway. Data from a phase I trial of sutimlimab with patients with chronic/refractory ITP demonstrated increased platelet counts—in some cases improvements very soon after the drug was administered.
Plasma cells, otherwise known as the antibody factories, are another target under investigation. Daratumumab, which already is approved to treat myeloma as an anti‑CD38 antibody, is being evaluated for treatment of ITP in the DART study (NCT04703621). TAK‑079 (mezagitamab) is another anti‑CD38 monoclonal antibody being evaluated in treatment of primary ITP (NCT0278924). If therapeutic intervention can reduce the number of long-lived plasma cells, there is potential to induce responses in many patients whose disease has been difficult to treat.
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