New Drug Approvals in Nonmalignant Hematology

In 2018, the U.S. Food and Drug Administration (FDA) set a record for the number of approvals for new therapies – or new indications for previously approved therapies – for people living with blood disorders: There were 38 approvals in hematology, including 12 new molecular entities.

With so many new agents reshaping the treatment landscape, the American Society of Hematology (ASH) and the FDA partnered to bring hematologists practical information about using these agents during the “ASH-FDA Symposium on New Drug Approvals” at the 2018 ASH Annual Meeting. Experts convened to offer clinical and regulatory perspectives on the newly available therapies in two sessions focusing on therapies for malignant and nonmalignant hematology.

In his overview of the new hematologic approvals in 2018, Angelo de Claro, MD, from the FDA’s Office of Hematology and Oncology Products (OHOP), highlighted the large percentage of therapies approved for pediatric patients. “Pediatric approvals constituted a quarter of the FDA hematology approvals,” he said. “This represents continued success of established frameworks to increase pediatric drug development.”

Here, we report on the newly approved agents with nonmalignant hematologic indications from 2018:

  • emapalumab – approved November 20, 2018, for the treatment of adult and pediatric patients with primary hemophagocytic lymphohistiocytosis (pHLH) that is refractory to, recurrent after, progressive after, or intolerant to conventional therapy
  • eltrombopag – approved November 16, 2018, for the firstline treatment of adult and pediatric patients with severe aplastic anemia (sAA)
  • emicizumab – approved October 4, 2018, as prophylaxis to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients with hemophilia A with or without factor VIII (FVIII) inhibitors

The session featured clinicians with significant experience with these agents discussing treatment challenges, including identification of the appropriate population, dosing, and and adverse events (AEs).


“HLH is a rare, life-threatening syndrome characterized by hyperinflammation, and, if untreated, it is always fatal in the first few months after diagnosis,” Dr. de Claro said during his discussion of emapalumab’s approval. The only cure for HLH is allogeneic hematopoietic cell transplantation (alloHCT), and, prior to the new agent’s approval, the conventional approach was reducing hyperinflammation, typically with dexamethasone and etoposide. This was accompanied by immunosuppression of variable severity.

In her review of the FDA’s decision to approve emapalumab, Margaret Merino, MD, highlighted the toxicity of conventional therapy, noting that pre-transplant mortality rates range from 20 to 29 percent – largely due to progressive disease or therapy-related complications.

Based on data suggesting a pathogenic role for interferon-gamma (IFN-𝛾), researchers hypothesized that neutralizing the anti-IFN-𝛾 antibody could be effective in the treatment of pHLH, Franco Locatelli, MD, PhD, from the Bambino Gesù Children’s Hospital IRCCS in Rome, Italy, explained. Dr. Locatelli was a principal investigator of the phase II/III pivotal trial of emapalumab. Emapalumab binds to IFN-𝛾, blocking signal transduction of the IFN-𝛾 pathway.

The drug was shown to be effective in the NI-0501-04 and NI-0501-05 studies, in which 34 children with pHLH received between four and eight weeks of treatment with emapalumab 1 mg/kg per day, every three to four days. Emapalumab could be increased up to 10 mg/kg per day, based on clinical and laboratory responses. Patients received concomitant dexamethasone at doses of 5 to 10 mg/m2.

The overall response rate (defined as normalization or ≥50% improvement from baseline of fever, splenomegaly, cytopenias, hyperferritinemia, fibrinogen or D-dimer levels, and central nervous system abnormalities) was 63 percent in patients with relapsed/refractory disease and 64.7 percent in the entire cohort.

Seven of these patients achieved a complete response, Dr. Locatelli added, and 70 percent of patients were able to receive an alloHCT. Responses appeared to be durable, with a median duration of response (until alloHCT conditioning) of 33 days in the relapsed/refractory group and 33.5 days in the entire population.

The safety profiles were considered acceptable, Dr. Merino reported, and were “similar to rates experienced by patients receiving conventional therapies.” These included hypertension, infusion-related reactions, infection, and fever.

“[Children with pHLH] often [present with] and [are] fighting associated infections, and current firstline therapy often is ineffective,” said Leslie S. Kean, MD, PhD, from Boston Children’s Hospital, who discussed the practical considerations for using emapalumab in the clinic.

Given what she called “the IFN-𝛾 effect,” Dr. Kean said that the high rate of infections (56%) was expected. “IFN-𝛾 has complex effects as an immune modulator and blocking IFN-𝛾 may have untoward negative effects,” she explained. “Patients with HLH already have an underlying [risk of infection], so it is difficult to understand whether a drug increases the risk of infection in these patients in the absence of a randomized trial.”

“Secondline approval is appropriate,” Dr. Kean concluded, “given small trial size and open questions concerning the real-world risks of infection, nonengraftment, and paradoxical immune-activating effects.”

It is important to note, Dr. Locatelli said, that “treatment with emapalumab allows us to transplant patients in better condition because we can spare them the extra toxicity associated with steroids and etoposide.” The clinical trials data of emapalumab also suggest that IFN-𝛾 plays a key role in mediating graft rejection, “so this drug could be useful in preventing the occurrence of graft failure in this condition,” he added.


The oral thrombopoietin receptor agonist eltrombopag was initially approved in 2014 for patients with previously treated sAA, and the most recent approval extends its use to the frontline setting. Nicole Gormley, MD, from the FDA’s OHOP, discussed the agency’s decision to expand the indication, citing data from the pivotal phase I/II trial, which enrolled 153 patients with sAA.

All participants received the same dose of eltrombopag (but had different treatment start days and durations of treatment) plus standard immunosuppressive therapy (horse antithymocyte globulin [ATG] and cyclosporine). Seventy-nine percent of patients responded to treatment, with a median response duration of 24.3 months (range = 23 months to not estimable). The complete response rate was 44 percent, which compared favorably with historical controls of ATG/cyclosporine alone (27%).

Given the risks of hepatotoxicity, the agent was approved with dose modification guidelines and recommendations for close monitoring.

In her discussion of eltrombopag’s expanded indication, Cynthia Dunbar, MD, from the National Heart, Lung, and Blood Institute, also cited the favorable comparison with historical control data, noting that only 12 percent of patients treated with standard therapies “had anything resembling normalization of their blood counts.”

Dr. Dunbar agreed that hepatotoxicity, as well as the serious skin reactions that occurred in eltrombopag-treated patients, is a concern for clinical practice. By monitoring patients closely – at least through ATG therapy and until hospital discharge – and following criteria for stopping or holding eltrombopag outlined in its prescribing information, she said that clinicians can avoid prematurely stopping the drug. “It’s very important, in terms of salvaging stem cells in these patients, to give the drug as early as possible at the maximal dose tolerated,” Dr. Dunbar said.

The rates of cytogenetic evolution to myelodysplastic syndromes or acute myeloid leukemia were low (approximately 8%) in eltrombopag-treated patients and were similar to those experienced by patients receiving ATG/cyclosporine alone.

These data have been “encouraging so far,” Dr. Dunbar said, but despite high hopes “that [eltrombopag] would result in a lower rate of relapse … there doesn’t seem to be a decreased rate of relapse from our historical cohorts.” The relapse rates appeared to be quite high, regardless of whether eltrombopag was stopped at six months or 24 months (32% and 14%, respectively).

Eltrombopag is a welcome new treatment option for patients living with sAA, but Dr. Dunbar expressed restraint about how extensively it will change practice. “Adding eltrombopag to initial [horse ATG and cyclophosphamide] is indicated because of the higher response rate and the more rapid and higher counts [achieved] with this therapy,” she said, but “at this point, I don’t think it should change decisions regarding transplant.”


In November 2017, the FDA approved the bispecific monoclonal antibody emicizumab for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients with hemophilia A and FVIII inhibitors based on results from the phase III HAVEN 1 and 2 trials. With findings from the HAVEN 3 trial, the FDA expanded its indication in 2018 to include patients without inhibitors.

Laurel Menapace, MD, from the FDA’s OHOP, shared results from these pivotal trials, which randomized patients with hemophilia A to receive emicizumab prophylaxis or no prophylaxis, with an option to cross over after 24 weeks of treatment. Emicizumab prophylaxis significantly lowered annual bleeding rates (from 38.2 without prophylaxis to 1.3 to 1.5 with prophylaxis) and incidence of treated bleeds (from 47.6 to 2.5 to 2.6, respectively).

There were no patient deaths on the study, and few patients discontinued treatment due to AEs. “The FDA and the pharmaceutical sponsor were concerned particularly with de novo FVIII inhibitor development, which was not observed on the study,” Dr. Menapace said, discussing safety events of clinical importance. “Furthermore, there was no evidence of neutralizing anti-drug antibodies that resulted in loss of efficacy in HAVEN 3.”

No events of thrombotic microangiography or thrombosis were observed in the trial, although Dr. Menapace noted that the agent’s approval mandates continued post-marketing surveillance.

Barbara Konkle, MD, from BloodWorks Northwest and the University of Washington, discussed the role of emicizumab in the management of patients with hemophilia A, citing the agent’s ease of administration. “[Currently available replacement products] require intravenous infusions every other day to at least twice weekly, which is quite a burden to the patient and family,” she explained. “There also are venous access challenges, so subcutaneous administration has long been a hope for this patient population.”

However, Dr. Konkle warned that “emicizumab will not prevent all bleeding, so we have to have a plan for [patients who experience] breakthrough bleeding, who are undergoing surgery, or who have major bleeding.” She continued, “Patients still need to have a bypassing [agent available] and education about using [the factor] at home, as well as close contact with providers.”

She also outlined another practical concern: Emicizumab can interfere with -based assays and results may not reflect the efficacy of the drug. “The fear is that a patient will go to a hospital not familiar with this drug, tell the provider he is on this great new drug, and his PTT will be normal. He’d be taken for major surgery without having a backup factor in case of bleeding,” she said.

While applauding the approval of an agent with a lower treatment burden, Dr. Konkle also expressed concerns that the less frequent dosing may inadvertently lead to lapses in follow-up. “When we have a highly effective therapy that doesn’t require administration very frequently and is not very difficult to administer, our patients and their families may not want to visit us very frequently,” she said. “But because we have a number of issues with this new therapy that we need to get more information on, I think it is especially critical that these patients be followed in specialized hemophilia treatment centers where [specialized monitoring and follow-up] can be performed.”