Treatment Options Expanding for Benign Hematologic Disorders

Nathan T. Connell, MD, MPH

The addition of eltrombopag (Promacta) has expanded the treatment armamentarium for patients with benign hematologic disorders such as severe aplastic anemia and immune thrombocytopenia (ITP), said Nathan T. Connell, MD, MPH.

“Frontline eltrombopag along with antithymocyte globulin (ATG) for patients who are not candidates for transplant is a promising option,” said Connell. “In terms of ITP, we now have another medication in our armamentarium that we can use to treat patients who are refractory or relapse quickly after the use of steroids.”

Patients with thrombotic thrombocytopenic purpura (TTP), particularly those who present with severe neurologic symptoms, may potentially derive the most benefit from caplacizumab-yhdp (Cablivi), along with traditional therapies, he added.

While recent advances have been made in these spaces, the rarity of these disorders is an obstacle for researchers, making it more difficult to develop adequate clinical trials, Connell stressed.

In an interview at the 2019 OncLive^® State of the Science Summit™ on Hematologic Malignancies, Connell, chief of hematology at Brigham and Women's Faulkner Hospital and assistant professor of medicine at Harvard Medical School, shared key updates in the rapidly evolving treatment paradigms of benign hematologic disorders.

OncLive: What developments have occurred in the frontline treatment of severe aplastic anemia?

Connell: A couple years ago, there was a bit of a controversy over the appropriate steps to take in [the treatment of patients with] severe aplastic anemia. We knew that in patients under the age of 50, hematopoietic stem cell transplant [would be] the frontline therapy. However, what was [the best approach to take] in patients over the age of 50, which is probably the more common population? This was unclear. We know that it's an immune disorder at its most basic, and so some form of immunosuppressive therapy is useful. We also know that the use of medication called ATG is also very effective. Several years ago, there were different forms of ATG being used. One study compared horse-ATG versus rabbit-ATG; it was clear that horse-ATG resulted in better outcomes.

Along the way, eltrombopag was introduced. Although this agent is used in ITP, it showed that it might have some value in aplastic anemia as well. Recently, it has been combined with ATG in different dosing schema in an attempt to find out which [dose would be] the best [dose].

What were the findings of this research?

There were a couple of different cohorts. The study compared patients in the clinical trial with historical controls that had received ATG alone. [Investigators] found that patients who received eltrombopag had better survival and did better overall in terms of their count recovery. There were a couple different options. You could start the ATG always on the first 4 days, but then give eltrombopag upfront, or you could delay eltrombopag or only give it for about 6 months. All of the patients had benefit, but it seemed that adding it in right at the beginning and continuing for 6 months of therapy provided the best outcomes.

Could you speak to recent advances made in ITP and TTP?

One of the great things I spoke about [in my presentation] was the new data for ITP and TTP. ITP is an immune process by which the immune system clears out platelets, and patients develop very low platelet counts and, ultimately, bleeding. We know that the use of corticosteroids works, but [this approach] doesn't work very well in every patient. Many patients require additional therapies in order to maintain remission. Second-line therapy for these patients has typically been splenectomy, which is also very effective but carries the risk of thrombosis and long-term infection; it is also a major surgery. Rituximab (Rituxan) was used several years ago. That agent was introduced into ITP and works well, but at 5 years, it only has a 20% response rate.

There’s also a new medication called fostamatinib (Tavalisse) that came out in the last year. This is a novel therapy that reduces the antibody-mediated clearance of platelets and antibody production in general. It's attractive for patients who have been through other lines of therapy.

Could you expand on the use of fostamatinib in the relapsed/refractory setting?

The clinical trials with fostamatinib that were published last year [included] patients that had fairly refractory disease. Most patients had at least 3 prior lines of therapy and the average duration of prior treatment was almost 8 years. About 18% of patients got a response, which doesn't seem like a lot, but when you consider the population [as those who haven’t] responded to many other lines of therapy, it actually seems interesting that by going through a different mechanism you can get a response. [The agent] was also studied in an extension study, so patients who initially achieved a response seemed to have a continued response if they stayed on the medication.

What other approaches are under investigation for TTP?

One is the idea of combining therapies together. TTP has severe thrombocytopenia associated with it. The therapy for that has been therapeutic plasma exchange, with the addition of rituximab, and just within the last few months, we've had the addition of caplacizumab. This drug appears to shorten time to platelet count responses, and it seems to have an effect in patients with the most severe disease.

Caplacizumab in TTP was evaluated in two trials: the phase II TITAN trial and the phase III HERCULES trial. At the 2018 ASH Annual Meeting, there was a combined analysis showing that more than 200 patients had a shortened time to platelet count recovery, fewer days on plasma exchange, and what appeared to be a survival benefit by giving this medication early.

What other agents are you excited about?

All of the data about the different anticoagulants are exciting. We have had an explosion in the last 10 years of available options for anticoagulation in patients. With that comes a concern of what to do about bleeding in these patients. We now have target-specific anticoagulants and we have targeted reversal agents that work for many of these newer agents.

One is that these drugs seem to have fewer bleeding complications to begin with compared with warfarin (Coumadin, Jantoven). Those patients who are on a direct anticoagulant are less likely to die from a major bleed compared with those on warfarin. That was in the setting before we could have a reversal agent available. Now that we have these agents, it's going to become easier to manage patients and reassure them that these agents are best for them.

One of the challenges with these agents that has come up has been getting adequate data for use of different medications in certain populations. For instance, we now have all of these directed oral anticoagulants available for the treatment of thrombosis in general, but determining which ones are the best ones to use in different cancer populations can be difficult.

There was a clinical trial using the agent edoxaban (Savaysa) that was published, but it hasn't been taken up with great availability in terms of insurance coverage. Many physicians are putting patients on other direct anticoagulants such as apixaban (Eliquis). There are data to support its use in small trials, but we still have an ongoing active clinical trial trying to determine the efficacy and safety of apixaban in cancer-associated venous thromboembolism. We also have data for rivaroxaban (Xarelto) and apixaban as ambulatory prophylaxis.

What other challenges still need to be addressed in this space?

There are a couple of challenges. One is that most benign hematologic disorders are fairly rare, so getting a large enough patient population to conduct an adequate clinical trial can be very challenging. A lot of multicenter collaboration is required in order to be able to work on these patients. When you talk about a disease like severe aplastic anemia, in large academic centers, you may see one case once a month or once every other month, whereas out in community practices, many hematologists may see it once every few years.

It's also difficult because some of the therapies may be quite intense, requiring a special level of monitoring. It's important that patients have access to centers and undergo very quick evaluation.