Andrew D. Bowser

SAN DIEGO – A single infusion of tisagenlecleucel (Kymriah) continues to demonstrate high efficacy a year and a half after pediatric and young adult patients with relapsed or refractory acute lymphoblastic leukemia (ALL) were enrolled in the pivotal ELIANA trial, Stephan A. Grupp, MD, PhD, reported at a press conference at the annual meeting of the American Society of Hematology.

Neil Osterweil/MDedge News

Of patients in complete remission after receiving the chimeric antigen receptor (CAR) T-cell therapy, 66% were still in remission at 18 months of follow-up and median survival has yet to be reached.

“We think the efficacy is sustained and excellent,” said Dr. Grupp, of the University of Pennsylvania, Philadelphia. “These are durable complete responses even without further therapy. We haven’t reached median duration of response or overall survival, and we can manage toxicity, so I think this is clearly an opportunity for us to treat our patients both in America and across the world.”

The results of ELIANA were the basis for the approval of tisagenlecleucel (Kymriah) for relapsed/refractory B-cell ALL in the United States, and for subsequent approvals by health authorities in the European Union, Switzerland, and Canada.

The international, single-arm, open-label, phase 2 ELIANA trial included 97 patients aged 3-24 years with relapsed or refractory B-cell ALL, most of whom had previously undergone a hematopoietic stem cell transplant. Of those patients, 79 patients went on to receive a single infusion of the CAR T-cell therapy.

The rate of overall remission, defined as the rate of complete remission or complete remission with incomplete blood count recovery, was 82% (65 patients). Among those patients, 66% were still in remission at 18 months, while overall survival was “excellent” at 70%, Dr. Grupp said, and the median overall survival was not reached.

Adverse events prevalence remained relatively unchanged since the previous analyses, according to Dr. Grupp, who added that appropriately trained personnel were able to effectively manage those adverse events across study sites. Cytokine release syndrome (CRS) occurred in 77% of patients. All cases were reversible; 39% received tocilizumab for treatment of CRS with or without other anticytokine therapies; 48% required ICU-level care for CRS, with a median ICU stay of 7 days.

The other most common grade 3/4 nonhematologic adverse events were neutropenia with a body temperature exceeding 38.3° C (62% within 8 weeks of infusion), hypoxia (20%), and hypotension (20%). Grade 3 neurologic effects occurred in 13% of patients, and none had cerebral edema. Based on laboratory results, 43% had grade 3/4 thrombocytopenia and 54% had neutropenia not resolved by day 28; most of these events resolved to grade 2 or less by 3 months.

There were 25 postinfusion deaths, with 2 occurring within 30 days (1 because of disease progression, 1 because of cerebral hemorrhage). Of the 23 deaths after 30 days (range, 53-859 days), 18 were caused by disease progression. The other deaths were caused by encephalitis, systemic mycosis, vasoocclusive hepatobiliary disorder related to allogeneic SCT, bacterial lung infection, and an unknown reason after study withdrawal.

Follow-up is ongoing in the ELIANA study, which is supported by Novartis, the maker of Kymriah.

Dr. Grupp reported research funding from Novartis, consultancy with Novartis, Jazz Pharmaceuticals, and Adaptimmune Therapeutics, and patents or royalties with the University of Pennsylvania.

SOURCE: Grupp SA et al. ASH 2018, Abstract 895.

SAN DIEGO – A single infusion of tisagenlecleucel (Kymriah) continues to demonstrate high efficacy a year and a half after pediatric and young adult patients with relapsed or refractory acute lymphoblastic leukemia (ALL) were enrolled in the pivotal ELIANA trial, Stephan A. Grupp, MD, PhD, reported at a press conference at the annual meeting of the American Society of Hematology.

Neil Osterweil/MDedge News

Of patients in complete remission after receiving the chimeric antigen receptor (CAR) T-cell therapy, 66% were still in remission at 18 months of follow-up and median survival has yet to be reached.

“We think the efficacy is sustained and excellent,” said Dr. Grupp, of the University of Pennsylvania, Philadelphia. “These are durable complete responses even without further therapy. We haven’t reached median duration of response or overall survival, and we can manage toxicity, so I think this is clearly an opportunity for us to treat our patients both in America and across the world.”

The results of ELIANA were the basis for the approval of tisagenlecleucel (Kymriah) for relapsed/refractory B-cell ALL in the United States, and for subsequent approvals by health authorities in the European Union, Switzerland, and Canada.

The international, single-arm, open-label, phase 2 ELIANA trial included 97 patients aged 3-24 years with relapsed or refractory B-cell ALL, most of whom had previously undergone a hematopoietic stem cell transplant. Of those patients, 79 patients went on to receive a single infusion of the CAR T-cell therapy.

The rate of overall remission, defined as the rate of complete remission or complete remission with incomplete blood count recovery, was 82% (65 patients). Among those patients, 66% were still in remission at 18 months, while overall survival was “excellent” at 70%, Dr. Grupp said, and the median overall survival was not reached.

Adverse events prevalence remained relatively unchanged since the previous analyses, according to Dr. Grupp, who added that appropriately trained personnel were able to effectively manage those adverse events across study sites. Cytokine release syndrome (CRS) occurred in 77% of patients. All cases were reversible; 39% received tocilizumab for treatment of CRS with or without other anticytokine therapies; 48% required ICU-level care for CRS, with a median ICU stay of 7 days.

The other most common grade 3/4 nonhematologic adverse events were neutropenia with a body temperature exceeding 38.3° C (62% within 8 weeks of infusion), hypoxia (20%), and hypotension (20%). Grade 3 neurologic effects occurred in 13% of patients, and none had cerebral edema. Based on laboratory results, 43% had grade 3/4 thrombocytopenia and 54% had neutropenia not resolved by day 28; most of these events resolved to grade 2 or less by 3 months.

There were 25 postinfusion deaths, with 2 occurring within 30 days (1 because of disease progression, 1 because of cerebral hemorrhage). Of the 23 deaths after 30 days (range, 53-859 days), 18 were caused by disease progression. The other deaths were caused by encephalitis, systemic mycosis, vasoocclusive hepatobiliary disorder related to allogeneic SCT, bacterial lung infection, and an unknown reason after study withdrawal.

Follow-up is ongoing in the ELIANA study, which is supported by Novartis, the maker of Kymriah.

Dr. Grupp reported research funding from Novartis, consultancy with Novartis, Jazz Pharmaceuticals, and Adaptimmune Therapeutics, and patents or royalties with the University of Pennsylvania.

SOURCE: Grupp SA et al. ASH 2018, Abstract 895.

SAN DIEGO – A single infusion of tisagenlecleucel (Kymriah) continues to demonstrate high efficacy a year and a half after pediatric and young adult patients with relapsed or refractory acute lymphoblastic leukemia (ALL) were enrolled in the pivotal ELIANA trial, Stephan A. Grupp, MD, PhD, reported at a press conference at the annual meeting of the American Society of Hematology.

Neil Osterweil/MDedge News

Of patients in complete remission after receiving the chimeric antigen receptor (CAR) T-cell therapy, 66% were still in remission at 18 months of follow-up and median survival has yet to be reached.

“We think the efficacy is sustained and excellent,” said Dr. Grupp, of the University of Pennsylvania, Philadelphia. “These are durable complete responses even without further therapy. We haven’t reached median duration of response or overall survival, and we can manage toxicity, so I think this is clearly an opportunity for us to treat our patients both in America and across the world.”

The results of ELIANA were the basis for the approval of tisagenlecleucel (Kymriah) for relapsed/refractory B-cell ALL in the United States, and for subsequent approvals by health authorities in the European Union, Switzerland, and Canada.

The international, single-arm, open-label, phase 2 ELIANA trial included 97 patients aged 3-24 years with relapsed or refractory B-cell ALL, most of whom had previously undergone a hematopoietic stem cell transplant. Of those patients, 79 patients went on to receive a single infusion of the CAR T-cell therapy.

The rate of overall remission, defined as the rate of complete remission or complete remission with incomplete blood count recovery, was 82% (65 patients). Among those patients, 66% were still in remission at 18 months, while overall survival was “excellent” at 70%, Dr. Grupp said, and the median overall survival was not reached.

Adverse events prevalence remained relatively unchanged since the previous analyses, according to Dr. Grupp, who added that appropriately trained personnel were able to effectively manage those adverse events across study sites. Cytokine release syndrome (CRS) occurred in 77% of patients. All cases were reversible; 39% received tocilizumab for treatment of CRS with or without other anticytokine therapies; 48% required ICU-level care for CRS, with a median ICU stay of 7 days.

The other most common grade 3/4 nonhematologic adverse events were neutropenia with a body temperature exceeding 38.3° C (62% within 8 weeks of infusion), hypoxia (20%), and hypotension (20%). Grade 3 neurologic effects occurred in 13% of patients, and none had cerebral edema. Based on laboratory results, 43% had grade 3/4 thrombocytopenia and 54% had neutropenia not resolved by day 28; most of these events resolved to grade 2 or less by 3 months.

There were 25 postinfusion deaths, with 2 occurring within 30 days (1 because of disease progression, 1 because of cerebral hemorrhage). Of the 23 deaths after 30 days (range, 53-859 days), 18 were caused by disease progression. The other deaths were caused by encephalitis, systemic mycosis, vasoocclusive hepatobiliary disorder related to allogeneic SCT, bacterial lung infection, and an unknown reason after study withdrawal.

Follow-up is ongoing in the ELIANA study, which is supported by Novartis, the maker of Kymriah.

Dr. Grupp reported research funding from Novartis, consultancy with Novartis, Jazz Pharmaceuticals, and Adaptimmune Therapeutics, and patents or royalties with the University of Pennsylvania.

SOURCE: Grupp SA et al. ASH 2018, Abstract 895.

SAN DIEGO – A novel erythroid maturation agent significantly reduced transfusion burden versus placebo in patients with anemia caused by myelodysplastic syndromes (MDS) and ringed sideroblasts, results of a randomized, phase 3 trial demonstrate.

Luspatercept was “very well tolerated” and responses were durable, with approximately 40% of patients remaining transfusion free after 1 year of therapy, said Alan F. List, MD, of Moffitt Cancer Center, Tampa.

“Luspatercept is a potential new therapy that we think could be very effective in patients with lower-risk MDS with ringed sideroblasts who are red blood cell transfusion–dependent,” said Dr. List, senior author of the MEDALIST trial, said in a press conference at the annual meeting of the American Society of Hematology.

The first-in-class erythroid maturation agent is being developed as a treatment for anemia related to MDS and beta-thalassemia, Dr. List said.

In a separate randomized, placebo-controlled, phase 3 study presented at ASH 2018, Maria Domenica Cappellini, MD, of the University of Milan, reported that, in beta-thalassemia patients who were transfusion dependent, luspatercept treatment resulted in a statistically significant reductions in transfusion burden versus placebo, and was generally well tolerated.

Luspatercept is a soluble receptor chimera that binds to an array of ligands in the transforming growth factor–beta superfamily, which is known to be important in suppressing erythropoiesis in patients with MDS, Dr. List said.

The MDS study included patients with very low–, low-, or intermediate-risk disease and ringed sideroblasts who were RBC transfusion–dependent and were refractory to, unresponsive to, or ineligible for first-line treatment with an erythropoiesis-stimulating agent (ESA).

A total of 153 patients were randomly allocated to luspatercept 1.0 mg/kg, administered subcutaneously every 21 days for at least 24 weeks, while 76 were randomized to placebo every 21 days. The primary end point was the proportion of patients achieving RBC transfusion independence for at least 8 weeks during the first 24 weeks of treatment.

A total of 37.9% of luspatercept-treated patients achieved that primary endpoint, compared with 13.2% of placebo-treated patient (P less than .0001), Dr. List reported. The luspatercept-treated patients also had a 52.9% rate of erythroid response, compared with 11.8% in the placebo group (P less than .0001).

There were no differences in treatment-emergent adverse events, severe adverse events, or frequency of progression of acute myeloid leukemia. “This was a very clean drug and a very safe drug,” he said.

The decision to study luspatercept in patients with ringed sideroblasts was based on results of a large, phase 2 European study showing a higher response rate in that subset of MDS patients, according to Dr. List.

That study also included a small number of patients who had not previously received an ESA. Currently underway is a phase 3 trial looking at luspatercept in ESA-naive, lower-risk MDS patients with anemia who require RBC transfusions.

Luspatercept would be a useful therapy to have in clinic for patients with ring sideroblasts, who represent about 25% of patients overall, according to MDS expert David Steensma, MD, of Dana-Farber Cancer Institute and Harvard Medical School, Boston.

“It’s been 12 years since we had an FDA [Food and Drug Administration]-approved drug in MDS, and there have been seven in acute myeloid leukemia in the last year and a half, so it’s our turn, I think,” said Dr. Steensma, who moderated the press conference.

Dr. List reported research funding from Celgene.

SOURCE: List AF et al. ASH 2018, Abstract 1.

SAN DIEGO – A novel erythroid maturation agent significantly reduced transfusion burden versus placebo in patients with anemia caused by myelodysplastic syndromes (MDS) and ringed sideroblasts, results of a randomized, phase 3 trial demonstrate.

Luspatercept was “very well tolerated” and responses were durable, with approximately 40% of patients remaining transfusion free after 1 year of therapy, said Alan F. List, MD, of Moffitt Cancer Center, Tampa.

“Luspatercept is a potential new therapy that we think could be very effective in patients with lower-risk MDS with ringed sideroblasts who are red blood cell transfusion–dependent,” said Dr. List, senior author of the MEDALIST trial, said in a press conference at the annual meeting of the American Society of Hematology.

The first-in-class erythroid maturation agent is being developed as a treatment for anemia related to MDS and beta-thalassemia, Dr. List said.

In a separate randomized, placebo-controlled, phase 3 study presented at ASH 2018, Maria Domenica Cappellini, MD, of the University of Milan, reported that, in beta-thalassemia patients who were transfusion dependent, luspatercept treatment resulted in a statistically significant reductions in transfusion burden versus placebo, and was generally well tolerated.

Luspatercept is a soluble receptor chimera that binds to an array of ligands in the transforming growth factor–beta superfamily, which is known to be important in suppressing erythropoiesis in patients with MDS, Dr. List said.

The MDS study included patients with very low–, low-, or intermediate-risk disease and ringed sideroblasts who were RBC transfusion–dependent and were refractory to, unresponsive to, or ineligible for first-line treatment with an erythropoiesis-stimulating agent (ESA).

A total of 153 patients were randomly allocated to luspatercept 1.0 mg/kg, administered subcutaneously every 21 days for at least 24 weeks, while 76 were randomized to placebo every 21 days. The primary end point was the proportion of patients achieving RBC transfusion independence for at least 8 weeks during the first 24 weeks of treatment.

A total of 37.9% of luspatercept-treated patients achieved that primary endpoint, compared with 13.2% of placebo-treated patient (P less than .0001), Dr. List reported. The luspatercept-treated patients also had a 52.9% rate of erythroid response, compared with 11.8% in the placebo group (P less than .0001).

There were no differences in treatment-emergent adverse events, severe adverse events, or frequency of progression of acute myeloid leukemia. “This was a very clean drug and a very safe drug,” he said.

The decision to study luspatercept in patients with ringed sideroblasts was based on results of a large, phase 2 European study showing a higher response rate in that subset of MDS patients, according to Dr. List.

That study also included a small number of patients who had not previously received an ESA. Currently underway is a phase 3 trial looking at luspatercept in ESA-naive, lower-risk MDS patients with anemia who require RBC transfusions.

Luspatercept would be a useful therapy to have in clinic for patients with ring sideroblasts, who represent about 25% of patients overall, according to MDS expert David Steensma, MD, of Dana-Farber Cancer Institute and Harvard Medical School, Boston.

“It’s been 12 years since we had an FDA [Food and Drug Administration]-approved drug in MDS, and there have been seven in acute myeloid leukemia in the last year and a half, so it’s our turn, I think,” said Dr. Steensma, who moderated the press conference.

Dr. List reported research funding from Celgene.

SOURCE: List AF et al. ASH 2018, Abstract 1.

SAN DIEGO – A novel erythroid maturation agent significantly reduced transfusion burden versus placebo in patients with anemia caused by myelodysplastic syndromes (MDS) and ringed sideroblasts, results of a randomized, phase 3 trial demonstrate.

Luspatercept was “very well tolerated” and responses were durable, with approximately 40% of patients remaining transfusion free after 1 year of therapy, said Alan F. List, MD, of Moffitt Cancer Center, Tampa.

“Luspatercept is a potential new therapy that we think could be very effective in patients with lower-risk MDS with ringed sideroblasts who are red blood cell transfusion–dependent,” said Dr. List, senior author of the MEDALIST trial, said in a press conference at the annual meeting of the American Society of Hematology.

The first-in-class erythroid maturation agent is being developed as a treatment for anemia related to MDS and beta-thalassemia, Dr. List said.

In a separate randomized, placebo-controlled, phase 3 study presented at ASH 2018, Maria Domenica Cappellini, MD, of the University of Milan, reported that, in beta-thalassemia patients who were transfusion dependent, luspatercept treatment resulted in a statistically significant reductions in transfusion burden versus placebo, and was generally well tolerated.

Luspatercept is a soluble receptor chimera that binds to an array of ligands in the transforming growth factor–beta superfamily, which is known to be important in suppressing erythropoiesis in patients with MDS, Dr. List said.

The MDS study included patients with very low–, low-, or intermediate-risk disease and ringed sideroblasts who were RBC transfusion–dependent and were refractory to, unresponsive to, or ineligible for first-line treatment with an erythropoiesis-stimulating agent (ESA).

A total of 153 patients were randomly allocated to luspatercept 1.0 mg/kg, administered subcutaneously every 21 days for at least 24 weeks, while 76 were randomized to placebo every 21 days. The primary end point was the proportion of patients achieving RBC transfusion independence for at least 8 weeks during the first 24 weeks of treatment.

A total of 37.9% of luspatercept-treated patients achieved that primary endpoint, compared with 13.2% of placebo-treated patient (P less than .0001), Dr. List reported. The luspatercept-treated patients also had a 52.9% rate of erythroid response, compared with 11.8% in the placebo group (P less than .0001).

There were no differences in treatment-emergent adverse events, severe adverse events, or frequency of progression of acute myeloid leukemia. “This was a very clean drug and a very safe drug,” he said.

The decision to study luspatercept in patients with ringed sideroblasts was based on results of a large, phase 2 European study showing a higher response rate in that subset of MDS patients, according to Dr. List.

That study also included a small number of patients who had not previously received an ESA. Currently underway is a phase 3 trial looking at luspatercept in ESA-naive, lower-risk MDS patients with anemia who require RBC transfusions.

Luspatercept would be a useful therapy to have in clinic for patients with ring sideroblasts, who represent about 25% of patients overall, according to MDS expert David Steensma, MD, of Dana-Farber Cancer Institute and Harvard Medical School, Boston.

“It’s been 12 years since we had an FDA [Food and Drug Administration]-approved drug in MDS, and there have been seven in acute myeloid leukemia in the last year and a half, so it’s our turn, I think,” said Dr. Steensma, who moderated the press conference.

Dr. List reported research funding from Celgene.

SOURCE: List AF et al. ASH 2018, Abstract 1.

SAN DIEGO – A hematopoietic cell transplant following chimeric antigen receptor (CAR) T-cell therapy for B-cell acute lymphocytic leukemia (B-ALL) may reduce late relapse risk in certain patients, a retrospective analysis suggests.

Corinne Summers, MD, of Seattle Children’s Hospital, and her colleagues evaluated the potential benefits of allogeneic hematopoietic cell transplant (HCT) in 50 pediatric and young adult B-ALL patients who had sustained leukemic remission after receiving SCRI-CAR19v1, a CD19-specific CAR T-cell product.

Leukemia-free survival was significantly improved for patients with no history of HCT who received CD19 CAR T-cell therapy followed by consolidative HCT, Dr. Summers reported at the annual meeting of the American Society of Hematology.

However, the benefits of consolidative HCT are unclear for patients with a history of HCT, Dr. Summers said at the meeting, noting that larger studies are needed.

In her video interview at ASH 2018, Dr. Summers talked more about the challenges of late leukemic relapse and the potential role of HCT after CAR T-cell therapy.

Dr. Summers reported no disclosures related to her presentation.

SAN DIEGO – A hematopoietic cell transplant following chimeric antigen receptor (CAR) T-cell therapy for B-cell acute lymphocytic leukemia (B-ALL) may reduce late relapse risk in certain patients, a retrospective analysis suggests.

Corinne Summers, MD, of Seattle Children’s Hospital, and her colleagues evaluated the potential benefits of allogeneic hematopoietic cell transplant (HCT) in 50 pediatric and young adult B-ALL patients who had sustained leukemic remission after receiving SCRI-CAR19v1, a CD19-specific CAR T-cell product.

Leukemia-free survival was significantly improved for patients with no history of HCT who received CD19 CAR T-cell therapy followed by consolidative HCT, Dr. Summers reported at the annual meeting of the American Society of Hematology.

However, the benefits of consolidative HCT are unclear for patients with a history of HCT, Dr. Summers said at the meeting, noting that larger studies are needed.

In her video interview at ASH 2018, Dr. Summers talked more about the challenges of late leukemic relapse and the potential role of HCT after CAR T-cell therapy.

Dr. Summers reported no disclosures related to her presentation.

SAN DIEGO – A hematopoietic cell transplant following chimeric antigen receptor (CAR) T-cell therapy for B-cell acute lymphocytic leukemia (B-ALL) may reduce late relapse risk in certain patients, a retrospective analysis suggests.

Corinne Summers, MD, of Seattle Children’s Hospital, and her colleagues evaluated the potential benefits of allogeneic hematopoietic cell transplant (HCT) in 50 pediatric and young adult B-ALL patients who had sustained leukemic remission after receiving SCRI-CAR19v1, a CD19-specific CAR T-cell product.

Leukemia-free survival was significantly improved for patients with no history of HCT who received CD19 CAR T-cell therapy followed by consolidative HCT, Dr. Summers reported at the annual meeting of the American Society of Hematology.

However, the benefits of consolidative HCT are unclear for patients with a history of HCT, Dr. Summers said at the meeting, noting that larger studies are needed.

In her video interview at ASH 2018, Dr. Summers talked more about the challenges of late leukemic relapse and the potential role of HCT after CAR T-cell therapy.

Dr. Summers reported no disclosures related to her presentation.

SAN DIEGO – Daily hydroxyurea treatment for sickle cell disease is feasible, safe, and effective for children in sub-Saharan Africa, according to the results of a large open-label, phase 1-2, international trial.

Andrew Bowser/MDedge News

Hydroxyurea was associated with reduced rates of malaria and other infections, resulting in improved survival, according to Léon Tshilolo, MD, PhD, of Centre Hospitalier Monkole in Kinshasa, the Democratic Republic of the Congo.

“Based on that data, we believe that wider access to hydroxyurea for sickle cell anemia has the potential to save millions of lives in Africa,” Dr. Tshilolo said in a press conference at the annual meeting of the American Society of Hematology.

Use of hydroxyurea has been limited in Africa because of cost, access issues, and challenges associated with laboratory monitoring, according to the researchers.

Moreover, most of the data on the efficacy of hydroxyurea come from studies conducted in the United States, Europe, and other high-income settings, said the study’s senior author Russell E. Ware, MD, PhD, of Cincinnati Children’s Hospital Center.

“Now that there’s data in an African setting, I think this will go a long way to advancing [hydroxyurea therapy] and encouraging governments, organizations, and pharmaceutical companies to bring it in,” Dr. Ware said in an interview.

In the study by Dr. Ware, Dr. Tshilolo, and their colleagues, 606 children in four sub-Saharan African countries completed a 2-month pretreatment screening phase designed to capture baseline clinical and laboratory data. The children, who were aged 1-10 years, were started at 15-20 mg/kg of hydroxyurea for 6 months, followed by escalation to the maximum tolerated dose.

With a median of 2.5 years of treatment, treated children experienced less pain and anemia, fewer cases of malaria and other infections, and lower rates of transfusions and death versus rates observed in the pretreatment screening phase of the trial.

The rate of vasoocclusive pain during hydroxyurea treatment was 44.6 events per 100 patient-years, compared with 98.3 events per 100 patient-years in the pretreatment period (incidence rate ratio, 0.45; 95% confidence interval, 0.37-0.56), according to data simultaneously published in the New England Journal of Medicine.

Malaria infection rates were 22.9 events per 100 patient-years in the hydroxyurea treatment period versus 46.9 events in the pretreatment period (IRR, 0.49; 95% CI, 0.37-0.66). Rates of nonmalaria infections were 90.0 events per 100 patient-years in the hydroxyurea treatment period versus 142.5 events per 100 patient-years in the pretreatment period (IRR, 0.62; 95% CI, 0.53-0.72).

Dr. Tshilolo said investigators were “encouraged” by the reduced infection rates, particularly in light of previous concerns that hydroxyurea could suppress the immune system and put children at risk for malaria.

Death rates were 1.1 per 100 patient-years in the hydroxyurea group and 3.6 per 100 patient-years in the pretreatment period (IR, 0.30; 95% CI, 0.10-0.88). Dose-limiting toxic events occurred in 5.1% of the children, which was below the protocol-specified threshold for safety, Dr. Tshilolo added.

Dr. Tshilolo reported grants from the National Institutes of Health/National Heart, Lung, and Blood Institute and Cincinnati Children’s Research Foundation, along with nonfinancial support from Bristol-Myers Squibb. Dr. Ware reported grants from the NIH/NHLBI and Bristol-Myers Squibb.

SOURCE: Tshilolo L et al. ASH 2018, Abstract 3.

SAN DIEGO – Daily hydroxyurea treatment for sickle cell disease is feasible, safe, and effective for children in sub-Saharan Africa, according to the results of a large open-label, phase 1-2, international trial.

Andrew Bowser/MDedge News

Hydroxyurea was associated with reduced rates of malaria and other infections, resulting in improved survival, according to Léon Tshilolo, MD, PhD, of Centre Hospitalier Monkole in Kinshasa, the Democratic Republic of the Congo.

“Based on that data, we believe that wider access to hydroxyurea for sickle cell anemia has the potential to save millions of lives in Africa,” Dr. Tshilolo said in a press conference at the annual meeting of the American Society of Hematology.

Use of hydroxyurea has been limited in Africa because of cost, access issues, and challenges associated with laboratory monitoring, according to the researchers.

Moreover, most of the data on the efficacy of hydroxyurea come from studies conducted in the United States, Europe, and other high-income settings, said the study’s senior author Russell E. Ware, MD, PhD, of Cincinnati Children’s Hospital Center.

“Now that there’s data in an African setting, I think this will go a long way to advancing [hydroxyurea therapy] and encouraging governments, organizations, and pharmaceutical companies to bring it in,” Dr. Ware said in an interview.

In the study by Dr. Ware, Dr. Tshilolo, and their colleagues, 606 children in four sub-Saharan African countries completed a 2-month pretreatment screening phase designed to capture baseline clinical and laboratory data. The children, who were aged 1-10 years, were started at 15-20 mg/kg of hydroxyurea for 6 months, followed by escalation to the maximum tolerated dose.

With a median of 2.5 years of treatment, treated children experienced less pain and anemia, fewer cases of malaria and other infections, and lower rates of transfusions and death versus rates observed in the pretreatment screening phase of the trial.

The rate of vasoocclusive pain during hydroxyurea treatment was 44.6 events per 100 patient-years, compared with 98.3 events per 100 patient-years in the pretreatment period (incidence rate ratio, 0.45; 95% confidence interval, 0.37-0.56), according to data simultaneously published in the New England Journal of Medicine.

Malaria infection rates were 22.9 events per 100 patient-years in the hydroxyurea treatment period versus 46.9 events in the pretreatment period (IRR, 0.49; 95% CI, 0.37-0.66). Rates of nonmalaria infections were 90.0 events per 100 patient-years in the hydroxyurea treatment period versus 142.5 events per 100 patient-years in the pretreatment period (IRR, 0.62; 95% CI, 0.53-0.72).

Dr. Tshilolo said investigators were “encouraged” by the reduced infection rates, particularly in light of previous concerns that hydroxyurea could suppress the immune system and put children at risk for malaria.

Death rates were 1.1 per 100 patient-years in the hydroxyurea group and 3.6 per 100 patient-years in the pretreatment period (IR, 0.30; 95% CI, 0.10-0.88). Dose-limiting toxic events occurred in 5.1% of the children, which was below the protocol-specified threshold for safety, Dr. Tshilolo added.

Dr. Tshilolo reported grants from the National Institutes of Health/National Heart, Lung, and Blood Institute and Cincinnati Children’s Research Foundation, along with nonfinancial support from Bristol-Myers Squibb. Dr. Ware reported grants from the NIH/NHLBI and Bristol-Myers Squibb.

SOURCE: Tshilolo L et al. ASH 2018, Abstract 3.

SAN DIEGO – Daily hydroxyurea treatment for sickle cell disease is feasible, safe, and effective for children in sub-Saharan Africa, according to the results of a large open-label, phase 1-2, international trial.

Andrew Bowser/MDedge News

Hydroxyurea was associated with reduced rates of malaria and other infections, resulting in improved survival, according to Léon Tshilolo, MD, PhD, of Centre Hospitalier Monkole in Kinshasa, the Democratic Republic of the Congo.

“Based on that data, we believe that wider access to hydroxyurea for sickle cell anemia has the potential to save millions of lives in Africa,” Dr. Tshilolo said in a press conference at the annual meeting of the American Society of Hematology.

Use of hydroxyurea has been limited in Africa because of cost, access issues, and challenges associated with laboratory monitoring, according to the researchers.

Moreover, most of the data on the efficacy of hydroxyurea come from studies conducted in the United States, Europe, and other high-income settings, said the study’s senior author Russell E. Ware, MD, PhD, of Cincinnati Children’s Hospital Center.

“Now that there’s data in an African setting, I think this will go a long way to advancing [hydroxyurea therapy] and encouraging governments, organizations, and pharmaceutical companies to bring it in,” Dr. Ware said in an interview.

In the study by Dr. Ware, Dr. Tshilolo, and their colleagues, 606 children in four sub-Saharan African countries completed a 2-month pretreatment screening phase designed to capture baseline clinical and laboratory data. The children, who were aged 1-10 years, were started at 15-20 mg/kg of hydroxyurea for 6 months, followed by escalation to the maximum tolerated dose.

With a median of 2.5 years of treatment, treated children experienced less pain and anemia, fewer cases of malaria and other infections, and lower rates of transfusions and death versus rates observed in the pretreatment screening phase of the trial.

The rate of vasoocclusive pain during hydroxyurea treatment was 44.6 events per 100 patient-years, compared with 98.3 events per 100 patient-years in the pretreatment period (incidence rate ratio, 0.45; 95% confidence interval, 0.37-0.56), according to data simultaneously published in the New England Journal of Medicine.

Malaria infection rates were 22.9 events per 100 patient-years in the hydroxyurea treatment period versus 46.9 events in the pretreatment period (IRR, 0.49; 95% CI, 0.37-0.66). Rates of nonmalaria infections were 90.0 events per 100 patient-years in the hydroxyurea treatment period versus 142.5 events per 100 patient-years in the pretreatment period (IRR, 0.62; 95% CI, 0.53-0.72).

Dr. Tshilolo said investigators were “encouraged” by the reduced infection rates, particularly in light of previous concerns that hydroxyurea could suppress the immune system and put children at risk for malaria.

Death rates were 1.1 per 100 patient-years in the hydroxyurea group and 3.6 per 100 patient-years in the pretreatment period (IR, 0.30; 95% CI, 0.10-0.88). Dose-limiting toxic events occurred in 5.1% of the children, which was below the protocol-specified threshold for safety, Dr. Tshilolo added.

Dr. Tshilolo reported grants from the National Institutes of Health/National Heart, Lung, and Blood Institute and Cincinnati Children’s Research Foundation, along with nonfinancial support from Bristol-Myers Squibb. Dr. Ware reported grants from the NIH/NHLBI and Bristol-Myers Squibb.

SOURCE: Tshilolo L et al. ASH 2018, Abstract 3.

SAN DIEGO – A smartphone app that included artificial intelligence elements was associated with improved pain outcomes and reduced hospital admissions in patients with advanced cancers.

Pain severity significantly decreased among patients randomized to use the app versus control patients who received only palliative care, researchers reported at the Palliative and Supportive Care in Oncology Symposium.

The risk of pain-related hospital admissions was significantly lower for those who used the pain tracking app, called ePAL, though anxiety scores were higher in the app users, the investigators said, and no difference between arms was noted in quality of life or global symptom scores.

The ePAL app prompts patients three times per week to track their pain levels and, depending on the severity of pain, will use an algorithm to guide patients through their symptoms, or, in patients with persistent or worsening pain, connect them directly with the palliative care service for additional assessment.

The app also includes pain management tips, among other educational content, provides the ability to request pain prescription refills, and creates a summary of the patient’s pain condition for the provider, said Mihir M. Kamdar, MD, associate director of palliative care at Massachusetts General Hospital in Boston.

“The provider can actually start the visit with that information, instead of having to spend several minutes trying to recap what might or might not have happened since the last clinic visit,” Dr. Kamdar said.

The study included 112 English-speaking adult patients with stage IV solid cancers and moderate to severe pain who were being followed in a palliative care clinic. They were randomly assigned to receive the ePAL app plus standard of care or standard of care alone; 39 patients in the app group and 40 in the control arm completed the 8-week evaluation.

Pain severity, the primary study endpoint, decreased over time in the intervention group, from a composite Brief Pain Inventory score of 3.74 at enrollment to 2.99 at 8 weeks, while in the control group, the scores were 4.02 at enrollment and 4.05 at 8 weeks (P = .017 for intervention versus control), Dr. Kamdar reported.

Risk of pain-related hospital admissions was significantly lower in the intervention group, according to Dr. Kamdar. The per-patient risk of an inpatient admission was 0.071 and 0.232 for the intervention and controls groups, respectively, with a risk ratio of 0.31 (95% CI, 0.11-0.89; P = .018).

Anxiety was increased in the app users, as measured by the Generalized Anxiety Disorder 7-item scale, with a significant difference between the app and control groups at 8 weeks (P = .015). However, the change was in a range considered mild and was not seen in patients who used the app more than two times per week.

Negative attitudes toward cancer pain treatment decreased significantly in the app group, as shown by a lower score on the Barriers Questionnaire II at 8 weeks (P = .042), Dr. Kamdar reported.

The app and study were supported by the McKesson Foundation’s Mobilizing for Health Initiative. Dr. Kamdar reported stock/ownership and consulting/advisory role disclosures related to Amorsa Therapeutics.

SOURCE: Kamdar MM et al. PallOnc 2018, Abstract 76.

SAN DIEGO – A smartphone app that included artificial intelligence elements was associated with improved pain outcomes and reduced hospital admissions in patients with advanced cancers.

Pain severity significantly decreased among patients randomized to use the app versus control patients who received only palliative care, researchers reported at the Palliative and Supportive Care in Oncology Symposium.

The risk of pain-related hospital admissions was significantly lower for those who used the pain tracking app, called ePAL, though anxiety scores were higher in the app users, the investigators said, and no difference between arms was noted in quality of life or global symptom scores.

The ePAL app prompts patients three times per week to track their pain levels and, depending on the severity of pain, will use an algorithm to guide patients through their symptoms, or, in patients with persistent or worsening pain, connect them directly with the palliative care service for additional assessment.

The app also includes pain management tips, among other educational content, provides the ability to request pain prescription refills, and creates a summary of the patient’s pain condition for the provider, said Mihir M. Kamdar, MD, associate director of palliative care at Massachusetts General Hospital in Boston.

“The provider can actually start the visit with that information, instead of having to spend several minutes trying to recap what might or might not have happened since the last clinic visit,” Dr. Kamdar said.

The study included 112 English-speaking adult patients with stage IV solid cancers and moderate to severe pain who were being followed in a palliative care clinic. They were randomly assigned to receive the ePAL app plus standard of care or standard of care alone; 39 patients in the app group and 40 in the control arm completed the 8-week evaluation.

Pain severity, the primary study endpoint, decreased over time in the intervention group, from a composite Brief Pain Inventory score of 3.74 at enrollment to 2.99 at 8 weeks, while in the control group, the scores were 4.02 at enrollment and 4.05 at 8 weeks (P = .017 for intervention versus control), Dr. Kamdar reported.

Risk of pain-related hospital admissions was significantly lower in the intervention group, according to Dr. Kamdar. The per-patient risk of an inpatient admission was 0.071 and 0.232 for the intervention and controls groups, respectively, with a risk ratio of 0.31 (95% CI, 0.11-0.89; P = .018).

Anxiety was increased in the app users, as measured by the Generalized Anxiety Disorder 7-item scale, with a significant difference between the app and control groups at 8 weeks (P = .015). However, the change was in a range considered mild and was not seen in patients who used the app more than two times per week.

Negative attitudes toward cancer pain treatment decreased significantly in the app group, as shown by a lower score on the Barriers Questionnaire II at 8 weeks (P = .042), Dr. Kamdar reported.

The app and study were supported by the McKesson Foundation’s Mobilizing for Health Initiative. Dr. Kamdar reported stock/ownership and consulting/advisory role disclosures related to Amorsa Therapeutics.

SOURCE: Kamdar MM et al. PallOnc 2018, Abstract 76.

SAN DIEGO – A smartphone app that included artificial intelligence elements was associated with improved pain outcomes and reduced hospital admissions in patients with advanced cancers.

Pain severity significantly decreased among patients randomized to use the app versus control patients who received only palliative care, researchers reported at the Palliative and Supportive Care in Oncology Symposium.

The risk of pain-related hospital admissions was significantly lower for those who used the pain tracking app, called ePAL, though anxiety scores were higher in the app users, the investigators said, and no difference between arms was noted in quality of life or global symptom scores.

The ePAL app prompts patients three times per week to track their pain levels and, depending on the severity of pain, will use an algorithm to guide patients through their symptoms, or, in patients with persistent or worsening pain, connect them directly with the palliative care service for additional assessment.

The app also includes pain management tips, among other educational content, provides the ability to request pain prescription refills, and creates a summary of the patient’s pain condition for the provider, said Mihir M. Kamdar, MD, associate director of palliative care at Massachusetts General Hospital in Boston.

“The provider can actually start the visit with that information, instead of having to spend several minutes trying to recap what might or might not have happened since the last clinic visit,” Dr. Kamdar said.

The study included 112 English-speaking adult patients with stage IV solid cancers and moderate to severe pain who were being followed in a palliative care clinic. They were randomly assigned to receive the ePAL app plus standard of care or standard of care alone; 39 patients in the app group and 40 in the control arm completed the 8-week evaluation.

Pain severity, the primary study endpoint, decreased over time in the intervention group, from a composite Brief Pain Inventory score of 3.74 at enrollment to 2.99 at 8 weeks, while in the control group, the scores were 4.02 at enrollment and 4.05 at 8 weeks (P = .017 for intervention versus control), Dr. Kamdar reported.

Risk of pain-related hospital admissions was significantly lower in the intervention group, according to Dr. Kamdar. The per-patient risk of an inpatient admission was 0.071 and 0.232 for the intervention and controls groups, respectively, with a risk ratio of 0.31 (95% CI, 0.11-0.89; P = .018).

Anxiety was increased in the app users, as measured by the Generalized Anxiety Disorder 7-item scale, with a significant difference between the app and control groups at 8 weeks (P = .015). However, the change was in a range considered mild and was not seen in patients who used the app more than two times per week.

Negative attitudes toward cancer pain treatment decreased significantly in the app group, as shown by a lower score on the Barriers Questionnaire II at 8 weeks (P = .042), Dr. Kamdar reported.

The app and study were supported by the McKesson Foundation’s Mobilizing for Health Initiative. Dr. Kamdar reported stock/ownership and consulting/advisory role disclosures related to Amorsa Therapeutics.

SOURCE: Kamdar MM et al. PallOnc 2018, Abstract 76.

Photo from St. Jude Children’s Research Hospital

Sickle cell disease (SCD) will take center stage at the 2018 ASH Annual Meeting, according to a recent press briefing.

During the briefing, ASH President Alexis A. Thompson, MD, highlighted four “abstracts to watch” that focus on SCD.

These abstracts cover a pilot study of gene therapy, long-term outcomes of haploidentical hematopoietic stem cell transplant (haplo-HSCT), mortality rates in SCD patients prescribed opioids, and outcomes with hydroxyurea (HU) among patients in sub-Saharan Africa.

“These are all quite different aspects of work being done,” said Dr. Thompson, of Ann and Robert H. Lurie Children’s Hospital of Chicago in Illinois.

Gene therapy

In the pilot study of gene therapy (abstract 1023), investigators used a microRNA-adapted short hairpin RNA lentiviral vector targeting BCL11A for autologous gene therapy in SCD patients.

Preclinical research had shown that this approach could induce fetal hemoglobin in human erythroid cells and “largely” attenuate the hematologic effects of SCD in a murine model, according to investigators.

Initial results from the pilot study suggest this approach is feasible in humans as well. In the first patient infused, investigators observed “rapid” induction of fetal hemoglobin and “marked attenuation of hemolysis in the early phase of autologous reconstitution.”

“We’re looking forward to seeing this initial presentation on their findings with this first administration to humans,” Dr. Thompson said.

Haplo-HSCT

In another study (abstract 162), investigators assessed long-term health-related quality of life in high-risk SCD patients who underwent familial haplo-HSCT.

The patients received myeloablative conditioning and familial haplo-HSCT using CD34 enrichment and mononuclear cell (CD3) addback.

Two years from haplo-HSCT, patients had significant improvements in emotional and physical health-related quality of life, among other outcomes of interest, including neurocognitive outcomes.

Opioid use

A third study (abstract 315) indicates that opioid use is not associated with in-hospital mortality in SCD patients.

This is interesting in the context of the national opioid epidemic, Dr. Thompson said.

Investigators looked at data from the National Inpatient Sample and found no significant increase in in-hospital mortality in SCD patients from 1998 through 2013. This can be compared to the 350% increase in non-SCD opioid prescription-related deaths from 1999 through 2013.

“It should alleviate many concerns about patients with sickle cell who, for legitimate reasons, may require high doses of opioids,” Dr. Thompson said. “While I think we’re being very mindful about opioid use in this patient population, they certainly do need these high doses, but there does not seem to be an extraordinary risk of death associated with their use.”

HU in sub-Saharan Africa

Dr. Thompson said a fourth study worth watching is REACH (abstract 3), a trial of HU in 635 children in sub-Saharan Africa.

The study provides the first prospective data showing the feasibility, safety, and benefits of HU use in this population, according to investigators.

The findings are “quite encouraging,” Dr. Thompson said.

She added that the results looked “very similar” to the United States experience and demonstrated effective clinical trial design and execution in a lower-resource country.

Photo from St. Jude Children’s Research Hospital

Sickle cell disease (SCD) will take center stage at the 2018 ASH Annual Meeting, according to a recent press briefing.

During the briefing, ASH President Alexis A. Thompson, MD, highlighted four “abstracts to watch” that focus on SCD.

These abstracts cover a pilot study of gene therapy, long-term outcomes of haploidentical hematopoietic stem cell transplant (haplo-HSCT), mortality rates in SCD patients prescribed opioids, and outcomes with hydroxyurea (HU) among patients in sub-Saharan Africa.

“These are all quite different aspects of work being done,” said Dr. Thompson, of Ann and Robert H. Lurie Children’s Hospital of Chicago in Illinois.

Gene therapy

In the pilot study of gene therapy (abstract 1023), investigators used a microRNA-adapted short hairpin RNA lentiviral vector targeting BCL11A for autologous gene therapy in SCD patients.

Preclinical research had shown that this approach could induce fetal hemoglobin in human erythroid cells and “largely” attenuate the hematologic effects of SCD in a murine model, according to investigators.

Initial results from the pilot study suggest this approach is feasible in humans as well. In the first patient infused, investigators observed “rapid” induction of fetal hemoglobin and “marked attenuation of hemolysis in the early phase of autologous reconstitution.”

“We’re looking forward to seeing this initial presentation on their findings with this first administration to humans,” Dr. Thompson said.

Haplo-HSCT

In another study (abstract 162), investigators assessed long-term health-related quality of life in high-risk SCD patients who underwent familial haplo-HSCT.

The patients received myeloablative conditioning and familial haplo-HSCT using CD34 enrichment and mononuclear cell (CD3) addback.

Two years from haplo-HSCT, patients had significant improvements in emotional and physical health-related quality of life, among other outcomes of interest, including neurocognitive outcomes.

Opioid use

A third study (abstract 315) indicates that opioid use is not associated with in-hospital mortality in SCD patients.

This is interesting in the context of the national opioid epidemic, Dr. Thompson said.

Investigators looked at data from the National Inpatient Sample and found no significant increase in in-hospital mortality in SCD patients from 1998 through 2013. This can be compared to the 350% increase in non-SCD opioid prescription-related deaths from 1999 through 2013.

“It should alleviate many concerns about patients with sickle cell who, for legitimate reasons, may require high doses of opioids,” Dr. Thompson said. “While I think we’re being very mindful about opioid use in this patient population, they certainly do need these high doses, but there does not seem to be an extraordinary risk of death associated with their use.”

HU in sub-Saharan Africa

Dr. Thompson said a fourth study worth watching is REACH (abstract 3), a trial of HU in 635 children in sub-Saharan Africa.

The study provides the first prospective data showing the feasibility, safety, and benefits of HU use in this population, according to investigators.

The findings are “quite encouraging,” Dr. Thompson said.

She added that the results looked “very similar” to the United States experience and demonstrated effective clinical trial design and execution in a lower-resource country.

Photo from St. Jude Children’s Research Hospital

Sickle cell disease (SCD) will take center stage at the 2018 ASH Annual Meeting, according to a recent press briefing.

During the briefing, ASH President Alexis A. Thompson, MD, highlighted four “abstracts to watch” that focus on SCD.

These abstracts cover a pilot study of gene therapy, long-term outcomes of haploidentical hematopoietic stem cell transplant (haplo-HSCT), mortality rates in SCD patients prescribed opioids, and outcomes with hydroxyurea (HU) among patients in sub-Saharan Africa.

“These are all quite different aspects of work being done,” said Dr. Thompson, of Ann and Robert H. Lurie Children’s Hospital of Chicago in Illinois.

Gene therapy

In the pilot study of gene therapy (abstract 1023), investigators used a microRNA-adapted short hairpin RNA lentiviral vector targeting BCL11A for autologous gene therapy in SCD patients.

Preclinical research had shown that this approach could induce fetal hemoglobin in human erythroid cells and “largely” attenuate the hematologic effects of SCD in a murine model, according to investigators.

Initial results from the pilot study suggest this approach is feasible in humans as well. In the first patient infused, investigators observed “rapid” induction of fetal hemoglobin and “marked attenuation of hemolysis in the early phase of autologous reconstitution.”

“We’re looking forward to seeing this initial presentation on their findings with this first administration to humans,” Dr. Thompson said.

Haplo-HSCT

In another study (abstract 162), investigators assessed long-term health-related quality of life in high-risk SCD patients who underwent familial haplo-HSCT.

The patients received myeloablative conditioning and familial haplo-HSCT using CD34 enrichment and mononuclear cell (CD3) addback.

Two years from haplo-HSCT, patients had significant improvements in emotional and physical health-related quality of life, among other outcomes of interest, including neurocognitive outcomes.

Opioid use

A third study (abstract 315) indicates that opioid use is not associated with in-hospital mortality in SCD patients.

This is interesting in the context of the national opioid epidemic, Dr. Thompson said.

Investigators looked at data from the National Inpatient Sample and found no significant increase in in-hospital mortality in SCD patients from 1998 through 2013. This can be compared to the 350% increase in non-SCD opioid prescription-related deaths from 1999 through 2013.

“It should alleviate many concerns about patients with sickle cell who, for legitimate reasons, may require high doses of opioids,” Dr. Thompson said. “While I think we’re being very mindful about opioid use in this patient population, they certainly do need these high doses, but there does not seem to be an extraordinary risk of death associated with their use.”

HU in sub-Saharan Africa

Dr. Thompson said a fourth study worth watching is REACH (abstract 3), a trial of HU in 635 children in sub-Saharan Africa.

The study provides the first prospective data showing the feasibility, safety, and benefits of HU use in this population, according to investigators.

The findings are “quite encouraging,” Dr. Thompson said.

She added that the results looked “very similar” to the United States experience and demonstrated effective clinical trial design and execution in a lower-resource country.

Photo from Penn Medicine

Several studies set to be presented at the 2018 ASH Annual Meeting provide new insights regarding chimeric antigen receptor (CAR) T-cell therapies.

One study suggests ibrutinib may enhance CAR T-cell therapy in patients with chronic lymphocytic leukemia (CLL), and another suggests checkpoint inhibitors can augment CAR T-cell therapy in certain patients with B-cell acute lymphoblastic leukemia (ALL).

Two additional studies indicate that responses to tisagenlecleucel are durable in both ALL and diffuse large B-cell lymphoma (DLBCL).

A fifth study suggests hematopoietic stem cell transplant (HSCT) may reduce the risk of relapse after CAR T-cell therapy.

ASH Secretary Robert A. Brodsky, MD, of Johns Hopkins University in Baltimore, Maryland, discussed these studies during a media briefing ahead of the ASH Annual Meeting.

Ibrutinib

In the ibrutinib study (abstract 299), patients received the BTK inhibitor starting 2 weeks prior to leukapheresis and continued until 3 months after treatment with JCAR014.

Data suggest this strategy may improve responses and decrease the incidence of severe cytokine release syndrome in patients with relapsed or refractory CLL.

Responses occurred in 88% of patients who received ibrutinib and 56% of those who did not.

Grade 3-5 cytokine release syndrome occurred in 5 of 19 patients (26%) in the no-ibrutinib cohort and 0 of 17 patients in the ibrutinib cohort.

These findings are “early and preliminary but very exciting” Dr. Brodsky said.

Checkpoint inhibitors

Early results of the checkpoint inhibitor study (abstract 556) suggest that pembrolizumab or nivolumab may augment CD19-directed CAR T-cell therapy.

The 14 patients studied had early CAR T-cell loss, partial response, or no response to CAR T-cell therapy. Thirteen patients had B-cell ALL, and one had B lymphoblastic lymphoma.

CD19-directed CAR T-cell therapy consisted of tisagenlecleucel in four patients and CTL119 in 10. Thirteen patients received pembrolizumab, and one received nivolumab.

Three of six patients who had early B-cell recovery re-established B-cell aplasia with the addition of a checkpoint inhibitor. In two patients, B-cell aplasia persists with ongoing pembrolizumab.

Four patients who did not respond to or relapsed after their initial CAR T-cell therapy had a partial (n=2) or complete response (n=2) with the addition of pembrolizumab.

There were additional partial responses in the remaining four patients. However, one of these patients (with CD19-dim/negative disease) progressed.

“The idea was if you can give pembrolizumab, you can take the brakes off, and maybe you can reinitiate the immune attack,” Dr. Brodsky said.

“[This is a] very small [study with] preliminary data but very exciting that it is safe to give checkpoint inhibitors with CAR T cells, and it may be efficacious at getting the immune response back.”

Tisagenlecleucel follow-up

One of the two tisagenlecleucel updates (abstract 895) consists of data from the ELIANA trial, which includes pediatric and young adult patients with relapsed/refractory ALL.

The overall response rate was 82% (65/79). Of the 65 responders, 29 were still in response at follow-up.

The probability of relapse-free survival was 66% at 12 months and 18 months.

“These are some very fast-growing tumors, and these are refractory, resistant patients, so, as we get further and further out, it’s more encouraging to see that there are durable responses,” Dr. Brodsky said.

The other tisagenlecleucel update (abstract 1684) is from the JULIET trial, which includes adults with relapsed or refractory DLBCL (n=99).

The overall response rate was 54%. The probability of relapse-free survival was 66% at 6 months and 64% at both 12 months and 18 months.

HSCT consolidation

Dr. Brodsky also discussed long-term follow-up from a phase 1/2 trial of SCRI-CAR19v1, a CD19-specific CAR T-cell product, in patients with relapsed/refractory ALL (abstract 967).

Of the 50 evaluable patients, 17 had no history of HSCT prior to CAR T-cell therapy.

Three of the 17 patients did not proceed to HSCT after CAR T-cell therapy, and two of these patients relapsed. Of the 14 patients who did undergo HSCT after CAR T-cell therapy, two relapsed.

There were 33 patients with a prior history of HSCT, and 10 of them had another HSCT after CAR T-cell therapy. Five of them are still alive and in remission.

Of the 23 patients who did not undergo another HSCT, eight are still in remission.

“This study is very small, and it’s retrospective, but it suggests that bone marrow transplant is a good way to consolidate the remission after CAR T-cell therapy,” Dr. Brodsky said.

Photo from Penn Medicine

Several studies set to be presented at the 2018 ASH Annual Meeting provide new insights regarding chimeric antigen receptor (CAR) T-cell therapies.

One study suggests ibrutinib may enhance CAR T-cell therapy in patients with chronic lymphocytic leukemia (CLL), and another suggests checkpoint inhibitors can augment CAR T-cell therapy in certain patients with B-cell acute lymphoblastic leukemia (ALL).

Two additional studies indicate that responses to tisagenlecleucel are durable in both ALL and diffuse large B-cell lymphoma (DLBCL).

A fifth study suggests hematopoietic stem cell transplant (HSCT) may reduce the risk of relapse after CAR T-cell therapy.

ASH Secretary Robert A. Brodsky, MD, of Johns Hopkins University in Baltimore, Maryland, discussed these studies during a media briefing ahead of the ASH Annual Meeting.

Ibrutinib

In the ibrutinib study (abstract 299), patients received the BTK inhibitor starting 2 weeks prior to leukapheresis and continued until 3 months after treatment with JCAR014.

Data suggest this strategy may improve responses and decrease the incidence of severe cytokine release syndrome in patients with relapsed or refractory CLL.

Responses occurred in 88% of patients who received ibrutinib and 56% of those who did not.

Grade 3-5 cytokine release syndrome occurred in 5 of 19 patients (26%) in the no-ibrutinib cohort and 0 of 17 patients in the ibrutinib cohort.

These findings are “early and preliminary but very exciting” Dr. Brodsky said.

Checkpoint inhibitors

Early results of the checkpoint inhibitor study (abstract 556) suggest that pembrolizumab or nivolumab may augment CD19-directed CAR T-cell therapy.

The 14 patients studied had early CAR T-cell loss, partial response, or no response to CAR T-cell therapy. Thirteen patients had B-cell ALL, and one had B lymphoblastic lymphoma.

CD19-directed CAR T-cell therapy consisted of tisagenlecleucel in four patients and CTL119 in 10. Thirteen patients received pembrolizumab, and one received nivolumab.

Three of six patients who had early B-cell recovery re-established B-cell aplasia with the addition of a checkpoint inhibitor. In two patients, B-cell aplasia persists with ongoing pembrolizumab.

Four patients who did not respond to or relapsed after their initial CAR T-cell therapy had a partial (n=2) or complete response (n=2) with the addition of pembrolizumab.

There were additional partial responses in the remaining four patients. However, one of these patients (with CD19-dim/negative disease) progressed.

“The idea was if you can give pembrolizumab, you can take the brakes off, and maybe you can reinitiate the immune attack,” Dr. Brodsky said.

“[This is a] very small [study with] preliminary data but very exciting that it is safe to give checkpoint inhibitors with CAR T cells, and it may be efficacious at getting the immune response back.”

Tisagenlecleucel follow-up

One of the two tisagenlecleucel updates (abstract 895) consists of data from the ELIANA trial, which includes pediatric and young adult patients with relapsed/refractory ALL.

The overall response rate was 82% (65/79). Of the 65 responders, 29 were still in response at follow-up.

The probability of relapse-free survival was 66% at 12 months and 18 months.

“These are some very fast-growing tumors, and these are refractory, resistant patients, so, as we get further and further out, it’s more encouraging to see that there are durable responses,” Dr. Brodsky said.

The other tisagenlecleucel update (abstract 1684) is from the JULIET trial, which includes adults with relapsed or refractory DLBCL (n=99).

The overall response rate was 54%. The probability of relapse-free survival was 66% at 6 months and 64% at both 12 months and 18 months.

HSCT consolidation

Dr. Brodsky also discussed long-term follow-up from a phase 1/2 trial of SCRI-CAR19v1, a CD19-specific CAR T-cell product, in patients with relapsed/refractory ALL (abstract 967).

Of the 50 evaluable patients, 17 had no history of HSCT prior to CAR T-cell therapy.

Three of the 17 patients did not proceed to HSCT after CAR T-cell therapy, and two of these patients relapsed. Of the 14 patients who did undergo HSCT after CAR T-cell therapy, two relapsed.

There were 33 patients with a prior history of HSCT, and 10 of them had another HSCT after CAR T-cell therapy. Five of them are still alive and in remission.

Of the 23 patients who did not undergo another HSCT, eight are still in remission.

“This study is very small, and it’s retrospective, but it suggests that bone marrow transplant is a good way to consolidate the remission after CAR T-cell therapy,” Dr. Brodsky said.

Photo from Penn Medicine

Several studies set to be presented at the 2018 ASH Annual Meeting provide new insights regarding chimeric antigen receptor (CAR) T-cell therapies.

One study suggests ibrutinib may enhance CAR T-cell therapy in patients with chronic lymphocytic leukemia (CLL), and another suggests checkpoint inhibitors can augment CAR T-cell therapy in certain patients with B-cell acute lymphoblastic leukemia (ALL).

Two additional studies indicate that responses to tisagenlecleucel are durable in both ALL and diffuse large B-cell lymphoma (DLBCL).

A fifth study suggests hematopoietic stem cell transplant (HSCT) may reduce the risk of relapse after CAR T-cell therapy.

ASH Secretary Robert A. Brodsky, MD, of Johns Hopkins University in Baltimore, Maryland, discussed these studies during a media briefing ahead of the ASH Annual Meeting.

Ibrutinib

In the ibrutinib study (abstract 299), patients received the BTK inhibitor starting 2 weeks prior to leukapheresis and continued until 3 months after treatment with JCAR014.

Data suggest this strategy may improve responses and decrease the incidence of severe cytokine release syndrome in patients with relapsed or refractory CLL.

Responses occurred in 88% of patients who received ibrutinib and 56% of those who did not.

Grade 3-5 cytokine release syndrome occurred in 5 of 19 patients (26%) in the no-ibrutinib cohort and 0 of 17 patients in the ibrutinib cohort.

These findings are “early and preliminary but very exciting” Dr. Brodsky said.

Checkpoint inhibitors

Early results of the checkpoint inhibitor study (abstract 556) suggest that pembrolizumab or nivolumab may augment CD19-directed CAR T-cell therapy.

The 14 patients studied had early CAR T-cell loss, partial response, or no response to CAR T-cell therapy. Thirteen patients had B-cell ALL, and one had B lymphoblastic lymphoma.

CD19-directed CAR T-cell therapy consisted of tisagenlecleucel in four patients and CTL119 in 10. Thirteen patients received pembrolizumab, and one received nivolumab.

Three of six patients who had early B-cell recovery re-established B-cell aplasia with the addition of a checkpoint inhibitor. In two patients, B-cell aplasia persists with ongoing pembrolizumab.

Four patients who did not respond to or relapsed after their initial CAR T-cell therapy had a partial (n=2) or complete response (n=2) with the addition of pembrolizumab.

There were additional partial responses in the remaining four patients. However, one of these patients (with CD19-dim/negative disease) progressed.

“The idea was if you can give pembrolizumab, you can take the brakes off, and maybe you can reinitiate the immune attack,” Dr. Brodsky said.

“[This is a] very small [study with] preliminary data but very exciting that it is safe to give checkpoint inhibitors with CAR T cells, and it may be efficacious at getting the immune response back.”

Tisagenlecleucel follow-up

One of the two tisagenlecleucel updates (abstract 895) consists of data from the ELIANA trial, which includes pediatric and young adult patients with relapsed/refractory ALL.

The overall response rate was 82% (65/79). Of the 65 responders, 29 were still in response at follow-up.

The probability of relapse-free survival was 66% at 12 months and 18 months.

“These are some very fast-growing tumors, and these are refractory, resistant patients, so, as we get further and further out, it’s more encouraging to see that there are durable responses,” Dr. Brodsky said.

The other tisagenlecleucel update (abstract 1684) is from the JULIET trial, which includes adults with relapsed or refractory DLBCL (n=99).

The overall response rate was 54%. The probability of relapse-free survival was 66% at 6 months and 64% at both 12 months and 18 months.

HSCT consolidation

Dr. Brodsky also discussed long-term follow-up from a phase 1/2 trial of SCRI-CAR19v1, a CD19-specific CAR T-cell product, in patients with relapsed/refractory ALL (abstract 967).

Of the 50 evaluable patients, 17 had no history of HSCT prior to CAR T-cell therapy.

Three of the 17 patients did not proceed to HSCT after CAR T-cell therapy, and two of these patients relapsed. Of the 14 patients who did undergo HSCT after CAR T-cell therapy, two relapsed.

There were 33 patients with a prior history of HSCT, and 10 of them had another HSCT after CAR T-cell therapy. Five of them are still alive and in remission.

Of the 23 patients who did not undergo another HSCT, eight are still in remission.

“This study is very small, and it’s retrospective, but it suggests that bone marrow transplant is a good way to consolidate the remission after CAR T-cell therapy,” Dr. Brodsky said.

Micrograph showing MM

A retrospective study suggests haploidentical hematopoietic stem cell transplant (haplo-HSCT) is feasible in patients with multiply relapsed or high-risk multiple myeloma (MM).

Investigators said haplo-HSCT produced an “acceptable” rate of non-relapse mortality (NRM)—21% at 1 year—in such patients.

“Our results demonstrate that [haplo-HSCT] can be safely performed in appropriate patients with MM who lack an HLA-matched sibling or unrelated donor,” the investigators wrote in Biology of Blood and Marrow Transplantation.

The research was conducted by Firoozeh Sahebi, MD, of City of Hope Medical Center in Duarte, California, and her colleagues.

The team analyzed data from 96 MM patients who had failed at least one previous autologous transplant and underwent haplo-HSCT between 2008 and 2016.

The patients had a median age of 54.9 (range, 36.6-73.3), and 65.6% were male. At baseline, 37.5% of patients were in very good partial response or better, 31.2% were in partial response, 13.5% had stable disease, and 17.7% had relapsed disease.

The median follow-up was 24 months. Almost all patients (97%) achieved neutrophil engraftment by day 28, and 75% had recovery of platelets by day 60.

Grade 2-4 acute graft-vs-host-disease occurred in 39% of patients by 100 days. Chronic graft-vs-host-disease was seen in 46% of patients at 2 years.

The rate of NRM was 21% at 1 year and 26% at 2 years. The cumulative risk of relapse and progression was 50% at 1 year and 56% at 2 years.

The 2-year progression-free survival (PFS) was 17%, and the 2-year overall survival (OS) was 48%.

In a univariate analysis, bone marrow transplant was associated with significantly better OS than peripheral blood transplant (P=0.001). However, there was no significant difference in PFS between the two.

NRM was lower with bone marrow transplant (P=0.016), and there was a trend toward a higher relapse rate with bone marrow (P=0.083).

The use of cyclophosphamide after transplant was associated with significantly better OS (P=0.009) but not PFS, NRM, or relapse.

Other factors—such as disease status and conditioning regimen—had no significant impact on survival, NRM, or relapse.

The investigators said they had no conflicts of interest related to this research.

Micrograph showing MM

A retrospective study suggests haploidentical hematopoietic stem cell transplant (haplo-HSCT) is feasible in patients with multiply relapsed or high-risk multiple myeloma (MM).

Investigators said haplo-HSCT produced an “acceptable” rate of non-relapse mortality (NRM)—21% at 1 year—in such patients.

“Our results demonstrate that [haplo-HSCT] can be safely performed in appropriate patients with MM who lack an HLA-matched sibling or unrelated donor,” the investigators wrote in Biology of Blood and Marrow Transplantation.

The research was conducted by Firoozeh Sahebi, MD, of City of Hope Medical Center in Duarte, California, and her colleagues.

The team analyzed data from 96 MM patients who had failed at least one previous autologous transplant and underwent haplo-HSCT between 2008 and 2016.

The patients had a median age of 54.9 (range, 36.6-73.3), and 65.6% were male. At baseline, 37.5% of patients were in very good partial response or better, 31.2% were in partial response, 13.5% had stable disease, and 17.7% had relapsed disease.

The median follow-up was 24 months. Almost all patients (97%) achieved neutrophil engraftment by day 28, and 75% had recovery of platelets by day 60.

Grade 2-4 acute graft-vs-host-disease occurred in 39% of patients by 100 days. Chronic graft-vs-host-disease was seen in 46% of patients at 2 years.

The rate of NRM was 21% at 1 year and 26% at 2 years. The cumulative risk of relapse and progression was 50% at 1 year and 56% at 2 years.

The 2-year progression-free survival (PFS) was 17%, and the 2-year overall survival (OS) was 48%.

In a univariate analysis, bone marrow transplant was associated with significantly better OS than peripheral blood transplant (P=0.001). However, there was no significant difference in PFS between the two.

NRM was lower with bone marrow transplant (P=0.016), and there was a trend toward a higher relapse rate with bone marrow (P=0.083).

The use of cyclophosphamide after transplant was associated with significantly better OS (P=0.009) but not PFS, NRM, or relapse.

Other factors—such as disease status and conditioning regimen—had no significant impact on survival, NRM, or relapse.

The investigators said they had no conflicts of interest related to this research.

Micrograph showing MM

A retrospective study suggests haploidentical hematopoietic stem cell transplant (haplo-HSCT) is feasible in patients with multiply relapsed or high-risk multiple myeloma (MM).

Investigators said haplo-HSCT produced an “acceptable” rate of non-relapse mortality (NRM)—21% at 1 year—in such patients.

“Our results demonstrate that [haplo-HSCT] can be safely performed in appropriate patients with MM who lack an HLA-matched sibling or unrelated donor,” the investigators wrote in Biology of Blood and Marrow Transplantation.

The research was conducted by Firoozeh Sahebi, MD, of City of Hope Medical Center in Duarte, California, and her colleagues.

The team analyzed data from 96 MM patients who had failed at least one previous autologous transplant and underwent haplo-HSCT between 2008 and 2016.

The patients had a median age of 54.9 (range, 36.6-73.3), and 65.6% were male. At baseline, 37.5% of patients were in very good partial response or better, 31.2% were in partial response, 13.5% had stable disease, and 17.7% had relapsed disease.

The median follow-up was 24 months. Almost all patients (97%) achieved neutrophil engraftment by day 28, and 75% had recovery of platelets by day 60.

Grade 2-4 acute graft-vs-host-disease occurred in 39% of patients by 100 days. Chronic graft-vs-host-disease was seen in 46% of patients at 2 years.

The rate of NRM was 21% at 1 year and 26% at 2 years. The cumulative risk of relapse and progression was 50% at 1 year and 56% at 2 years.

The 2-year progression-free survival (PFS) was 17%, and the 2-year overall survival (OS) was 48%.

In a univariate analysis, bone marrow transplant was associated with significantly better OS than peripheral blood transplant (P=0.001). However, there was no significant difference in PFS between the two.

NRM was lower with bone marrow transplant (P=0.016), and there was a trend toward a higher relapse rate with bone marrow (P=0.083).

The use of cyclophosphamide after transplant was associated with significantly better OS (P=0.009) but not PFS, NRM, or relapse.

Other factors—such as disease status and conditioning regimen—had no significant impact on survival, NRM, or relapse.

The investigators said they had no conflicts of interest related to this research.

Two probiotic products containing strains of Lactobacillus rhamnosus failed to prevent moderate-to-severe gastroenteritis in children, according to the results of large, randomized trials published in the New England Journal of Medicine.

Neither probiotic formulation significantly reduced duration of diarrhea or vomiting, or improved endpoints such as daycare absenteeism in the double-blind, placebo-controlled trials, which together included 1,857 infants or children with acute infectious gastroenteritis treated in the United States or Canada.

In one of the two trials, conducted at 10 U.S. pediatric emergency departments, a 5-day course of L. rhamnosus GG did not improve outcomes, versus placebo, according to investigators, led by David Schnadower, MD, of Cincinnati (Ohio) Children’s Hospital Medical Center.

Results of the trial, which comprised 971 children aged 3 months to 4 years, sharply contrast with results of previous studies and meta-analyses suggesting probiotics do improve outcomes in children with acute gastroenteritis.

However, those studies were hampered by small sample sizes, lack of probiotic quality control, and endpoints “of questionable relevance,” among other limitations, according to Dr. Schnadower and his coauthors.

“The rigor of our research design calls into question recommendations to use L. rhamnosus GG in the treatment of children with acute gastroenteritis,” the authors said in their published report.

Moderate to severe gastroenteritis within 14 days of enrollment, the trial’s primary endpoint, occurred in 11.8% of children who received the probiotic, and in 12.6% of those who received placebo (P = .83).

Diarrhea duration was similar, at 49.7 hours and 50.9 hours in the probiotic and placebo groups, respectively (P = .26). Likewise, there were no significant differences in duration of vomiting, daycare absenteeism, or rate of household transmission between the study arms, investigators reported.

In the Canadian trial, which was similar to the U.S. trial but conducted independently, a probiotic product containing L. rhamnosus R0011 and L. helveticus R0052 also showed no significant benefit over placebo in reducing incidence of moderate to severe gastroenteritis within 14 days of enrollment.

That endpoint occurred in 26.1% of children assigned to probiotics, and 24.7% assigned to placebo (P = .72). The trial comprised 886 children 3-48 months presenting to one of six pediatric emergency departments in Canada.

As in the U.S. trial, investigators said there were no significant differences in diarrhea duration, at 52.5 and 55.5 hours in the probiotic and placebo groups, respectively (P = .31). And there were no significant differences in duration of vomiting, unscheduled health care provider visits, or adverse events.

Both trials used a modified Vesikari scale symptom score of 9 or higher (range, 0-20) to define moderate to severe gastroenteritis.

Rather than focusing on a single symptom such as diarrhea, the modified Vesikari scale score shows a “constellation of symptoms” associated with gastroenteritis, according to the Canadian investigators, led by Stephen B. Freedman, MDCM, of the department of pediatrics at Alberta Children’s Hospital and Research Institute, University of Calgary.

Although the use of composite measures has been questioned, the modified Vesikari scale is externally validated and produced consistent findings for individual symptoms, according to the authors. “Analysis of all individual score elements supported the conclusions based on our primary outcome,” they wrote.

Despite the findings, the conclusions about the particular probiotic product evaluated in the trial cannot be generalized to others in the market, according to Dr. Freedman and his colleagues. Other “large, well conducted trials have aroused similar concerns regarding the effectiveness of probiotics for other conditions,” they added. “Nonetheless, there may be specific indications and populations that will benefit from alternative probiotic agents.”

The U.S. study was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, among other sources. Dr. Schnadower reported that he received grants from the NICHD and nonfinancial support from iHealth.

The Canadian study was supported by the Canadian Institutes of Health Research, among other sources. Dr. Freedman reported that he received nonfinancial support from Calgary Laboratory Services, Copan Italia, Lallemand Health Solutions, Luminex, and ProvLab Alberta, along with grants from the Canadian Institutes of Health Research and Alberta Children’s Hospital Foundation.

Visit the AGA GI Patient Center for information that you can share with your patients about probiotics. 

SOURCES: Schnadower D et al. N Engl J Med. 2018 Nov 22;379(21):2002-14; Freedman SB et al. N Engl J Med. 2018 Nov 22;379(21);2015-26.

Two probiotic products containing strains of Lactobacillus rhamnosus failed to prevent moderate-to-severe gastroenteritis in children, according to the results of large, randomized trials published in the New England Journal of Medicine.

Neither probiotic formulation significantly reduced duration of diarrhea or vomiting, or improved endpoints such as daycare absenteeism in the double-blind, placebo-controlled trials, which together included 1,857 infants or children with acute infectious gastroenteritis treated in the United States or Canada.

In one of the two trials, conducted at 10 U.S. pediatric emergency departments, a 5-day course of L. rhamnosus GG did not improve outcomes, versus placebo, according to investigators, led by David Schnadower, MD, of Cincinnati (Ohio) Children’s Hospital Medical Center.

Results of the trial, which comprised 971 children aged 3 months to 4 years, sharply contrast with results of previous studies and meta-analyses suggesting probiotics do improve outcomes in children with acute gastroenteritis.

However, those studies were hampered by small sample sizes, lack of probiotic quality control, and endpoints “of questionable relevance,” among other limitations, according to Dr. Schnadower and his coauthors.

“The rigor of our research design calls into question recommendations to use L. rhamnosus GG in the treatment of children with acute gastroenteritis,” the authors said in their published report.

Moderate to severe gastroenteritis within 14 days of enrollment, the trial’s primary endpoint, occurred in 11.8% of children who received the probiotic, and in 12.6% of those who received placebo (P = .83).

Diarrhea duration was similar, at 49.7 hours and 50.9 hours in the probiotic and placebo groups, respectively (P = .26). Likewise, there were no significant differences in duration of vomiting, daycare absenteeism, or rate of household transmission between the study arms, investigators reported.

In the Canadian trial, which was similar to the U.S. trial but conducted independently, a probiotic product containing L. rhamnosus R0011 and L. helveticus R0052 also showed no significant benefit over placebo in reducing incidence of moderate to severe gastroenteritis within 14 days of enrollment.

That endpoint occurred in 26.1% of children assigned to probiotics, and 24.7% assigned to placebo (P = .72). The trial comprised 886 children 3-48 months presenting to one of six pediatric emergency departments in Canada.

As in the U.S. trial, investigators said there were no significant differences in diarrhea duration, at 52.5 and 55.5 hours in the probiotic and placebo groups, respectively (P = .31). And there were no significant differences in duration of vomiting, unscheduled health care provider visits, or adverse events.

Both trials used a modified Vesikari scale symptom score of 9 or higher (range, 0-20) to define moderate to severe gastroenteritis.

Rather than focusing on a single symptom such as diarrhea, the modified Vesikari scale score shows a “constellation of symptoms” associated with gastroenteritis, according to the Canadian investigators, led by Stephen B. Freedman, MDCM, of the department of pediatrics at Alberta Children’s Hospital and Research Institute, University of Calgary.

Although the use of composite measures has been questioned, the modified Vesikari scale is externally validated and produced consistent findings for individual symptoms, according to the authors. “Analysis of all individual score elements supported the conclusions based on our primary outcome,” they wrote.

Despite the findings, the conclusions about the particular probiotic product evaluated in the trial cannot be generalized to others in the market, according to Dr. Freedman and his colleagues. Other “large, well conducted trials have aroused similar concerns regarding the effectiveness of probiotics for other conditions,” they added. “Nonetheless, there may be specific indications and populations that will benefit from alternative probiotic agents.”

The U.S. study was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, among other sources. Dr. Schnadower reported that he received grants from the NICHD and nonfinancial support from iHealth.

The Canadian study was supported by the Canadian Institutes of Health Research, among other sources. Dr. Freedman reported that he received nonfinancial support from Calgary Laboratory Services, Copan Italia, Lallemand Health Solutions, Luminex, and ProvLab Alberta, along with grants from the Canadian Institutes of Health Research and Alberta Children’s Hospital Foundation.

Visit the AGA GI Patient Center for information that you can share with your patients about probiotics. 

SOURCES: Schnadower D et al. N Engl J Med. 2018 Nov 22;379(21):2002-14; Freedman SB et al. N Engl J Med. 2018 Nov 22;379(21);2015-26.

Two probiotic products containing strains of Lactobacillus rhamnosus failed to prevent moderate-to-severe gastroenteritis in children, according to the results of large, randomized trials published in the New England Journal of Medicine.

Neither probiotic formulation significantly reduced duration of diarrhea or vomiting, or improved endpoints such as daycare absenteeism in the double-blind, placebo-controlled trials, which together included 1,857 infants or children with acute infectious gastroenteritis treated in the United States or Canada.

In one of the two trials, conducted at 10 U.S. pediatric emergency departments, a 5-day course of L. rhamnosus GG did not improve outcomes, versus placebo, according to investigators, led by David Schnadower, MD, of Cincinnati (Ohio) Children’s Hospital Medical Center.

Results of the trial, which comprised 971 children aged 3 months to 4 years, sharply contrast with results of previous studies and meta-analyses suggesting probiotics do improve outcomes in children with acute gastroenteritis.

However, those studies were hampered by small sample sizes, lack of probiotic quality control, and endpoints “of questionable relevance,” among other limitations, according to Dr. Schnadower and his coauthors.

“The rigor of our research design calls into question recommendations to use L. rhamnosus GG in the treatment of children with acute gastroenteritis,” the authors said in their published report.

Moderate to severe gastroenteritis within 14 days of enrollment, the trial’s primary endpoint, occurred in 11.8% of children who received the probiotic, and in 12.6% of those who received placebo (P = .83).

Diarrhea duration was similar, at 49.7 hours and 50.9 hours in the probiotic and placebo groups, respectively (P = .26). Likewise, there were no significant differences in duration of vomiting, daycare absenteeism, or rate of household transmission between the study arms, investigators reported.

In the Canadian trial, which was similar to the U.S. trial but conducted independently, a probiotic product containing L. rhamnosus R0011 and L. helveticus R0052 also showed no significant benefit over placebo in reducing incidence of moderate to severe gastroenteritis within 14 days of enrollment.

That endpoint occurred in 26.1% of children assigned to probiotics, and 24.7% assigned to placebo (P = .72). The trial comprised 886 children 3-48 months presenting to one of six pediatric emergency departments in Canada.

As in the U.S. trial, investigators said there were no significant differences in diarrhea duration, at 52.5 and 55.5 hours in the probiotic and placebo groups, respectively (P = .31). And there were no significant differences in duration of vomiting, unscheduled health care provider visits, or adverse events.

Both trials used a modified Vesikari scale symptom score of 9 or higher (range, 0-20) to define moderate to severe gastroenteritis.

Rather than focusing on a single symptom such as diarrhea, the modified Vesikari scale score shows a “constellation of symptoms” associated with gastroenteritis, according to the Canadian investigators, led by Stephen B. Freedman, MDCM, of the department of pediatrics at Alberta Children’s Hospital and Research Institute, University of Calgary.

Although the use of composite measures has been questioned, the modified Vesikari scale is externally validated and produced consistent findings for individual symptoms, according to the authors. “Analysis of all individual score elements supported the conclusions based on our primary outcome,” they wrote.

Despite the findings, the conclusions about the particular probiotic product evaluated in the trial cannot be generalized to others in the market, according to Dr. Freedman and his colleagues. Other “large, well conducted trials have aroused similar concerns regarding the effectiveness of probiotics for other conditions,” they added. “Nonetheless, there may be specific indications and populations that will benefit from alternative probiotic agents.”

The U.S. study was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, among other sources. Dr. Schnadower reported that he received grants from the NICHD and nonfinancial support from iHealth.

The Canadian study was supported by the Canadian Institutes of Health Research, among other sources. Dr. Freedman reported that he received nonfinancial support from Calgary Laboratory Services, Copan Italia, Lallemand Health Solutions, Luminex, and ProvLab Alberta, along with grants from the Canadian Institutes of Health Research and Alberta Children’s Hospital Foundation.

Visit the AGA GI Patient Center for information that you can share with your patients about probiotics. 

SOURCES: Schnadower D et al. N Engl J Med. 2018 Nov 22;379(21):2002-14; Freedman SB et al. N Engl J Med. 2018 Nov 22;379(21);2015-26.

Two probiotic products containing strains of Lactobacillus rhamnosus failed to prevent moderate-to-severe gastroenteritis in children, according to the results of large, randomized trials published in the New England Journal of Medicine.

Neither probiotic formulation significantly reduced duration of diarrhea or vomiting, or improved endpoints such as daycare absenteeism in the double-blind, placebo-controlled trials, which together included 1,857 infants or children with acute infectious gastroenteritis treated in the United States or Canada.

In one of the two trials, conducted at 10 U.S. pediatric emergency departments, a 5-day course of L. rhamnosus GG did not improve outcomes, versus placebo, according to investigators, led by David Schnadower, MD, of Cincinnati (Ohio) Children’s Hospital Medical Center.

Results of the trial, which comprised 971 children aged 3 months to 4 years, sharply contrast with results of previous studies and meta-analyses suggesting probiotics do improve outcomes in children with acute gastroenteritis.

However, those studies were hampered by small sample sizes, lack of probiotic quality control, and endpoints “of questionable relevance,” among other limitations, according to Dr. Schnadower and his coauthors.

“The rigor of our research design calls into question recommendations to use L. rhamnosus GG in the treatment of children with acute gastroenteritis,” the authors said in their published report.

Moderate to severe gastroenteritis within 14 days of enrollment, the trial’s primary endpoint, occurred in 11.8% of children who received the probiotic, and in 12.6% of those who received placebo (P = .83).

Diarrhea duration was similar, at 49.7 hours and 50.9 hours in the probiotic and placebo groups, respectively (P = .26). Likewise, there were no significant differences in duration of vomiting, daycare absenteeism, or rate of household transmission between the study arms, investigators reported.

In the Canadian trial, which was similar to the U.S. trial but conducted independently, a probiotic product containing L. rhamnosus R0011 and L. helveticus R0052 also showed no significant benefit over placebo in reducing incidence of moderate to severe gastroenteritis within 14 days of enrollment.

That endpoint occurred in 26.1% of children assigned to probiotics, and 24.7% assigned to placebo (P = .72). The trial comprised 886 children 3-48 months presenting to one of six pediatric emergency departments in Canada.

As in the U.S. trial, investigators said there were no significant differences in diarrhea duration, at 52.5 and 55.5 hours in the probiotic and placebo groups, respectively (P = .31). And there were no significant differences in duration of vomiting, unscheduled health care provider visits, or adverse events.

Both trials used a modified Vesikari scale symptom score of 9 or higher (range, 0-20) to define moderate to severe gastroenteritis.

Rather than focusing on a single symptom such as diarrhea, the modified Vesikari scale score shows a “constellation of symptoms” associated with gastroenteritis, according to the Canadian investigators, led by Stephen B. Freedman, MDCM, of the department of pediatrics at Alberta Children’s Hospital and Research Institute, University of Calgary.

Although the use of composite measures has been questioned, the modified Vesikari scale is externally validated and produced consistent findings for individual symptoms, according to the authors. “Analysis of all individual score elements supported the conclusions based on our primary outcome,” they wrote.

Despite the findings, the conclusions about the particular probiotic product evaluated in the trial cannot be generalized to others in the market, according to Dr. Freedman and his colleagues. Other “large, well conducted trials have aroused similar concerns regarding the effectiveness of probiotics for other conditions,” they added. “Nonetheless, there may be specific indications and populations that will benefit from alternative probiotic agents.”

The U.S. study was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, among other sources. Dr. Schnadower reported that he received grants from the NICHD and nonfinancial support from iHealth.

The Canadian study was supported by the Canadian Institutes of Health Research, among other sources. Dr. Freedman reported that he received nonfinancial support from Calgary Laboratory Services, Copan Italia, Lallemand Health Solutions, Luminex, and ProvLab Alberta, along with grants from the Canadian Institutes of Health Research and Alberta Children’s Hospital Foundation.

SOURCES: Schnadower D et al. N Engl J Med. 2018 Nov 22;379(21):2002-14; Freedman SB et al. N Engl J Med. 2018 Nov 22;379(21);2015-26.

Two probiotic products containing strains of Lactobacillus rhamnosus failed to prevent moderate-to-severe gastroenteritis in children, according to the results of large, randomized trials published in the New England Journal of Medicine.

Neither probiotic formulation significantly reduced duration of diarrhea or vomiting, or improved endpoints such as daycare absenteeism in the double-blind, placebo-controlled trials, which together included 1,857 infants or children with acute infectious gastroenteritis treated in the United States or Canada.

In one of the two trials, conducted at 10 U.S. pediatric emergency departments, a 5-day course of L. rhamnosus GG did not improve outcomes, versus placebo, according to investigators, led by David Schnadower, MD, of Cincinnati (Ohio) Children’s Hospital Medical Center.

Results of the trial, which comprised 971 children aged 3 months to 4 years, sharply contrast with results of previous studies and meta-analyses suggesting probiotics do improve outcomes in children with acute gastroenteritis.

However, those studies were hampered by small sample sizes, lack of probiotic quality control, and endpoints “of questionable relevance,” among other limitations, according to Dr. Schnadower and his coauthors.

“The rigor of our research design calls into question recommendations to use L. rhamnosus GG in the treatment of children with acute gastroenteritis,” the authors said in their published report.

Moderate to severe gastroenteritis within 14 days of enrollment, the trial’s primary endpoint, occurred in 11.8% of children who received the probiotic, and in 12.6% of those who received placebo (P = .83).

Diarrhea duration was similar, at 49.7 hours and 50.9 hours in the probiotic and placebo groups, respectively (P = .26). Likewise, there were no significant differences in duration of vomiting, daycare absenteeism, or rate of household transmission between the study arms, investigators reported.

In the Canadian trial, which was similar to the U.S. trial but conducted independently, a probiotic product containing L. rhamnosus R0011 and L. helveticus R0052 also showed no significant benefit over placebo in reducing incidence of moderate to severe gastroenteritis within 14 days of enrollment.

That endpoint occurred in 26.1% of children assigned to probiotics, and 24.7% assigned to placebo (P = .72). The trial comprised 886 children 3-48 months presenting to one of six pediatric emergency departments in Canada.

As in the U.S. trial, investigators said there were no significant differences in diarrhea duration, at 52.5 and 55.5 hours in the probiotic and placebo groups, respectively (P = .31). And there were no significant differences in duration of vomiting, unscheduled health care provider visits, or adverse events.

Both trials used a modified Vesikari scale symptom score of 9 or higher (range, 0-20) to define moderate to severe gastroenteritis.

Rather than focusing on a single symptom such as diarrhea, the modified Vesikari scale score shows a “constellation of symptoms” associated with gastroenteritis, according to the Canadian investigators, led by Stephen B. Freedman, MDCM, of the department of pediatrics at Alberta Children’s Hospital and Research Institute, University of Calgary.

Although the use of composite measures has been questioned, the modified Vesikari scale is externally validated and produced consistent findings for individual symptoms, according to the authors. “Analysis of all individual score elements supported the conclusions based on our primary outcome,” they wrote.

Despite the findings, the conclusions about the particular probiotic product evaluated in the trial cannot be generalized to others in the market, according to Dr. Freedman and his colleagues. Other “large, well conducted trials have aroused similar concerns regarding the effectiveness of probiotics for other conditions,” they added. “Nonetheless, there may be specific indications and populations that will benefit from alternative probiotic agents.”

The U.S. study was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, among other sources. Dr. Schnadower reported that he received grants from the NICHD and nonfinancial support from iHealth.

The Canadian study was supported by the Canadian Institutes of Health Research, among other sources. Dr. Freedman reported that he received nonfinancial support from Calgary Laboratory Services, Copan Italia, Lallemand Health Solutions, Luminex, and ProvLab Alberta, along with grants from the Canadian Institutes of Health Research and Alberta Children’s Hospital Foundation.

SOURCES: Schnadower D et al. N Engl J Med. 2018 Nov 22;379(21):2002-14; Freedman SB et al. N Engl J Med. 2018 Nov 22;379(21);2015-26.

Two probiotic products containing strains of Lactobacillus rhamnosus failed to prevent moderate-to-severe gastroenteritis in children, according to the results of large, randomized trials published in the New England Journal of Medicine.

Neither probiotic formulation significantly reduced duration of diarrhea or vomiting, or improved endpoints such as daycare absenteeism in the double-blind, placebo-controlled trials, which together included 1,857 infants or children with acute infectious gastroenteritis treated in the United States or Canada.

In one of the two trials, conducted at 10 U.S. pediatric emergency departments, a 5-day course of L. rhamnosus GG did not improve outcomes, versus placebo, according to investigators, led by David Schnadower, MD, of Cincinnati (Ohio) Children’s Hospital Medical Center.

Results of the trial, which comprised 971 children aged 3 months to 4 years, sharply contrast with results of previous studies and meta-analyses suggesting probiotics do improve outcomes in children with acute gastroenteritis.

However, those studies were hampered by small sample sizes, lack of probiotic quality control, and endpoints “of questionable relevance,” among other limitations, according to Dr. Schnadower and his coauthors.

“The rigor of our research design calls into question recommendations to use L. rhamnosus GG in the treatment of children with acute gastroenteritis,” the authors said in their published report.

Moderate to severe gastroenteritis within 14 days of enrollment, the trial’s primary endpoint, occurred in 11.8% of children who received the probiotic, and in 12.6% of those who received placebo (P = .83).

Diarrhea duration was similar, at 49.7 hours and 50.9 hours in the probiotic and placebo groups, respectively (P = .26). Likewise, there were no significant differences in duration of vomiting, daycare absenteeism, or rate of household transmission between the study arms, investigators reported.

In the Canadian trial, which was similar to the U.S. trial but conducted independently, a probiotic product containing L. rhamnosus R0011 and L. helveticus R0052 also showed no significant benefit over placebo in reducing incidence of moderate to severe gastroenteritis within 14 days of enrollment.

That endpoint occurred in 26.1% of children assigned to probiotics, and 24.7% assigned to placebo (P = .72). The trial comprised 886 children 3-48 months presenting to one of six pediatric emergency departments in Canada.

As in the U.S. trial, investigators said there were no significant differences in diarrhea duration, at 52.5 and 55.5 hours in the probiotic and placebo groups, respectively (P = .31). And there were no significant differences in duration of vomiting, unscheduled health care provider visits, or adverse events.

Both trials used a modified Vesikari scale symptom score of 9 or higher (range, 0-20) to define moderate to severe gastroenteritis.

Rather than focusing on a single symptom such as diarrhea, the modified Vesikari scale score shows a “constellation of symptoms” associated with gastroenteritis, according to the Canadian investigators, led by Stephen B. Freedman, MDCM, of the department of pediatrics at Alberta Children’s Hospital and Research Institute, University of Calgary.

Although the use of composite measures has been questioned, the modified Vesikari scale is externally validated and produced consistent findings for individual symptoms, according to the authors. “Analysis of all individual score elements supported the conclusions based on our primary outcome,” they wrote.

Despite the findings, the conclusions about the particular probiotic product evaluated in the trial cannot be generalized to others in the market, according to Dr. Freedman and his colleagues. Other “large, well conducted trials have aroused similar concerns regarding the effectiveness of probiotics for other conditions,” they added. “Nonetheless, there may be specific indications and populations that will benefit from alternative probiotic agents.”

The U.S. study was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, among other sources. Dr. Schnadower reported that he received grants from the NICHD and nonfinancial support from iHealth.

The Canadian study was supported by the Canadian Institutes of Health Research, among other sources. Dr. Freedman reported that he received nonfinancial support from Calgary Laboratory Services, Copan Italia, Lallemand Health Solutions, Luminex, and ProvLab Alberta, along with grants from the Canadian Institutes of Health Research and Alberta Children’s Hospital Foundation.

SOURCES: Schnadower D et al. N Engl J Med. 2018 Nov 22;379(21):2002-14; Freedman SB et al. N Engl J Med. 2018 Nov 22;379(21);2015-26.