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Azacitidine alone comparable to AZA combos for most MDS patients
A 3-arm phase 2 study of azacitidine alone or in combination with lenalidomide or vorinostat in patients with higher-risk myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML) has shown the combination therapies to have similar overall response rates (ORR) to azacitidine monotherapy. Based on these findings, investigators did not choose either combination arm for phase 3 testing of overall survival.
However, patients with CMML treated with the azacitidine-lenalidomide combination had twice the ORR compared with azacitidine monotherapy, they reported.
And patients with certain mutations, such as DNMT3A, BCOR, and NRAS, had higher overall response rates, although only those with the DNMT3A mutation were significant.
Mikkael A. Sekeres, MD, of the Cleveland Clinic in Cleveland, Ohio, and colleagues reported these findings in the Journal of Clinical Oncology on behalf of the North American Intergroup Study SWOG S117.
Doses of azacitidine were the same for monotherapy and combination arms: 75 mg/m2/day intravenously or subcutaneously on days 1 to 7 of a 28-day cycle.
Patients in the lenalidomide arm received 10 mg/day orally of that drug on days 1 to 21, and patients in the vorinostat arm received 300 mg twice daily orally on days 3 to 9.
Patient characteristics
Patients had MDS of IPSS Intermediate-2 or higher or bone marrow blasts 5% or greater. Patients with CMML had fewer than 20% blasts.
The investigators randomized 277 patients to receive either azacitidine alone (n=92), azacitidine plus lenalidomide (n=93), or azacitidine plus vorinostat (n=92).
Patients were a median age of 70 years (range, 28 to 93). Eighty-five patients (31%) were female, 53 (19%) had CMML, and 18 (6%) had treatment-related MDS. More than half the patients were transfusion-dependent at baseline.
Baseline characteristics were similar across the 3 arms. The investigators noted that the baseline characteristics were also similar across the 90 centers participating in the study, whether they were an MDS Center of Excellence or a high-volume center.
Adverse events
For the most part, therapy-related adverse events were similar across the arms.
Rates of grade 3 or higher febrile neutropenia and infection and infestations were similar for all 3 cohorts: 89% for azaciditine monotherapy, 91% for the lenalidomide combination, and 91% for the vorinostat combination.
However, the vorinostat arm had more grade 3 or higher gastrointestinal toxicities (14 patients, 15%) compared with the monotherapy arm (4 patients, 4%), P=0.02.
And patients receiving lenalidomide experienced more grade 3 or higher rash (14 patients, 16%) compared with patients receiving monotherapy (3 patients, 3%), P=0.005.
Patients in the combination arms stopped therapy at significantly higher rates than the monotherapy arm. Eight percent of patients receiving monotherapy stopped treatment compared with 20% in the lenalidomide arm and 21% in the vorinostat arm.
Patients in the combination arms also had more dose modifications not specified in the protocol than those in the monotherapy arm. Twenty-four percent receiving azacitidine monotherapy had non-protocol defined dose modifications, compared with 43% in the lenalidomide arm and 42% in the vorinostat arm.
Responses
The ORR for the entire study population was 38%.
Patients in the monotherapy arm had an ORR of 38%, those in the lenalidomide arm, 49%, and those in the vorinostate arm, 27%. Neither arm achieved significance compared with the monotherapy arm.
Patients who were treatment-naïve in the lenalidomide arm had a somewhat improved ORR compared with monotherapy, P=0.08.
The median duration of response for all cohorts was 15 months: 10 months for monotherapy, 14 months for lenalidomide, and 18 months for vorinostat.
Patients who were able to remain on therapy for 6 months or more in the lenalidomide arm achieved a higher ORR of 87% compared with monotherapy (62%, P=0.01). However, there was no difference in response duration with longer therapy.
The median overall survival (OS) was 17 months for all patients, 15 months for patients in the monotherapy group, 19 months for those in the lenalidomide arm, and 17 months for those in the vorinostat group.
CMML patients had similar OS across treatment arms, with the median not yet reached for patients in the monotherapy arm.
Subgroup responses
Patients with CMML in the lenalidomide arm had a significantly higher ORR than CMML patients in the monotherapy arm, 68% and 28%, respectively (P=0.02).
Median duration of response for CMML patients was 19 months, with no differences between the arms.
The investigators observed no differences in ORR for therapy-related MDS, IPSS subgroups, transfusion-dependent patients, or allogeneic transplant rates.
However, they noted ORR was better for patients with chromosome 5 abnormality regardless of treatment arm than for those without the abnormality (odds ratio, 2.17, P=0.008).
One hundred thirteen patients had mutational data available. They had a median number of 2 mutations (range, 0 to 7), with the most common being ASXL1 (n = 31), TET2 (n = 26), SRSF2 (n = 23), TP53 (n = 22), RUNX1 (n = 21), and U2AF1 (n = 19).
Patients with DNMT3A mutation had a significantly higher ORR than for patients without mutations, 67% and 34%, respectively P=0.025).
Patients with BCOR and NRAS mutations had numerically higher, but non-significant, ORR than non-mutated patients. Patients with BCOR mutation had a 57% ORR compared with 34% for non-mutated patients (P=0.23). Patients with NRAS mutation had a 60% ORR compared with 36% for non-mutated patients (P=0.28).
Patients with mutations in TET2 (P = .046) and TP53 (P = .003) had a worse response duration than those without mutations.
Response duration was significantly better with fewer mutations. For 2 or more mutations, the hazard ration was 6.86 versus no mutations (P=0.01).
The investigators believed under-dosing may have compromised response and survival in the combination arms. They suggested that studies focused on the subgroups that seemed to benefit from the combinations should be conducted. 
A 3-arm phase 2 study of azacitidine alone or in combination with lenalidomide or vorinostat in patients with higher-risk myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML) has shown the combination therapies to have similar overall response rates (ORR) to azacitidine monotherapy. Based on these findings, investigators did not choose either combination arm for phase 3 testing of overall survival.
However, patients with CMML treated with the azacitidine-lenalidomide combination had twice the ORR compared with azacitidine monotherapy, they reported.
And patients with certain mutations, such as DNMT3A, BCOR, and NRAS, had higher overall response rates, although only those with the DNMT3A mutation were significant.
Mikkael A. Sekeres, MD, of the Cleveland Clinic in Cleveland, Ohio, and colleagues reported these findings in the Journal of Clinical Oncology on behalf of the North American Intergroup Study SWOG S117.
Doses of azacitidine were the same for monotherapy and combination arms: 75 mg/m2/day intravenously or subcutaneously on days 1 to 7 of a 28-day cycle.
Patients in the lenalidomide arm received 10 mg/day orally of that drug on days 1 to 21, and patients in the vorinostat arm received 300 mg twice daily orally on days 3 to 9.
Patient characteristics
Patients had MDS of IPSS Intermediate-2 or higher or bone marrow blasts 5% or greater. Patients with CMML had fewer than 20% blasts.
The investigators randomized 277 patients to receive either azacitidine alone (n=92), azacitidine plus lenalidomide (n=93), or azacitidine plus vorinostat (n=92).
Patients were a median age of 70 years (range, 28 to 93). Eighty-five patients (31%) were female, 53 (19%) had CMML, and 18 (6%) had treatment-related MDS. More than half the patients were transfusion-dependent at baseline.
Baseline characteristics were similar across the 3 arms. The investigators noted that the baseline characteristics were also similar across the 90 centers participating in the study, whether they were an MDS Center of Excellence or a high-volume center.
Adverse events
For the most part, therapy-related adverse events were similar across the arms.
Rates of grade 3 or higher febrile neutropenia and infection and infestations were similar for all 3 cohorts: 89% for azaciditine monotherapy, 91% for the lenalidomide combination, and 91% for the vorinostat combination.
However, the vorinostat arm had more grade 3 or higher gastrointestinal toxicities (14 patients, 15%) compared with the monotherapy arm (4 patients, 4%), P=0.02.
And patients receiving lenalidomide experienced more grade 3 or higher rash (14 patients, 16%) compared with patients receiving monotherapy (3 patients, 3%), P=0.005.
Patients in the combination arms stopped therapy at significantly higher rates than the monotherapy arm. Eight percent of patients receiving monotherapy stopped treatment compared with 20% in the lenalidomide arm and 21% in the vorinostat arm.
Patients in the combination arms also had more dose modifications not specified in the protocol than those in the monotherapy arm. Twenty-four percent receiving azacitidine monotherapy had non-protocol defined dose modifications, compared with 43% in the lenalidomide arm and 42% in the vorinostat arm.
Responses
The ORR for the entire study population was 38%.
Patients in the monotherapy arm had an ORR of 38%, those in the lenalidomide arm, 49%, and those in the vorinostate arm, 27%. Neither arm achieved significance compared with the monotherapy arm.
Patients who were treatment-naïve in the lenalidomide arm had a somewhat improved ORR compared with monotherapy, P=0.08.
The median duration of response for all cohorts was 15 months: 10 months for monotherapy, 14 months for lenalidomide, and 18 months for vorinostat.
Patients who were able to remain on therapy for 6 months or more in the lenalidomide arm achieved a higher ORR of 87% compared with monotherapy (62%, P=0.01). However, there was no difference in response duration with longer therapy.
The median overall survival (OS) was 17 months for all patients, 15 months for patients in the monotherapy group, 19 months for those in the lenalidomide arm, and 17 months for those in the vorinostat group.
CMML patients had similar OS across treatment arms, with the median not yet reached for patients in the monotherapy arm.
Subgroup responses
Patients with CMML in the lenalidomide arm had a significantly higher ORR than CMML patients in the monotherapy arm, 68% and 28%, respectively (P=0.02).
Median duration of response for CMML patients was 19 months, with no differences between the arms.
The investigators observed no differences in ORR for therapy-related MDS, IPSS subgroups, transfusion-dependent patients, or allogeneic transplant rates.
However, they noted ORR was better for patients with chromosome 5 abnormality regardless of treatment arm than for those without the abnormality (odds ratio, 2.17, P=0.008).
One hundred thirteen patients had mutational data available. They had a median number of 2 mutations (range, 0 to 7), with the most common being ASXL1 (n = 31), TET2 (n = 26), SRSF2 (n = 23), TP53 (n = 22), RUNX1 (n = 21), and U2AF1 (n = 19).
Patients with DNMT3A mutation had a significantly higher ORR than for patients without mutations, 67% and 34%, respectively P=0.025).
Patients with BCOR and NRAS mutations had numerically higher, but non-significant, ORR than non-mutated patients. Patients with BCOR mutation had a 57% ORR compared with 34% for non-mutated patients (P=0.23). Patients with NRAS mutation had a 60% ORR compared with 36% for non-mutated patients (P=0.28).
Patients with mutations in TET2 (P = .046) and TP53 (P = .003) had a worse response duration than those without mutations.
Response duration was significantly better with fewer mutations. For 2 or more mutations, the hazard ration was 6.86 versus no mutations (P=0.01).
The investigators believed under-dosing may have compromised response and survival in the combination arms. They suggested that studies focused on the subgroups that seemed to benefit from the combinations should be conducted.
A 3-arm phase 2 study of azacitidine alone or in combination with lenalidomide or vorinostat in patients with higher-risk myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML) has shown the combination therapies to have similar overall response rates (ORR) to azacitidine monotherapy. Based on these findings, investigators did not choose either combination arm for phase 3 testing of overall survival.
However, patients with CMML treated with the azacitidine-lenalidomide combination had twice the ORR compared with azacitidine monotherapy, they reported.
And patients with certain mutations, such as DNMT3A, BCOR, and NRAS, had higher overall response rates, although only those with the DNMT3A mutation were significant.
Mikkael A. Sekeres, MD, of the Cleveland Clinic in Cleveland, Ohio, and colleagues reported these findings in the Journal of Clinical Oncology on behalf of the North American Intergroup Study SWOG S117.
Doses of azacitidine were the same for monotherapy and combination arms: 75 mg/m2/day intravenously or subcutaneously on days 1 to 7 of a 28-day cycle.
Patients in the lenalidomide arm received 10 mg/day orally of that drug on days 1 to 21, and patients in the vorinostat arm received 300 mg twice daily orally on days 3 to 9.
Patient characteristics
Patients had MDS of IPSS Intermediate-2 or higher or bone marrow blasts 5% or greater. Patients with CMML had fewer than 20% blasts.
The investigators randomized 277 patients to receive either azacitidine alone (n=92), azacitidine plus lenalidomide (n=93), or azacitidine plus vorinostat (n=92).
Patients were a median age of 70 years (range, 28 to 93). Eighty-five patients (31%) were female, 53 (19%) had CMML, and 18 (6%) had treatment-related MDS. More than half the patients were transfusion-dependent at baseline.
Baseline characteristics were similar across the 3 arms. The investigators noted that the baseline characteristics were also similar across the 90 centers participating in the study, whether they were an MDS Center of Excellence or a high-volume center.
Adverse events
For the most part, therapy-related adverse events were similar across the arms.
Rates of grade 3 or higher febrile neutropenia and infection and infestations were similar for all 3 cohorts: 89% for azaciditine monotherapy, 91% for the lenalidomide combination, and 91% for the vorinostat combination.
However, the vorinostat arm had more grade 3 or higher gastrointestinal toxicities (14 patients, 15%) compared with the monotherapy arm (4 patients, 4%), P=0.02.
And patients receiving lenalidomide experienced more grade 3 or higher rash (14 patients, 16%) compared with patients receiving monotherapy (3 patients, 3%), P=0.005.
Patients in the combination arms stopped therapy at significantly higher rates than the monotherapy arm. Eight percent of patients receiving monotherapy stopped treatment compared with 20% in the lenalidomide arm and 21% in the vorinostat arm.
Patients in the combination arms also had more dose modifications not specified in the protocol than those in the monotherapy arm. Twenty-four percent receiving azacitidine monotherapy had non-protocol defined dose modifications, compared with 43% in the lenalidomide arm and 42% in the vorinostat arm.
Responses
The ORR for the entire study population was 38%.
Patients in the monotherapy arm had an ORR of 38%, those in the lenalidomide arm, 49%, and those in the vorinostate arm, 27%. Neither arm achieved significance compared with the monotherapy arm.
Patients who were treatment-naïve in the lenalidomide arm had a somewhat improved ORR compared with monotherapy, P=0.08.
The median duration of response for all cohorts was 15 months: 10 months for monotherapy, 14 months for lenalidomide, and 18 months for vorinostat.
Patients who were able to remain on therapy for 6 months or more in the lenalidomide arm achieved a higher ORR of 87% compared with monotherapy (62%, P=0.01). However, there was no difference in response duration with longer therapy.
The median overall survival (OS) was 17 months for all patients, 15 months for patients in the monotherapy group, 19 months for those in the lenalidomide arm, and 17 months for those in the vorinostat group.
CMML patients had similar OS across treatment arms, with the median not yet reached for patients in the monotherapy arm.
Subgroup responses
Patients with CMML in the lenalidomide arm had a significantly higher ORR than CMML patients in the monotherapy arm, 68% and 28%, respectively (P=0.02).
Median duration of response for CMML patients was 19 months, with no differences between the arms.
The investigators observed no differences in ORR for therapy-related MDS, IPSS subgroups, transfusion-dependent patients, or allogeneic transplant rates.
However, they noted ORR was better for patients with chromosome 5 abnormality regardless of treatment arm than for those without the abnormality (odds ratio, 2.17, P=0.008).
One hundred thirteen patients had mutational data available. They had a median number of 2 mutations (range, 0 to 7), with the most common being ASXL1 (n = 31), TET2 (n = 26), SRSF2 (n = 23), TP53 (n = 22), RUNX1 (n = 21), and U2AF1 (n = 19).
Patients with DNMT3A mutation had a significantly higher ORR than for patients without mutations, 67% and 34%, respectively P=0.025).
Patients with BCOR and NRAS mutations had numerically higher, but non-significant, ORR than non-mutated patients. Patients with BCOR mutation had a 57% ORR compared with 34% for non-mutated patients (P=0.23). Patients with NRAS mutation had a 60% ORR compared with 36% for non-mutated patients (P=0.28).
Patients with mutations in TET2 (P = .046) and TP53 (P = .003) had a worse response duration than those without mutations.
Response duration was significantly better with fewer mutations. For 2 or more mutations, the hazard ration was 6.86 versus no mutations (P=0.01).
The investigators believed under-dosing may have compromised response and survival in the combination arms. They suggested that studies focused on the subgroups that seemed to benefit from the combinations should be conducted.
Gene plays key role in iron homeostasis
A gene known to prevent autoimmune diseases is a key regulator in iron uptake, according to research published in Cell Reports.
“We found previously that, when mice lack the gene Regnase-1, they suffer from severe autoimmune diseases and anemia,” said study author Masanori Yoshinaga, MD, of Kyoto University in Japan.
“At first, we assumed that anemia was a secondary effect, but, after detailed analysis, we found that the 2 symptoms develop independently.”
Continued study of mice with a Regnase-1 mutation revealed a functional defect in the principal site for iron absorption in the body, the duodenum.
“The next step was to find the role of Regnase-1 in iron-uptake maintenance,” Dr Yoshinaga said. “We started by looking at the most important iron-uptake gene, Transferrin Receptor 1, or TfR1.”
“Our results showed that Regnase-1 degrades the mRNA of TfR1, thereby inhibiting the synthesis of the TfR1 protein and, additionally, that it likely regulates other important iron-controlling genes.”
“Further analysis of Regnase-1 in iron-related homeostasis may provide insight into the mechanisms causing anemia and other iron-related disorders, perhaps eventually leading to new methods of treatment,” said study author Osamu Takeuchi, MD, PhD, of Kyoto University.
A gene known to prevent autoimmune diseases is a key regulator in iron uptake, according to research published in Cell Reports.
“We found previously that, when mice lack the gene Regnase-1, they suffer from severe autoimmune diseases and anemia,” said study author Masanori Yoshinaga, MD, of Kyoto University in Japan.
“At first, we assumed that anemia was a secondary effect, but, after detailed analysis, we found that the 2 symptoms develop independently.”
Continued study of mice with a Regnase-1 mutation revealed a functional defect in the principal site for iron absorption in the body, the duodenum.
“The next step was to find the role of Regnase-1 in iron-uptake maintenance,” Dr Yoshinaga said. “We started by looking at the most important iron-uptake gene, Transferrin Receptor 1, or TfR1.”
“Our results showed that Regnase-1 degrades the mRNA of TfR1, thereby inhibiting the synthesis of the TfR1 protein and, additionally, that it likely regulates other important iron-controlling genes.”
“Further analysis of Regnase-1 in iron-related homeostasis may provide insight into the mechanisms causing anemia and other iron-related disorders, perhaps eventually leading to new methods of treatment,” said study author Osamu Takeuchi, MD, PhD, of Kyoto University.
A gene known to prevent autoimmune diseases is a key regulator in iron uptake, according to research published in Cell Reports.
“We found previously that, when mice lack the gene Regnase-1, they suffer from severe autoimmune diseases and anemia,” said study author Masanori Yoshinaga, MD, of Kyoto University in Japan.
“At first, we assumed that anemia was a secondary effect, but, after detailed analysis, we found that the 2 symptoms develop independently.”
Continued study of mice with a Regnase-1 mutation revealed a functional defect in the principal site for iron absorption in the body, the duodenum.
“The next step was to find the role of Regnase-1 in iron-uptake maintenance,” Dr Yoshinaga said. “We started by looking at the most important iron-uptake gene, Transferrin Receptor 1, or TfR1.”
“Our results showed that Regnase-1 degrades the mRNA of TfR1, thereby inhibiting the synthesis of the TfR1 protein and, additionally, that it likely regulates other important iron-controlling genes.”
“Further analysis of Regnase-1 in iron-related homeostasis may provide insight into the mechanisms causing anemia and other iron-related disorders, perhaps eventually leading to new methods of treatment,” said study author Osamu Takeuchi, MD, PhD, of Kyoto University.
Authority on hematologic malignancies dies
Physician, researcher, and educator H. Jean Khoury, MD, recently passed away.
He died on Monday, May 22, at the age of 50, after a year-long battle with esophageal cancer.
Dr Khoury led the division of hematology at Winship Cancer Institute of Emory University in Atlanta, Georgia.
He was considered an authority on hematologic malignancies, particularly chronic myeloid leukemia (CML), acute leukemia, and myelodysplastic syndromes (MDS).
Dr Khoury joined Winship Cancer Institute in 2004 as director of the Leukemia Service and associate professor in the Emory School of Medicine.
In 2009, he was promoted to professor and director of the Division of Hematology in the Department of Hematology and Medical Oncology, and he was later named to the R. Randall Rollins Chair in Oncology.
“We are all deeply grieving the loss of this remarkable man who gave so much to Winship,” said Walter J. Curran, Jr, MD, Winship Cancer Institute’s executive director.
“His enthusiasm and love for his patients and his commitment to lessening the burden of cancer for all has been unwavering throughout his life.”
A native of Beirut, Lebanon, Dr Khoury came to the Winship Cancer Institute from Washington University in St Louis, Missouri, where he served on the faculty after completing a fellowship in hematology-oncology.
He earned his medical degree from the Université Catholique de Louvain in Brussels, Belgium, and completed a residency in internal medicine at Memorial Medical Center in Savannah, Georgia.
Dr Khoury was recruited to Winship Cancer Institute by Fadlo R. Khuri, MD, former deputy director of the institute and now president of the American University of Beirut. What he first saw in Dr Khoury was someone who was “in the best sense, a disruptive presence.”
“What you always want in a leader is someone who’s not afraid to be wrong, to take risks,” Dr Khuri said. “Being wrong disrupts the pattern, and Jean was very brave. He didn’t like business as usual, and that showed in the way he took about redeveloping the hematology division, the leukemia program, and his interactions with the transplant division, with faculty, and all across Winship.”
According to his colleagues, Dr Khoury’s guiding principle was how to improve his patients’ lives, whether through research discoveries or through compassionate care.
Even after being diagnosed with cancer himself, Dr Khoury continued to see patients and carry on his work in the clinic and his research.
Dr Khoury pioneered the development of personalized treatment for CML patients and better approaches to improve quality of life for survivors. His research focused on drug development in leukemia and MDS, genomic abnormalities in leukemia, development of cost-effective practice models, and outcome analysis of bone marrow transplant.
He conducted several leukemia and transplant clinical trials, including trials that led to the approval of drugs such as imatinib, dasatinib, and nilotinib.
Dr Khoury received the Georgia Cancer Coalition Distinguished Cancer Scholarship, which allowed for establishment of the Hematological Disorders Tissue Bank at Emory, which now contains annotated germline and somatic samples from more than 800 patients with various hematologic disorders.
Dr Khoury died at home with his family by his side. He is survived by his wife, Angela, and 3 children, Mikhail, Iman, and Alya.
In lieu of flowers, the family requests that contributions be made to a new fund at Winship Cancer Institute that will memorialize the life and work of Dr Khoury by supporting a fellowship program that was so meaningful to him.
Contributions, marked in Memory of Dr H. Jean Khoury, can be sent to Winship Cancer Institute of Emory University, Office of Gift Records, Emory University, 1762 Clifton Rd. NE, Suite 1400, Atlanta, GA 30322. Gifts can also be made online.
There will be a memorial service for Dr Khoury on Wednesday, May 31, at 4:30 pm at Glenn Memorial Church, 1652 North Decatur Road in Atlanta, Georgia.
Physician, researcher, and educator H. Jean Khoury, MD, recently passed away.
He died on Monday, May 22, at the age of 50, after a year-long battle with esophageal cancer.
Dr Khoury led the division of hematology at Winship Cancer Institute of Emory University in Atlanta, Georgia.
He was considered an authority on hematologic malignancies, particularly chronic myeloid leukemia (CML), acute leukemia, and myelodysplastic syndromes (MDS).
Dr Khoury joined Winship Cancer Institute in 2004 as director of the Leukemia Service and associate professor in the Emory School of Medicine.
In 2009, he was promoted to professor and director of the Division of Hematology in the Department of Hematology and Medical Oncology, and he was later named to the R. Randall Rollins Chair in Oncology.
“We are all deeply grieving the loss of this remarkable man who gave so much to Winship,” said Walter J. Curran, Jr, MD, Winship Cancer Institute’s executive director.
“His enthusiasm and love for his patients and his commitment to lessening the burden of cancer for all has been unwavering throughout his life.”
A native of Beirut, Lebanon, Dr Khoury came to the Winship Cancer Institute from Washington University in St Louis, Missouri, where he served on the faculty after completing a fellowship in hematology-oncology.
He earned his medical degree from the Université Catholique de Louvain in Brussels, Belgium, and completed a residency in internal medicine at Memorial Medical Center in Savannah, Georgia.
Dr Khoury was recruited to Winship Cancer Institute by Fadlo R. Khuri, MD, former deputy director of the institute and now president of the American University of Beirut. What he first saw in Dr Khoury was someone who was “in the best sense, a disruptive presence.”
“What you always want in a leader is someone who’s not afraid to be wrong, to take risks,” Dr Khuri said. “Being wrong disrupts the pattern, and Jean was very brave. He didn’t like business as usual, and that showed in the way he took about redeveloping the hematology division, the leukemia program, and his interactions with the transplant division, with faculty, and all across Winship.”
According to his colleagues, Dr Khoury’s guiding principle was how to improve his patients’ lives, whether through research discoveries or through compassionate care.
Even after being diagnosed with cancer himself, Dr Khoury continued to see patients and carry on his work in the clinic and his research.
Dr Khoury pioneered the development of personalized treatment for CML patients and better approaches to improve quality of life for survivors. His research focused on drug development in leukemia and MDS, genomic abnormalities in leukemia, development of cost-effective practice models, and outcome analysis of bone marrow transplant.
He conducted several leukemia and transplant clinical trials, including trials that led to the approval of drugs such as imatinib, dasatinib, and nilotinib.
Dr Khoury received the Georgia Cancer Coalition Distinguished Cancer Scholarship, which allowed for establishment of the Hematological Disorders Tissue Bank at Emory, which now contains annotated germline and somatic samples from more than 800 patients with various hematologic disorders.
Dr Khoury died at home with his family by his side. He is survived by his wife, Angela, and 3 children, Mikhail, Iman, and Alya.
In lieu of flowers, the family requests that contributions be made to a new fund at Winship Cancer Institute that will memorialize the life and work of Dr Khoury by supporting a fellowship program that was so meaningful to him.
Contributions, marked in Memory of Dr H. Jean Khoury, can be sent to Winship Cancer Institute of Emory University, Office of Gift Records, Emory University, 1762 Clifton Rd. NE, Suite 1400, Atlanta, GA 30322. Gifts can also be made online.
There will be a memorial service for Dr Khoury on Wednesday, May 31, at 4:30 pm at Glenn Memorial Church, 1652 North Decatur Road in Atlanta, Georgia.
Physician, researcher, and educator H. Jean Khoury, MD, recently passed away.
He died on Monday, May 22, at the age of 50, after a year-long battle with esophageal cancer.
Dr Khoury led the division of hematology at Winship Cancer Institute of Emory University in Atlanta, Georgia.
He was considered an authority on hematologic malignancies, particularly chronic myeloid leukemia (CML), acute leukemia, and myelodysplastic syndromes (MDS).
Dr Khoury joined Winship Cancer Institute in 2004 as director of the Leukemia Service and associate professor in the Emory School of Medicine.
In 2009, he was promoted to professor and director of the Division of Hematology in the Department of Hematology and Medical Oncology, and he was later named to the R. Randall Rollins Chair in Oncology.
“We are all deeply grieving the loss of this remarkable man who gave so much to Winship,” said Walter J. Curran, Jr, MD, Winship Cancer Institute’s executive director.
“His enthusiasm and love for his patients and his commitment to lessening the burden of cancer for all has been unwavering throughout his life.”
A native of Beirut, Lebanon, Dr Khoury came to the Winship Cancer Institute from Washington University in St Louis, Missouri, where he served on the faculty after completing a fellowship in hematology-oncology.
He earned his medical degree from the Université Catholique de Louvain in Brussels, Belgium, and completed a residency in internal medicine at Memorial Medical Center in Savannah, Georgia.
Dr Khoury was recruited to Winship Cancer Institute by Fadlo R. Khuri, MD, former deputy director of the institute and now president of the American University of Beirut. What he first saw in Dr Khoury was someone who was “in the best sense, a disruptive presence.”
“What you always want in a leader is someone who’s not afraid to be wrong, to take risks,” Dr Khuri said. “Being wrong disrupts the pattern, and Jean was very brave. He didn’t like business as usual, and that showed in the way he took about redeveloping the hematology division, the leukemia program, and his interactions with the transplant division, with faculty, and all across Winship.”
According to his colleagues, Dr Khoury’s guiding principle was how to improve his patients’ lives, whether through research discoveries or through compassionate care.
Even after being diagnosed with cancer himself, Dr Khoury continued to see patients and carry on his work in the clinic and his research.
Dr Khoury pioneered the development of personalized treatment for CML patients and better approaches to improve quality of life for survivors. His research focused on drug development in leukemia and MDS, genomic abnormalities in leukemia, development of cost-effective practice models, and outcome analysis of bone marrow transplant.
He conducted several leukemia and transplant clinical trials, including trials that led to the approval of drugs such as imatinib, dasatinib, and nilotinib.
Dr Khoury received the Georgia Cancer Coalition Distinguished Cancer Scholarship, which allowed for establishment of the Hematological Disorders Tissue Bank at Emory, which now contains annotated germline and somatic samples from more than 800 patients with various hematologic disorders.
Dr Khoury died at home with his family by his side. He is survived by his wife, Angela, and 3 children, Mikhail, Iman, and Alya.
In lieu of flowers, the family requests that contributions be made to a new fund at Winship Cancer Institute that will memorialize the life and work of Dr Khoury by supporting a fellowship program that was so meaningful to him.
Contributions, marked in Memory of Dr H. Jean Khoury, can be sent to Winship Cancer Institute of Emory University, Office of Gift Records, Emory University, 1762 Clifton Rd. NE, Suite 1400, Atlanta, GA 30322. Gifts can also be made online.
There will be a memorial service for Dr Khoury on Wednesday, May 31, at 4:30 pm at Glenn Memorial Church, 1652 North Decatur Road in Atlanta, Georgia.
FDA panel backs licensure for epoetin alfa biosimilar
A Food and Drug Administration advisory committee voted overwhelmingly in support of licensure for Epoetin Hospira as a biosimilar product to epoetin alfa (Epogen/Procrit) for all approved Epogen/Procrit indications.
Most committee members who voted “yes” said they were hesitant to do so, however, because of safety concerns, particularly in HIV and oncology patients.
“I voted yes. I came in with concerns about the HIV and oncology patients. However, I do believe ... after hearing the justification, that it meets the [FDA regulatory guideline],” said temporary voting member and patient representative Karen E. Arscott, DO, of the Commonwealth Medical College, Scranton, Penn. “I would like to see extensive follow-up in these two population groups,” she said.
The concerns about HIV and oncology patients are related to the potential for immunogenicity-related events. Some members noted that the study populations were likely too small to detect these rare events.
Scott A. Waldman, MD, of Thomas Jefferson University, Philadelphia, also a temporary member, said he voted “yes” because there was “no substantial difference analytically, biologically, or clinically in what was tested.”
“I think the residual uncertainty of immunogenicity and hypersensitivity and the extrapolation across different patient populations will emerge in postmarketing surveillance. I think that’s when we’ll get the clearest picture of whether there really is any uncertainty in how these drugs perform,” he said.
For one member, however, the concerns were enough for a “no” vote.
“The analytical, clinical, and preclinical data support biosimilarity, and I strongly support approval for indications 1 and 4 based on the clinical data ... but I have residual concerns about lack of data, immunogenicity, basic safety data in patients with HIV and cancer and, for that reason, voted no for the broader indication,” said Thomas S. Uldrick, MD, of the HIV & AIDS Malignancy Branch at the Center for Cancer Research, National Cancer Institute, Bethesda, Md.
Gregory J. Riely, MD, of Memorial Sloan-Kettering Cancer Center in New York expressed similar concerns but said he found the data compelling.
“I understand the concerns around immunogenicity for HIV and cancer patients. I was somewhat reassured by the nonclinical data showing an absence of increased immunogenicity for this biosimilar,” he said.
To support its BLA for Epoetin Hospira, Hospira submitted data from four studies comparing it with the U.S.-licensed Epogen/Procrit and presented an analytical biosimilarity assessment and a nonclinical, clinical pharmacology and clinical biosimilarity assessment. The FDA analysis of the data considered chemistry, manufacturing, and controls, as well as pharmacology/toxicology, immunogenicity, clinical pharmacology, and clinical efficacy and safety.
Sumant Ramachandra, MD, of Pfizer Essential Health noted that the company is not currently seeking an interchangeability designation and that, while this is the first application for a biosimilar product to Amgen’s Epogen/Procrit product, which was approved in 1989, a “highly related epoetin product” from Pfizer (Retacrit) has been available in Europe for 9 years, with more than 363,000 patient years of treatment administered.
The demonstration of biosimilarity in the Epoetin Hospira data presented to the FDA, coupled with well-characterized nature of the reference product, “together support extrapolation across all conditions of use for the reference product,” he said, noting that the data demonstrate that the mechanism of action for both the biosimilar and reference product is the same, and that the immunogenicity profiles are consistent.
The FDA assessment of the data led to a similar conclusion that no clinically significant differences were found between the biosimilar and reference product.
Among other concerns expressed by advisory committee members and/or the public were in regard to the extrapolation of data from patients with chronic kidney disease on hemodialysis to other indications (although this is considered acceptable, according to FDA regulations) and to populations that weren’t studied and about the possibility that Epoetin Hospira would be forced on patients inappropriately, despite the fact that Hospira is not seeking an interchangeability designation. Patients and others speaking on behalf of various patient groups and advocacy organizations called for safeguards against such inappropriate substitution.
Acting committee chair, Brian I. Rini, MD, of the Cleveland Clinic Taussig Cancer Clinic, Ohio, said he voted “yes” because the product met all regulatory requirements but agreed that the “need for vigilance is exceedingly important not only for this drug but for all drugs in this circumstance.”
The FDA, which usually follows the recommendations of its advisory committees, will now consider the BLA for Epoetin Hospira.
In a statement released after the vote, Diem Nguyen, Pfizer Essential Health global president, Americas, said the committee’s recommendation for approval “reinforces the potential value of biosimilars in expanding access to additional high-quality treatment options for the patients in the U.S. who need them.”
The advisory committee members were screened and found to have no relevant conflicts of interest.
A Food and Drug Administration advisory committee voted overwhelmingly in support of licensure for Epoetin Hospira as a biosimilar product to epoetin alfa (Epogen/Procrit) for all approved Epogen/Procrit indications.
Most committee members who voted “yes” said they were hesitant to do so, however, because of safety concerns, particularly in HIV and oncology patients.
“I voted yes. I came in with concerns about the HIV and oncology patients. However, I do believe ... after hearing the justification, that it meets the [FDA regulatory guideline],” said temporary voting member and patient representative Karen E. Arscott, DO, of the Commonwealth Medical College, Scranton, Penn. “I would like to see extensive follow-up in these two population groups,” she said.
The concerns about HIV and oncology patients are related to the potential for immunogenicity-related events. Some members noted that the study populations were likely too small to detect these rare events.
Scott A. Waldman, MD, of Thomas Jefferson University, Philadelphia, also a temporary member, said he voted “yes” because there was “no substantial difference analytically, biologically, or clinically in what was tested.”
“I think the residual uncertainty of immunogenicity and hypersensitivity and the extrapolation across different patient populations will emerge in postmarketing surveillance. I think that’s when we’ll get the clearest picture of whether there really is any uncertainty in how these drugs perform,” he said.
For one member, however, the concerns were enough for a “no” vote.
“The analytical, clinical, and preclinical data support biosimilarity, and I strongly support approval for indications 1 and 4 based on the clinical data ... but I have residual concerns about lack of data, immunogenicity, basic safety data in patients with HIV and cancer and, for that reason, voted no for the broader indication,” said Thomas S. Uldrick, MD, of the HIV & AIDS Malignancy Branch at the Center for Cancer Research, National Cancer Institute, Bethesda, Md.
Gregory J. Riely, MD, of Memorial Sloan-Kettering Cancer Center in New York expressed similar concerns but said he found the data compelling.
“I understand the concerns around immunogenicity for HIV and cancer patients. I was somewhat reassured by the nonclinical data showing an absence of increased immunogenicity for this biosimilar,” he said.
To support its BLA for Epoetin Hospira, Hospira submitted data from four studies comparing it with the U.S.-licensed Epogen/Procrit and presented an analytical biosimilarity assessment and a nonclinical, clinical pharmacology and clinical biosimilarity assessment. The FDA analysis of the data considered chemistry, manufacturing, and controls, as well as pharmacology/toxicology, immunogenicity, clinical pharmacology, and clinical efficacy and safety.
Sumant Ramachandra, MD, of Pfizer Essential Health noted that the company is not currently seeking an interchangeability designation and that, while this is the first application for a biosimilar product to Amgen’s Epogen/Procrit product, which was approved in 1989, a “highly related epoetin product” from Pfizer (Retacrit) has been available in Europe for 9 years, with more than 363,000 patient years of treatment administered.
The demonstration of biosimilarity in the Epoetin Hospira data presented to the FDA, coupled with well-characterized nature of the reference product, “together support extrapolation across all conditions of use for the reference product,” he said, noting that the data demonstrate that the mechanism of action for both the biosimilar and reference product is the same, and that the immunogenicity profiles are consistent.
The FDA assessment of the data led to a similar conclusion that no clinically significant differences were found between the biosimilar and reference product.
Among other concerns expressed by advisory committee members and/or the public were in regard to the extrapolation of data from patients with chronic kidney disease on hemodialysis to other indications (although this is considered acceptable, according to FDA regulations) and to populations that weren’t studied and about the possibility that Epoetin Hospira would be forced on patients inappropriately, despite the fact that Hospira is not seeking an interchangeability designation. Patients and others speaking on behalf of various patient groups and advocacy organizations called for safeguards against such inappropriate substitution.
Acting committee chair, Brian I. Rini, MD, of the Cleveland Clinic Taussig Cancer Clinic, Ohio, said he voted “yes” because the product met all regulatory requirements but agreed that the “need for vigilance is exceedingly important not only for this drug but for all drugs in this circumstance.”
The FDA, which usually follows the recommendations of its advisory committees, will now consider the BLA for Epoetin Hospira.
In a statement released after the vote, Diem Nguyen, Pfizer Essential Health global president, Americas, said the committee’s recommendation for approval “reinforces the potential value of biosimilars in expanding access to additional high-quality treatment options for the patients in the U.S. who need them.”
The advisory committee members were screened and found to have no relevant conflicts of interest.
A Food and Drug Administration advisory committee voted overwhelmingly in support of licensure for Epoetin Hospira as a biosimilar product to epoetin alfa (Epogen/Procrit) for all approved Epogen/Procrit indications.
Most committee members who voted “yes” said they were hesitant to do so, however, because of safety concerns, particularly in HIV and oncology patients.
“I voted yes. I came in with concerns about the HIV and oncology patients. However, I do believe ... after hearing the justification, that it meets the [FDA regulatory guideline],” said temporary voting member and patient representative Karen E. Arscott, DO, of the Commonwealth Medical College, Scranton, Penn. “I would like to see extensive follow-up in these two population groups,” she said.
The concerns about HIV and oncology patients are related to the potential for immunogenicity-related events. Some members noted that the study populations were likely too small to detect these rare events.
Scott A. Waldman, MD, of Thomas Jefferson University, Philadelphia, also a temporary member, said he voted “yes” because there was “no substantial difference analytically, biologically, or clinically in what was tested.”
“I think the residual uncertainty of immunogenicity and hypersensitivity and the extrapolation across different patient populations will emerge in postmarketing surveillance. I think that’s when we’ll get the clearest picture of whether there really is any uncertainty in how these drugs perform,” he said.
For one member, however, the concerns were enough for a “no” vote.
“The analytical, clinical, and preclinical data support biosimilarity, and I strongly support approval for indications 1 and 4 based on the clinical data ... but I have residual concerns about lack of data, immunogenicity, basic safety data in patients with HIV and cancer and, for that reason, voted no for the broader indication,” said Thomas S. Uldrick, MD, of the HIV & AIDS Malignancy Branch at the Center for Cancer Research, National Cancer Institute, Bethesda, Md.
Gregory J. Riely, MD, of Memorial Sloan-Kettering Cancer Center in New York expressed similar concerns but said he found the data compelling.
“I understand the concerns around immunogenicity for HIV and cancer patients. I was somewhat reassured by the nonclinical data showing an absence of increased immunogenicity for this biosimilar,” he said.
To support its BLA for Epoetin Hospira, Hospira submitted data from four studies comparing it with the U.S.-licensed Epogen/Procrit and presented an analytical biosimilarity assessment and a nonclinical, clinical pharmacology and clinical biosimilarity assessment. The FDA analysis of the data considered chemistry, manufacturing, and controls, as well as pharmacology/toxicology, immunogenicity, clinical pharmacology, and clinical efficacy and safety.
Sumant Ramachandra, MD, of Pfizer Essential Health noted that the company is not currently seeking an interchangeability designation and that, while this is the first application for a biosimilar product to Amgen’s Epogen/Procrit product, which was approved in 1989, a “highly related epoetin product” from Pfizer (Retacrit) has been available in Europe for 9 years, with more than 363,000 patient years of treatment administered.
The demonstration of biosimilarity in the Epoetin Hospira data presented to the FDA, coupled with well-characterized nature of the reference product, “together support extrapolation across all conditions of use for the reference product,” he said, noting that the data demonstrate that the mechanism of action for both the biosimilar and reference product is the same, and that the immunogenicity profiles are consistent.
The FDA assessment of the data led to a similar conclusion that no clinically significant differences were found between the biosimilar and reference product.
Among other concerns expressed by advisory committee members and/or the public were in regard to the extrapolation of data from patients with chronic kidney disease on hemodialysis to other indications (although this is considered acceptable, according to FDA regulations) and to populations that weren’t studied and about the possibility that Epoetin Hospira would be forced on patients inappropriately, despite the fact that Hospira is not seeking an interchangeability designation. Patients and others speaking on behalf of various patient groups and advocacy organizations called for safeguards against such inappropriate substitution.
Acting committee chair, Brian I. Rini, MD, of the Cleveland Clinic Taussig Cancer Clinic, Ohio, said he voted “yes” because the product met all regulatory requirements but agreed that the “need for vigilance is exceedingly important not only for this drug but for all drugs in this circumstance.”
The FDA, which usually follows the recommendations of its advisory committees, will now consider the BLA for Epoetin Hospira.
In a statement released after the vote, Diem Nguyen, Pfizer Essential Health global president, Americas, said the committee’s recommendation for approval “reinforces the potential value of biosimilars in expanding access to additional high-quality treatment options for the patients in the U.S. who need them.”
The advisory committee members were screened and found to have no relevant conflicts of interest.
Key clinical point:
Major finding: The data demonstrate that the mechanism of action for both the biosimilar and reference product is the same, and that the immunogenicity profiles are consistent.
Data source: An FDA advisory committee review of epoetin alfa biosimilar Epoetin Hospira.
Disclosures: The advisory committee members were screened and found to have no relevant conflicts of interest.
FDA advisory committee supports L-glutamine for SCD
The available data on the use of L-glutamine powder for treating sickle cell disease is favorable in terms of the agent’s overall benefit-risk profile, a majority of the Food and Drug Administration’s Oncologic Drugs Advisory Committee agreed during a meeting May 24.
L-glutamine powder, which is used as an oral solution for treating sickle cell disease, showed moderate benefit in a phase III study and a smaller phase II study, and if approved by the FDA – which usually follows the recommendations of its advisory committees – would be only the second treatment approved for the debilitating and sometimes deadly disease. The first, hydroxyurea, was approved for use in adults in 1998.
The committee voted 10-3 in favor of L-glutamate, after hearing from representatives of the new drug marketing applicant, Emmaus Medical, about the efficacy and safety data, as well as from FDA representatives who analyzed the data, physicians who treat sickle cell patients, patient advocates, and patients and their family members who gave emotional testimony in favor of approving this treatment.
“This is clearly a bad disease. It’s worse than cancer in many ways. I think probably mostly from a stigma standpoint it has a desperate need [for treatments],” said acting committee chair Brian I. Rini, MD, who voted in favor of the agent.
While there were some concerns about the data, including questions about methodologies, differential dropout rates between study arms, baseline characteristics that may have affected outcomes, and discrepancies between the Emmaus Medical data and the FDA’s analyses of the data, “all seemed to come down in favor of the agent,” Dr. Rini said, citing its “modest but consistent benefit” and low risk.
“I think one thing that’s strikingly clear is that even any sort of modest benefit in this community, given the sequelae of crises, is significant; it doesn’t take much to produce a clinical impact, and that should be motivation to study more drugs in this disease,” he said.
Another focus among those who voted “yes” was on the overwhelming need for treatment for sickle cell patients, who spend “a hugely disproportionate part of their life in the health care system, and who have had a tremendous burden imposed on them by their disease,” according to Harold J. Burstein, MD, PhD, of Dana-Farber Cancer Institute in Boston, who said he was swayed by the low risk of toxicity and the corroborating evidence in the phase II and III trials.
“What I took away was that one fewer hospital visit per year was a clinically compelling benefit for any individual or family or hospital that might be caring for patients with sickle cell disease,” he said, referencing a finding that treated patients had three visits, compared with four visits among patients in the placebo group, in the phase III study.
The data presented to the committee during the meeting by Yutaka Niihara, MD, of Emmaus Medical, included findings from a phase III randomized, placebo-controlled multicenter study (GLUSCC09-01) involving patients aged 5 years and older with sickle cell disease or beta-0 thalassemia who had at least two episodes of painful crises within the 12 months prior to screening. A total of 152 patients were randomized to receive oral L-glutamine at a dose of 0.3 mg/kg per day for 48 weeks followed by a 3-week tapering period, and 78 received placebo.
The Emmaus Medical analysis demonstrated a significant decrease in crisis events (median of 3 vs. 4) among treatment vs. placebo group patients, and the time to second crisis was delayed by 79 days in the treatment group (hazard ratio 0.68). The analysis, however, was complicated by the differential dropout rates (36% vs. 24% in the treatment and placebo arms, respectively), necessitating the use of imputation methods. Various methods were used to handle the missing data, and the findings with each of them favored L-glutamine, but each had important limitations, and while the FDA’s analysis of the various approaches showed that each favored L-glutamine over placebo with a range of reduction in the rates of crises from 0.4 to 0.9, this contributed to the decision by some panel member to vote against the agent.
The phase II study (Study 10478), which had a similar design, failed to meet its specified significance level for primary efficacy analysis, but showed a trend in favor of L-glutamine vs. placebo, Dr. Niihara said.
As for safety, Dr. Niihara reported that a safety population of 187 patients treated with L-glutamine and 111 treated with placebo in the phase II and III studies showed that most patients experienced a treatment-emergent adverse event – most often sickle cell anemia with crisis (66% and 72% in the groups, respectively) and acute chest syndrome (7% and 19%, respectively). Treatment-emergent adverse events led to withdrawal in 2.7% and 0.9% of patients, respectively. The most common adverse reactions were constipation, nausea, headache, cough, pain in the extremities, back pain, chest pain, and abdominal pain.
Bernard F. Cole, PhD, who was among the “no” votes, said he had concerns about “the limitations resulting from differential dropout” rates, which may have artificially shifted the risk profile.
“As a result of those limitations, it’s not clear whether patients at higher risk of a [sickle cell crisis] event might have disproportionately dropped out of the L-glutamine arm,” he explained. “My hope is that the sponsors can more thoroughly address the limitations of this pivotal trial with the FDA,” said Dr. Cole, a professor in the department of mathematics and statistics at the University of Vermont, Burlington.
Dr. Rini, despite his “yes” vote, agreed with the need for more data, noting that additional data analysis could help when it comes to clinical application of L-glutamine.
Specifically, more data regarding duration of therapy and quality data collection that “borrows from the cancer world ... in terms of rigor or data collection,” is needed, he said.
The committee members had no relevant conflicts of interests to disclose.
The available data on the use of L-glutamine powder for treating sickle cell disease is favorable in terms of the agent’s overall benefit-risk profile, a majority of the Food and Drug Administration’s Oncologic Drugs Advisory Committee agreed during a meeting May 24.
L-glutamine powder, which is used as an oral solution for treating sickle cell disease, showed moderate benefit in a phase III study and a smaller phase II study, and if approved by the FDA – which usually follows the recommendations of its advisory committees – would be only the second treatment approved for the debilitating and sometimes deadly disease. The first, hydroxyurea, was approved for use in adults in 1998.
The committee voted 10-3 in favor of L-glutamate, after hearing from representatives of the new drug marketing applicant, Emmaus Medical, about the efficacy and safety data, as well as from FDA representatives who analyzed the data, physicians who treat sickle cell patients, patient advocates, and patients and their family members who gave emotional testimony in favor of approving this treatment.
“This is clearly a bad disease. It’s worse than cancer in many ways. I think probably mostly from a stigma standpoint it has a desperate need [for treatments],” said acting committee chair Brian I. Rini, MD, who voted in favor of the agent.
While there were some concerns about the data, including questions about methodologies, differential dropout rates between study arms, baseline characteristics that may have affected outcomes, and discrepancies between the Emmaus Medical data and the FDA’s analyses of the data, “all seemed to come down in favor of the agent,” Dr. Rini said, citing its “modest but consistent benefit” and low risk.
“I think one thing that’s strikingly clear is that even any sort of modest benefit in this community, given the sequelae of crises, is significant; it doesn’t take much to produce a clinical impact, and that should be motivation to study more drugs in this disease,” he said.
Another focus among those who voted “yes” was on the overwhelming need for treatment for sickle cell patients, who spend “a hugely disproportionate part of their life in the health care system, and who have had a tremendous burden imposed on them by their disease,” according to Harold J. Burstein, MD, PhD, of Dana-Farber Cancer Institute in Boston, who said he was swayed by the low risk of toxicity and the corroborating evidence in the phase II and III trials.
“What I took away was that one fewer hospital visit per year was a clinically compelling benefit for any individual or family or hospital that might be caring for patients with sickle cell disease,” he said, referencing a finding that treated patients had three visits, compared with four visits among patients in the placebo group, in the phase III study.
The data presented to the committee during the meeting by Yutaka Niihara, MD, of Emmaus Medical, included findings from a phase III randomized, placebo-controlled multicenter study (GLUSCC09-01) involving patients aged 5 years and older with sickle cell disease or beta-0 thalassemia who had at least two episodes of painful crises within the 12 months prior to screening. A total of 152 patients were randomized to receive oral L-glutamine at a dose of 0.3 mg/kg per day for 48 weeks followed by a 3-week tapering period, and 78 received placebo.
The Emmaus Medical analysis demonstrated a significant decrease in crisis events (median of 3 vs. 4) among treatment vs. placebo group patients, and the time to second crisis was delayed by 79 days in the treatment group (hazard ratio 0.68). The analysis, however, was complicated by the differential dropout rates (36% vs. 24% in the treatment and placebo arms, respectively), necessitating the use of imputation methods. Various methods were used to handle the missing data, and the findings with each of them favored L-glutamine, but each had important limitations, and while the FDA’s analysis of the various approaches showed that each favored L-glutamine over placebo with a range of reduction in the rates of crises from 0.4 to 0.9, this contributed to the decision by some panel member to vote against the agent.
The phase II study (Study 10478), which had a similar design, failed to meet its specified significance level for primary efficacy analysis, but showed a trend in favor of L-glutamine vs. placebo, Dr. Niihara said.
As for safety, Dr. Niihara reported that a safety population of 187 patients treated with L-glutamine and 111 treated with placebo in the phase II and III studies showed that most patients experienced a treatment-emergent adverse event – most often sickle cell anemia with crisis (66% and 72% in the groups, respectively) and acute chest syndrome (7% and 19%, respectively). Treatment-emergent adverse events led to withdrawal in 2.7% and 0.9% of patients, respectively. The most common adverse reactions were constipation, nausea, headache, cough, pain in the extremities, back pain, chest pain, and abdominal pain.
Bernard F. Cole, PhD, who was among the “no” votes, said he had concerns about “the limitations resulting from differential dropout” rates, which may have artificially shifted the risk profile.
“As a result of those limitations, it’s not clear whether patients at higher risk of a [sickle cell crisis] event might have disproportionately dropped out of the L-glutamine arm,” he explained. “My hope is that the sponsors can more thoroughly address the limitations of this pivotal trial with the FDA,” said Dr. Cole, a professor in the department of mathematics and statistics at the University of Vermont, Burlington.
Dr. Rini, despite his “yes” vote, agreed with the need for more data, noting that additional data analysis could help when it comes to clinical application of L-glutamine.
Specifically, more data regarding duration of therapy and quality data collection that “borrows from the cancer world ... in terms of rigor or data collection,” is needed, he said.
The committee members had no relevant conflicts of interests to disclose.
The available data on the use of L-glutamine powder for treating sickle cell disease is favorable in terms of the agent’s overall benefit-risk profile, a majority of the Food and Drug Administration’s Oncologic Drugs Advisory Committee agreed during a meeting May 24.
L-glutamine powder, which is used as an oral solution for treating sickle cell disease, showed moderate benefit in a phase III study and a smaller phase II study, and if approved by the FDA – which usually follows the recommendations of its advisory committees – would be only the second treatment approved for the debilitating and sometimes deadly disease. The first, hydroxyurea, was approved for use in adults in 1998.
The committee voted 10-3 in favor of L-glutamate, after hearing from representatives of the new drug marketing applicant, Emmaus Medical, about the efficacy and safety data, as well as from FDA representatives who analyzed the data, physicians who treat sickle cell patients, patient advocates, and patients and their family members who gave emotional testimony in favor of approving this treatment.
“This is clearly a bad disease. It’s worse than cancer in many ways. I think probably mostly from a stigma standpoint it has a desperate need [for treatments],” said acting committee chair Brian I. Rini, MD, who voted in favor of the agent.
While there were some concerns about the data, including questions about methodologies, differential dropout rates between study arms, baseline characteristics that may have affected outcomes, and discrepancies between the Emmaus Medical data and the FDA’s analyses of the data, “all seemed to come down in favor of the agent,” Dr. Rini said, citing its “modest but consistent benefit” and low risk.
“I think one thing that’s strikingly clear is that even any sort of modest benefit in this community, given the sequelae of crises, is significant; it doesn’t take much to produce a clinical impact, and that should be motivation to study more drugs in this disease,” he said.
Another focus among those who voted “yes” was on the overwhelming need for treatment for sickle cell patients, who spend “a hugely disproportionate part of their life in the health care system, and who have had a tremendous burden imposed on them by their disease,” according to Harold J. Burstein, MD, PhD, of Dana-Farber Cancer Institute in Boston, who said he was swayed by the low risk of toxicity and the corroborating evidence in the phase II and III trials.
“What I took away was that one fewer hospital visit per year was a clinically compelling benefit for any individual or family or hospital that might be caring for patients with sickle cell disease,” he said, referencing a finding that treated patients had three visits, compared with four visits among patients in the placebo group, in the phase III study.
The data presented to the committee during the meeting by Yutaka Niihara, MD, of Emmaus Medical, included findings from a phase III randomized, placebo-controlled multicenter study (GLUSCC09-01) involving patients aged 5 years and older with sickle cell disease or beta-0 thalassemia who had at least two episodes of painful crises within the 12 months prior to screening. A total of 152 patients were randomized to receive oral L-glutamine at a dose of 0.3 mg/kg per day for 48 weeks followed by a 3-week tapering period, and 78 received placebo.
The Emmaus Medical analysis demonstrated a significant decrease in crisis events (median of 3 vs. 4) among treatment vs. placebo group patients, and the time to second crisis was delayed by 79 days in the treatment group (hazard ratio 0.68). The analysis, however, was complicated by the differential dropout rates (36% vs. 24% in the treatment and placebo arms, respectively), necessitating the use of imputation methods. Various methods were used to handle the missing data, and the findings with each of them favored L-glutamine, but each had important limitations, and while the FDA’s analysis of the various approaches showed that each favored L-glutamine over placebo with a range of reduction in the rates of crises from 0.4 to 0.9, this contributed to the decision by some panel member to vote against the agent.
The phase II study (Study 10478), which had a similar design, failed to meet its specified significance level for primary efficacy analysis, but showed a trend in favor of L-glutamine vs. placebo, Dr. Niihara said.
As for safety, Dr. Niihara reported that a safety population of 187 patients treated with L-glutamine and 111 treated with placebo in the phase II and III studies showed that most patients experienced a treatment-emergent adverse event – most often sickle cell anemia with crisis (66% and 72% in the groups, respectively) and acute chest syndrome (7% and 19%, respectively). Treatment-emergent adverse events led to withdrawal in 2.7% and 0.9% of patients, respectively. The most common adverse reactions were constipation, nausea, headache, cough, pain in the extremities, back pain, chest pain, and abdominal pain.
Bernard F. Cole, PhD, who was among the “no” votes, said he had concerns about “the limitations resulting from differential dropout” rates, which may have artificially shifted the risk profile.
“As a result of those limitations, it’s not clear whether patients at higher risk of a [sickle cell crisis] event might have disproportionately dropped out of the L-glutamine arm,” he explained. “My hope is that the sponsors can more thoroughly address the limitations of this pivotal trial with the FDA,” said Dr. Cole, a professor in the department of mathematics and statistics at the University of Vermont, Burlington.
Dr. Rini, despite his “yes” vote, agreed with the need for more data, noting that additional data analysis could help when it comes to clinical application of L-glutamine.
Specifically, more data regarding duration of therapy and quality data collection that “borrows from the cancer world ... in terms of rigor or data collection,” is needed, he said.
The committee members had no relevant conflicts of interests to disclose.
Key clinical point:
Major finding: In a phase III study, there was a significant decrease in crisis events (median of 3 vs. 4) among treatment vs. placebo group patients.
Data source: A total of 152 patients were randomized to receive oral L-glutamine at a dose of 0.3 mg/kg per day for 48 weeks followed by a 3-week tapering period, and 78 received placebo.
Disclosures: The committee members had no relevant conflicts of interests to disclose.
FDA approves new formulation of deferasirox
The US Food and Drug Administration (FDA) has approved a new formulation of deferasirox known as Jadenu Sprinkle granules.
The granules are approved for use in the same population as Jadenu film-coated tablets.
Both formulations of Jadenu have accelerated approval from the FDA for the treatment of chronic iron overload due to blood transfusions in patients age 2 and older.
The formulations also have accelerated FDA approval for the treatment of chronic iron overload in patients age 10 and older with non-transfusion-dependent-thalassemia and a liver iron concentration of at least 5 mg Fe per gram of dry weight and a serum ferritin greater than 300 mcg/L.
Continued FDA approval for Jadenu in these indications may be contingent upon verification and description of clinical benefit in confirmatory trials.
Jadenu Sprinkle granules are intended for patients who have difficulty swallowing whole tablets. The granules can be sprinkled over soft foods (eg, yogurt or applesauce) prior to consumption.
Like Jadenu film-coated tablets, Jadenu Sprinkle granules are available in 3 strengths—90 mg, 180 mg, and 360 mg.
Both formulations of Jadenu are products of Novartis. For more details on Jadenu, see the prescribing information.
The US Food and Drug Administration (FDA) has approved a new formulation of deferasirox known as Jadenu Sprinkle granules.
The granules are approved for use in the same population as Jadenu film-coated tablets.
Both formulations of Jadenu have accelerated approval from the FDA for the treatment of chronic iron overload due to blood transfusions in patients age 2 and older.
The formulations also have accelerated FDA approval for the treatment of chronic iron overload in patients age 10 and older with non-transfusion-dependent-thalassemia and a liver iron concentration of at least 5 mg Fe per gram of dry weight and a serum ferritin greater than 300 mcg/L.
Continued FDA approval for Jadenu in these indications may be contingent upon verification and description of clinical benefit in confirmatory trials.
Jadenu Sprinkle granules are intended for patients who have difficulty swallowing whole tablets. The granules can be sprinkled over soft foods (eg, yogurt or applesauce) prior to consumption.
Like Jadenu film-coated tablets, Jadenu Sprinkle granules are available in 3 strengths—90 mg, 180 mg, and 360 mg.
Both formulations of Jadenu are products of Novartis. For more details on Jadenu, see the prescribing information.
The US Food and Drug Administration (FDA) has approved a new formulation of deferasirox known as Jadenu Sprinkle granules.
The granules are approved for use in the same population as Jadenu film-coated tablets.
Both formulations of Jadenu have accelerated approval from the FDA for the treatment of chronic iron overload due to blood transfusions in patients age 2 and older.
The formulations also have accelerated FDA approval for the treatment of chronic iron overload in patients age 10 and older with non-transfusion-dependent-thalassemia and a liver iron concentration of at least 5 mg Fe per gram of dry weight and a serum ferritin greater than 300 mcg/L.
Continued FDA approval for Jadenu in these indications may be contingent upon verification and description of clinical benefit in confirmatory trials.
Jadenu Sprinkle granules are intended for patients who have difficulty swallowing whole tablets. The granules can be sprinkled over soft foods (eg, yogurt or applesauce) prior to consumption.
Like Jadenu film-coated tablets, Jadenu Sprinkle granules are available in 3 strengths—90 mg, 180 mg, and 360 mg.
Both formulations of Jadenu are products of Novartis. For more details on Jadenu, see the prescribing information.
Severe hospital-acquired anemia linked to readmission, death
Severe hospital-acquired anemia (HAA) may increase a person’s risk of hospital readmission and death, a new study suggests.
Researchers studied more than 11,000 patients admitted to 6 Texas hospitals and found that a third of the patients developed HAA.
The team also found that severe HAA was associated with a higher risk of death or readmission, even after the researchers adjusted for other factors.
They reported these findings in the Journal of Hospital Medicine.
“This study shines a spotlight on a very common but underappreciated risk of hospitalization, hospital-acquired anemia, which has traditionally been viewed as an incidental change in the red blood count of no significance,” said study author Ethan Halm, MD, of the University of Texas Southwestern Medical Center in Dallas.
“However, our results showed that hospital-acquired anemia was associated with worse clinical outcomes after leaving the hospital, so it needs to be taken more seriously.”
Dr Halm and his colleagues looked at consecutive medicine discharges between November 1, 2009, and October 30, 2010, from 6 hospitals in Texas (safety-net, teaching, and nonteaching).
Of the 11,309 patients studied, 33.1% developed HAA. Most (21.6%) had mild HAA, followed by moderate HAA (10.1%), and severe HAA (1.4%).
The study’s primary outcome was a composite of 30-day mortality and nonelective readmission. This occurred in 9.7% of patients without HAA and 16.4% of those with severe HAA.
The researchers found that severe HAA was independently associated with a 39% increase in the odds of meeting the primary outcome (readmission or 30-day mortality).
The team noted that 85% of patients with severe HAA underwent a major procedure, had a discharge diagnosis of hemorrhage, and/or a discharge diagnosis of hemorrhagic disorder.
The researchers identified 2 potentially modifiable predictors of moderate or severe HAA. These were length of hospital stay (adjusted odds ratio=1.26 per day) and undergoing a major procedure (adjusted odds ratio=5.09).
“Our findings suggest that reducing blood loss during major surgeries and reducing unnecessary testing during hospital stays may lower a patient’s risk of developing severe hospital-acquired anemia, and potentially improve their recovery,” said Anil N. Makam, MD, of the University of Texas Southwestern Medical Center.
In the future, the researchers hope to examine other patient-centered outcomes that may be related to HAA, such as fatigue, functional impairment, and the trajectory of post-hospital recovery.
Severe hospital-acquired anemia (HAA) may increase a person’s risk of hospital readmission and death, a new study suggests.
Researchers studied more than 11,000 patients admitted to 6 Texas hospitals and found that a third of the patients developed HAA.
The team also found that severe HAA was associated with a higher risk of death or readmission, even after the researchers adjusted for other factors.
They reported these findings in the Journal of Hospital Medicine.
“This study shines a spotlight on a very common but underappreciated risk of hospitalization, hospital-acquired anemia, which has traditionally been viewed as an incidental change in the red blood count of no significance,” said study author Ethan Halm, MD, of the University of Texas Southwestern Medical Center in Dallas.
“However, our results showed that hospital-acquired anemia was associated with worse clinical outcomes after leaving the hospital, so it needs to be taken more seriously.”
Dr Halm and his colleagues looked at consecutive medicine discharges between November 1, 2009, and October 30, 2010, from 6 hospitals in Texas (safety-net, teaching, and nonteaching).
Of the 11,309 patients studied, 33.1% developed HAA. Most (21.6%) had mild HAA, followed by moderate HAA (10.1%), and severe HAA (1.4%).
The study’s primary outcome was a composite of 30-day mortality and nonelective readmission. This occurred in 9.7% of patients without HAA and 16.4% of those with severe HAA.
The researchers found that severe HAA was independently associated with a 39% increase in the odds of meeting the primary outcome (readmission or 30-day mortality).
The team noted that 85% of patients with severe HAA underwent a major procedure, had a discharge diagnosis of hemorrhage, and/or a discharge diagnosis of hemorrhagic disorder.
The researchers identified 2 potentially modifiable predictors of moderate or severe HAA. These were length of hospital stay (adjusted odds ratio=1.26 per day) and undergoing a major procedure (adjusted odds ratio=5.09).
“Our findings suggest that reducing blood loss during major surgeries and reducing unnecessary testing during hospital stays may lower a patient’s risk of developing severe hospital-acquired anemia, and potentially improve their recovery,” said Anil N. Makam, MD, of the University of Texas Southwestern Medical Center.
In the future, the researchers hope to examine other patient-centered outcomes that may be related to HAA, such as fatigue, functional impairment, and the trajectory of post-hospital recovery.
Severe hospital-acquired anemia (HAA) may increase a person’s risk of hospital readmission and death, a new study suggests.
Researchers studied more than 11,000 patients admitted to 6 Texas hospitals and found that a third of the patients developed HAA.
The team also found that severe HAA was associated with a higher risk of death or readmission, even after the researchers adjusted for other factors.
They reported these findings in the Journal of Hospital Medicine.
“This study shines a spotlight on a very common but underappreciated risk of hospitalization, hospital-acquired anemia, which has traditionally been viewed as an incidental change in the red blood count of no significance,” said study author Ethan Halm, MD, of the University of Texas Southwestern Medical Center in Dallas.
“However, our results showed that hospital-acquired anemia was associated with worse clinical outcomes after leaving the hospital, so it needs to be taken more seriously.”
Dr Halm and his colleagues looked at consecutive medicine discharges between November 1, 2009, and October 30, 2010, from 6 hospitals in Texas (safety-net, teaching, and nonteaching).
Of the 11,309 patients studied, 33.1% developed HAA. Most (21.6%) had mild HAA, followed by moderate HAA (10.1%), and severe HAA (1.4%).
The study’s primary outcome was a composite of 30-day mortality and nonelective readmission. This occurred in 9.7% of patients without HAA and 16.4% of those with severe HAA.
The researchers found that severe HAA was independently associated with a 39% increase in the odds of meeting the primary outcome (readmission or 30-day mortality).
The team noted that 85% of patients with severe HAA underwent a major procedure, had a discharge diagnosis of hemorrhage, and/or a discharge diagnosis of hemorrhagic disorder.
The researchers identified 2 potentially modifiable predictors of moderate or severe HAA. These were length of hospital stay (adjusted odds ratio=1.26 per day) and undergoing a major procedure (adjusted odds ratio=5.09).
“Our findings suggest that reducing blood loss during major surgeries and reducing unnecessary testing during hospital stays may lower a patient’s risk of developing severe hospital-acquired anemia, and potentially improve their recovery,” said Anil N. Makam, MD, of the University of Texas Southwestern Medical Center.
In the future, the researchers hope to examine other patient-centered outcomes that may be related to HAA, such as fatigue, functional impairment, and the trajectory of post-hospital recovery.
Drug receives rare pediatric disease designation for SCD
The US Food and Drug Administration (FDA) has granted rare pediatric disease designation to IMR-687, a product intended to treat sickle cell disease (SCD).
IMR-687 is the first SCD candidate to be designated as a drug for a rare pediatric disease, and this designation builds upon the FDA’s earlier granting of orphan designation for IMR-687.
IMR-687 is a selective inhibitor of phosphodiesterase-9 (PDE9i) in blood cells. It was specifically designed to address the underlying pathology of SCD.
In preclinical studies, IMR-687 demonstrated the ability to increase fetal globin. This prevented the polymerization of sickled hemoglobin and reduced red blood cell sickling, leukocytosis, and the occlusion of blood vessels.
Researchers presented these results at the 2016 ASH Annual Meeting.
Imara Inc., the company developing IMR-687, is conducting a phase 1a trial of the product in healthy volunteers.
If the trial has a positive outcome (results are expected this summer), Imara will initiate a phase 2a study in adults with SCD later this year. The company expects to initiate a phase 2 study in pediatric patients in 2018.
About rare pediatric disease designation
Rare pediatric disease designation is granted to drugs that show promise to treat orphan diseases affecting fewer than 200,000 patients in the US, primarily patients age 18 or younger.
The designation provides incentives to advance the development of drugs for rare disease, including access to the FDA’s expedited review and approval programs.
Under the FDA’s Rare Pediatric Disease Priority Review Voucher Program, a sponsor with rare pediatric disease designation who receives an approval of a new drug application is eligible for a voucher that can be redeemed to obtain priority review for any subsequent marketing application.
About orphan designation
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
The US Food and Drug Administration (FDA) has granted rare pediatric disease designation to IMR-687, a product intended to treat sickle cell disease (SCD).
IMR-687 is the first SCD candidate to be designated as a drug for a rare pediatric disease, and this designation builds upon the FDA’s earlier granting of orphan designation for IMR-687.
IMR-687 is a selective inhibitor of phosphodiesterase-9 (PDE9i) in blood cells. It was specifically designed to address the underlying pathology of SCD.
In preclinical studies, IMR-687 demonstrated the ability to increase fetal globin. This prevented the polymerization of sickled hemoglobin and reduced red blood cell sickling, leukocytosis, and the occlusion of blood vessels.
Researchers presented these results at the 2016 ASH Annual Meeting.
Imara Inc., the company developing IMR-687, is conducting a phase 1a trial of the product in healthy volunteers.
If the trial has a positive outcome (results are expected this summer), Imara will initiate a phase 2a study in adults with SCD later this year. The company expects to initiate a phase 2 study in pediatric patients in 2018.
About rare pediatric disease designation
Rare pediatric disease designation is granted to drugs that show promise to treat orphan diseases affecting fewer than 200,000 patients in the US, primarily patients age 18 or younger.
The designation provides incentives to advance the development of drugs for rare disease, including access to the FDA’s expedited review and approval programs.
Under the FDA’s Rare Pediatric Disease Priority Review Voucher Program, a sponsor with rare pediatric disease designation who receives an approval of a new drug application is eligible for a voucher that can be redeemed to obtain priority review for any subsequent marketing application.
About orphan designation
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
The US Food and Drug Administration (FDA) has granted rare pediatric disease designation to IMR-687, a product intended to treat sickle cell disease (SCD).
IMR-687 is the first SCD candidate to be designated as a drug for a rare pediatric disease, and this designation builds upon the FDA’s earlier granting of orphan designation for IMR-687.
IMR-687 is a selective inhibitor of phosphodiesterase-9 (PDE9i) in blood cells. It was specifically designed to address the underlying pathology of SCD.
In preclinical studies, IMR-687 demonstrated the ability to increase fetal globin. This prevented the polymerization of sickled hemoglobin and reduced red blood cell sickling, leukocytosis, and the occlusion of blood vessels.
Researchers presented these results at the 2016 ASH Annual Meeting.
Imara Inc., the company developing IMR-687, is conducting a phase 1a trial of the product in healthy volunteers.
If the trial has a positive outcome (results are expected this summer), Imara will initiate a phase 2a study in adults with SCD later this year. The company expects to initiate a phase 2 study in pediatric patients in 2018.
About rare pediatric disease designation
Rare pediatric disease designation is granted to drugs that show promise to treat orphan diseases affecting fewer than 200,000 patients in the US, primarily patients age 18 or younger.
The designation provides incentives to advance the development of drugs for rare disease, including access to the FDA’s expedited review and approval programs.
Under the FDA’s Rare Pediatric Disease Priority Review Voucher Program, a sponsor with rare pediatric disease designation who receives an approval of a new drug application is eligible for a voucher that can be redeemed to obtain priority review for any subsequent marketing application.
About orphan designation
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
Oral iron of no benefit in heart failure with iron deficiency
High-dose oral iron therapy doesn’t improve exercise capacity in the estimated 50% of patients with symptomatic heart failure who also have iron deficiency, according to a report published online May 16 in JAMA.
Iron deficiency in patients with HF, regardless of their hemoglobin status, is associated with reduced functional capacity, poorer quality of life, and increased mortality. Iron plays a crucial role in the delivery and utilization of oxygen, and “cells with high-energy demands, including skeletal and cardiac myocytes, are particularly sensitive to depleted iron stores,” said Gregory D. Lewis, MD, of the pulmonary critical care unit of Massachusetts General Hospital, Boston, and his associates.
The IRONOUT study was conducted at 23 U.S. medical centers, where outcomes after 16 weeks of oral iron therapy (150 mg twice daily) were compared against matching placebo in 225 patients. The median patient age was 63 years, and the median duration of HF was 5.7 years. Ischemic heart disease was the primary cause of HF in 78% of the study participants.
These patients had low LVEF and poor exercise capacity, despite having high rates of guideline-directed treatment with medications.
The primary endpoint was a change in peak oxygen uptake (peak VO2) at the conclusion of treatment, a measure that “reflects the multiple mechanisms by which iron repletion is expected to improve systemic oxygen delivery and utilization.” Change in peak VO2 was not significantly different between the 111 participants who took oral iron supplements (+23 mL/min) and the 114 who took placebo (–2 mL/min), the investigators wrote (JAMA Pediatr. 2017 May 16. doi: 10.1001/jama.2017.5427).
In subgroup analyses, oral iron also failed to improve peak VO2 in any subgroup of patients: neither men nor women; neither those with decreased hemoglobin nor those with normal hemoglobin levels; nor patients with or without venous congestion at baseline. Oral iron also failed to improve secondary endpoints including 6-minute walk distance, quality of life scores, NT-proBNP levels, and ventilatory efficiency.
In contrast to previous studies of IV iron repletion, oral iron supplementation “produced minimal improvement in iron stores, implicating the route of administration rather than the strategy of iron repletion in the lack of clinical benefit,” Dr. Lewis and his associates said.
This study was funded by the National Heart, Lung, and Blood Institute, which also conceived, designed, and conducted the trial. Dr. Lewis reported ties to Abbott, Novartis, Shape Systems, Stealth Bio Therapeutics, Ironwood, Cheetah Medical, Luitpold, and SoniVie. His associates reported ties to numerous industry sources.
High-dose oral iron therapy doesn’t improve exercise capacity in the estimated 50% of patients with symptomatic heart failure who also have iron deficiency, according to a report published online May 16 in JAMA.
Iron deficiency in patients with HF, regardless of their hemoglobin status, is associated with reduced functional capacity, poorer quality of life, and increased mortality. Iron plays a crucial role in the delivery and utilization of oxygen, and “cells with high-energy demands, including skeletal and cardiac myocytes, are particularly sensitive to depleted iron stores,” said Gregory D. Lewis, MD, of the pulmonary critical care unit of Massachusetts General Hospital, Boston, and his associates.
The IRONOUT study was conducted at 23 U.S. medical centers, where outcomes after 16 weeks of oral iron therapy (150 mg twice daily) were compared against matching placebo in 225 patients. The median patient age was 63 years, and the median duration of HF was 5.7 years. Ischemic heart disease was the primary cause of HF in 78% of the study participants.
These patients had low LVEF and poor exercise capacity, despite having high rates of guideline-directed treatment with medications.
The primary endpoint was a change in peak oxygen uptake (peak VO2) at the conclusion of treatment, a measure that “reflects the multiple mechanisms by which iron repletion is expected to improve systemic oxygen delivery and utilization.” Change in peak VO2 was not significantly different between the 111 participants who took oral iron supplements (+23 mL/min) and the 114 who took placebo (–2 mL/min), the investigators wrote (JAMA Pediatr. 2017 May 16. doi: 10.1001/jama.2017.5427).
In subgroup analyses, oral iron also failed to improve peak VO2 in any subgroup of patients: neither men nor women; neither those with decreased hemoglobin nor those with normal hemoglobin levels; nor patients with or without venous congestion at baseline. Oral iron also failed to improve secondary endpoints including 6-minute walk distance, quality of life scores, NT-proBNP levels, and ventilatory efficiency.
In contrast to previous studies of IV iron repletion, oral iron supplementation “produced minimal improvement in iron stores, implicating the route of administration rather than the strategy of iron repletion in the lack of clinical benefit,” Dr. Lewis and his associates said.
This study was funded by the National Heart, Lung, and Blood Institute, which also conceived, designed, and conducted the trial. Dr. Lewis reported ties to Abbott, Novartis, Shape Systems, Stealth Bio Therapeutics, Ironwood, Cheetah Medical, Luitpold, and SoniVie. His associates reported ties to numerous industry sources.
High-dose oral iron therapy doesn’t improve exercise capacity in the estimated 50% of patients with symptomatic heart failure who also have iron deficiency, according to a report published online May 16 in JAMA.
Iron deficiency in patients with HF, regardless of their hemoglobin status, is associated with reduced functional capacity, poorer quality of life, and increased mortality. Iron plays a crucial role in the delivery and utilization of oxygen, and “cells with high-energy demands, including skeletal and cardiac myocytes, are particularly sensitive to depleted iron stores,” said Gregory D. Lewis, MD, of the pulmonary critical care unit of Massachusetts General Hospital, Boston, and his associates.
The IRONOUT study was conducted at 23 U.S. medical centers, where outcomes after 16 weeks of oral iron therapy (150 mg twice daily) were compared against matching placebo in 225 patients. The median patient age was 63 years, and the median duration of HF was 5.7 years. Ischemic heart disease was the primary cause of HF in 78% of the study participants.
These patients had low LVEF and poor exercise capacity, despite having high rates of guideline-directed treatment with medications.
The primary endpoint was a change in peak oxygen uptake (peak VO2) at the conclusion of treatment, a measure that “reflects the multiple mechanisms by which iron repletion is expected to improve systemic oxygen delivery and utilization.” Change in peak VO2 was not significantly different between the 111 participants who took oral iron supplements (+23 mL/min) and the 114 who took placebo (–2 mL/min), the investigators wrote (JAMA Pediatr. 2017 May 16. doi: 10.1001/jama.2017.5427).
In subgroup analyses, oral iron also failed to improve peak VO2 in any subgroup of patients: neither men nor women; neither those with decreased hemoglobin nor those with normal hemoglobin levels; nor patients with or without venous congestion at baseline. Oral iron also failed to improve secondary endpoints including 6-minute walk distance, quality of life scores, NT-proBNP levels, and ventilatory efficiency.
In contrast to previous studies of IV iron repletion, oral iron supplementation “produced minimal improvement in iron stores, implicating the route of administration rather than the strategy of iron repletion in the lack of clinical benefit,” Dr. Lewis and his associates said.
This study was funded by the National Heart, Lung, and Blood Institute, which also conceived, designed, and conducted the trial. Dr. Lewis reported ties to Abbott, Novartis, Shape Systems, Stealth Bio Therapeutics, Ironwood, Cheetah Medical, Luitpold, and SoniVie. His associates reported ties to numerous industry sources.
Key clinical point: High-dose oral iron therapy doesn’t improve exercise capacity in the estimated 50% of patients with symptomatic heart failure and iron deficiency.
Major finding: Change in peak VO2 was not significantly different between the 111 participants who took oral iron supplements (+23 mL/min) and the 114 who took placebo (–2 mL/min).
Data source: A multicenter, randomized, double-blind, placebo-controlled phase II trial involving 225 patients treated for 16 weeks.
Disclosures: This study was funded by the National Heart, Lung, and Blood Institute (NCT02188784), which also conceived, designed, and conducted the trial. Dr. Lewis reported ties to Abbott, Novartis, Shape Systems, Stealth Bio Therapeutics, Ironwood, Cheetah Medical, Luitpold, and SoniVie. His associates reported ties to numerous industry sources.
Iron-transporting molecule could treat anemia, iron overload
Researchers say they have identified a small molecule that can transport iron when typical transport routes are mutated or absent.
The molecule, hinokitiol, was able to move iron into or out of cells by wrapping around iron atoms and shuttling them across the membrane layer.
Hinokitiol promoted gut iron absorption in rats and mice deficient in iron transport complexes, and it promoted hemoglobin production in zebrafish that otherwise couldn’t transport iron effectively.
The researchers believe these findings, published in Science, may lead to new treatments for disorders associated with iron metabolism, such as anemias and hemochromatosis.
“The long-term therapeutic implications of our work with hinokitiol points to potentially using this chemical to correct anemias caused by genetic deficiencies of iron transporters required for normal red cell formation,” said study author Barry Paw, MD, PhD, of Brigham and Women’s Hospital in Boston, Massachusetts.
“At the same time, hinokitiol has the potential to correct iron-overload syndromes, such as hemochromatosis. More extensive clinical trials are necessary to work out the full potential of hinokitiol and to identify potential toxicities that we have not identified using preclinical models.”
Dr Paw and his colleagues discovered the potential of hinokitiol when screening for a molecule that could restore growth to yeast lacking an iron transporter complex. Hinokitiol is a natural product originally isolated from the Taiwanese hinoki tree.
The researchers found that hinokitiol could transport iron across the yeast cellular membrane in mutant yeasts lacking their major iron uptake transporters. Three hinokitiol molecules can wrap around an iron atom and transport it directly across the membrane where the missing protein should be.
The team also tested hinokitiol in mice, rats, and zebrafish that were missing iron-transport proteins.
Orally administered hinokitiol restored iron uptake in the guts of ferroportin-deficient mice and DMT1-deficient rats, and adding hinokitiol to a tank housing DMT1- and mitoferrin-deficient zebrafish prompted hemoglobin production in the fish.
The researchers also found that hinokitiol restored iron transport in human cells taken from the lining of the gut.
“We found that hinokitiol can restore iron transport within cells, out of cells, or both,” Dr Paw said. “It can also promote iron gut absorption and the creation of hemoglobin in some of our models. These findings suggest that small molecules like hinokitiol that can mimic the biological function of a missing protein may have potential for treating human diseases.”
Researchers say they have identified a small molecule that can transport iron when typical transport routes are mutated or absent.
The molecule, hinokitiol, was able to move iron into or out of cells by wrapping around iron atoms and shuttling them across the membrane layer.
Hinokitiol promoted gut iron absorption in rats and mice deficient in iron transport complexes, and it promoted hemoglobin production in zebrafish that otherwise couldn’t transport iron effectively.
The researchers believe these findings, published in Science, may lead to new treatments for disorders associated with iron metabolism, such as anemias and hemochromatosis.
“The long-term therapeutic implications of our work with hinokitiol points to potentially using this chemical to correct anemias caused by genetic deficiencies of iron transporters required for normal red cell formation,” said study author Barry Paw, MD, PhD, of Brigham and Women’s Hospital in Boston, Massachusetts.
“At the same time, hinokitiol has the potential to correct iron-overload syndromes, such as hemochromatosis. More extensive clinical trials are necessary to work out the full potential of hinokitiol and to identify potential toxicities that we have not identified using preclinical models.”
Dr Paw and his colleagues discovered the potential of hinokitiol when screening for a molecule that could restore growth to yeast lacking an iron transporter complex. Hinokitiol is a natural product originally isolated from the Taiwanese hinoki tree.
The researchers found that hinokitiol could transport iron across the yeast cellular membrane in mutant yeasts lacking their major iron uptake transporters. Three hinokitiol molecules can wrap around an iron atom and transport it directly across the membrane where the missing protein should be.
The team also tested hinokitiol in mice, rats, and zebrafish that were missing iron-transport proteins.
Orally administered hinokitiol restored iron uptake in the guts of ferroportin-deficient mice and DMT1-deficient rats, and adding hinokitiol to a tank housing DMT1- and mitoferrin-deficient zebrafish prompted hemoglobin production in the fish.
The researchers also found that hinokitiol restored iron transport in human cells taken from the lining of the gut.
“We found that hinokitiol can restore iron transport within cells, out of cells, or both,” Dr Paw said. “It can also promote iron gut absorption and the creation of hemoglobin in some of our models. These findings suggest that small molecules like hinokitiol that can mimic the biological function of a missing protein may have potential for treating human diseases.”
Researchers say they have identified a small molecule that can transport iron when typical transport routes are mutated or absent.
The molecule, hinokitiol, was able to move iron into or out of cells by wrapping around iron atoms and shuttling them across the membrane layer.
Hinokitiol promoted gut iron absorption in rats and mice deficient in iron transport complexes, and it promoted hemoglobin production in zebrafish that otherwise couldn’t transport iron effectively.
The researchers believe these findings, published in Science, may lead to new treatments for disorders associated with iron metabolism, such as anemias and hemochromatosis.
“The long-term therapeutic implications of our work with hinokitiol points to potentially using this chemical to correct anemias caused by genetic deficiencies of iron transporters required for normal red cell formation,” said study author Barry Paw, MD, PhD, of Brigham and Women’s Hospital in Boston, Massachusetts.
“At the same time, hinokitiol has the potential to correct iron-overload syndromes, such as hemochromatosis. More extensive clinical trials are necessary to work out the full potential of hinokitiol and to identify potential toxicities that we have not identified using preclinical models.”
Dr Paw and his colleagues discovered the potential of hinokitiol when screening for a molecule that could restore growth to yeast lacking an iron transporter complex. Hinokitiol is a natural product originally isolated from the Taiwanese hinoki tree.
The researchers found that hinokitiol could transport iron across the yeast cellular membrane in mutant yeasts lacking their major iron uptake transporters. Three hinokitiol molecules can wrap around an iron atom and transport it directly across the membrane where the missing protein should be.
The team also tested hinokitiol in mice, rats, and zebrafish that were missing iron-transport proteins.
Orally administered hinokitiol restored iron uptake in the guts of ferroportin-deficient mice and DMT1-deficient rats, and adding hinokitiol to a tank housing DMT1- and mitoferrin-deficient zebrafish prompted hemoglobin production in the fish.
The researchers also found that hinokitiol restored iron transport in human cells taken from the lining of the gut.
“We found that hinokitiol can restore iron transport within cells, out of cells, or both,” Dr Paw said. “It can also promote iron gut absorption and the creation of hemoglobin in some of our models. These findings suggest that small molecules like hinokitiol that can mimic the biological function of a missing protein may have potential for treating human diseases.”