Hematology

New guidelines from the American Society of Hematology “strongly recommend” using no thromboprophylaxis over using parenteral thromboprophylaxis in ambulatory patients receiving cancer chemotherapy who have low venous thromboembolism (VTE) risk, and using no thromboprophylaxis over oral thromboprophylaxis with vitamin K antagonists in those at any VTE risk level.

The evidence-based guidelines for the prevention and treatment of VTE in patient with cancer, published online in Blood Advances, also include a “conditional recommendation” for using either thromboprophylaxis with the direct oral anticoagulants (DOACs) apixaban or rivaroxaban or using no thromboprophylaxis in ambulatory patients with intermediate risk and using the DOACs over no thromboprophylaxis in those with high VTE risk.

The purpose of the guidelines, which also address VTE prophylaxis in hospitalized patients with cancer and the use of anticoagulation for VTE treatment in patients with cancer, is to provide clinical decision support for shared decision-making by patients and clinicians, Gary H. Lyman, MD, of Fred Hutchinson Cancer Research Center, Seattle and Marc Carrier, MD, of the University of Ottawa, and their colleagues from the multidisciplinary guidelines panel explained.

“The recommendations take into consideration the strength of the evidence, risks of mortality, VTE, and bleeding, as well as quality of life, acceptability, and cost considerations,” they wrote, noting that VTE is a common complication in patients with cancer, who are at markedly increased risk for morbidity and mortality from VTE.
 

Levels of evidence

The panel members relied on updated and original systematic evidence reviews. Conditional recommendations, as opposed to strong recommendations, are defined by the panel as “suggestions,” and all 33 recommendations that make up the guidelines include a statement on the strength of the relevant evidence.

For example, the thromboprophylaxis recommendations for low, intermediate, and high VTE risk are made based on “moderate certainty in the evidence of effects,” and the recommendation for no thromboprophylaxis over oral thromboprophylaxis with vitamin K antagonists is a strong recommendation based on “very low certainty in the evidence of benefits, but high certainty about the harms.”

The guidelines panel also strongly recommends, based on moderate certainty in the evidence of effects, using low-molecular-weight heparin over unfractionated heparin for the initial treatment of VTE in patients with cancer, and suggests, based on “very low certainty in the evidence of effects,” using LMWH over fondaparinux in this setting.

In addition to primary prophylaxis in ambulatory and hospitalized patients and initial VTE treatment, they also address primary prophylaxis for patients with cancer who have a central venous catheter, VTE treatment in surgical patients with cancer, short-term VTE treatment, and long-term VTE treatment.

For example, the guidelines panel conditionally recommends:

• Not using parenteral or oral thromboprophylaxis in patients with cancer and a central venous catheter
• Using LMWH or fondaparinux for surgical patients with cancer
• Using DOACS for the short-term treatment of VTE, and LMWH or DOACs for the long-term treatment of VTE in patients with cancer.

The perils of VTE

VTE in patients with cancer can interfere with treatment, increase mortality risk, and increase costs, the authors noted, adding that VTE can also adversely affect cancer patients’ quality of life.

“Some have even reported the experience of VTE to be more upsetting than that of the cancer,” they wrote. “More than 50% of thrombotic events occur within 3 months of the cancer diagnosis, a time when most cancer treatments will be underway. Patients, who are still coming to terms with a recent cancer diagnosis, often view the occurrence of VTE as a further threat to life, confirmation of the severity of their condition, and a poor prognostic sign.”

Therefore, the new guidelines aim to reduce VTE frequency, risk of bleeding complications, morbidity, and costs, thereby improving quality of life and the patient experience, the authors said, noting that three other recent guidelines on VTEs in patients with cancer have been published: the 2019 American Society of Clinical Oncology guidelines, the 2019 International Initiative on Thrombosis and Cancer guidelines, and the 2020 National Comprehensive Cancer Network guidelines.

The ASH guidelines are similar in many ways to the other guidelines, but differ in some ways, as well. An example is the timing of initiation of pharmacological thromboprophylaxis in patients undergoing cancer-related major abdominal surgery. The ASCO and ITAC guidelines advise starting thromboprophylaxis preoperatively, whereas the ASH guidelines recommend initiating thromboprophylaxis postoperatively, citing “the limited advantages to initiating thromboprophylaxis preoperatively, in addition to the potential bleeding and logistical considerations associated with neuraxial anesthesia.”

These differences highlight a lack of data in that setting and the need for additional studies, the authors said.
 

ASH vs. ASCO

James Douketis, MD, a practicing clinician and professor of medicine at McMaster University, Hamilton, Ont., highlighted another difference between the ASH and ASCO guidelines.

“For the treatment of [cancer-associated thrombosis], ASCO gives a strong recommendation to use LMWH or DOACs (with some caveats), which is easy to follow. ASH, on the other hand, suggests LMWH or a DOAC for the first 7-10 days, DOACs for the first 3-6 months, and back to LMWH or DOACs after 6 months,” he said in an interview.

The recommendation is “very evidence based but ambiguous and not helpful for the practicing clinician,” added Dr. Douketis, who helped develop the ITAC guidelines, but was not part of the ASH or ASCO guideline panels.

ASCO also provides a clear recommendation for giving VTE prophylaxis for 4 weeks after cancer surgery in patients with high VTE risk, whereas ASH gives “a somewhat vague recommendation” for thromboprophylaxis after hospital discharge.

The guidelines are “pretty well aligned” with respect to recommendations on VTE prophylaxis in medical cancer patients receiving chemotherapy, and although the “extremely academic” ASH guidelines were developed by “a superb team using the same evidence and excellent methodology,” they are interpreted in slightly different ways and fall short when it comes to being clinician friendly, Dr. Douketis said.

“At the end of day, for practicing clinicians, the ASH guidelines don’t provide a message that’s easy to digest,” he added.

ASH has, however, provided a resource page that includes tools and information for implementing the guidelines in clinical practice, and will maintain the guidelines “through surveillance for new evidence, ongoing review by experts, and regular revisions,” the authors said.

sworcester@mdedge.com

New guidelines from the American Society of Hematology “strongly recommend” using no thromboprophylaxis over using parenteral thromboprophylaxis in ambulatory patients receiving cancer chemotherapy who have low venous thromboembolism (VTE) risk, and using no thromboprophylaxis over oral thromboprophylaxis with vitamin K antagonists in those at any VTE risk level.

The evidence-based guidelines for the prevention and treatment of VTE in patient with cancer, published online in Blood Advances, also include a “conditional recommendation” for using either thromboprophylaxis with the direct oral anticoagulants (DOACs) apixaban or rivaroxaban or using no thromboprophylaxis in ambulatory patients with intermediate risk and using the DOACs over no thromboprophylaxis in those with high VTE risk.

The purpose of the guidelines, which also address VTE prophylaxis in hospitalized patients with cancer and the use of anticoagulation for VTE treatment in patients with cancer, is to provide clinical decision support for shared decision-making by patients and clinicians, Gary H. Lyman, MD, of Fred Hutchinson Cancer Research Center, Seattle and Marc Carrier, MD, of the University of Ottawa, and their colleagues from the multidisciplinary guidelines panel explained.

“The recommendations take into consideration the strength of the evidence, risks of mortality, VTE, and bleeding, as well as quality of life, acceptability, and cost considerations,” they wrote, noting that VTE is a common complication in patients with cancer, who are at markedly increased risk for morbidity and mortality from VTE.
 

Levels of evidence

The panel members relied on updated and original systematic evidence reviews. Conditional recommendations, as opposed to strong recommendations, are defined by the panel as “suggestions,” and all 33 recommendations that make up the guidelines include a statement on the strength of the relevant evidence.

For example, the thromboprophylaxis recommendations for low, intermediate, and high VTE risk are made based on “moderate certainty in the evidence of effects,” and the recommendation for no thromboprophylaxis over oral thromboprophylaxis with vitamin K antagonists is a strong recommendation based on “very low certainty in the evidence of benefits, but high certainty about the harms.”

The guidelines panel also strongly recommends, based on moderate certainty in the evidence of effects, using low-molecular-weight heparin over unfractionated heparin for the initial treatment of VTE in patients with cancer, and suggests, based on “very low certainty in the evidence of effects,” using LMWH over fondaparinux in this setting.

In addition to primary prophylaxis in ambulatory and hospitalized patients and initial VTE treatment, they also address primary prophylaxis for patients with cancer who have a central venous catheter, VTE treatment in surgical patients with cancer, short-term VTE treatment, and long-term VTE treatment.

For example, the guidelines panel conditionally recommends:

• Not using parenteral or oral thromboprophylaxis in patients with cancer and a central venous catheter
• Using LMWH or fondaparinux for surgical patients with cancer
• Using DOACS for the short-term treatment of VTE, and LMWH or DOACs for the long-term treatment of VTE in patients with cancer.

The perils of VTE

VTE in patients with cancer can interfere with treatment, increase mortality risk, and increase costs, the authors noted, adding that VTE can also adversely affect cancer patients’ quality of life.

“Some have even reported the experience of VTE to be more upsetting than that of the cancer,” they wrote. “More than 50% of thrombotic events occur within 3 months of the cancer diagnosis, a time when most cancer treatments will be underway. Patients, who are still coming to terms with a recent cancer diagnosis, often view the occurrence of VTE as a further threat to life, confirmation of the severity of their condition, and a poor prognostic sign.”

Therefore, the new guidelines aim to reduce VTE frequency, risk of bleeding complications, morbidity, and costs, thereby improving quality of life and the patient experience, the authors said, noting that three other recent guidelines on VTEs in patients with cancer have been published: the 2019 American Society of Clinical Oncology guidelines, the 2019 International Initiative on Thrombosis and Cancer guidelines, and the 2020 National Comprehensive Cancer Network guidelines.

The ASH guidelines are similar in many ways to the other guidelines, but differ in some ways, as well. An example is the timing of initiation of pharmacological thromboprophylaxis in patients undergoing cancer-related major abdominal surgery. The ASCO and ITAC guidelines advise starting thromboprophylaxis preoperatively, whereas the ASH guidelines recommend initiating thromboprophylaxis postoperatively, citing “the limited advantages to initiating thromboprophylaxis preoperatively, in addition to the potential bleeding and logistical considerations associated with neuraxial anesthesia.”

These differences highlight a lack of data in that setting and the need for additional studies, the authors said.
 

ASH vs. ASCO

James Douketis, MD, a practicing clinician and professor of medicine at McMaster University, Hamilton, Ont., highlighted another difference between the ASH and ASCO guidelines.

“For the treatment of [cancer-associated thrombosis], ASCO gives a strong recommendation to use LMWH or DOACs (with some caveats), which is easy to follow. ASH, on the other hand, suggests LMWH or a DOAC for the first 7-10 days, DOACs for the first 3-6 months, and back to LMWH or DOACs after 6 months,” he said in an interview.

The recommendation is “very evidence based but ambiguous and not helpful for the practicing clinician,” added Dr. Douketis, who helped develop the ITAC guidelines, but was not part of the ASH or ASCO guideline panels.

ASCO also provides a clear recommendation for giving VTE prophylaxis for 4 weeks after cancer surgery in patients with high VTE risk, whereas ASH gives “a somewhat vague recommendation” for thromboprophylaxis after hospital discharge.

The guidelines are “pretty well aligned” with respect to recommendations on VTE prophylaxis in medical cancer patients receiving chemotherapy, and although the “extremely academic” ASH guidelines were developed by “a superb team using the same evidence and excellent methodology,” they are interpreted in slightly different ways and fall short when it comes to being clinician friendly, Dr. Douketis said.

“At the end of day, for practicing clinicians, the ASH guidelines don’t provide a message that’s easy to digest,” he added.

ASH has, however, provided a resource page that includes tools and information for implementing the guidelines in clinical practice, and will maintain the guidelines “through surveillance for new evidence, ongoing review by experts, and regular revisions,” the authors said.

sworcester@mdedge.com

New guidelines from the American Society of Hematology “strongly recommend” using no thromboprophylaxis over using parenteral thromboprophylaxis in ambulatory patients receiving cancer chemotherapy who have low venous thromboembolism (VTE) risk, and using no thromboprophylaxis over oral thromboprophylaxis with vitamin K antagonists in those at any VTE risk level.

The evidence-based guidelines for the prevention and treatment of VTE in patient with cancer, published online in Blood Advances, also include a “conditional recommendation” for using either thromboprophylaxis with the direct oral anticoagulants (DOACs) apixaban or rivaroxaban or using no thromboprophylaxis in ambulatory patients with intermediate risk and using the DOACs over no thromboprophylaxis in those with high VTE risk.

The purpose of the guidelines, which also address VTE prophylaxis in hospitalized patients with cancer and the use of anticoagulation for VTE treatment in patients with cancer, is to provide clinical decision support for shared decision-making by patients and clinicians, Gary H. Lyman, MD, of Fred Hutchinson Cancer Research Center, Seattle and Marc Carrier, MD, of the University of Ottawa, and their colleagues from the multidisciplinary guidelines panel explained.

“The recommendations take into consideration the strength of the evidence, risks of mortality, VTE, and bleeding, as well as quality of life, acceptability, and cost considerations,” they wrote, noting that VTE is a common complication in patients with cancer, who are at markedly increased risk for morbidity and mortality from VTE.
 

Levels of evidence

The panel members relied on updated and original systematic evidence reviews. Conditional recommendations, as opposed to strong recommendations, are defined by the panel as “suggestions,” and all 33 recommendations that make up the guidelines include a statement on the strength of the relevant evidence.

For example, the thromboprophylaxis recommendations for low, intermediate, and high VTE risk are made based on “moderate certainty in the evidence of effects,” and the recommendation for no thromboprophylaxis over oral thromboprophylaxis with vitamin K antagonists is a strong recommendation based on “very low certainty in the evidence of benefits, but high certainty about the harms.”

The guidelines panel also strongly recommends, based on moderate certainty in the evidence of effects, using low-molecular-weight heparin over unfractionated heparin for the initial treatment of VTE in patients with cancer, and suggests, based on “very low certainty in the evidence of effects,” using LMWH over fondaparinux in this setting.

In addition to primary prophylaxis in ambulatory and hospitalized patients and initial VTE treatment, they also address primary prophylaxis for patients with cancer who have a central venous catheter, VTE treatment in surgical patients with cancer, short-term VTE treatment, and long-term VTE treatment.

For example, the guidelines panel conditionally recommends:

• Not using parenteral or oral thromboprophylaxis in patients with cancer and a central venous catheter
• Using LMWH or fondaparinux for surgical patients with cancer
• Using DOACS for the short-term treatment of VTE, and LMWH or DOACs for the long-term treatment of VTE in patients with cancer.

The perils of VTE

VTE in patients with cancer can interfere with treatment, increase mortality risk, and increase costs, the authors noted, adding that VTE can also adversely affect cancer patients’ quality of life.

“Some have even reported the experience of VTE to be more upsetting than that of the cancer,” they wrote. “More than 50% of thrombotic events occur within 3 months of the cancer diagnosis, a time when most cancer treatments will be underway. Patients, who are still coming to terms with a recent cancer diagnosis, often view the occurrence of VTE as a further threat to life, confirmation of the severity of their condition, and a poor prognostic sign.”

Therefore, the new guidelines aim to reduce VTE frequency, risk of bleeding complications, morbidity, and costs, thereby improving quality of life and the patient experience, the authors said, noting that three other recent guidelines on VTEs in patients with cancer have been published: the 2019 American Society of Clinical Oncology guidelines, the 2019 International Initiative on Thrombosis and Cancer guidelines, and the 2020 National Comprehensive Cancer Network guidelines.

The ASH guidelines are similar in many ways to the other guidelines, but differ in some ways, as well. An example is the timing of initiation of pharmacological thromboprophylaxis in patients undergoing cancer-related major abdominal surgery. The ASCO and ITAC guidelines advise starting thromboprophylaxis preoperatively, whereas the ASH guidelines recommend initiating thromboprophylaxis postoperatively, citing “the limited advantages to initiating thromboprophylaxis preoperatively, in addition to the potential bleeding and logistical considerations associated with neuraxial anesthesia.”

These differences highlight a lack of data in that setting and the need for additional studies, the authors said.
 

ASH vs. ASCO

James Douketis, MD, a practicing clinician and professor of medicine at McMaster University, Hamilton, Ont., highlighted another difference between the ASH and ASCO guidelines.

“For the treatment of [cancer-associated thrombosis], ASCO gives a strong recommendation to use LMWH or DOACs (with some caveats), which is easy to follow. ASH, on the other hand, suggests LMWH or a DOAC for the first 7-10 days, DOACs for the first 3-6 months, and back to LMWH or DOACs after 6 months,” he said in an interview.

The recommendation is “very evidence based but ambiguous and not helpful for the practicing clinician,” added Dr. Douketis, who helped develop the ITAC guidelines, but was not part of the ASH or ASCO guideline panels.

ASCO also provides a clear recommendation for giving VTE prophylaxis for 4 weeks after cancer surgery in patients with high VTE risk, whereas ASH gives “a somewhat vague recommendation” for thromboprophylaxis after hospital discharge.

The guidelines are “pretty well aligned” with respect to recommendations on VTE prophylaxis in medical cancer patients receiving chemotherapy, and although the “extremely academic” ASH guidelines were developed by “a superb team using the same evidence and excellent methodology,” they are interpreted in slightly different ways and fall short when it comes to being clinician friendly, Dr. Douketis said.

“At the end of day, for practicing clinicians, the ASH guidelines don’t provide a message that’s easy to digest,” he added.

ASH has, however, provided a resource page that includes tools and information for implementing the guidelines in clinical practice, and will maintain the guidelines “through surveillance for new evidence, ongoing review by experts, and regular revisions,” the authors said.

sworcester@mdedge.com

Despite their similar functions, each current and emerging therapy for treating hemophilia has a unique safety profile, and each needs to be weighed apart from agents both within and outside its pharmacologic class, a hemophilia specialist said.

“My view is that each new molecule coming to the hemophilia space, including variant factor molecules, needs to be scrutinized separately, without class assumptions or extrapolations, and it’s clear that thrombosis risk has become a priority safety consideration,” said Dan Hart, MBChB, MRCP, FRCPath, PhD, from Barts and the London School of Medicine and Dentistry.

He reviewed the comparative safety of standard and novel therapies for hemophilia at the annual congress of the European Association for Haemophilia and Allied Disorders.
 

Factor inhibitors

Inhibitors occur in both hemophilia A and hemophilia B, and are primarily seen in patients with childhood exposure to factor concentrates. Inhibitors, which include anti–factor VIII and factor IX alloantibodies, are more common among patients with severe hemophilia and those with more disruptive factor VIII and factor IX mutations.

“There can be transient vs. persistent inhibitors, and arguably the more you look, the more you find, but clinically we never miss high-titer inhibitors that have a big impact on individuals and the subsequent decisions about management,” he said.
 

Hamster vs. human

It’s currently unclear whether there is an immunologic advantage for previously untreated patients to be started on factor VIII concentrates derived from recombinant human cells lines, or from products derived from Chinese hamster ovary (CHO) or baby hamster kidney (BHK) cell lines, Dr. Hart said.

“We need to ensure that we’re not selective about comparator choice for new products in the absence of head-to-head studies,” he said.
 

Route of administration matters

Inhibitors appear to be a more common occurrence among patients who received factor concentrates subcutaneously, compared with intravenously, Dr. Hart noted, pointing to a 2011 study indicating a background annual risk of 5 cases of inhibitor development per 1,000 treatment years in previously treated patients who received intravenous therapy (Blood. 2011 Jun 9;117[23]:6367-70).

In contrast, in a phase 1 trial of subcutaneous turoctocog alfa pegol, 5 out of 26 patients had detectable N8-GP–binding antibodies after 42-91 exposure days. Of these patients, one developed an inhibitor to factor VIII, and anti–N8-GP antibody appearance was associated with a decline in factor VIII plasma activity in four of the five patients. In addition, five patients reported a total of nine bleeding episodes requiring treatment during prophylaxis. As a result of this trial, further clinical development of the subcutaneous version was suspended. (J Thromb Haemost. 2020 Feb;18[2]:341-51).

Other subcutaneously administered factors are currently in development, Dr. Hart noted.
 

Nonfactor inhibitors?

“The nonfactor agents do have the risk of generating antibodies: Monoclonal antibodies outside the hemophilia setting provoke antidrug antibodies,” he said.

Although there is no consensus regarding which assay can best monitor antidrug antibodies (ADA), enzyme-linked immunosorbent assay (ELISA) can detect neutralizing antibodies and other antibodies.

In the hemophilia setting, surrogate markers for loss of drug efficacy include longer activated partial thromboplastin time (ATTP) or a drop in serum drug levels. Worsening bleeding phenotype can also be a marker for loss of efficacy, albeit an imperfect one.

Emicizumab (Hemlibara), the first nonfactor monoclonal agent to make it to market, has the largest dataset available, and evidence suggests a rate of neutralizing antibodies with this agent of less than 1% in the HAVEN clinical trial series, but 5.2% in the single-arm STASEY trial.

“We shouldn’t assume that other biophenotypics will have a similar ADA rate, and this needs to be evaluated for each molecule, as it will need to be for other monoclonals” such as anti–tissue factor pathway (TFPI) antibodies, Dr. Hart emphasized.
 

Pegylation

Pegylated compounds include polyethylene glycol, an inert polymer, covalently bound to the therapeutic protein to extend its half-life, and theoretically, reduce immunogenicity.

Many patients may already have exposure to pegylated products in the form of peginterferon to treat hepatitis C, consumer products such as toothpaste, cough medicine, and cosmetics, and, more recently, in vaccines against COVID-19.

Safety considerations with pegylated agents in hemophilia include concerns about accumulation of polyethylene glycol (PEG), although “some of the preclinical models looking at excretion of PEG are difficult to interpret in my view, and people debate about whether studies are long enough, but it’s undoubtedly the case that toxicology dosing is order of magnitude higher than the routine dosing in hemophilia,” he said.

After more than 5 years of experience with pegylated products there is no clinical evidence of concern, although “it’s not clear, actually, what we’re looking for, whether it’s a clinical parameter, or imaging or histological parameter.”

Patients may also not have lifelong exposure to pegylated products, as it is unlikely that they will stay on the same product for decades, Dr. Hart said.
 

Thrombosis

As of June 30, 2020, more than 7,200 persons with hemophilia have received emicizumab, and there have been 23 reported thrombotic events, 19 of which occurred in the postmarketing period. Of the reported cases, six patients had a myocardial infarction, and all of these patients had at least one cardiovascular risk factor.

The antithrombin agent fitusiran was associated with one fatal thrombotic event in a phase 2, open-label extension trial, leading to a pause and resumption with mitigation protocols, but that trial has since been paused again because of additional, nonfatal thrombotic events.

Nonfatal thrombotic events have also occurred in clinical trials for the investigational anti-TFPI monoclonal antibodies BAY 1093884 and concizumab, but none have thus far been reported in phase 3 trial of marstacimab.

“We need renewed efforts for prospective reporting and independent review of all adverse events of all agents, old and new: This will need some guidance nationally and internationally, and I think the relevant trial [serious adverse events] need to be reported in peer review literature, and clinicaltrials.gov updated in a timely manner, regardless of whether that strategy was successful or unsuccessful,” Dr. Hart said.
 

Risk with longer-acting agents?

In the question and answer following his presentation, Christoph Königs, MD, PhD, from University Hospital Frankfurt, asked whether there was potential for increased thrombosis risk with second-generation extended half-life (EHL) molecules in clinical trials.

“As we edge towards normalization of hemostasis, clearly the other non–hemophilia dependent issues of thrombosis risk come into play,” Dr. Hart acknowledged. “I think it will be an inevitability that there will be events, and we need to understand what the denominators are – hence my pitch for there being a renewed effort to try and collate sufficient data that we can really define events happening with people treated with standard half-life [products] through into the novel agents,” he said.

Dr. Hart disclosed grant/research support and speaker bureau activities for Bayer, Octapharma, Takeda, and others. Dr. Königs has reported no relevant disclosures.

Despite their similar functions, each current and emerging therapy for treating hemophilia has a unique safety profile, and each needs to be weighed apart from agents both within and outside its pharmacologic class, a hemophilia specialist said.

“My view is that each new molecule coming to the hemophilia space, including variant factor molecules, needs to be scrutinized separately, without class assumptions or extrapolations, and it’s clear that thrombosis risk has become a priority safety consideration,” said Dan Hart, MBChB, MRCP, FRCPath, PhD, from Barts and the London School of Medicine and Dentistry.

He reviewed the comparative safety of standard and novel therapies for hemophilia at the annual congress of the European Association for Haemophilia and Allied Disorders.
 

Factor inhibitors

Inhibitors occur in both hemophilia A and hemophilia B, and are primarily seen in patients with childhood exposure to factor concentrates. Inhibitors, which include anti–factor VIII and factor IX alloantibodies, are more common among patients with severe hemophilia and those with more disruptive factor VIII and factor IX mutations.

“There can be transient vs. persistent inhibitors, and arguably the more you look, the more you find, but clinically we never miss high-titer inhibitors that have a big impact on individuals and the subsequent decisions about management,” he said.
 

Hamster vs. human

It’s currently unclear whether there is an immunologic advantage for previously untreated patients to be started on factor VIII concentrates derived from recombinant human cells lines, or from products derived from Chinese hamster ovary (CHO) or baby hamster kidney (BHK) cell lines, Dr. Hart said.

“We need to ensure that we’re not selective about comparator choice for new products in the absence of head-to-head studies,” he said.
 

Route of administration matters

Inhibitors appear to be a more common occurrence among patients who received factor concentrates subcutaneously, compared with intravenously, Dr. Hart noted, pointing to a 2011 study indicating a background annual risk of 5 cases of inhibitor development per 1,000 treatment years in previously treated patients who received intravenous therapy (Blood. 2011 Jun 9;117[23]:6367-70).

In contrast, in a phase 1 trial of subcutaneous turoctocog alfa pegol, 5 out of 26 patients had detectable N8-GP–binding antibodies after 42-91 exposure days. Of these patients, one developed an inhibitor to factor VIII, and anti–N8-GP antibody appearance was associated with a decline in factor VIII plasma activity in four of the five patients. In addition, five patients reported a total of nine bleeding episodes requiring treatment during prophylaxis. As a result of this trial, further clinical development of the subcutaneous version was suspended. (J Thromb Haemost. 2020 Feb;18[2]:341-51).

Other subcutaneously administered factors are currently in development, Dr. Hart noted.
 

Nonfactor inhibitors?

“The nonfactor agents do have the risk of generating antibodies: Monoclonal antibodies outside the hemophilia setting provoke antidrug antibodies,” he said.

Although there is no consensus regarding which assay can best monitor antidrug antibodies (ADA), enzyme-linked immunosorbent assay (ELISA) can detect neutralizing antibodies and other antibodies.

In the hemophilia setting, surrogate markers for loss of drug efficacy include longer activated partial thromboplastin time (ATTP) or a drop in serum drug levels. Worsening bleeding phenotype can also be a marker for loss of efficacy, albeit an imperfect one.

Emicizumab (Hemlibara), the first nonfactor monoclonal agent to make it to market, has the largest dataset available, and evidence suggests a rate of neutralizing antibodies with this agent of less than 1% in the HAVEN clinical trial series, but 5.2% in the single-arm STASEY trial.

“We shouldn’t assume that other biophenotypics will have a similar ADA rate, and this needs to be evaluated for each molecule, as it will need to be for other monoclonals” such as anti–tissue factor pathway (TFPI) antibodies, Dr. Hart emphasized.
 

Pegylation

Pegylated compounds include polyethylene glycol, an inert polymer, covalently bound to the therapeutic protein to extend its half-life, and theoretically, reduce immunogenicity.

Many patients may already have exposure to pegylated products in the form of peginterferon to treat hepatitis C, consumer products such as toothpaste, cough medicine, and cosmetics, and, more recently, in vaccines against COVID-19.

Safety considerations with pegylated agents in hemophilia include concerns about accumulation of polyethylene glycol (PEG), although “some of the preclinical models looking at excretion of PEG are difficult to interpret in my view, and people debate about whether studies are long enough, but it’s undoubtedly the case that toxicology dosing is order of magnitude higher than the routine dosing in hemophilia,” he said.

After more than 5 years of experience with pegylated products there is no clinical evidence of concern, although “it’s not clear, actually, what we’re looking for, whether it’s a clinical parameter, or imaging or histological parameter.”

Patients may also not have lifelong exposure to pegylated products, as it is unlikely that they will stay on the same product for decades, Dr. Hart said.
 

Thrombosis

As of June 30, 2020, more than 7,200 persons with hemophilia have received emicizumab, and there have been 23 reported thrombotic events, 19 of which occurred in the postmarketing period. Of the reported cases, six patients had a myocardial infarction, and all of these patients had at least one cardiovascular risk factor.

The antithrombin agent fitusiran was associated with one fatal thrombotic event in a phase 2, open-label extension trial, leading to a pause and resumption with mitigation protocols, but that trial has since been paused again because of additional, nonfatal thrombotic events.

Nonfatal thrombotic events have also occurred in clinical trials for the investigational anti-TFPI monoclonal antibodies BAY 1093884 and concizumab, but none have thus far been reported in phase 3 trial of marstacimab.

“We need renewed efforts for prospective reporting and independent review of all adverse events of all agents, old and new: This will need some guidance nationally and internationally, and I think the relevant trial [serious adverse events] need to be reported in peer review literature, and clinicaltrials.gov updated in a timely manner, regardless of whether that strategy was successful or unsuccessful,” Dr. Hart said.
 

Risk with longer-acting agents?

In the question and answer following his presentation, Christoph Königs, MD, PhD, from University Hospital Frankfurt, asked whether there was potential for increased thrombosis risk with second-generation extended half-life (EHL) molecules in clinical trials.

“As we edge towards normalization of hemostasis, clearly the other non–hemophilia dependent issues of thrombosis risk come into play,” Dr. Hart acknowledged. “I think it will be an inevitability that there will be events, and we need to understand what the denominators are – hence my pitch for there being a renewed effort to try and collate sufficient data that we can really define events happening with people treated with standard half-life [products] through into the novel agents,” he said.

Dr. Hart disclosed grant/research support and speaker bureau activities for Bayer, Octapharma, Takeda, and others. Dr. Königs has reported no relevant disclosures.

Despite their similar functions, each current and emerging therapy for treating hemophilia has a unique safety profile, and each needs to be weighed apart from agents both within and outside its pharmacologic class, a hemophilia specialist said.

“My view is that each new molecule coming to the hemophilia space, including variant factor molecules, needs to be scrutinized separately, without class assumptions or extrapolations, and it’s clear that thrombosis risk has become a priority safety consideration,” said Dan Hart, MBChB, MRCP, FRCPath, PhD, from Barts and the London School of Medicine and Dentistry.

He reviewed the comparative safety of standard and novel therapies for hemophilia at the annual congress of the European Association for Haemophilia and Allied Disorders.
 

Factor inhibitors

Inhibitors occur in both hemophilia A and hemophilia B, and are primarily seen in patients with childhood exposure to factor concentrates. Inhibitors, which include anti–factor VIII and factor IX alloantibodies, are more common among patients with severe hemophilia and those with more disruptive factor VIII and factor IX mutations.

“There can be transient vs. persistent inhibitors, and arguably the more you look, the more you find, but clinically we never miss high-titer inhibitors that have a big impact on individuals and the subsequent decisions about management,” he said.
 

Hamster vs. human

It’s currently unclear whether there is an immunologic advantage for previously untreated patients to be started on factor VIII concentrates derived from recombinant human cells lines, or from products derived from Chinese hamster ovary (CHO) or baby hamster kidney (BHK) cell lines, Dr. Hart said.

“We need to ensure that we’re not selective about comparator choice for new products in the absence of head-to-head studies,” he said.
 

Route of administration matters

Inhibitors appear to be a more common occurrence among patients who received factor concentrates subcutaneously, compared with intravenously, Dr. Hart noted, pointing to a 2011 study indicating a background annual risk of 5 cases of inhibitor development per 1,000 treatment years in previously treated patients who received intravenous therapy (Blood. 2011 Jun 9;117[23]:6367-70).

In contrast, in a phase 1 trial of subcutaneous turoctocog alfa pegol, 5 out of 26 patients had detectable N8-GP–binding antibodies after 42-91 exposure days. Of these patients, one developed an inhibitor to factor VIII, and anti–N8-GP antibody appearance was associated with a decline in factor VIII plasma activity in four of the five patients. In addition, five patients reported a total of nine bleeding episodes requiring treatment during prophylaxis. As a result of this trial, further clinical development of the subcutaneous version was suspended. (J Thromb Haemost. 2020 Feb;18[2]:341-51).

Other subcutaneously administered factors are currently in development, Dr. Hart noted.
 

Nonfactor inhibitors?

“The nonfactor agents do have the risk of generating antibodies: Monoclonal antibodies outside the hemophilia setting provoke antidrug antibodies,” he said.

Although there is no consensus regarding which assay can best monitor antidrug antibodies (ADA), enzyme-linked immunosorbent assay (ELISA) can detect neutralizing antibodies and other antibodies.

In the hemophilia setting, surrogate markers for loss of drug efficacy include longer activated partial thromboplastin time (ATTP) or a drop in serum drug levels. Worsening bleeding phenotype can also be a marker for loss of efficacy, albeit an imperfect one.

Emicizumab (Hemlibara), the first nonfactor monoclonal agent to make it to market, has the largest dataset available, and evidence suggests a rate of neutralizing antibodies with this agent of less than 1% in the HAVEN clinical trial series, but 5.2% in the single-arm STASEY trial.

“We shouldn’t assume that other biophenotypics will have a similar ADA rate, and this needs to be evaluated for each molecule, as it will need to be for other monoclonals” such as anti–tissue factor pathway (TFPI) antibodies, Dr. Hart emphasized.
 

Pegylation

Pegylated compounds include polyethylene glycol, an inert polymer, covalently bound to the therapeutic protein to extend its half-life, and theoretically, reduce immunogenicity.

Many patients may already have exposure to pegylated products in the form of peginterferon to treat hepatitis C, consumer products such as toothpaste, cough medicine, and cosmetics, and, more recently, in vaccines against COVID-19.

Safety considerations with pegylated agents in hemophilia include concerns about accumulation of polyethylene glycol (PEG), although “some of the preclinical models looking at excretion of PEG are difficult to interpret in my view, and people debate about whether studies are long enough, but it’s undoubtedly the case that toxicology dosing is order of magnitude higher than the routine dosing in hemophilia,” he said.

After more than 5 years of experience with pegylated products there is no clinical evidence of concern, although “it’s not clear, actually, what we’re looking for, whether it’s a clinical parameter, or imaging or histological parameter.”

Patients may also not have lifelong exposure to pegylated products, as it is unlikely that they will stay on the same product for decades, Dr. Hart said.
 

Thrombosis

As of June 30, 2020, more than 7,200 persons with hemophilia have received emicizumab, and there have been 23 reported thrombotic events, 19 of which occurred in the postmarketing period. Of the reported cases, six patients had a myocardial infarction, and all of these patients had at least one cardiovascular risk factor.

The antithrombin agent fitusiran was associated with one fatal thrombotic event in a phase 2, open-label extension trial, leading to a pause and resumption with mitigation protocols, but that trial has since been paused again because of additional, nonfatal thrombotic events.

Nonfatal thrombotic events have also occurred in clinical trials for the investigational anti-TFPI monoclonal antibodies BAY 1093884 and concizumab, but none have thus far been reported in phase 3 trial of marstacimab.

“We need renewed efforts for prospective reporting and independent review of all adverse events of all agents, old and new: This will need some guidance nationally and internationally, and I think the relevant trial [serious adverse events] need to be reported in peer review literature, and clinicaltrials.gov updated in a timely manner, regardless of whether that strategy was successful or unsuccessful,” Dr. Hart said.
 

Risk with longer-acting agents?

In the question and answer following his presentation, Christoph Königs, MD, PhD, from University Hospital Frankfurt, asked whether there was potential for increased thrombosis risk with second-generation extended half-life (EHL) molecules in clinical trials.

“As we edge towards normalization of hemostasis, clearly the other non–hemophilia dependent issues of thrombosis risk come into play,” Dr. Hart acknowledged. “I think it will be an inevitability that there will be events, and we need to understand what the denominators are – hence my pitch for there being a renewed effort to try and collate sufficient data that we can really define events happening with people treated with standard half-life [products] through into the novel agents,” he said.

Dr. Hart disclosed grant/research support and speaker bureau activities for Bayer, Octapharma, Takeda, and others. Dr. Königs has reported no relevant disclosures.

Steroids are usually the first choice of therapy for the treatment of patients with graft-vs.-host disease (GVHD), but complications from steroid use may carry a high financial cost, investigators caution.

Among 689 patients with a diagnosis of GVHD following a hematopoietic stem cell transplant (HSCT) who received steroids, 685 (97%) had at least one steroid-related complication, resulting in nearly $165,000 in mean health-care costs over 24 months, said Elizabeth J. Bell, PhD, MPH, an epidemiologist at Optum Inc.

“For both acute and chronic GVHD, the standard of care for first-line treatment is systemic steroids. The complications associated with steroid treatment are well known. However, the health-care resources utilized and the costs incurred by these patients are not well-quantified,” she said at the Transplantation & Cellular Therapies Meetings (Abstract 12).

Dr. Bell reported the results of a retrospective database analysis on costs associated with steroid complications in HSCT recipients at the meeting, which was held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.

She and colleagues from Optum, Incyte, and the University of Minnesota in Minneapolis looked at data on 689 patients with a diagnosis of GVHD after HSCT who received systemic steroids from July 1, 2010, through Aug. 31, 2019. The data were extracted from the Optum Research database, and included U.S. commercial and Medicare Advantage patients.

They looked at total complications and steroid-associated complications in each of four categories: infections; metabolic or endocrine complications (for example, diabetes, dyslipidemia); gastrointestinal (GI) complications (e.g., peptic ulcer disease); and bone or muscle complications (myopathy, etc).

They estimated costs based on International Classification of Diseases (ICD) codes for any steroid complications during the 24 months after steroid initiation, including those complications that may have been present at the time of GVHD diagnosis.

The median patient age was 55 years, and 60% of the sample were male. The mean Charlson Comorbidity Index score at baseline was 3.

Overall, 22% of patients had only acute GVHD, 21% had only chronic GVHD, and 39% had both acute and chronic disease. The GVHD type was unspecified in the remaining 18%.

The median time from GVHD diagnosis to initiating steroids was 30 days for patients with both acute and chronic disease, as well as those with both presentations. The median time to initiation was 36 days for patients with unspecified GVHD type.

The median cumulative duration of steroid use over 24 months was 62 days for patients with acute GVHD, 208 days for those with chronic GVHD, 166 days for those with both, and 74 days for patients with unspecified GVHD type.

As noted before, complications occurred in 97% of patients, with infections being the most common complications, occurring in 80% of patients, followed by metabolic/endocrine complications in 32%, gastrointestinal in 29%, and bone/muscle complications in 20%.

For the 665 patients who had any steroid-related complication, the mean costs of steroid-associated care in the 24 months after they were started on steroids was $164,787, and the median cost was $50,834.

Health care costs were highest among patients with infections, at a mean of $167,473, and a median of $57,680, followed by bone/muscle conditions ($75,289 and $2,057, respectively), GI conditions ($67,861 and $3,360), and metabolic or endocrine conditions ($47, 101 and $1,164).

In all categories, hospitalizations accounted for the large majority of costs.

Two-thirds (66%) of patients who experienced any steroid-related complication required hospitalization, primarily for infections.

Among all patients with complications, the median cumulative hospital stay over 24 months was 20 days, with bone/muscle complications and infections associated with a median of 19 and 18 days of hospitalization, respectively.

Dr. Bell acknowledged that the study was limited by use of ICD coding to identify steroid complication-related health-care utilization and costs, which can be imprecise, and by the fact that the analysis included only complications resulting in health care use as documented in medical claims. In addition, the investigators noted that they could not control for the possibility that steroids exacerbated conditions that existed at baseline.

“These findings emphasize the need to cautiously evaluate the treatment options for patients with GVHD. Future study with medical records is needed to provide insights on the clinical aspects of the complications (e.g., severity and suspected causality),” Dr. Bell and colleagues concluded in the study’s abstract.
 

Definitions questioned

An HSCT specialist approached for comment said that the findings of the study made sense, but she had questions regarding the study methodology.

“I would intuitively think that steroid-associated complications are a major cause of health care use in GVHD patients and it’s interesting to see that there is emerging data to support this hypothesis,” HSCT specialist Hélène Schoemans, MD of the University of Leuven, Belgium, said in an interview.

She noted, however, that “it is surprising that the period of steroid initiation was the same for acute and chronic GVHD,” and questioned whether that anomalous finding could be due to the study’s definition of acute and chronic GVHD or to how the period from baseline to steroid initiation was defined.

The questions about the definitions and timing of therapy make it uncertain as to whether the complications reported were caused by steroids or by some other factor, she suggested.

The study was supported by Optum Inc. Dr. Bell is an employee of the company, and a paid consultant of Incyte. Dr. Schoemans has received travel expenses from Celgene, Abbvie, and Incyte; is part of the advisory boards for Incyte; and has received speakers fees from Novartis, Incyte, Jazz Pharmaceuticals, and Takeda.

Steroids are usually the first choice of therapy for the treatment of patients with graft-vs.-host disease (GVHD), but complications from steroid use may carry a high financial cost, investigators caution.

Among 689 patients with a diagnosis of GVHD following a hematopoietic stem cell transplant (HSCT) who received steroids, 685 (97%) had at least one steroid-related complication, resulting in nearly $165,000 in mean health-care costs over 24 months, said Elizabeth J. Bell, PhD, MPH, an epidemiologist at Optum Inc.

“For both acute and chronic GVHD, the standard of care for first-line treatment is systemic steroids. The complications associated with steroid treatment are well known. However, the health-care resources utilized and the costs incurred by these patients are not well-quantified,” she said at the Transplantation & Cellular Therapies Meetings (Abstract 12).

Dr. Bell reported the results of a retrospective database analysis on costs associated with steroid complications in HSCT recipients at the meeting, which was held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.

She and colleagues from Optum, Incyte, and the University of Minnesota in Minneapolis looked at data on 689 patients with a diagnosis of GVHD after HSCT who received systemic steroids from July 1, 2010, through Aug. 31, 2019. The data were extracted from the Optum Research database, and included U.S. commercial and Medicare Advantage patients.

They looked at total complications and steroid-associated complications in each of four categories: infections; metabolic or endocrine complications (for example, diabetes, dyslipidemia); gastrointestinal (GI) complications (e.g., peptic ulcer disease); and bone or muscle complications (myopathy, etc).

They estimated costs based on International Classification of Diseases (ICD) codes for any steroid complications during the 24 months after steroid initiation, including those complications that may have been present at the time of GVHD diagnosis.

The median patient age was 55 years, and 60% of the sample were male. The mean Charlson Comorbidity Index score at baseline was 3.

Overall, 22% of patients had only acute GVHD, 21% had only chronic GVHD, and 39% had both acute and chronic disease. The GVHD type was unspecified in the remaining 18%.

The median time from GVHD diagnosis to initiating steroids was 30 days for patients with both acute and chronic disease, as well as those with both presentations. The median time to initiation was 36 days for patients with unspecified GVHD type.

The median cumulative duration of steroid use over 24 months was 62 days for patients with acute GVHD, 208 days for those with chronic GVHD, 166 days for those with both, and 74 days for patients with unspecified GVHD type.

As noted before, complications occurred in 97% of patients, with infections being the most common complications, occurring in 80% of patients, followed by metabolic/endocrine complications in 32%, gastrointestinal in 29%, and bone/muscle complications in 20%.

For the 665 patients who had any steroid-related complication, the mean costs of steroid-associated care in the 24 months after they were started on steroids was $164,787, and the median cost was $50,834.

Health care costs were highest among patients with infections, at a mean of $167,473, and a median of $57,680, followed by bone/muscle conditions ($75,289 and $2,057, respectively), GI conditions ($67,861 and $3,360), and metabolic or endocrine conditions ($47, 101 and $1,164).

In all categories, hospitalizations accounted for the large majority of costs.

Two-thirds (66%) of patients who experienced any steroid-related complication required hospitalization, primarily for infections.

Among all patients with complications, the median cumulative hospital stay over 24 months was 20 days, with bone/muscle complications and infections associated with a median of 19 and 18 days of hospitalization, respectively.

Dr. Bell acknowledged that the study was limited by use of ICD coding to identify steroid complication-related health-care utilization and costs, which can be imprecise, and by the fact that the analysis included only complications resulting in health care use as documented in medical claims. In addition, the investigators noted that they could not control for the possibility that steroids exacerbated conditions that existed at baseline.

“These findings emphasize the need to cautiously evaluate the treatment options for patients with GVHD. Future study with medical records is needed to provide insights on the clinical aspects of the complications (e.g., severity and suspected causality),” Dr. Bell and colleagues concluded in the study’s abstract.
 

Definitions questioned

An HSCT specialist approached for comment said that the findings of the study made sense, but she had questions regarding the study methodology.

“I would intuitively think that steroid-associated complications are a major cause of health care use in GVHD patients and it’s interesting to see that there is emerging data to support this hypothesis,” HSCT specialist Hélène Schoemans, MD of the University of Leuven, Belgium, said in an interview.

She noted, however, that “it is surprising that the period of steroid initiation was the same for acute and chronic GVHD,” and questioned whether that anomalous finding could be due to the study’s definition of acute and chronic GVHD or to how the period from baseline to steroid initiation was defined.

The questions about the definitions and timing of therapy make it uncertain as to whether the complications reported were caused by steroids or by some other factor, she suggested.

The study was supported by Optum Inc. Dr. Bell is an employee of the company, and a paid consultant of Incyte. Dr. Schoemans has received travel expenses from Celgene, Abbvie, and Incyte; is part of the advisory boards for Incyte; and has received speakers fees from Novartis, Incyte, Jazz Pharmaceuticals, and Takeda.

Steroids are usually the first choice of therapy for the treatment of patients with graft-vs.-host disease (GVHD), but complications from steroid use may carry a high financial cost, investigators caution.

Among 689 patients with a diagnosis of GVHD following a hematopoietic stem cell transplant (HSCT) who received steroids, 685 (97%) had at least one steroid-related complication, resulting in nearly $165,000 in mean health-care costs over 24 months, said Elizabeth J. Bell, PhD, MPH, an epidemiologist at Optum Inc.

“For both acute and chronic GVHD, the standard of care for first-line treatment is systemic steroids. The complications associated with steroid treatment are well known. However, the health-care resources utilized and the costs incurred by these patients are not well-quantified,” she said at the Transplantation & Cellular Therapies Meetings (Abstract 12).

Dr. Bell reported the results of a retrospective database analysis on costs associated with steroid complications in HSCT recipients at the meeting, which was held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.

She and colleagues from Optum, Incyte, and the University of Minnesota in Minneapolis looked at data on 689 patients with a diagnosis of GVHD after HSCT who received systemic steroids from July 1, 2010, through Aug. 31, 2019. The data were extracted from the Optum Research database, and included U.S. commercial and Medicare Advantage patients.

They looked at total complications and steroid-associated complications in each of four categories: infections; metabolic or endocrine complications (for example, diabetes, dyslipidemia); gastrointestinal (GI) complications (e.g., peptic ulcer disease); and bone or muscle complications (myopathy, etc).

They estimated costs based on International Classification of Diseases (ICD) codes for any steroid complications during the 24 months after steroid initiation, including those complications that may have been present at the time of GVHD diagnosis.

The median patient age was 55 years, and 60% of the sample were male. The mean Charlson Comorbidity Index score at baseline was 3.

Overall, 22% of patients had only acute GVHD, 21% had only chronic GVHD, and 39% had both acute and chronic disease. The GVHD type was unspecified in the remaining 18%.

The median time from GVHD diagnosis to initiating steroids was 30 days for patients with both acute and chronic disease, as well as those with both presentations. The median time to initiation was 36 days for patients with unspecified GVHD type.

The median cumulative duration of steroid use over 24 months was 62 days for patients with acute GVHD, 208 days for those with chronic GVHD, 166 days for those with both, and 74 days for patients with unspecified GVHD type.

As noted before, complications occurred in 97% of patients, with infections being the most common complications, occurring in 80% of patients, followed by metabolic/endocrine complications in 32%, gastrointestinal in 29%, and bone/muscle complications in 20%.

For the 665 patients who had any steroid-related complication, the mean costs of steroid-associated care in the 24 months after they were started on steroids was $164,787, and the median cost was $50,834.

Health care costs were highest among patients with infections, at a mean of $167,473, and a median of $57,680, followed by bone/muscle conditions ($75,289 and $2,057, respectively), GI conditions ($67,861 and $3,360), and metabolic or endocrine conditions ($47, 101 and $1,164).

In all categories, hospitalizations accounted for the large majority of costs.

Two-thirds (66%) of patients who experienced any steroid-related complication required hospitalization, primarily for infections.

Among all patients with complications, the median cumulative hospital stay over 24 months was 20 days, with bone/muscle complications and infections associated with a median of 19 and 18 days of hospitalization, respectively.

Dr. Bell acknowledged that the study was limited by use of ICD coding to identify steroid complication-related health-care utilization and costs, which can be imprecise, and by the fact that the analysis included only complications resulting in health care use as documented in medical claims. In addition, the investigators noted that they could not control for the possibility that steroids exacerbated conditions that existed at baseline.

“These findings emphasize the need to cautiously evaluate the treatment options for patients with GVHD. Future study with medical records is needed to provide insights on the clinical aspects of the complications (e.g., severity and suspected causality),” Dr. Bell and colleagues concluded in the study’s abstract.
 

Definitions questioned

An HSCT specialist approached for comment said that the findings of the study made sense, but she had questions regarding the study methodology.

“I would intuitively think that steroid-associated complications are a major cause of health care use in GVHD patients and it’s interesting to see that there is emerging data to support this hypothesis,” HSCT specialist Hélène Schoemans, MD of the University of Leuven, Belgium, said in an interview.

She noted, however, that “it is surprising that the period of steroid initiation was the same for acute and chronic GVHD,” and questioned whether that anomalous finding could be due to the study’s definition of acute and chronic GVHD or to how the period from baseline to steroid initiation was defined.

The questions about the definitions and timing of therapy make it uncertain as to whether the complications reported were caused by steroids or by some other factor, she suggested.

The study was supported by Optum Inc. Dr. Bell is an employee of the company, and a paid consultant of Incyte. Dr. Schoemans has received travel expenses from Celgene, Abbvie, and Incyte; is part of the advisory boards for Incyte; and has received speakers fees from Novartis, Incyte, Jazz Pharmaceuticals, and Takeda.

Real-world experience with chimeric antigen receptor (CAR) T-cell therapies for large B-cell lymphomas compares favorably with experience in commercial and trial settings and provides new insights for predicting outcomes, according to Paolo Corradini, MD.

The 12-month duration of response (DOR) and progression-free survival (PFS) rates in 152 real-world patients treated with tisagenlecleucel (tisa-cel; Kymriah) for an approved indication were 48.4% and 26.4%, respectively, data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) and published in November 2020 in Blood Advances showed.

Those results are similar to the findings of the pivotal phase 2 JULIET trial evaluating tisa-cel in patients with DLBCL who relapsed or were refractory to at least two prior lines of therapy, Dr. Corradini said at the third European CAR T-cell Meeting, jointly sponsored by the European Society for Blood and Marrow Transplantation and the European Hematology Association.

A clinical update of the JULIET trial, as presented by Dr. Corradini and colleagues in a poster at the 2020 annual conference of the American Society of Hematology, showed a relapse-free probability of 60.4% at 24 and 30 months among 61 patients with an initial response.

The 12- and 36-month PFS rates as of February 2020, with median follow-up of 40.3 months, were 33% and 31%, respectively, and no new safety signals were identified, said Dr. Corradini, chair of hematology at the University of Milan.

Similarly, real-world data from the U.S. Lymphoma CAR T Consortium showing median PFS of 8.3 months at median follow-up of 12.9 months in 275 patients treated with axicabtagene ciloleucel (axi-cel; YESCARTA) were comparable with outcomes in the ZUMA-1 registrational trial, he noted.

An ongoing response was seen at 2 years in 39% of patients in ZUMA-1, and 3-year survival was 47%, according to an update reported at ASH 2019.

Of note, 43% of patients in the real-world study, which was published in the Journal of Clinical Oncology in September 2020, would not have met ZUMA-1 eligibility criteria because of comorbidities at the time of leukapheresis.
 

Predicting outcomes

The real-world data also demonstrated that performance status and lactate dehydrogenase (LDH) levels can predict outcomes: Patients with poor Eastern Cooperative Oncology Group performance status of 2-4 versus less than 2, and elevated LDH had shorter PFS and overall survival (OS) on both univariate and multivariate analysis, Dr. Corradini noted.

A subsequent multicenter study showed similar response rates of 70% and 68% in ZUMA-1-eligible and noneligible patients, but significantly improved DOR, PFS, and OS outcomes among the ZUMA-1-eligible patients.

The authors also looked for “clinical predictive factors or some easy clinical biomarkers to predict the outcomes in our patients receiving CAR T-cells,” and found that C-reactive protein levels of more than 30 mg at infusion were associated with poorer DOR, PFS, and OS, he said.

In 60 patients in another U.S. study of both tisa-cel- and axi-cel-treated patients at Memorial Sloan Kettering Cancer Center, 1-year event-free survival and OS were 40% and 69%, and Dr. Corradini’s experience with 55 patients at the University of Milan similarly showed 1-year PFS and OS of 40% and 70%, respectively.

“So all these studies support the notion that the results of CAR T-cells in real-world practice are durable for our patients, and are very similar to results obtained in the studies,” he said.

Other factors that have been shown to be associated with poor outcomes after CAR T-cell therapy include systemic bridging therapy, high metabolic tumor volume, and extranodal involvement; patients with these characteristics, along with those who have poor ECOG performance status or elevated LDH or CRP levels, do not comprise “a group to exclude from CAR T-cell therapy, but rather ... a group for whom there is an unmet need with our currently available treatments,” he said, adding: “So, it’s a group for which we have to do clinical trials and studies to improve the outcomes of our patient with large B-cell lymphomas.”

“These are all real-world data with commercially available products, he noted.
 

Product selection

Tisa-cel received Food and Drug Administration approval in 2017 and is used to treat relapsed or refractory acute lymphoblastic leukemia in those aged up to 25 years, and non-Hodgkin lymphoma that has relapsed or is refractory after at least two prior lines of therapy.

Axi-cel was also approved in 2017 for relapsed/refractory non-Hodgkin lymphoma, and in February 2021, after Dr. Corradini’s meeting presentation, the FDA granted a third approval to lisocabtagene maraleucel (liso-cel; Breyanzi) for this indication.

The information to date from both the trial and real-world settings are limited with respect to showing any differences in outcomes between the CAR T-cell products, but provide “an initial suggestion” that outcomes with tisa-cel and axi-cel are comparable, he said, adding that decisions should be strictly based on product registration data given the absence of reliable data for choosing one product over another.

Dr. Corradini reported honoraria and/or payment for travel and accommodations from Abbvie, Amgen, Bristol-Myers Squibb, Celgene, Daiichi Sankyo, and a number of other pharmaceutical companies.

sworcester@mdedge.com

Real-world experience with chimeric antigen receptor (CAR) T-cell therapies for large B-cell lymphomas compares favorably with experience in commercial and trial settings and provides new insights for predicting outcomes, according to Paolo Corradini, MD.

The 12-month duration of response (DOR) and progression-free survival (PFS) rates in 152 real-world patients treated with tisagenlecleucel (tisa-cel; Kymriah) for an approved indication were 48.4% and 26.4%, respectively, data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) and published in November 2020 in Blood Advances showed.

Those results are similar to the findings of the pivotal phase 2 JULIET trial evaluating tisa-cel in patients with DLBCL who relapsed or were refractory to at least two prior lines of therapy, Dr. Corradini said at the third European CAR T-cell Meeting, jointly sponsored by the European Society for Blood and Marrow Transplantation and the European Hematology Association.

A clinical update of the JULIET trial, as presented by Dr. Corradini and colleagues in a poster at the 2020 annual conference of the American Society of Hematology, showed a relapse-free probability of 60.4% at 24 and 30 months among 61 patients with an initial response.

The 12- and 36-month PFS rates as of February 2020, with median follow-up of 40.3 months, were 33% and 31%, respectively, and no new safety signals were identified, said Dr. Corradini, chair of hematology at the University of Milan.

Similarly, real-world data from the U.S. Lymphoma CAR T Consortium showing median PFS of 8.3 months at median follow-up of 12.9 months in 275 patients treated with axicabtagene ciloleucel (axi-cel; YESCARTA) were comparable with outcomes in the ZUMA-1 registrational trial, he noted.

An ongoing response was seen at 2 years in 39% of patients in ZUMA-1, and 3-year survival was 47%, according to an update reported at ASH 2019.

Of note, 43% of patients in the real-world study, which was published in the Journal of Clinical Oncology in September 2020, would not have met ZUMA-1 eligibility criteria because of comorbidities at the time of leukapheresis.
 

Predicting outcomes

The real-world data also demonstrated that performance status and lactate dehydrogenase (LDH) levels can predict outcomes: Patients with poor Eastern Cooperative Oncology Group performance status of 2-4 versus less than 2, and elevated LDH had shorter PFS and overall survival (OS) on both univariate and multivariate analysis, Dr. Corradini noted.

A subsequent multicenter study showed similar response rates of 70% and 68% in ZUMA-1-eligible and noneligible patients, but significantly improved DOR, PFS, and OS outcomes among the ZUMA-1-eligible patients.

The authors also looked for “clinical predictive factors or some easy clinical biomarkers to predict the outcomes in our patients receiving CAR T-cells,” and found that C-reactive protein levels of more than 30 mg at infusion were associated with poorer DOR, PFS, and OS, he said.

In 60 patients in another U.S. study of both tisa-cel- and axi-cel-treated patients at Memorial Sloan Kettering Cancer Center, 1-year event-free survival and OS were 40% and 69%, and Dr. Corradini’s experience with 55 patients at the University of Milan similarly showed 1-year PFS and OS of 40% and 70%, respectively.

“So all these studies support the notion that the results of CAR T-cells in real-world practice are durable for our patients, and are very similar to results obtained in the studies,” he said.

Other factors that have been shown to be associated with poor outcomes after CAR T-cell therapy include systemic bridging therapy, high metabolic tumor volume, and extranodal involvement; patients with these characteristics, along with those who have poor ECOG performance status or elevated LDH or CRP levels, do not comprise “a group to exclude from CAR T-cell therapy, but rather ... a group for whom there is an unmet need with our currently available treatments,” he said, adding: “So, it’s a group for which we have to do clinical trials and studies to improve the outcomes of our patient with large B-cell lymphomas.”

“These are all real-world data with commercially available products, he noted.
 

Product selection

Tisa-cel received Food and Drug Administration approval in 2017 and is used to treat relapsed or refractory acute lymphoblastic leukemia in those aged up to 25 years, and non-Hodgkin lymphoma that has relapsed or is refractory after at least two prior lines of therapy.

Axi-cel was also approved in 2017 for relapsed/refractory non-Hodgkin lymphoma, and in February 2021, after Dr. Corradini’s meeting presentation, the FDA granted a third approval to lisocabtagene maraleucel (liso-cel; Breyanzi) for this indication.

The information to date from both the trial and real-world settings are limited with respect to showing any differences in outcomes between the CAR T-cell products, but provide “an initial suggestion” that outcomes with tisa-cel and axi-cel are comparable, he said, adding that decisions should be strictly based on product registration data given the absence of reliable data for choosing one product over another.

Dr. Corradini reported honoraria and/or payment for travel and accommodations from Abbvie, Amgen, Bristol-Myers Squibb, Celgene, Daiichi Sankyo, and a number of other pharmaceutical companies.

sworcester@mdedge.com

Real-world experience with chimeric antigen receptor (CAR) T-cell therapies for large B-cell lymphomas compares favorably with experience in commercial and trial settings and provides new insights for predicting outcomes, according to Paolo Corradini, MD.

The 12-month duration of response (DOR) and progression-free survival (PFS) rates in 152 real-world patients treated with tisagenlecleucel (tisa-cel; Kymriah) for an approved indication were 48.4% and 26.4%, respectively, data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) and published in November 2020 in Blood Advances showed.

Those results are similar to the findings of the pivotal phase 2 JULIET trial evaluating tisa-cel in patients with DLBCL who relapsed or were refractory to at least two prior lines of therapy, Dr. Corradini said at the third European CAR T-cell Meeting, jointly sponsored by the European Society for Blood and Marrow Transplantation and the European Hematology Association.

A clinical update of the JULIET trial, as presented by Dr. Corradini and colleagues in a poster at the 2020 annual conference of the American Society of Hematology, showed a relapse-free probability of 60.4% at 24 and 30 months among 61 patients with an initial response.

The 12- and 36-month PFS rates as of February 2020, with median follow-up of 40.3 months, were 33% and 31%, respectively, and no new safety signals were identified, said Dr. Corradini, chair of hematology at the University of Milan.

Similarly, real-world data from the U.S. Lymphoma CAR T Consortium showing median PFS of 8.3 months at median follow-up of 12.9 months in 275 patients treated with axicabtagene ciloleucel (axi-cel; YESCARTA) were comparable with outcomes in the ZUMA-1 registrational trial, he noted.

An ongoing response was seen at 2 years in 39% of patients in ZUMA-1, and 3-year survival was 47%, according to an update reported at ASH 2019.

Of note, 43% of patients in the real-world study, which was published in the Journal of Clinical Oncology in September 2020, would not have met ZUMA-1 eligibility criteria because of comorbidities at the time of leukapheresis.
 

Predicting outcomes

The real-world data also demonstrated that performance status and lactate dehydrogenase (LDH) levels can predict outcomes: Patients with poor Eastern Cooperative Oncology Group performance status of 2-4 versus less than 2, and elevated LDH had shorter PFS and overall survival (OS) on both univariate and multivariate analysis, Dr. Corradini noted.

A subsequent multicenter study showed similar response rates of 70% and 68% in ZUMA-1-eligible and noneligible patients, but significantly improved DOR, PFS, and OS outcomes among the ZUMA-1-eligible patients.

The authors also looked for “clinical predictive factors or some easy clinical biomarkers to predict the outcomes in our patients receiving CAR T-cells,” and found that C-reactive protein levels of more than 30 mg at infusion were associated with poorer DOR, PFS, and OS, he said.

In 60 patients in another U.S. study of both tisa-cel- and axi-cel-treated patients at Memorial Sloan Kettering Cancer Center, 1-year event-free survival and OS were 40% and 69%, and Dr. Corradini’s experience with 55 patients at the University of Milan similarly showed 1-year PFS and OS of 40% and 70%, respectively.

“So all these studies support the notion that the results of CAR T-cells in real-world practice are durable for our patients, and are very similar to results obtained in the studies,” he said.

Other factors that have been shown to be associated with poor outcomes after CAR T-cell therapy include systemic bridging therapy, high metabolic tumor volume, and extranodal involvement; patients with these characteristics, along with those who have poor ECOG performance status or elevated LDH or CRP levels, do not comprise “a group to exclude from CAR T-cell therapy, but rather ... a group for whom there is an unmet need with our currently available treatments,” he said, adding: “So, it’s a group for which we have to do clinical trials and studies to improve the outcomes of our patient with large B-cell lymphomas.”

“These are all real-world data with commercially available products, he noted.
 

Product selection

Tisa-cel received Food and Drug Administration approval in 2017 and is used to treat relapsed or refractory acute lymphoblastic leukemia in those aged up to 25 years, and non-Hodgkin lymphoma that has relapsed or is refractory after at least two prior lines of therapy.

Axi-cel was also approved in 2017 for relapsed/refractory non-Hodgkin lymphoma, and in February 2021, after Dr. Corradini’s meeting presentation, the FDA granted a third approval to lisocabtagene maraleucel (liso-cel; Breyanzi) for this indication.

The information to date from both the trial and real-world settings are limited with respect to showing any differences in outcomes between the CAR T-cell products, but provide “an initial suggestion” that outcomes with tisa-cel and axi-cel are comparable, he said, adding that decisions should be strictly based on product registration data given the absence of reliable data for choosing one product over another.

Dr. Corradini reported honoraria and/or payment for travel and accommodations from Abbvie, Amgen, Bristol-Myers Squibb, Celgene, Daiichi Sankyo, and a number of other pharmaceutical companies.

sworcester@mdedge.com

Factor VIII replacement therapies and gene therapy may soon reduce the need for factor VIII concentrate in hemophilia A, but concentrate, a staple of therapy for hemophilia A since the 1950s, will still likely have a role in certain circumstances, a hematology expert said.

“Factor VIII concentrate therapy should still be available for hemophilia A therapy in the future, for the treatment of breakthrough bleeds in non–factor substitution therapy cases, to obtain retain reliable levels of laboratory-measurable hemostatic activity, for enhanced global access to hemophilia A therapy, and finally – and somewhat speculatively – to treat nonhemostatic functions if these are better defined in future preclinical investigations,” said David Lillicrap, MD, from Queen’s University in Kingston, Ont.

He discussed factor VIII biology and the pros and cons of alternatives to factor VIII concentrate at the annual congress of the European Association for Haemophilia and Allied Disorders.
 

One factor, multiple sources

It has been known since at least the late 1960s and early ‘70s that the liver is a significant source of factor VIII, primarily through liver sinusoidal endothelial cells (LSECs), but more recent studies have revealed other, nonhepatic sites of factor VIII expression, including the kidneys, lungs, spleen, lymph nodes, heat, intestines, skin an pulmonary artery, he said.

Endothelial cells proven to express factor VIII included LSECs, lymphatic endothelium, glomerular endothelium, and high endothelial venules.

“This information suggests that maybe a site of factor VIII synthesis could be important for a function that we do not yet appreciate. This is speculation, of course, but this is an unusual and enigmatic group of cells, and perhaps we’re missing something here that’s biologically important,” he said.

In addition to hemophilia, factor VIII deficiency may contribute to nonhemostatic pathologies, such as osteopenia/osteoporosis and hypertension, the latter possibly related to multiple renal bleeds or endothelial cell vasomotor dysfunction, he noted.

Despite decades-long experience with factor VIII concentrates, there are still uncertainties regarding optimal effective dosing, and about the mechanisms and management of factor VIII immunogenicity, both primary inhibitor development and immune tolerance induction, Dr. Lillicrap said.
 

Alternative therapies

Both factor VIII mimetics such as emicizumab (Hemlibra) and hemostasis rebalancing agents such as fitusiran, anti–tissue factor pathway inhibitor (TFPI) antibody and activated protein C serine protease inhibitor (APC serpin) require only infrequent subcutaneous administration, are efficacious in patients with factor VIII inhibitors, and are supported by either robust phase 3 data (in the case of mimetics) or evidence from late-phase clinical trials (in the case of the rebalancing agents).

However, “for the factor VIII mimetics we know that only partial factor VIII mimetic function, somewhere in the region of 10%-15% is obtained, and because of this, breakthrough bleeds do occur in these patients,” he said.

Additionally, the mimetics have been associated with rare, sometimes poorly explained thromboembolic complications, especially when they are given concurrently with activated prothrombin complex concentrate. Mimetic are also associated with infrequent development of antidrug antibodies, and “the fact that the factor VIII mimetic function is always ‘on’ is potentially a problem.”

For the rebalancing hemostasis agents, there are concerns about the ability to respond to dynamic challenges to the hemostatic system, such as sepsis or following trauma. These agents are also associated, albeit infrequently, with thromboembolic events, and they are somewhat difficult to monitor, he said.
 

Gene therapy

Gene therapy for hemophilia has the advantages of a single administration for a long-term effect, avoiding the peaks and troughs associated with substitution therapy, and the potential for being less immunogenic than factor VIII protein replacement.

The downside of gene therapy is that some patients may be ineligible for it because of preexisting immunity in about 50% of the population to the adeno-associated virus vectors used to carry the corrective gene.

Additional limitations are the occurrence in about 60% of patients of early although usually transient hepatotoxicity, significant variability in the factor levels ultimately attained, uncertainties about the durability of response, and the potential for long-term genotoxicity, Dr. Lillicrap said.
 

Tolerance for factor VIII

In the question and answer session following the presentation, session moderator Hervé Chambost, MD, from University Hospital La Timone and Aix-Marseille University, both in Marseille, France, asked whether there was a role for factor VIII and immune tolerance therapy (ITI) among patients who have been treated with non–factor replacement therapy.

“Is it important to have an antigenic pressure to maintain factor VIII or not for these patients?” he asked.

“I think this is a critical issue, and it’s an issue that we don’t yet have objective evidence for,” Dr. Lillicrap replied. “But the idea that we need to introduce some antigenic exposure to factor VIII in these individuals is a reasonable one, whether that be with intermittent exposure to factor VIII – weekly, monthly – we simply have no idea, but I think factor VIII will still be required in these patients because of breakthrough bleeds in patients who have been treated with non–factor replacement. So maintaining tolerance is a critical issue, and we need to develop maybe prospective trials to look at what those protocols are going to be to maintain tolerance in these patients.”

“As important, if not more so, is whether children should be tolerized at all,” commented Dan Hart, PhD, from Barts and the London School of Medicine and Dentistry, who also presented data during the session.

“The U.K. currently takes the view that, in children, new inhibitors arising may be delayed into the latter part of the first decade of their life if they have not had factors as their first choice but have had [replacement] on demand. I think we are heading into challenging times of understanding how to deliver ITI to larger children, how acceptable that is, and how we do it, but enabling [factor] VIII to be used long term rather than tolerating a chronic inhibitor I think is a really important issue where we need to head toward some consensus,” he said.

No funding source was reported. Dr. Lillicrap disclosed research funding from and advisory roles for several pharmaceutical companies. Dr. Hart disclosed grant/research support and speakers bureau activity for various companies. Dr. Chambost has previously reported no disclosures relevant to the topic at hand.

Factor VIII replacement therapies and gene therapy may soon reduce the need for factor VIII concentrate in hemophilia A, but concentrate, a staple of therapy for hemophilia A since the 1950s, will still likely have a role in certain circumstances, a hematology expert said.

“Factor VIII concentrate therapy should still be available for hemophilia A therapy in the future, for the treatment of breakthrough bleeds in non–factor substitution therapy cases, to obtain retain reliable levels of laboratory-measurable hemostatic activity, for enhanced global access to hemophilia A therapy, and finally – and somewhat speculatively – to treat nonhemostatic functions if these are better defined in future preclinical investigations,” said David Lillicrap, MD, from Queen’s University in Kingston, Ont.

He discussed factor VIII biology and the pros and cons of alternatives to factor VIII concentrate at the annual congress of the European Association for Haemophilia and Allied Disorders.
 

One factor, multiple sources

It has been known since at least the late 1960s and early ‘70s that the liver is a significant source of factor VIII, primarily through liver sinusoidal endothelial cells (LSECs), but more recent studies have revealed other, nonhepatic sites of factor VIII expression, including the kidneys, lungs, spleen, lymph nodes, heat, intestines, skin an pulmonary artery, he said.

Endothelial cells proven to express factor VIII included LSECs, lymphatic endothelium, glomerular endothelium, and high endothelial venules.

“This information suggests that maybe a site of factor VIII synthesis could be important for a function that we do not yet appreciate. This is speculation, of course, but this is an unusual and enigmatic group of cells, and perhaps we’re missing something here that’s biologically important,” he said.

In addition to hemophilia, factor VIII deficiency may contribute to nonhemostatic pathologies, such as osteopenia/osteoporosis and hypertension, the latter possibly related to multiple renal bleeds or endothelial cell vasomotor dysfunction, he noted.

Despite decades-long experience with factor VIII concentrates, there are still uncertainties regarding optimal effective dosing, and about the mechanisms and management of factor VIII immunogenicity, both primary inhibitor development and immune tolerance induction, Dr. Lillicrap said.
 

Alternative therapies

Both factor VIII mimetics such as emicizumab (Hemlibra) and hemostasis rebalancing agents such as fitusiran, anti–tissue factor pathway inhibitor (TFPI) antibody and activated protein C serine protease inhibitor (APC serpin) require only infrequent subcutaneous administration, are efficacious in patients with factor VIII inhibitors, and are supported by either robust phase 3 data (in the case of mimetics) or evidence from late-phase clinical trials (in the case of the rebalancing agents).

However, “for the factor VIII mimetics we know that only partial factor VIII mimetic function, somewhere in the region of 10%-15% is obtained, and because of this, breakthrough bleeds do occur in these patients,” he said.

Additionally, the mimetics have been associated with rare, sometimes poorly explained thromboembolic complications, especially when they are given concurrently with activated prothrombin complex concentrate. Mimetic are also associated with infrequent development of antidrug antibodies, and “the fact that the factor VIII mimetic function is always ‘on’ is potentially a problem.”

For the rebalancing hemostasis agents, there are concerns about the ability to respond to dynamic challenges to the hemostatic system, such as sepsis or following trauma. These agents are also associated, albeit infrequently, with thromboembolic events, and they are somewhat difficult to monitor, he said.
 

Gene therapy

Gene therapy for hemophilia has the advantages of a single administration for a long-term effect, avoiding the peaks and troughs associated with substitution therapy, and the potential for being less immunogenic than factor VIII protein replacement.

The downside of gene therapy is that some patients may be ineligible for it because of preexisting immunity in about 50% of the population to the adeno-associated virus vectors used to carry the corrective gene.

Additional limitations are the occurrence in about 60% of patients of early although usually transient hepatotoxicity, significant variability in the factor levels ultimately attained, uncertainties about the durability of response, and the potential for long-term genotoxicity, Dr. Lillicrap said.
 

Tolerance for factor VIII

In the question and answer session following the presentation, session moderator Hervé Chambost, MD, from University Hospital La Timone and Aix-Marseille University, both in Marseille, France, asked whether there was a role for factor VIII and immune tolerance therapy (ITI) among patients who have been treated with non–factor replacement therapy.

“Is it important to have an antigenic pressure to maintain factor VIII or not for these patients?” he asked.

“I think this is a critical issue, and it’s an issue that we don’t yet have objective evidence for,” Dr. Lillicrap replied. “But the idea that we need to introduce some antigenic exposure to factor VIII in these individuals is a reasonable one, whether that be with intermittent exposure to factor VIII – weekly, monthly – we simply have no idea, but I think factor VIII will still be required in these patients because of breakthrough bleeds in patients who have been treated with non–factor replacement. So maintaining tolerance is a critical issue, and we need to develop maybe prospective trials to look at what those protocols are going to be to maintain tolerance in these patients.”

“As important, if not more so, is whether children should be tolerized at all,” commented Dan Hart, PhD, from Barts and the London School of Medicine and Dentistry, who also presented data during the session.

“The U.K. currently takes the view that, in children, new inhibitors arising may be delayed into the latter part of the first decade of their life if they have not had factors as their first choice but have had [replacement] on demand. I think we are heading into challenging times of understanding how to deliver ITI to larger children, how acceptable that is, and how we do it, but enabling [factor] VIII to be used long term rather than tolerating a chronic inhibitor I think is a really important issue where we need to head toward some consensus,” he said.

No funding source was reported. Dr. Lillicrap disclosed research funding from and advisory roles for several pharmaceutical companies. Dr. Hart disclosed grant/research support and speakers bureau activity for various companies. Dr. Chambost has previously reported no disclosures relevant to the topic at hand.

Factor VIII replacement therapies and gene therapy may soon reduce the need for factor VIII concentrate in hemophilia A, but concentrate, a staple of therapy for hemophilia A since the 1950s, will still likely have a role in certain circumstances, a hematology expert said.

“Factor VIII concentrate therapy should still be available for hemophilia A therapy in the future, for the treatment of breakthrough bleeds in non–factor substitution therapy cases, to obtain retain reliable levels of laboratory-measurable hemostatic activity, for enhanced global access to hemophilia A therapy, and finally – and somewhat speculatively – to treat nonhemostatic functions if these are better defined in future preclinical investigations,” said David Lillicrap, MD, from Queen’s University in Kingston, Ont.

He discussed factor VIII biology and the pros and cons of alternatives to factor VIII concentrate at the annual congress of the European Association for Haemophilia and Allied Disorders.
 

One factor, multiple sources

It has been known since at least the late 1960s and early ‘70s that the liver is a significant source of factor VIII, primarily through liver sinusoidal endothelial cells (LSECs), but more recent studies have revealed other, nonhepatic sites of factor VIII expression, including the kidneys, lungs, spleen, lymph nodes, heat, intestines, skin an pulmonary artery, he said.

Endothelial cells proven to express factor VIII included LSECs, lymphatic endothelium, glomerular endothelium, and high endothelial venules.

“This information suggests that maybe a site of factor VIII synthesis could be important for a function that we do not yet appreciate. This is speculation, of course, but this is an unusual and enigmatic group of cells, and perhaps we’re missing something here that’s biologically important,” he said.

In addition to hemophilia, factor VIII deficiency may contribute to nonhemostatic pathologies, such as osteopenia/osteoporosis and hypertension, the latter possibly related to multiple renal bleeds or endothelial cell vasomotor dysfunction, he noted.

Despite decades-long experience with factor VIII concentrates, there are still uncertainties regarding optimal effective dosing, and about the mechanisms and management of factor VIII immunogenicity, both primary inhibitor development and immune tolerance induction, Dr. Lillicrap said.
 

Alternative therapies

Both factor VIII mimetics such as emicizumab (Hemlibra) and hemostasis rebalancing agents such as fitusiran, anti–tissue factor pathway inhibitor (TFPI) antibody and activated protein C serine protease inhibitor (APC serpin) require only infrequent subcutaneous administration, are efficacious in patients with factor VIII inhibitors, and are supported by either robust phase 3 data (in the case of mimetics) or evidence from late-phase clinical trials (in the case of the rebalancing agents).

However, “for the factor VIII mimetics we know that only partial factor VIII mimetic function, somewhere in the region of 10%-15% is obtained, and because of this, breakthrough bleeds do occur in these patients,” he said.

Additionally, the mimetics have been associated with rare, sometimes poorly explained thromboembolic complications, especially when they are given concurrently with activated prothrombin complex concentrate. Mimetic are also associated with infrequent development of antidrug antibodies, and “the fact that the factor VIII mimetic function is always ‘on’ is potentially a problem.”

For the rebalancing hemostasis agents, there are concerns about the ability to respond to dynamic challenges to the hemostatic system, such as sepsis or following trauma. These agents are also associated, albeit infrequently, with thromboembolic events, and they are somewhat difficult to monitor, he said.
 

Gene therapy

Gene therapy for hemophilia has the advantages of a single administration for a long-term effect, avoiding the peaks and troughs associated with substitution therapy, and the potential for being less immunogenic than factor VIII protein replacement.

The downside of gene therapy is that some patients may be ineligible for it because of preexisting immunity in about 50% of the population to the adeno-associated virus vectors used to carry the corrective gene.

Additional limitations are the occurrence in about 60% of patients of early although usually transient hepatotoxicity, significant variability in the factor levels ultimately attained, uncertainties about the durability of response, and the potential for long-term genotoxicity, Dr. Lillicrap said.
 

Tolerance for factor VIII

In the question and answer session following the presentation, session moderator Hervé Chambost, MD, from University Hospital La Timone and Aix-Marseille University, both in Marseille, France, asked whether there was a role for factor VIII and immune tolerance therapy (ITI) among patients who have been treated with non–factor replacement therapy.

“Is it important to have an antigenic pressure to maintain factor VIII or not for these patients?” he asked.

“I think this is a critical issue, and it’s an issue that we don’t yet have objective evidence for,” Dr. Lillicrap replied. “But the idea that we need to introduce some antigenic exposure to factor VIII in these individuals is a reasonable one, whether that be with intermittent exposure to factor VIII – weekly, monthly – we simply have no idea, but I think factor VIII will still be required in these patients because of breakthrough bleeds in patients who have been treated with non–factor replacement. So maintaining tolerance is a critical issue, and we need to develop maybe prospective trials to look at what those protocols are going to be to maintain tolerance in these patients.”

“As important, if not more so, is whether children should be tolerized at all,” commented Dan Hart, PhD, from Barts and the London School of Medicine and Dentistry, who also presented data during the session.

“The U.K. currently takes the view that, in children, new inhibitors arising may be delayed into the latter part of the first decade of their life if they have not had factors as their first choice but have had [replacement] on demand. I think we are heading into challenging times of understanding how to deliver ITI to larger children, how acceptable that is, and how we do it, but enabling [factor] VIII to be used long term rather than tolerating a chronic inhibitor I think is a really important issue where we need to head toward some consensus,” he said.

No funding source was reported. Dr. Lillicrap disclosed research funding from and advisory roles for several pharmaceutical companies. Dr. Hart disclosed grant/research support and speakers bureau activity for various companies. Dr. Chambost has previously reported no disclosures relevant to the topic at hand.

Immunogenicity of the high-dose influenza vaccine (HD IIV3) in patients with chronic lymphocytic leukemia (CLL) and monoclonal B-cell lymphocytosis (MBL, the precursor state to CLL) was found lower than reported in healthy adults according to a report in Vaccine.

In addition, immunogenicity to influenza B was found to be greater in those patients with MBL, compared with those with CLL.

“Acute and chronic leukemia patients hospitalized with influenza infection document a case fatality rate of 25%-37%,” according to Jennifer A. Whitaker, MD, of the Mayo Clinic, Rochester, Minn., and colleagues in pointing out the importance of their study.

The prospective pilot study assessed the humoral immune responses of patients to the 2013-2014 and 2014-2015 HD IIV3 (Fluzone High-Dose; Sanofi Pasteur), which was administered as part of routine clinical care in 30 patients (17 with previously untreated CLL and 13 with MBL). The median patient age was 69.5 years.

The primary outcomes were seroconversion and seroprotection, as measured by hemagglutination inhibition assay (HAI).
 

Lower response rate

At day 28 post vaccination, the seroprotection rates for the overall cohort were 19/30 (63.3%) for A/H1N1, 21/23 (91.3%) for A/H3N2, and 13/30 (43.3%) for influenza B. Patients with MBL achieved significantly higher day 28 HAI geometric mean titers (GMT), compared with CLL patients (54.1 vs. 12.1]; P = .01), In addition, MBL patients achieved higher day 28 seroprotection rates against the influenza B vaccine strain virus than did those with CLL (76.9% vs. 17.6%; P = .002). Seroconversion rates for the overall cohort were 3/30 (10%) for A/H1N1; 5/23 (21.7%) for A/H3N2; and 3/30 (10%) for influenza B. No individual with CLL demonstrated seroconversion for influenza B, according to the researchers.

“Our studies reinforce rigorous adherence to vaccination strategies in patients with hematologic malignancy, including those with CLL, given the increased risk of serious complications among those experiencing influenza infection,” the authors stated.

“Even suboptimal responses to influenza vaccination can provide partial protection, reduce hospitalization rates, and/or prevent serious disease complications. Given the recent major issue with novel and aggressive viruses such COVID-19, we absolutely must continue with larger prospective studies to confirm these findings and evaluate vaccine effectiveness in preventing influenza or other novel viruses in these populations,” the researchers concluded.

This study was funded by the National Institutes of Health. Dr. Whitaker reported having no disclosures. Several of the coauthors reported financial relationships with a variety of pharmaceutical and biotechnology companies.

mlesney@mdedge.com

Immunogenicity of the high-dose influenza vaccine (HD IIV3) in patients with chronic lymphocytic leukemia (CLL) and monoclonal B-cell lymphocytosis (MBL, the precursor state to CLL) was found lower than reported in healthy adults according to a report in Vaccine.

In addition, immunogenicity to influenza B was found to be greater in those patients with MBL, compared with those with CLL.

“Acute and chronic leukemia patients hospitalized with influenza infection document a case fatality rate of 25%-37%,” according to Jennifer A. Whitaker, MD, of the Mayo Clinic, Rochester, Minn., and colleagues in pointing out the importance of their study.

The prospective pilot study assessed the humoral immune responses of patients to the 2013-2014 and 2014-2015 HD IIV3 (Fluzone High-Dose; Sanofi Pasteur), which was administered as part of routine clinical care in 30 patients (17 with previously untreated CLL and 13 with MBL). The median patient age was 69.5 years.

The primary outcomes were seroconversion and seroprotection, as measured by hemagglutination inhibition assay (HAI).
 

Lower response rate

At day 28 post vaccination, the seroprotection rates for the overall cohort were 19/30 (63.3%) for A/H1N1, 21/23 (91.3%) for A/H3N2, and 13/30 (43.3%) for influenza B. Patients with MBL achieved significantly higher day 28 HAI geometric mean titers (GMT), compared with CLL patients (54.1 vs. 12.1]; P = .01), In addition, MBL patients achieved higher day 28 seroprotection rates against the influenza B vaccine strain virus than did those with CLL (76.9% vs. 17.6%; P = .002). Seroconversion rates for the overall cohort were 3/30 (10%) for A/H1N1; 5/23 (21.7%) for A/H3N2; and 3/30 (10%) for influenza B. No individual with CLL demonstrated seroconversion for influenza B, according to the researchers.

“Our studies reinforce rigorous adherence to vaccination strategies in patients with hematologic malignancy, including those with CLL, given the increased risk of serious complications among those experiencing influenza infection,” the authors stated.

“Even suboptimal responses to influenza vaccination can provide partial protection, reduce hospitalization rates, and/or prevent serious disease complications. Given the recent major issue with novel and aggressive viruses such COVID-19, we absolutely must continue with larger prospective studies to confirm these findings and evaluate vaccine effectiveness in preventing influenza or other novel viruses in these populations,” the researchers concluded.

This study was funded by the National Institutes of Health. Dr. Whitaker reported having no disclosures. Several of the coauthors reported financial relationships with a variety of pharmaceutical and biotechnology companies.

mlesney@mdedge.com

Immunogenicity of the high-dose influenza vaccine (HD IIV3) in patients with chronic lymphocytic leukemia (CLL) and monoclonal B-cell lymphocytosis (MBL, the precursor state to CLL) was found lower than reported in healthy adults according to a report in Vaccine.

In addition, immunogenicity to influenza B was found to be greater in those patients with MBL, compared with those with CLL.

“Acute and chronic leukemia patients hospitalized with influenza infection document a case fatality rate of 25%-37%,” according to Jennifer A. Whitaker, MD, of the Mayo Clinic, Rochester, Minn., and colleagues in pointing out the importance of their study.

The prospective pilot study assessed the humoral immune responses of patients to the 2013-2014 and 2014-2015 HD IIV3 (Fluzone High-Dose; Sanofi Pasteur), which was administered as part of routine clinical care in 30 patients (17 with previously untreated CLL and 13 with MBL). The median patient age was 69.5 years.

The primary outcomes were seroconversion and seroprotection, as measured by hemagglutination inhibition assay (HAI).
 

Lower response rate

At day 28 post vaccination, the seroprotection rates for the overall cohort were 19/30 (63.3%) for A/H1N1, 21/23 (91.3%) for A/H3N2, and 13/30 (43.3%) for influenza B. Patients with MBL achieved significantly higher day 28 HAI geometric mean titers (GMT), compared with CLL patients (54.1 vs. 12.1]; P = .01), In addition, MBL patients achieved higher day 28 seroprotection rates against the influenza B vaccine strain virus than did those with CLL (76.9% vs. 17.6%; P = .002). Seroconversion rates for the overall cohort were 3/30 (10%) for A/H1N1; 5/23 (21.7%) for A/H3N2; and 3/30 (10%) for influenza B. No individual with CLL demonstrated seroconversion for influenza B, according to the researchers.

“Our studies reinforce rigorous adherence to vaccination strategies in patients with hematologic malignancy, including those with CLL, given the increased risk of serious complications among those experiencing influenza infection,” the authors stated.

“Even suboptimal responses to influenza vaccination can provide partial protection, reduce hospitalization rates, and/or prevent serious disease complications. Given the recent major issue with novel and aggressive viruses such COVID-19, we absolutely must continue with larger prospective studies to confirm these findings and evaluate vaccine effectiveness in preventing influenza or other novel viruses in these populations,” the researchers concluded.

This study was funded by the National Institutes of Health. Dr. Whitaker reported having no disclosures. Several of the coauthors reported financial relationships with a variety of pharmaceutical and biotechnology companies.

mlesney@mdedge.com

The Food and Drug Administration has approved lisocabtagene maraleucel (Breyanzi), a chimeric antigen receptor (CAR) T-cell product for the treatment of adults with certain types of relapsed or refractory large B-cell lymphoma who relapse or fail to respond to at least two systemic treatments.

The new approval comes with a risk evaluation and mitigation strategy (REMS) because of the risk for serious adverse events, including cytokine release syndrome (CRS).

The product, from Juno Therapeutics, a Bristol Myers Squibb company, is the third gene therapy to receive FDA approval for non-Hodgkin lymphoma, including diffuse large B-cell lymphoma (DLBCL). DLBCL is the most common type of non-Hodgkin lymphoma in adults, accounting for about a third of the approximately 77,000 cases diagnosed each year in the United States.

The FDA previously granted Breyanzi orphan drug, regenerative medicine advanced therapy (RMAT), and breakthrough therapy designations. The product is the first therapy with an RMAT designation to be licensed by the agency.

The new approval is based on efficacy and safety demonstrated in a pivotal phase 1 trial of more than 250 adults with relapsed or refractory large B-cell lymphoma. The complete remission rate after treatment with Breyanzi was 54%. 

“Treatment with Breyanzi has the potential to cause severe side effects. The labeling carries a boxed warning for cytokine release syndrome (CRS), which is a systemic response to the activation and proliferation of CAR T cells, causing high fever and flu-like symptoms and neurologic toxicities,” the FDA explained. “Both CRS and neurological events can be life-threatening.”

Other side effects, which typically present within 1-2 weeks after treatment, include hypersensitivity reactions, serious infections, low blood cell counts, and a weakened immune system, but some side effects may occur later.

The REMS requires special certification for facilities that dispense the product and “specifies that patients be informed of the signs and symptoms of CRS and neurological toxicities following infusion – and of the importance of promptly returning to the treatment site if they develop fever or other adverse reactions after receiving treatment with Breyanzi,” the FDA noted.

Breyanzi is not indicated for patients with primary central nervous system lymphoma, the FDA noted.

Facility certification involves training to recognize and manage the risks of CRS and neurologic toxicities.

A postmarketing study to further evaluate the long-term safety will also be required.

A version of this article first appeared on Medscape.com.

The Food and Drug Administration has approved lisocabtagene maraleucel (Breyanzi), a chimeric antigen receptor (CAR) T-cell product for the treatment of adults with certain types of relapsed or refractory large B-cell lymphoma who relapse or fail to respond to at least two systemic treatments.

The new approval comes with a risk evaluation and mitigation strategy (REMS) because of the risk for serious adverse events, including cytokine release syndrome (CRS).

The product, from Juno Therapeutics, a Bristol Myers Squibb company, is the third gene therapy to receive FDA approval for non-Hodgkin lymphoma, including diffuse large B-cell lymphoma (DLBCL). DLBCL is the most common type of non-Hodgkin lymphoma in adults, accounting for about a third of the approximately 77,000 cases diagnosed each year in the United States.

The FDA previously granted Breyanzi orphan drug, regenerative medicine advanced therapy (RMAT), and breakthrough therapy designations. The product is the first therapy with an RMAT designation to be licensed by the agency.

The new approval is based on efficacy and safety demonstrated in a pivotal phase 1 trial of more than 250 adults with relapsed or refractory large B-cell lymphoma. The complete remission rate after treatment with Breyanzi was 54%. 

“Treatment with Breyanzi has the potential to cause severe side effects. The labeling carries a boxed warning for cytokine release syndrome (CRS), which is a systemic response to the activation and proliferation of CAR T cells, causing high fever and flu-like symptoms and neurologic toxicities,” the FDA explained. “Both CRS and neurological events can be life-threatening.”

Other side effects, which typically present within 1-2 weeks after treatment, include hypersensitivity reactions, serious infections, low blood cell counts, and a weakened immune system, but some side effects may occur later.

The REMS requires special certification for facilities that dispense the product and “specifies that patients be informed of the signs and symptoms of CRS and neurological toxicities following infusion – and of the importance of promptly returning to the treatment site if they develop fever or other adverse reactions after receiving treatment with Breyanzi,” the FDA noted.

Breyanzi is not indicated for patients with primary central nervous system lymphoma, the FDA noted.

Facility certification involves training to recognize and manage the risks of CRS and neurologic toxicities.

A postmarketing study to further evaluate the long-term safety will also be required.

A version of this article first appeared on Medscape.com.

The Food and Drug Administration has approved lisocabtagene maraleucel (Breyanzi), a chimeric antigen receptor (CAR) T-cell product for the treatment of adults with certain types of relapsed or refractory large B-cell lymphoma who relapse or fail to respond to at least two systemic treatments.

The new approval comes with a risk evaluation and mitigation strategy (REMS) because of the risk for serious adverse events, including cytokine release syndrome (CRS).

The product, from Juno Therapeutics, a Bristol Myers Squibb company, is the third gene therapy to receive FDA approval for non-Hodgkin lymphoma, including diffuse large B-cell lymphoma (DLBCL). DLBCL is the most common type of non-Hodgkin lymphoma in adults, accounting for about a third of the approximately 77,000 cases diagnosed each year in the United States.

The FDA previously granted Breyanzi orphan drug, regenerative medicine advanced therapy (RMAT), and breakthrough therapy designations. The product is the first therapy with an RMAT designation to be licensed by the agency.

The new approval is based on efficacy and safety demonstrated in a pivotal phase 1 trial of more than 250 adults with relapsed or refractory large B-cell lymphoma. The complete remission rate after treatment with Breyanzi was 54%. 

“Treatment with Breyanzi has the potential to cause severe side effects. The labeling carries a boxed warning for cytokine release syndrome (CRS), which is a systemic response to the activation and proliferation of CAR T cells, causing high fever and flu-like symptoms and neurologic toxicities,” the FDA explained. “Both CRS and neurological events can be life-threatening.”

Other side effects, which typically present within 1-2 weeks after treatment, include hypersensitivity reactions, serious infections, low blood cell counts, and a weakened immune system, but some side effects may occur later.

The REMS requires special certification for facilities that dispense the product and “specifies that patients be informed of the signs and symptoms of CRS and neurological toxicities following infusion – and of the importance of promptly returning to the treatment site if they develop fever or other adverse reactions after receiving treatment with Breyanzi,” the FDA noted.

Breyanzi is not indicated for patients with primary central nervous system lymphoma, the FDA noted.

Facility certification involves training to recognize and manage the risks of CRS and neurologic toxicities.

A postmarketing study to further evaluate the long-term safety will also be required.

A version of this article first appeared on Medscape.com.

For now at least, total body irradiation (TBI) plus etoposide remains the conditioning regimen of choice for children undergoing allogeneic hematopoietic stem cell transplant for acute lymphoblastic leukemia (ALL), according to an open-label, phase 3 trial from Europe.

The investigators sought to answer a question many physicians have raised: With improvements in human leukocyte antigen typing, better graft-versus-host disease prophylaxis, and other advances, can myeloablative chemotherapy conditioning replace TBI, which is more toxic?

The downstream effects of TBI can include secondary malignancies and cataracts, as well as impaired growth and impaired gonadal and cognitive function.

But the answer to that question is no, or at least, not yet.

The phase 3 trial included individuals with ALL who were aged 4-21 years at time of transplant. They were randomly assigned to receive either fractionated TBI at 12 Gy plus etoposide or chemotherapy based on a myeloablative regimen: fludarabine, thiotepa, and either busulfan or treosulfan.

The trial was stopped after 413 patients had undergone randomization – quite a bit short of the 1,000-patient goal. The trial was terminated because TBI proved clearly superior on an interim analysis at a median follow-up of 2.1 years.

The results showed that 72% of the TBI group – but only 51% of the chemotherapy arm – were relapse free at 2 years with no graft-versus-host disease (P = .0003).

The 2-year treatment-related mortality rate was 2% in the TBI group but 9% with chemotherapy conditioning (P = .03).

The study was published Feb. 1, 2020, in the Journal of Clinical Oncology.

“We recommend TBI plus etoposide conditioning for patients [aged over] 4 years old with high-risk ALL undergoing allogeneic HSCT [hematopoietic stem cell transplant],” they concluded. The investigators were led by Christina Peters, MD, a pediatrics professor at the St. Anna Children’s Cancer Research Institute, Vienna.

The benefits of TBI held on multivariate analysis and across subgroups, including children in their first and second remissions and among those with high-risk cytogenetics. Relapse risk factors, such as age at transplant, leukemic phenotype, and molecular aberrations, did not significantly affect outcomes, the authors reported.

Given that relapses plateaued with TBI at 2.5 years but were still on the upswing for patients who underwent chemoconditioning, “it is unlikely that secondary malignancies after TBI could jeopardize the survival advantage,” they wrote.

“So does this mean that the HCT community is forever chained to TBI as a standard of care? Certainly, it means that without very sound rationale to deviate, a TBI-based preparative regimen is the preferred therapy at present,” Michael Pulsipher, MD, head of blood and marrow transplantation at Children’s Hospital Los Angeles, commented in an accompanying editorial.

However, “there are approaches under study currently that may define patients who do not need TBI for high rates of cure,” he suggested. Those approaches include selecting patients with the deepest remissions and using KIR-favorable haplotype to harness natural killer cell activity.

“In our new world of chimeric antigen receptor T-cells and immunotherapies, surely we can find safer paths to success,” Dr. Pulsipher wrote.

With regard to patient selection, the investigators noted that a recent review that included more than 3,000 children with ALL found no overall survival benefit with TBI versus chemoconditioning for patients in first complete remission but worse outcomes with chemoconditioning among patients in second complete remission. “A similar trend was observed in our subgroup analyses; however, our study was not powered to assess statistical significance in a sample size of 413 patients,” they wrote.

Minimal residual disease did not influence survival outcomes, probably because the investigators were aggressive in inducing deep remission in their patients before transplant, so for most patients, MRD was undetectable or very low beforehand.

The study was funded by Amgen, Jazz Pharmaceuticals, Neovii, Medac, and others. Dr. Peters and coauthors, as well as Dr. Pulsipher have disclosed numerous ties with those and/or other companies.

A version of this article first appeared on Medscape.com.

For now at least, total body irradiation (TBI) plus etoposide remains the conditioning regimen of choice for children undergoing allogeneic hematopoietic stem cell transplant for acute lymphoblastic leukemia (ALL), according to an open-label, phase 3 trial from Europe.

The investigators sought to answer a question many physicians have raised: With improvements in human leukocyte antigen typing, better graft-versus-host disease prophylaxis, and other advances, can myeloablative chemotherapy conditioning replace TBI, which is more toxic?

The downstream effects of TBI can include secondary malignancies and cataracts, as well as impaired growth and impaired gonadal and cognitive function.

But the answer to that question is no, or at least, not yet.

The phase 3 trial included individuals with ALL who were aged 4-21 years at time of transplant. They were randomly assigned to receive either fractionated TBI at 12 Gy plus etoposide or chemotherapy based on a myeloablative regimen: fludarabine, thiotepa, and either busulfan or treosulfan.

The trial was stopped after 413 patients had undergone randomization – quite a bit short of the 1,000-patient goal. The trial was terminated because TBI proved clearly superior on an interim analysis at a median follow-up of 2.1 years.

The results showed that 72% of the TBI group – but only 51% of the chemotherapy arm – were relapse free at 2 years with no graft-versus-host disease (P = .0003).

The 2-year treatment-related mortality rate was 2% in the TBI group but 9% with chemotherapy conditioning (P = .03).

The study was published Feb. 1, 2020, in the Journal of Clinical Oncology.

“We recommend TBI plus etoposide conditioning for patients [aged over] 4 years old with high-risk ALL undergoing allogeneic HSCT [hematopoietic stem cell transplant],” they concluded. The investigators were led by Christina Peters, MD, a pediatrics professor at the St. Anna Children’s Cancer Research Institute, Vienna.

The benefits of TBI held on multivariate analysis and across subgroups, including children in their first and second remissions and among those with high-risk cytogenetics. Relapse risk factors, such as age at transplant, leukemic phenotype, and molecular aberrations, did not significantly affect outcomes, the authors reported.

Given that relapses plateaued with TBI at 2.5 years but were still on the upswing for patients who underwent chemoconditioning, “it is unlikely that secondary malignancies after TBI could jeopardize the survival advantage,” they wrote.

“So does this mean that the HCT community is forever chained to TBI as a standard of care? Certainly, it means that without very sound rationale to deviate, a TBI-based preparative regimen is the preferred therapy at present,” Michael Pulsipher, MD, head of blood and marrow transplantation at Children’s Hospital Los Angeles, commented in an accompanying editorial.

However, “there are approaches under study currently that may define patients who do not need TBI for high rates of cure,” he suggested. Those approaches include selecting patients with the deepest remissions and using KIR-favorable haplotype to harness natural killer cell activity.

“In our new world of chimeric antigen receptor T-cells and immunotherapies, surely we can find safer paths to success,” Dr. Pulsipher wrote.

With regard to patient selection, the investigators noted that a recent review that included more than 3,000 children with ALL found no overall survival benefit with TBI versus chemoconditioning for patients in first complete remission but worse outcomes with chemoconditioning among patients in second complete remission. “A similar trend was observed in our subgroup analyses; however, our study was not powered to assess statistical significance in a sample size of 413 patients,” they wrote.

Minimal residual disease did not influence survival outcomes, probably because the investigators were aggressive in inducing deep remission in their patients before transplant, so for most patients, MRD was undetectable or very low beforehand.

The study was funded by Amgen, Jazz Pharmaceuticals, Neovii, Medac, and others. Dr. Peters and coauthors, as well as Dr. Pulsipher have disclosed numerous ties with those and/or other companies.

A version of this article first appeared on Medscape.com.

For now at least, total body irradiation (TBI) plus etoposide remains the conditioning regimen of choice for children undergoing allogeneic hematopoietic stem cell transplant for acute lymphoblastic leukemia (ALL), according to an open-label, phase 3 trial from Europe.

The investigators sought to answer a question many physicians have raised: With improvements in human leukocyte antigen typing, better graft-versus-host disease prophylaxis, and other advances, can myeloablative chemotherapy conditioning replace TBI, which is more toxic?

The downstream effects of TBI can include secondary malignancies and cataracts, as well as impaired growth and impaired gonadal and cognitive function.

But the answer to that question is no, or at least, not yet.

The phase 3 trial included individuals with ALL who were aged 4-21 years at time of transplant. They were randomly assigned to receive either fractionated TBI at 12 Gy plus etoposide or chemotherapy based on a myeloablative regimen: fludarabine, thiotepa, and either busulfan or treosulfan.

The trial was stopped after 413 patients had undergone randomization – quite a bit short of the 1,000-patient goal. The trial was terminated because TBI proved clearly superior on an interim analysis at a median follow-up of 2.1 years.

The results showed that 72% of the TBI group – but only 51% of the chemotherapy arm – were relapse free at 2 years with no graft-versus-host disease (P = .0003).

The 2-year treatment-related mortality rate was 2% in the TBI group but 9% with chemotherapy conditioning (P = .03).

The study was published Feb. 1, 2020, in the Journal of Clinical Oncology.

“We recommend TBI plus etoposide conditioning for patients [aged over] 4 years old with high-risk ALL undergoing allogeneic HSCT [hematopoietic stem cell transplant],” they concluded. The investigators were led by Christina Peters, MD, a pediatrics professor at the St. Anna Children’s Cancer Research Institute, Vienna.

The benefits of TBI held on multivariate analysis and across subgroups, including children in their first and second remissions and among those with high-risk cytogenetics. Relapse risk factors, such as age at transplant, leukemic phenotype, and molecular aberrations, did not significantly affect outcomes, the authors reported.

Given that relapses plateaued with TBI at 2.5 years but were still on the upswing for patients who underwent chemoconditioning, “it is unlikely that secondary malignancies after TBI could jeopardize the survival advantage,” they wrote.

“So does this mean that the HCT community is forever chained to TBI as a standard of care? Certainly, it means that without very sound rationale to deviate, a TBI-based preparative regimen is the preferred therapy at present,” Michael Pulsipher, MD, head of blood and marrow transplantation at Children’s Hospital Los Angeles, commented in an accompanying editorial.

However, “there are approaches under study currently that may define patients who do not need TBI for high rates of cure,” he suggested. Those approaches include selecting patients with the deepest remissions and using KIR-favorable haplotype to harness natural killer cell activity.

“In our new world of chimeric antigen receptor T-cells and immunotherapies, surely we can find safer paths to success,” Dr. Pulsipher wrote.

With regard to patient selection, the investigators noted that a recent review that included more than 3,000 children with ALL found no overall survival benefit with TBI versus chemoconditioning for patients in first complete remission but worse outcomes with chemoconditioning among patients in second complete remission. “A similar trend was observed in our subgroup analyses; however, our study was not powered to assess statistical significance in a sample size of 413 patients,” they wrote.

Minimal residual disease did not influence survival outcomes, probably because the investigators were aggressive in inducing deep remission in their patients before transplant, so for most patients, MRD was undetectable or very low beforehand.

The study was funded by Amgen, Jazz Pharmaceuticals, Neovii, Medac, and others. Dr. Peters and coauthors, as well as Dr. Pulsipher have disclosed numerous ties with those and/or other companies.

A version of this article first appeared on Medscape.com.

Despite the high mortality rate for acquired hemophilia and the availability of suggested drug treatments, there are no randomized, controlled studies to inform doctors of the best therapies for their patients.

Immunoabsorption therapy (IA) is one such treatment that has been proposed as valid because of its ability to remove factor VIII clotting inhibitors from the bloodstream, but the data on its effectiveness are limited, according to Michael Esteves Pereira, of the Bern (Switzerland) University Hospital and the University of Bern, and colleagues.

In order to help answer the question of the benefits of IA for treating acquired hemophilia, the researchers performed a retrospective study assessing observational data as well as a systemic review and meta-analysis of published literature. They found evidence that the therapy was effective, but suggest that more confirmatory studies are needed, according to their report published online in Transfusion Medicine Reviews.

Data from the authors’ institution were available for 12 patients with acquired hemophilia treated since 2002. The median age was 76 years and four patients were women. The bleeding phenotype was extensive bruising and/or muscle hematomas in nine patients, gastrointestinal bleeding in two patients, and extensive bleeding after tooth extraction in one patient. Their data were added to the 10 published studies included in the literature review, resulting in a total of 118 patients.
 

Promising results

The author’s single institution analysis showed that IA treatment stopped bleeding in nine patients, while three patients did not respond. At 3 months, the median factor VIII increased to 80 IU/dL (considered complete remission) and the median inhibitor titer decreased to 0.15 BU/mL.

The pooled proportion of the meta-analysis patients treated with IA who achieved factor VIII recovery defined as complete remission was 86% (95% confidence interval, 76%-94%). The pooled proportion of patients with a reduction of the inhibitor titer was 95% (95% CI, 83%-100%), while the pooled mortality was 7% (95% CI, 0%-18%). Sensitivity analyses did not reveal any significant differences in retrospective studies or in studies using different absorbing agents.

In addition, there were few reported side effects, most of which were considered mild, according to the researchers. These included nausea and vomiting, paresthesia, and mild hypotension. The authors did suggest that, as a central venous catheter is often used, patients were exposed to an added risk of bleeding and infection.

“At our institution, IA is considered on a case-by-case base rather than a strict cutoff level. Strong arguments are life-threatening bleeding complications, inhibitor titers 20 BU/mL or greater, or failed immunosuppressive treatment with corticosteroids and cyclophosphamide using an established dose regimen,” the researchers stated.

“Even though firm evidence is still lacking and the actual ‘added value’ of IA cannot be adequately assessed, we believe that IA might be a beneficial adjunctive treatment modality in some patients with acquired hemophilia. It was associated with a complete remission in the majority of patients, most of whom are at high risk of bleeding,” the researchers added.

The authors reported that they had no relevant disclosures.

mlesney@mdedge.com

Despite the high mortality rate for acquired hemophilia and the availability of suggested drug treatments, there are no randomized, controlled studies to inform doctors of the best therapies for their patients.

Immunoabsorption therapy (IA) is one such treatment that has been proposed as valid because of its ability to remove factor VIII clotting inhibitors from the bloodstream, but the data on its effectiveness are limited, according to Michael Esteves Pereira, of the Bern (Switzerland) University Hospital and the University of Bern, and colleagues.

In order to help answer the question of the benefits of IA for treating acquired hemophilia, the researchers performed a retrospective study assessing observational data as well as a systemic review and meta-analysis of published literature. They found evidence that the therapy was effective, but suggest that more confirmatory studies are needed, according to their report published online in Transfusion Medicine Reviews.

Data from the authors’ institution were available for 12 patients with acquired hemophilia treated since 2002. The median age was 76 years and four patients were women. The bleeding phenotype was extensive bruising and/or muscle hematomas in nine patients, gastrointestinal bleeding in two patients, and extensive bleeding after tooth extraction in one patient. Their data were added to the 10 published studies included in the literature review, resulting in a total of 118 patients.
 

Promising results

The author’s single institution analysis showed that IA treatment stopped bleeding in nine patients, while three patients did not respond. At 3 months, the median factor VIII increased to 80 IU/dL (considered complete remission) and the median inhibitor titer decreased to 0.15 BU/mL.

The pooled proportion of the meta-analysis patients treated with IA who achieved factor VIII recovery defined as complete remission was 86% (95% confidence interval, 76%-94%). The pooled proportion of patients with a reduction of the inhibitor titer was 95% (95% CI, 83%-100%), while the pooled mortality was 7% (95% CI, 0%-18%). Sensitivity analyses did not reveal any significant differences in retrospective studies or in studies using different absorbing agents.

In addition, there were few reported side effects, most of which were considered mild, according to the researchers. These included nausea and vomiting, paresthesia, and mild hypotension. The authors did suggest that, as a central venous catheter is often used, patients were exposed to an added risk of bleeding and infection.

“At our institution, IA is considered on a case-by-case base rather than a strict cutoff level. Strong arguments are life-threatening bleeding complications, inhibitor titers 20 BU/mL or greater, or failed immunosuppressive treatment with corticosteroids and cyclophosphamide using an established dose regimen,” the researchers stated.

“Even though firm evidence is still lacking and the actual ‘added value’ of IA cannot be adequately assessed, we believe that IA might be a beneficial adjunctive treatment modality in some patients with acquired hemophilia. It was associated with a complete remission in the majority of patients, most of whom are at high risk of bleeding,” the researchers added.

The authors reported that they had no relevant disclosures.

mlesney@mdedge.com

Despite the high mortality rate for acquired hemophilia and the availability of suggested drug treatments, there are no randomized, controlled studies to inform doctors of the best therapies for their patients.

Immunoabsorption therapy (IA) is one such treatment that has been proposed as valid because of its ability to remove factor VIII clotting inhibitors from the bloodstream, but the data on its effectiveness are limited, according to Michael Esteves Pereira, of the Bern (Switzerland) University Hospital and the University of Bern, and colleagues.

In order to help answer the question of the benefits of IA for treating acquired hemophilia, the researchers performed a retrospective study assessing observational data as well as a systemic review and meta-analysis of published literature. They found evidence that the therapy was effective, but suggest that more confirmatory studies are needed, according to their report published online in Transfusion Medicine Reviews.

Data from the authors’ institution were available for 12 patients with acquired hemophilia treated since 2002. The median age was 76 years and four patients were women. The bleeding phenotype was extensive bruising and/or muscle hematomas in nine patients, gastrointestinal bleeding in two patients, and extensive bleeding after tooth extraction in one patient. Their data were added to the 10 published studies included in the literature review, resulting in a total of 118 patients.
 

Promising results

The author’s single institution analysis showed that IA treatment stopped bleeding in nine patients, while three patients did not respond. At 3 months, the median factor VIII increased to 80 IU/dL (considered complete remission) and the median inhibitor titer decreased to 0.15 BU/mL.

The pooled proportion of the meta-analysis patients treated with IA who achieved factor VIII recovery defined as complete remission was 86% (95% confidence interval, 76%-94%). The pooled proportion of patients with a reduction of the inhibitor titer was 95% (95% CI, 83%-100%), while the pooled mortality was 7% (95% CI, 0%-18%). Sensitivity analyses did not reveal any significant differences in retrospective studies or in studies using different absorbing agents.

In addition, there were few reported side effects, most of which were considered mild, according to the researchers. These included nausea and vomiting, paresthesia, and mild hypotension. The authors did suggest that, as a central venous catheter is often used, patients were exposed to an added risk of bleeding and infection.

“At our institution, IA is considered on a case-by-case base rather than a strict cutoff level. Strong arguments are life-threatening bleeding complications, inhibitor titers 20 BU/mL or greater, or failed immunosuppressive treatment with corticosteroids and cyclophosphamide using an established dose regimen,” the researchers stated.

“Even though firm evidence is still lacking and the actual ‘added value’ of IA cannot be adequately assessed, we believe that IA might be a beneficial adjunctive treatment modality in some patients with acquired hemophilia. It was associated with a complete remission in the majority of patients, most of whom are at high risk of bleeding,” the researchers added.

The authors reported that they had no relevant disclosures.

mlesney@mdedge.com

Background: The PARTHENON clinical development program has conducted several clinical trials to assess the effectiveness of ticagrelor in multiple cardiovascular diseases. A prior study revealed the addition of ticagrelor to aspirin in patients with history of MI showed a small benefit in cardiovascular outcomes but with increased bleeding risk. While this effect was seen in both patients with and without diabetes, the absolute benefit for those with diabetes was considered large because of their higher baseline risk. Given this, investigators wanted to know if addition of ticagrelor to aspirin could also be beneficial in diabetics with known coronary disease but without history of MI or stroke.

Further studies into risk stratification based on prothrombotic versus bleeding risk could be beneficial in identifying specific groups that could benefit from DAPT. Conclusions from this study suggest the benefit of DAPT in diabetics does not outweigh its risk.

Bottom line: Addition of ticagrelor to aspirin in diabetic patients with stable coronary disease and no prior MI or stroke is not recommended.

Citation: Steg PG et al. Ticagrelor in patients with stable coronary disease and diabetes. N Eng J Med. 2019 Oct 3;381(14):1309-20.

Dr. Breitbach is assistant professor of medicine, hospital medicine, at the Rocky Mountain Veterans Affairs Regional Medical Center, Aurora, Colo.

Background: The PARTHENON clinical development program has conducted several clinical trials to assess the effectiveness of ticagrelor in multiple cardiovascular diseases. A prior study revealed the addition of ticagrelor to aspirin in patients with history of MI showed a small benefit in cardiovascular outcomes but with increased bleeding risk. While this effect was seen in both patients with and without diabetes, the absolute benefit for those with diabetes was considered large because of their higher baseline risk. Given this, investigators wanted to know if addition of ticagrelor to aspirin could also be beneficial in diabetics with known coronary disease but without history of MI or stroke.

Further studies into risk stratification based on prothrombotic versus bleeding risk could be beneficial in identifying specific groups that could benefit from DAPT. Conclusions from this study suggest the benefit of DAPT in diabetics does not outweigh its risk.

Bottom line: Addition of ticagrelor to aspirin in diabetic patients with stable coronary disease and no prior MI or stroke is not recommended.

Citation: Steg PG et al. Ticagrelor in patients with stable coronary disease and diabetes. N Eng J Med. 2019 Oct 3;381(14):1309-20.

Dr. Breitbach is assistant professor of medicine, hospital medicine, at the Rocky Mountain Veterans Affairs Regional Medical Center, Aurora, Colo.

Background: The PARTHENON clinical development program has conducted several clinical trials to assess the effectiveness of ticagrelor in multiple cardiovascular diseases. A prior study revealed the addition of ticagrelor to aspirin in patients with history of MI showed a small benefit in cardiovascular outcomes but with increased bleeding risk. While this effect was seen in both patients with and without diabetes, the absolute benefit for those with diabetes was considered large because of their higher baseline risk. Given this, investigators wanted to know if addition of ticagrelor to aspirin could also be beneficial in diabetics with known coronary disease but without history of MI or stroke.

Further studies into risk stratification based on prothrombotic versus bleeding risk could be beneficial in identifying specific groups that could benefit from DAPT. Conclusions from this study suggest the benefit of DAPT in diabetics does not outweigh its risk.

Bottom line: Addition of ticagrelor to aspirin in diabetic patients with stable coronary disease and no prior MI or stroke is not recommended.

Citation: Steg PG et al. Ticagrelor in patients with stable coronary disease and diabetes. N Eng J Med. 2019 Oct 3;381(14):1309-20.

Dr. Breitbach is assistant professor of medicine, hospital medicine, at the Rocky Mountain Veterans Affairs Regional Medical Center, Aurora, Colo.