Newly Approved Drugs: How to Use Them in Practice

In 2016, the U.S. Food and Drug Administration (FDA) approved several new therapies for the treatment of hematologic disorders, marking several “firsts” for hematology, including the first hematologic indication for the programmed death-1 (PD-1) inhibitor nivolumab, the first recombinant von Willebrand factor (vWF), and the first coagulation factor-albumin fusion protein for hemophilia B. But how should these new agents be incorporated into clinical practice?

At the 2016 ASH Annual Meeting, experts discussed the clinical applications of these newly approved agents in the “Special Education Session on Newly Approved Drugs”:

  • nivolumab – approved May 17, 2016, for the treatment of classical Hodgkin lymphoma (cHL) that has relapsed or progressed after autologous hematopoietic cell transplantation (AHCT) and post-AHCT brentuximab vedotin
  • recombinant vWF – approved December 8, 2015, for on-demand treatment and control of bleeding episodes in adults diagnosed with von Willebrand disease (vWD)
  • coagulation factor IX (recombinant) albumin fusion protein/antihemophilic factor (recombinant) – approved March 4, 2016, for the treatment of hemophilia B

The session, chaired by ASH Clinical News Editor-in-Chief Mikkael A. Sekeres, MD, MS, director of the leukemia program at Cleveland Clinic in Ohio and former chair of the Oncologic Drugs Advisory Committee at FDA, was adapted from ASH’s webinar series on newly approved drugs. The webinars feature clinicians with significant experience with the agents discussing treatment challenges, including identification of the appropriate population, dosing, side effects and adverse events (AEs), and off-label use.


Stephen Ansell, MD, PhD, professor of medicine at the Mayo Clinic in Rochester, Minnesota, discussed nivolumab, a monoclonal antibody that targets PD-1 receptors on T cells. The FDA approved nivolumab as an orphan drug based on results from two multicenter studies evaluating the drug’s safety and efficacy in patients with relapsed/refractory cHL, in which nivolumab led to an objective response rate of 65 percent and an estimated duration of response of 8.7 months.

“What’s exciting about this approval is that we have benefited from all the hard work done in the solid tumor space that showed that blocking PD-1 is highly effective in diseases such as melanoma, lung cancer, and a variety of other solid tumors,” Dr. Ansell told ASH Clinical News. “That has now translated into high efficacy in HL, as well as in other lymphomas.”

The drug is approved for use in patients with relapsed/refractory disease that has progressed following frontline therapy, AHCT, and brentuximab vedotin. In clinical trials, patients have experienced “very high” response rates with the PD-1 inhibitor, Dr. Ansell reported.

Expressing optimism about the future role of nivolumab in the treatment of cHL, Dr. Ansell said, “It has been a great option for many patients, but it is not yet approved for use before HCT, after HCT, or as frontline therapy.” Ongoing research, he added, will hopefully answer questions about whether nivolumab can be used as an earlier line of therapy. “Ideally, we would like to not have to use [PD-1 inhibitors] only when people have suffered through multiple treatment failures, so it would be fantastic to incorporate this into frontline therapy or as a treatment after the first disease progression.”

Nivolumab carries a boxed warning for complications with AHCT that occurs following therapy with nivolumab. As with any immunotherapy, Dr. Ansell noted, immune-mediated inflammation can occur, but he is encouraged that “these have been relatively uncommon events.” The most common immune-mediated AEs (reported in ≥10% of patients) in the pivotal trials included rash, pruritus, musculoskeletal pain, nausea, peripheral neuropathy, and infusion-related reactions.

Recombinant von Willebrand Factor

Joan Cox Gill, MD, director of the Comprehensive Center for Bleeding Disorders and professor of pediatrics and medicine at the BloodCenter of Wisconsin in Milwaukee, spoke about recombinant vWF, which is the only recombinant agent approved for on-demand treatment and control of bleeding episodes in adults diagnosed with vWD.

“Having a recombinant vWF available is great because we prefer to not have to give patients plasma-derived products, which carry a theoretic risk of virus transmission,” Dr. Gill told ASH Clinical News. “Though virus transmission is infrequent, the advantage of recombinant proteins is that we don’t have to rely on the number of available donors to produce enough plasma-derived products.”

Recombinant vWF also offers clinicians greater control than conventional products, she explained. Many patients with vWD are missing both vWF and factor VIII (FVIII), but “unfortunately, the plasma-derived products have a fixed ratio of vWF to FVIII. To get to the correct hemostatic combination, we usually end up overdosing one or the other factor.” Because recombinant vWF does not contain FVIII, though, it is possible to calculate the appropriate amount of vWF and titrate FVIII to reach hemostasis.

Dr. Gill envisions that patients with vWD could eventually manage their side effects at home, similar to the way many patients with hemophilia are able to treat themselves prophylactically or manage their bleeding episodes at home. However, she noted that will be an “educational challenge” for clinicians. Cost is also a concern, as recombinant vWF costs approximately $1 more per unit than plasma-derived products.

Coagulation Factor IX (Recombinant) Albumin Fusion Protein

Steven Pipe, MD, director of the Coagulation Laboratory and the Laurence A. Boxer, MD, Research Professor of Pediatrics and Communicable Diseases at the University of Michigan Medical School in Ann Arbor, shared his experiences with recombinant coagulation factor IX-albumin fusion protein, the first approved coagulation factor-albumin fusion protein product for children and adults with hemophilia B and the second approved factor IX fusion protein product.

“With the advent of these extended half-life factor molecules, we have an opportunity to shift the way we deliver prophylaxis to prevent bleeding,” Dr. Pipe told ASH Clinical News. “If you look at the waves of therapy over the years, we went from having no treatment, then on-demand-only treatment, then, in the last couple decades, aggressive prophylaxis.”

The new fusion product allows for less-frequent dosing – an infusion once every two weeks after bleeding is well controlled – while also maintaining high efficacy. The observed factor trough levels are “substantially higher than we could ever achieve before with aggressive prophylactic regimens,” Dr. Pipe said, adding that the ease of use is a major advantage of this fusion product. “It’s very easy for patients to incorporate a weekly dose into their busy lives. Once a patient has been on these products, they are not asking to go back to the conventional agents.”

Recombinant coagulation factor IX-albumin fusion protein is also indicated for the management of perioperative bleeding, and Dr. Pipe predicts that it will change standard treatment. “Patients who are undergoing a major surgery are typically admitted to the hospital, and [their levels] are corrected up to the normal range with frequent infusions,” he explained. However, with this new factor-fusion product, patients can safely be treated with a single preoperative infusion and maintain normal ranges. “It will change the paradigms of managing a patient for surgery,” Dr. Pipe said. “If this is typically an outpatient procedure, you may now be able to do an outpatient procedure with a hemophilia patient with these agents.”