Breaking Down Developments in Benign Hematologic Malignancies

Daria V. Babushok, MD, PhD

Treatment options continue to expand in the field of benign hematologic malignancies, such as aplastic anemia, paroxysmal nocturnal hemoglobinuria (PNH), and immune thrombocytopenic purpura (TTP), said Daria V. Babushok, MD, PhD, adding that more work still needs to be done.

In aplastic anemia, treatment still depends on the availability of a matched related donor in patients who are under 40 years of age, added Babushok. In those for whom a matched related donor is unavailable, the standard of care is eltrombopag (Promacta) in combination with immunosuppressive therapy. The FDA expanded the approval of the agent in November 2018 to include newly diagnosed adult and pediatric patients aged ≥2 years with severe disease.

“In general, the outcomes of patients receiving this [regimen] are quite good,” said Babushok. “By 6 months, you could expect 70% to 80% overall response rates and complete response rates as high as 30%, which has really revolutionized treatment in aplastic anemia.”

In terms of PNH, the two complement inhibitors eculizumab (Soliris) and ravulizumab-cwvz (Ultomiris) are being investigated in head-to-head trials—the 301 and 302 studies. Although the drugs are very similar, Babushok said that the most prominent difference lies in the half-life of ravulizumab, which is about 3 times longer than that of eculizumab.

“This really translates into a much more manageable and convenient treatment schedule and many patients prefer that for quality-of-life reasons,” she explained.

Steroids remain a mainstay of treatment in ITP, Babushok added, but other second-line agents have emerged within the past few years, such as rituximab (Rituxan), romiplostim, eltrombopag, and the newest agent, fostamatinib (Tavalisse), which was approved in April 2018 for the treatment of thrombocytopenia in adult patients with chronic ITP who have had insufficient response to a previous treatment.

In an interview during the 2019 OncLive^® State of the Science Summit™ on Hematologic Malignancies, Babushok, an assistant professor of medicine, University of Pennsylvania, provided insight into the latest developments in the treatment of patients with benign hematologic malignancies.

OncLive: What does the current treatment paradigm look like for aplastic anemia?

Babushok: If you have established a diagnosis of aplastic anemia, then treatment still relies very much on the availability of a matched related donor in patients who are under the age of 40. This is also shifting a little bit. In pediatric patients, for example, an ongoing study is looking at upfront, unmatched, unrelated donor transplant as opposed to immunosuppressive therapy. Currently, the standard of care for those patients who do not have a matched related donor is to proceed with immunosuppressive treatment plus eltrombopag, which is a thrombopoietin mimetic therapy that is now introduced upfront in addition to immunosuppression with antithymocyte globulin and cyclosporine.

What advances have been made in the treatment of the rare blood disorder PNH?

PNH is a highly related condition. In someone who you suspect might have PNH, the evaluation is fairly straightforward. You send flow cytometry and that will tell you whether the patient has a PNH clone. The treatment decision is guided by the size of the PNH clone. You look at the PNH clones and granulocytes and then see whether the patient actually has hemolysis. There's a big distinction between finding a small PNH clone, which is likely insignificant, and someone who presents with profound hemolysis and has a very large clone; the latter is someone who is at risk for significant hemolytic anemia, thrombotic events, etc. That patient really should be treated with complement inhibitors.

In 2019, we have 2 approved complement inhibitors, one is eculizumab, the second is ravulizumab; those 2 agents have been compared head-to-head in 2 different trials. One is the 301 study, which looks at treatment-naïve, newly diagnosed patients with PNH, as well as the 302 study, which is of previously treated patients who are now being switched to ravulizumab.

In this head-to-head randomized comparison, the 2 drugs were [found to be] virtually equivalent. What's different is the half-life of ravulizumab, which is nearly three times higher than that for eculizumab. For eculizumab, the treatment [is given] every 2 weeks, while for ravulizumab, it's [given] every 2 months. Both agents require immunization with the meningococcal vaccine as well as for all encapsulated organisms.

Have any developments been made in ITP?

In ITP in general, we are still using steroids upfront. Steroids alone are still currently the recommended treatment based on the recent update [to] evidence-based guidelines from ASH. Dexamethasone versus prednisone has been evaluated in multiple prospective randomized trials. In general, it appears that the long-term stable response in ITP is fairly equivalent, whether you choose to do pulses of dexamethasone or whether you do prolonged prednisone therapy. However, perhaps the short-term response is better with dexamethasone.

For second-line treatment, we now have 4 different classes of agents or approaches that can be used. The tried-and-true splenectomy is still very much in [use] and it has a very good long-term response rate of approximately 60%. However, now some of the other agents, such as rituximab, can also be used. We still have thrombopoietin mimetics, such as romiplostim and eltrombopag.

The new kid on the block is fostamatinib, which is a SYK inhibitor. In a recent study randomizing [patients to receive] this agent or placebo, we have roughly an 18% overall long-term response rate [with the agent]. The population that was studied was very heavily pretreated and highly refractory, and this response rate was still quite good. Perhaps when we compare its use on an equal playing field, the response rate may be [even] better. However, in general, I believe all of these approaches are very valuable and it's exciting to have new treatments for this disease.