Novel Treatments Expand Second-Line Options in ITP

Ivy P. Altomare, MD

Although steroids remain the standard frontline treatment for patients with immune thrombocytopenia (ITP), the armamentarium in the second-line setting is rapidly expanding, according to Ivy P. Altomare, MD.

"Fortunately, ITP, being a chronic and rare disease, has a plethora of exciting and effective therapies that do not cause long-term immunosuppression and are well tolerated. Moreover, patients can stay on [these treatments] for a prolonged period of time with excellent quality of life,” said Altomare.

The thrombopoietin (TPO) receptor agonists—–eltrombopag (Promacta), romiplostim (Nplate), and avatrombopag (Doptelet)––have demonstrated particular success in this setting. All 3 agonists are approved for patients with ITP who have an insufficient response to corticosteroids, immunoglobulins, or splenectomy.

Additionally, novel classes of agents, such as neonatal Fc receptor (FcRn) inhibitors are being investigated in ongoing clinical trials, explained Altomare.

Despite these advances, challenges regarding diagnosis and management of patients with highly refractory disease require additional research and development.

In an interview with OncLive, Altomare, an associate professor of medicine in the Department of Medicine at Duke University School of Medicine, and medical oncologist at Duke Cancer Network, discussed the prognosis of patients with ITP, available treatment options, and emerging treatment modalities on the horizon.

OncLive: What is the prognosis of patients with ITP?

Altomare: In adults, ITP is generally a chronic disease that will relapse and remit throughout a patient's lifetime. It is typically something that patients live with. There is a risk of serious bleeding. The [worst-case scenario] is spontaneous intracerebral hemorrhage (ICH); however, the rate is quite low.

Fortunately, if a patient's platelets are able to be maintained in a safe range, ITP is not fatal.

We now have many effective therapies that [prevent] serious bleeding and ICH and also reduce the long-term immunosuppression of historical therapy.

What treatment options are available for patients?

The first line of treatment for patients with ITP is steroids; that is unlikely to change. Steroids are effective in most patients; however, most patients will relapse. Durable responses to steroids only occur in about 30% of patients after 2 years. As such, most patients will need a second-line option relatively soon in their treatment course.

We have ever-expanding options in the second-line setting. However, we don't have head-to-head trials comparing 1 therapy with another, so the choice is based on shared decision making between the patient and the provider.

Could you expand some of the second-line therapies that are available to patients?

We do not have great clinical predictors or biomarkers to inform which therapy should be used and in what sequence. The choice is arbitrary.

Fortunately, we many effective therapies. TPO receptor agonists have demonstrated very high response rates in patients with chronic ITP, and they do not cause long-term immunosuppression. We have 3 agents in this class that are approved by the FDA: eltrombopag, romiplostim, and avatrombopag. Treatment selection is based on patient preference, physician experience, and payers, but all of these agents are very effective.

There is also fostamatinib disodium hexahydrate (fostamatinib; Tavalisse), which is an oral spleen tyrosine kinase (Syk) inhibitor. That agent works in a completely different way to target the Syk pathway and inhibit the macrophage phagocytosis of autoantibody-coated platelets.

Fostamatinib is very effective in certain patients. An abstract presented at the 2019 ASH Annual Meeting demonstrated that using fostamatinib in earlier lines of therapy can lead to strong response rates. That is a viable option in both the relapsed/refractory setting, as well as earlier on in a patient's disease course.

What are some of the remaining challenges in ITP?

Managing patients with ITP can be very challenging for a number of reasons. Making the initial diagnosis can be challenging because we do not have a singular test to reliably tell us that a patient has ITP. Instead, we rely on clinical diagnosis.

Patients with highly refractory ITP are a challenging cohort of patients to treat, but our therapeutic options are expanding. However, it is always challenging when patients are not responding [to treatment], and they rapidly cycle through multiple lines of therapy.

Of course, we always use our best drugs up front. If patients do relapse or progress on treatments, we turn to drugs that are associated with increased toxicity and likely more immunosuppression.

Additionally, patients who have who have ITP and active bleeding or a strong risk of bleeding and a blood clot are the patients who keep us up in the middle of the night. There needs to be a balance between bleeding and clotting. We want to prevent thrombosis, which can be fatal, but also prevent the risk of bleeding.

The TPO receptor agonists do predispose patients to deep vein thrombosis (DVT) and venous thromboembolism (VTE). Fostamatinib does not appear to have that same association. There was also an abstract presented at the 2019 ASH Annual Meeting discussing the risk of thrombosis among the clinical trials in which fostamatinib was tested. There does not seem to be a high rate of thrombosis in the FIT [trials] experience. It is wonderful to have treatment options that do not increase the risk of thrombosis for those patients who are at risk of DVT and VTE.

Are there any promising agents under investigation?

More exciting agents are coming down pipeline, including FcRn antibodies, BTK inhibitors, and low-dose decitabine. Many therapies are currently in phase 3 clinical trials. Having more treatment options for patients is always a good thing.

The FcRn inhibitors are a class of agents that, at this point, are administered intravenously or subcutaneously. We've seen very strong phase 2 data at the 2019 ASH Annual Meeting for both of the developed FcRn inhibitors, efgartigimod (ARGX-113) and rozanolixizumab (UCB7665). Phase 3 trials for both of these agents are ongoing. There is a lot of buzz with this class of agents. The FcRn pathway is a key pathway in preserving intact immunoglobulin and recycling it. Inhibiting the pathway is a potent way to degrade an IgG molecule. These classes of drugs are effective in autoimmune diseases, particularly in ITP.