CLINICAL NEWS
Hematology Pipeline Update
levels declined in 10 patients , eight of whom had a decrease greater than 50 percent . BM biopsies also revealed that six patients experienced a decrease in BM mast cell infiltrates , three of whom had a decrease greater than 50 percent from baseline and one of whom had no residual BM mast cells .
Although the data are preliminary , the authors reported “ marked improvements in disease symptoms and burden ” across all patients at all dose levels – a secondary objective of the study . The improvements included symptomatic relief of allergy symptoms and a decreased use of corticosteroids to manage such symptoms , improved urticaria pigmentosa ( an allergy-mediated rash common in SM patients ), and increased albumin / weight gain ( indicating improvements in malabsorption ).
REFERENCE
Drummond M , DeAngelo DJ , Deininger MW , et al . Preliminary safety and clinical activity in a phase 1 study of BLU-285 , a potent , highly-selective inhibitor of KIT D816V in advanced systemic mastocytosis ( SM ). Abstract # 477 . Presented at the 2016 ASH Annual Meeting , December 4 , 2016 ; San Diego , California .
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 .
Nivolumab 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 immunemediated 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 ondemand-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 IXalbumin 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 .” ●
28 ASH Clinical News March 2017