Robert L. Talley, MD, discusses current and potential future standards of care in idiopathic thrombocytopenic purpura and thrombotic thrombocytopenic purpura.
Robert L. Talley, MD
Although the presentations of idiopathic thrombocytopenic purpura (ITP) and thrombotic thrombocytopenic purpura (TTP) differ, therapies for both blood disorders are greatly needed for patients who have exhausted the current available treatments, explained Robert L. Talley, MD.
ITP is often characterized as a diagnosis of exclusion with a bone marrow examination, explained Talley. Once diagnosed, it can be managed with frontline steroids, followed by fostamatinib (Tavalisse), thrombopoietin (TPO) receptor agonists, including romiplostim (Nplate) and eltrombopag (Promacta), immunosuppressive agents, and possibly splenectomy.
In April 2018, the FDA approved the SYK inhibitor fostamatinib as a second-line therapy for patients with chronic ITP who failed frontline therapy. Additionally, in December 2018, the FDA approved romiplostim for the treatment of pediatric patients aged ≥1 year with ITP for at least 6 months who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.
In November 2018, the FDA accepted a supplemental new drug application (sNDA) for avatrombopag (Doptelet), as a second-line treatment for patients with chronic ITP.1 The sNDA was based on positive data from the phase III Amendment 02 trial, in which avatrombopag demonstrated a prolonged platelet count ≥50 x 109/L compared with placebo.2
TTP however, manifests in an abrupt presentation of neurologic deficits, anemia, or thrombocytopenia and requires immediate intervention with plasma exchange and immunosuppressive therapy, after which physicians can consider agents such as rituximab (Rituxan) or eculizumab (Soliris), said Talley.
In February 2019, the FDA approved caplacizumab (Cablivi) in combination with plasma exchange and immunosuppressive therapy for patients ≥18 years with acquired TTP. The approval of the nanobody was based on results from the phase III HERCULES trial, which revealed a statistically significant reduction in time to platelet count response and acquired TTP-related death or recurrence.3
In an interview during the 2019 OncLive® State of the Science Summit™ on Hematologic Malignancies, Talley, a hematologist/medical oncologist at Centerpoint Medical Center, Sarah Cannon Cancer Institute, discussed current and potential future standards of care in IPT and TTP.Talley: Fostamatinib represents a brand new way to help people achieve a better platelet count so that they don't have bleeding or bruising; it supplements and compliments other modalities that patients may have exhausted.ITP is more or less a diagnosis of exclusion. If a patient has a low isolated platelet count and no other primary disease, then ITP becomes a diagnosis of exclusion. Serologic testing is something that has been discussed for a long time and was a subject of an ASH Clinical Practice Guidelines report in 2011. I wonder if it’s going to find more prominence over time. One doesn't need to do a bone marrow examination, but if there are other complicating medical diagnoses, then it's probably a good idea to do a bone marrow examination.
TTP is different altogether; it's sudden, explosive, and fatal as opposed to ITP, unless the platelet count is extremely low. In TTP, one has to make a diagnosis quickly. Even with the best therapies, there is still a [significant] mortality rate. Many of those patients are not old with many comorbidities; they are otherwise healthy.There are some patients with ITP who are refractory to all of the therapies that we have. Steroids are great therapies; you can see a short-term response in about 70% of patients who are treated with high-dose steroids. Complications from steroids begin to be [accumulate] when patients need continuous steroids.
The older the patient and the higher the steroid dose, the more complications result. The other therapies carry finite complications with them, such as splenectomy; it’s fairly safe, but we would all love to avoid surgery. Additionally, the TPO receptor agonists are wonderful therapies. We have salvaged patients with them, but the expense is daunting for patients with limited means.For ITP, high-dose steroids are acknowledged as [the predominant] first-line therapy with either prednisone or high-dose dexamethasone; that regimen salvages many patients. There is some advantage to adding an early immunosuppressive agent to rituximab.
Splenectomy is a very good therapy, but it carries the complication rates of surgery with it, even in the best of hands. Then, following splenectomy, there is the potential for opportunistic infections or overwhelming infections. TPO receptor agonists are wonderful additions to the armamentarium; it has to be used continuously, although there are a few people who are able to come off those therapies.
I don't know that there are any biological predictors [that indicate who can come off therapy], but there are some patients who are able to come off that therapy with a sustained platelet count. An attenuated steroid, such as danazol, is also a good option for some patients. An immunosuppressive with azathioprine (Imuran) is also a good therapy. The standard therapies capture most patients. However, most adults end up having chronic ITP.
The options for TTP are more restricted. One has to act quickly to provide plasma exchange. Plasma exchange provides a source of ADAMTS13, which is depleted in TTP. The exchange removes the autoantibodies. It's important to get that therapy started promptly. Immunosuppressive therapy used concurrently to suppress antibodies [against ADAMTS13] is equally important. How one stops the whole process, however, has been a mystery. Rituximab is another immunosuppressive that can be used to treat [patients with] TTP. Eculizumab has been a godsend, but we still have a way to go.Caplacizumab-yhdp [is] a new drug for TTP. Extending the treatment until the ADAMTS13 assay shows a rise above 10% may be another important practice-changing strategy. Doing so in the phase III HERCULES trial showed a decrease in the recurrence rate of TTP.