Anemia

ORLANDO – Sevuparin, a novel nonanticoagulant heparinoid drug, showed no efficacy for acute vaso-occlusive crisis (VOC) in patients with sickle cell disease (SCD) in the randomized, controlled, phase 2 TVOC01 trial, but its promising safety and broad mechanism of action warrant further exploration in the prodromal VOC setting, according to investigators.

Dr_Microbe/Thinkstock

Time to VOC resolution – the primary study endpoint – was similar at about 168 hours in 71 hospitalized patients randomized to receive sevuparin and in 76 who received placebo (intention-to-treat hazard ratio, 0.89), Bart J. Biemond, MD, explained during a presentation of the findings at the annual meeting of the American Society of Hematology.

A per-protocol analysis based on the 69 and 75 patients dosed in the treatment and placebo arms, respectively, showed a similar result (HR, 0.81), said Dr. Biemond of the department of clinical hematology, Amsterdam UMC, Academic Medical Center, the Netherlands.

Secondary endpoints, including mean change in pain intensity from baseline on a visual analogue scale (VAS), duration of severest pain measured as time to achieve a 30% reduction in VAS score from baseline, and cumulative use of parenteral opioids, also did not differ between the treatment and placebo arms, he added.

Patients in the global, double-blind, multicenter trial were aged 12-50 years (median, 22 years) with any type of SCD. They were enrolled from 16 sites in 7 countries to receive a loading dose of 3 mg/kg of sevuparin and continuous 18 mg/kg per day infusions or placebo. Patients in both arms also received standard-of-care and parenteral opioid therapy.

The groups were generally balanced with respect to demographic and baseline characteristics, Dr. Biemond said, noting that the treatment was safe: No serious adverse events occurred, and any mild-to-moderate adverse events were transient.

The findings were disappointing given the lack of approved treatment options other than pain management for acute VOC in hospitalized patients with SCD, and they were somewhat surprising given that preclinical and clinical data in recent years have demonstrated that “you can actually prevent those crises by antiadhesive strategies,” he said.

“So we hypothesized that, if you perform such an antiadhesive strategy in a patient already having a crisis and admitted in the hospital, you may shorten their period of admission and perhaps also shorten the severity of their pain,” he said.

In fact, a single-center, randomized, controlled trial conducted by Qari et al. in 2007 (Thromb Haemost. 2007 Aug;98[2]:392-6) showed that full-dose tinzaparin reduced pain severity and duration of admission among sickle cell patients with acute VOC – perhaps because of the antiadhesive properties of heparin – but that study was never repeated, Dr. Biemond said, noting that those antiadhesive properties have been well documented in animal studies.

“Heparin is able to inhibit P-selectin, L-selectin, thrombospondin, fibronectin, and von Willebrand activity, which are all involved in vaso-occlusion in patients with sickle cell disease, and very likely also involved during a vaso-occlusive crisis,” he explained, adding that sevuparin, a low-molecular-weight heparin without functional antithrombin binding domain, seemed to be a good candidate for testing that hypothesis.

“It has no anticoagulant effects on factor Xa and IIa,” he said. “It retains, however, its antiadhesive and antiaggregation properties.”

Since it has no anticoagulation activity, it can be dosed at up to 20-fold the therapeutic dose of low-molecular-weight heparin to optimize the antiadhesive effects, he noted.

However, the data indicate that “antiadhesive therapies are clearly not effective in patients with vaso-occlusive crisis,” he said, noting that this was also affirmed by a similar 2019 study of the investigational panselectin inhibitor rivipansel, as reported in a Pfizer press release.

Intriguingly, the difference between the current study and the 2007 study by Qari et al. raises questions about whether anticoagulation, rather than antiadhesion, helped resolve VOC in that study, he said, noting that future studies should focus on whether that is the case.

As for the role of antiadhesive therapy, the mode of action of sevuparin and the current findings taken together suggest that future studies should also assess whether it can be used to prevent VOC.

“Perhaps sevuparin could be administered to patients in a prodromal phase – just before a real vaso-occlusive crisis appears – to prevent such a crisis from happening,” he said. “It would be interesting to use the drug that way.”

Dr. Biemond reported research funding from Sanquin and honoraria from Novartis and GBT.

[email protected]

SOURCE: Biemond B et al. ASH 2019, Abstract 614.

ORLANDO – Sevuparin, a novel nonanticoagulant heparinoid drug, showed no efficacy for acute vaso-occlusive crisis (VOC) in patients with sickle cell disease (SCD) in the randomized, controlled, phase 2 TVOC01 trial, but its promising safety and broad mechanism of action warrant further exploration in the prodromal VOC setting, according to investigators.

Dr_Microbe/Thinkstock

Time to VOC resolution – the primary study endpoint – was similar at about 168 hours in 71 hospitalized patients randomized to receive sevuparin and in 76 who received placebo (intention-to-treat hazard ratio, 0.89), Bart J. Biemond, MD, explained during a presentation of the findings at the annual meeting of the American Society of Hematology.

A per-protocol analysis based on the 69 and 75 patients dosed in the treatment and placebo arms, respectively, showed a similar result (HR, 0.81), said Dr. Biemond of the department of clinical hematology, Amsterdam UMC, Academic Medical Center, the Netherlands.

Secondary endpoints, including mean change in pain intensity from baseline on a visual analogue scale (VAS), duration of severest pain measured as time to achieve a 30% reduction in VAS score from baseline, and cumulative use of parenteral opioids, also did not differ between the treatment and placebo arms, he added.

Patients in the global, double-blind, multicenter trial were aged 12-50 years (median, 22 years) with any type of SCD. They were enrolled from 16 sites in 7 countries to receive a loading dose of 3 mg/kg of sevuparin and continuous 18 mg/kg per day infusions or placebo. Patients in both arms also received standard-of-care and parenteral opioid therapy.

The groups were generally balanced with respect to demographic and baseline characteristics, Dr. Biemond said, noting that the treatment was safe: No serious adverse events occurred, and any mild-to-moderate adverse events were transient.

The findings were disappointing given the lack of approved treatment options other than pain management for acute VOC in hospitalized patients with SCD, and they were somewhat surprising given that preclinical and clinical data in recent years have demonstrated that “you can actually prevent those crises by antiadhesive strategies,” he said.

“So we hypothesized that, if you perform such an antiadhesive strategy in a patient already having a crisis and admitted in the hospital, you may shorten their period of admission and perhaps also shorten the severity of their pain,” he said.

In fact, a single-center, randomized, controlled trial conducted by Qari et al. in 2007 (Thromb Haemost. 2007 Aug;98[2]:392-6) showed that full-dose tinzaparin reduced pain severity and duration of admission among sickle cell patients with acute VOC – perhaps because of the antiadhesive properties of heparin – but that study was never repeated, Dr. Biemond said, noting that those antiadhesive properties have been well documented in animal studies.

“Heparin is able to inhibit P-selectin, L-selectin, thrombospondin, fibronectin, and von Willebrand activity, which are all involved in vaso-occlusion in patients with sickle cell disease, and very likely also involved during a vaso-occlusive crisis,” he explained, adding that sevuparin, a low-molecular-weight heparin without functional antithrombin binding domain, seemed to be a good candidate for testing that hypothesis.

“It has no anticoagulant effects on factor Xa and IIa,” he said. “It retains, however, its antiadhesive and antiaggregation properties.”

Since it has no anticoagulation activity, it can be dosed at up to 20-fold the therapeutic dose of low-molecular-weight heparin to optimize the antiadhesive effects, he noted.

However, the data indicate that “antiadhesive therapies are clearly not effective in patients with vaso-occlusive crisis,” he said, noting that this was also affirmed by a similar 2019 study of the investigational panselectin inhibitor rivipansel, as reported in a Pfizer press release.

Intriguingly, the difference between the current study and the 2007 study by Qari et al. raises questions about whether anticoagulation, rather than antiadhesion, helped resolve VOC in that study, he said, noting that future studies should focus on whether that is the case.

As for the role of antiadhesive therapy, the mode of action of sevuparin and the current findings taken together suggest that future studies should also assess whether it can be used to prevent VOC.

“Perhaps sevuparin could be administered to patients in a prodromal phase – just before a real vaso-occlusive crisis appears – to prevent such a crisis from happening,” he said. “It would be interesting to use the drug that way.”

Dr. Biemond reported research funding from Sanquin and honoraria from Novartis and GBT.

[email protected]

SOURCE: Biemond B et al. ASH 2019, Abstract 614.

ORLANDO – Sevuparin, a novel nonanticoagulant heparinoid drug, showed no efficacy for acute vaso-occlusive crisis (VOC) in patients with sickle cell disease (SCD) in the randomized, controlled, phase 2 TVOC01 trial, but its promising safety and broad mechanism of action warrant further exploration in the prodromal VOC setting, according to investigators.

Dr_Microbe/Thinkstock

Time to VOC resolution – the primary study endpoint – was similar at about 168 hours in 71 hospitalized patients randomized to receive sevuparin and in 76 who received placebo (intention-to-treat hazard ratio, 0.89), Bart J. Biemond, MD, explained during a presentation of the findings at the annual meeting of the American Society of Hematology.

A per-protocol analysis based on the 69 and 75 patients dosed in the treatment and placebo arms, respectively, showed a similar result (HR, 0.81), said Dr. Biemond of the department of clinical hematology, Amsterdam UMC, Academic Medical Center, the Netherlands.

Secondary endpoints, including mean change in pain intensity from baseline on a visual analogue scale (VAS), duration of severest pain measured as time to achieve a 30% reduction in VAS score from baseline, and cumulative use of parenteral opioids, also did not differ between the treatment and placebo arms, he added.

Patients in the global, double-blind, multicenter trial were aged 12-50 years (median, 22 years) with any type of SCD. They were enrolled from 16 sites in 7 countries to receive a loading dose of 3 mg/kg of sevuparin and continuous 18 mg/kg per day infusions or placebo. Patients in both arms also received standard-of-care and parenteral opioid therapy.

The groups were generally balanced with respect to demographic and baseline characteristics, Dr. Biemond said, noting that the treatment was safe: No serious adverse events occurred, and any mild-to-moderate adverse events were transient.

The findings were disappointing given the lack of approved treatment options other than pain management for acute VOC in hospitalized patients with SCD, and they were somewhat surprising given that preclinical and clinical data in recent years have demonstrated that “you can actually prevent those crises by antiadhesive strategies,” he said.

“So we hypothesized that, if you perform such an antiadhesive strategy in a patient already having a crisis and admitted in the hospital, you may shorten their period of admission and perhaps also shorten the severity of their pain,” he said.

In fact, a single-center, randomized, controlled trial conducted by Qari et al. in 2007 (Thromb Haemost. 2007 Aug;98[2]:392-6) showed that full-dose tinzaparin reduced pain severity and duration of admission among sickle cell patients with acute VOC – perhaps because of the antiadhesive properties of heparin – but that study was never repeated, Dr. Biemond said, noting that those antiadhesive properties have been well documented in animal studies.

“Heparin is able to inhibit P-selectin, L-selectin, thrombospondin, fibronectin, and von Willebrand activity, which are all involved in vaso-occlusion in patients with sickle cell disease, and very likely also involved during a vaso-occlusive crisis,” he explained, adding that sevuparin, a low-molecular-weight heparin without functional antithrombin binding domain, seemed to be a good candidate for testing that hypothesis.

“It has no anticoagulant effects on factor Xa and IIa,” he said. “It retains, however, its antiadhesive and antiaggregation properties.”

Since it has no anticoagulation activity, it can be dosed at up to 20-fold the therapeutic dose of low-molecular-weight heparin to optimize the antiadhesive effects, he noted.

However, the data indicate that “antiadhesive therapies are clearly not effective in patients with vaso-occlusive crisis,” he said, noting that this was also affirmed by a similar 2019 study of the investigational panselectin inhibitor rivipansel, as reported in a Pfizer press release.

Intriguingly, the difference between the current study and the 2007 study by Qari et al. raises questions about whether anticoagulation, rather than antiadhesion, helped resolve VOC in that study, he said, noting that future studies should focus on whether that is the case.

As for the role of antiadhesive therapy, the mode of action of sevuparin and the current findings taken together suggest that future studies should also assess whether it can be used to prevent VOC.

“Perhaps sevuparin could be administered to patients in a prodromal phase – just before a real vaso-occlusive crisis appears – to prevent such a crisis from happening,” he said. “It would be interesting to use the drug that way.”

Dr. Biemond reported research funding from Sanquin and honoraria from Novartis and GBT.

[email protected]

SOURCE: Biemond B et al. ASH 2019, Abstract 614.

The introduction of eculizumab, a monoclonal antibody targeting C5 of the complement cascade, revolutionized the treatment of paroxysmal nocturnal hemoglobinuria (PNH), a rare hematologic disorder characterized by complement-mediated intravascular hemolysis, bone marrow failure, and thrombophilia. Treatment options for PNH were limited before eculizumab was approved by the Food and Drug Administration in 2007.

Its use resulted in the inhibition of intravascular hemolysis, hemoglobin stabilization, and substantial reductions in transfusion requirements. Moreover, eculizumab had the unexpected effect of reducing the risk of thromboembolic complications, the most severe complication of PNH. Patients treated with eculizumab experienced fewer thrombotic events (4%), compared with historical cohorts (27%). Importantly, 5-year overall survival rates for patients with PNH taking eculizumab improved more than 90%, compared wity the 80% reported historically.

More than 10 years later, we are tasked with assessing the impact of this drug. Unquestionably, eculizumab has done more for PNH than we could have hoped for. However, 10 years of additional data reveal the limitations of this groundbreaking therapy. Despite the overall sustained response and survival benefit, hematologic response remains variable. Complete normalization of hemoglobin occurs in less than one-third of patients. Transfusion requirements persist in many patients. Residual anemia during eculizumab therapy is at least partly attributed to bone marrow failure, a feature the complement inhibition does not address. Still, pharmacokinetic limitations of the drug also contribute to the lack of complete responses. There is residual intravascular hemolysis because of insufficient inhibition of C5 and the emergence of C3-mediated extravascular hemolysis constitutes an unanticipated mechanistic complication of all C5-mediated therapies.

The last few years have seen a surge in novel anticomplement agents, which improve upon the already well-established inhibition of C5 but also explore the efficacy of targeting earlier aspects of the complement pathway. During the American Society of Hematology (ASH) annual meeting, we had exciting updates on some of the promising new kids on the block.

Ravulizumab, the newest C5 monoclonal antibody approved by the FDA for PNH, displays more robust C5 inhibition, thereby reducing the breakthrough hemolysis still seen with eculizumab use. Crovalimab, also an anti-C5 humanized antibody, is engineered with Sequential Monoclonal Antibody Recycling Technology that improves the half-life of the drug and facilitates subcutaneous dosing while still achieving complete C5 inhibition. Some of the most exciting data is on danicopan, a small-molecule factor D inhibitor that targets the alternative pathway thereby inhibiting C3 convertase and blocking extravascular hemolysis. It has shown promise as a stand-alone agent, as well as with combined C5 inhibition, while promising safety, a reasonable concern as we explore the long-term risks of targeting the proximal complement pathway.

I was recently asked to comment on how the new complement inhibitors are addressing unmet needs in PNH. While the recent presentations at ASH demonstrate an improvement on the efficacy of C5 inhibition, pharmacokinetics, and drug delivery – all which translate to improved hemoglobin and reduced breakthrough hemolysis for PNH patients – I am most excited at the promise this new generation of drugs holds for other diseases. Since its approval for PNH, eculizumab has also been approved for use in atypical hemolytic uremic syndrome (aHUS), myasthenia gravis, and neuromyelitis optica spectrum disorder.

Perhaps the greatest potential I envision for the new generation of drugs is in aHUS, a chronic disease characterized by hemolytic anemia, thrombocytopenia, and end-stage renal disease that cannot be cured with renal transplantation. The pathophysiology involves dysregulation of complement activation because of genetic mutations or autoantibodies to key proteins in the complement cascade. Though we have experienced some success with eculizumab, responses can be incomplete, particularly in patients with C5 mutations. The newer drugs offer the opportunity to inhibit complement activation at both proximal and distal aspects of the cascade, which may prove ideal in a disease in which the affected protein is not consistent. Moreover, preclinical and clinical trials have shown promise for these novel complement inhibitors in other autoimmune diseases: antibody-mediated vasculitis, C3 glomerulopathy, catastrophic antibody syndrome, membranous nephropathy, and lupus nephritis.

The surge of new complement inhibitors could revolutionize our strategy for treatment of autoimmune-mediated diseases, in which downstream complement activation can manifest with life-threatening tissue injury. Inhibition of complement offers a promising strategy for blocking downstream immune-mediated effector mechanisms of injury common in several autoimmune diseases.

As the results from various clinical trials come to fruition, it will be exciting to determine how to best use this new generation of drugs to target new diseases and whether the next decade is poised to eclipse the progress in complement therapy already established by eculizumab.
 

Dr. Sosa is a benign hematologist at Fox Chase Cancer Center in Philadelphia. Her research interests are in thromboembolic disease, with a focus in racial and gender disparities.

The introduction of eculizumab, a monoclonal antibody targeting C5 of the complement cascade, revolutionized the treatment of paroxysmal nocturnal hemoglobinuria (PNH), a rare hematologic disorder characterized by complement-mediated intravascular hemolysis, bone marrow failure, and thrombophilia. Treatment options for PNH were limited before eculizumab was approved by the Food and Drug Administration in 2007.

Its use resulted in the inhibition of intravascular hemolysis, hemoglobin stabilization, and substantial reductions in transfusion requirements. Moreover, eculizumab had the unexpected effect of reducing the risk of thromboembolic complications, the most severe complication of PNH. Patients treated with eculizumab experienced fewer thrombotic events (4%), compared with historical cohorts (27%). Importantly, 5-year overall survival rates for patients with PNH taking eculizumab improved more than 90%, compared wity the 80% reported historically.

More than 10 years later, we are tasked with assessing the impact of this drug. Unquestionably, eculizumab has done more for PNH than we could have hoped for. However, 10 years of additional data reveal the limitations of this groundbreaking therapy. Despite the overall sustained response and survival benefit, hematologic response remains variable. Complete normalization of hemoglobin occurs in less than one-third of patients. Transfusion requirements persist in many patients. Residual anemia during eculizumab therapy is at least partly attributed to bone marrow failure, a feature the complement inhibition does not address. Still, pharmacokinetic limitations of the drug also contribute to the lack of complete responses. There is residual intravascular hemolysis because of insufficient inhibition of C5 and the emergence of C3-mediated extravascular hemolysis constitutes an unanticipated mechanistic complication of all C5-mediated therapies.

The last few years have seen a surge in novel anticomplement agents, which improve upon the already well-established inhibition of C5 but also explore the efficacy of targeting earlier aspects of the complement pathway. During the American Society of Hematology (ASH) annual meeting, we had exciting updates on some of the promising new kids on the block.

Ravulizumab, the newest C5 monoclonal antibody approved by the FDA for PNH, displays more robust C5 inhibition, thereby reducing the breakthrough hemolysis still seen with eculizumab use. Crovalimab, also an anti-C5 humanized antibody, is engineered with Sequential Monoclonal Antibody Recycling Technology that improves the half-life of the drug and facilitates subcutaneous dosing while still achieving complete C5 inhibition. Some of the most exciting data is on danicopan, a small-molecule factor D inhibitor that targets the alternative pathway thereby inhibiting C3 convertase and blocking extravascular hemolysis. It has shown promise as a stand-alone agent, as well as with combined C5 inhibition, while promising safety, a reasonable concern as we explore the long-term risks of targeting the proximal complement pathway.

I was recently asked to comment on how the new complement inhibitors are addressing unmet needs in PNH. While the recent presentations at ASH demonstrate an improvement on the efficacy of C5 inhibition, pharmacokinetics, and drug delivery – all which translate to improved hemoglobin and reduced breakthrough hemolysis for PNH patients – I am most excited at the promise this new generation of drugs holds for other diseases. Since its approval for PNH, eculizumab has also been approved for use in atypical hemolytic uremic syndrome (aHUS), myasthenia gravis, and neuromyelitis optica spectrum disorder.

Perhaps the greatest potential I envision for the new generation of drugs is in aHUS, a chronic disease characterized by hemolytic anemia, thrombocytopenia, and end-stage renal disease that cannot be cured with renal transplantation. The pathophysiology involves dysregulation of complement activation because of genetic mutations or autoantibodies to key proteins in the complement cascade. Though we have experienced some success with eculizumab, responses can be incomplete, particularly in patients with C5 mutations. The newer drugs offer the opportunity to inhibit complement activation at both proximal and distal aspects of the cascade, which may prove ideal in a disease in which the affected protein is not consistent. Moreover, preclinical and clinical trials have shown promise for these novel complement inhibitors in other autoimmune diseases: antibody-mediated vasculitis, C3 glomerulopathy, catastrophic antibody syndrome, membranous nephropathy, and lupus nephritis.

The surge of new complement inhibitors could revolutionize our strategy for treatment of autoimmune-mediated diseases, in which downstream complement activation can manifest with life-threatening tissue injury. Inhibition of complement offers a promising strategy for blocking downstream immune-mediated effector mechanisms of injury common in several autoimmune diseases.

As the results from various clinical trials come to fruition, it will be exciting to determine how to best use this new generation of drugs to target new diseases and whether the next decade is poised to eclipse the progress in complement therapy already established by eculizumab.
 

Dr. Sosa is a benign hematologist at Fox Chase Cancer Center in Philadelphia. Her research interests are in thromboembolic disease, with a focus in racial and gender disparities.

The introduction of eculizumab, a monoclonal antibody targeting C5 of the complement cascade, revolutionized the treatment of paroxysmal nocturnal hemoglobinuria (PNH), a rare hematologic disorder characterized by complement-mediated intravascular hemolysis, bone marrow failure, and thrombophilia. Treatment options for PNH were limited before eculizumab was approved by the Food and Drug Administration in 2007.

Its use resulted in the inhibition of intravascular hemolysis, hemoglobin stabilization, and substantial reductions in transfusion requirements. Moreover, eculizumab had the unexpected effect of reducing the risk of thromboembolic complications, the most severe complication of PNH. Patients treated with eculizumab experienced fewer thrombotic events (4%), compared with historical cohorts (27%). Importantly, 5-year overall survival rates for patients with PNH taking eculizumab improved more than 90%, compared wity the 80% reported historically.

More than 10 years later, we are tasked with assessing the impact of this drug. Unquestionably, eculizumab has done more for PNH than we could have hoped for. However, 10 years of additional data reveal the limitations of this groundbreaking therapy. Despite the overall sustained response and survival benefit, hematologic response remains variable. Complete normalization of hemoglobin occurs in less than one-third of patients. Transfusion requirements persist in many patients. Residual anemia during eculizumab therapy is at least partly attributed to bone marrow failure, a feature the complement inhibition does not address. Still, pharmacokinetic limitations of the drug also contribute to the lack of complete responses. There is residual intravascular hemolysis because of insufficient inhibition of C5 and the emergence of C3-mediated extravascular hemolysis constitutes an unanticipated mechanistic complication of all C5-mediated therapies.

The last few years have seen a surge in novel anticomplement agents, which improve upon the already well-established inhibition of C5 but also explore the efficacy of targeting earlier aspects of the complement pathway. During the American Society of Hematology (ASH) annual meeting, we had exciting updates on some of the promising new kids on the block.

Ravulizumab, the newest C5 monoclonal antibody approved by the FDA for PNH, displays more robust C5 inhibition, thereby reducing the breakthrough hemolysis still seen with eculizumab use. Crovalimab, also an anti-C5 humanized antibody, is engineered with Sequential Monoclonal Antibody Recycling Technology that improves the half-life of the drug and facilitates subcutaneous dosing while still achieving complete C5 inhibition. Some of the most exciting data is on danicopan, a small-molecule factor D inhibitor that targets the alternative pathway thereby inhibiting C3 convertase and blocking extravascular hemolysis. It has shown promise as a stand-alone agent, as well as with combined C5 inhibition, while promising safety, a reasonable concern as we explore the long-term risks of targeting the proximal complement pathway.

I was recently asked to comment on how the new complement inhibitors are addressing unmet needs in PNH. While the recent presentations at ASH demonstrate an improvement on the efficacy of C5 inhibition, pharmacokinetics, and drug delivery – all which translate to improved hemoglobin and reduced breakthrough hemolysis for PNH patients – I am most excited at the promise this new generation of drugs holds for other diseases. Since its approval for PNH, eculizumab has also been approved for use in atypical hemolytic uremic syndrome (aHUS), myasthenia gravis, and neuromyelitis optica spectrum disorder.

Perhaps the greatest potential I envision for the new generation of drugs is in aHUS, a chronic disease characterized by hemolytic anemia, thrombocytopenia, and end-stage renal disease that cannot be cured with renal transplantation. The pathophysiology involves dysregulation of complement activation because of genetic mutations or autoantibodies to key proteins in the complement cascade. Though we have experienced some success with eculizumab, responses can be incomplete, particularly in patients with C5 mutations. The newer drugs offer the opportunity to inhibit complement activation at both proximal and distal aspects of the cascade, which may prove ideal in a disease in which the affected protein is not consistent. Moreover, preclinical and clinical trials have shown promise for these novel complement inhibitors in other autoimmune diseases: antibody-mediated vasculitis, C3 glomerulopathy, catastrophic antibody syndrome, membranous nephropathy, and lupus nephritis.

The surge of new complement inhibitors could revolutionize our strategy for treatment of autoimmune-mediated diseases, in which downstream complement activation can manifest with life-threatening tissue injury. Inhibition of complement offers a promising strategy for blocking downstream immune-mediated effector mechanisms of injury common in several autoimmune diseases.

As the results from various clinical trials come to fruition, it will be exciting to determine how to best use this new generation of drugs to target new diseases and whether the next decade is poised to eclipse the progress in complement therapy already established by eculizumab.
 

Dr. Sosa is a benign hematologist at Fox Chase Cancer Center in Philadelphia. Her research interests are in thromboembolic disease, with a focus in racial and gender disparities.

ORLANDO – A gene therapy approach that targets a major repressor of fetal hemoglobin appears to be acceptably safe and to mitigate the pathology of sickle cell disease among the five patients infused so far, an investigator reported at the annual meeting of the American Society of Hematology.

Andrew D. Bowser/MDedge News

Knocking down BCL11A using a lentiviral vector-based approach resulted in effective induction of fetal hemoglobin and significant attenuation of the sickling phenotype, with no vector-related adverse events, investigator Erica B. Esrick, MD, of Children’s Hospital Boston, said during the meeting’s late-breaking abstracts session.

The single-center pilot and feasibility study, originally designed to include a total of seven patients, now has an expanded enrollment goal of 15 patients, and a multicenter phase 2/3 study is planned that will enroll a larger group of patients with sickle cell disease, according to Dr. Esrick.

BCL11A represents a promising target in sickle cell disease because of its regulation of the fetal-adult hemoglobin switch at the gamma-globin locus, investigators said in their late-breaking study abstract.

Dr. Esrick described BCH-BB694, a lentiviral vector encoding a BCL11A-targeting small hairpin RNA embedded in a microRNA scaffold (shmiR). “The advantage of this approach is that it harnesses the physiologic switch machinery, simultaneously increasing fetal hemoglobin and decreasing sickle hemoglobin, thus maintaining the alpha to beta globin ratio in the cell,” she said.

The results of the pilot study of the shmiR vector approach, although preliminary and in need of longer follow-up, contribute to a larger body of research showing that multiple gene therapy approaches hold promise in this disease, said Robert Brodsky, MD, professor of medicine and director of the division of hematology at Johns Hopkins School of Medicine, Baltimore.

“The exciting thing is that there are now multiple ways of going at this previously incurable disease,” Dr. Brodsky, who was not involved in the research, said during a press conference.

Development of the gene therapy described by Dr. Esrick involves mobilization of the patient’s peripheral stem cells using plerixafor, followed by selection of CD34+ cells that were transduced with the shmiR lentiviral vector, followed by infusion of gene modified cells into the patient after a busulfan conditioning regimen.

“In our treated patients, we’ve seen a consistent and substantial induction in fetal hemoglobin,” Dr. Esrick said, noting that the longest follow-up to date for the five treated patients is now 18 months.

The patients, who range in age from 12 to 26 years, are producing and maintaining very high numbers of F cells, or erythrocytes with measurable fetal hemoglobin, she said.

Total fetal hemoglobin has increased and remained stable at between 23% and 43% for the five patients, who are producing “stably high” average amounts of fetal hemoglobin per F cell, at 10 to 16 picograms of fetal hemoglobin per cell, while 37% to 62% of the F cells’ total hemoglobin is fetal hemoglobin, she added.

Following gene therapy, treated patients have had no instances of vaso-occlusive pain crises, respiratory events, or neurologic events. No patients have required transfusion, except one with severe underlying vascular disease for whom post–gene therapy transfusions were planned, she said.

Validated assays at the single-cell level are needed to better understand the effect of this gene therapy and eventually compare it to other therapeutic approaches in sickle cell disease, according to Dr. Esrick.

“We’re collaborating with several colleagues on exploratory assays to accomplish this,” she said, adding that the work is ongoing.

Dr. Esrick reported having no disclosures. Her coauthors reported disclosures related to Alerion Biosciences, Novartis, Orchard Therapeutics, Roche, AstraZeneca, and bluebird bio, among others.

SOURCE: Esrick EB et al. ASH 2019. Abstract LBA-5.

ORLANDO – A gene therapy approach that targets a major repressor of fetal hemoglobin appears to be acceptably safe and to mitigate the pathology of sickle cell disease among the five patients infused so far, an investigator reported at the annual meeting of the American Society of Hematology.

Andrew D. Bowser/MDedge News

Knocking down BCL11A using a lentiviral vector-based approach resulted in effective induction of fetal hemoglobin and significant attenuation of the sickling phenotype, with no vector-related adverse events, investigator Erica B. Esrick, MD, of Children’s Hospital Boston, said during the meeting’s late-breaking abstracts session.

The single-center pilot and feasibility study, originally designed to include a total of seven patients, now has an expanded enrollment goal of 15 patients, and a multicenter phase 2/3 study is planned that will enroll a larger group of patients with sickle cell disease, according to Dr. Esrick.

BCL11A represents a promising target in sickle cell disease because of its regulation of the fetal-adult hemoglobin switch at the gamma-globin locus, investigators said in their late-breaking study abstract.

Dr. Esrick described BCH-BB694, a lentiviral vector encoding a BCL11A-targeting small hairpin RNA embedded in a microRNA scaffold (shmiR). “The advantage of this approach is that it harnesses the physiologic switch machinery, simultaneously increasing fetal hemoglobin and decreasing sickle hemoglobin, thus maintaining the alpha to beta globin ratio in the cell,” she said.

The results of the pilot study of the shmiR vector approach, although preliminary and in need of longer follow-up, contribute to a larger body of research showing that multiple gene therapy approaches hold promise in this disease, said Robert Brodsky, MD, professor of medicine and director of the division of hematology at Johns Hopkins School of Medicine, Baltimore.

“The exciting thing is that there are now multiple ways of going at this previously incurable disease,” Dr. Brodsky, who was not involved in the research, said during a press conference.

Development of the gene therapy described by Dr. Esrick involves mobilization of the patient’s peripheral stem cells using plerixafor, followed by selection of CD34+ cells that were transduced with the shmiR lentiviral vector, followed by infusion of gene modified cells into the patient after a busulfan conditioning regimen.

“In our treated patients, we’ve seen a consistent and substantial induction in fetal hemoglobin,” Dr. Esrick said, noting that the longest follow-up to date for the five treated patients is now 18 months.

The patients, who range in age from 12 to 26 years, are producing and maintaining very high numbers of F cells, or erythrocytes with measurable fetal hemoglobin, she said.

Total fetal hemoglobin has increased and remained stable at between 23% and 43% for the five patients, who are producing “stably high” average amounts of fetal hemoglobin per F cell, at 10 to 16 picograms of fetal hemoglobin per cell, while 37% to 62% of the F cells’ total hemoglobin is fetal hemoglobin, she added.

Following gene therapy, treated patients have had no instances of vaso-occlusive pain crises, respiratory events, or neurologic events. No patients have required transfusion, except one with severe underlying vascular disease for whom post–gene therapy transfusions were planned, she said.

Validated assays at the single-cell level are needed to better understand the effect of this gene therapy and eventually compare it to other therapeutic approaches in sickle cell disease, according to Dr. Esrick.

“We’re collaborating with several colleagues on exploratory assays to accomplish this,” she said, adding that the work is ongoing.

Dr. Esrick reported having no disclosures. Her coauthors reported disclosures related to Alerion Biosciences, Novartis, Orchard Therapeutics, Roche, AstraZeneca, and bluebird bio, among others.

SOURCE: Esrick EB et al. ASH 2019. Abstract LBA-5.

ORLANDO – A gene therapy approach that targets a major repressor of fetal hemoglobin appears to be acceptably safe and to mitigate the pathology of sickle cell disease among the five patients infused so far, an investigator reported at the annual meeting of the American Society of Hematology.

Andrew D. Bowser/MDedge News

Knocking down BCL11A using a lentiviral vector-based approach resulted in effective induction of fetal hemoglobin and significant attenuation of the sickling phenotype, with no vector-related adverse events, investigator Erica B. Esrick, MD, of Children’s Hospital Boston, said during the meeting’s late-breaking abstracts session.

The single-center pilot and feasibility study, originally designed to include a total of seven patients, now has an expanded enrollment goal of 15 patients, and a multicenter phase 2/3 study is planned that will enroll a larger group of patients with sickle cell disease, according to Dr. Esrick.

BCL11A represents a promising target in sickle cell disease because of its regulation of the fetal-adult hemoglobin switch at the gamma-globin locus, investigators said in their late-breaking study abstract.

Dr. Esrick described BCH-BB694, a lentiviral vector encoding a BCL11A-targeting small hairpin RNA embedded in a microRNA scaffold (shmiR). “The advantage of this approach is that it harnesses the physiologic switch machinery, simultaneously increasing fetal hemoglobin and decreasing sickle hemoglobin, thus maintaining the alpha to beta globin ratio in the cell,” she said.

The results of the pilot study of the shmiR vector approach, although preliminary and in need of longer follow-up, contribute to a larger body of research showing that multiple gene therapy approaches hold promise in this disease, said Robert Brodsky, MD, professor of medicine and director of the division of hematology at Johns Hopkins School of Medicine, Baltimore.

“The exciting thing is that there are now multiple ways of going at this previously incurable disease,” Dr. Brodsky, who was not involved in the research, said during a press conference.

Development of the gene therapy described by Dr. Esrick involves mobilization of the patient’s peripheral stem cells using plerixafor, followed by selection of CD34+ cells that were transduced with the shmiR lentiviral vector, followed by infusion of gene modified cells into the patient after a busulfan conditioning regimen.

“In our treated patients, we’ve seen a consistent and substantial induction in fetal hemoglobin,” Dr. Esrick said, noting that the longest follow-up to date for the five treated patients is now 18 months.

The patients, who range in age from 12 to 26 years, are producing and maintaining very high numbers of F cells, or erythrocytes with measurable fetal hemoglobin, she said.

Total fetal hemoglobin has increased and remained stable at between 23% and 43% for the five patients, who are producing “stably high” average amounts of fetal hemoglobin per F cell, at 10 to 16 picograms of fetal hemoglobin per cell, while 37% to 62% of the F cells’ total hemoglobin is fetal hemoglobin, she added.

Following gene therapy, treated patients have had no instances of vaso-occlusive pain crises, respiratory events, or neurologic events. No patients have required transfusion, except one with severe underlying vascular disease for whom post–gene therapy transfusions were planned, she said.

Validated assays at the single-cell level are needed to better understand the effect of this gene therapy and eventually compare it to other therapeutic approaches in sickle cell disease, according to Dr. Esrick.

“We’re collaborating with several colleagues on exploratory assays to accomplish this,” she said, adding that the work is ongoing.

Dr. Esrick reported having no disclosures. Her coauthors reported disclosures related to Alerion Biosciences, Novartis, Orchard Therapeutics, Roche, AstraZeneca, and bluebird bio, among others.

SOURCE: Esrick EB et al. ASH 2019. Abstract LBA-5.

ORLANDO – It is good practice to consult with a pulmonary hypertension (PH) expert before referring a patient with sickle cell disease (SCD) for right-heart catheterization or PH evaluation, according to new American Society of Hematology guidelines for the screening and management of cardiopulmonary and kidney disease in patients with SCD.

Sharon Worcester/MDedge News

That “Good Practice” recommendation is one of several included in the evidence-based guidelines published Dec. 10 in Blood Advances and highlighted during a Special Education Session at the annual ASH meeting.

The guidelines provide 10 main recommendations intended to “support patients, clinicians, and other health care professionals in their decisions about screening, diagnosis, and management of cardiopulmonary and renal complications of SCD,” wrote Robert I. Liem, MD, of Ann & Robert H. Lurie Children’s Hospital of Chicago and colleagues.

The recommendations, agreed upon by a multidisciplinary guideline panel, relate to screening, diagnosis, and management of PH, pulmonary arterial hypertension (PAH), hypertension, proteinuria and chronic kidney disease, and venous thromboembolism (VTE). Most are “conditional,” as opposed to “strong,” because of a paucity of direct, high-quality outcomes data, and they are accompanied by the Good Practice Statements, descriptive remarks and caveats based on the available data, as well as suggestions for future research.

At the special ASH session, Ankit A. Desai, MD, highlighted some of the recommendations and discussed considerations for their practical application.

The Good Practice Statement on consulting a specialist before referring a patient for PH relates specifically to Recommendations 2a and 2b on the management of abnormal echocardiography, explained Dr. Desai of Indiana University, Indianapolis.

For asymptomatic children and adults with SCD and an isolated peak tricuspid regurgitant jet velocity (TRJV) of at least 2.5-2.9 m/s on echocardiography, the panel recommends against right-heart catheterization (Recommendation 2a, conditional), he said.

For children and adults with SCD and a peak TRJV of at least 2.5 m/s who also have a reduced 6-minute walk distance (6MWD) and/or elevated N-terminal proB-type natriuretic peptide (NT-proBNP), the panel supports right-heart catheterization (Recommendation 2b, conditional).

Sharon Worcester/MDedge News

Dr. Desai noted that the 2.5 m/s threshold was found to be suboptimal when used as the sole criteria for right-heart catheterization. Using that threshold alone is associated with “moderate to large” harms, such as starting inappropriate PH-specific therapies and/or performing unnecessary right-heart catheterization. However, when used in combination with 6MWD, the predictive capacity improved significantly, and the risk for potential harm was low, he explained.

Another Good Practice Statement included in the guidelines, and relevant to these recommendations on managing abnormal echocardiography, addresses the importance of basing decisions about the need for right-heart catheterization on echocardiograms obtained at steady state rather than during acute illness, such as during hospitalization for pain or acute chest syndrome.

This is in part because of technical factors, Dr. Desai said.

“We know that repeating [echocardiography] is something that should be considered in patients because ... results vary – sometimes quite a bit – from study to study,” he said.

As for the cutoff values for 6MWD and NT-proBNP, “a decent amount of literature” suggests that less than 333 m and less than 160 pg/ml, respectively, are good thresholds, he said.

“Importantly, this should all be taken in the context of good clinical judgment ... along with discussion with a PH expert,” he added.

The full guidelines are available, along with additional ASH guidelines on immune thrombocytopenia and prevention of venous thromboembolism in surgical hospitalized patients, at the ASH publications website.

Of note, the SCD guidelines on cardiopulmonary disease and kidney disease are one of five sets of SCD guidelines that have been in development; these are the first of those to be published. The remaining four sets of guidelines will address pain, cerebrovascular complications, transfusion, and hematopoietic stem cell transplant. All will be published in Blood Advances, and according to Dr. Liem, the transfusion medicine guidelines have been accepted and should be published in January 2020, followed by those for cerebrovascular complications. Publication of the pain and transplant guidelines are anticipated later in 2020.

Dr. Liem and Dr. Desai reported having no conflicts of interest.

[email protected]

ORLANDO – It is good practice to consult with a pulmonary hypertension (PH) expert before referring a patient with sickle cell disease (SCD) for right-heart catheterization or PH evaluation, according to new American Society of Hematology guidelines for the screening and management of cardiopulmonary and kidney disease in patients with SCD.

Sharon Worcester/MDedge News

That “Good Practice” recommendation is one of several included in the evidence-based guidelines published Dec. 10 in Blood Advances and highlighted during a Special Education Session at the annual ASH meeting.

The guidelines provide 10 main recommendations intended to “support patients, clinicians, and other health care professionals in their decisions about screening, diagnosis, and management of cardiopulmonary and renal complications of SCD,” wrote Robert I. Liem, MD, of Ann & Robert H. Lurie Children’s Hospital of Chicago and colleagues.

The recommendations, agreed upon by a multidisciplinary guideline panel, relate to screening, diagnosis, and management of PH, pulmonary arterial hypertension (PAH), hypertension, proteinuria and chronic kidney disease, and venous thromboembolism (VTE). Most are “conditional,” as opposed to “strong,” because of a paucity of direct, high-quality outcomes data, and they are accompanied by the Good Practice Statements, descriptive remarks and caveats based on the available data, as well as suggestions for future research.

At the special ASH session, Ankit A. Desai, MD, highlighted some of the recommendations and discussed considerations for their practical application.

The Good Practice Statement on consulting a specialist before referring a patient for PH relates specifically to Recommendations 2a and 2b on the management of abnormal echocardiography, explained Dr. Desai of Indiana University, Indianapolis.

For asymptomatic children and adults with SCD and an isolated peak tricuspid regurgitant jet velocity (TRJV) of at least 2.5-2.9 m/s on echocardiography, the panel recommends against right-heart catheterization (Recommendation 2a, conditional), he said.

For children and adults with SCD and a peak TRJV of at least 2.5 m/s who also have a reduced 6-minute walk distance (6MWD) and/or elevated N-terminal proB-type natriuretic peptide (NT-proBNP), the panel supports right-heart catheterization (Recommendation 2b, conditional).

Sharon Worcester/MDedge News

Dr. Desai noted that the 2.5 m/s threshold was found to be suboptimal when used as the sole criteria for right-heart catheterization. Using that threshold alone is associated with “moderate to large” harms, such as starting inappropriate PH-specific therapies and/or performing unnecessary right-heart catheterization. However, when used in combination with 6MWD, the predictive capacity improved significantly, and the risk for potential harm was low, he explained.

Another Good Practice Statement included in the guidelines, and relevant to these recommendations on managing abnormal echocardiography, addresses the importance of basing decisions about the need for right-heart catheterization on echocardiograms obtained at steady state rather than during acute illness, such as during hospitalization for pain or acute chest syndrome.

This is in part because of technical factors, Dr. Desai said.

“We know that repeating [echocardiography] is something that should be considered in patients because ... results vary – sometimes quite a bit – from study to study,” he said.

As for the cutoff values for 6MWD and NT-proBNP, “a decent amount of literature” suggests that less than 333 m and less than 160 pg/ml, respectively, are good thresholds, he said.

“Importantly, this should all be taken in the context of good clinical judgment ... along with discussion with a PH expert,” he added.

The full guidelines are available, along with additional ASH guidelines on immune thrombocytopenia and prevention of venous thromboembolism in surgical hospitalized patients, at the ASH publications website.

Of note, the SCD guidelines on cardiopulmonary disease and kidney disease are one of five sets of SCD guidelines that have been in development; these are the first of those to be published. The remaining four sets of guidelines will address pain, cerebrovascular complications, transfusion, and hematopoietic stem cell transplant. All will be published in Blood Advances, and according to Dr. Liem, the transfusion medicine guidelines have been accepted and should be published in January 2020, followed by those for cerebrovascular complications. Publication of the pain and transplant guidelines are anticipated later in 2020.

Dr. Liem and Dr. Desai reported having no conflicts of interest.

[email protected]

ORLANDO – It is good practice to consult with a pulmonary hypertension (PH) expert before referring a patient with sickle cell disease (SCD) for right-heart catheterization or PH evaluation, according to new American Society of Hematology guidelines for the screening and management of cardiopulmonary and kidney disease in patients with SCD.

Sharon Worcester/MDedge News

That “Good Practice” recommendation is one of several included in the evidence-based guidelines published Dec. 10 in Blood Advances and highlighted during a Special Education Session at the annual ASH meeting.

The guidelines provide 10 main recommendations intended to “support patients, clinicians, and other health care professionals in their decisions about screening, diagnosis, and management of cardiopulmonary and renal complications of SCD,” wrote Robert I. Liem, MD, of Ann & Robert H. Lurie Children’s Hospital of Chicago and colleagues.

The recommendations, agreed upon by a multidisciplinary guideline panel, relate to screening, diagnosis, and management of PH, pulmonary arterial hypertension (PAH), hypertension, proteinuria and chronic kidney disease, and venous thromboembolism (VTE). Most are “conditional,” as opposed to “strong,” because of a paucity of direct, high-quality outcomes data, and they are accompanied by the Good Practice Statements, descriptive remarks and caveats based on the available data, as well as suggestions for future research.

At the special ASH session, Ankit A. Desai, MD, highlighted some of the recommendations and discussed considerations for their practical application.

The Good Practice Statement on consulting a specialist before referring a patient for PH relates specifically to Recommendations 2a and 2b on the management of abnormal echocardiography, explained Dr. Desai of Indiana University, Indianapolis.

For asymptomatic children and adults with SCD and an isolated peak tricuspid regurgitant jet velocity (TRJV) of at least 2.5-2.9 m/s on echocardiography, the panel recommends against right-heart catheterization (Recommendation 2a, conditional), he said.

For children and adults with SCD and a peak TRJV of at least 2.5 m/s who also have a reduced 6-minute walk distance (6MWD) and/or elevated N-terminal proB-type natriuretic peptide (NT-proBNP), the panel supports right-heart catheterization (Recommendation 2b, conditional).

Sharon Worcester/MDedge News

Dr. Desai noted that the 2.5 m/s threshold was found to be suboptimal when used as the sole criteria for right-heart catheterization. Using that threshold alone is associated with “moderate to large” harms, such as starting inappropriate PH-specific therapies and/or performing unnecessary right-heart catheterization. However, when used in combination with 6MWD, the predictive capacity improved significantly, and the risk for potential harm was low, he explained.

Another Good Practice Statement included in the guidelines, and relevant to these recommendations on managing abnormal echocardiography, addresses the importance of basing decisions about the need for right-heart catheterization on echocardiograms obtained at steady state rather than during acute illness, such as during hospitalization for pain or acute chest syndrome.

This is in part because of technical factors, Dr. Desai said.

“We know that repeating [echocardiography] is something that should be considered in patients because ... results vary – sometimes quite a bit – from study to study,” he said.

As for the cutoff values for 6MWD and NT-proBNP, “a decent amount of literature” suggests that less than 333 m and less than 160 pg/ml, respectively, are good thresholds, he said.

“Importantly, this should all be taken in the context of good clinical judgment ... along with discussion with a PH expert,” he added.

The full guidelines are available, along with additional ASH guidelines on immune thrombocytopenia and prevention of venous thromboembolism in surgical hospitalized patients, at the ASH publications website.

Of note, the SCD guidelines on cardiopulmonary disease and kidney disease are one of five sets of SCD guidelines that have been in development; these are the first of those to be published. The remaining four sets of guidelines will address pain, cerebrovascular complications, transfusion, and hematopoietic stem cell transplant. All will be published in Blood Advances, and according to Dr. Liem, the transfusion medicine guidelines have been accepted and should be published in January 2020, followed by those for cerebrovascular complications. Publication of the pain and transplant guidelines are anticipated later in 2020.

Dr. Liem and Dr. Desai reported having no conflicts of interest.

[email protected]

ORLANDO – An investigational selective inhibitor of the complement pathway, sutimlimab, induced rapid and sustained benefits in patients with cold agglutinin disease, a rare autoimmune hemolytic anemia with no currently approved effective therapies.

Neil Osterweil/MDedge News

Among 24 patients with cold agglutinin disease who received at least one dose of sutimlimab in a phase 3 trial, 20 had a mean increase in hemoglobin of at least 1 g/dL, and 17 remained transfusion free from weeks 5 to 26 following sutimlimab infusion.

“Sutimlimab has the potential to change treatment practices for patients with this disease,” said lead author Alexander Röth, MD, from the University of Duisburg-Essen (Germany), at a late-breaking abstract session at the annual meeting of the American Society of Hematology.

Mean total bilirubin rapidly normalized within 1-3 weeks of infusion of sutimlimab, and patients had a mean improvement of 11 points on the Functional Assessment of Chronic Illness Therapy–Fatigue scale (FACIT-F), indicating a substantial improvement in their quality of life, Dr. Röth said.

Cold agglutinin disease is an acquired hemolytic anemia with an underlying lymphoproliferative disorder. The estimated prevalence of the disease is 16 per 1 million persons. The disease is characterized by hemolysis driven by activation of the complement pathway, leading to opsonization of erythrocytes (coating of erythrocytes with particles that facilitate phagocytosis and other immune reactions), extravascular hemolysis (primarily in the liver), intravascular hemolysis, and anemia.

Patients experience severe fatigue and poor quality of life, as well as increased risk for thrombosis and mortality, compared with matched cohorts.

Sutimlimab is a humanized monoclonal antibody that blocks the C1s component of the classical complement pathway, thereby stopping pathway activation while leaving alternative lectin pathways intact.

Dr. Röth presented results of the phase 3, open-label Cardinal study. Patients with cold agglutinin disease with baseline hemoglobin of 10 g/dL or less, active hemolysis signaled by total bilirubin levels above normal, and at least one blood transfusion within the past 6 months were eligible for the study. Patients with secondary cold agglutinin syndrome or rituximab therapy within the last 3 months or combination therapies within the last 6 months were excluded.

Sutimlimab was delivered intravenously at a dose of 6.5 g for patients under 75 kg in weight and 7.5 g for those 75 kg and over at day 0 and 7, then every 2 weeks thereafter.

A total of 24 patients with a mean age of 71 years were enrolled. Of the 24 patients, 15 (62.5%) were women.

The patients had received a mean of 3.2 transfusions (range 1-19) in the previous 6 months, and 15 had received one or more prior targeted therapies for the disease within the last 5 years. The mean baseline hemoglobin level was 8.6 (range 4.9-11.1) g/dL.

Hemoglobin levels increased rapidly after the first infusion, with a mean increase of 1.2 g/dL at the end of week 1, and 2.3 g/dL after week 3.

The estimated mean increase at treatment assessment (an average of weeks 23, 25, and 26) – the primary endpoint – was 2.6 g/dL, exceeding the prespecified increase of at least 2 g/dL. Normalization of hemoglobin to 12 g/dL or greater was an alternative primary endpoint. The trial met the primary endpoint, with 13 of 24 patients (54.2%) achieving either of the two prespecified events.

The mean overall hemoglobin level was maintained above 11 g/dL after week 3. Of the 24 patients, 20 had hemoglobin increases of 1 g/dL or greater.

Mean total bilirubin, a marker of hemolysis, dropped markedly within hours of infusion and was normalized by week 3.

As noted before, patient quality of life, as measured by the FACIT-F scale, improved by a mean of 11 points from a mean baseline of 32 out of 52 points.

All but two patients had one or more treatment-emergent adverse events, and seven of these patients had a serious treatment-related event, although none of the serious events were thought to be related to sutimlimab. One patient with liver cancer died from causes deemed unrelated to the drug. There were no meningococcal infections.

All 22 patients who completed the 26 weeks of therapy continued on an extended safety phase of the study.

The study results demonstrate that targeting the complement pathways is an novel and effective approach to managing cold agglutinin disease, Dr. Röth concluded.

Neil Osterweil/MDedge News

In a press briefing the day before the presentation, moderator Robert Brodsky, MD, professor of medicine and director of the division of hematology at Johns Hopkins School, Baltimore, who treats patients with cold agglutinin disease, said that the results “are very exciting.”

“These patients are very difficult to treat and there really is no approved drug,” he said. “Right now, we usually use [rituximab] first line, but only half of those patients respond, and usually it only lasts for 6 months or so, so this is a welcome addition.”

Sutimlimab was granted Breakthrough Therapy designation by the Food and Drug Administration, and Orphan Drug status by the FDA, European Medicines Agency, and the Pharmaceuticals and Medical Devices Agency in Japan.

The study was supported by Sanofi. Dr. Röth reported financial relationships with Sanofi and other companies.

SOURCE: Röth A et al. ASH 2019, Abstract LBA-2.

ORLANDO – An investigational selective inhibitor of the complement pathway, sutimlimab, induced rapid and sustained benefits in patients with cold agglutinin disease, a rare autoimmune hemolytic anemia with no currently approved effective therapies.

Neil Osterweil/MDedge News

Among 24 patients with cold agglutinin disease who received at least one dose of sutimlimab in a phase 3 trial, 20 had a mean increase in hemoglobin of at least 1 g/dL, and 17 remained transfusion free from weeks 5 to 26 following sutimlimab infusion.

“Sutimlimab has the potential to change treatment practices for patients with this disease,” said lead author Alexander Röth, MD, from the University of Duisburg-Essen (Germany), at a late-breaking abstract session at the annual meeting of the American Society of Hematology.

Mean total bilirubin rapidly normalized within 1-3 weeks of infusion of sutimlimab, and patients had a mean improvement of 11 points on the Functional Assessment of Chronic Illness Therapy–Fatigue scale (FACIT-F), indicating a substantial improvement in their quality of life, Dr. Röth said.

Cold agglutinin disease is an acquired hemolytic anemia with an underlying lymphoproliferative disorder. The estimated prevalence of the disease is 16 per 1 million persons. The disease is characterized by hemolysis driven by activation of the complement pathway, leading to opsonization of erythrocytes (coating of erythrocytes with particles that facilitate phagocytosis and other immune reactions), extravascular hemolysis (primarily in the liver), intravascular hemolysis, and anemia.

Patients experience severe fatigue and poor quality of life, as well as increased risk for thrombosis and mortality, compared with matched cohorts.

Sutimlimab is a humanized monoclonal antibody that blocks the C1s component of the classical complement pathway, thereby stopping pathway activation while leaving alternative lectin pathways intact.

Dr. Röth presented results of the phase 3, open-label Cardinal study. Patients with cold agglutinin disease with baseline hemoglobin of 10 g/dL or less, active hemolysis signaled by total bilirubin levels above normal, and at least one blood transfusion within the past 6 months were eligible for the study. Patients with secondary cold agglutinin syndrome or rituximab therapy within the last 3 months or combination therapies within the last 6 months were excluded.

Sutimlimab was delivered intravenously at a dose of 6.5 g for patients under 75 kg in weight and 7.5 g for those 75 kg and over at day 0 and 7, then every 2 weeks thereafter.

A total of 24 patients with a mean age of 71 years were enrolled. Of the 24 patients, 15 (62.5%) were women.

The patients had received a mean of 3.2 transfusions (range 1-19) in the previous 6 months, and 15 had received one or more prior targeted therapies for the disease within the last 5 years. The mean baseline hemoglobin level was 8.6 (range 4.9-11.1) g/dL.

Hemoglobin levels increased rapidly after the first infusion, with a mean increase of 1.2 g/dL at the end of week 1, and 2.3 g/dL after week 3.

The estimated mean increase at treatment assessment (an average of weeks 23, 25, and 26) – the primary endpoint – was 2.6 g/dL, exceeding the prespecified increase of at least 2 g/dL. Normalization of hemoglobin to 12 g/dL or greater was an alternative primary endpoint. The trial met the primary endpoint, with 13 of 24 patients (54.2%) achieving either of the two prespecified events.

The mean overall hemoglobin level was maintained above 11 g/dL after week 3. Of the 24 patients, 20 had hemoglobin increases of 1 g/dL or greater.

Mean total bilirubin, a marker of hemolysis, dropped markedly within hours of infusion and was normalized by week 3.

As noted before, patient quality of life, as measured by the FACIT-F scale, improved by a mean of 11 points from a mean baseline of 32 out of 52 points.

All but two patients had one or more treatment-emergent adverse events, and seven of these patients had a serious treatment-related event, although none of the serious events were thought to be related to sutimlimab. One patient with liver cancer died from causes deemed unrelated to the drug. There were no meningococcal infections.

All 22 patients who completed the 26 weeks of therapy continued on an extended safety phase of the study.

The study results demonstrate that targeting the complement pathways is an novel and effective approach to managing cold agglutinin disease, Dr. Röth concluded.

Neil Osterweil/MDedge News

In a press briefing the day before the presentation, moderator Robert Brodsky, MD, professor of medicine and director of the division of hematology at Johns Hopkins School, Baltimore, who treats patients with cold agglutinin disease, said that the results “are very exciting.”

“These patients are very difficult to treat and there really is no approved drug,” he said. “Right now, we usually use [rituximab] first line, but only half of those patients respond, and usually it only lasts for 6 months or so, so this is a welcome addition.”

Sutimlimab was granted Breakthrough Therapy designation by the Food and Drug Administration, and Orphan Drug status by the FDA, European Medicines Agency, and the Pharmaceuticals and Medical Devices Agency in Japan.

The study was supported by Sanofi. Dr. Röth reported financial relationships with Sanofi and other companies.

SOURCE: Röth A et al. ASH 2019, Abstract LBA-2.

ORLANDO – An investigational selective inhibitor of the complement pathway, sutimlimab, induced rapid and sustained benefits in patients with cold agglutinin disease, a rare autoimmune hemolytic anemia with no currently approved effective therapies.

Neil Osterweil/MDedge News

Among 24 patients with cold agglutinin disease who received at least one dose of sutimlimab in a phase 3 trial, 20 had a mean increase in hemoglobin of at least 1 g/dL, and 17 remained transfusion free from weeks 5 to 26 following sutimlimab infusion.

“Sutimlimab has the potential to change treatment practices for patients with this disease,” said lead author Alexander Röth, MD, from the University of Duisburg-Essen (Germany), at a late-breaking abstract session at the annual meeting of the American Society of Hematology.

Mean total bilirubin rapidly normalized within 1-3 weeks of infusion of sutimlimab, and patients had a mean improvement of 11 points on the Functional Assessment of Chronic Illness Therapy–Fatigue scale (FACIT-F), indicating a substantial improvement in their quality of life, Dr. Röth said.

Cold agglutinin disease is an acquired hemolytic anemia with an underlying lymphoproliferative disorder. The estimated prevalence of the disease is 16 per 1 million persons. The disease is characterized by hemolysis driven by activation of the complement pathway, leading to opsonization of erythrocytes (coating of erythrocytes with particles that facilitate phagocytosis and other immune reactions), extravascular hemolysis (primarily in the liver), intravascular hemolysis, and anemia.

Patients experience severe fatigue and poor quality of life, as well as increased risk for thrombosis and mortality, compared with matched cohorts.

Sutimlimab is a humanized monoclonal antibody that blocks the C1s component of the classical complement pathway, thereby stopping pathway activation while leaving alternative lectin pathways intact.

Dr. Röth presented results of the phase 3, open-label Cardinal study. Patients with cold agglutinin disease with baseline hemoglobin of 10 g/dL or less, active hemolysis signaled by total bilirubin levels above normal, and at least one blood transfusion within the past 6 months were eligible for the study. Patients with secondary cold agglutinin syndrome or rituximab therapy within the last 3 months or combination therapies within the last 6 months were excluded.

Sutimlimab was delivered intravenously at a dose of 6.5 g for patients under 75 kg in weight and 7.5 g for those 75 kg and over at day 0 and 7, then every 2 weeks thereafter.

A total of 24 patients with a mean age of 71 years were enrolled. Of the 24 patients, 15 (62.5%) were women.

The patients had received a mean of 3.2 transfusions (range 1-19) in the previous 6 months, and 15 had received one or more prior targeted therapies for the disease within the last 5 years. The mean baseline hemoglobin level was 8.6 (range 4.9-11.1) g/dL.

Hemoglobin levels increased rapidly after the first infusion, with a mean increase of 1.2 g/dL at the end of week 1, and 2.3 g/dL after week 3.

The estimated mean increase at treatment assessment (an average of weeks 23, 25, and 26) – the primary endpoint – was 2.6 g/dL, exceeding the prespecified increase of at least 2 g/dL. Normalization of hemoglobin to 12 g/dL or greater was an alternative primary endpoint. The trial met the primary endpoint, with 13 of 24 patients (54.2%) achieving either of the two prespecified events.

The mean overall hemoglobin level was maintained above 11 g/dL after week 3. Of the 24 patients, 20 had hemoglobin increases of 1 g/dL or greater.

Mean total bilirubin, a marker of hemolysis, dropped markedly within hours of infusion and was normalized by week 3.

As noted before, patient quality of life, as measured by the FACIT-F scale, improved by a mean of 11 points from a mean baseline of 32 out of 52 points.

All but two patients had one or more treatment-emergent adverse events, and seven of these patients had a serious treatment-related event, although none of the serious events were thought to be related to sutimlimab. One patient with liver cancer died from causes deemed unrelated to the drug. There were no meningococcal infections.

All 22 patients who completed the 26 weeks of therapy continued on an extended safety phase of the study.

The study results demonstrate that targeting the complement pathways is an novel and effective approach to managing cold agglutinin disease, Dr. Röth concluded.

Neil Osterweil/MDedge News

In a press briefing the day before the presentation, moderator Robert Brodsky, MD, professor of medicine and director of the division of hematology at Johns Hopkins School, Baltimore, who treats patients with cold agglutinin disease, said that the results “are very exciting.”

“These patients are very difficult to treat and there really is no approved drug,” he said. “Right now, we usually use [rituximab] first line, but only half of those patients respond, and usually it only lasts for 6 months or so, so this is a welcome addition.”

Sutimlimab was granted Breakthrough Therapy designation by the Food and Drug Administration, and Orphan Drug status by the FDA, European Medicines Agency, and the Pharmaceuticals and Medical Devices Agency in Japan.

The study was supported by Sanofi. Dr. Röth reported financial relationships with Sanofi and other companies.

SOURCE: Röth A et al. ASH 2019, Abstract LBA-2.

ORLANDO – There’s a new Choosing Wisely list in hematology focused specifically on children, with five tests or procedures that experts advise should be avoided, with some exceptions.

The list, which was produced by an expert panel with representatives from the American Society of Hematology and the American Society of Pediatric Hematology/Oncology (ASPHO), includes five tests or procedures that are considered unnecessary. The recommendations were released at the annual meeting of the American Society of Hematology.

The five recommendations are:

• Don’t perform routine preoperative hemostatic testing in an otherwise healthy child with no prior personal or family history of bleeding.
• Don’t transfuse platelets in a nonbleeding pediatric patient with a platelet count greater than 10,000/mcL, unless other signs of bleeding are present, or if the patient is set to undergo an invasive procedure.
• Don’t order thrombophilia testing on children with venous access-associated thrombosis in the absence of a positive family history.
• Don’t transfuse packed RBCs for iron-deficiency anemia in asymptomatic pediatric patients when there is no evidence of hemodynamic instability or active bleeding.
• Don’t routinely administer granulocyte colony–stimulating factor (G-CSF) for empiric treatment of pediatric patients with asymptomatic autoimmune neutropenia in the absence of recurrent or severe bacterial and/or fungal infections.

This is the third Choosing Wisely list produced by ASH. The group released the first list in 2013 and the second in 2014. But officials at both ASH and ASPHO have received feedback over the years that there should also be a pediatric-focused list in hematology, said Sarah O’Brien, MD, of Nationwide Children’s Hospital in Columbus, Ohio, and cochair of the expert panel that put together the recommendations.

Hemostatic testing

The panel recommended against preoperative hemostatic screening in healthy children with no personal or family history of excessive bleeding because the test does not effectively predict who will have unexpected surgical bleeding. The testing could instead identify artifacts or disorders unrelated to bleeding risk, such as factor XII deficiency or an infection-associated, transient lupus anticoagulant, according to Veronica H. Flood, MD, of the Medical College of Wisconsin, Milwaukee, and a member of the expert panel.

Performing this type of testing also adds cost and stress for families, and often delays surgery.

A look at the current literature reveals that there is little evidence to support coagulation testing in healthy children undergoing surgery. “Despite all this evidence, there remain practitioners who perform such screening on a regular basis,” Dr. Flood said.

For physicians concerned about bleeding risk, Dr. Flood said that existing guidelines support taking a bleeding history in preoperative patients. “This may take a little more time, but in the end will result in better results and less expense.”

Platelet transfusion

The panel recommended against platelet transfusion in nonbleeding pediatric patients with hypoproliferative thrombocytopenia and a platelet count greater than 10,000/mcL. The caveats for this recommendation are that it does not apply if there are other signs or symptoms of bleeding, if the patient is undergoing an invasive procedure, if the patient is aged 1 year or younger, or if the patient has immune-mediated thrombocytopenia, according to Rachel Bercovitz, MD, of the Ann & Robert H. Lurie Children’s Hospital of Chicago and a member of the expert panel.

Previous studies on the platelet transfusions in patients with hematologic malignancies have shown that 10,000/mcL is the appropriate threshold, with no difference in bleeding above that number and increased bleeding below it, Dr. Bercovitz said.

Additionally, while platelet transfusion is a safe procedure, Dr. Bercovitz said, it is not without acute and long-term risks.

Cost is also a factor. “Platelets are a limited and expensive resource,” she said.

Thrombophilia testing

Thrombophilia testing in children with a central venous catheter-associated thrombosis was once common practice but should be avoided, explained Leslie J. Raffini, MD, of the Children’s Hospital of Philadelphia and a member of the expert panel.

Thrombophilia does not influence the initial management of a first episode of provoked venous thrombosis, it does not inform the intensity of duration of anticoagulant therapy, and it does not predict recurrence of venous thrombosis in children, Dr. Raffini said.

In the 2013 Choosing Wisely list, ASH made the same recommendation against testing in adult patients with venous thromboembolism occurring in the setting of major transient risk factors. Thrombophilia testing is also expensive, often has to be repeated, and can be misinterpreted, Dr. Raffini said.

Packed RBC transfusion

The panel recommended against transfusion with packed RBCs for children with iron-deficiency anemia who have no symptoms and no evidence of hemodynamic instability or active bleeding. Transfusion is appropriate if children are symptomatic or are hemodynamically unstable, said Patrick T. McGann, MD, of Cincinnati Children’s Hospital and a member of the expert panel.

Rather than jump to transfusion, Dr. McGann said this group of asymptomatic and hemodynamically stable children should be treated for their iron deficiency through oral or intravenous iron. “This is not about ignoring iron deficiency.”

Both are effective treatments with multiple options available, he said. But sending a child to the hospital for transfusion is a costly option that is stressful for families and only provides a temporary solution to the issue, since treatment of the underlying iron deficiency still needs to be addressed, Dr. McGann said.

G-CSF treatment

The panel also recommended against routine administration of G-CSF in children with asymptomatic autoimmune neutropenia. Peter E. Newburger, MD, of Boston Children’s Hospital and a member of the expert guideline panel, said that there is limited evidence available and no published guidelines in this area, so the panel was guided by expert opinion.

In most cases, G-CSF is not necessary because autoimmune neutropenia resolves spontaneously by age 4-5 years and the risk of serious infection is extremely low. Appropriate management includes antibiotics for acute bacterial infection, good dental hygiene, and continued immunizations, Dr. Newburger said.

G-CSF may be appropriate in limited cases to improve quality of life, but it should be started at a low dose of 1-2 mcg/kg.

In cases of serious infection, Dr. Newburger said physicians should consider alternative diagnoses, such as congenital neutropenia or myelodysplastic syndromes.

[email protected]

ORLANDO – There’s a new Choosing Wisely list in hematology focused specifically on children, with five tests or procedures that experts advise should be avoided, with some exceptions.

The list, which was produced by an expert panel with representatives from the American Society of Hematology and the American Society of Pediatric Hematology/Oncology (ASPHO), includes five tests or procedures that are considered unnecessary. The recommendations were released at the annual meeting of the American Society of Hematology.

The five recommendations are:

• Don’t perform routine preoperative hemostatic testing in an otherwise healthy child with no prior personal or family history of bleeding.
• Don’t transfuse platelets in a nonbleeding pediatric patient with a platelet count greater than 10,000/mcL, unless other signs of bleeding are present, or if the patient is set to undergo an invasive procedure.
• Don’t order thrombophilia testing on children with venous access-associated thrombosis in the absence of a positive family history.
• Don’t transfuse packed RBCs for iron-deficiency anemia in asymptomatic pediatric patients when there is no evidence of hemodynamic instability or active bleeding.
• Don’t routinely administer granulocyte colony–stimulating factor (G-CSF) for empiric treatment of pediatric patients with asymptomatic autoimmune neutropenia in the absence of recurrent or severe bacterial and/or fungal infections.

This is the third Choosing Wisely list produced by ASH. The group released the first list in 2013 and the second in 2014. But officials at both ASH and ASPHO have received feedback over the years that there should also be a pediatric-focused list in hematology, said Sarah O’Brien, MD, of Nationwide Children’s Hospital in Columbus, Ohio, and cochair of the expert panel that put together the recommendations.

Hemostatic testing

The panel recommended against preoperative hemostatic screening in healthy children with no personal or family history of excessive bleeding because the test does not effectively predict who will have unexpected surgical bleeding. The testing could instead identify artifacts or disorders unrelated to bleeding risk, such as factor XII deficiency or an infection-associated, transient lupus anticoagulant, according to Veronica H. Flood, MD, of the Medical College of Wisconsin, Milwaukee, and a member of the expert panel.

Performing this type of testing also adds cost and stress for families, and often delays surgery.

A look at the current literature reveals that there is little evidence to support coagulation testing in healthy children undergoing surgery. “Despite all this evidence, there remain practitioners who perform such screening on a regular basis,” Dr. Flood said.

For physicians concerned about bleeding risk, Dr. Flood said that existing guidelines support taking a bleeding history in preoperative patients. “This may take a little more time, but in the end will result in better results and less expense.”

Platelet transfusion

The panel recommended against platelet transfusion in nonbleeding pediatric patients with hypoproliferative thrombocytopenia and a platelet count greater than 10,000/mcL. The caveats for this recommendation are that it does not apply if there are other signs or symptoms of bleeding, if the patient is undergoing an invasive procedure, if the patient is aged 1 year or younger, or if the patient has immune-mediated thrombocytopenia, according to Rachel Bercovitz, MD, of the Ann & Robert H. Lurie Children’s Hospital of Chicago and a member of the expert panel.

Previous studies on the platelet transfusions in patients with hematologic malignancies have shown that 10,000/mcL is the appropriate threshold, with no difference in bleeding above that number and increased bleeding below it, Dr. Bercovitz said.

Additionally, while platelet transfusion is a safe procedure, Dr. Bercovitz said, it is not without acute and long-term risks.

Cost is also a factor. “Platelets are a limited and expensive resource,” she said.

Thrombophilia testing

Thrombophilia testing in children with a central venous catheter-associated thrombosis was once common practice but should be avoided, explained Leslie J. Raffini, MD, of the Children’s Hospital of Philadelphia and a member of the expert panel.

Thrombophilia does not influence the initial management of a first episode of provoked venous thrombosis, it does not inform the intensity of duration of anticoagulant therapy, and it does not predict recurrence of venous thrombosis in children, Dr. Raffini said.

In the 2013 Choosing Wisely list, ASH made the same recommendation against testing in adult patients with venous thromboembolism occurring in the setting of major transient risk factors. Thrombophilia testing is also expensive, often has to be repeated, and can be misinterpreted, Dr. Raffini said.

Packed RBC transfusion

The panel recommended against transfusion with packed RBCs for children with iron-deficiency anemia who have no symptoms and no evidence of hemodynamic instability or active bleeding. Transfusion is appropriate if children are symptomatic or are hemodynamically unstable, said Patrick T. McGann, MD, of Cincinnati Children’s Hospital and a member of the expert panel.

Rather than jump to transfusion, Dr. McGann said this group of asymptomatic and hemodynamically stable children should be treated for their iron deficiency through oral or intravenous iron. “This is not about ignoring iron deficiency.”

Both are effective treatments with multiple options available, he said. But sending a child to the hospital for transfusion is a costly option that is stressful for families and only provides a temporary solution to the issue, since treatment of the underlying iron deficiency still needs to be addressed, Dr. McGann said.

G-CSF treatment

The panel also recommended against routine administration of G-CSF in children with asymptomatic autoimmune neutropenia. Peter E. Newburger, MD, of Boston Children’s Hospital and a member of the expert guideline panel, said that there is limited evidence available and no published guidelines in this area, so the panel was guided by expert opinion.

In most cases, G-CSF is not necessary because autoimmune neutropenia resolves spontaneously by age 4-5 years and the risk of serious infection is extremely low. Appropriate management includes antibiotics for acute bacterial infection, good dental hygiene, and continued immunizations, Dr. Newburger said.

G-CSF may be appropriate in limited cases to improve quality of life, but it should be started at a low dose of 1-2 mcg/kg.

In cases of serious infection, Dr. Newburger said physicians should consider alternative diagnoses, such as congenital neutropenia or myelodysplastic syndromes.

[email protected]

ORLANDO – There’s a new Choosing Wisely list in hematology focused specifically on children, with five tests or procedures that experts advise should be avoided, with some exceptions.

The list, which was produced by an expert panel with representatives from the American Society of Hematology and the American Society of Pediatric Hematology/Oncology (ASPHO), includes five tests or procedures that are considered unnecessary. The recommendations were released at the annual meeting of the American Society of Hematology.

The five recommendations are:

• Don’t perform routine preoperative hemostatic testing in an otherwise healthy child with no prior personal or family history of bleeding.
• Don’t transfuse platelets in a nonbleeding pediatric patient with a platelet count greater than 10,000/mcL, unless other signs of bleeding are present, or if the patient is set to undergo an invasive procedure.
• Don’t order thrombophilia testing on children with venous access-associated thrombosis in the absence of a positive family history.
• Don’t transfuse packed RBCs for iron-deficiency anemia in asymptomatic pediatric patients when there is no evidence of hemodynamic instability or active bleeding.
• Don’t routinely administer granulocyte colony–stimulating factor (G-CSF) for empiric treatment of pediatric patients with asymptomatic autoimmune neutropenia in the absence of recurrent or severe bacterial and/or fungal infections.

This is the third Choosing Wisely list produced by ASH. The group released the first list in 2013 and the second in 2014. But officials at both ASH and ASPHO have received feedback over the years that there should also be a pediatric-focused list in hematology, said Sarah O’Brien, MD, of Nationwide Children’s Hospital in Columbus, Ohio, and cochair of the expert panel that put together the recommendations.

Hemostatic testing

The panel recommended against preoperative hemostatic screening in healthy children with no personal or family history of excessive bleeding because the test does not effectively predict who will have unexpected surgical bleeding. The testing could instead identify artifacts or disorders unrelated to bleeding risk, such as factor XII deficiency or an infection-associated, transient lupus anticoagulant, according to Veronica H. Flood, MD, of the Medical College of Wisconsin, Milwaukee, and a member of the expert panel.

Performing this type of testing also adds cost and stress for families, and often delays surgery.

A look at the current literature reveals that there is little evidence to support coagulation testing in healthy children undergoing surgery. “Despite all this evidence, there remain practitioners who perform such screening on a regular basis,” Dr. Flood said.

For physicians concerned about bleeding risk, Dr. Flood said that existing guidelines support taking a bleeding history in preoperative patients. “This may take a little more time, but in the end will result in better results and less expense.”

Platelet transfusion

The panel recommended against platelet transfusion in nonbleeding pediatric patients with hypoproliferative thrombocytopenia and a platelet count greater than 10,000/mcL. The caveats for this recommendation are that it does not apply if there are other signs or symptoms of bleeding, if the patient is undergoing an invasive procedure, if the patient is aged 1 year or younger, or if the patient has immune-mediated thrombocytopenia, according to Rachel Bercovitz, MD, of the Ann & Robert H. Lurie Children’s Hospital of Chicago and a member of the expert panel.

Previous studies on the platelet transfusions in patients with hematologic malignancies have shown that 10,000/mcL is the appropriate threshold, with no difference in bleeding above that number and increased bleeding below it, Dr. Bercovitz said.

Additionally, while platelet transfusion is a safe procedure, Dr. Bercovitz said, it is not without acute and long-term risks.

Cost is also a factor. “Platelets are a limited and expensive resource,” she said.

Thrombophilia testing

Thrombophilia testing in children with a central venous catheter-associated thrombosis was once common practice but should be avoided, explained Leslie J. Raffini, MD, of the Children’s Hospital of Philadelphia and a member of the expert panel.

Thrombophilia does not influence the initial management of a first episode of provoked venous thrombosis, it does not inform the intensity of duration of anticoagulant therapy, and it does not predict recurrence of venous thrombosis in children, Dr. Raffini said.

In the 2013 Choosing Wisely list, ASH made the same recommendation against testing in adult patients with venous thromboembolism occurring in the setting of major transient risk factors. Thrombophilia testing is also expensive, often has to be repeated, and can be misinterpreted, Dr. Raffini said.

Packed RBC transfusion

The panel recommended against transfusion with packed RBCs for children with iron-deficiency anemia who have no symptoms and no evidence of hemodynamic instability or active bleeding. Transfusion is appropriate if children are symptomatic or are hemodynamically unstable, said Patrick T. McGann, MD, of Cincinnati Children’s Hospital and a member of the expert panel.

Rather than jump to transfusion, Dr. McGann said this group of asymptomatic and hemodynamically stable children should be treated for their iron deficiency through oral or intravenous iron. “This is not about ignoring iron deficiency.”

Both are effective treatments with multiple options available, he said. But sending a child to the hospital for transfusion is a costly option that is stressful for families and only provides a temporary solution to the issue, since treatment of the underlying iron deficiency still needs to be addressed, Dr. McGann said.

G-CSF treatment

The panel also recommended against routine administration of G-CSF in children with asymptomatic autoimmune neutropenia. Peter E. Newburger, MD, of Boston Children’s Hospital and a member of the expert guideline panel, said that there is limited evidence available and no published guidelines in this area, so the panel was guided by expert opinion.

In most cases, G-CSF is not necessary because autoimmune neutropenia resolves spontaneously by age 4-5 years and the risk of serious infection is extremely low. Appropriate management includes antibiotics for acute bacterial infection, good dental hygiene, and continued immunizations, Dr. Newburger said.

G-CSF may be appropriate in limited cases to improve quality of life, but it should be started at a low dose of 1-2 mcg/kg.

In cases of serious infection, Dr. Newburger said physicians should consider alternative diagnoses, such as congenital neutropenia or myelodysplastic syndromes.

[email protected]

ORLANDO – Oral arginine supplementation significantly increased plasma arginine levels and improved acute pain-related outcomes in Nigerian children with sickle cell disease in a randomized, placebo-controlled, phase 2 trial.

Andrew Bowser/MDedge News

Of 68 children with a mean age of 10 years who were hospitalized with vaso-occlusive crisis involving severe pain and treated with standard pain management, 35 were randomized to receive adjuvant oral L-arginine at a dose of 100 mg/kg every 8 hours for 5 days or until discharge, and 33 received placebo. Those in the arginine arm experienced a 125% increase in their plasma arginine level, compared with a 29% increase in the placebo arm, Richard Onalo, FC Paed, reported during a press briefing at the annual meeting of the American Society of Hematology.

“This was statistically significant,” Dr. Onalo, of the department of pediatrics at the University of Abuja, Nigeria, said of the difference between the two arms. “Also, the global bioavailability ratio increased by 59% in the arginine arm.”

Low plasma arginine levels are associated with acute pain requiring hospitalization in Nigerian children with sickle cell disease, and have also been shown in a prior study in the United States to predict pediatric vaso-occlusion, Dr. Onalo said, adding that arginine supplementation, which has known opioid-sparing effects, was found in another phase 2, randomized, placebo-controlled U.S. study to significantly decrease pain scores.

In the current study, the increase in arginine bioavailability inversely correlated with Medication Quantification Scale scores, which were 73 vs. 120 in the arginine and placebo arms, respectively (r = -0.35; P = .02), indicating reduced analgesic use in the arginine arm, he said.

“Clinically, the patients in the arginine arm also tended to have a faster resolution in their pain score,” he said.

Despite similar baseline Numerical Pain Scale (PS) scores (8.7 and 8.4 on a 0-10 scale), day 5 pain scores were 1.2 vs. 2.0, and the mean daily rate of decline was 1.5 vs. 1.1 cm/day.

Crisis resolution was achieved by 25% of the patients in the arginine arm in about 72 hours, compared with about 120 hours in the placebo arms.

“By day 5, 54% of patients on arginine were already home, as compared with just 24% in the placebo arm, and this was found to be clinically and statistically significant,” Dr. Onalo said, noting that mean hospital length of stay was 110 hours vs. 156 hours in the arginine and placebo arms, respectively.

A non–statistically significant decrease in mean total opioid dose was also observed in the arginine vs. placebo arms (3.8 vs 5.1 mg/kg; P = .11).

Arginine supplementation in this study was safe; no serious treatment-related adverse events occurred, and there were no significant differences between the groups in the incidence of adverse events. Dr. Onalo noted, however, that a trend toward more vomiting was observed in the arginine versus the placebo arm (20% vs. 3%, P = .07).

Severe vaso-occlusive pain episodes are a major cause of morbidity and mortality in sickle cell disease, and based on the prior findings – and the lack of data regarding the role of arginine for treating acute sickle cell-related vaso-occlusive pain episodes in sub-Saharan Africa – Dr. Onalo and colleagues set out to assess its role in that setting.

“Also, we are interested in finding a molecule that can be used easily by the patient at home, and also can be [self-administered],” he said.

Children enrolled in the double-blind study had a severe vaso-occlusive pain episode, defined by a PS score of at least 7 on a scale of 0-10, at one of two major hospitals in Abuja, Nigeria. All patients received pain management, including opioid and nonopioid analgesics, per institutional practice.

The findings reinforce the role of arginine in vaso-occlusive pain episodes, and suggest that oral arginine is a promising adjuvant therapy for vaso-occlusive crisis management in patients with sickle cell disease, he said.

“We recommend a phase 3 multicenter clinical trial,” he added.

As for a potential role for arginine in this setting in the United States, prevention trials in the U.S. have thus far been negative, said Julie Panepinto, MD, the press briefing moderator and a pediatric hematologist-oncologist at Children’s Hospital of Wisconsin, Milwaukee.

Sharon Worcester/MDedge News

“This is my first knowledge of use in the acute setting,” said Dr. Panepinto, also a professor at the Medical College of Wisconsin in Milwaukee. “There is going to be some future work looking at use of arginine in the U.S. for patients presenting with pain.”

For now, however, it’s too early to say that all patients should be started on arginine, she said, adding that more information is needed, including about appropriate dosing.

Nonetheless, it’s encouraging to see positive findings, she noted.

“We’ve been looking at and thinking about arginine for a long time, so I think this is a really exciting study ... that should lead us to future work to really understand better how to use the medication,” she said.

Dr. Onalo reported having no disclosures. Dr. Panepinto has received research funding from the National Institutes of Health and the Health Resources and Services Administration.

[email protected]

SOURCE: Onalo R et al. ASH 2019, Abstract 613.

ORLANDO – Oral arginine supplementation significantly increased plasma arginine levels and improved acute pain-related outcomes in Nigerian children with sickle cell disease in a randomized, placebo-controlled, phase 2 trial.

Andrew Bowser/MDedge News

Of 68 children with a mean age of 10 years who were hospitalized with vaso-occlusive crisis involving severe pain and treated with standard pain management, 35 were randomized to receive adjuvant oral L-arginine at a dose of 100 mg/kg every 8 hours for 5 days or until discharge, and 33 received placebo. Those in the arginine arm experienced a 125% increase in their plasma arginine level, compared with a 29% increase in the placebo arm, Richard Onalo, FC Paed, reported during a press briefing at the annual meeting of the American Society of Hematology.

“This was statistically significant,” Dr. Onalo, of the department of pediatrics at the University of Abuja, Nigeria, said of the difference between the two arms. “Also, the global bioavailability ratio increased by 59% in the arginine arm.”

Low plasma arginine levels are associated with acute pain requiring hospitalization in Nigerian children with sickle cell disease, and have also been shown in a prior study in the United States to predict pediatric vaso-occlusion, Dr. Onalo said, adding that arginine supplementation, which has known opioid-sparing effects, was found in another phase 2, randomized, placebo-controlled U.S. study to significantly decrease pain scores.

In the current study, the increase in arginine bioavailability inversely correlated with Medication Quantification Scale scores, which were 73 vs. 120 in the arginine and placebo arms, respectively (r = -0.35; P = .02), indicating reduced analgesic use in the arginine arm, he said.

“Clinically, the patients in the arginine arm also tended to have a faster resolution in their pain score,” he said.

Despite similar baseline Numerical Pain Scale (PS) scores (8.7 and 8.4 on a 0-10 scale), day 5 pain scores were 1.2 vs. 2.0, and the mean daily rate of decline was 1.5 vs. 1.1 cm/day.

Crisis resolution was achieved by 25% of the patients in the arginine arm in about 72 hours, compared with about 120 hours in the placebo arms.

“By day 5, 54% of patients on arginine were already home, as compared with just 24% in the placebo arm, and this was found to be clinically and statistically significant,” Dr. Onalo said, noting that mean hospital length of stay was 110 hours vs. 156 hours in the arginine and placebo arms, respectively.

A non–statistically significant decrease in mean total opioid dose was also observed in the arginine vs. placebo arms (3.8 vs 5.1 mg/kg; P = .11).

Arginine supplementation in this study was safe; no serious treatment-related adverse events occurred, and there were no significant differences between the groups in the incidence of adverse events. Dr. Onalo noted, however, that a trend toward more vomiting was observed in the arginine versus the placebo arm (20% vs. 3%, P = .07).

Severe vaso-occlusive pain episodes are a major cause of morbidity and mortality in sickle cell disease, and based on the prior findings – and the lack of data regarding the role of arginine for treating acute sickle cell-related vaso-occlusive pain episodes in sub-Saharan Africa – Dr. Onalo and colleagues set out to assess its role in that setting.

“Also, we are interested in finding a molecule that can be used easily by the patient at home, and also can be [self-administered],” he said.

Children enrolled in the double-blind study had a severe vaso-occlusive pain episode, defined by a PS score of at least 7 on a scale of 0-10, at one of two major hospitals in Abuja, Nigeria. All patients received pain management, including opioid and nonopioid analgesics, per institutional practice.

The findings reinforce the role of arginine in vaso-occlusive pain episodes, and suggest that oral arginine is a promising adjuvant therapy for vaso-occlusive crisis management in patients with sickle cell disease, he said.

“We recommend a phase 3 multicenter clinical trial,” he added.

As for a potential role for arginine in this setting in the United States, prevention trials in the U.S. have thus far been negative, said Julie Panepinto, MD, the press briefing moderator and a pediatric hematologist-oncologist at Children’s Hospital of Wisconsin, Milwaukee.

Sharon Worcester/MDedge News

“This is my first knowledge of use in the acute setting,” said Dr. Panepinto, also a professor at the Medical College of Wisconsin in Milwaukee. “There is going to be some future work looking at use of arginine in the U.S. for patients presenting with pain.”

For now, however, it’s too early to say that all patients should be started on arginine, she said, adding that more information is needed, including about appropriate dosing.

Nonetheless, it’s encouraging to see positive findings, she noted.

“We’ve been looking at and thinking about arginine for a long time, so I think this is a really exciting study ... that should lead us to future work to really understand better how to use the medication,” she said.

Dr. Onalo reported having no disclosures. Dr. Panepinto has received research funding from the National Institutes of Health and the Health Resources and Services Administration.

[email protected]

SOURCE: Onalo R et al. ASH 2019, Abstract 613.

ORLANDO – Oral arginine supplementation significantly increased plasma arginine levels and improved acute pain-related outcomes in Nigerian children with sickle cell disease in a randomized, placebo-controlled, phase 2 trial.

Andrew Bowser/MDedge News

Of 68 children with a mean age of 10 years who were hospitalized with vaso-occlusive crisis involving severe pain and treated with standard pain management, 35 were randomized to receive adjuvant oral L-arginine at a dose of 100 mg/kg every 8 hours for 5 days or until discharge, and 33 received placebo. Those in the arginine arm experienced a 125% increase in their plasma arginine level, compared with a 29% increase in the placebo arm, Richard Onalo, FC Paed, reported during a press briefing at the annual meeting of the American Society of Hematology.

“This was statistically significant,” Dr. Onalo, of the department of pediatrics at the University of Abuja, Nigeria, said of the difference between the two arms. “Also, the global bioavailability ratio increased by 59% in the arginine arm.”

Low plasma arginine levels are associated with acute pain requiring hospitalization in Nigerian children with sickle cell disease, and have also been shown in a prior study in the United States to predict pediatric vaso-occlusion, Dr. Onalo said, adding that arginine supplementation, which has known opioid-sparing effects, was found in another phase 2, randomized, placebo-controlled U.S. study to significantly decrease pain scores.

In the current study, the increase in arginine bioavailability inversely correlated with Medication Quantification Scale scores, which were 73 vs. 120 in the arginine and placebo arms, respectively (r = -0.35; P = .02), indicating reduced analgesic use in the arginine arm, he said.

“Clinically, the patients in the arginine arm also tended to have a faster resolution in their pain score,” he said.

Despite similar baseline Numerical Pain Scale (PS) scores (8.7 and 8.4 on a 0-10 scale), day 5 pain scores were 1.2 vs. 2.0, and the mean daily rate of decline was 1.5 vs. 1.1 cm/day.

Crisis resolution was achieved by 25% of the patients in the arginine arm in about 72 hours, compared with about 120 hours in the placebo arms.

“By day 5, 54% of patients on arginine were already home, as compared with just 24% in the placebo arm, and this was found to be clinically and statistically significant,” Dr. Onalo said, noting that mean hospital length of stay was 110 hours vs. 156 hours in the arginine and placebo arms, respectively.

A non–statistically significant decrease in mean total opioid dose was also observed in the arginine vs. placebo arms (3.8 vs 5.1 mg/kg; P = .11).

Arginine supplementation in this study was safe; no serious treatment-related adverse events occurred, and there were no significant differences between the groups in the incidence of adverse events. Dr. Onalo noted, however, that a trend toward more vomiting was observed in the arginine versus the placebo arm (20% vs. 3%, P = .07).

Severe vaso-occlusive pain episodes are a major cause of morbidity and mortality in sickle cell disease, and based on the prior findings – and the lack of data regarding the role of arginine for treating acute sickle cell-related vaso-occlusive pain episodes in sub-Saharan Africa – Dr. Onalo and colleagues set out to assess its role in that setting.

“Also, we are interested in finding a molecule that can be used easily by the patient at home, and also can be [self-administered],” he said.

Children enrolled in the double-blind study had a severe vaso-occlusive pain episode, defined by a PS score of at least 7 on a scale of 0-10, at one of two major hospitals in Abuja, Nigeria. All patients received pain management, including opioid and nonopioid analgesics, per institutional practice.

The findings reinforce the role of arginine in vaso-occlusive pain episodes, and suggest that oral arginine is a promising adjuvant therapy for vaso-occlusive crisis management in patients with sickle cell disease, he said.

“We recommend a phase 3 multicenter clinical trial,” he added.

As for a potential role for arginine in this setting in the United States, prevention trials in the U.S. have thus far been negative, said Julie Panepinto, MD, the press briefing moderator and a pediatric hematologist-oncologist at Children’s Hospital of Wisconsin, Milwaukee.

Sharon Worcester/MDedge News

“This is my first knowledge of use in the acute setting,” said Dr. Panepinto, also a professor at the Medical College of Wisconsin in Milwaukee. “There is going to be some future work looking at use of arginine in the U.S. for patients presenting with pain.”

For now, however, it’s too early to say that all patients should be started on arginine, she said, adding that more information is needed, including about appropriate dosing.

Nonetheless, it’s encouraging to see positive findings, she noted.

“We’ve been looking at and thinking about arginine for a long time, so I think this is a really exciting study ... that should lead us to future work to really understand better how to use the medication,” she said.

Dr. Onalo reported having no disclosures. Dr. Panepinto has received research funding from the National Institutes of Health and the Health Resources and Services Administration.

[email protected]

SOURCE: Onalo R et al. ASH 2019, Abstract 613.

ORLANDO – Preclinical research suggests nuclear factor I X is a fetal hemoglobin repressor, a finding that could have implications for the treatment of sickle cell disease.

Researchers found that knocking down nuclear factor I X (NFIX) in adult erythroblasts induced fetal hemoglobin expression in a vast majority of cells, and the total amount of fetal hemoglobin in those cells was about 40%. The target level of fetal hemoglobin for sickle cell patients to become asymptomatic is 30%, according to study investigator Jeffrey R. Shearstone, PhD, of Syros Pharmaceuticals in Cambridge, Mass. He made these remarks during a press conference at the annual meeting of the American Society of Hematology. Mudit Chaand, PhD, also of Syros, is scheduled to present the study at the meeting on Dec. 9, 2019.

“While this is obviously a preclinical, investigational study, to see levels of induction in primary cells and cell lines of 40% is very encouraging and shows that [NFIX] is a very potent fetal hemoglobin repressor,” Dr. Shearstone said. “We see this discovery as, potentially, a new avenue for therapeutic intervention in sickle cell disease, but there’s still a lot of work to be done.”

Syros researchers began this study by comparing erythroblasts derived from cord blood, which have high levels of fetal hemoglobin, and erythroblasts derived from bone marrow, which have low levels of fetal hemoglobin. The team’s goal was to identify transcription factors that might regulate the repression of fetal hemoglobin in adult cells.

Chromatin accessibility mapping pointed to NFIX as a hemoglobin repressor. The researchers observed increased accessibility at the NFIX promoter and elevated NFIX messenger RNA in adult cells.

To confirm NFIX’s role as a repressor of fetal hemoglobin, the researchers used short hairpin RNA to knock down NFIX in primary erythroblasts and cell lines.

“By knocking down NFIX, we saw a very robust induction of fetal hemoglobin,” Dr. Shearstone said. “We saw nearly 100% of cells in which NFIX was knocked down express fetal hemoglobin. This level of induction compared very favorably to probably the two most potent known repressors of fetal hemoglobin, ZBTB7A and BCL11A.”

Specifically, 86%-97% of cells with NFIX knockdown expressed fetal hemoglobin, compared with 16% of control cells, 88% of cells with BCL11A knockdown, and 91% of cells with ZBTB7A knockdown.

The total amount of fetal hemoglobin in erythroblasts with NFIX knockdown was 39%-40%.

The researchers plan to conduct additional studies to validate these results, examine how NFIX directly binds at the fetal globin promoter, determine if NFIX interacts with any previously identified fetal hemoglobin repressors, and investigate how NFIX can be shut down in patients with sickle cell disease. The researchers’ ultimate goal is to develop a small molecule that would target NFIX.

All researchers involved in this work are employees of Syros Pharmaceuticals.

[email protected]

SOURCE: Shearstone JR et al. ASH 2019, Abstract 821.

ORLANDO – Preclinical research suggests nuclear factor I X is a fetal hemoglobin repressor, a finding that could have implications for the treatment of sickle cell disease.

Researchers found that knocking down nuclear factor I X (NFIX) in adult erythroblasts induced fetal hemoglobin expression in a vast majority of cells, and the total amount of fetal hemoglobin in those cells was about 40%. The target level of fetal hemoglobin for sickle cell patients to become asymptomatic is 30%, according to study investigator Jeffrey R. Shearstone, PhD, of Syros Pharmaceuticals in Cambridge, Mass. He made these remarks during a press conference at the annual meeting of the American Society of Hematology. Mudit Chaand, PhD, also of Syros, is scheduled to present the study at the meeting on Dec. 9, 2019.

“While this is obviously a preclinical, investigational study, to see levels of induction in primary cells and cell lines of 40% is very encouraging and shows that [NFIX] is a very potent fetal hemoglobin repressor,” Dr. Shearstone said. “We see this discovery as, potentially, a new avenue for therapeutic intervention in sickle cell disease, but there’s still a lot of work to be done.”

Syros researchers began this study by comparing erythroblasts derived from cord blood, which have high levels of fetal hemoglobin, and erythroblasts derived from bone marrow, which have low levels of fetal hemoglobin. The team’s goal was to identify transcription factors that might regulate the repression of fetal hemoglobin in adult cells.

Chromatin accessibility mapping pointed to NFIX as a hemoglobin repressor. The researchers observed increased accessibility at the NFIX promoter and elevated NFIX messenger RNA in adult cells.

To confirm NFIX’s role as a repressor of fetal hemoglobin, the researchers used short hairpin RNA to knock down NFIX in primary erythroblasts and cell lines.

“By knocking down NFIX, we saw a very robust induction of fetal hemoglobin,” Dr. Shearstone said. “We saw nearly 100% of cells in which NFIX was knocked down express fetal hemoglobin. This level of induction compared very favorably to probably the two most potent known repressors of fetal hemoglobin, ZBTB7A and BCL11A.”

Specifically, 86%-97% of cells with NFIX knockdown expressed fetal hemoglobin, compared with 16% of control cells, 88% of cells with BCL11A knockdown, and 91% of cells with ZBTB7A knockdown.

The total amount of fetal hemoglobin in erythroblasts with NFIX knockdown was 39%-40%.

The researchers plan to conduct additional studies to validate these results, examine how NFIX directly binds at the fetal globin promoter, determine if NFIX interacts with any previously identified fetal hemoglobin repressors, and investigate how NFIX can be shut down in patients with sickle cell disease. The researchers’ ultimate goal is to develop a small molecule that would target NFIX.

All researchers involved in this work are employees of Syros Pharmaceuticals.

[email protected]

SOURCE: Shearstone JR et al. ASH 2019, Abstract 821.

ORLANDO – Preclinical research suggests nuclear factor I X is a fetal hemoglobin repressor, a finding that could have implications for the treatment of sickle cell disease.

Researchers found that knocking down nuclear factor I X (NFIX) in adult erythroblasts induced fetal hemoglobin expression in a vast majority of cells, and the total amount of fetal hemoglobin in those cells was about 40%. The target level of fetal hemoglobin for sickle cell patients to become asymptomatic is 30%, according to study investigator Jeffrey R. Shearstone, PhD, of Syros Pharmaceuticals in Cambridge, Mass. He made these remarks during a press conference at the annual meeting of the American Society of Hematology. Mudit Chaand, PhD, also of Syros, is scheduled to present the study at the meeting on Dec. 9, 2019.

“While this is obviously a preclinical, investigational study, to see levels of induction in primary cells and cell lines of 40% is very encouraging and shows that [NFIX] is a very potent fetal hemoglobin repressor,” Dr. Shearstone said. “We see this discovery as, potentially, a new avenue for therapeutic intervention in sickle cell disease, but there’s still a lot of work to be done.”

Syros researchers began this study by comparing erythroblasts derived from cord blood, which have high levels of fetal hemoglobin, and erythroblasts derived from bone marrow, which have low levels of fetal hemoglobin. The team’s goal was to identify transcription factors that might regulate the repression of fetal hemoglobin in adult cells.

Chromatin accessibility mapping pointed to NFIX as a hemoglobin repressor. The researchers observed increased accessibility at the NFIX promoter and elevated NFIX messenger RNA in adult cells.

To confirm NFIX’s role as a repressor of fetal hemoglobin, the researchers used short hairpin RNA to knock down NFIX in primary erythroblasts and cell lines.

“By knocking down NFIX, we saw a very robust induction of fetal hemoglobin,” Dr. Shearstone said. “We saw nearly 100% of cells in which NFIX was knocked down express fetal hemoglobin. This level of induction compared very favorably to probably the two most potent known repressors of fetal hemoglobin, ZBTB7A and BCL11A.”

Specifically, 86%-97% of cells with NFIX knockdown expressed fetal hemoglobin, compared with 16% of control cells, 88% of cells with BCL11A knockdown, and 91% of cells with ZBTB7A knockdown.

The total amount of fetal hemoglobin in erythroblasts with NFIX knockdown was 39%-40%.

The researchers plan to conduct additional studies to validate these results, examine how NFIX directly binds at the fetal globin promoter, determine if NFIX interacts with any previously identified fetal hemoglobin repressors, and investigate how NFIX can be shut down in patients with sickle cell disease. The researchers’ ultimate goal is to develop a small molecule that would target NFIX.

All researchers involved in this work are employees of Syros Pharmaceuticals.

[email protected]

SOURCE: Shearstone JR et al. ASH 2019, Abstract 821.

ORLANDO – While most children with sickle cell disease receive inpatient care at a single center, care starts to become fragmented in young adulthood, with patients admitted to as many as five centers or more over time, results of a retrospective study suggest.

Andrew D. Bowser/MDedge News

Nearly 60% of children between aged10-17 years were seen at just one facility over the course of 7 years in the analysis, which was based on analysis of data for nearly 7,000 patients seen in California during 1991-2016.

That contrasted sharply with young adults, aged 18-25 years, only about 20% of whom were admitted to one facility, said senior study author Anjlee Mahajan, MD, of the University of California, Davis, adding that another 20% were seen at five or more centers over a 7-year follow-up period.

Fragmentation of care didn’t increase the risk of death in this study, as investigators hypothesized it might. However, the outcomes and the quality of care among young adults with SCD who received inpatient care at multiple facilities nevertheless was likely to be affected, Dr. Mahajan said at the annual meeting of the American Society of Hematology.

“Imagine what that would be like to have a chronic, debilitating illness and to have to go to multiple different hospitals, during this vulnerable time period in your life, and being seen by different care providers who may not know you and may not have all of your records as well,” she said in a press conference at the meeting.

Providers and the health care system need to work harder to ensure young adults receive comprehensive and coordinated care, especially at a time when therapeutic advances are improving the treatment of this disease, according to the investigator.

“When you’re seen at one center, you can have a specific pain plan, and maybe when you are going into the emergency room and being admitted, your sickle cell care provider might come and visit you in the hospital or at least be in contact with your team,” Dr. Mahajan said in an interview. “That may not happen if you’re going to be seen at five different hospitals in 7 years.”

Encouraging the concept of “medical home” for SCD may be help ease transition from pediatric to adult care, thereby reducing fragmentation of care for young adults, according to Julie A. Panepinto, MD, professor of pediatric hematology and the director of the center for clinical effectiveness research at the Children’s Research Institute, Medical College of Wisconsin, Milwaukee.

“That 18- to 30-year-old age group historically and repeatedly over time is shown to be the age that relies on the emergency department and that has a higher mortality as they transition,” Dr. Panepinto said in an interview. “So ideally, you would have a pediatric program that’s comprehensive and that can transition an adult patient to a very similar setting with knowledgeable providers in SCD across the spectrum, from the emergency department to the hospital to the outpatient clinic.”

Dr. Mahajan reported no disclosures related to her group’s study. Coauthors provided disclosures related to Pfizer and Janssen.

SOURCE: Shatola A et al. ASH 2019. Abstract 4667.

ORLANDO – While most children with sickle cell disease receive inpatient care at a single center, care starts to become fragmented in young adulthood, with patients admitted to as many as five centers or more over time, results of a retrospective study suggest.

Andrew D. Bowser/MDedge News

Nearly 60% of children between aged10-17 years were seen at just one facility over the course of 7 years in the analysis, which was based on analysis of data for nearly 7,000 patients seen in California during 1991-2016.

That contrasted sharply with young adults, aged 18-25 years, only about 20% of whom were admitted to one facility, said senior study author Anjlee Mahajan, MD, of the University of California, Davis, adding that another 20% were seen at five or more centers over a 7-year follow-up period.

Fragmentation of care didn’t increase the risk of death in this study, as investigators hypothesized it might. However, the outcomes and the quality of care among young adults with SCD who received inpatient care at multiple facilities nevertheless was likely to be affected, Dr. Mahajan said at the annual meeting of the American Society of Hematology.

“Imagine what that would be like to have a chronic, debilitating illness and to have to go to multiple different hospitals, during this vulnerable time period in your life, and being seen by different care providers who may not know you and may not have all of your records as well,” she said in a press conference at the meeting.

Providers and the health care system need to work harder to ensure young adults receive comprehensive and coordinated care, especially at a time when therapeutic advances are improving the treatment of this disease, according to the investigator.

“When you’re seen at one center, you can have a specific pain plan, and maybe when you are going into the emergency room and being admitted, your sickle cell care provider might come and visit you in the hospital or at least be in contact with your team,” Dr. Mahajan said in an interview. “That may not happen if you’re going to be seen at five different hospitals in 7 years.”

Encouraging the concept of “medical home” for SCD may be help ease transition from pediatric to adult care, thereby reducing fragmentation of care for young adults, according to Julie A. Panepinto, MD, professor of pediatric hematology and the director of the center for clinical effectiveness research at the Children’s Research Institute, Medical College of Wisconsin, Milwaukee.

“That 18- to 30-year-old age group historically and repeatedly over time is shown to be the age that relies on the emergency department and that has a higher mortality as they transition,” Dr. Panepinto said in an interview. “So ideally, you would have a pediatric program that’s comprehensive and that can transition an adult patient to a very similar setting with knowledgeable providers in SCD across the spectrum, from the emergency department to the hospital to the outpatient clinic.”

Dr. Mahajan reported no disclosures related to her group’s study. Coauthors provided disclosures related to Pfizer and Janssen.

SOURCE: Shatola A et al. ASH 2019. Abstract 4667.

ORLANDO – While most children with sickle cell disease receive inpatient care at a single center, care starts to become fragmented in young adulthood, with patients admitted to as many as five centers or more over time, results of a retrospective study suggest.

Andrew D. Bowser/MDedge News

Nearly 60% of children between aged10-17 years were seen at just one facility over the course of 7 years in the analysis, which was based on analysis of data for nearly 7,000 patients seen in California during 1991-2016.

That contrasted sharply with young adults, aged 18-25 years, only about 20% of whom were admitted to one facility, said senior study author Anjlee Mahajan, MD, of the University of California, Davis, adding that another 20% were seen at five or more centers over a 7-year follow-up period.

Fragmentation of care didn’t increase the risk of death in this study, as investigators hypothesized it might. However, the outcomes and the quality of care among young adults with SCD who received inpatient care at multiple facilities nevertheless was likely to be affected, Dr. Mahajan said at the annual meeting of the American Society of Hematology.

“Imagine what that would be like to have a chronic, debilitating illness and to have to go to multiple different hospitals, during this vulnerable time period in your life, and being seen by different care providers who may not know you and may not have all of your records as well,” she said in a press conference at the meeting.

Providers and the health care system need to work harder to ensure young adults receive comprehensive and coordinated care, especially at a time when therapeutic advances are improving the treatment of this disease, according to the investigator.

“When you’re seen at one center, you can have a specific pain plan, and maybe when you are going into the emergency room and being admitted, your sickle cell care provider might come and visit you in the hospital or at least be in contact with your team,” Dr. Mahajan said in an interview. “That may not happen if you’re going to be seen at five different hospitals in 7 years.”

Encouraging the concept of “medical home” for SCD may be help ease transition from pediatric to adult care, thereby reducing fragmentation of care for young adults, according to Julie A. Panepinto, MD, professor of pediatric hematology and the director of the center for clinical effectiveness research at the Children’s Research Institute, Medical College of Wisconsin, Milwaukee.

“That 18- to 30-year-old age group historically and repeatedly over time is shown to be the age that relies on the emergency department and that has a higher mortality as they transition,” Dr. Panepinto said in an interview. “So ideally, you would have a pediatric program that’s comprehensive and that can transition an adult patient to a very similar setting with knowledgeable providers in SCD across the spectrum, from the emergency department to the hospital to the outpatient clinic.”

Dr. Mahajan reported no disclosures related to her group’s study. Coauthors provided disclosures related to Pfizer and Janssen.

SOURCE: Shatola A et al. ASH 2019. Abstract 4667.

In this edition of “How I Will Treat My Next Patient,” I highlight two recent drug approvals by the Food and Drug Administration – crizanlizumab for sickle cell patients with painful crises and zanubrutinib for mantle cell lymphoma (MCL) patients in relapse.

Crizanlizumab

P-selectin is an adhesion molecule expressed on activated vascular endothelial cells and platelets. It is a key molecule in the initiation of leukocyte rolling on vessel walls and promotes firm attachment and extravasation to underlying tissues during inflammation. Up-regulation of P-selectin on endothelial cells and platelets contributes to the cell-cell interactions involved in the pathogenesis of sickle cell pain crises.

The SUSTAIN study was a multisite, placebo-controlled, randomized phase 2 trial of two different dosage levels of intravenous crizanlizumab (2.5 mg/kg or 5 mg/kg for 52 weeks), a humanized anti–P-selectin antibody, examining its effect on pain crises in patients with sickle cell disease. The primary endpoint was the annual rate of sickle cell pain crises, with a variety of clinically relevant secondary endpoints. The target population had 2-10 pain crises in the 12 months before enrollment. Patients on a stable dose of hydroxyurea for at least the most recent 3 months were allowed to enter, but if patients were not receiving hydroxyurea, it could not be initiated during the trial. Patients who were undergoing chronic red-cell transfusion therapy were excluded.

Among 198 enrolled patients, 35% did not complete the 52 weeks of treatment. Discontinuations were equally balanced among patients assigned to the high-dose, low-dose, and placebo cohorts. Adverse events associated with crizanlizumab included back pain, nausea, pyrexia, and arthralgia. Serious adverse events occurred in 55 patients, with 5 deaths, all of which were unrelated to treatment. Crizanlizumab did not augment hemolysis or bacterial infections.

In the efficacy analysis, patients receiving high-dose crizanlizumab had a median annual rate of 1.63 health care visits for sickle cell pain crises, compared with 2.98 visits for placebo patients (P = .01). In comparison with placebo, high-dose crizanlizumab also delayed the first pain crisis after starting treatment (4.1 months vs. 1.4 months), delayed the median time to a second pain crisis, and decreased the median number of pain crises annually.

More than twice as many high-dose crizanlizumab patients had no pain crisis episodes, compared with placebo patients. In general, differences were more striking in patients who were not taking hydroxyurea and who had non–hemoglobin SS disease. Differences in the primary endpoint between low-dose crizanlizumab and placebo were numerically, but not statistically, different.

How these results influence practice

It has been over 20 years since a new agent (hydroxyurea) was approved for sickle cell patients and, despite its use, sickle cell pain crises remain a frequent problem. Pain crises are associated with worse quality of life and increased risk of death. A promising advance is badly needed, especially in an era in which sensitivity to providers’ role in the opioid addiction crisis is highly scrutinized and may contribute to future undertreatment of pain episodes. This is especially true for patients from areas with high levels of opioid misuse.

The SUSTAIN trial was international, multi-institutional, placebo-controlled, and inclusive. These attributes enhance the likelihood that crizanlizumab will enhance patient care in routine practice. As an intravenous agent, monitoring adherence and toxicity are less challenging than with hydroxyurea. Despite these factors, however, there are some concerns. Crizanlizumab was not free of toxicity, quality of life via the Brief Pain Inventory used in the trial was not improved, and changes in the pain-severity and pain-interference domains were small. Treatment in SUSTAIN ensued for 52 weeks, so the emergence of late neutralizing antibodies and late toxicities with longer-term therapy will require careful postmarketing assessment.

These concerns notwithstanding, anyone who has cared for sickle cell patients would be excited about the potential benefits crizanlizumab could bring to patient care.
 

Zanubrutinib

The FDA has approved zanubrutinib for the treatment of MCL in adult patients who have received at least one prior therapy. The approval is based on the results of two studies in which overall response rate was the primary endpoint.

BGB-3111-206 (NCT03206970) was a phase 2, open-label, multicenter, single-arm trial of 86 patients with MCL who received at least one prior therapy. Zanubrutinib was given orally at 160 mg twice daily until disease progression or unacceptable toxicity. BGB-3111-AU-003 (NCT 02343120) was a phase 1/2, open-label, dose-escalation trial of B-cell malignancies, including 32 previously treated MCL patients treated with zanubrutinib at 160 mg twice daily or 320 mg once daily.

In the phase 2 trial, 18fluorodeoxyglucose (FDG)–PET scans were required and the ORR was 84% (95% confidence interval, 74%-91%), with a complete response rate of 59% (95% CI, 48%-70%) and a median response duration of 19.5 months (95% CI, 16.6% to not estimable). In the phase 1/2 dose-escalation trial, FDG-PET scans were not required and the ORR was 84% (95% CI, 67%-95%), with a complete response rate of 22% (95% CI, 9%-40%) and a median response duration of 18.5 months (95% CI, 12.6% to not estimable). In both trials, median follow-up on study was about 18 months.

The most common adverse reactions were cytopenias, upper respiratory tract infection, rash, bruising, diarrhea, and cough. The most common serious adverse reactions were pneumonia in 11% and hemorrhage in 5% of patients. Of 118 MCL patients, 8 stopped therapy because of an adverse event, most frequently pneumonia (3.4%).

How these results influence practice

Unfortunately, the therapy of recurrent MCL is noncurative, because of the rapid development of treatment resistance. There are multiple single-and multiagent chemotherapy regimens that may be tried, many incorporating immunotherapy options such as anti-CD20- or Bruton tyrosine kinase (BTK)–targeted agents. Given the limited efficacy of these agents, temporary nature of remissions, and paucity of data comparing these various treatment options, participation in clinical trials is encouraged whenever possible.

Outside of a clinical trial, zanubrutinib joins ibrutinib and acalabrutinib as approved single-agent BTK inhibitors for adult MCL patients in relapse. The impressive ORR and response duration reported for zanubrutinib are similar to the results achieved with the other agents, but the toxicity pattern may be slightly different.

As in the treatment of hormonally sensitive breast cancer, clinicians and patients benefit when they have multiple similar, equally efficacious oral agents with slightly different toxicity patterns so that quality of life can be improved and treatment duration maximized before treatment resistance develops and a more toxic and/or inconvenient therapy needs to be employed.

Whether zanubrutinib has benefits beyond those for MCL patients in relapse will depend on the results of confirmatory trials and patient-reported outcome data.

Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.

In this edition of “How I Will Treat My Next Patient,” I highlight two recent drug approvals by the Food and Drug Administration – crizanlizumab for sickle cell patients with painful crises and zanubrutinib for mantle cell lymphoma (MCL) patients in relapse.

Crizanlizumab

P-selectin is an adhesion molecule expressed on activated vascular endothelial cells and platelets. It is a key molecule in the initiation of leukocyte rolling on vessel walls and promotes firm attachment and extravasation to underlying tissues during inflammation. Up-regulation of P-selectin on endothelial cells and platelets contributes to the cell-cell interactions involved in the pathogenesis of sickle cell pain crises.

The SUSTAIN study was a multisite, placebo-controlled, randomized phase 2 trial of two different dosage levels of intravenous crizanlizumab (2.5 mg/kg or 5 mg/kg for 52 weeks), a humanized anti–P-selectin antibody, examining its effect on pain crises in patients with sickle cell disease. The primary endpoint was the annual rate of sickle cell pain crises, with a variety of clinically relevant secondary endpoints. The target population had 2-10 pain crises in the 12 months before enrollment. Patients on a stable dose of hydroxyurea for at least the most recent 3 months were allowed to enter, but if patients were not receiving hydroxyurea, it could not be initiated during the trial. Patients who were undergoing chronic red-cell transfusion therapy were excluded.

Among 198 enrolled patients, 35% did not complete the 52 weeks of treatment. Discontinuations were equally balanced among patients assigned to the high-dose, low-dose, and placebo cohorts. Adverse events associated with crizanlizumab included back pain, nausea, pyrexia, and arthralgia. Serious adverse events occurred in 55 patients, with 5 deaths, all of which were unrelated to treatment. Crizanlizumab did not augment hemolysis or bacterial infections.

In the efficacy analysis, patients receiving high-dose crizanlizumab had a median annual rate of 1.63 health care visits for sickle cell pain crises, compared with 2.98 visits for placebo patients (P = .01). In comparison with placebo, high-dose crizanlizumab also delayed the first pain crisis after starting treatment (4.1 months vs. 1.4 months), delayed the median time to a second pain crisis, and decreased the median number of pain crises annually.

More than twice as many high-dose crizanlizumab patients had no pain crisis episodes, compared with placebo patients. In general, differences were more striking in patients who were not taking hydroxyurea and who had non–hemoglobin SS disease. Differences in the primary endpoint between low-dose crizanlizumab and placebo were numerically, but not statistically, different.

How these results influence practice

It has been over 20 years since a new agent (hydroxyurea) was approved for sickle cell patients and, despite its use, sickle cell pain crises remain a frequent problem. Pain crises are associated with worse quality of life and increased risk of death. A promising advance is badly needed, especially in an era in which sensitivity to providers’ role in the opioid addiction crisis is highly scrutinized and may contribute to future undertreatment of pain episodes. This is especially true for patients from areas with high levels of opioid misuse.

The SUSTAIN trial was international, multi-institutional, placebo-controlled, and inclusive. These attributes enhance the likelihood that crizanlizumab will enhance patient care in routine practice. As an intravenous agent, monitoring adherence and toxicity are less challenging than with hydroxyurea. Despite these factors, however, there are some concerns. Crizanlizumab was not free of toxicity, quality of life via the Brief Pain Inventory used in the trial was not improved, and changes in the pain-severity and pain-interference domains were small. Treatment in SUSTAIN ensued for 52 weeks, so the emergence of late neutralizing antibodies and late toxicities with longer-term therapy will require careful postmarketing assessment.

These concerns notwithstanding, anyone who has cared for sickle cell patients would be excited about the potential benefits crizanlizumab could bring to patient care.
 

Zanubrutinib

The FDA has approved zanubrutinib for the treatment of MCL in adult patients who have received at least one prior therapy. The approval is based on the results of two studies in which overall response rate was the primary endpoint.

BGB-3111-206 (NCT03206970) was a phase 2, open-label, multicenter, single-arm trial of 86 patients with MCL who received at least one prior therapy. Zanubrutinib was given orally at 160 mg twice daily until disease progression or unacceptable toxicity. BGB-3111-AU-003 (NCT 02343120) was a phase 1/2, open-label, dose-escalation trial of B-cell malignancies, including 32 previously treated MCL patients treated with zanubrutinib at 160 mg twice daily or 320 mg once daily.

In the phase 2 trial, 18fluorodeoxyglucose (FDG)–PET scans were required and the ORR was 84% (95% confidence interval, 74%-91%), with a complete response rate of 59% (95% CI, 48%-70%) and a median response duration of 19.5 months (95% CI, 16.6% to not estimable). In the phase 1/2 dose-escalation trial, FDG-PET scans were not required and the ORR was 84% (95% CI, 67%-95%), with a complete response rate of 22% (95% CI, 9%-40%) and a median response duration of 18.5 months (95% CI, 12.6% to not estimable). In both trials, median follow-up on study was about 18 months.

The most common adverse reactions were cytopenias, upper respiratory tract infection, rash, bruising, diarrhea, and cough. The most common serious adverse reactions were pneumonia in 11% and hemorrhage in 5% of patients. Of 118 MCL patients, 8 stopped therapy because of an adverse event, most frequently pneumonia (3.4%).

How these results influence practice

Unfortunately, the therapy of recurrent MCL is noncurative, because of the rapid development of treatment resistance. There are multiple single-and multiagent chemotherapy regimens that may be tried, many incorporating immunotherapy options such as anti-CD20- or Bruton tyrosine kinase (BTK)–targeted agents. Given the limited efficacy of these agents, temporary nature of remissions, and paucity of data comparing these various treatment options, participation in clinical trials is encouraged whenever possible.

Outside of a clinical trial, zanubrutinib joins ibrutinib and acalabrutinib as approved single-agent BTK inhibitors for adult MCL patients in relapse. The impressive ORR and response duration reported for zanubrutinib are similar to the results achieved with the other agents, but the toxicity pattern may be slightly different.

As in the treatment of hormonally sensitive breast cancer, clinicians and patients benefit when they have multiple similar, equally efficacious oral agents with slightly different toxicity patterns so that quality of life can be improved and treatment duration maximized before treatment resistance develops and a more toxic and/or inconvenient therapy needs to be employed.

Whether zanubrutinib has benefits beyond those for MCL patients in relapse will depend on the results of confirmatory trials and patient-reported outcome data.

Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.

In this edition of “How I Will Treat My Next Patient,” I highlight two recent drug approvals by the Food and Drug Administration – crizanlizumab for sickle cell patients with painful crises and zanubrutinib for mantle cell lymphoma (MCL) patients in relapse.

Crizanlizumab

P-selectin is an adhesion molecule expressed on activated vascular endothelial cells and platelets. It is a key molecule in the initiation of leukocyte rolling on vessel walls and promotes firm attachment and extravasation to underlying tissues during inflammation. Up-regulation of P-selectin on endothelial cells and platelets contributes to the cell-cell interactions involved in the pathogenesis of sickle cell pain crises.

The SUSTAIN study was a multisite, placebo-controlled, randomized phase 2 trial of two different dosage levels of intravenous crizanlizumab (2.5 mg/kg or 5 mg/kg for 52 weeks), a humanized anti–P-selectin antibody, examining its effect on pain crises in patients with sickle cell disease. The primary endpoint was the annual rate of sickle cell pain crises, with a variety of clinically relevant secondary endpoints. The target population had 2-10 pain crises in the 12 months before enrollment. Patients on a stable dose of hydroxyurea for at least the most recent 3 months were allowed to enter, but if patients were not receiving hydroxyurea, it could not be initiated during the trial. Patients who were undergoing chronic red-cell transfusion therapy were excluded.

Among 198 enrolled patients, 35% did not complete the 52 weeks of treatment. Discontinuations were equally balanced among patients assigned to the high-dose, low-dose, and placebo cohorts. Adverse events associated with crizanlizumab included back pain, nausea, pyrexia, and arthralgia. Serious adverse events occurred in 55 patients, with 5 deaths, all of which were unrelated to treatment. Crizanlizumab did not augment hemolysis or bacterial infections.

In the efficacy analysis, patients receiving high-dose crizanlizumab had a median annual rate of 1.63 health care visits for sickle cell pain crises, compared with 2.98 visits for placebo patients (P = .01). In comparison with placebo, high-dose crizanlizumab also delayed the first pain crisis after starting treatment (4.1 months vs. 1.4 months), delayed the median time to a second pain crisis, and decreased the median number of pain crises annually.

More than twice as many high-dose crizanlizumab patients had no pain crisis episodes, compared with placebo patients. In general, differences were more striking in patients who were not taking hydroxyurea and who had non–hemoglobin SS disease. Differences in the primary endpoint between low-dose crizanlizumab and placebo were numerically, but not statistically, different.

How these results influence practice

It has been over 20 years since a new agent (hydroxyurea) was approved for sickle cell patients and, despite its use, sickle cell pain crises remain a frequent problem. Pain crises are associated with worse quality of life and increased risk of death. A promising advance is badly needed, especially in an era in which sensitivity to providers’ role in the opioid addiction crisis is highly scrutinized and may contribute to future undertreatment of pain episodes. This is especially true for patients from areas with high levels of opioid misuse.

The SUSTAIN trial was international, multi-institutional, placebo-controlled, and inclusive. These attributes enhance the likelihood that crizanlizumab will enhance patient care in routine practice. As an intravenous agent, monitoring adherence and toxicity are less challenging than with hydroxyurea. Despite these factors, however, there are some concerns. Crizanlizumab was not free of toxicity, quality of life via the Brief Pain Inventory used in the trial was not improved, and changes in the pain-severity and pain-interference domains were small. Treatment in SUSTAIN ensued for 52 weeks, so the emergence of late neutralizing antibodies and late toxicities with longer-term therapy will require careful postmarketing assessment.

These concerns notwithstanding, anyone who has cared for sickle cell patients would be excited about the potential benefits crizanlizumab could bring to patient care.
 

Zanubrutinib

The FDA has approved zanubrutinib for the treatment of MCL in adult patients who have received at least one prior therapy. The approval is based on the results of two studies in which overall response rate was the primary endpoint.

BGB-3111-206 (NCT03206970) was a phase 2, open-label, multicenter, single-arm trial of 86 patients with MCL who received at least one prior therapy. Zanubrutinib was given orally at 160 mg twice daily until disease progression or unacceptable toxicity. BGB-3111-AU-003 (NCT 02343120) was a phase 1/2, open-label, dose-escalation trial of B-cell malignancies, including 32 previously treated MCL patients treated with zanubrutinib at 160 mg twice daily or 320 mg once daily.

In the phase 2 trial, 18fluorodeoxyglucose (FDG)–PET scans were required and the ORR was 84% (95% confidence interval, 74%-91%), with a complete response rate of 59% (95% CI, 48%-70%) and a median response duration of 19.5 months (95% CI, 16.6% to not estimable). In the phase 1/2 dose-escalation trial, FDG-PET scans were not required and the ORR was 84% (95% CI, 67%-95%), with a complete response rate of 22% (95% CI, 9%-40%) and a median response duration of 18.5 months (95% CI, 12.6% to not estimable). In both trials, median follow-up on study was about 18 months.

The most common adverse reactions were cytopenias, upper respiratory tract infection, rash, bruising, diarrhea, and cough. The most common serious adverse reactions were pneumonia in 11% and hemorrhage in 5% of patients. Of 118 MCL patients, 8 stopped therapy because of an adverse event, most frequently pneumonia (3.4%).

How these results influence practice

Unfortunately, the therapy of recurrent MCL is noncurative, because of the rapid development of treatment resistance. There are multiple single-and multiagent chemotherapy regimens that may be tried, many incorporating immunotherapy options such as anti-CD20- or Bruton tyrosine kinase (BTK)–targeted agents. Given the limited efficacy of these agents, temporary nature of remissions, and paucity of data comparing these various treatment options, participation in clinical trials is encouraged whenever possible.

Outside of a clinical trial, zanubrutinib joins ibrutinib and acalabrutinib as approved single-agent BTK inhibitors for adult MCL patients in relapse. The impressive ORR and response duration reported for zanubrutinib are similar to the results achieved with the other agents, but the toxicity pattern may be slightly different.

As in the treatment of hormonally sensitive breast cancer, clinicians and patients benefit when they have multiple similar, equally efficacious oral agents with slightly different toxicity patterns so that quality of life can be improved and treatment duration maximized before treatment resistance develops and a more toxic and/or inconvenient therapy needs to be employed.

Whether zanubrutinib has benefits beyond those for MCL patients in relapse will depend on the results of confirmatory trials and patient-reported outcome data.

Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.