Anemia

Eytan Stein, MD

Photo courtesy of ASH

SAN DIEGO—Daily treatment with enasidenib monotherapy in patients with mutated IDH2-positive myelodysplastic syndromes (MDS) induced responses in the majority of patients treated, according to a presentation at the 2016 ASH Annual Meeting.

The study was a portion of a larger phase 1/2 trial of the agent in patients with acute myeloid leukemia (AML) and other hematologic malignancies, so the subset was relatively small, numbering 17 patients.

Nevertheless, enasidenib was well tolerated and induced responses in these predominantly higher-risk patients.

Enasidenib (AG-221/CC-9007) is a selective, oral, potent inhibitor of mutant IDH2 (mIDH2), which produces 2-HG and thus alters DNA methylation and blocks cellular differentiation of hematopoietic progenitor cells.

Approximately 15% of AML patients and 5% of MDS patients have mIDH2. So investigators undertook the study to evaluate the safety and efficacy of enasidenib monotherapy in these diseases.

Eytan Stein, MD, of Memorial Sloan Kettering Cancer Center in New York, New York, presented the analysis of enasidenib in mIDH2-positive MDS patients as abstract 343.*

Study design

MDS patients were allowed to enroll during the dose-escalation and expansion phase of the study, Dr Stein explained.

Patients had to be 18 or older and have an advanced hematologic malignancy with mutated IDH2—relapsed or refractory AML, relapsed or refractory MDS, untreated AML, or other hematologic malignancy with mIDH2.

MDS patients could not be candidates for other therapies, had to be IPSS-R high risk, and had to have relapsed or refractory RAEB-1/RAEB-2 disease.

Investigators also performed co-molecular profiling using next-generation sequencing with a FoundationOne® Heme Panel.

All patients received daily oral enasidenib at 100 mg daily in 28-day cycles.

Patient characteristics

The study accrued a total of 239 patients—176 with relapsed or refractory AML, 37 with untreated AML, 9 with another hematologic malignancy, and 17 with MDS.

The median age of the MDS patients was 67 (range, 45-78), and 71% were male. All had the IDH2 mutation, 88% had R140 mutations, and 12% had R172.

Thirteen patients (76%) had an ECOG performance status of 0-1, and 4 (24%) had a performance status of 2.

A little more than a third (35%) of patients had 2 or more prior anti-cancer regimens.

Two patients (12%) received prior lenalidomide therapy, 8 (47%) received other treatments, including sorafenib (n=2) and vosaroxin, epoetin alfa, pracinostat, cytarabine plus clofarabine, ruxolitinib, and rigosertib (n=1 each). Four patients (24%) were untreated.

“I want to make the point,” Dr Stein said, “that, of those patients, three quarters of them, 76% [n=13], had received a prior hypomethylating agent, really understanding that this is a very poor-risk group of patients that we are studying here.”

About half of patients (47%) had intermediate-2/high IPSS risk status, good MDS cytogenetic risk, and high/very high IPSS-R risk status.

Adverse events

Grade 3-4 treatment-emergent adverse events (AEs) occurring in 2 or more patients were hyperbilirubinemia (n=5), pneumonia (n=4), thrombocytopenia (n=4), anemia (n=3), hypokalemia (n=3), dyspnea (n=2), and tumor lysis syndrome (n=2).

“As I’ve said in a number of meetings where I’ve talked about IDH2 inhibitors, and specifically enasidenib, the hyperbilirubinemia that is seen with this drug is an indirect hyperbilirubinemia,” Dr Stein said.

“A known off-target effect of this drug is inhibition of the UGT1a1 enzyme, which conjugates bilirubin, and this indirect hyperbilirubinemia, which is typically relatively mild [and] does not appear to have any clinical sequelae.”

Investigators considered 9 of the AEs reported for 6 patients to be drug-related.

Four serious enasidenib-related AEs included tumor lysis syndrome (n=2), increased blood bilirubin (n=1), and transaminitis (n=1).

There were no treatment-related deaths.

Response and survival

Ten of 17 patients (59%) achieved an overall response, defined as complete response (CR) plus partial response, plus marrow CR, plus hematologic improvement (HI).

One patient achieved CR, 1 had a partial response, 3 had marrow CR, and 5 had HI.

Dr Stein noted that, of the 13 patients who had received prior hypomethylating agent therapy, 7 (54%) had a response with enasidenib.

Of the patients who attained HI, 2 had trilineage and 2 had bilineage improvement.

The median time to response was 21 days (range, 10-87), and the median number of treatment cycles was 3.0.

Patients remained on study for up to 24 months. Four patients in hematologic remission are still on study, and 3 patients proceeded to stem cell or bone marrow transplant, Dr Stein said.

Two patients discontinued because of investigator decision, and 8 discontinued therapy due to death or disease progression.

The limitation of the study regarding overall survival, Dr Stein said, is that the number is very small.

At a median follow-up of 7.5 months, the median overall survival was not reached.

“So I’m not arguing that this is the end word of this,” he said. “This is going to be dynamic as more patients come on these studies. But I think it’s a nice indication that this treatment appears to be well-tolerated and doing good for a large subset of patients.”

Co-occurring mutations

The investigators also analyzed co-occurring mutations in 13 MDS patients.

The small patient population prevented the investigators from making definitive conclusions regarding potential correlations between response and co-mutations.

Nevertheless, Dr Stein said the analysis revealed something “very, very intriguing.”

He noted that 7 patients had ASXL1 mutations, and “those are typically patients who are bad actors.”

“Five of those 7 patients had a response,” Dr Stein said. “And of those 5, 3 of them had received a prior hypomethylating agent. I think it’s at least food for thought that you can salvage a patient who has failed a hypomethylating agent, with poor risk disease. I think this is very, very exciting.”

Celgene Corporation and its collaborator, Agios Pharmaceuticals, sponsored the trial.

*Information in the abstract differs from the presentation.

Eytan Stein, MD

Photo courtesy of ASH

SAN DIEGO—Daily treatment with enasidenib monotherapy in patients with mutated IDH2-positive myelodysplastic syndromes (MDS) induced responses in the majority of patients treated, according to a presentation at the 2016 ASH Annual Meeting.

The study was a portion of a larger phase 1/2 trial of the agent in patients with acute myeloid leukemia (AML) and other hematologic malignancies, so the subset was relatively small, numbering 17 patients.

Nevertheless, enasidenib was well tolerated and induced responses in these predominantly higher-risk patients.

Enasidenib (AG-221/CC-9007) is a selective, oral, potent inhibitor of mutant IDH2 (mIDH2), which produces 2-HG and thus alters DNA methylation and blocks cellular differentiation of hematopoietic progenitor cells.

Approximately 15% of AML patients and 5% of MDS patients have mIDH2. So investigators undertook the study to evaluate the safety and efficacy of enasidenib monotherapy in these diseases.

Eytan Stein, MD, of Memorial Sloan Kettering Cancer Center in New York, New York, presented the analysis of enasidenib in mIDH2-positive MDS patients as abstract 343.*

Study design

MDS patients were allowed to enroll during the dose-escalation and expansion phase of the study, Dr Stein explained.

Patients had to be 18 or older and have an advanced hematologic malignancy with mutated IDH2—relapsed or refractory AML, relapsed or refractory MDS, untreated AML, or other hematologic malignancy with mIDH2.

MDS patients could not be candidates for other therapies, had to be IPSS-R high risk, and had to have relapsed or refractory RAEB-1/RAEB-2 disease.

Investigators also performed co-molecular profiling using next-generation sequencing with a FoundationOne® Heme Panel.

All patients received daily oral enasidenib at 100 mg daily in 28-day cycles.

Patient characteristics

The study accrued a total of 239 patients—176 with relapsed or refractory AML, 37 with untreated AML, 9 with another hematologic malignancy, and 17 with MDS.

The median age of the MDS patients was 67 (range, 45-78), and 71% were male. All had the IDH2 mutation, 88% had R140 mutations, and 12% had R172.

Thirteen patients (76%) had an ECOG performance status of 0-1, and 4 (24%) had a performance status of 2.

A little more than a third (35%) of patients had 2 or more prior anti-cancer regimens.

Two patients (12%) received prior lenalidomide therapy, 8 (47%) received other treatments, including sorafenib (n=2) and vosaroxin, epoetin alfa, pracinostat, cytarabine plus clofarabine, ruxolitinib, and rigosertib (n=1 each). Four patients (24%) were untreated.

“I want to make the point,” Dr Stein said, “that, of those patients, three quarters of them, 76% [n=13], had received a prior hypomethylating agent, really understanding that this is a very poor-risk group of patients that we are studying here.”

About half of patients (47%) had intermediate-2/high IPSS risk status, good MDS cytogenetic risk, and high/very high IPSS-R risk status.

Adverse events

Grade 3-4 treatment-emergent adverse events (AEs) occurring in 2 or more patients were hyperbilirubinemia (n=5), pneumonia (n=4), thrombocytopenia (n=4), anemia (n=3), hypokalemia (n=3), dyspnea (n=2), and tumor lysis syndrome (n=2).

“As I’ve said in a number of meetings where I’ve talked about IDH2 inhibitors, and specifically enasidenib, the hyperbilirubinemia that is seen with this drug is an indirect hyperbilirubinemia,” Dr Stein said.

“A known off-target effect of this drug is inhibition of the UGT1a1 enzyme, which conjugates bilirubin, and this indirect hyperbilirubinemia, which is typically relatively mild [and] does not appear to have any clinical sequelae.”

Investigators considered 9 of the AEs reported for 6 patients to be drug-related.

Four serious enasidenib-related AEs included tumor lysis syndrome (n=2), increased blood bilirubin (n=1), and transaminitis (n=1).

There were no treatment-related deaths.

Response and survival

Ten of 17 patients (59%) achieved an overall response, defined as complete response (CR) plus partial response, plus marrow CR, plus hematologic improvement (HI).

One patient achieved CR, 1 had a partial response, 3 had marrow CR, and 5 had HI.

Dr Stein noted that, of the 13 patients who had received prior hypomethylating agent therapy, 7 (54%) had a response with enasidenib.

Of the patients who attained HI, 2 had trilineage and 2 had bilineage improvement.

The median time to response was 21 days (range, 10-87), and the median number of treatment cycles was 3.0.

Patients remained on study for up to 24 months. Four patients in hematologic remission are still on study, and 3 patients proceeded to stem cell or bone marrow transplant, Dr Stein said.

Two patients discontinued because of investigator decision, and 8 discontinued therapy due to death or disease progression.

The limitation of the study regarding overall survival, Dr Stein said, is that the number is very small.

At a median follow-up of 7.5 months, the median overall survival was not reached.

“So I’m not arguing that this is the end word of this,” he said. “This is going to be dynamic as more patients come on these studies. But I think it’s a nice indication that this treatment appears to be well-tolerated and doing good for a large subset of patients.”

Co-occurring mutations

The investigators also analyzed co-occurring mutations in 13 MDS patients.

The small patient population prevented the investigators from making definitive conclusions regarding potential correlations between response and co-mutations.

Nevertheless, Dr Stein said the analysis revealed something “very, very intriguing.”

He noted that 7 patients had ASXL1 mutations, and “those are typically patients who are bad actors.”

“Five of those 7 patients had a response,” Dr Stein said. “And of those 5, 3 of them had received a prior hypomethylating agent. I think it’s at least food for thought that you can salvage a patient who has failed a hypomethylating agent, with poor risk disease. I think this is very, very exciting.”

Celgene Corporation and its collaborator, Agios Pharmaceuticals, sponsored the trial.

*Information in the abstract differs from the presentation.

Eytan Stein, MD

Photo courtesy of ASH

SAN DIEGO—Daily treatment with enasidenib monotherapy in patients with mutated IDH2-positive myelodysplastic syndromes (MDS) induced responses in the majority of patients treated, according to a presentation at the 2016 ASH Annual Meeting.

The study was a portion of a larger phase 1/2 trial of the agent in patients with acute myeloid leukemia (AML) and other hematologic malignancies, so the subset was relatively small, numbering 17 patients.

Nevertheless, enasidenib was well tolerated and induced responses in these predominantly higher-risk patients.

Enasidenib (AG-221/CC-9007) is a selective, oral, potent inhibitor of mutant IDH2 (mIDH2), which produces 2-HG and thus alters DNA methylation and blocks cellular differentiation of hematopoietic progenitor cells.

Approximately 15% of AML patients and 5% of MDS patients have mIDH2. So investigators undertook the study to evaluate the safety and efficacy of enasidenib monotherapy in these diseases.

Eytan Stein, MD, of Memorial Sloan Kettering Cancer Center in New York, New York, presented the analysis of enasidenib in mIDH2-positive MDS patients as abstract 343.*

Study design

MDS patients were allowed to enroll during the dose-escalation and expansion phase of the study, Dr Stein explained.

Patients had to be 18 or older and have an advanced hematologic malignancy with mutated IDH2—relapsed or refractory AML, relapsed or refractory MDS, untreated AML, or other hematologic malignancy with mIDH2.

MDS patients could not be candidates for other therapies, had to be IPSS-R high risk, and had to have relapsed or refractory RAEB-1/RAEB-2 disease.

Investigators also performed co-molecular profiling using next-generation sequencing with a FoundationOne® Heme Panel.

All patients received daily oral enasidenib at 100 mg daily in 28-day cycles.

Patient characteristics

The study accrued a total of 239 patients—176 with relapsed or refractory AML, 37 with untreated AML, 9 with another hematologic malignancy, and 17 with MDS.

The median age of the MDS patients was 67 (range, 45-78), and 71% were male. All had the IDH2 mutation, 88% had R140 mutations, and 12% had R172.

Thirteen patients (76%) had an ECOG performance status of 0-1, and 4 (24%) had a performance status of 2.

A little more than a third (35%) of patients had 2 or more prior anti-cancer regimens.

Two patients (12%) received prior lenalidomide therapy, 8 (47%) received other treatments, including sorafenib (n=2) and vosaroxin, epoetin alfa, pracinostat, cytarabine plus clofarabine, ruxolitinib, and rigosertib (n=1 each). Four patients (24%) were untreated.

“I want to make the point,” Dr Stein said, “that, of those patients, three quarters of them, 76% [n=13], had received a prior hypomethylating agent, really understanding that this is a very poor-risk group of patients that we are studying here.”

About half of patients (47%) had intermediate-2/high IPSS risk status, good MDS cytogenetic risk, and high/very high IPSS-R risk status.

Adverse events

Grade 3-4 treatment-emergent adverse events (AEs) occurring in 2 or more patients were hyperbilirubinemia (n=5), pneumonia (n=4), thrombocytopenia (n=4), anemia (n=3), hypokalemia (n=3), dyspnea (n=2), and tumor lysis syndrome (n=2).

“As I’ve said in a number of meetings where I’ve talked about IDH2 inhibitors, and specifically enasidenib, the hyperbilirubinemia that is seen with this drug is an indirect hyperbilirubinemia,” Dr Stein said.

“A known off-target effect of this drug is inhibition of the UGT1a1 enzyme, which conjugates bilirubin, and this indirect hyperbilirubinemia, which is typically relatively mild [and] does not appear to have any clinical sequelae.”

Investigators considered 9 of the AEs reported for 6 patients to be drug-related.

Four serious enasidenib-related AEs included tumor lysis syndrome (n=2), increased blood bilirubin (n=1), and transaminitis (n=1).

There were no treatment-related deaths.

Response and survival

Ten of 17 patients (59%) achieved an overall response, defined as complete response (CR) plus partial response, plus marrow CR, plus hematologic improvement (HI).

One patient achieved CR, 1 had a partial response, 3 had marrow CR, and 5 had HI.

Dr Stein noted that, of the 13 patients who had received prior hypomethylating agent therapy, 7 (54%) had a response with enasidenib.

Of the patients who attained HI, 2 had trilineage and 2 had bilineage improvement.

The median time to response was 21 days (range, 10-87), and the median number of treatment cycles was 3.0.

Patients remained on study for up to 24 months. Four patients in hematologic remission are still on study, and 3 patients proceeded to stem cell or bone marrow transplant, Dr Stein said.

Two patients discontinued because of investigator decision, and 8 discontinued therapy due to death or disease progression.

The limitation of the study regarding overall survival, Dr Stein said, is that the number is very small.

At a median follow-up of 7.5 months, the median overall survival was not reached.

“So I’m not arguing that this is the end word of this,” he said. “This is going to be dynamic as more patients come on these studies. But I think it’s a nice indication that this treatment appears to be well-tolerated and doing good for a large subset of patients.”

Co-occurring mutations

The investigators also analyzed co-occurring mutations in 13 MDS patients.

The small patient population prevented the investigators from making definitive conclusions regarding potential correlations between response and co-mutations.

Nevertheless, Dr Stein said the analysis revealed something “very, very intriguing.”

He noted that 7 patients had ASXL1 mutations, and “those are typically patients who are bad actors.”

“Five of those 7 patients had a response,” Dr Stein said. “And of those 5, 3 of them had received a prior hypomethylating agent. I think it’s at least food for thought that you can salvage a patient who has failed a hypomethylating agent, with poor risk disease. I think this is very, very exciting.”

Celgene Corporation and its collaborator, Agios Pharmaceuticals, sponsored the trial.

*Information in the abstract differs from the presentation.

Micrograph showing sickled

and normal red blood cells

Image by Graham Beards

Researchers say they have identified a genetic risk profile that can be used to predict which patients with sickle cell anemia (SCA) are likely to develop chronic kidney disease (CKD).

The team found evidence to suggest that a profile incorporating APOL1 G1/G2, α-thalassemia, and BCL11A can help physicians categorize SCA patients as having a high or low risk of CKD.

The researchers reported these findings in Haematologica.

Identifying SCA patients at the greatest risk of CKD can help physicians develop proactive, individualized strategies to reduce the high rate of early mortality due to CKD, said study author Santosh Saraf, MD, of the University of Illinois at Chicago.

“We looked at the genetic factors already known to be associated with kidney disease or the degree of red blood cell hemolysis and examined the relationship they had with the condition in sickle cell patients,” Dr Saraf said.

“Our hypothesis was that a genetic risk profile that integrated APOL1, α-thalassemia, and BCL11A would improve our ability to predict a patient’s risk for developing chronic kidney disease.”

To test this theory, Dr Saraf and his colleagues recruited 262 adult patients with SCA treated at a single center between 2010 and 2016. The team collected patient data, drew blood, analyzed genetic markers, and prospectively followed the patients to see if they developed CKD.

Stratification

The researchers used their genetic profile to stratify patients according to risk for CKD.

Patients were considered high-risk if they had APOL1 G1/G2 and wild-type BCL11A but did not have α-thalassemia.

Patients were considered low-risk if they were negative for APOL1 G1/G2 but had α-thalassemia (either α-/αα or α-/α-) and the BCL11A rs1427407 T allele (either G/T or T/T).

The researchers defined all other combinations as intermediate-risk.

The team found the genetic profile identified SCA patients at high and low risk for albuminuria or an estimated glomerular filtration rate less than 60 mL/min/1.73m².

The researchers also said application of the genetic profile revealed progressively higher rates of CKD progression.

Mechanisms

Dr Saraf and his colleagues noted that homozygosity or compound heterozygosity for APOL1 G1/G2 is the strongest genetic association for CKD in African Americans, and APOL1 G1/G2 is associated with proteinuria and albuminuria in SCA patients.

The researchers pointed out that APOL1 G1/G2 variants associate with CKD in African

Americans by unknown mechanisms, but the team found an association with

hemolysis in SCA, as reflected by hemoglobinuria.

As for α-thalassemia, it’s associated with reduced hemolysis and protection from albuminuria. The researchers said α-thalassemia reduces hemolysis in SCA by decreasing the

intra-erythrocyte concentration of sickle hemoglobin (HbS) and reducing

HbS polymerization.

Finally, Dr Saraf and his colleagues noted that BCL11A rs1427407 leads to higher fetal hemoglobin (HbF) levels, reduced hemolysis, and amelioration of SCA-related complications. The team said the BCL11A rs1427407 T variant leads to decreased function of BCL11A at the HbF promoter and therefore increases HbF, leading to decreased HbS polymerization.

“The results of this study are encouraging,” Dr Saraf said. “By understanding more about the genetic risk factors of kidney disease in sickle cell patients, we are one step closer to improving the length and quality of life for the millions of people worldwide living with sickle cell disease.”

“Using combinations of genes to better predict complications in sickle cell anemia is a new approach,” added study author Victor Gordeuk, MD, of the University of Illinois at Chicago.

“The results of this study indicate that it is effective and probably can be improved on in the future to be an important part of our evaluation of patients.”

The researchers said the small sample size and observational nature of this study are limitations, and they hope to validate the results with larger studies.

Micrograph showing sickled

and normal red blood cells

Image by Graham Beards

Researchers say they have identified a genetic risk profile that can be used to predict which patients with sickle cell anemia (SCA) are likely to develop chronic kidney disease (CKD).

The team found evidence to suggest that a profile incorporating APOL1 G1/G2, α-thalassemia, and BCL11A can help physicians categorize SCA patients as having a high or low risk of CKD.

The researchers reported these findings in Haematologica.

Identifying SCA patients at the greatest risk of CKD can help physicians develop proactive, individualized strategies to reduce the high rate of early mortality due to CKD, said study author Santosh Saraf, MD, of the University of Illinois at Chicago.

“We looked at the genetic factors already known to be associated with kidney disease or the degree of red blood cell hemolysis and examined the relationship they had with the condition in sickle cell patients,” Dr Saraf said.

“Our hypothesis was that a genetic risk profile that integrated APOL1, α-thalassemia, and BCL11A would improve our ability to predict a patient’s risk for developing chronic kidney disease.”

To test this theory, Dr Saraf and his colleagues recruited 262 adult patients with SCA treated at a single center between 2010 and 2016. The team collected patient data, drew blood, analyzed genetic markers, and prospectively followed the patients to see if they developed CKD.

Stratification

The researchers used their genetic profile to stratify patients according to risk for CKD.

Patients were considered high-risk if they had APOL1 G1/G2 and wild-type BCL11A but did not have α-thalassemia.

Patients were considered low-risk if they were negative for APOL1 G1/G2 but had α-thalassemia (either α-/αα or α-/α-) and the BCL11A rs1427407 T allele (either G/T or T/T).

The researchers defined all other combinations as intermediate-risk.

The team found the genetic profile identified SCA patients at high and low risk for albuminuria or an estimated glomerular filtration rate less than 60 mL/min/1.73m².

The researchers also said application of the genetic profile revealed progressively higher rates of CKD progression.

Mechanisms

Dr Saraf and his colleagues noted that homozygosity or compound heterozygosity for APOL1 G1/G2 is the strongest genetic association for CKD in African Americans, and APOL1 G1/G2 is associated with proteinuria and albuminuria in SCA patients.

The researchers pointed out that APOL1 G1/G2 variants associate with CKD in African

Americans by unknown mechanisms, but the team found an association with

hemolysis in SCA, as reflected by hemoglobinuria.

As for α-thalassemia, it’s associated with reduced hemolysis and protection from albuminuria. The researchers said α-thalassemia reduces hemolysis in SCA by decreasing the

intra-erythrocyte concentration of sickle hemoglobin (HbS) and reducing

HbS polymerization.

Finally, Dr Saraf and his colleagues noted that BCL11A rs1427407 leads to higher fetal hemoglobin (HbF) levels, reduced hemolysis, and amelioration of SCA-related complications. The team said the BCL11A rs1427407 T variant leads to decreased function of BCL11A at the HbF promoter and therefore increases HbF, leading to decreased HbS polymerization.

“The results of this study are encouraging,” Dr Saraf said. “By understanding more about the genetic risk factors of kidney disease in sickle cell patients, we are one step closer to improving the length and quality of life for the millions of people worldwide living with sickle cell disease.”

“Using combinations of genes to better predict complications in sickle cell anemia is a new approach,” added study author Victor Gordeuk, MD, of the University of Illinois at Chicago.

“The results of this study indicate that it is effective and probably can be improved on in the future to be an important part of our evaluation of patients.”

The researchers said the small sample size and observational nature of this study are limitations, and they hope to validate the results with larger studies.

Micrograph showing sickled

and normal red blood cells

Image by Graham Beards

Researchers say they have identified a genetic risk profile that can be used to predict which patients with sickle cell anemia (SCA) are likely to develop chronic kidney disease (CKD).

The team found evidence to suggest that a profile incorporating APOL1 G1/G2, α-thalassemia, and BCL11A can help physicians categorize SCA patients as having a high or low risk of CKD.

The researchers reported these findings in Haematologica.

Identifying SCA patients at the greatest risk of CKD can help physicians develop proactive, individualized strategies to reduce the high rate of early mortality due to CKD, said study author Santosh Saraf, MD, of the University of Illinois at Chicago.

“We looked at the genetic factors already known to be associated with kidney disease or the degree of red blood cell hemolysis and examined the relationship they had with the condition in sickle cell patients,” Dr Saraf said.

“Our hypothesis was that a genetic risk profile that integrated APOL1, α-thalassemia, and BCL11A would improve our ability to predict a patient’s risk for developing chronic kidney disease.”

To test this theory, Dr Saraf and his colleagues recruited 262 adult patients with SCA treated at a single center between 2010 and 2016. The team collected patient data, drew blood, analyzed genetic markers, and prospectively followed the patients to see if they developed CKD.

Stratification

The researchers used their genetic profile to stratify patients according to risk for CKD.

Patients were considered high-risk if they had APOL1 G1/G2 and wild-type BCL11A but did not have α-thalassemia.

Patients were considered low-risk if they were negative for APOL1 G1/G2 but had α-thalassemia (either α-/αα or α-/α-) and the BCL11A rs1427407 T allele (either G/T or T/T).

The researchers defined all other combinations as intermediate-risk.

The team found the genetic profile identified SCA patients at high and low risk for albuminuria or an estimated glomerular filtration rate less than 60 mL/min/1.73m².

The researchers also said application of the genetic profile revealed progressively higher rates of CKD progression.

Mechanisms

Dr Saraf and his colleagues noted that homozygosity or compound heterozygosity for APOL1 G1/G2 is the strongest genetic association for CKD in African Americans, and APOL1 G1/G2 is associated with proteinuria and albuminuria in SCA patients.

The researchers pointed out that APOL1 G1/G2 variants associate with CKD in African

Americans by unknown mechanisms, but the team found an association with

hemolysis in SCA, as reflected by hemoglobinuria.

As for α-thalassemia, it’s associated with reduced hemolysis and protection from albuminuria. The researchers said α-thalassemia reduces hemolysis in SCA by decreasing the

intra-erythrocyte concentration of sickle hemoglobin (HbS) and reducing

HbS polymerization.

Finally, Dr Saraf and his colleagues noted that BCL11A rs1427407 leads to higher fetal hemoglobin (HbF) levels, reduced hemolysis, and amelioration of SCA-related complications. The team said the BCL11A rs1427407 T variant leads to decreased function of BCL11A at the HbF promoter and therefore increases HbF, leading to decreased HbS polymerization.

“The results of this study are encouraging,” Dr Saraf said. “By understanding more about the genetic risk factors of kidney disease in sickle cell patients, we are one step closer to improving the length and quality of life for the millions of people worldwide living with sickle cell disease.”

“Using combinations of genes to better predict complications in sickle cell anemia is a new approach,” added study author Victor Gordeuk, MD, of the University of Illinois at Chicago.

“The results of this study indicate that it is effective and probably can be improved on in the future to be an important part of our evaluation of patients.”

The researchers said the small sample size and observational nature of this study are limitations, and they hope to validate the results with larger studies.

Kenneth Ataga, MD

Photo courtesy of ASH

SAN DIEGO—The first-in-class humanized anti-P-selectin antibody SelG1, also known as crizanlizumab, significantly reduced sickle cell pain crises (SCPC) when compared to placebo in the phase 2 SUSTAIN trial.

The higher dose of SelG1 tested reduced the annual rate of SCPC by 45% (P=0.01) and the annual rate of uncomplicated SCPC by 63% (P=0.015).

Acute painful crises are the primary cause for patients with sickle cell disease (SCD) to seek medical attention.

Kenneth I. Ataga, MD, of the University of North Carolina at Chapel Hill, explained that upregulation of P-selectin on endothelial cells and platelets contributes to the cell-cell interaction involved in the pathogenesis of SCPC. SelG1 binds to P-selectin and inhibits its interaction with P-selectin glycoprotein ligand 1.

Dr Ataga presented results from the SUSTAIN study during the plenary session of the 2016 ASH Annual Meeting (abstract 1).

The study was also published in NEJM. The research was sponsored by Selexys Pharmaceuticals Corporation, which was recently acquired by Novartis.

Patient population

A total of 198 patients were randomized, 67 to high-dose SelG1 (5.0 mg/kg), 66 to low-dose SelG1 (2.5 mg/kg), and 65 to placebo.

They received a loading dose in the first 2 weeks of treatment, followed by monthly dosing for a year.

Patients had to have a diagnosis of SCD, including genotypes HbSS, HbSC, HbSb⁰-thalassemia, or HbSB⁺-thalassemia.

They had to have at least 2 but not more than 10 acute sickle-related pain events within 12 months of study entry.

Patients ranged in age from 16 to 57 years, about 70% had HbSS, and 60% were on concomitant hydroxyurea therapy.

Patients not already receiving hydroxyurea were not permitted to start it during the study. And patients could not be on chronic transfusion therapy.

Study endpoints

The primary endpoint was the annual rate of adjudicated SCPC.

“Painful crisis was defined as an active episode of pain, and it was felt to be related to sickle cell disease-specific events and no other medically defined causes,” Dr Ataga explained.

The pain episodes also had to result in a visit to a medical facility and require treatment with parenteral or oral narcotics or parenteral nonsteroidal anti-inflammatory drugs.

The definition of SCPC included not only typical painful episodes but also acute chest syndrome (ACS), hepatic or splenic sequestration, and priapism.

Secondary endpoints included the annual rate of days hospitalized, time to first and second SCPC, the annual rate of uncomplicated pain crises, and the annual rate of ACS, among others.

Efficacy

The median annual rate of SCPC was 1.63 in the high-dose arm, 2.01 in the low-dose arm, and 2.98 in the placebo arm, amounting to a significant 45.3% reduction with the higher dose of SelG1 compared to placebo. The low dose resulted in a reduction of 32.6% compared to placebo, but this was not significant.

Twenty-four patients in the high-dose arm had an SCPC rate of 0, compared with 12 in the low-dose arm and 11 on placebo.

SCD genotype or concomitant hydroxyurea use did not impact these results.

Patients in the high-dose arm had a median annual rate of 4 hospitalization days, compared with 6.87 in both the low-dose and placebo groups. The difference was not significant, although the reduction in the high-dose arm was 41.8%.

The median annual rate of uncomplicated SCPC was 1.08 in the high-dose arm, 2.00 in the low-dose arm, and 2.91 in the placebo arm. Uncomplicated SCPC excluded ACS, splenic or hepatic sequestration, and priapism.

The reduction in the high-dose arm compared to placebo was significant, at 62.9% (P=0.015).

“The rate of ACS was pretty rare,” Dr Ataga said, “so the median rate across the various groups was 0.”

And time to the first SCPC was 4.1 months (P=0.001) in the high-dose group, 2.2 months (P=0.136) in the low-dose group, and 1.4 months in the placebo group.

“The curves separated pretty early,” Dr Ataga noted, “and were maintained throughout the course of the treatment phase, suggesting that the beneficial effect of SelG1 manifested pretty early following initiation of treatment.”

The time to second event was also significant in the high-dose arm compared to placebo, at 10.3 months and 5.1 months, respectively (P=0.022).

Safety

One or more adverse events occurred in over 85% of patients in each group.

Adverse events that occurred in at least 10% of SelG1-treated patients and amounted to at least double the number in the placebo group were arthralgia, diarrhea, pruritus, vomiting, and chest pain.

Five patients died while on study, but none of these deaths were related to the study drug.

Despite the adverse events, Dr Ataga said the drug was, overall, well-tolerated among the patients who received treatment.

Kenneth Ataga, MD

Photo courtesy of ASH

SAN DIEGO—The first-in-class humanized anti-P-selectin antibody SelG1, also known as crizanlizumab, significantly reduced sickle cell pain crises (SCPC) when compared to placebo in the phase 2 SUSTAIN trial.

The higher dose of SelG1 tested reduced the annual rate of SCPC by 45% (P=0.01) and the annual rate of uncomplicated SCPC by 63% (P=0.015).

Acute painful crises are the primary cause for patients with sickle cell disease (SCD) to seek medical attention.

Kenneth I. Ataga, MD, of the University of North Carolina at Chapel Hill, explained that upregulation of P-selectin on endothelial cells and platelets contributes to the cell-cell interaction involved in the pathogenesis of SCPC. SelG1 binds to P-selectin and inhibits its interaction with P-selectin glycoprotein ligand 1.

Dr Ataga presented results from the SUSTAIN study during the plenary session of the 2016 ASH Annual Meeting (abstract 1).

The study was also published in NEJM. The research was sponsored by Selexys Pharmaceuticals Corporation, which was recently acquired by Novartis.

Patient population

A total of 198 patients were randomized, 67 to high-dose SelG1 (5.0 mg/kg), 66 to low-dose SelG1 (2.5 mg/kg), and 65 to placebo.

They received a loading dose in the first 2 weeks of treatment, followed by monthly dosing for a year.

Patients had to have a diagnosis of SCD, including genotypes HbSS, HbSC, HbSb⁰-thalassemia, or HbSB⁺-thalassemia.

They had to have at least 2 but not more than 10 acute sickle-related pain events within 12 months of study entry.

Patients ranged in age from 16 to 57 years, about 70% had HbSS, and 60% were on concomitant hydroxyurea therapy.

Patients not already receiving hydroxyurea were not permitted to start it during the study. And patients could not be on chronic transfusion therapy.

Study endpoints

The primary endpoint was the annual rate of adjudicated SCPC.

“Painful crisis was defined as an active episode of pain, and it was felt to be related to sickle cell disease-specific events and no other medically defined causes,” Dr Ataga explained.

The pain episodes also had to result in a visit to a medical facility and require treatment with parenteral or oral narcotics or parenteral nonsteroidal anti-inflammatory drugs.

The definition of SCPC included not only typical painful episodes but also acute chest syndrome (ACS), hepatic or splenic sequestration, and priapism.

Secondary endpoints included the annual rate of days hospitalized, time to first and second SCPC, the annual rate of uncomplicated pain crises, and the annual rate of ACS, among others.

Efficacy

The median annual rate of SCPC was 1.63 in the high-dose arm, 2.01 in the low-dose arm, and 2.98 in the placebo arm, amounting to a significant 45.3% reduction with the higher dose of SelG1 compared to placebo. The low dose resulted in a reduction of 32.6% compared to placebo, but this was not significant.

Twenty-four patients in the high-dose arm had an SCPC rate of 0, compared with 12 in the low-dose arm and 11 on placebo.

SCD genotype or concomitant hydroxyurea use did not impact these results.

Patients in the high-dose arm had a median annual rate of 4 hospitalization days, compared with 6.87 in both the low-dose and placebo groups. The difference was not significant, although the reduction in the high-dose arm was 41.8%.

The median annual rate of uncomplicated SCPC was 1.08 in the high-dose arm, 2.00 in the low-dose arm, and 2.91 in the placebo arm. Uncomplicated SCPC excluded ACS, splenic or hepatic sequestration, and priapism.

The reduction in the high-dose arm compared to placebo was significant, at 62.9% (P=0.015).

“The rate of ACS was pretty rare,” Dr Ataga said, “so the median rate across the various groups was 0.”

And time to the first SCPC was 4.1 months (P=0.001) in the high-dose group, 2.2 months (P=0.136) in the low-dose group, and 1.4 months in the placebo group.

“The curves separated pretty early,” Dr Ataga noted, “and were maintained throughout the course of the treatment phase, suggesting that the beneficial effect of SelG1 manifested pretty early following initiation of treatment.”

The time to second event was also significant in the high-dose arm compared to placebo, at 10.3 months and 5.1 months, respectively (P=0.022).

Safety

One or more adverse events occurred in over 85% of patients in each group.

Adverse events that occurred in at least 10% of SelG1-treated patients and amounted to at least double the number in the placebo group were arthralgia, diarrhea, pruritus, vomiting, and chest pain.

Five patients died while on study, but none of these deaths were related to the study drug.

Despite the adverse events, Dr Ataga said the drug was, overall, well-tolerated among the patients who received treatment.

Kenneth Ataga, MD

Photo courtesy of ASH

SAN DIEGO—The first-in-class humanized anti-P-selectin antibody SelG1, also known as crizanlizumab, significantly reduced sickle cell pain crises (SCPC) when compared to placebo in the phase 2 SUSTAIN trial.

The higher dose of SelG1 tested reduced the annual rate of SCPC by 45% (P=0.01) and the annual rate of uncomplicated SCPC by 63% (P=0.015).

Acute painful crises are the primary cause for patients with sickle cell disease (SCD) to seek medical attention.

Kenneth I. Ataga, MD, of the University of North Carolina at Chapel Hill, explained that upregulation of P-selectin on endothelial cells and platelets contributes to the cell-cell interaction involved in the pathogenesis of SCPC. SelG1 binds to P-selectin and inhibits its interaction with P-selectin glycoprotein ligand 1.

Dr Ataga presented results from the SUSTAIN study during the plenary session of the 2016 ASH Annual Meeting (abstract 1).

The study was also published in NEJM. The research was sponsored by Selexys Pharmaceuticals Corporation, which was recently acquired by Novartis.

Patient population

A total of 198 patients were randomized, 67 to high-dose SelG1 (5.0 mg/kg), 66 to low-dose SelG1 (2.5 mg/kg), and 65 to placebo.

They received a loading dose in the first 2 weeks of treatment, followed by monthly dosing for a year.

Patients had to have a diagnosis of SCD, including genotypes HbSS, HbSC, HbSb⁰-thalassemia, or HbSB⁺-thalassemia.

They had to have at least 2 but not more than 10 acute sickle-related pain events within 12 months of study entry.

Patients ranged in age from 16 to 57 years, about 70% had HbSS, and 60% were on concomitant hydroxyurea therapy.

Patients not already receiving hydroxyurea were not permitted to start it during the study. And patients could not be on chronic transfusion therapy.

Study endpoints

The primary endpoint was the annual rate of adjudicated SCPC.

“Painful crisis was defined as an active episode of pain, and it was felt to be related to sickle cell disease-specific events and no other medically defined causes,” Dr Ataga explained.

The pain episodes also had to result in a visit to a medical facility and require treatment with parenteral or oral narcotics or parenteral nonsteroidal anti-inflammatory drugs.

The definition of SCPC included not only typical painful episodes but also acute chest syndrome (ACS), hepatic or splenic sequestration, and priapism.

Secondary endpoints included the annual rate of days hospitalized, time to first and second SCPC, the annual rate of uncomplicated pain crises, and the annual rate of ACS, among others.

Efficacy

The median annual rate of SCPC was 1.63 in the high-dose arm, 2.01 in the low-dose arm, and 2.98 in the placebo arm, amounting to a significant 45.3% reduction with the higher dose of SelG1 compared to placebo. The low dose resulted in a reduction of 32.6% compared to placebo, but this was not significant.

Twenty-four patients in the high-dose arm had an SCPC rate of 0, compared with 12 in the low-dose arm and 11 on placebo.

SCD genotype or concomitant hydroxyurea use did not impact these results.

Patients in the high-dose arm had a median annual rate of 4 hospitalization days, compared with 6.87 in both the low-dose and placebo groups. The difference was not significant, although the reduction in the high-dose arm was 41.8%.

The median annual rate of uncomplicated SCPC was 1.08 in the high-dose arm, 2.00 in the low-dose arm, and 2.91 in the placebo arm. Uncomplicated SCPC excluded ACS, splenic or hepatic sequestration, and priapism.

The reduction in the high-dose arm compared to placebo was significant, at 62.9% (P=0.015).

“The rate of ACS was pretty rare,” Dr Ataga said, “so the median rate across the various groups was 0.”

And time to the first SCPC was 4.1 months (P=0.001) in the high-dose group, 2.2 months (P=0.136) in the low-dose group, and 1.4 months in the placebo group.

“The curves separated pretty early,” Dr Ataga noted, “and were maintained throughout the course of the treatment phase, suggesting that the beneficial effect of SelG1 manifested pretty early following initiation of treatment.”

The time to second event was also significant in the high-dose arm compared to placebo, at 10.3 months and 5.1 months, respectively (P=0.022).

Safety

One or more adverse events occurred in over 85% of patients in each group.

Adverse events that occurred in at least 10% of SelG1-treated patients and amounted to at least double the number in the placebo group were arthralgia, diarrhea, pruritus, vomiting, and chest pain.

Five patients died while on study, but none of these deaths were related to the study drug.

Despite the adverse events, Dr Ataga said the drug was, overall, well-tolerated among the patients who received treatment.

Andy Futreal, PhD

Photo courtesy of

MD Anderson Cancer Center

SAN DIEGO―Clonal hematopoiesis could be used as a predictive marker to identify cancer patients at risk of developing therapy-related myeloid neoplasms (t-MNs), according to researchers.

The team conducted a case-control study, which showed that patients who developed t-MNs—acute myeloid leukemia and myelodysplastic syndromes—were significantly more likely than patients without t-MNs to have clonal hematopoiesis at the time of primary cancer diagnosis.

“Based on these findings, we believe pre-leukemic mutations may function as a new biomarker that would predict t-MN development,” said Andy Futreal, PhD, of The University of Texas MD Anderson Cancer Center in Houston.

Dr Futreal and his colleagues reported these findings in The Lancet Oncology.

Co-author Koichi Takashi, MD, also of MD Anderson, presented the findings at the 2016 ASH Annual Meeting (abstract 38).

Initial cohort

The researchers analyzed data on patients treated at MD Anderson from 1997 to 2015.

The 14 cases the team identified had been treated for a primary cancer and later developed t-MNs. The 54 age-matched control subjects had been treated for lymphoma, received combination chemotherapy, and did not develop t-MNs after at least 5 years of follow-up.

For both cases and controls, the researchers performed gene sequencing on pre-treatment peripheral blood samples. For cases, the researchers also performed targeted gene sequencing on bone marrow samples taken at t-MN diagnosis.

“We found that prevalence of pre-leukemic mutations was significantly higher in patients who developed t-MNs versus those who did not,” Dr Futreal said.

Clonal hematopoiesis was present in 71% of cases (n=10) and 31% of controls (n=17).

“We found genetic mutations that are present in t-MNs leukemia samples actually could be found in blood samples obtained at the time of their original cancer diagnosis,” Dr Takashi noted.

Overall, the cumulative incidence of t-MNs at 5 years was significantly higher in patients with clonal hematopoiesis than in those without it—30% and 7%, respectively (P=0.016).

Validation cohort

The researchers also assessed clonal hematopoiesis in an external cohort of 74 patients with lymphoma who were treated in a trial of front-line chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone, with or without melatonin.

In this cohort, 7% (n=5) of patients developed t-MNs. Eighty percent of these patients (n=4) had clonal hematopoiesis.

Of the 69 patients who did not develop t-MNs, 16% (n=11) had clonal hematopoiesis.

The cumulative incidence of t-MNs at 10 years was significantly higher in patients with clonal hematopoiesis than in those without it—29% and 0%, respectively (P=0.0009).

Multivariate analysis suggested clonal hematopoiesis significantly increased the risk of t-MNs, with a hazard ratio of 13.7 (P=0.013).

“[W]e believe the data suggest potential approaches of screening for clonal hematopoiesis in cancer patients that may identify patients at risk of developing t-MNs, although further studies are needed,” Dr Takashi concluded.

Andy Futreal, PhD

Photo courtesy of

MD Anderson Cancer Center

SAN DIEGO―Clonal hematopoiesis could be used as a predictive marker to identify cancer patients at risk of developing therapy-related myeloid neoplasms (t-MNs), according to researchers.

The team conducted a case-control study, which showed that patients who developed t-MNs—acute myeloid leukemia and myelodysplastic syndromes—were significantly more likely than patients without t-MNs to have clonal hematopoiesis at the time of primary cancer diagnosis.

“Based on these findings, we believe pre-leukemic mutations may function as a new biomarker that would predict t-MN development,” said Andy Futreal, PhD, of The University of Texas MD Anderson Cancer Center in Houston.

Dr Futreal and his colleagues reported these findings in The Lancet Oncology.

Co-author Koichi Takashi, MD, also of MD Anderson, presented the findings at the 2016 ASH Annual Meeting (abstract 38).

Initial cohort

The researchers analyzed data on patients treated at MD Anderson from 1997 to 2015.

The 14 cases the team identified had been treated for a primary cancer and later developed t-MNs. The 54 age-matched control subjects had been treated for lymphoma, received combination chemotherapy, and did not develop t-MNs after at least 5 years of follow-up.

For both cases and controls, the researchers performed gene sequencing on pre-treatment peripheral blood samples. For cases, the researchers also performed targeted gene sequencing on bone marrow samples taken at t-MN diagnosis.

“We found that prevalence of pre-leukemic mutations was significantly higher in patients who developed t-MNs versus those who did not,” Dr Futreal said.

Clonal hematopoiesis was present in 71% of cases (n=10) and 31% of controls (n=17).

“We found genetic mutations that are present in t-MNs leukemia samples actually could be found in blood samples obtained at the time of their original cancer diagnosis,” Dr Takashi noted.

Overall, the cumulative incidence of t-MNs at 5 years was significantly higher in patients with clonal hematopoiesis than in those without it—30% and 7%, respectively (P=0.016).

Validation cohort

The researchers also assessed clonal hematopoiesis in an external cohort of 74 patients with lymphoma who were treated in a trial of front-line chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone, with or without melatonin.

In this cohort, 7% (n=5) of patients developed t-MNs. Eighty percent of these patients (n=4) had clonal hematopoiesis.

Of the 69 patients who did not develop t-MNs, 16% (n=11) had clonal hematopoiesis.

The cumulative incidence of t-MNs at 10 years was significantly higher in patients with clonal hematopoiesis than in those without it—29% and 0%, respectively (P=0.0009).

Multivariate analysis suggested clonal hematopoiesis significantly increased the risk of t-MNs, with a hazard ratio of 13.7 (P=0.013).

“[W]e believe the data suggest potential approaches of screening for clonal hematopoiesis in cancer patients that may identify patients at risk of developing t-MNs, although further studies are needed,” Dr Takashi concluded.

Andy Futreal, PhD

Photo courtesy of

MD Anderson Cancer Center

SAN DIEGO―Clonal hematopoiesis could be used as a predictive marker to identify cancer patients at risk of developing therapy-related myeloid neoplasms (t-MNs), according to researchers.

The team conducted a case-control study, which showed that patients who developed t-MNs—acute myeloid leukemia and myelodysplastic syndromes—were significantly more likely than patients without t-MNs to have clonal hematopoiesis at the time of primary cancer diagnosis.

“Based on these findings, we believe pre-leukemic mutations may function as a new biomarker that would predict t-MN development,” said Andy Futreal, PhD, of The University of Texas MD Anderson Cancer Center in Houston.

Dr Futreal and his colleagues reported these findings in The Lancet Oncology.

Co-author Koichi Takashi, MD, also of MD Anderson, presented the findings at the 2016 ASH Annual Meeting (abstract 38).

Initial cohort

The researchers analyzed data on patients treated at MD Anderson from 1997 to 2015.

The 14 cases the team identified had been treated for a primary cancer and later developed t-MNs. The 54 age-matched control subjects had been treated for lymphoma, received combination chemotherapy, and did not develop t-MNs after at least 5 years of follow-up.

For both cases and controls, the researchers performed gene sequencing on pre-treatment peripheral blood samples. For cases, the researchers also performed targeted gene sequencing on bone marrow samples taken at t-MN diagnosis.

“We found that prevalence of pre-leukemic mutations was significantly higher in patients who developed t-MNs versus those who did not,” Dr Futreal said.

Clonal hematopoiesis was present in 71% of cases (n=10) and 31% of controls (n=17).

“We found genetic mutations that are present in t-MNs leukemia samples actually could be found in blood samples obtained at the time of their original cancer diagnosis,” Dr Takashi noted.

Overall, the cumulative incidence of t-MNs at 5 years was significantly higher in patients with clonal hematopoiesis than in those without it—30% and 7%, respectively (P=0.016).

Validation cohort

The researchers also assessed clonal hematopoiesis in an external cohort of 74 patients with lymphoma who were treated in a trial of front-line chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone, with or without melatonin.

In this cohort, 7% (n=5) of patients developed t-MNs. Eighty percent of these patients (n=4) had clonal hematopoiesis.

Of the 69 patients who did not develop t-MNs, 16% (n=11) had clonal hematopoiesis.

The cumulative incidence of t-MNs at 10 years was significantly higher in patients with clonal hematopoiesis than in those without it—29% and 0%, respectively (P=0.0009).

Multivariate analysis suggested clonal hematopoiesis significantly increased the risk of t-MNs, with a hazard ratio of 13.7 (P=0.013).

“[W]e believe the data suggest potential approaches of screening for clonal hematopoiesis in cancer patients that may identify patients at risk of developing t-MNs, although further studies are needed,” Dr Takashi concluded.

Structure of PTEN

Researchers say they have discovered an important molecular link between Fanconi anemia (FA) and PTEN, a gene associated with uterine, prostate, and brain cancer.

They say this discovery enhances our understanding of the molecular basis of Fanconi anemia and could lead to improved treatment outcomes for both Fanconi anemia and cancer patients.

The researchers detailed their discovery in Scientific Reports.

They explained that Fanconi anemia proteins function primarily in DNA interstrand crosslink (ICL) repair, and they wanted to determine the role of the PTEN phosphatase in this process.

“The PTEN gene codes for a phosphatase—an enzyme that removes phosphate groups from proteins,” said study author Niall Howlett, PhD, of the University of Rhode Island in Kingston, Rhode Island.

“Many Fanconi anemia proteins have phosphate groups attached to them when they become activated. However, how these phosphate groups are removed is poorly understood.”

With this in mind, the researchers performed an experiment to determine if Fanconi anemia and PTEN are biochemically linked.

The team knew that cells from Fanconi anemia patients are sensitive to ICL-inducing agents, so they set out to determine if PTEN-deficient cells are sensitive to these agents as well.

“By testing if cells with mutations in the PTEN gene were also sensitive to [ICL-inducing] agents, we discovered that Fanconi anemia patient cells and PTEN-deficient cells were practically indistinguishable in terms of sensitivity to these drugs,” Dr Howlett said.

“This strongly suggested that the Fanconi anemia proteins and PTEN might work together to repair the DNA damage caused by [ICL-inducing] agents.”

Using epistasis analysis, Dr Howlett and his colleagues found that Fanconi anemia proteins and PTEN do indeed function together in ICL repair.

“Before this work, Fanconi anemia and PTEN weren’t even on the same radar,” Dr Howlett said. “This is really important to understanding how this disease arises and what its molecular underpinnings are. The more we can find out about its molecular basis, the more likely we are to come up with strategies to treat the disease.”

Dr Howlett and his colleagues believe their research is equally important to cancer patients. Since this study showed that cells missing PTEN are highly sensitive to ICL-inducing agents, the team believes it should be possible to predict whether a particular cancer patient will respond to this class of drugs by conducting a simple DNA test.

“We can now predict that if a patient has cancer associated with mutations in PTEN, then it is likely that the cancer will be sensitive to [ICL-inducing] agents,” Dr Howlett said. “This could lead to improved outcomes for patients with certain types of PTEN mutations.”

Structure of PTEN

Researchers say they have discovered an important molecular link between Fanconi anemia (FA) and PTEN, a gene associated with uterine, prostate, and brain cancer.

They say this discovery enhances our understanding of the molecular basis of Fanconi anemia and could lead to improved treatment outcomes for both Fanconi anemia and cancer patients.

The researchers detailed their discovery in Scientific Reports.

They explained that Fanconi anemia proteins function primarily in DNA interstrand crosslink (ICL) repair, and they wanted to determine the role of the PTEN phosphatase in this process.

“The PTEN gene codes for a phosphatase—an enzyme that removes phosphate groups from proteins,” said study author Niall Howlett, PhD, of the University of Rhode Island in Kingston, Rhode Island.

“Many Fanconi anemia proteins have phosphate groups attached to them when they become activated. However, how these phosphate groups are removed is poorly understood.”

With this in mind, the researchers performed an experiment to determine if Fanconi anemia and PTEN are biochemically linked.

The team knew that cells from Fanconi anemia patients are sensitive to ICL-inducing agents, so they set out to determine if PTEN-deficient cells are sensitive to these agents as well.

“By testing if cells with mutations in the PTEN gene were also sensitive to [ICL-inducing] agents, we discovered that Fanconi anemia patient cells and PTEN-deficient cells were practically indistinguishable in terms of sensitivity to these drugs,” Dr Howlett said.

“This strongly suggested that the Fanconi anemia proteins and PTEN might work together to repair the DNA damage caused by [ICL-inducing] agents.”

Using epistasis analysis, Dr Howlett and his colleagues found that Fanconi anemia proteins and PTEN do indeed function together in ICL repair.

“Before this work, Fanconi anemia and PTEN weren’t even on the same radar,” Dr Howlett said. “This is really important to understanding how this disease arises and what its molecular underpinnings are. The more we can find out about its molecular basis, the more likely we are to come up with strategies to treat the disease.”

Dr Howlett and his colleagues believe their research is equally important to cancer patients. Since this study showed that cells missing PTEN are highly sensitive to ICL-inducing agents, the team believes it should be possible to predict whether a particular cancer patient will respond to this class of drugs by conducting a simple DNA test.

“We can now predict that if a patient has cancer associated with mutations in PTEN, then it is likely that the cancer will be sensitive to [ICL-inducing] agents,” Dr Howlett said. “This could lead to improved outcomes for patients with certain types of PTEN mutations.”

Structure of PTEN

Researchers say they have discovered an important molecular link between Fanconi anemia (FA) and PTEN, a gene associated with uterine, prostate, and brain cancer.

They say this discovery enhances our understanding of the molecular basis of Fanconi anemia and could lead to improved treatment outcomes for both Fanconi anemia and cancer patients.

The researchers detailed their discovery in Scientific Reports.

They explained that Fanconi anemia proteins function primarily in DNA interstrand crosslink (ICL) repair, and they wanted to determine the role of the PTEN phosphatase in this process.

“The PTEN gene codes for a phosphatase—an enzyme that removes phosphate groups from proteins,” said study author Niall Howlett, PhD, of the University of Rhode Island in Kingston, Rhode Island.

“Many Fanconi anemia proteins have phosphate groups attached to them when they become activated. However, how these phosphate groups are removed is poorly understood.”

With this in mind, the researchers performed an experiment to determine if Fanconi anemia and PTEN are biochemically linked.

The team knew that cells from Fanconi anemia patients are sensitive to ICL-inducing agents, so they set out to determine if PTEN-deficient cells are sensitive to these agents as well.

“By testing if cells with mutations in the PTEN gene were also sensitive to [ICL-inducing] agents, we discovered that Fanconi anemia patient cells and PTEN-deficient cells were practically indistinguishable in terms of sensitivity to these drugs,” Dr Howlett said.

“This strongly suggested that the Fanconi anemia proteins and PTEN might work together to repair the DNA damage caused by [ICL-inducing] agents.”

Using epistasis analysis, Dr Howlett and his colleagues found that Fanconi anemia proteins and PTEN do indeed function together in ICL repair.

“Before this work, Fanconi anemia and PTEN weren’t even on the same radar,” Dr Howlett said. “This is really important to understanding how this disease arises and what its molecular underpinnings are. The more we can find out about its molecular basis, the more likely we are to come up with strategies to treat the disease.”

Dr Howlett and his colleagues believe their research is equally important to cancer patients. Since this study showed that cells missing PTEN are highly sensitive to ICL-inducing agents, the team believes it should be possible to predict whether a particular cancer patient will respond to this class of drugs by conducting a simple DNA test.

“We can now predict that if a patient has cancer associated with mutations in PTEN, then it is likely that the cancer will be sensitive to [ICL-inducing] agents,” Dr Howlett said. “This could lead to improved outcomes for patients with certain types of PTEN mutations.”

SAN DIEGO – Whether hydroxyurea can avert a first stroke in children with sickle cell disease is a question that may be answered by a soon-to-be-started trial in Nigeria.

An estimated 15,000 children with sickle cell anemia have strokes each year in Nigeria, which is considered to have the largest burden of sickle cell disease in the world. Without treatment, about half of those children will have a second stroke within 2 years.

With completion of its feasibility trial results, SPIN (Primary Stroke Prevention in Children With Sickle Cell Anemia in Nigeria) will begin to examine two doses of hydroxyurea therapy, 20 mg/kg per day and 10 mg/kg per day, to determine whether the drug can prevent a first stroke in high-risk children.

In a video interview, Najibah A. Galadanci, MBBS, MPH, of Aminu Kano (Nigeria) Teaching Hospital, discusses how SPIN is addressing the unresolved clinical issue of hydroxyurea’s risks and benefits in children, and how research in Nigeria may provide adequate patient numbers to address a wide range of clinical questions about sickle cell disease.

[email protected]

On Twitter @maryjodales

SAN DIEGO – Whether hydroxyurea can avert a first stroke in children with sickle cell disease is a question that may be answered by a soon-to-be-started trial in Nigeria.

An estimated 15,000 children with sickle cell anemia have strokes each year in Nigeria, which is considered to have the largest burden of sickle cell disease in the world. Without treatment, about half of those children will have a second stroke within 2 years.

With completion of its feasibility trial results, SPIN (Primary Stroke Prevention in Children With Sickle Cell Anemia in Nigeria) will begin to examine two doses of hydroxyurea therapy, 20 mg/kg per day and 10 mg/kg per day, to determine whether the drug can prevent a first stroke in high-risk children.

In a video interview, Najibah A. Galadanci, MBBS, MPH, of Aminu Kano (Nigeria) Teaching Hospital, discusses how SPIN is addressing the unresolved clinical issue of hydroxyurea’s risks and benefits in children, and how research in Nigeria may provide adequate patient numbers to address a wide range of clinical questions about sickle cell disease.

[email protected]

On Twitter @maryjodales

SAN DIEGO – Whether hydroxyurea can avert a first stroke in children with sickle cell disease is a question that may be answered by a soon-to-be-started trial in Nigeria.

An estimated 15,000 children with sickle cell anemia have strokes each year in Nigeria, which is considered to have the largest burden of sickle cell disease in the world. Without treatment, about half of those children will have a second stroke within 2 years.

With completion of its feasibility trial results, SPIN (Primary Stroke Prevention in Children With Sickle Cell Anemia in Nigeria) will begin to examine two doses of hydroxyurea therapy, 20 mg/kg per day and 10 mg/kg per day, to determine whether the drug can prevent a first stroke in high-risk children.

In a video interview, Najibah A. Galadanci, MBBS, MPH, of Aminu Kano (Nigeria) Teaching Hospital, discusses how SPIN is addressing the unresolved clinical issue of hydroxyurea’s risks and benefits in children, and how research in Nigeria may provide adequate patient numbers to address a wide range of clinical questions about sickle cell disease.

[email protected]

On Twitter @maryjodales

Interior view of San Diego

Convention Center, site of

the 2016 ASH Annual Meeting

SAN DIEGO—Results of a phase 1 study suggest that SCD-101, a botanical extract based on an herbal medicine used in Nigeria to treat sickle cell disease (SCD), can reduce pain and fatigue in people with SCD.

The anti-sickling drug also improves the shape of red blood cells but doesn’t produce a change in hemoglobin, according to researchers.

Peter Gillette, MD, of SUNY Downstate in Brooklyn, New York, reported these results at the 2016 ASH Annual Meeting (abstract 121*).

A 6-month phase 2b study conducted previously in Nigeria showed that the herbal medicine Niprisan reduced pain crises and school absenteeism and raised hemoglobin levels compared to placebo.

Based on this study and positive preclinical activity, Dr Gillette and his colleagues undertook a phase 1 study to determine the safety of escalating doses of SCD-101.

Dr Gillette pointed out that Niprisan had been produced commercially in Nigeria but was later removed by the government from the commercial market because of production problems.

The researchers evaluated 23 patients with homozygous SCD or S/beta0 thalassemia.

Patients were aged 18 to 55 years with hemoglobin F of 15% or less and hemoglobin levels between 6.0 and 9.5 g/dL.

Patients could not have had hydroxyurea treatment within 6 months of enrollment, red blood cell transfusion within 3 months, or hospitalization within 4 weeks.

Patients received SCD-101 orally for 28 days administered 2 times daily (BID) or 3 times daily (TID). Doses were 550 mg BID, 1100 mg BID, 2200 mg BID, 4400 mg BID, and 2750 mg TID.

Dr Gillette explained that by distributing the highest dose 3 times over the course of a day, the researchers were able to decrease the side effects of bloating and flatulence on the highest dose.

“Interestingly, with the dose-distributed TID, we found that the hemoglobin had increased by 10%,” he said. “In other words, it appears that the effects are very short-acting, and that by going from a Q12 to a Q8 dosage, the hemoglobin suddenly looks like it might be significant, although this is not a significant change.”

Laboratory outcomes included hemoglobin and hemolysis (LDH, bilirubin, and reticulocyte measurements). Patient-reported outcomes included pain and fatigue.

The most common adverse events (AEs) were pain, flatulence, bloating, diarrhea, constipation, nausea, and headache.

Seven patients in the 2200 mg BID and 4400 mg BID cohorts had dose-related bloating, gas, flatulence or diarrhea, which subsided in a few days.

Patients in the 2750 mg TID cohort did not experience gas side effects.

The gastrointestinal symptoms were most likely dose-related from an excipient of SCD-101, Dr Gillette said.

He and his colleagues found no significant side effects after 28 days of dosing, and there were no dose reductions or interruptions due to drug-related AEs.

There were also no laboratory or electrocardiogram abnormalities.

“Almost all pain AEs stopped by day 13 in 22 of 23 patients,” Dr Gillette said.

“And unexpectedly, patients began to report that they slept better and had improved energy and cognition,” he noted.

Six patients in the 2200 and 4400 mg BID cohorts reported reduced fatigue as measured by the PROMIS fatigue questionnaire.

And 2 patients with ankle ulcers in the 2 highest dose cohorts reported improved healing.

Two weeks after treatment stopped, patients were almost back to baseline in terms of their chronic pain and fatigue levels, Dr Gillette said.

A parallel design, double-blind, placebo-controlled pilot study of the 2750 mg TID dose is ongoing.

Future studies include a crossover-design, exploratory study of the 2750 mg TID dose and a phase 2 parallel design study of the 2200 mg BID and 2750 mg TID doses.

While the researchers are uncertain about the mechanism of action of SCD-101, they hypothesize that its effects could be due to increased vascular flow, increased oxygen delivery, or a reduction in inflammation.

“This is a promising drug potentially for low-income countries or middle-income countries elsewhere in the world where gene therapy and transplant are really not that feasible,” Dr Gillette said.

Research for this study was supported in part by the National Heart, Lung, and Blood Institute and National Center for Complementary and Integrative Health of the National Institutes of Health.

*Information presented at the meeting differs from the abstract.

Interior view of San Diego

Convention Center, site of

the 2016 ASH Annual Meeting

SAN DIEGO—Results of a phase 1 study suggest that SCD-101, a botanical extract based on an herbal medicine used in Nigeria to treat sickle cell disease (SCD), can reduce pain and fatigue in people with SCD.

The anti-sickling drug also improves the shape of red blood cells but doesn’t produce a change in hemoglobin, according to researchers.

Peter Gillette, MD, of SUNY Downstate in Brooklyn, New York, reported these results at the 2016 ASH Annual Meeting (abstract 121*).

A 6-month phase 2b study conducted previously in Nigeria showed that the herbal medicine Niprisan reduced pain crises and school absenteeism and raised hemoglobin levels compared to placebo.

Based on this study and positive preclinical activity, Dr Gillette and his colleagues undertook a phase 1 study to determine the safety of escalating doses of SCD-101.

Dr Gillette pointed out that Niprisan had been produced commercially in Nigeria but was later removed by the government from the commercial market because of production problems.

The researchers evaluated 23 patients with homozygous SCD or S/beta0 thalassemia.

Patients were aged 18 to 55 years with hemoglobin F of 15% or less and hemoglobin levels between 6.0 and 9.5 g/dL.

Patients could not have had hydroxyurea treatment within 6 months of enrollment, red blood cell transfusion within 3 months, or hospitalization within 4 weeks.

Patients received SCD-101 orally for 28 days administered 2 times daily (BID) or 3 times daily (TID). Doses were 550 mg BID, 1100 mg BID, 2200 mg BID, 4400 mg BID, and 2750 mg TID.

Dr Gillette explained that by distributing the highest dose 3 times over the course of a day, the researchers were able to decrease the side effects of bloating and flatulence on the highest dose.

“Interestingly, with the dose-distributed TID, we found that the hemoglobin had increased by 10%,” he said. “In other words, it appears that the effects are very short-acting, and that by going from a Q12 to a Q8 dosage, the hemoglobin suddenly looks like it might be significant, although this is not a significant change.”

Laboratory outcomes included hemoglobin and hemolysis (LDH, bilirubin, and reticulocyte measurements). Patient-reported outcomes included pain and fatigue.

The most common adverse events (AEs) were pain, flatulence, bloating, diarrhea, constipation, nausea, and headache.

Seven patients in the 2200 mg BID and 4400 mg BID cohorts had dose-related bloating, gas, flatulence or diarrhea, which subsided in a few days.

Patients in the 2750 mg TID cohort did not experience gas side effects.

The gastrointestinal symptoms were most likely dose-related from an excipient of SCD-101, Dr Gillette said.

He and his colleagues found no significant side effects after 28 days of dosing, and there were no dose reductions or interruptions due to drug-related AEs.

There were also no laboratory or electrocardiogram abnormalities.

“Almost all pain AEs stopped by day 13 in 22 of 23 patients,” Dr Gillette said.

“And unexpectedly, patients began to report that they slept better and had improved energy and cognition,” he noted.

Six patients in the 2200 and 4400 mg BID cohorts reported reduced fatigue as measured by the PROMIS fatigue questionnaire.

And 2 patients with ankle ulcers in the 2 highest dose cohorts reported improved healing.

Two weeks after treatment stopped, patients were almost back to baseline in terms of their chronic pain and fatigue levels, Dr Gillette said.

A parallel design, double-blind, placebo-controlled pilot study of the 2750 mg TID dose is ongoing.

Future studies include a crossover-design, exploratory study of the 2750 mg TID dose and a phase 2 parallel design study of the 2200 mg BID and 2750 mg TID doses.

While the researchers are uncertain about the mechanism of action of SCD-101, they hypothesize that its effects could be due to increased vascular flow, increased oxygen delivery, or a reduction in inflammation.

“This is a promising drug potentially for low-income countries or middle-income countries elsewhere in the world where gene therapy and transplant are really not that feasible,” Dr Gillette said.

Research for this study was supported in part by the National Heart, Lung, and Blood Institute and National Center for Complementary and Integrative Health of the National Institutes of Health.

*Information presented at the meeting differs from the abstract.

Interior view of San Diego

Convention Center, site of

the 2016 ASH Annual Meeting

SAN DIEGO—Results of a phase 1 study suggest that SCD-101, a botanical extract based on an herbal medicine used in Nigeria to treat sickle cell disease (SCD), can reduce pain and fatigue in people with SCD.

The anti-sickling drug also improves the shape of red blood cells but doesn’t produce a change in hemoglobin, according to researchers.

Peter Gillette, MD, of SUNY Downstate in Brooklyn, New York, reported these results at the 2016 ASH Annual Meeting (abstract 121*).

A 6-month phase 2b study conducted previously in Nigeria showed that the herbal medicine Niprisan reduced pain crises and school absenteeism and raised hemoglobin levels compared to placebo.

Based on this study and positive preclinical activity, Dr Gillette and his colleagues undertook a phase 1 study to determine the safety of escalating doses of SCD-101.

Dr Gillette pointed out that Niprisan had been produced commercially in Nigeria but was later removed by the government from the commercial market because of production problems.

The researchers evaluated 23 patients with homozygous SCD or S/beta0 thalassemia.

Patients were aged 18 to 55 years with hemoglobin F of 15% or less and hemoglobin levels between 6.0 and 9.5 g/dL.

Patients could not have had hydroxyurea treatment within 6 months of enrollment, red blood cell transfusion within 3 months, or hospitalization within 4 weeks.

Patients received SCD-101 orally for 28 days administered 2 times daily (BID) or 3 times daily (TID). Doses were 550 mg BID, 1100 mg BID, 2200 mg BID, 4400 mg BID, and 2750 mg TID.

Dr Gillette explained that by distributing the highest dose 3 times over the course of a day, the researchers were able to decrease the side effects of bloating and flatulence on the highest dose.

“Interestingly, with the dose-distributed TID, we found that the hemoglobin had increased by 10%,” he said. “In other words, it appears that the effects are very short-acting, and that by going from a Q12 to a Q8 dosage, the hemoglobin suddenly looks like it might be significant, although this is not a significant change.”

Laboratory outcomes included hemoglobin and hemolysis (LDH, bilirubin, and reticulocyte measurements). Patient-reported outcomes included pain and fatigue.

The most common adverse events (AEs) were pain, flatulence, bloating, diarrhea, constipation, nausea, and headache.

Seven patients in the 2200 mg BID and 4400 mg BID cohorts had dose-related bloating, gas, flatulence or diarrhea, which subsided in a few days.

Patients in the 2750 mg TID cohort did not experience gas side effects.

The gastrointestinal symptoms were most likely dose-related from an excipient of SCD-101, Dr Gillette said.

He and his colleagues found no significant side effects after 28 days of dosing, and there were no dose reductions or interruptions due to drug-related AEs.

There were also no laboratory or electrocardiogram abnormalities.

“Almost all pain AEs stopped by day 13 in 22 of 23 patients,” Dr Gillette said.

“And unexpectedly, patients began to report that they slept better and had improved energy and cognition,” he noted.

Six patients in the 2200 and 4400 mg BID cohorts reported reduced fatigue as measured by the PROMIS fatigue questionnaire.

And 2 patients with ankle ulcers in the 2 highest dose cohorts reported improved healing.

Two weeks after treatment stopped, patients were almost back to baseline in terms of their chronic pain and fatigue levels, Dr Gillette said.

A parallel design, double-blind, placebo-controlled pilot study of the 2750 mg TID dose is ongoing.

Future studies include a crossover-design, exploratory study of the 2750 mg TID dose and a phase 2 parallel design study of the 2200 mg BID and 2750 mg TID doses.

While the researchers are uncertain about the mechanism of action of SCD-101, they hypothesize that its effects could be due to increased vascular flow, increased oxygen delivery, or a reduction in inflammation.

“This is a promising drug potentially for low-income countries or middle-income countries elsewhere in the world where gene therapy and transplant are really not that feasible,” Dr Gillette said.

Research for this study was supported in part by the National Heart, Lung, and Blood Institute and National Center for Complementary and Integrative Health of the National Institutes of Health.

*Information presented at the meeting differs from the abstract.

An industry-funded phase II trial has shown that high doses of the experimental drug crizanlizumab significantly reduced the number of dangerous “pain crises” in subjects with sickle cell disease.

The median per-year rate of pain crises was 45.3% lower among those who took the high dose of crizanlizumab, compared with the placebo group (P = .01) More than a third of the subjects who took the high dose reported no pain crises during the treatment phase, more than double the rate among the placebo group.

The trial findings were released at the annual meeting of the American Society of Hematology and published simultaneously in the New England Journal of Medicine (doi: 10.1056/NEJMoa1611770).

The American Society of Hematology estimates that 70,000-100,000 people in the United States have sickle cell anemia and some patients are treated with hydroxyurea (Hydrea) are available. According to background material provided in the trial report, however, hydroxyurea has limited value, and some patients still face the prospect of pain crises which can lead to end-organ damage, and early death.

The SUSTAIN trial focuses on pain crises, also known as vaso-occlusive and sickle cell crises, which can occur without warning when sickle cells block blood flow and decrease oxygen delivery.

Researchers led by Kenneth I. Ataga, MB, of the University of North Carolina, Chapel Hill, recruited 198 subjects who had sickle cell disease and who had experienced 2-10 pain crises related to their condition over the past year. They randomly assigned 67 subjects to receive a low 2.5-mg/kg dose of crizanlizumab (also known as SelG1), 66 to a high 5.0-mg/kg dose, and 65 to a placebo. Crizanlizumab is an antibody against the molecule P-selectin, whose up-regulation in certain cells and platelets is thought to contribute to vaso-occlusion and sickle cell pain crises.

All the doses were administered intravenously 14 times over a year at sites in Brazil, the United States, and Jamaica. Risk groups for sickle cell include people of African and South American descent, among groups.

The first two doses were loading doses given at 2-week intervals, and the rest were given at 4-week intervals.

Subjects were aged 16-63 years; the median age was 29 for the two crizanlizumab groups and 26 for the placebo group. The percentage of black subjects ranged from 90% to 94% in each group, and the percentage of female subjects ranged from 52% to 58%.

Some subjects, but not all, were taking hydroxyurea. If they were taking the drug, they needed to have been on it for at least 6 months prior to the trial, and at least the last 3 months at a steady dose. Those who didn’t take hydroxyurea weren’t allowed to start taking it.

The researchers found that the median number of pain crises per year was 1.63 in the high-dose group, 2.01 in the low-dose group, and 2.98 in the placebo group. That translates to a 45.3% lower rate for the high-dose group than placebo (P = .01) and a 32.6% lower rate for low-dose than placebo (P = .18).

A total of 36% of the subjects in the high-dose group had no pain crises during the treatment phase, compared with 18% and 17% in the low-dose and placebo groups, respectively.

In a per-protocol analysis of 125 subjects, the researchers found similar numbers for median pain crises and no pain crises with one exception: The rate of annual pain crises was only 8.3% lower for the low-dose group than the placebo (P = .13).

Overall, the researchers wrote, the rates of adverse and serious adverse events were “similar” among all the subjects regardless of their randomized group.

Five patients died during the trial: two from the high dose group, one in the low dose group, and two in the placebo group. Among serious adverse events, pyrexia and pneumonia occurred more frequently in at least one of the crizanlizumab groups than in the placebo group, but their levels were low at zero to three cases of each event in the three groups.

The researchers noted that they didn’t detect any antibody response against crizanlizumab. However, “longer follow-up and monitoring are necessary to ensure that late neutralizing antibodies do not emerge that might limit the ability to administer crizanlizumab on a long-term basis.”

The study was funded by Selexys Pharmaceuticals, which received grants from the National Heart, Lung, and Blood Institute and the Food and Drug Administration’s Orphan Products Grant Program. Dr. Ataga reports personal fees from Selexys Pharmaceuticals. The other authors report various disclosures or none. The complete list of disclosures is available at NEJM.org.

An industry-funded phase II trial has shown that high doses of the experimental drug crizanlizumab significantly reduced the number of dangerous “pain crises” in subjects with sickle cell disease.

The median per-year rate of pain crises was 45.3% lower among those who took the high dose of crizanlizumab, compared with the placebo group (P = .01) More than a third of the subjects who took the high dose reported no pain crises during the treatment phase, more than double the rate among the placebo group.

The trial findings were released at the annual meeting of the American Society of Hematology and published simultaneously in the New England Journal of Medicine (doi: 10.1056/NEJMoa1611770).

The American Society of Hematology estimates that 70,000-100,000 people in the United States have sickle cell anemia and some patients are treated with hydroxyurea (Hydrea) are available. According to background material provided in the trial report, however, hydroxyurea has limited value, and some patients still face the prospect of pain crises which can lead to end-organ damage, and early death.

The SUSTAIN trial focuses on pain crises, also known as vaso-occlusive and sickle cell crises, which can occur without warning when sickle cells block blood flow and decrease oxygen delivery.

Researchers led by Kenneth I. Ataga, MB, of the University of North Carolina, Chapel Hill, recruited 198 subjects who had sickle cell disease and who had experienced 2-10 pain crises related to their condition over the past year. They randomly assigned 67 subjects to receive a low 2.5-mg/kg dose of crizanlizumab (also known as SelG1), 66 to a high 5.0-mg/kg dose, and 65 to a placebo. Crizanlizumab is an antibody against the molecule P-selectin, whose up-regulation in certain cells and platelets is thought to contribute to vaso-occlusion and sickle cell pain crises.

All the doses were administered intravenously 14 times over a year at sites in Brazil, the United States, and Jamaica. Risk groups for sickle cell include people of African and South American descent, among groups.

The first two doses were loading doses given at 2-week intervals, and the rest were given at 4-week intervals.

Subjects were aged 16-63 years; the median age was 29 for the two crizanlizumab groups and 26 for the placebo group. The percentage of black subjects ranged from 90% to 94% in each group, and the percentage of female subjects ranged from 52% to 58%.

Some subjects, but not all, were taking hydroxyurea. If they were taking the drug, they needed to have been on it for at least 6 months prior to the trial, and at least the last 3 months at a steady dose. Those who didn’t take hydroxyurea weren’t allowed to start taking it.

The researchers found that the median number of pain crises per year was 1.63 in the high-dose group, 2.01 in the low-dose group, and 2.98 in the placebo group. That translates to a 45.3% lower rate for the high-dose group than placebo (P = .01) and a 32.6% lower rate for low-dose than placebo (P = .18).

A total of 36% of the subjects in the high-dose group had no pain crises during the treatment phase, compared with 18% and 17% in the low-dose and placebo groups, respectively.

In a per-protocol analysis of 125 subjects, the researchers found similar numbers for median pain crises and no pain crises with one exception: The rate of annual pain crises was only 8.3% lower for the low-dose group than the placebo (P = .13).

Overall, the researchers wrote, the rates of adverse and serious adverse events were “similar” among all the subjects regardless of their randomized group.

Five patients died during the trial: two from the high dose group, one in the low dose group, and two in the placebo group. Among serious adverse events, pyrexia and pneumonia occurred more frequently in at least one of the crizanlizumab groups than in the placebo group, but their levels were low at zero to three cases of each event in the three groups.

The researchers noted that they didn’t detect any antibody response against crizanlizumab. However, “longer follow-up and monitoring are necessary to ensure that late neutralizing antibodies do not emerge that might limit the ability to administer crizanlizumab on a long-term basis.”

The study was funded by Selexys Pharmaceuticals, which received grants from the National Heart, Lung, and Blood Institute and the Food and Drug Administration’s Orphan Products Grant Program. Dr. Ataga reports personal fees from Selexys Pharmaceuticals. The other authors report various disclosures or none. The complete list of disclosures is available at NEJM.org.

An industry-funded phase II trial has shown that high doses of the experimental drug crizanlizumab significantly reduced the number of dangerous “pain crises” in subjects with sickle cell disease.

The median per-year rate of pain crises was 45.3% lower among those who took the high dose of crizanlizumab, compared with the placebo group (P = .01) More than a third of the subjects who took the high dose reported no pain crises during the treatment phase, more than double the rate among the placebo group.

The trial findings were released at the annual meeting of the American Society of Hematology and published simultaneously in the New England Journal of Medicine (doi: 10.1056/NEJMoa1611770).

The American Society of Hematology estimates that 70,000-100,000 people in the United States have sickle cell anemia and some patients are treated with hydroxyurea (Hydrea) are available. According to background material provided in the trial report, however, hydroxyurea has limited value, and some patients still face the prospect of pain crises which can lead to end-organ damage, and early death.

The SUSTAIN trial focuses on pain crises, also known as vaso-occlusive and sickle cell crises, which can occur without warning when sickle cells block blood flow and decrease oxygen delivery.

Researchers led by Kenneth I. Ataga, MB, of the University of North Carolina, Chapel Hill, recruited 198 subjects who had sickle cell disease and who had experienced 2-10 pain crises related to their condition over the past year. They randomly assigned 67 subjects to receive a low 2.5-mg/kg dose of crizanlizumab (also known as SelG1), 66 to a high 5.0-mg/kg dose, and 65 to a placebo. Crizanlizumab is an antibody against the molecule P-selectin, whose up-regulation in certain cells and platelets is thought to contribute to vaso-occlusion and sickle cell pain crises.

All the doses were administered intravenously 14 times over a year at sites in Brazil, the United States, and Jamaica. Risk groups for sickle cell include people of African and South American descent, among groups.

The first two doses were loading doses given at 2-week intervals, and the rest were given at 4-week intervals.

Subjects were aged 16-63 years; the median age was 29 for the two crizanlizumab groups and 26 for the placebo group. The percentage of black subjects ranged from 90% to 94% in each group, and the percentage of female subjects ranged from 52% to 58%.

Some subjects, but not all, were taking hydroxyurea. If they were taking the drug, they needed to have been on it for at least 6 months prior to the trial, and at least the last 3 months at a steady dose. Those who didn’t take hydroxyurea weren’t allowed to start taking it.

The researchers found that the median number of pain crises per year was 1.63 in the high-dose group, 2.01 in the low-dose group, and 2.98 in the placebo group. That translates to a 45.3% lower rate for the high-dose group than placebo (P = .01) and a 32.6% lower rate for low-dose than placebo (P = .18).

A total of 36% of the subjects in the high-dose group had no pain crises during the treatment phase, compared with 18% and 17% in the low-dose and placebo groups, respectively.

In a per-protocol analysis of 125 subjects, the researchers found similar numbers for median pain crises and no pain crises with one exception: The rate of annual pain crises was only 8.3% lower for the low-dose group than the placebo (P = .13).

Overall, the researchers wrote, the rates of adverse and serious adverse events were “similar” among all the subjects regardless of their randomized group.

Five patients died during the trial: two from the high dose group, one in the low dose group, and two in the placebo group. Among serious adverse events, pyrexia and pneumonia occurred more frequently in at least one of the crizanlizumab groups than in the placebo group, but their levels were low at zero to three cases of each event in the three groups.

The researchers noted that they didn’t detect any antibody response against crizanlizumab. However, “longer follow-up and monitoring are necessary to ensure that late neutralizing antibodies do not emerge that might limit the ability to administer crizanlizumab on a long-term basis.”

The study was funded by Selexys Pharmaceuticals, which received grants from the National Heart, Lung, and Blood Institute and the Food and Drug Administration’s Orphan Products Grant Program. Dr. Ataga reports personal fees from Selexys Pharmaceuticals. The other authors report various disclosures or none. The complete list of disclosures is available at NEJM.org.

CHICAGO – Ferric citrate was safe and effective for treatment of iron-deficiency anemia in patients who had non–dialysis-dependent chronic kidney disease (NDD-CKD), based on data from a phase III, randomized, double-blind study.

The responses were durable, and none of the patients received erythropoiesis-stimulating agents (ESAs), presenter Pablo Pergola, MD, PhD, of Renal Associates, San Antonio, said in an interview at a meeting sponsored by the American Society of Nephrology.

Brian Hoyle/Frontline Medical News

CHICAGO – Ferric citrate was safe and effective for treatment of iron-deficiency anemia in patients who had non–dialysis-dependent chronic kidney disease (NDD-CKD), based on data from a phase III, randomized, double-blind study.

The responses were durable, and none of the patients received erythropoiesis-stimulating agents (ESAs), presenter Pablo Pergola, MD, PhD, of Renal Associates, San Antonio, said in an interview at a meeting sponsored by the American Society of Nephrology.

Brian Hoyle/Frontline Medical News

CHICAGO – Ferric citrate was safe and effective for treatment of iron-deficiency anemia in patients who had non–dialysis-dependent chronic kidney disease (NDD-CKD), based on data from a phase III, randomized, double-blind study.

The responses were durable, and none of the patients received erythropoiesis-stimulating agents (ESAs), presenter Pablo Pergola, MD, PhD, of Renal Associates, San Antonio, said in an interview at a meeting sponsored by the American Society of Nephrology.

Brian Hoyle/Frontline Medical News

A sickled red blood cell

beside a normal one

Image by Betty Pace

The European Commission (EC) has designated GBT440 as an orphan medicinal product for the treatment of sickle cell disease (SCD).

GBT440 is being developed as a potentially disease-modifying therapy for SCD. The drug works by increasing hemoglobin’s affinity for oxygen.

Since oxygenated sickle hemoglobin does not polymerize, it is believed that GBT440 blocks polymerization and the resultant sickling of red blood cells.

If GBT440 can restore normal hemoglobin function and improve oxygen delivery, the drug may be capable of modifying the progression of SCD.

Preclinical research published in the British Journal of Haematology earlier this year suggests that GBT440 is disease-modifying.

Early results from an ongoing phase 1/2 study of GBT440, which were presented at the 2015 ASH Annual Meeting, appeared promising as well.

Results from that study suggest that GBT440 can increase hemoglobin levels while decreasing reticulocyte counts, erythropoietin levels, and sickle cell counts.

Researchers also found the drug to be well tolerated, with no serious adverse events attributed to GBT440.

“Receiving orphan designation from the EC marks a significant milestone both for the SCD community and for GBT [Global Blood Therapeutics Inc.],” said Ted W. Love, MD, president and chief executive officer of Global Blood Therapeutics Inc., the company developing GBT440.

“SCD is a devastatingly severe disease with limited treatment options, and this designation, together with our fast track and orphan drug designations by the United States Food and Drug Administration, reflect the recognition of the broader regulatory community of this urgent unmet medical need.”

The EC grants orphan designation to therapies intended to treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.

Orphan designation provides the company developing a drug with regulatory and financial incentives, including protocol assistance, 10 years of market exclusivity once the drug is approved, and reductions in, or exemptions from, fees.

A sickled red blood cell

beside a normal one

Image by Betty Pace

The European Commission (EC) has designated GBT440 as an orphan medicinal product for the treatment of sickle cell disease (SCD).

GBT440 is being developed as a potentially disease-modifying therapy for SCD. The drug works by increasing hemoglobin’s affinity for oxygen.

Since oxygenated sickle hemoglobin does not polymerize, it is believed that GBT440 blocks polymerization and the resultant sickling of red blood cells.

If GBT440 can restore normal hemoglobin function and improve oxygen delivery, the drug may be capable of modifying the progression of SCD.

Preclinical research published in the British Journal of Haematology earlier this year suggests that GBT440 is disease-modifying.

Early results from an ongoing phase 1/2 study of GBT440, which were presented at the 2015 ASH Annual Meeting, appeared promising as well.

Results from that study suggest that GBT440 can increase hemoglobin levels while decreasing reticulocyte counts, erythropoietin levels, and sickle cell counts.

Researchers also found the drug to be well tolerated, with no serious adverse events attributed to GBT440.

“Receiving orphan designation from the EC marks a significant milestone both for the SCD community and for GBT [Global Blood Therapeutics Inc.],” said Ted W. Love, MD, president and chief executive officer of Global Blood Therapeutics Inc., the company developing GBT440.

“SCD is a devastatingly severe disease with limited treatment options, and this designation, together with our fast track and orphan drug designations by the United States Food and Drug Administration, reflect the recognition of the broader regulatory community of this urgent unmet medical need.”

The EC grants orphan designation to therapies intended to treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.

Orphan designation provides the company developing a drug with regulatory and financial incentives, including protocol assistance, 10 years of market exclusivity once the drug is approved, and reductions in, or exemptions from, fees.

A sickled red blood cell

beside a normal one

Image by Betty Pace

The European Commission (EC) has designated GBT440 as an orphan medicinal product for the treatment of sickle cell disease (SCD).

GBT440 is being developed as a potentially disease-modifying therapy for SCD. The drug works by increasing hemoglobin’s affinity for oxygen.

Since oxygenated sickle hemoglobin does not polymerize, it is believed that GBT440 blocks polymerization and the resultant sickling of red blood cells.

If GBT440 can restore normal hemoglobin function and improve oxygen delivery, the drug may be capable of modifying the progression of SCD.

Preclinical research published in the British Journal of Haematology earlier this year suggests that GBT440 is disease-modifying.

Early results from an ongoing phase 1/2 study of GBT440, which were presented at the 2015 ASH Annual Meeting, appeared promising as well.

Results from that study suggest that GBT440 can increase hemoglobin levels while decreasing reticulocyte counts, erythropoietin levels, and sickle cell counts.

Researchers also found the drug to be well tolerated, with no serious adverse events attributed to GBT440.

“Receiving orphan designation from the EC marks a significant milestone both for the SCD community and for GBT [Global Blood Therapeutics Inc.],” said Ted W. Love, MD, president and chief executive officer of Global Blood Therapeutics Inc., the company developing GBT440.

“SCD is a devastatingly severe disease with limited treatment options, and this designation, together with our fast track and orphan drug designations by the United States Food and Drug Administration, reflect the recognition of the broader regulatory community of this urgent unmet medical need.”

The EC grants orphan designation to therapies intended to treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.

Orphan designation provides the company developing a drug with regulatory and financial incentives, including protocol assistance, 10 years of market exclusivity once the drug is approved, and reductions in, or exemptions from, fees.