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GLUTOX: Identifying nonceliac gluten sensitivity
WASHINGTON – A simple dietary challenge may help identify nonceliac gluten sensitivity in patients with gastrointestinal functional disorders, results of the ongoing, randomized GLUTOX trial suggest.
Nonceliac gluten sensitivity is an emergent syndrome that causes mainly gastrointestinal symptoms and has been thought to be present in about 6% of the population. The problem is that there is no established or well-defined diagnostic flow chart to identify these patients, study author Dr. Luca Elli said at the annual Digestive Disease Week.
To determine whether gluten induces symptoms in patients responding positively to a gluten-free diet and identify those potentially affected by nonceliac gluten sensitivity, GLUTOX enrolled 100 adults with functional GI symptoms and placed them on a gluten-free diet for 21 days. Severity of symptoms was measured before and after the diet using a 10-cm visual analogue scale (VAS) and the 36-item Short Form Health Survey (SF-36).
Patients with at least a 3-cm improvement in baseline VAS were then double-blind, randomly assigned to gluten (5.6 g per day) or placebo capsules for 7 days, followed by a 7-day washout period, and then crossed over to another 7-day cycle of gluten or placebo capsules.
At baseline, the mean age was 38 years, 90% of patients were female, 55 had irritable bowel syndrome, 36 functional dyspepsia, and 9 had other unspecified functional nonspecific gastrointestinal symptoms by ROME III criteria.
Patients with celiac disease or a wheat allergy or who were on an ongoing gluten-free diet were excluded.
In all, 81 patients reported a symptomatic improvement from baseline after the 21-day gluten-free-diet (mean VAS 7.5 vs. 3.3; P value = .001), Dr. Elli, from Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan reported in a distinguished abstract plenary session.
“All of the symptoms we found were reduced by the gluten-free diet, but especially patient satisfaction about stool consistency, bloating, and the global satisfaction were improved in an important way,” he said.
Symptom improvements were also associated with significant improvements in the SF-36 physical component summary and mental component summary. Most responders were female (88%); 48 had irritable bowel syndrome, 25 dyspepsia, and 8 other.
After the gluten capsule challenge, 25 of the 81 gluten-free diet responders had a severe symptomatic relapse especially in stool consistency satisfaction, bloating, and abdominal pain, Dr. Elli said.
The relapses were also associated with a significant decrease in SF-36 physical and mental component summaries.
No demographic or biochemical parameters were significantly associated with a response to the gluten challenge, Dr. Elli said. Most of those having a response were female (96%); 13 had irritable bowel syndrome, 10 dyspepsia, and 2 other.
The sequence of the gluten and placebo capsules also had no effect on the results.
If the data are confirmed, it’s possible the double-blind challenge could be used to select gluten-free diet responders and inserted into the diagnostic flow chart for patients with gastrointestinal functional disorders, Dr. Elli said.
A very important open issue is also the 56% of enrolled subjects who responded to the gluten-free diet, but did not show symptoms with the gluten double-blind challenge, he added.
During a discussion of the results, attendees questioned whether the study design, particularly the failure to biopsy patients for celiac disease at enrollment and the short 7-day washout period, was sufficient to answer the question of identifying patients with nonceliac gluten sensitivity.
Session comoderator Dr. Bernd Schnabl, from University of California–San Diego, agreed that the study design was not ideal and that the study would have been strengthened by using biopsy to rule out patients with celiac disease. That said, the study represents a start.
“If we can stratify these patients and re-challenge them longer, it could be helpful in identifying a subpopulation of functional patients who might benefit from a gluten-free diet,” he said.
On Twitter @pwendl
WASHINGTON – A simple dietary challenge may help identify nonceliac gluten sensitivity in patients with gastrointestinal functional disorders, results of the ongoing, randomized GLUTOX trial suggest.
Nonceliac gluten sensitivity is an emergent syndrome that causes mainly gastrointestinal symptoms and has been thought to be present in about 6% of the population. The problem is that there is no established or well-defined diagnostic flow chart to identify these patients, study author Dr. Luca Elli said at the annual Digestive Disease Week.
To determine whether gluten induces symptoms in patients responding positively to a gluten-free diet and identify those potentially affected by nonceliac gluten sensitivity, GLUTOX enrolled 100 adults with functional GI symptoms and placed them on a gluten-free diet for 21 days. Severity of symptoms was measured before and after the diet using a 10-cm visual analogue scale (VAS) and the 36-item Short Form Health Survey (SF-36).
Patients with at least a 3-cm improvement in baseline VAS were then double-blind, randomly assigned to gluten (5.6 g per day) or placebo capsules for 7 days, followed by a 7-day washout period, and then crossed over to another 7-day cycle of gluten or placebo capsules.
At baseline, the mean age was 38 years, 90% of patients were female, 55 had irritable bowel syndrome, 36 functional dyspepsia, and 9 had other unspecified functional nonspecific gastrointestinal symptoms by ROME III criteria.
Patients with celiac disease or a wheat allergy or who were on an ongoing gluten-free diet were excluded.
In all, 81 patients reported a symptomatic improvement from baseline after the 21-day gluten-free-diet (mean VAS 7.5 vs. 3.3; P value = .001), Dr. Elli, from Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan reported in a distinguished abstract plenary session.
“All of the symptoms we found were reduced by the gluten-free diet, but especially patient satisfaction about stool consistency, bloating, and the global satisfaction were improved in an important way,” he said.
Symptom improvements were also associated with significant improvements in the SF-36 physical component summary and mental component summary. Most responders were female (88%); 48 had irritable bowel syndrome, 25 dyspepsia, and 8 other.
After the gluten capsule challenge, 25 of the 81 gluten-free diet responders had a severe symptomatic relapse especially in stool consistency satisfaction, bloating, and abdominal pain, Dr. Elli said.
The relapses were also associated with a significant decrease in SF-36 physical and mental component summaries.
No demographic or biochemical parameters were significantly associated with a response to the gluten challenge, Dr. Elli said. Most of those having a response were female (96%); 13 had irritable bowel syndrome, 10 dyspepsia, and 2 other.
The sequence of the gluten and placebo capsules also had no effect on the results.
If the data are confirmed, it’s possible the double-blind challenge could be used to select gluten-free diet responders and inserted into the diagnostic flow chart for patients with gastrointestinal functional disorders, Dr. Elli said.
A very important open issue is also the 56% of enrolled subjects who responded to the gluten-free diet, but did not show symptoms with the gluten double-blind challenge, he added.
During a discussion of the results, attendees questioned whether the study design, particularly the failure to biopsy patients for celiac disease at enrollment and the short 7-day washout period, was sufficient to answer the question of identifying patients with nonceliac gluten sensitivity.
Session comoderator Dr. Bernd Schnabl, from University of California–San Diego, agreed that the study design was not ideal and that the study would have been strengthened by using biopsy to rule out patients with celiac disease. That said, the study represents a start.
“If we can stratify these patients and re-challenge them longer, it could be helpful in identifying a subpopulation of functional patients who might benefit from a gluten-free diet,” he said.
On Twitter @pwendl
WASHINGTON – A simple dietary challenge may help identify nonceliac gluten sensitivity in patients with gastrointestinal functional disorders, results of the ongoing, randomized GLUTOX trial suggest.
Nonceliac gluten sensitivity is an emergent syndrome that causes mainly gastrointestinal symptoms and has been thought to be present in about 6% of the population. The problem is that there is no established or well-defined diagnostic flow chart to identify these patients, study author Dr. Luca Elli said at the annual Digestive Disease Week.
To determine whether gluten induces symptoms in patients responding positively to a gluten-free diet and identify those potentially affected by nonceliac gluten sensitivity, GLUTOX enrolled 100 adults with functional GI symptoms and placed them on a gluten-free diet for 21 days. Severity of symptoms was measured before and after the diet using a 10-cm visual analogue scale (VAS) and the 36-item Short Form Health Survey (SF-36).
Patients with at least a 3-cm improvement in baseline VAS were then double-blind, randomly assigned to gluten (5.6 g per day) or placebo capsules for 7 days, followed by a 7-day washout period, and then crossed over to another 7-day cycle of gluten or placebo capsules.
At baseline, the mean age was 38 years, 90% of patients were female, 55 had irritable bowel syndrome, 36 functional dyspepsia, and 9 had other unspecified functional nonspecific gastrointestinal symptoms by ROME III criteria.
Patients with celiac disease or a wheat allergy or who were on an ongoing gluten-free diet were excluded.
In all, 81 patients reported a symptomatic improvement from baseline after the 21-day gluten-free-diet (mean VAS 7.5 vs. 3.3; P value = .001), Dr. Elli, from Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan reported in a distinguished abstract plenary session.
“All of the symptoms we found were reduced by the gluten-free diet, but especially patient satisfaction about stool consistency, bloating, and the global satisfaction were improved in an important way,” he said.
Symptom improvements were also associated with significant improvements in the SF-36 physical component summary and mental component summary. Most responders were female (88%); 48 had irritable bowel syndrome, 25 dyspepsia, and 8 other.
After the gluten capsule challenge, 25 of the 81 gluten-free diet responders had a severe symptomatic relapse especially in stool consistency satisfaction, bloating, and abdominal pain, Dr. Elli said.
The relapses were also associated with a significant decrease in SF-36 physical and mental component summaries.
No demographic or biochemical parameters were significantly associated with a response to the gluten challenge, Dr. Elli said. Most of those having a response were female (96%); 13 had irritable bowel syndrome, 10 dyspepsia, and 2 other.
The sequence of the gluten and placebo capsules also had no effect on the results.
If the data are confirmed, it’s possible the double-blind challenge could be used to select gluten-free diet responders and inserted into the diagnostic flow chart for patients with gastrointestinal functional disorders, Dr. Elli said.
A very important open issue is also the 56% of enrolled subjects who responded to the gluten-free diet, but did not show symptoms with the gluten double-blind challenge, he added.
During a discussion of the results, attendees questioned whether the study design, particularly the failure to biopsy patients for celiac disease at enrollment and the short 7-day washout period, was sufficient to answer the question of identifying patients with nonceliac gluten sensitivity.
Session comoderator Dr. Bernd Schnabl, from University of California–San Diego, agreed that the study design was not ideal and that the study would have been strengthened by using biopsy to rule out patients with celiac disease. That said, the study represents a start.
“If we can stratify these patients and re-challenge them longer, it could be helpful in identifying a subpopulation of functional patients who might benefit from a gluten-free diet,” he said.
On Twitter @pwendl
AT DDW® 2015
Key clinical point: A randomized, double-blind dietary challenge may be useful in identifying nonceliac gluten sensitivity.
Major finding: More than 30% of patients with functional gastrointestinal disorders were classified as possibly having nonceliac gluten sensitivity.
Data source: Randomized, double-blind study in 100 patients with suspected nonceliac gluten sensitivity.
Disclosures: The study was funded by Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico. Dr. Elli reported consulting fees from and serving on an advisory committee or review panel for the Dr. Schär Institute.
P13K inhibitors TGR-1202, duvelisib found clinically active in CLL
VIENNA – The investigational P13K-delta inhibitor TGR-1202 was clinically active in relapsed or refractory chronic lymphocytic leukemia and other hematologic malignancies in an ongoing phase I trial.
TGR-1202 is entering an increasingly crowded field of P13 kinase inhibitors including idelalisib (Zydelig) and duvelisib, but a more benign safety profile may separate it from the pack.
“It has a different AE [adverse event] profile, compared with some of the other agents, with a little less on the hepatotoxicity side and, at least to date, we actually haven’t seen any evidence of colitis,” Dr. Owen O’Connor said at the annual congress of the European Hematology Association.
Citing recently reported data, grade 3/4 diarrhea/colitis occurs in 10%-22% of patients treated with idelalisib, idelalisib plus ofatumumab, or duvelisib versus just 1% of all 137 patients treated in TGR-1202 studies to date, he noted.
TGR-1202 also has less grade 3/4 pneumonia (4%) and elevated liver enzymes (2%), compared with rates of 13%-16% and 13%-17%, respectively, for the other P13K therapies.
Further, just 4% of all patients have discontinued TGR-1202 because of adverse events vs. 12% on idelalisib, 31% on idelalisib plus ofatumumab, and 33% on duvelisib.
“I think this may bode well as we think about how to combine P13 kinase inhibitors into other regimens to try to look at various combination regimens,” said Dr. O’Connor, director of the Center for Lymphoid Malignancies at Columbia University in New York.
He presented data on 66 patients with relapsed or refractory B- or T-cell malignancies including non-Hodgkin lymphoma, chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia and Hodgkin lymphoma. More than half (55%) had received at least three prior therapies (range 1-14) and 52% were refractory to the most recent regimen.
The dose-escalation study evaluated TGR-1202 once-daily at doses of 50 mg to 1,800 mg and a micronized formulation dosed at 200 mg to 1,800 mg.
The most common adverse event of any grade was nausea (41%), diarrhea and fatigue (32% each), headache and vomiting (23% each), and cough (21%), Dr. O’Connor said. Grade 3 or 4 adverse events were neutropenia (11%), anemia (8%), hypokalemia and dyspnea (5% each), and diarrhea and constipation (2% each).
A strong dose-response relationship was observed among 51 patients evaluable for efficacy, with higher doses of TGR-1202 (1,200-mg initial formulation or ≥ 600 mg micronized) demonstrating rapid and profound responses, he said.
In the CLL subgroup, 14 of 16 patients (88%) achieved a nodal partial response and 10 (63%) achieved a response per International Workshop on CLL (iwCLL) criteria.
Of the 12 evaluable patients with follicular lymphoma, 5 achieved a partial response (nodal reduction > 50%), with 3 of the 6 patients treated at higher doses reaching a partial response.
A heavily pretreated patient with Hodgkin lymphoma also achieved a near-complete response, Dr. O’Connor said.
At the time of the analysis, 37 of 66 patients had received micronized TGR-1202 at doses ≥ 800 mg. Of these, 25 remain on study and have reached a median progression-free survival of 9.5 months.
Expansion cohorts are enrolling at 800 mg and 1,200 mg of the micronized formulation, and are the targeted doses for phase II studies in development, he said.
Duvelisib
In a separate presentation during the same session, phase I results showed twice-daily duvelisib 25 mg resulted in an overall response rate of 88%, including 15 partial responses in 17 evaluable patients with treatment-naive CLL.
All but one of nine patients with a deleterious P53 mutation or 17p deletion achieved a partial response, Dr. Susan O’Brien of University of California, Irvine, reported.
“The advantage of duvelisib is that responses are more rapid than with other single agent B-cell receptors,” she said in an interview.
The median time to iwCLL response was 3.7 months, with 7 of the 15 responses occurring by the first assessment (cycle 3, day 1).
Pharmacodynamic and mechanism of action studies show duvelisib, an oral P13K-delta/gamma inhibitor, produces rapid inhibition of phosphorylation of AKT (pAKT) sustained through cycle 2, day 1 and near-complete inhibition of CLL proliferation (Ki67) following 1 cycle of duvelisib.
Key serum chemokines and cytokines known to contribute to CLL growth and survival also decreased following duvelisib, suggesting modulation of the tumor microenvironment, Dr. O’Brien said.
Of the 18 patients treated in the CLL expansion cohort, 10 remain on treatment and 8 discontinued treatment, including 6 patients who discontinued treatment because of adverse events. The median time on treatment was 14 months (range 1-20 months). Adverse events were mostly grade 1 or 2, reversible, and clinically manageable, she said.
The most common grade 3 adverse events were diarrhea (22%) and liver enzyme elevations (17%), with grade 4 neutropenia occurring in 28%.
In 16 patients with baseline computed tomography assessments, 88% achieved a nodal response (≥ 50% reduction in measurable area of disease) and all had a PR per iwCLL.
Median progression-free and overall survival had not been reached, with a 92% PFS rate and 94% survival rate at 18 months, Dr. O’Brien said. One patient died during follow-up, about 5 months after the last duvelisib dose.
Based on the pharmacodynamic/pharmacokinetic profile and clinical activity, the 25-mg twice-daily dose has been selected for phase III evaluation, she said.
On Twitter@pwendl
VIENNA – The investigational P13K-delta inhibitor TGR-1202 was clinically active in relapsed or refractory chronic lymphocytic leukemia and other hematologic malignancies in an ongoing phase I trial.
TGR-1202 is entering an increasingly crowded field of P13 kinase inhibitors including idelalisib (Zydelig) and duvelisib, but a more benign safety profile may separate it from the pack.
“It has a different AE [adverse event] profile, compared with some of the other agents, with a little less on the hepatotoxicity side and, at least to date, we actually haven’t seen any evidence of colitis,” Dr. Owen O’Connor said at the annual congress of the European Hematology Association.
Citing recently reported data, grade 3/4 diarrhea/colitis occurs in 10%-22% of patients treated with idelalisib, idelalisib plus ofatumumab, or duvelisib versus just 1% of all 137 patients treated in TGR-1202 studies to date, he noted.
TGR-1202 also has less grade 3/4 pneumonia (4%) and elevated liver enzymes (2%), compared with rates of 13%-16% and 13%-17%, respectively, for the other P13K therapies.
Further, just 4% of all patients have discontinued TGR-1202 because of adverse events vs. 12% on idelalisib, 31% on idelalisib plus ofatumumab, and 33% on duvelisib.
“I think this may bode well as we think about how to combine P13 kinase inhibitors into other regimens to try to look at various combination regimens,” said Dr. O’Connor, director of the Center for Lymphoid Malignancies at Columbia University in New York.
He presented data on 66 patients with relapsed or refractory B- or T-cell malignancies including non-Hodgkin lymphoma, chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia and Hodgkin lymphoma. More than half (55%) had received at least three prior therapies (range 1-14) and 52% were refractory to the most recent regimen.
The dose-escalation study evaluated TGR-1202 once-daily at doses of 50 mg to 1,800 mg and a micronized formulation dosed at 200 mg to 1,800 mg.
The most common adverse event of any grade was nausea (41%), diarrhea and fatigue (32% each), headache and vomiting (23% each), and cough (21%), Dr. O’Connor said. Grade 3 or 4 adverse events were neutropenia (11%), anemia (8%), hypokalemia and dyspnea (5% each), and diarrhea and constipation (2% each).
A strong dose-response relationship was observed among 51 patients evaluable for efficacy, with higher doses of TGR-1202 (1,200-mg initial formulation or ≥ 600 mg micronized) demonstrating rapid and profound responses, he said.
In the CLL subgroup, 14 of 16 patients (88%) achieved a nodal partial response and 10 (63%) achieved a response per International Workshop on CLL (iwCLL) criteria.
Of the 12 evaluable patients with follicular lymphoma, 5 achieved a partial response (nodal reduction > 50%), with 3 of the 6 patients treated at higher doses reaching a partial response.
A heavily pretreated patient with Hodgkin lymphoma also achieved a near-complete response, Dr. O’Connor said.
At the time of the analysis, 37 of 66 patients had received micronized TGR-1202 at doses ≥ 800 mg. Of these, 25 remain on study and have reached a median progression-free survival of 9.5 months.
Expansion cohorts are enrolling at 800 mg and 1,200 mg of the micronized formulation, and are the targeted doses for phase II studies in development, he said.
Duvelisib
In a separate presentation during the same session, phase I results showed twice-daily duvelisib 25 mg resulted in an overall response rate of 88%, including 15 partial responses in 17 evaluable patients with treatment-naive CLL.
All but one of nine patients with a deleterious P53 mutation or 17p deletion achieved a partial response, Dr. Susan O’Brien of University of California, Irvine, reported.
“The advantage of duvelisib is that responses are more rapid than with other single agent B-cell receptors,” she said in an interview.
The median time to iwCLL response was 3.7 months, with 7 of the 15 responses occurring by the first assessment (cycle 3, day 1).
Pharmacodynamic and mechanism of action studies show duvelisib, an oral P13K-delta/gamma inhibitor, produces rapid inhibition of phosphorylation of AKT (pAKT) sustained through cycle 2, day 1 and near-complete inhibition of CLL proliferation (Ki67) following 1 cycle of duvelisib.
Key serum chemokines and cytokines known to contribute to CLL growth and survival also decreased following duvelisib, suggesting modulation of the tumor microenvironment, Dr. O’Brien said.
Of the 18 patients treated in the CLL expansion cohort, 10 remain on treatment and 8 discontinued treatment, including 6 patients who discontinued treatment because of adverse events. The median time on treatment was 14 months (range 1-20 months). Adverse events were mostly grade 1 or 2, reversible, and clinically manageable, she said.
The most common grade 3 adverse events were diarrhea (22%) and liver enzyme elevations (17%), with grade 4 neutropenia occurring in 28%.
In 16 patients with baseline computed tomography assessments, 88% achieved a nodal response (≥ 50% reduction in measurable area of disease) and all had a PR per iwCLL.
Median progression-free and overall survival had not been reached, with a 92% PFS rate and 94% survival rate at 18 months, Dr. O’Brien said. One patient died during follow-up, about 5 months after the last duvelisib dose.
Based on the pharmacodynamic/pharmacokinetic profile and clinical activity, the 25-mg twice-daily dose has been selected for phase III evaluation, she said.
On Twitter@pwendl
VIENNA – The investigational P13K-delta inhibitor TGR-1202 was clinically active in relapsed or refractory chronic lymphocytic leukemia and other hematologic malignancies in an ongoing phase I trial.
TGR-1202 is entering an increasingly crowded field of P13 kinase inhibitors including idelalisib (Zydelig) and duvelisib, but a more benign safety profile may separate it from the pack.
“It has a different AE [adverse event] profile, compared with some of the other agents, with a little less on the hepatotoxicity side and, at least to date, we actually haven’t seen any evidence of colitis,” Dr. Owen O’Connor said at the annual congress of the European Hematology Association.
Citing recently reported data, grade 3/4 diarrhea/colitis occurs in 10%-22% of patients treated with idelalisib, idelalisib plus ofatumumab, or duvelisib versus just 1% of all 137 patients treated in TGR-1202 studies to date, he noted.
TGR-1202 also has less grade 3/4 pneumonia (4%) and elevated liver enzymes (2%), compared with rates of 13%-16% and 13%-17%, respectively, for the other P13K therapies.
Further, just 4% of all patients have discontinued TGR-1202 because of adverse events vs. 12% on idelalisib, 31% on idelalisib plus ofatumumab, and 33% on duvelisib.
“I think this may bode well as we think about how to combine P13 kinase inhibitors into other regimens to try to look at various combination regimens,” said Dr. O’Connor, director of the Center for Lymphoid Malignancies at Columbia University in New York.
He presented data on 66 patients with relapsed or refractory B- or T-cell malignancies including non-Hodgkin lymphoma, chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia and Hodgkin lymphoma. More than half (55%) had received at least three prior therapies (range 1-14) and 52% were refractory to the most recent regimen.
The dose-escalation study evaluated TGR-1202 once-daily at doses of 50 mg to 1,800 mg and a micronized formulation dosed at 200 mg to 1,800 mg.
The most common adverse event of any grade was nausea (41%), diarrhea and fatigue (32% each), headache and vomiting (23% each), and cough (21%), Dr. O’Connor said. Grade 3 or 4 adverse events were neutropenia (11%), anemia (8%), hypokalemia and dyspnea (5% each), and diarrhea and constipation (2% each).
A strong dose-response relationship was observed among 51 patients evaluable for efficacy, with higher doses of TGR-1202 (1,200-mg initial formulation or ≥ 600 mg micronized) demonstrating rapid and profound responses, he said.
In the CLL subgroup, 14 of 16 patients (88%) achieved a nodal partial response and 10 (63%) achieved a response per International Workshop on CLL (iwCLL) criteria.
Of the 12 evaluable patients with follicular lymphoma, 5 achieved a partial response (nodal reduction > 50%), with 3 of the 6 patients treated at higher doses reaching a partial response.
A heavily pretreated patient with Hodgkin lymphoma also achieved a near-complete response, Dr. O’Connor said.
At the time of the analysis, 37 of 66 patients had received micronized TGR-1202 at doses ≥ 800 mg. Of these, 25 remain on study and have reached a median progression-free survival of 9.5 months.
Expansion cohorts are enrolling at 800 mg and 1,200 mg of the micronized formulation, and are the targeted doses for phase II studies in development, he said.
Duvelisib
In a separate presentation during the same session, phase I results showed twice-daily duvelisib 25 mg resulted in an overall response rate of 88%, including 15 partial responses in 17 evaluable patients with treatment-naive CLL.
All but one of nine patients with a deleterious P53 mutation or 17p deletion achieved a partial response, Dr. Susan O’Brien of University of California, Irvine, reported.
“The advantage of duvelisib is that responses are more rapid than with other single agent B-cell receptors,” she said in an interview.
The median time to iwCLL response was 3.7 months, with 7 of the 15 responses occurring by the first assessment (cycle 3, day 1).
Pharmacodynamic and mechanism of action studies show duvelisib, an oral P13K-delta/gamma inhibitor, produces rapid inhibition of phosphorylation of AKT (pAKT) sustained through cycle 2, day 1 and near-complete inhibition of CLL proliferation (Ki67) following 1 cycle of duvelisib.
Key serum chemokines and cytokines known to contribute to CLL growth and survival also decreased following duvelisib, suggesting modulation of the tumor microenvironment, Dr. O’Brien said.
Of the 18 patients treated in the CLL expansion cohort, 10 remain on treatment and 8 discontinued treatment, including 6 patients who discontinued treatment because of adverse events. The median time on treatment was 14 months (range 1-20 months). Adverse events were mostly grade 1 or 2, reversible, and clinically manageable, she said.
The most common grade 3 adverse events were diarrhea (22%) and liver enzyme elevations (17%), with grade 4 neutropenia occurring in 28%.
In 16 patients with baseline computed tomography assessments, 88% achieved a nodal response (≥ 50% reduction in measurable area of disease) and all had a PR per iwCLL.
Median progression-free and overall survival had not been reached, with a 92% PFS rate and 94% survival rate at 18 months, Dr. O’Brien said. One patient died during follow-up, about 5 months after the last duvelisib dose.
Based on the pharmacodynamic/pharmacokinetic profile and clinical activity, the 25-mg twice-daily dose has been selected for phase III evaluation, she said.
On Twitter@pwendl
AT THE EHA CONGRESS
Key clinical point: The investigational P13K inhibitors TGR-1202 and duvelisib were clinically active in phase I trials.
Major finding: TGR-1202 prompted an iwCLL response in 63% of 16 patients with relapsed or refractory CLL, while duvelisib did so in 88% of 17 treatment-naive CLL patients.
Data source: Two phase I studies in CLL and other hematologic malignancies.
Disclosures: TG Therapeutics sponsored the TGR-1202 study. Dr. Owen and several co-authors reported financial ties with TG Therapeutics. Infinity Pharmaceuticals sponsored the duvelisib study. Dr. O’Brien disclosed that eight coinvestigators are employees of Infinity.
Surgical bleeding risk ‘remarkable’ with platelet disorders
VIENNA – Inherited platelet function disorders are associated with a significant bleeding risk during surgery, a retrospective, multicenter study shows.
“The frequency of excessive bleeding assessed by one of three criteria at surgery is pretty remarkable because we had rates ranging from 13% to about 19% depending on the assessment criteria,” Dr. Paolo Gresele said at the annual congress of the European Hematology Association.
Any excessive bleeding by any criteria took place in about 23% of patients.
Although conventionally considered rare, inherited platelet function disorders (IPFD) are more frequent than previously thought, and recent advances in their diagnosis have expanded the forms and number of reported patients.
Only a handful of case reports or small case series have evaluated the bleeding risk associated with surgery in patients with IPFD. As a result, the exact bleeding risk and most appropriate management options in IPFD are not known, Dr. Gresele of University of Perugia (Italy) said.
He reported on a retrospective study involving patients with IPFD enrolled at 42 centers from 16 countries. The median age of the 205 patients was 35 years, and 56% were women; 89 had Glanzmann thrombasthenia, 46 had primary secretion defect, 14 had combined alpha-delta granule deficiency, 11 had Hermansky-Pudlak syndrome, 9 had gray platelet syndrome, and 36 had other forms of IPFD.
Data were collected from 389 procedures, of which 54.5% were surgeries, 30% were dental procedures, and 15.5% were invasive procedures. The most frequent surgeries were otolaryngologic, abdominal, orthopedic, gynecologic, urologic, and dermatologic.
The frequency of excessive bleeding at surgery was about 19.7% by the Bleeding Academic Research Consortium (BARC) bleeding classification, 17% by subjective evaluation by the surgeon or patient, and 13% based on duration of bleeding at surgery of at least 6 or more hours, Dr. Gresele said.
The World Health Organization (WHO) bleeding scale before surgery was quite predictive of excessive bleeding at surgery, with patients at grade 3 and 4 having an odds ratio for excessive bleeding of 9.22 and 28, respectively, compared with patients at grade 0, he said.
Somewhat unexpectedly, the most serious bleeders based on a BARC of at least 2 or more at surgery were patients with Hermansky-Pudlak syndrome, Glanzmann thrombasthenia, and gray platelet syndrome. Those with primary secretion defect and combined alpha-delta granule deficiency had a relatively low risk of bleeding at surgery, he said.
The procedures associated with more excessive bleeding were urologic surgery, gynecologic surgery, and abdominal surgery.
Preparation for surgery was made in 82% of procedures and included prophylactic platelet transfusions in 38.5%, desmopressin (DDAVP) in about 19%, antifibrinolytic agents in about 12%, factor VIIa in less than 10%, and other interventions such as cryoprecipitate, fibrinogen, fresh frozen plasma, intravenous immunoglobulin, suture, and local hemostatic agent in less than 5%.
Generally all measures had a good ability to prevent excessive bleeding, bringing rates down to about 20% or less, Dr. Gresele said. The two exceptions were no prophylaxis and “other” interventions, where the bleeding rate reached a high of about 45% for the latter. In contrast, bleeding risk was significantly reduced when any prophylaxis (odds ratio, 0.38) or DDAVP (OR, 0.24) were used.
In 87 cases, however, emergency treatment for excessive bleeding was required, he said. Platelet transfusions were the most common treatment, given in roughly half of patients, followed by antifibrinolytic agents. The success rate was about 80% for all measures, except for “other” interventions, which had a success rate of about 65%.
“Treatment of excessive bleeding is made mostly with platelet transfusions or antifibrinolytic agents and is able to stop bleeding in many, but not all cases,” Dr. Gresele concluded.
On Twitter @pwendl
VIENNA – Inherited platelet function disorders are associated with a significant bleeding risk during surgery, a retrospective, multicenter study shows.
“The frequency of excessive bleeding assessed by one of three criteria at surgery is pretty remarkable because we had rates ranging from 13% to about 19% depending on the assessment criteria,” Dr. Paolo Gresele said at the annual congress of the European Hematology Association.
Any excessive bleeding by any criteria took place in about 23% of patients.
Although conventionally considered rare, inherited platelet function disorders (IPFD) are more frequent than previously thought, and recent advances in their diagnosis have expanded the forms and number of reported patients.
Only a handful of case reports or small case series have evaluated the bleeding risk associated with surgery in patients with IPFD. As a result, the exact bleeding risk and most appropriate management options in IPFD are not known, Dr. Gresele of University of Perugia (Italy) said.
He reported on a retrospective study involving patients with IPFD enrolled at 42 centers from 16 countries. The median age of the 205 patients was 35 years, and 56% were women; 89 had Glanzmann thrombasthenia, 46 had primary secretion defect, 14 had combined alpha-delta granule deficiency, 11 had Hermansky-Pudlak syndrome, 9 had gray platelet syndrome, and 36 had other forms of IPFD.
Data were collected from 389 procedures, of which 54.5% were surgeries, 30% were dental procedures, and 15.5% were invasive procedures. The most frequent surgeries were otolaryngologic, abdominal, orthopedic, gynecologic, urologic, and dermatologic.
The frequency of excessive bleeding at surgery was about 19.7% by the Bleeding Academic Research Consortium (BARC) bleeding classification, 17% by subjective evaluation by the surgeon or patient, and 13% based on duration of bleeding at surgery of at least 6 or more hours, Dr. Gresele said.
The World Health Organization (WHO) bleeding scale before surgery was quite predictive of excessive bleeding at surgery, with patients at grade 3 and 4 having an odds ratio for excessive bleeding of 9.22 and 28, respectively, compared with patients at grade 0, he said.
Somewhat unexpectedly, the most serious bleeders based on a BARC of at least 2 or more at surgery were patients with Hermansky-Pudlak syndrome, Glanzmann thrombasthenia, and gray platelet syndrome. Those with primary secretion defect and combined alpha-delta granule deficiency had a relatively low risk of bleeding at surgery, he said.
The procedures associated with more excessive bleeding were urologic surgery, gynecologic surgery, and abdominal surgery.
Preparation for surgery was made in 82% of procedures and included prophylactic platelet transfusions in 38.5%, desmopressin (DDAVP) in about 19%, antifibrinolytic agents in about 12%, factor VIIa in less than 10%, and other interventions such as cryoprecipitate, fibrinogen, fresh frozen plasma, intravenous immunoglobulin, suture, and local hemostatic agent in less than 5%.
Generally all measures had a good ability to prevent excessive bleeding, bringing rates down to about 20% or less, Dr. Gresele said. The two exceptions were no prophylaxis and “other” interventions, where the bleeding rate reached a high of about 45% for the latter. In contrast, bleeding risk was significantly reduced when any prophylaxis (odds ratio, 0.38) or DDAVP (OR, 0.24) were used.
In 87 cases, however, emergency treatment for excessive bleeding was required, he said. Platelet transfusions were the most common treatment, given in roughly half of patients, followed by antifibrinolytic agents. The success rate was about 80% for all measures, except for “other” interventions, which had a success rate of about 65%.
“Treatment of excessive bleeding is made mostly with platelet transfusions or antifibrinolytic agents and is able to stop bleeding in many, but not all cases,” Dr. Gresele concluded.
On Twitter @pwendl
VIENNA – Inherited platelet function disorders are associated with a significant bleeding risk during surgery, a retrospective, multicenter study shows.
“The frequency of excessive bleeding assessed by one of three criteria at surgery is pretty remarkable because we had rates ranging from 13% to about 19% depending on the assessment criteria,” Dr. Paolo Gresele said at the annual congress of the European Hematology Association.
Any excessive bleeding by any criteria took place in about 23% of patients.
Although conventionally considered rare, inherited platelet function disorders (IPFD) are more frequent than previously thought, and recent advances in their diagnosis have expanded the forms and number of reported patients.
Only a handful of case reports or small case series have evaluated the bleeding risk associated with surgery in patients with IPFD. As a result, the exact bleeding risk and most appropriate management options in IPFD are not known, Dr. Gresele of University of Perugia (Italy) said.
He reported on a retrospective study involving patients with IPFD enrolled at 42 centers from 16 countries. The median age of the 205 patients was 35 years, and 56% were women; 89 had Glanzmann thrombasthenia, 46 had primary secretion defect, 14 had combined alpha-delta granule deficiency, 11 had Hermansky-Pudlak syndrome, 9 had gray platelet syndrome, and 36 had other forms of IPFD.
Data were collected from 389 procedures, of which 54.5% were surgeries, 30% were dental procedures, and 15.5% were invasive procedures. The most frequent surgeries were otolaryngologic, abdominal, orthopedic, gynecologic, urologic, and dermatologic.
The frequency of excessive bleeding at surgery was about 19.7% by the Bleeding Academic Research Consortium (BARC) bleeding classification, 17% by subjective evaluation by the surgeon or patient, and 13% based on duration of bleeding at surgery of at least 6 or more hours, Dr. Gresele said.
The World Health Organization (WHO) bleeding scale before surgery was quite predictive of excessive bleeding at surgery, with patients at grade 3 and 4 having an odds ratio for excessive bleeding of 9.22 and 28, respectively, compared with patients at grade 0, he said.
Somewhat unexpectedly, the most serious bleeders based on a BARC of at least 2 or more at surgery were patients with Hermansky-Pudlak syndrome, Glanzmann thrombasthenia, and gray platelet syndrome. Those with primary secretion defect and combined alpha-delta granule deficiency had a relatively low risk of bleeding at surgery, he said.
The procedures associated with more excessive bleeding were urologic surgery, gynecologic surgery, and abdominal surgery.
Preparation for surgery was made in 82% of procedures and included prophylactic platelet transfusions in 38.5%, desmopressin (DDAVP) in about 19%, antifibrinolytic agents in about 12%, factor VIIa in less than 10%, and other interventions such as cryoprecipitate, fibrinogen, fresh frozen plasma, intravenous immunoglobulin, suture, and local hemostatic agent in less than 5%.
Generally all measures had a good ability to prevent excessive bleeding, bringing rates down to about 20% or less, Dr. Gresele said. The two exceptions were no prophylaxis and “other” interventions, where the bleeding rate reached a high of about 45% for the latter. In contrast, bleeding risk was significantly reduced when any prophylaxis (odds ratio, 0.38) or DDAVP (OR, 0.24) were used.
In 87 cases, however, emergency treatment for excessive bleeding was required, he said. Platelet transfusions were the most common treatment, given in roughly half of patients, followed by antifibrinolytic agents. The success rate was about 80% for all measures, except for “other” interventions, which had a success rate of about 65%.
“Treatment of excessive bleeding is made mostly with platelet transfusions or antifibrinolytic agents and is able to stop bleeding in many, but not all cases,” Dr. Gresele concluded.
On Twitter @pwendl
AT THE EHA CONGRESS
Key clinical point: Inherited platelet function disorders are associated with a significant surgical bleeding risk.
Major finding: The frequency of excessive bleeding ranged from about 13% to about 19%.
Data source: Retrospective, multicenter study in 205 patients with inherited platelet function disorders and 389 procedures.
Disclosures: Dr. Gesele reported no financial disclosures.
Advanced age no barrier to continuous myeloma regimen
VIENNA – Elderly patients over age 75 with newly diagnosed multiple myeloma derive the same survival benefits from continuous lenalidomide and low-dose dexamethasone as those under 75, according to a new analysis of the pivotal phase III FIRST trial.
In those older than 75 years, continuous lenalidomide (Revlimid) and low-dose dexamethasone demonstrated a 14-month overall survival advantage (hazard ratio, 0.72; 95% confidence interval, 0.54-0.96) and 20% reduction in the risk of progression or death (HR, 0.80; 95% CI, 0.62-1.03) compared with melphalan (Alkeran) plus prednisone and thalidomide (MPT).
“With dose adjustment and monitoring, this continuous len-dex arm was effective and safe, even in very elderly and frail patients. This [trial] establishes this regimen as a global standard of care for transplant-ineligible patients,” Dr. Thierry Facon said at the annual congress of the European Hematology Association.
FIRST is the largest randomized trial in this setting and allocated 1,623 patients to lenalidomide plus low-dose dexamethasone in 28-day cycles until disease progression (Rd continuous) or 18 cycles of the same regimen for 72 weeks (Rd 18) or 12 cycles of MPT for 72 weeks.
In an interim analysis published in the New England Journal of Medicine (2014 [doi:10.1056/nejmoa1402551]) treatment with Rd continuous reduced the risk of progression or death by 28% and the risk of death by 22%, compared with MPT, a standard therapy for transplant-ineligible patients.
The new analysis is important because it is the first to examine the impact of age on the efficacy and safety of Rd continuous. Multiple myeloma is a disease of the elderly, with roughly one-third of patients diagnosed at more than 75 years, according to Dr. Facon of University Hospital Huriez, Lille, France.
Overall, 567 patients were older than 75 years (median 79 years) and 1,056 were 75 years or less (median 70 years). Starting doses for the very elderly group were reduced from 40 mg to 20 mg for dexamethasone; from 200 mg to 100 mg for thalidomide; and from 0.25 mg/kg to 0.20 mg/kg for melphalan. In patients with low blood count or impaired renal function, melphalan dose was reduced from 0.125 kg/mg to 0.10 mg/kg. All patients received thromboprophylaxis.
Median progression-free survival (PFS) in the 75-year and younger group was 28.1 months with Rd continuous, 21.6 months with Rd 18, and 22.4 months with MPT (Rd continuous vs. MPT: HR, 0.64; 95% CI, 0.53-0.77). The 4-year PFS rates were 37%, 15%, and 13%, Dr. Facon said.
In the very elderly group, median PFS reached 20.3 months, 19.4 months, and 19.8 months (HR, 0.80, also noted above), with 4-year PFS rates of 26%, 10%, and 11%.
“This is something quite important, illustrating the benefit of continuous therapy in terms of PFS,” he said.
Of note, median PFS in the interim analysis was similar at 25.5 months for Rd continuous, 20.7 months for Rd 18, and 21.2 months for MPT.
In the new analysis, overall survival in the 75 years and younger group was 60.9 months with Rd continuous, 60.6 months with Rd 18, and 55.3 months with MPT (Rd continuous vs. MPT: HR, 0.76, 95% CI, 0.60-0.96). The 4-year overall survival (OS) rates were 64%, 61%, and 57%.
Among the very elderly, median OS was 52.3 months with Rd continuous, 45.7 with Rd 18, and 37.8 months with MPT (HR, 0.72, also noted above), with 4-year OS rates of 52%, 48%, and 39%.
Duration of response was improved with Rd continuous treatment, irrespective of age, Dr. Facon said. The median duration for Rd continuous was 37 months in those aged 75 years and younger and 27 months in the very elderly, compared with 21-22 months for all other treatments.
Dose reductions due to adverse events were less common in those aged 75 years and under for Rd continuous than for MPT (37% vs. 52%), as were treatment discontinuations (21% vs. 26%). More very elderly patients required dose reductions for Rd continuous than MPT (44% vs. 36%), but fewer went on to discontinue Rd continuous (26% vs 29%), he said.
Rates of grade 3/4 neutropenia, the most common hematologic adverse event occurring in at least 5% of patients, were lower with Rd continuous and Rd 18 than with MPT in those aged 75 years and younger (28% vs. 25% vs. 47%) and in the very elderly (29% vs. 29% vs. 40%).
There is possibly a difference in cardiac events, which moved from 6% with MPT to 12% with Rd continuous in patients aged 75 years and younger and from 13% with MPT to 12% with Rd continuous in the very elderly, “but otherwise the results were quite similar, especially for neurologic toxicity and thromboembolic events,” he said.
During a discussion of the results, Dr. Facon acknowledged that the survival difference between the Rd continuous and Rd 18 groups was marginal and said additional insights will come from the final survival analysis as well as the recently published quality of life analyses.
When asked whether he would prefer Rd to VMP (bortezomib, melphalan, and prednisone), Dr. Facon said both regimens are standards of care in transplant-ineligible myeloma patients and cautioned against making cross-trial comparisons between FIRST and the older VISTA study of VMP.
“I would just say that these two regimens are effective and safe regimens, and it is also a discussion with your patients,” he said. “You may say that’s an easy answer, but I think it’s a fair answer.”
In February, the Food and Drug Administration expanded the indication for lenalidomide in combination with dexamethasone to include patients with newly diagnosed multiple myeloma.
FIRST was funded by Intergroupe Francophone du Myélome and Celgene. Dr. Facon reported consulting for and honoraria from Celgene.
On Twitter @pwendl
VIENNA – Elderly patients over age 75 with newly diagnosed multiple myeloma derive the same survival benefits from continuous lenalidomide and low-dose dexamethasone as those under 75, according to a new analysis of the pivotal phase III FIRST trial.
In those older than 75 years, continuous lenalidomide (Revlimid) and low-dose dexamethasone demonstrated a 14-month overall survival advantage (hazard ratio, 0.72; 95% confidence interval, 0.54-0.96) and 20% reduction in the risk of progression or death (HR, 0.80; 95% CI, 0.62-1.03) compared with melphalan (Alkeran) plus prednisone and thalidomide (MPT).
“With dose adjustment and monitoring, this continuous len-dex arm was effective and safe, even in very elderly and frail patients. This [trial] establishes this regimen as a global standard of care for transplant-ineligible patients,” Dr. Thierry Facon said at the annual congress of the European Hematology Association.
FIRST is the largest randomized trial in this setting and allocated 1,623 patients to lenalidomide plus low-dose dexamethasone in 28-day cycles until disease progression (Rd continuous) or 18 cycles of the same regimen for 72 weeks (Rd 18) or 12 cycles of MPT for 72 weeks.
In an interim analysis published in the New England Journal of Medicine (2014 [doi:10.1056/nejmoa1402551]) treatment with Rd continuous reduced the risk of progression or death by 28% and the risk of death by 22%, compared with MPT, a standard therapy for transplant-ineligible patients.
The new analysis is important because it is the first to examine the impact of age on the efficacy and safety of Rd continuous. Multiple myeloma is a disease of the elderly, with roughly one-third of patients diagnosed at more than 75 years, according to Dr. Facon of University Hospital Huriez, Lille, France.
Overall, 567 patients were older than 75 years (median 79 years) and 1,056 were 75 years or less (median 70 years). Starting doses for the very elderly group were reduced from 40 mg to 20 mg for dexamethasone; from 200 mg to 100 mg for thalidomide; and from 0.25 mg/kg to 0.20 mg/kg for melphalan. In patients with low blood count or impaired renal function, melphalan dose was reduced from 0.125 kg/mg to 0.10 mg/kg. All patients received thromboprophylaxis.
Median progression-free survival (PFS) in the 75-year and younger group was 28.1 months with Rd continuous, 21.6 months with Rd 18, and 22.4 months with MPT (Rd continuous vs. MPT: HR, 0.64; 95% CI, 0.53-0.77). The 4-year PFS rates were 37%, 15%, and 13%, Dr. Facon said.
In the very elderly group, median PFS reached 20.3 months, 19.4 months, and 19.8 months (HR, 0.80, also noted above), with 4-year PFS rates of 26%, 10%, and 11%.
“This is something quite important, illustrating the benefit of continuous therapy in terms of PFS,” he said.
Of note, median PFS in the interim analysis was similar at 25.5 months for Rd continuous, 20.7 months for Rd 18, and 21.2 months for MPT.
In the new analysis, overall survival in the 75 years and younger group was 60.9 months with Rd continuous, 60.6 months with Rd 18, and 55.3 months with MPT (Rd continuous vs. MPT: HR, 0.76, 95% CI, 0.60-0.96). The 4-year overall survival (OS) rates were 64%, 61%, and 57%.
Among the very elderly, median OS was 52.3 months with Rd continuous, 45.7 with Rd 18, and 37.8 months with MPT (HR, 0.72, also noted above), with 4-year OS rates of 52%, 48%, and 39%.
Duration of response was improved with Rd continuous treatment, irrespective of age, Dr. Facon said. The median duration for Rd continuous was 37 months in those aged 75 years and younger and 27 months in the very elderly, compared with 21-22 months for all other treatments.
Dose reductions due to adverse events were less common in those aged 75 years and under for Rd continuous than for MPT (37% vs. 52%), as were treatment discontinuations (21% vs. 26%). More very elderly patients required dose reductions for Rd continuous than MPT (44% vs. 36%), but fewer went on to discontinue Rd continuous (26% vs 29%), he said.
Rates of grade 3/4 neutropenia, the most common hematologic adverse event occurring in at least 5% of patients, were lower with Rd continuous and Rd 18 than with MPT in those aged 75 years and younger (28% vs. 25% vs. 47%) and in the very elderly (29% vs. 29% vs. 40%).
There is possibly a difference in cardiac events, which moved from 6% with MPT to 12% with Rd continuous in patients aged 75 years and younger and from 13% with MPT to 12% with Rd continuous in the very elderly, “but otherwise the results were quite similar, especially for neurologic toxicity and thromboembolic events,” he said.
During a discussion of the results, Dr. Facon acknowledged that the survival difference between the Rd continuous and Rd 18 groups was marginal and said additional insights will come from the final survival analysis as well as the recently published quality of life analyses.
When asked whether he would prefer Rd to VMP (bortezomib, melphalan, and prednisone), Dr. Facon said both regimens are standards of care in transplant-ineligible myeloma patients and cautioned against making cross-trial comparisons between FIRST and the older VISTA study of VMP.
“I would just say that these two regimens are effective and safe regimens, and it is also a discussion with your patients,” he said. “You may say that’s an easy answer, but I think it’s a fair answer.”
In February, the Food and Drug Administration expanded the indication for lenalidomide in combination with dexamethasone to include patients with newly diagnosed multiple myeloma.
FIRST was funded by Intergroupe Francophone du Myélome and Celgene. Dr. Facon reported consulting for and honoraria from Celgene.
On Twitter @pwendl
VIENNA – Elderly patients over age 75 with newly diagnosed multiple myeloma derive the same survival benefits from continuous lenalidomide and low-dose dexamethasone as those under 75, according to a new analysis of the pivotal phase III FIRST trial.
In those older than 75 years, continuous lenalidomide (Revlimid) and low-dose dexamethasone demonstrated a 14-month overall survival advantage (hazard ratio, 0.72; 95% confidence interval, 0.54-0.96) and 20% reduction in the risk of progression or death (HR, 0.80; 95% CI, 0.62-1.03) compared with melphalan (Alkeran) plus prednisone and thalidomide (MPT).
“With dose adjustment and monitoring, this continuous len-dex arm was effective and safe, even in very elderly and frail patients. This [trial] establishes this regimen as a global standard of care for transplant-ineligible patients,” Dr. Thierry Facon said at the annual congress of the European Hematology Association.
FIRST is the largest randomized trial in this setting and allocated 1,623 patients to lenalidomide plus low-dose dexamethasone in 28-day cycles until disease progression (Rd continuous) or 18 cycles of the same regimen for 72 weeks (Rd 18) or 12 cycles of MPT for 72 weeks.
In an interim analysis published in the New England Journal of Medicine (2014 [doi:10.1056/nejmoa1402551]) treatment with Rd continuous reduced the risk of progression or death by 28% and the risk of death by 22%, compared with MPT, a standard therapy for transplant-ineligible patients.
The new analysis is important because it is the first to examine the impact of age on the efficacy and safety of Rd continuous. Multiple myeloma is a disease of the elderly, with roughly one-third of patients diagnosed at more than 75 years, according to Dr. Facon of University Hospital Huriez, Lille, France.
Overall, 567 patients were older than 75 years (median 79 years) and 1,056 were 75 years or less (median 70 years). Starting doses for the very elderly group were reduced from 40 mg to 20 mg for dexamethasone; from 200 mg to 100 mg for thalidomide; and from 0.25 mg/kg to 0.20 mg/kg for melphalan. In patients with low blood count or impaired renal function, melphalan dose was reduced from 0.125 kg/mg to 0.10 mg/kg. All patients received thromboprophylaxis.
Median progression-free survival (PFS) in the 75-year and younger group was 28.1 months with Rd continuous, 21.6 months with Rd 18, and 22.4 months with MPT (Rd continuous vs. MPT: HR, 0.64; 95% CI, 0.53-0.77). The 4-year PFS rates were 37%, 15%, and 13%, Dr. Facon said.
In the very elderly group, median PFS reached 20.3 months, 19.4 months, and 19.8 months (HR, 0.80, also noted above), with 4-year PFS rates of 26%, 10%, and 11%.
“This is something quite important, illustrating the benefit of continuous therapy in terms of PFS,” he said.
Of note, median PFS in the interim analysis was similar at 25.5 months for Rd continuous, 20.7 months for Rd 18, and 21.2 months for MPT.
In the new analysis, overall survival in the 75 years and younger group was 60.9 months with Rd continuous, 60.6 months with Rd 18, and 55.3 months with MPT (Rd continuous vs. MPT: HR, 0.76, 95% CI, 0.60-0.96). The 4-year overall survival (OS) rates were 64%, 61%, and 57%.
Among the very elderly, median OS was 52.3 months with Rd continuous, 45.7 with Rd 18, and 37.8 months with MPT (HR, 0.72, also noted above), with 4-year OS rates of 52%, 48%, and 39%.
Duration of response was improved with Rd continuous treatment, irrespective of age, Dr. Facon said. The median duration for Rd continuous was 37 months in those aged 75 years and younger and 27 months in the very elderly, compared with 21-22 months for all other treatments.
Dose reductions due to adverse events were less common in those aged 75 years and under for Rd continuous than for MPT (37% vs. 52%), as were treatment discontinuations (21% vs. 26%). More very elderly patients required dose reductions for Rd continuous than MPT (44% vs. 36%), but fewer went on to discontinue Rd continuous (26% vs 29%), he said.
Rates of grade 3/4 neutropenia, the most common hematologic adverse event occurring in at least 5% of patients, were lower with Rd continuous and Rd 18 than with MPT in those aged 75 years and younger (28% vs. 25% vs. 47%) and in the very elderly (29% vs. 29% vs. 40%).
There is possibly a difference in cardiac events, which moved from 6% with MPT to 12% with Rd continuous in patients aged 75 years and younger and from 13% with MPT to 12% with Rd continuous in the very elderly, “but otherwise the results were quite similar, especially for neurologic toxicity and thromboembolic events,” he said.
During a discussion of the results, Dr. Facon acknowledged that the survival difference between the Rd continuous and Rd 18 groups was marginal and said additional insights will come from the final survival analysis as well as the recently published quality of life analyses.
When asked whether he would prefer Rd to VMP (bortezomib, melphalan, and prednisone), Dr. Facon said both regimens are standards of care in transplant-ineligible myeloma patients and cautioned against making cross-trial comparisons between FIRST and the older VISTA study of VMP.
“I would just say that these two regimens are effective and safe regimens, and it is also a discussion with your patients,” he said. “You may say that’s an easy answer, but I think it’s a fair answer.”
In February, the Food and Drug Administration expanded the indication for lenalidomide in combination with dexamethasone to include patients with newly diagnosed multiple myeloma.
FIRST was funded by Intergroupe Francophone du Myélome and Celgene. Dr. Facon reported consulting for and honoraria from Celgene.
On Twitter @pwendl
AT THE EHA CONGRESS
Key clinical point: Patients over age 75 draw the same survival benefit with continuous lenalidomide plus low-dose dexamethasone over MPT as their younger counterparts.
Major finding: Continuous lenalidomide plus low-dose dexamethasone provided a 14-month overall survival advantage and 20% reduction in the risk of progression or death, compared with MPT in patients over age 75.
Data source: Phase III trial in 1,623 transplant-ineligible patients with newly diagnosed multiple myeloma.
Disclosures: FIRST was funded by Intergroupe Francophone du Myélome and Celgene. Dr. Facon reported consulting for and honoraria from Celgene.
Transdermal testosterone tanks in poor ovarian responders
LISBON – Pretreatment with transdermal testosterone failed to improve outcomes in women with poor ovarian response who were undergoing intra-cytoplasmic sperm injection in a randomized clinical study.
The primary endpoint, number of cumulus-oocyte complexes (COCs) retrieved, was not significantly different with testosterone gel 10 mg applied to the thigh for 21 days before ovarian stimulation versus no pretreatment (median, 3.5 vs. 3.0; P = .91).
Further, no differences were observed in fertilization rates (66.7% vs. 66.7%; P = .97) or live birth rates per intention-to-treat analysis (7.7% vs. 8.3%; 95% confidence interval, –19.0 to +16.9).
“An improvement in {in vitro fertilization] outcome cannot be excluded using a larger dose of testosterone more than 10 mg or a pretreatment period longer than 21 days,” study author Dr. Julia Bosdou said at the annual meeting of the European Society of Human Reproduction and Embryology.
Because of sample size restrictions, no conclusions can be drawn regarding the probability of live birth, she added.
The study was designed to detect a difference of 1.5 COCs retrieved with a sample size of 42 patients. In all, 50 women who fulfilled the Bologna criteria for poor ovarian response were allocated to the testosterone group (n = 26) or control group (n = 24). All patients underwent a long follicular gonadotropin-releasing hormone agonist (GnRHa) protocol. Recombinant follicle-stimulating hormone (FSH) 300 IU daily was started on day 22 following GnRHa initiation.
The testosterone dose was based on published data showing a beneficial effect with a 21-day duration, said Dr. Bosdou of the Aristotle University of Thessaloniki (Greece).
Androgens have been suggested to play a critical role in early follicular development by enhancing ovarian sensitivity to FSH. A recent meta-analysis by the investigators of the current study also showed that pretreatment with transdermal testosterone increased clinical pregnancy and live birth rates in poor responders, but it was based on only two randomized trials (Hum. Reprod. Update 2012;18:127-45), she observed.
As expected, testosterone levels in the current study were significantly higher in the testosterone group than the control group on day 22 (median, 114 ng/dL vs. 20 ng/dL; P < .001). Duration of FSH stimulation was comparable between groups (12.5 days vs. 12 days; P = .48), Dr. Bosdou said.
Endometrial thickness on the day of human chorionic gonadotropin administration was significantly greater with testosterone pretreatment (median, 10.7 mm vs. 9 mm; P = .03).
No adverse events were reported in either group, she said.
The study was partially funded by a scholarship award to Dr. Bosdou from the Academy of Athens. Dr. Bosdou reported having no conflicts of interest.
On Twitter @pwendl
LISBON – Pretreatment with transdermal testosterone failed to improve outcomes in women with poor ovarian response who were undergoing intra-cytoplasmic sperm injection in a randomized clinical study.
The primary endpoint, number of cumulus-oocyte complexes (COCs) retrieved, was not significantly different with testosterone gel 10 mg applied to the thigh for 21 days before ovarian stimulation versus no pretreatment (median, 3.5 vs. 3.0; P = .91).
Further, no differences were observed in fertilization rates (66.7% vs. 66.7%; P = .97) or live birth rates per intention-to-treat analysis (7.7% vs. 8.3%; 95% confidence interval, –19.0 to +16.9).
“An improvement in {in vitro fertilization] outcome cannot be excluded using a larger dose of testosterone more than 10 mg or a pretreatment period longer than 21 days,” study author Dr. Julia Bosdou said at the annual meeting of the European Society of Human Reproduction and Embryology.
Because of sample size restrictions, no conclusions can be drawn regarding the probability of live birth, she added.
The study was designed to detect a difference of 1.5 COCs retrieved with a sample size of 42 patients. In all, 50 women who fulfilled the Bologna criteria for poor ovarian response were allocated to the testosterone group (n = 26) or control group (n = 24). All patients underwent a long follicular gonadotropin-releasing hormone agonist (GnRHa) protocol. Recombinant follicle-stimulating hormone (FSH) 300 IU daily was started on day 22 following GnRHa initiation.
The testosterone dose was based on published data showing a beneficial effect with a 21-day duration, said Dr. Bosdou of the Aristotle University of Thessaloniki (Greece).
Androgens have been suggested to play a critical role in early follicular development by enhancing ovarian sensitivity to FSH. A recent meta-analysis by the investigators of the current study also showed that pretreatment with transdermal testosterone increased clinical pregnancy and live birth rates in poor responders, but it was based on only two randomized trials (Hum. Reprod. Update 2012;18:127-45), she observed.
As expected, testosterone levels in the current study were significantly higher in the testosterone group than the control group on day 22 (median, 114 ng/dL vs. 20 ng/dL; P < .001). Duration of FSH stimulation was comparable between groups (12.5 days vs. 12 days; P = .48), Dr. Bosdou said.
Endometrial thickness on the day of human chorionic gonadotropin administration was significantly greater with testosterone pretreatment (median, 10.7 mm vs. 9 mm; P = .03).
No adverse events were reported in either group, she said.
The study was partially funded by a scholarship award to Dr. Bosdou from the Academy of Athens. Dr. Bosdou reported having no conflicts of interest.
On Twitter @pwendl
LISBON – Pretreatment with transdermal testosterone failed to improve outcomes in women with poor ovarian response who were undergoing intra-cytoplasmic sperm injection in a randomized clinical study.
The primary endpoint, number of cumulus-oocyte complexes (COCs) retrieved, was not significantly different with testosterone gel 10 mg applied to the thigh for 21 days before ovarian stimulation versus no pretreatment (median, 3.5 vs. 3.0; P = .91).
Further, no differences were observed in fertilization rates (66.7% vs. 66.7%; P = .97) or live birth rates per intention-to-treat analysis (7.7% vs. 8.3%; 95% confidence interval, –19.0 to +16.9).
“An improvement in {in vitro fertilization] outcome cannot be excluded using a larger dose of testosterone more than 10 mg or a pretreatment period longer than 21 days,” study author Dr. Julia Bosdou said at the annual meeting of the European Society of Human Reproduction and Embryology.
Because of sample size restrictions, no conclusions can be drawn regarding the probability of live birth, she added.
The study was designed to detect a difference of 1.5 COCs retrieved with a sample size of 42 patients. In all, 50 women who fulfilled the Bologna criteria for poor ovarian response were allocated to the testosterone group (n = 26) or control group (n = 24). All patients underwent a long follicular gonadotropin-releasing hormone agonist (GnRHa) protocol. Recombinant follicle-stimulating hormone (FSH) 300 IU daily was started on day 22 following GnRHa initiation.
The testosterone dose was based on published data showing a beneficial effect with a 21-day duration, said Dr. Bosdou of the Aristotle University of Thessaloniki (Greece).
Androgens have been suggested to play a critical role in early follicular development by enhancing ovarian sensitivity to FSH. A recent meta-analysis by the investigators of the current study also showed that pretreatment with transdermal testosterone increased clinical pregnancy and live birth rates in poor responders, but it was based on only two randomized trials (Hum. Reprod. Update 2012;18:127-45), she observed.
As expected, testosterone levels in the current study were significantly higher in the testosterone group than the control group on day 22 (median, 114 ng/dL vs. 20 ng/dL; P < .001). Duration of FSH stimulation was comparable between groups (12.5 days vs. 12 days; P = .48), Dr. Bosdou said.
Endometrial thickness on the day of human chorionic gonadotropin administration was significantly greater with testosterone pretreatment (median, 10.7 mm vs. 9 mm; P = .03).
No adverse events were reported in either group, she said.
The study was partially funded by a scholarship award to Dr. Bosdou from the Academy of Athens. Dr. Bosdou reported having no conflicts of interest.
On Twitter @pwendl
AT ESHRE 2015
Key clinical point: Pretreatment with transdermal testosterone did not improve the number of cumulus-oocyte complexes retrieved in poor ovarian responders.
Major finding: The median number of COCs retrieved was 3.5 in the testosterone group vs. 3 in the control group (P = .91).
Data source: A randomized, placebo-controlled trial in 50 poor ovarian responders.
Disclosures: The study was partially funded by a scholarship award to Dr. Bosdou from the Academy of Athens. Dr. Bosdou reported having no conflicts of interest.
Letrozole bests clomiphene again in infertile women with PCOS
LISBON – The aromatase inhibitor letrozole was associated with roughly a 42% increase in the pregnancy rate, compared with clomiphene citrate in infertile women with polycystic ovary syndrome in a double-blind, randomized study.
In an intention-to-treat analysis, the pregnancy rate was 61.2% with letrozole (Femara) versus 43% with clomiphene (P = .022). There also was a trend toward more live births with letrozole (48.8% vs. 35.4%; P = .089).
The per-protocol results were similar for pregnancy (61% vs. 43.2%; P = .029) and live births (48.1% vs. 35.1%; P = .108).
“We now have convincing evidence that letrozole is better than clomiphene and we should seriously consider moving on to letrozole,” principle investigator Dr. Saad Amer said at the annual meeting of the European Society of Human Reproduction and Embryology.
The results are consistent with the most recent Cochrane meta-analysis, which called for further research comparing letrozole with clomiphene as a primary ovulation induction agent in polycystic ovary syndrome (PCOS) because of low-quality evidence (Cochrane Database Syst. Rev. 2014 Feb. 24;2:CD010287).
A recent robust U.S. study (N. Engl. J. Med. 2014;371:119-29) showed higher live-birth and ovulation rates with letrozole vs. clomiphene in women with PCOS, but it included a markedly obese population with a mean body mass index (BMI) of 35 kg/m2 and thus does not reflect clinical practice worldwide, Dr. Amer said.
The current results are more generalizable, especially in Europe, because the patients fulfilled the widely accepted Rotterdam diagnostic criteria for PCOS and had a median BMI of 27.7 kg/m2 in the clomiphene group and 27.5 kg/m2 in the letrozole group, said Dr. Amer of the University of Nottingham in Derby, England.
The phase IV study evenly randomized 159 anovulatory women, aged 18-39 years, with a diagnosis of PCOS to one tablet of letrozole 2.5 mg or clomiphene 50 mg daily for 5 days, continuing until pregnancy or up to 6 cycles. If there was no response in the first cycle, the dose was increased to two tablets. If there was still no response, the patient was crossed over to the other treatment arm after a 6-week washout. Cycles were initially monitored with ultrasound follicle tracking, then mid-luteal serum progesterone measurements.
Among the 159 women in the intention-to-treat analysis, four conceived before treatment and four dropped out. The remaining 151 women included 77 given letrozole and 74 given clomiphene.
For the 60 women who crossed over, there was no significant difference in pregnancy and live birth rates between groups in either the intention-to-treat or per-protocol analyses.
Notably, however, 70.1% of women who started treatment with letrozole followed by clomiphene became pregnant vs. only 59.5% when the treatment strategy was reversed, while 56.2% started on letrozole and 49.4% started on clomiphene went on to a live birth.
“This tells us that if you take clomiphene first and then follow it with letrozole, you’re achieving almost the same result as just taking letrozole from the beginning,” Dr. Amer said.
The improved pregnancy rates, however, cannot be attributed to the effect of the endometrial factor, he said. Surprisingly, endometrial thickness was significantly greater in the clomiphene group than in the letrozole group (median, 9.0 mm vs. 8.4 mm; P = .002). Mono-follicular ovulation (83% vs. 85%) and multiple pregnancy (twins 0% vs. 6%) rates were similar.
No significant differences were observed between the clomiphene and letrozole groups in miscarriages (6 events vs. 9 events), ectopic pregnancies (0 vs. 1), or preterm births (2 vs. 4).
“Further research is required to investigate the mechanisms of increased pregnancy rates,” Dr. Amer said.
Serious adverse events included one hemorrhagic cyst in each group and a cholecystitis in the clomiphene group.
There was one fetal anomaly – a dilated left kidney – in the clomiphene group and none in the letrozole group, he said.
During a discussion of the results, reproductive medicine specialist Dr. Roy Homburg of Homerton University Hospital, London, said that it’s time for letrozole to recognized as the superior choice.
“Every study that has been done on the subject, every randomized controlled trial, every meta-analysis, every Cochrane database has shown exactly what you have shown – the superiority of letrozole over clomiphene,” Dr. Homburg said. “All this in addition to the fact that there are many more fetal abnormalities, congenital abnormalities with clomiphene rather than letrozole. I think it’s about time people start believing this and make sure letrozole is on-label rather than off-label.”
Dr. Amer agreed. “It’s now time for clomiphene to retire,” he said, receiving a round of applause from the audience.
The study was sponsored by Derby Hospitals NHS Foundation Trust. Dr. Amer reported having no financial disclosures.
On Twitter @pwendl
LISBON – The aromatase inhibitor letrozole was associated with roughly a 42% increase in the pregnancy rate, compared with clomiphene citrate in infertile women with polycystic ovary syndrome in a double-blind, randomized study.
In an intention-to-treat analysis, the pregnancy rate was 61.2% with letrozole (Femara) versus 43% with clomiphene (P = .022). There also was a trend toward more live births with letrozole (48.8% vs. 35.4%; P = .089).
The per-protocol results were similar for pregnancy (61% vs. 43.2%; P = .029) and live births (48.1% vs. 35.1%; P = .108).
“We now have convincing evidence that letrozole is better than clomiphene and we should seriously consider moving on to letrozole,” principle investigator Dr. Saad Amer said at the annual meeting of the European Society of Human Reproduction and Embryology.
The results are consistent with the most recent Cochrane meta-analysis, which called for further research comparing letrozole with clomiphene as a primary ovulation induction agent in polycystic ovary syndrome (PCOS) because of low-quality evidence (Cochrane Database Syst. Rev. 2014 Feb. 24;2:CD010287).
A recent robust U.S. study (N. Engl. J. Med. 2014;371:119-29) showed higher live-birth and ovulation rates with letrozole vs. clomiphene in women with PCOS, but it included a markedly obese population with a mean body mass index (BMI) of 35 kg/m2 and thus does not reflect clinical practice worldwide, Dr. Amer said.
The current results are more generalizable, especially in Europe, because the patients fulfilled the widely accepted Rotterdam diagnostic criteria for PCOS and had a median BMI of 27.7 kg/m2 in the clomiphene group and 27.5 kg/m2 in the letrozole group, said Dr. Amer of the University of Nottingham in Derby, England.
The phase IV study evenly randomized 159 anovulatory women, aged 18-39 years, with a diagnosis of PCOS to one tablet of letrozole 2.5 mg or clomiphene 50 mg daily for 5 days, continuing until pregnancy or up to 6 cycles. If there was no response in the first cycle, the dose was increased to two tablets. If there was still no response, the patient was crossed over to the other treatment arm after a 6-week washout. Cycles were initially monitored with ultrasound follicle tracking, then mid-luteal serum progesterone measurements.
Among the 159 women in the intention-to-treat analysis, four conceived before treatment and four dropped out. The remaining 151 women included 77 given letrozole and 74 given clomiphene.
For the 60 women who crossed over, there was no significant difference in pregnancy and live birth rates between groups in either the intention-to-treat or per-protocol analyses.
Notably, however, 70.1% of women who started treatment with letrozole followed by clomiphene became pregnant vs. only 59.5% when the treatment strategy was reversed, while 56.2% started on letrozole and 49.4% started on clomiphene went on to a live birth.
“This tells us that if you take clomiphene first and then follow it with letrozole, you’re achieving almost the same result as just taking letrozole from the beginning,” Dr. Amer said.
The improved pregnancy rates, however, cannot be attributed to the effect of the endometrial factor, he said. Surprisingly, endometrial thickness was significantly greater in the clomiphene group than in the letrozole group (median, 9.0 mm vs. 8.4 mm; P = .002). Mono-follicular ovulation (83% vs. 85%) and multiple pregnancy (twins 0% vs. 6%) rates were similar.
No significant differences were observed between the clomiphene and letrozole groups in miscarriages (6 events vs. 9 events), ectopic pregnancies (0 vs. 1), or preterm births (2 vs. 4).
“Further research is required to investigate the mechanisms of increased pregnancy rates,” Dr. Amer said.
Serious adverse events included one hemorrhagic cyst in each group and a cholecystitis in the clomiphene group.
There was one fetal anomaly – a dilated left kidney – in the clomiphene group and none in the letrozole group, he said.
During a discussion of the results, reproductive medicine specialist Dr. Roy Homburg of Homerton University Hospital, London, said that it’s time for letrozole to recognized as the superior choice.
“Every study that has been done on the subject, every randomized controlled trial, every meta-analysis, every Cochrane database has shown exactly what you have shown – the superiority of letrozole over clomiphene,” Dr. Homburg said. “All this in addition to the fact that there are many more fetal abnormalities, congenital abnormalities with clomiphene rather than letrozole. I think it’s about time people start believing this and make sure letrozole is on-label rather than off-label.”
Dr. Amer agreed. “It’s now time for clomiphene to retire,” he said, receiving a round of applause from the audience.
The study was sponsored by Derby Hospitals NHS Foundation Trust. Dr. Amer reported having no financial disclosures.
On Twitter @pwendl
LISBON – The aromatase inhibitor letrozole was associated with roughly a 42% increase in the pregnancy rate, compared with clomiphene citrate in infertile women with polycystic ovary syndrome in a double-blind, randomized study.
In an intention-to-treat analysis, the pregnancy rate was 61.2% with letrozole (Femara) versus 43% with clomiphene (P = .022). There also was a trend toward more live births with letrozole (48.8% vs. 35.4%; P = .089).
The per-protocol results were similar for pregnancy (61% vs. 43.2%; P = .029) and live births (48.1% vs. 35.1%; P = .108).
“We now have convincing evidence that letrozole is better than clomiphene and we should seriously consider moving on to letrozole,” principle investigator Dr. Saad Amer said at the annual meeting of the European Society of Human Reproduction and Embryology.
The results are consistent with the most recent Cochrane meta-analysis, which called for further research comparing letrozole with clomiphene as a primary ovulation induction agent in polycystic ovary syndrome (PCOS) because of low-quality evidence (Cochrane Database Syst. Rev. 2014 Feb. 24;2:CD010287).
A recent robust U.S. study (N. Engl. J. Med. 2014;371:119-29) showed higher live-birth and ovulation rates with letrozole vs. clomiphene in women with PCOS, but it included a markedly obese population with a mean body mass index (BMI) of 35 kg/m2 and thus does not reflect clinical practice worldwide, Dr. Amer said.
The current results are more generalizable, especially in Europe, because the patients fulfilled the widely accepted Rotterdam diagnostic criteria for PCOS and had a median BMI of 27.7 kg/m2 in the clomiphene group and 27.5 kg/m2 in the letrozole group, said Dr. Amer of the University of Nottingham in Derby, England.
The phase IV study evenly randomized 159 anovulatory women, aged 18-39 years, with a diagnosis of PCOS to one tablet of letrozole 2.5 mg or clomiphene 50 mg daily for 5 days, continuing until pregnancy or up to 6 cycles. If there was no response in the first cycle, the dose was increased to two tablets. If there was still no response, the patient was crossed over to the other treatment arm after a 6-week washout. Cycles were initially monitored with ultrasound follicle tracking, then mid-luteal serum progesterone measurements.
Among the 159 women in the intention-to-treat analysis, four conceived before treatment and four dropped out. The remaining 151 women included 77 given letrozole and 74 given clomiphene.
For the 60 women who crossed over, there was no significant difference in pregnancy and live birth rates between groups in either the intention-to-treat or per-protocol analyses.
Notably, however, 70.1% of women who started treatment with letrozole followed by clomiphene became pregnant vs. only 59.5% when the treatment strategy was reversed, while 56.2% started on letrozole and 49.4% started on clomiphene went on to a live birth.
“This tells us that if you take clomiphene first and then follow it with letrozole, you’re achieving almost the same result as just taking letrozole from the beginning,” Dr. Amer said.
The improved pregnancy rates, however, cannot be attributed to the effect of the endometrial factor, he said. Surprisingly, endometrial thickness was significantly greater in the clomiphene group than in the letrozole group (median, 9.0 mm vs. 8.4 mm; P = .002). Mono-follicular ovulation (83% vs. 85%) and multiple pregnancy (twins 0% vs. 6%) rates were similar.
No significant differences were observed between the clomiphene and letrozole groups in miscarriages (6 events vs. 9 events), ectopic pregnancies (0 vs. 1), or preterm births (2 vs. 4).
“Further research is required to investigate the mechanisms of increased pregnancy rates,” Dr. Amer said.
Serious adverse events included one hemorrhagic cyst in each group and a cholecystitis in the clomiphene group.
There was one fetal anomaly – a dilated left kidney – in the clomiphene group and none in the letrozole group, he said.
During a discussion of the results, reproductive medicine specialist Dr. Roy Homburg of Homerton University Hospital, London, said that it’s time for letrozole to recognized as the superior choice.
“Every study that has been done on the subject, every randomized controlled trial, every meta-analysis, every Cochrane database has shown exactly what you have shown – the superiority of letrozole over clomiphene,” Dr. Homburg said. “All this in addition to the fact that there are many more fetal abnormalities, congenital abnormalities with clomiphene rather than letrozole. I think it’s about time people start believing this and make sure letrozole is on-label rather than off-label.”
Dr. Amer agreed. “It’s now time for clomiphene to retire,” he said, receiving a round of applause from the audience.
The study was sponsored by Derby Hospitals NHS Foundation Trust. Dr. Amer reported having no financial disclosures.
On Twitter @pwendl
AT ESHRE 2015
Key clinical point: Letrozole is superior to clomiphene with regard to pregnancy rates in infertile women with PCOS.
Major finding: The pregnancy rate was 61.2% with letrozole versus 43% with clomiphene (P = .022).
Data source: A double-blind, randomized phase IV trial in 159 infertile women with polycystic ovarian syndrome.
Disclosures: The study was sponsored by Derby Hospitals NHS Foundation Trust. Dr. Amer reported having no financial disclosures.
ESHRE: Ectopic pregnancy rate with ART tumbles over time
LISBON – Advances in assisted reproductive technology (ART) have paid off, nearly halving the rate of ectopic pregnancy in the past 12 years.
The rate of ectopic pregnancy (EP) following ART progressively declined from 20 to 12 cases per thousand in a nationwide analysis of all ART pregnancies achieved in the United Kingdom between 2000 and 2012.
This trend appears to be related to a reduction in the incidence of tubal factor infertility, a lower number of embryos being transferred, and extended embryo culture, Dr. Nikolaos Polyzos said at the annual meeting of the European Society of Human Reproduction and Embryology.
Ectopic pregnancy (EP) is a rare event, occurring in only 2% of all spontaneous conceptions. ART has been consistently associated with higher rates of EP, which is the most common cause of mortality during the first trimester of pregnancy in the U.K., said Dr. Polyzos of the Centre for Reproductive Medicine at Vrije University Brussels.
Using the Human Fertilisation and Embryology Authority (HFEA) database, the investigators identified 684,247 ART cycles in the U.K. between 2000-2012, resulting in 212,877 pregnancies. After exclusion for various reasons including surrogacy, unspecified treatment, or missing data, 161,967 pregnancies were included in the analysis. Of these, 153,115 pregnancies occurred following in-vitro fertilization or intracytoplasmic sperm injection and 8,852 following intrauterine insemination.
The incidence of ectopic pregnancy was 1.4% over the 12-year study period.
In adjusted analyses, the most important independent risk factor for an ectopic pregnancy was tubal factor infertility, which more than doubled the risk (odds ratio, 2.23), Dr. Polyzos said.
Also significant was the number of embryos transferred (two vs. one; OR, 1.28; ≥ three vs. one; OR, 1.67) and extended embryo culture (day 3 vs. day 2; OR, 0.85; day 5 vs. day 2; OR, 0.73).
What this means in everyday clinical practice is that the probability of having an ectopic pregnancy is 29% per 1,000 pregnancies in a patient with tubal infertility if more than one embryo is transferred, he said. In contrast, the risk is more than three times lower at only 8.2% per 1,000 pregnancies in a patient who has a partner with male infertility and a single blastocyst transferred.
Details from the HFEA database showed that the proportion of infertile patients with tubal disease having ART progressively declined from 24% in 2000 to 12% in 2012. Tubal factor infertility accounts for about 14% of all infertility and is typically the result of Chlamydia trachomatis infection.
“Future efforts should promote national screening programs like the U.K.’s National Chlamydia Screening Programme. Although there is a discussion on how effective it is, I think it is very important we increase the uptake of these programs,” Dr. Polyzos said.
Efforts to promote widespread introduction of single-embryo transfer, which have been widely adopted in his own country, but less so in the United States, would lower the risk of EP even further, he added.
A recent U.S. analysis looking at the risk of EP associated with ART found that the rate of ectopic pregnancy was 1.6% when one embryo was transferred and 1.7%, 2.2%, and 2.5% when two, three, or four or more embryos were transferred, respectively. Overall, the EP rate declined from 2% in 2001 to 1.6% in 2011 based on 553,577 pregnancies reported during those years to the U.S. National ART Surveillance System (Obstet. Gynecol. 2015;125:70-8).
ESHRE did not require reports of financial disclosures.
On Twitter @pwendl
LISBON – Advances in assisted reproductive technology (ART) have paid off, nearly halving the rate of ectopic pregnancy in the past 12 years.
The rate of ectopic pregnancy (EP) following ART progressively declined from 20 to 12 cases per thousand in a nationwide analysis of all ART pregnancies achieved in the United Kingdom between 2000 and 2012.
This trend appears to be related to a reduction in the incidence of tubal factor infertility, a lower number of embryos being transferred, and extended embryo culture, Dr. Nikolaos Polyzos said at the annual meeting of the European Society of Human Reproduction and Embryology.
Ectopic pregnancy (EP) is a rare event, occurring in only 2% of all spontaneous conceptions. ART has been consistently associated with higher rates of EP, which is the most common cause of mortality during the first trimester of pregnancy in the U.K., said Dr. Polyzos of the Centre for Reproductive Medicine at Vrije University Brussels.
Using the Human Fertilisation and Embryology Authority (HFEA) database, the investigators identified 684,247 ART cycles in the U.K. between 2000-2012, resulting in 212,877 pregnancies. After exclusion for various reasons including surrogacy, unspecified treatment, or missing data, 161,967 pregnancies were included in the analysis. Of these, 153,115 pregnancies occurred following in-vitro fertilization or intracytoplasmic sperm injection and 8,852 following intrauterine insemination.
The incidence of ectopic pregnancy was 1.4% over the 12-year study period.
In adjusted analyses, the most important independent risk factor for an ectopic pregnancy was tubal factor infertility, which more than doubled the risk (odds ratio, 2.23), Dr. Polyzos said.
Also significant was the number of embryos transferred (two vs. one; OR, 1.28; ≥ three vs. one; OR, 1.67) and extended embryo culture (day 3 vs. day 2; OR, 0.85; day 5 vs. day 2; OR, 0.73).
What this means in everyday clinical practice is that the probability of having an ectopic pregnancy is 29% per 1,000 pregnancies in a patient with tubal infertility if more than one embryo is transferred, he said. In contrast, the risk is more than three times lower at only 8.2% per 1,000 pregnancies in a patient who has a partner with male infertility and a single blastocyst transferred.
Details from the HFEA database showed that the proportion of infertile patients with tubal disease having ART progressively declined from 24% in 2000 to 12% in 2012. Tubal factor infertility accounts for about 14% of all infertility and is typically the result of Chlamydia trachomatis infection.
“Future efforts should promote national screening programs like the U.K.’s National Chlamydia Screening Programme. Although there is a discussion on how effective it is, I think it is very important we increase the uptake of these programs,” Dr. Polyzos said.
Efforts to promote widespread introduction of single-embryo transfer, which have been widely adopted in his own country, but less so in the United States, would lower the risk of EP even further, he added.
A recent U.S. analysis looking at the risk of EP associated with ART found that the rate of ectopic pregnancy was 1.6% when one embryo was transferred and 1.7%, 2.2%, and 2.5% when two, three, or four or more embryos were transferred, respectively. Overall, the EP rate declined from 2% in 2001 to 1.6% in 2011 based on 553,577 pregnancies reported during those years to the U.S. National ART Surveillance System (Obstet. Gynecol. 2015;125:70-8).
ESHRE did not require reports of financial disclosures.
On Twitter @pwendl
LISBON – Advances in assisted reproductive technology (ART) have paid off, nearly halving the rate of ectopic pregnancy in the past 12 years.
The rate of ectopic pregnancy (EP) following ART progressively declined from 20 to 12 cases per thousand in a nationwide analysis of all ART pregnancies achieved in the United Kingdom between 2000 and 2012.
This trend appears to be related to a reduction in the incidence of tubal factor infertility, a lower number of embryos being transferred, and extended embryo culture, Dr. Nikolaos Polyzos said at the annual meeting of the European Society of Human Reproduction and Embryology.
Ectopic pregnancy (EP) is a rare event, occurring in only 2% of all spontaneous conceptions. ART has been consistently associated with higher rates of EP, which is the most common cause of mortality during the first trimester of pregnancy in the U.K., said Dr. Polyzos of the Centre for Reproductive Medicine at Vrije University Brussels.
Using the Human Fertilisation and Embryology Authority (HFEA) database, the investigators identified 684,247 ART cycles in the U.K. between 2000-2012, resulting in 212,877 pregnancies. After exclusion for various reasons including surrogacy, unspecified treatment, or missing data, 161,967 pregnancies were included in the analysis. Of these, 153,115 pregnancies occurred following in-vitro fertilization or intracytoplasmic sperm injection and 8,852 following intrauterine insemination.
The incidence of ectopic pregnancy was 1.4% over the 12-year study period.
In adjusted analyses, the most important independent risk factor for an ectopic pregnancy was tubal factor infertility, which more than doubled the risk (odds ratio, 2.23), Dr. Polyzos said.
Also significant was the number of embryos transferred (two vs. one; OR, 1.28; ≥ three vs. one; OR, 1.67) and extended embryo culture (day 3 vs. day 2; OR, 0.85; day 5 vs. day 2; OR, 0.73).
What this means in everyday clinical practice is that the probability of having an ectopic pregnancy is 29% per 1,000 pregnancies in a patient with tubal infertility if more than one embryo is transferred, he said. In contrast, the risk is more than three times lower at only 8.2% per 1,000 pregnancies in a patient who has a partner with male infertility and a single blastocyst transferred.
Details from the HFEA database showed that the proportion of infertile patients with tubal disease having ART progressively declined from 24% in 2000 to 12% in 2012. Tubal factor infertility accounts for about 14% of all infertility and is typically the result of Chlamydia trachomatis infection.
“Future efforts should promote national screening programs like the U.K.’s National Chlamydia Screening Programme. Although there is a discussion on how effective it is, I think it is very important we increase the uptake of these programs,” Dr. Polyzos said.
Efforts to promote widespread introduction of single-embryo transfer, which have been widely adopted in his own country, but less so in the United States, would lower the risk of EP even further, he added.
A recent U.S. analysis looking at the risk of EP associated with ART found that the rate of ectopic pregnancy was 1.6% when one embryo was transferred and 1.7%, 2.2%, and 2.5% when two, three, or four or more embryos were transferred, respectively. Overall, the EP rate declined from 2% in 2001 to 1.6% in 2011 based on 553,577 pregnancies reported during those years to the U.S. National ART Surveillance System (Obstet. Gynecol. 2015;125:70-8).
ESHRE did not require reports of financial disclosures.
On Twitter @pwendl
AT ESHRE 2015
Key clinical point: The rate of ectopic pregnancy following conception with assisted reproductive technology has almost halved in the past 12 years.
Major finding: The rate of ectopic pregnancy following ART declined from 20 to 12 cases per thousand between 2000 and 2012.
Data source: Registry analysis of 161,967 ART pregnancies.
Disclosures: ESHRE did not require reports of financial disclosures.
ESHRE: ART Does Not Hurt Academic Performance in Teens
LISBON – Conception by assisted reproductive technology is not associated with lower academic performance in adolescence, a large nationwide analysis showed.
In crude analyses, ART singletons had higher academic performance than spontaneously conceived singletons and ART twins performed as well as ART singletons. After adjustment for confounders, academic performance was similar between all singletons and between ART twins and ART singletons.
“These findings are very reassuring for the parents of ART children and for the ART society as a whole,” study author Anne Lærke Spangmose Pedersen said at the annual meeting of the European Society of Human Reproduction and Embryology.
ART children and twins in general have an increased risk of preterm delivery and low birth weight, but only a handful of studies have explored IQ in these children.
A recent study (BJOG 2014;121:1642-51) reported similar IQ, attention, and executive function in ART and non-ART children at age 5 years; however, no previous studies have included ninth-grade test scores in a complete national cohort of adolescents all conceived by ART, noted Ms. Pedersen, a medical student at Copenhagen University Hospital, Hvidovre, Denmark.
To do this, the investigators used compulsory national registers and the Danish IVF and Medical Birth Registry to identify 10,429 individuals born in Denmark from 1995 to 1998. This included all children conceived by ART (fresh embryo in-vitro fertilization and intracytoplasmic sperm injection), totaling 2,838 singletons and 1,930 twins, and a random sample of 5,661 non-ART singletons.
The primary outcome was the mean test score on the National Test, which is used for university entrance and completed by all ninth-grade students in Denmark at ages 15-16 years. Mandatory subjects include Danish, foreign languages, mathematics, and physics/chemistry, with scores ranging from –3 to +12 (mean 7). Scores were available for 2,544 ART singletons, 4,985 non-ART singletons, and 1,676 ART twins.
The mean test scores were 7.16 in ART singletons, 6.74 in non-ART singletons, and 7.21 in ART twins. The difference was statistically significant between ART and non-ART singletons (P < .001), but not between ART singletons and twins (P = .47), Ms. Pedersen said.
After adjustment for a variety of factors, including maternal age and socioeconomic status, which tend to be higher in ART families, the difference did not persist, she said.
“It’s not the final conclusion, but I think the data at this moment are reassuring,” session comoderator Dr. Willianne Nelenof Radboud University Nijmegen (the Netherlands) Medical Centre said in an interview. Like members of the audience, she said that data should be pooled from studies and that more data are needed from ART children and parents.
During the discussion of the results, Ms. Pedersen noted that preterm birth rates were significantly higher in ART singletons than non-ART singletons (4.6% vs. 2.7%; P < .001) and in ART twins, compared with ART singletons (22.8% vs. 4.6%; P < .001).
Ms. Pedersen reported having no financial disclosures.
LISBON – Conception by assisted reproductive technology is not associated with lower academic performance in adolescence, a large nationwide analysis showed.
In crude analyses, ART singletons had higher academic performance than spontaneously conceived singletons and ART twins performed as well as ART singletons. After adjustment for confounders, academic performance was similar between all singletons and between ART twins and ART singletons.
“These findings are very reassuring for the parents of ART children and for the ART society as a whole,” study author Anne Lærke Spangmose Pedersen said at the annual meeting of the European Society of Human Reproduction and Embryology.
ART children and twins in general have an increased risk of preterm delivery and low birth weight, but only a handful of studies have explored IQ in these children.
A recent study (BJOG 2014;121:1642-51) reported similar IQ, attention, and executive function in ART and non-ART children at age 5 years; however, no previous studies have included ninth-grade test scores in a complete national cohort of adolescents all conceived by ART, noted Ms. Pedersen, a medical student at Copenhagen University Hospital, Hvidovre, Denmark.
To do this, the investigators used compulsory national registers and the Danish IVF and Medical Birth Registry to identify 10,429 individuals born in Denmark from 1995 to 1998. This included all children conceived by ART (fresh embryo in-vitro fertilization and intracytoplasmic sperm injection), totaling 2,838 singletons and 1,930 twins, and a random sample of 5,661 non-ART singletons.
The primary outcome was the mean test score on the National Test, which is used for university entrance and completed by all ninth-grade students in Denmark at ages 15-16 years. Mandatory subjects include Danish, foreign languages, mathematics, and physics/chemistry, with scores ranging from –3 to +12 (mean 7). Scores were available for 2,544 ART singletons, 4,985 non-ART singletons, and 1,676 ART twins.
The mean test scores were 7.16 in ART singletons, 6.74 in non-ART singletons, and 7.21 in ART twins. The difference was statistically significant between ART and non-ART singletons (P < .001), but not between ART singletons and twins (P = .47), Ms. Pedersen said.
After adjustment for a variety of factors, including maternal age and socioeconomic status, which tend to be higher in ART families, the difference did not persist, she said.
“It’s not the final conclusion, but I think the data at this moment are reassuring,” session comoderator Dr. Willianne Nelenof Radboud University Nijmegen (the Netherlands) Medical Centre said in an interview. Like members of the audience, she said that data should be pooled from studies and that more data are needed from ART children and parents.
During the discussion of the results, Ms. Pedersen noted that preterm birth rates were significantly higher in ART singletons than non-ART singletons (4.6% vs. 2.7%; P < .001) and in ART twins, compared with ART singletons (22.8% vs. 4.6%; P < .001).
Ms. Pedersen reported having no financial disclosures.
LISBON – Conception by assisted reproductive technology is not associated with lower academic performance in adolescence, a large nationwide analysis showed.
In crude analyses, ART singletons had higher academic performance than spontaneously conceived singletons and ART twins performed as well as ART singletons. After adjustment for confounders, academic performance was similar between all singletons and between ART twins and ART singletons.
“These findings are very reassuring for the parents of ART children and for the ART society as a whole,” study author Anne Lærke Spangmose Pedersen said at the annual meeting of the European Society of Human Reproduction and Embryology.
ART children and twins in general have an increased risk of preterm delivery and low birth weight, but only a handful of studies have explored IQ in these children.
A recent study (BJOG 2014;121:1642-51) reported similar IQ, attention, and executive function in ART and non-ART children at age 5 years; however, no previous studies have included ninth-grade test scores in a complete national cohort of adolescents all conceived by ART, noted Ms. Pedersen, a medical student at Copenhagen University Hospital, Hvidovre, Denmark.
To do this, the investigators used compulsory national registers and the Danish IVF and Medical Birth Registry to identify 10,429 individuals born in Denmark from 1995 to 1998. This included all children conceived by ART (fresh embryo in-vitro fertilization and intracytoplasmic sperm injection), totaling 2,838 singletons and 1,930 twins, and a random sample of 5,661 non-ART singletons.
The primary outcome was the mean test score on the National Test, which is used for university entrance and completed by all ninth-grade students in Denmark at ages 15-16 years. Mandatory subjects include Danish, foreign languages, mathematics, and physics/chemistry, with scores ranging from –3 to +12 (mean 7). Scores were available for 2,544 ART singletons, 4,985 non-ART singletons, and 1,676 ART twins.
The mean test scores were 7.16 in ART singletons, 6.74 in non-ART singletons, and 7.21 in ART twins. The difference was statistically significant between ART and non-ART singletons (P < .001), but not between ART singletons and twins (P = .47), Ms. Pedersen said.
After adjustment for a variety of factors, including maternal age and socioeconomic status, which tend to be higher in ART families, the difference did not persist, she said.
“It’s not the final conclusion, but I think the data at this moment are reassuring,” session comoderator Dr. Willianne Nelenof Radboud University Nijmegen (the Netherlands) Medical Centre said in an interview. Like members of the audience, she said that data should be pooled from studies and that more data are needed from ART children and parents.
During the discussion of the results, Ms. Pedersen noted that preterm birth rates were significantly higher in ART singletons than non-ART singletons (4.6% vs. 2.7%; P < .001) and in ART twins, compared with ART singletons (22.8% vs. 4.6%; P < .001).
Ms. Pedersen reported having no financial disclosures.
AT ESHRE 2015
ESHRE: ART does not hurt academic performance in teens
LISBON – Conception by assisted reproductive technology is not associated with lower academic performance in adolescence, a large nationwide analysis showed.
In crude analyses, ART singletons had higher academic performance than spontaneously conceived singletons and ART twins performed as well as ART singletons. After adjustment for confounders, academic performance was similar between all singletons and between ART twins and ART singletons.
“These findings are very reassuring for the parents of ART children and for the ART society as a whole,” study author Anne Lærke Spangmose Pedersen said at the annual meeting of the European Society of Human Reproduction and Embryology.
ART children and twins in general have an increased risk of preterm delivery and low birth weight, but only a handful of studies have explored IQ in these children.
A recent study (BJOG 2014;121:1642-51) reported similar IQ, attention, and executive function in ART and non-ART children at age 5 years; however, no previous studies have included ninth-grade test scores in a complete national cohort of adolescents all conceived by ART, noted Ms. Pedersen, a medical student at Copenhagen University Hospital, Hvidovre, Denmark.
To do this, the investigators used compulsory national registers and the Danish IVF and Medical Birth Registry to identify 10,429 individuals born in Denmark from 1995 to 1998. This included all children conceived by ART (fresh embryo in-vitro fertilization and intracytoplasmic sperm injection), totaling 2,838 singletons and 1,930 twins, and a random sample of 5,661 non-ART singletons.
The primary outcome was the mean test score on the National Test, which is used for university entrance and completed by all ninth-grade students in Denmark at ages 15-16 years. Mandatory subjects include Danish, foreign languages, mathematics, and physics/chemistry, with scores ranging from –3 to +12 (mean 7). Scores were available for 2,544 ART singletons, 4,985 non-ART singletons, and 1,676 ART twins.
The mean test scores were 7.16 in ART singletons, 6.74 in non-ART singletons, and 7.21 in ART twins. The difference was statistically significant between ART and non-ART singletons (P < .001), but not between ART singletons and twins (P = .47), Ms. Pedersen said.
After adjustment for a variety of factors, including maternal age and socioeconomic status, which tend to be higher in ART families, the difference did not persist, she said.
“It’s not the final conclusion, but I think the data at this moment are reassuring,” session comoderator Dr. Willianne Nelenof Radboud University Nijmegen (the Netherlands) Medical Centre said in an interview. Like members of the audience, she said that data should be pooled from studies and that more data are needed from ART children and parents.
During the discussion of the results, Ms. Pedersen noted that preterm birth rates were significantly higher in ART singletons than non-ART singletons (4.6% vs. 2.7%; P < .001) and in ART twins, compared with ART singletons (22.8% vs. 4.6%; P < .001).
Ms. Pedersen reported having no financial disclosures.
On Twitter @pwendl
LISBON – Conception by assisted reproductive technology is not associated with lower academic performance in adolescence, a large nationwide analysis showed.
In crude analyses, ART singletons had higher academic performance than spontaneously conceived singletons and ART twins performed as well as ART singletons. After adjustment for confounders, academic performance was similar between all singletons and between ART twins and ART singletons.
“These findings are very reassuring for the parents of ART children and for the ART society as a whole,” study author Anne Lærke Spangmose Pedersen said at the annual meeting of the European Society of Human Reproduction and Embryology.
ART children and twins in general have an increased risk of preterm delivery and low birth weight, but only a handful of studies have explored IQ in these children.
A recent study (BJOG 2014;121:1642-51) reported similar IQ, attention, and executive function in ART and non-ART children at age 5 years; however, no previous studies have included ninth-grade test scores in a complete national cohort of adolescents all conceived by ART, noted Ms. Pedersen, a medical student at Copenhagen University Hospital, Hvidovre, Denmark.
To do this, the investigators used compulsory national registers and the Danish IVF and Medical Birth Registry to identify 10,429 individuals born in Denmark from 1995 to 1998. This included all children conceived by ART (fresh embryo in-vitro fertilization and intracytoplasmic sperm injection), totaling 2,838 singletons and 1,930 twins, and a random sample of 5,661 non-ART singletons.
The primary outcome was the mean test score on the National Test, which is used for university entrance and completed by all ninth-grade students in Denmark at ages 15-16 years. Mandatory subjects include Danish, foreign languages, mathematics, and physics/chemistry, with scores ranging from –3 to +12 (mean 7). Scores were available for 2,544 ART singletons, 4,985 non-ART singletons, and 1,676 ART twins.
The mean test scores were 7.16 in ART singletons, 6.74 in non-ART singletons, and 7.21 in ART twins. The difference was statistically significant between ART and non-ART singletons (P < .001), but not between ART singletons and twins (P = .47), Ms. Pedersen said.
After adjustment for a variety of factors, including maternal age and socioeconomic status, which tend to be higher in ART families, the difference did not persist, she said.
“It’s not the final conclusion, but I think the data at this moment are reassuring,” session comoderator Dr. Willianne Nelenof Radboud University Nijmegen (the Netherlands) Medical Centre said in an interview. Like members of the audience, she said that data should be pooled from studies and that more data are needed from ART children and parents.
During the discussion of the results, Ms. Pedersen noted that preterm birth rates were significantly higher in ART singletons than non-ART singletons (4.6% vs. 2.7%; P < .001) and in ART twins, compared with ART singletons (22.8% vs. 4.6%; P < .001).
Ms. Pedersen reported having no financial disclosures.
On Twitter @pwendl
LISBON – Conception by assisted reproductive technology is not associated with lower academic performance in adolescence, a large nationwide analysis showed.
In crude analyses, ART singletons had higher academic performance than spontaneously conceived singletons and ART twins performed as well as ART singletons. After adjustment for confounders, academic performance was similar between all singletons and between ART twins and ART singletons.
“These findings are very reassuring for the parents of ART children and for the ART society as a whole,” study author Anne Lærke Spangmose Pedersen said at the annual meeting of the European Society of Human Reproduction and Embryology.
ART children and twins in general have an increased risk of preterm delivery and low birth weight, but only a handful of studies have explored IQ in these children.
A recent study (BJOG 2014;121:1642-51) reported similar IQ, attention, and executive function in ART and non-ART children at age 5 years; however, no previous studies have included ninth-grade test scores in a complete national cohort of adolescents all conceived by ART, noted Ms. Pedersen, a medical student at Copenhagen University Hospital, Hvidovre, Denmark.
To do this, the investigators used compulsory national registers and the Danish IVF and Medical Birth Registry to identify 10,429 individuals born in Denmark from 1995 to 1998. This included all children conceived by ART (fresh embryo in-vitro fertilization and intracytoplasmic sperm injection), totaling 2,838 singletons and 1,930 twins, and a random sample of 5,661 non-ART singletons.
The primary outcome was the mean test score on the National Test, which is used for university entrance and completed by all ninth-grade students in Denmark at ages 15-16 years. Mandatory subjects include Danish, foreign languages, mathematics, and physics/chemistry, with scores ranging from –3 to +12 (mean 7). Scores were available for 2,544 ART singletons, 4,985 non-ART singletons, and 1,676 ART twins.
The mean test scores were 7.16 in ART singletons, 6.74 in non-ART singletons, and 7.21 in ART twins. The difference was statistically significant between ART and non-ART singletons (P < .001), but not between ART singletons and twins (P = .47), Ms. Pedersen said.
After adjustment for a variety of factors, including maternal age and socioeconomic status, which tend to be higher in ART families, the difference did not persist, she said.
“It’s not the final conclusion, but I think the data at this moment are reassuring,” session comoderator Dr. Willianne Nelenof Radboud University Nijmegen (the Netherlands) Medical Centre said in an interview. Like members of the audience, she said that data should be pooled from studies and that more data are needed from ART children and parents.
During the discussion of the results, Ms. Pedersen noted that preterm birth rates were significantly higher in ART singletons than non-ART singletons (4.6% vs. 2.7%; P < .001) and in ART twins, compared with ART singletons (22.8% vs. 4.6%; P < .001).
Ms. Pedersen reported having no financial disclosures.
On Twitter @pwendl
AT ESHRE 2015
Key clinical point: Conception by assisted reproductive technology is not associated with poorer academic performance in adolescence.
Major finding: Mean test scores were 7.16 for ART singletons, 6.74 for non-ART singletons, and 7.21 for ART twins.
Data source: Danish national cohort study in 10,429 adolescents.
Disclosures: Ms. Pedersen reported having no financial disclosures.
EHA: Inotuzumab rallies against refractory/relapsed ALL
VIENNA – The investigational agent inotuzumab ozagamicin more than doubled complete remission rates compared with standard therapy in relapsed or refractory acute lymphoblastic leukemia, preliminary results from the INO-VATE study show.
The co-primary endpoint of complete remission or CR with incomplete hematologic recovery (CRi) by independent review was achieved by 80.7% of patients treated with inotuzumab and 33.3% treated with standard of care (SOC) (P < .0001).
Significantly more CR/CRi responders treated with inotuzumab were minimal residual disease (MRD)-negative by multicolor flow cytometry (78.4% vs. 28.1%; P < .0001), Dr. Daniel DeAngelo reported in a late-breaking abstract (LBA2073) at the annual congress of the European Hematology Association.
“The fact that the response rate was astronomically high with a high MRD-negative status really allows this or this should be an opportunity for patients with relapsed/refractory disease,” he said in an interview.
Inotuzumab ozagamicin is an investigational anti-CD22 antibody conjugated to calicheamicin, an antitumor antibiotic. CD22 is expressed on the surface of about 90% of B-cell ALL cells.
Previous phase II studies reported strong initial antitumor activity and safety with inotuzumab in relapsed or refractory ALL, Dr. DeAngelo, of the Dana Farber Cancer Institute in Boston, said.
The ongoing phase III trial randomized 326 patients with relapsed/refractory CD22-positive ALL due for salvage 1 or 2 therapy to inotuzumab or SOC: either the FLAG regimen (fludarabine (Fludara)/cytarabine (Ara-C)/granulocyte colony-stimulating factor), Ara-C plus mitoxantrone (Novantrone), or high-dose Ara-C. The starting dose for inotuzumab was 1.8 mg/m2/cycle and was reduced to 1.5 mg/m2/cycle once CR/CRi was achieved. Patients were stratified by duration of first remission, salvage 1 or 2, and age.
The first 218 randomized patients were included in the intention-to-treat CR/CRi analysis, which was modified after excluding 13 patients from the SOC arm who refused to start treatment.
The patients’ median age was 47 years (ranging up to 79 years), two-thirds were salvage 1, and more than half had a remission duration of less than 12 months, an adverse prognostic feature.
Data for the co-primary endpoint of overall survival in all 326 patients are still blinded and not expected to mature until 2016, Dr. DeAngelo said.
CR/CRi analyses significantly favored inotuzumab in all stratification factors and baseline factors including peripheral blasts and CD22 expression. Cytogenetics are still being evaluated, but 11 of 14 (79%) patients with Philadelphia-positive karyotype achieved a CR or CRi, he said.
Median duration of remission among responders was 4.6 months in the inotuzumab arm and 3.1 months in the SOC arm (hazard ratio, 0.55; P = .016).
Safety assessed in 259 patients who received at least one dose of study drug showed similar incidence of grade 3 or higher adverse events in the inotuzumab and SOC arms (91% vs. 95%). There were 2 fatal events in the SOC arm and 4 in the inotuzumab arm: 2 veno-occlusive disease (VOD)/sinusoidal obstruction syndrome (SOS), both after poststudy transplant, 1 intestinal ischemia/septic shock, and 1 acute respiratory distress syndrome as a terminal event of pneumonia. In multivariate analysis, dual alkylator conditioning was the only significant covariate of VOD/SOS (P = .039), Dr. DeAngelo said.
An audience member chided the author for the short duration of remission, but session co-moderator Dr. Anthony Moorman, of Newcastle University, Newcastle upon Tyne, England, said it is not that concerning because of the aggressive nature of ALL.
“For all patients that have relapsed or refractory adult ALL, their responses are incredibly low. So any kind of complete remission is a major achievement in this patient population, especially if they are refractory or relapse after tyrosine kinase inhibitors or Philadelphia-positive,” he said in an interview.
“When you have an active agent that works with relapsed refractory disease, in this case leukemia, the goal is to move it up front,” Dr. DeAngelo told this publication.
Indeed, updated results presented at the meeting from M.D. Anderson Cancer Center of frontline inotuzumab added to low-intensity chemotherapy (Mini-hyper CVD) in elderly ALL patients were “provocative,” he added. CR rates reached 97% in the study, according to the abstract (S114).
VIENNA – The investigational agent inotuzumab ozagamicin more than doubled complete remission rates compared with standard therapy in relapsed or refractory acute lymphoblastic leukemia, preliminary results from the INO-VATE study show.
The co-primary endpoint of complete remission or CR with incomplete hematologic recovery (CRi) by independent review was achieved by 80.7% of patients treated with inotuzumab and 33.3% treated with standard of care (SOC) (P < .0001).
Significantly more CR/CRi responders treated with inotuzumab were minimal residual disease (MRD)-negative by multicolor flow cytometry (78.4% vs. 28.1%; P < .0001), Dr. Daniel DeAngelo reported in a late-breaking abstract (LBA2073) at the annual congress of the European Hematology Association.
“The fact that the response rate was astronomically high with a high MRD-negative status really allows this or this should be an opportunity for patients with relapsed/refractory disease,” he said in an interview.
Inotuzumab ozagamicin is an investigational anti-CD22 antibody conjugated to calicheamicin, an antitumor antibiotic. CD22 is expressed on the surface of about 90% of B-cell ALL cells.
Previous phase II studies reported strong initial antitumor activity and safety with inotuzumab in relapsed or refractory ALL, Dr. DeAngelo, of the Dana Farber Cancer Institute in Boston, said.
The ongoing phase III trial randomized 326 patients with relapsed/refractory CD22-positive ALL due for salvage 1 or 2 therapy to inotuzumab or SOC: either the FLAG regimen (fludarabine (Fludara)/cytarabine (Ara-C)/granulocyte colony-stimulating factor), Ara-C plus mitoxantrone (Novantrone), or high-dose Ara-C. The starting dose for inotuzumab was 1.8 mg/m2/cycle and was reduced to 1.5 mg/m2/cycle once CR/CRi was achieved. Patients were stratified by duration of first remission, salvage 1 or 2, and age.
The first 218 randomized patients were included in the intention-to-treat CR/CRi analysis, which was modified after excluding 13 patients from the SOC arm who refused to start treatment.
The patients’ median age was 47 years (ranging up to 79 years), two-thirds were salvage 1, and more than half had a remission duration of less than 12 months, an adverse prognostic feature.
Data for the co-primary endpoint of overall survival in all 326 patients are still blinded and not expected to mature until 2016, Dr. DeAngelo said.
CR/CRi analyses significantly favored inotuzumab in all stratification factors and baseline factors including peripheral blasts and CD22 expression. Cytogenetics are still being evaluated, but 11 of 14 (79%) patients with Philadelphia-positive karyotype achieved a CR or CRi, he said.
Median duration of remission among responders was 4.6 months in the inotuzumab arm and 3.1 months in the SOC arm (hazard ratio, 0.55; P = .016).
Safety assessed in 259 patients who received at least one dose of study drug showed similar incidence of grade 3 or higher adverse events in the inotuzumab and SOC arms (91% vs. 95%). There were 2 fatal events in the SOC arm and 4 in the inotuzumab arm: 2 veno-occlusive disease (VOD)/sinusoidal obstruction syndrome (SOS), both after poststudy transplant, 1 intestinal ischemia/septic shock, and 1 acute respiratory distress syndrome as a terminal event of pneumonia. In multivariate analysis, dual alkylator conditioning was the only significant covariate of VOD/SOS (P = .039), Dr. DeAngelo said.
An audience member chided the author for the short duration of remission, but session co-moderator Dr. Anthony Moorman, of Newcastle University, Newcastle upon Tyne, England, said it is not that concerning because of the aggressive nature of ALL.
“For all patients that have relapsed or refractory adult ALL, their responses are incredibly low. So any kind of complete remission is a major achievement in this patient population, especially if they are refractory or relapse after tyrosine kinase inhibitors or Philadelphia-positive,” he said in an interview.
“When you have an active agent that works with relapsed refractory disease, in this case leukemia, the goal is to move it up front,” Dr. DeAngelo told this publication.
Indeed, updated results presented at the meeting from M.D. Anderson Cancer Center of frontline inotuzumab added to low-intensity chemotherapy (Mini-hyper CVD) in elderly ALL patients were “provocative,” he added. CR rates reached 97% in the study, according to the abstract (S114).
VIENNA – The investigational agent inotuzumab ozagamicin more than doubled complete remission rates compared with standard therapy in relapsed or refractory acute lymphoblastic leukemia, preliminary results from the INO-VATE study show.
The co-primary endpoint of complete remission or CR with incomplete hematologic recovery (CRi) by independent review was achieved by 80.7% of patients treated with inotuzumab and 33.3% treated with standard of care (SOC) (P < .0001).
Significantly more CR/CRi responders treated with inotuzumab were minimal residual disease (MRD)-negative by multicolor flow cytometry (78.4% vs. 28.1%; P < .0001), Dr. Daniel DeAngelo reported in a late-breaking abstract (LBA2073) at the annual congress of the European Hematology Association.
“The fact that the response rate was astronomically high with a high MRD-negative status really allows this or this should be an opportunity for patients with relapsed/refractory disease,” he said in an interview.
Inotuzumab ozagamicin is an investigational anti-CD22 antibody conjugated to calicheamicin, an antitumor antibiotic. CD22 is expressed on the surface of about 90% of B-cell ALL cells.
Previous phase II studies reported strong initial antitumor activity and safety with inotuzumab in relapsed or refractory ALL, Dr. DeAngelo, of the Dana Farber Cancer Institute in Boston, said.
The ongoing phase III trial randomized 326 patients with relapsed/refractory CD22-positive ALL due for salvage 1 or 2 therapy to inotuzumab or SOC: either the FLAG regimen (fludarabine (Fludara)/cytarabine (Ara-C)/granulocyte colony-stimulating factor), Ara-C plus mitoxantrone (Novantrone), or high-dose Ara-C. The starting dose for inotuzumab was 1.8 mg/m2/cycle and was reduced to 1.5 mg/m2/cycle once CR/CRi was achieved. Patients were stratified by duration of first remission, salvage 1 or 2, and age.
The first 218 randomized patients were included in the intention-to-treat CR/CRi analysis, which was modified after excluding 13 patients from the SOC arm who refused to start treatment.
The patients’ median age was 47 years (ranging up to 79 years), two-thirds were salvage 1, and more than half had a remission duration of less than 12 months, an adverse prognostic feature.
Data for the co-primary endpoint of overall survival in all 326 patients are still blinded and not expected to mature until 2016, Dr. DeAngelo said.
CR/CRi analyses significantly favored inotuzumab in all stratification factors and baseline factors including peripheral blasts and CD22 expression. Cytogenetics are still being evaluated, but 11 of 14 (79%) patients with Philadelphia-positive karyotype achieved a CR or CRi, he said.
Median duration of remission among responders was 4.6 months in the inotuzumab arm and 3.1 months in the SOC arm (hazard ratio, 0.55; P = .016).
Safety assessed in 259 patients who received at least one dose of study drug showed similar incidence of grade 3 or higher adverse events in the inotuzumab and SOC arms (91% vs. 95%). There were 2 fatal events in the SOC arm and 4 in the inotuzumab arm: 2 veno-occlusive disease (VOD)/sinusoidal obstruction syndrome (SOS), both after poststudy transplant, 1 intestinal ischemia/septic shock, and 1 acute respiratory distress syndrome as a terminal event of pneumonia. In multivariate analysis, dual alkylator conditioning was the only significant covariate of VOD/SOS (P = .039), Dr. DeAngelo said.
An audience member chided the author for the short duration of remission, but session co-moderator Dr. Anthony Moorman, of Newcastle University, Newcastle upon Tyne, England, said it is not that concerning because of the aggressive nature of ALL.
“For all patients that have relapsed or refractory adult ALL, their responses are incredibly low. So any kind of complete remission is a major achievement in this patient population, especially if they are refractory or relapse after tyrosine kinase inhibitors or Philadelphia-positive,” he said in an interview.
“When you have an active agent that works with relapsed refractory disease, in this case leukemia, the goal is to move it up front,” Dr. DeAngelo told this publication.
Indeed, updated results presented at the meeting from M.D. Anderson Cancer Center of frontline inotuzumab added to low-intensity chemotherapy (Mini-hyper CVD) in elderly ALL patients were “provocative,” he added. CR rates reached 97% in the study, according to the abstract (S114).
AT THE EHA CONGRESS
Key clinical point: Inotuzumab ozagamicin shows promise as a new treatment option for relapsed or refractory acute lymphoblastic leukemia.
Major finding: The rate of complete remission or CR with incomplete hematologic recovery was 80.7% with inotuzumab vs. 28.1% with standard of care (P < .0001).
Data source: Randomized, phase III study in the first 218 of 326 patients.
Disclosures: Pfizer sponsored the study and funded editorial assistance supplied by Complete Heathcare Communications. Dr. De Angelo reported research support from Sigma Tau and consulting for Novartis, Sigma Tau, Bristol-Myers Squibb, Amgen, and Pfizer.
