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G-CHOP no better than R-CHOP in previously untreated DLBCL
SAN DIEGO—Substituting obinutuzumab for rituximab in combination with CHOP chemotherapy does not improve outcomes in patients with previously untreated diffuse large B-cell lymphoma (DLBCL), according to a study presented at the 2016 ASH Annual Meeting.
In this phase 3 trial, known as GOYA, researchers compared obinutuzumab plus CHOP (G-CHOP) to rituximab plus CHOP (R-CHOP) in patients with previously untreated DLBCL.
There were no significant differences between the treatment arms with regard to response rates, progression-free survival (PFS), or overall survival (OS).
In addition, grade 3-5 adverse events (AEs) and serious AEs were more common with G-CHOP than with R-CHOP.
“Rituximab plus CHOP remains the standard of care in this setting,” said study investigator Umberto Vitolo, MD, of the Universitaria Città della Salute e della Scienza di Torino in Torino, Italy.
“Further analyses of the data from this trial will inform and shape the direction of future research activities in DLBCL.”
Dr Vitolo presented results from GOYA at ASH as abstract 470.
Obinutuzumab is a glycoengineered, type II, anti-CD20 monoclonal antibody said to have greater direct cell death induction and antibody-dependent cellular cytotoxicity/phagocytosis activity than rituximab.
In the phase 2 GATHER trial, G-CHOP demonstrated manageable toxicity and promising preliminary efficacy in patients with advanced, untreated DLBCL.
So with the phase 3 GOYA trial, researchers wanted to compare G-CHOP to R-CHOP in DLBCL. The trial enrolled 1418 patients (median age 62) with previously untreated DLBCL.
Patients from 207 centers around the world were randomized to receive eight 21-day cycles of obinutuzumab at 1000 mg intravenously on days 1, 8, and 15 in cycle 1 and day 1 in cycles 2 to 8 (n=706) or rituximab at 375 mg/m2 intravenously on day 1 (n=712) in combination with 6 or 8 cycles of CHOP. Preplanned radiotherapy was allowed for bulky or extranodal disease.
Dr Vitolo said baseline characteristics were well balanced between the 2 treatment arms. Cell-of-origin distribution, as assessed by gene-expression profiling, was similar in both arms.
Virtually all (88%) of the patients received more than 90% of the planned cumulative dose of chemotherapy. Antibody dose delays were more common in the G-CHOP arm.
Efficacy
The median follow-up was 29 months.
For the primary endpoint of investigator-assessed PFS, there was no significant difference between the G-CHOP and R-CHOP arms. The 3-year PFS was 69.6% for G-CHOP and 66.9% for R-CHOP (hazard ratio [HR]=0.92, P=0.3868).
There were no clinically meaningful differences observed between the treatment arms in terms of secondary endpoints, including OS, end-of-treatment overall response rate, and complete response rate, with or without PET scanning.
At the end of treatment, the overall response rates, according to CT and PET, were 77.9% in the R-CHOP arm and 77.4% in the G-CHOP arm. The complete response rates were 59.5% and 56.7%, respectively.
The 3-year OS rate was 81.4% in the R-CHOP arm and 81.2% in the G-CHOP arm (HR=1.00, P=0.9982).
In a pre-specified subgroup analysis of investigator-assessed PFS, there was a slight trend toward improved PFS in favor of G-CHOP for patients with GCB DLBCL, with a 3-year PFS of 79% vs 70% for R-CHOP (HR=0.72).
Safety
No new safety signals were identified. Grade 3 or higher AEs and serious AEs were more common in the G-CHOP arm than the R-CHOP arm. The incidence of grade 3-5 AEs was 73.7% and 64.7%, respectively. The incidence of serious AEs was 42.6% and 37.6%, respectively.
Certain grade 3-5 AEs were more common with G-CHOP than R-CHOP, including neutropenia (46.2% vs 38.1%), infusion-related reactions (2.8% vs 0.6%), infections (19.2% vs 15.5%), and thrombocytopenia 4.4% vs 1.4%).
AEs resulting in withdrawal from treatment and AEs with fatal outcomes were slightly more common with G-CHOP than with R-CHOP. AEs leading to withdrawal occurred in 11.9% and 8.5% of patients, respectively.
Fatal AEs (listed by preferred term) in the G-CHOP arm included septic shock (n=6, 0.9%), pneumonia (n=5, 0.7%), death (n=3, 0.4%), pulmonary embolism (n=2, 1.3%), and cerebrovascular accident (n=2, 0.3%).
Fatal AEs in the R-CHOP arm included pneumonia (n=6, 0.9%), sepsis (n=3, 0.4%), cerebrovascular accident (n=2, 0.3%), and death (n=2, 0.3%). 
SAN DIEGO—Substituting obinutuzumab for rituximab in combination with CHOP chemotherapy does not improve outcomes in patients with previously untreated diffuse large B-cell lymphoma (DLBCL), according to a study presented at the 2016 ASH Annual Meeting.
In this phase 3 trial, known as GOYA, researchers compared obinutuzumab plus CHOP (G-CHOP) to rituximab plus CHOP (R-CHOP) in patients with previously untreated DLBCL.
There were no significant differences between the treatment arms with regard to response rates, progression-free survival (PFS), or overall survival (OS).
In addition, grade 3-5 adverse events (AEs) and serious AEs were more common with G-CHOP than with R-CHOP.
“Rituximab plus CHOP remains the standard of care in this setting,” said study investigator Umberto Vitolo, MD, of the Universitaria Città della Salute e della Scienza di Torino in Torino, Italy.
“Further analyses of the data from this trial will inform and shape the direction of future research activities in DLBCL.”
Dr Vitolo presented results from GOYA at ASH as abstract 470.
Obinutuzumab is a glycoengineered, type II, anti-CD20 monoclonal antibody said to have greater direct cell death induction and antibody-dependent cellular cytotoxicity/phagocytosis activity than rituximab.
In the phase 2 GATHER trial, G-CHOP demonstrated manageable toxicity and promising preliminary efficacy in patients with advanced, untreated DLBCL.
So with the phase 3 GOYA trial, researchers wanted to compare G-CHOP to R-CHOP in DLBCL. The trial enrolled 1418 patients (median age 62) with previously untreated DLBCL.
Patients from 207 centers around the world were randomized to receive eight 21-day cycles of obinutuzumab at 1000 mg intravenously on days 1, 8, and 15 in cycle 1 and day 1 in cycles 2 to 8 (n=706) or rituximab at 375 mg/m2 intravenously on day 1 (n=712) in combination with 6 or 8 cycles of CHOP. Preplanned radiotherapy was allowed for bulky or extranodal disease.
Dr Vitolo said baseline characteristics were well balanced between the 2 treatment arms. Cell-of-origin distribution, as assessed by gene-expression profiling, was similar in both arms.
Virtually all (88%) of the patients received more than 90% of the planned cumulative dose of chemotherapy. Antibody dose delays were more common in the G-CHOP arm.
Efficacy
The median follow-up was 29 months.
For the primary endpoint of investigator-assessed PFS, there was no significant difference between the G-CHOP and R-CHOP arms. The 3-year PFS was 69.6% for G-CHOP and 66.9% for R-CHOP (hazard ratio [HR]=0.92, P=0.3868).
There were no clinically meaningful differences observed between the treatment arms in terms of secondary endpoints, including OS, end-of-treatment overall response rate, and complete response rate, with or without PET scanning.
At the end of treatment, the overall response rates, according to CT and PET, were 77.9% in the R-CHOP arm and 77.4% in the G-CHOP arm. The complete response rates were 59.5% and 56.7%, respectively.
The 3-year OS rate was 81.4% in the R-CHOP arm and 81.2% in the G-CHOP arm (HR=1.00, P=0.9982).
In a pre-specified subgroup analysis of investigator-assessed PFS, there was a slight trend toward improved PFS in favor of G-CHOP for patients with GCB DLBCL, with a 3-year PFS of 79% vs 70% for R-CHOP (HR=0.72).
Safety
No new safety signals were identified. Grade 3 or higher AEs and serious AEs were more common in the G-CHOP arm than the R-CHOP arm. The incidence of grade 3-5 AEs was 73.7% and 64.7%, respectively. The incidence of serious AEs was 42.6% and 37.6%, respectively.
Certain grade 3-5 AEs were more common with G-CHOP than R-CHOP, including neutropenia (46.2% vs 38.1%), infusion-related reactions (2.8% vs 0.6%), infections (19.2% vs 15.5%), and thrombocytopenia 4.4% vs 1.4%).
AEs resulting in withdrawal from treatment and AEs with fatal outcomes were slightly more common with G-CHOP than with R-CHOP. AEs leading to withdrawal occurred in 11.9% and 8.5% of patients, respectively.
Fatal AEs (listed by preferred term) in the G-CHOP arm included septic shock (n=6, 0.9%), pneumonia (n=5, 0.7%), death (n=3, 0.4%), pulmonary embolism (n=2, 1.3%), and cerebrovascular accident (n=2, 0.3%).
Fatal AEs in the R-CHOP arm included pneumonia (n=6, 0.9%), sepsis (n=3, 0.4%), cerebrovascular accident (n=2, 0.3%), and death (n=2, 0.3%).
SAN DIEGO—Substituting obinutuzumab for rituximab in combination with CHOP chemotherapy does not improve outcomes in patients with previously untreated diffuse large B-cell lymphoma (DLBCL), according to a study presented at the 2016 ASH Annual Meeting.
In this phase 3 trial, known as GOYA, researchers compared obinutuzumab plus CHOP (G-CHOP) to rituximab plus CHOP (R-CHOP) in patients with previously untreated DLBCL.
There were no significant differences between the treatment arms with regard to response rates, progression-free survival (PFS), or overall survival (OS).
In addition, grade 3-5 adverse events (AEs) and serious AEs were more common with G-CHOP than with R-CHOP.
“Rituximab plus CHOP remains the standard of care in this setting,” said study investigator Umberto Vitolo, MD, of the Universitaria Città della Salute e della Scienza di Torino in Torino, Italy.
“Further analyses of the data from this trial will inform and shape the direction of future research activities in DLBCL.”
Dr Vitolo presented results from GOYA at ASH as abstract 470.
Obinutuzumab is a glycoengineered, type II, anti-CD20 monoclonal antibody said to have greater direct cell death induction and antibody-dependent cellular cytotoxicity/phagocytosis activity than rituximab.
In the phase 2 GATHER trial, G-CHOP demonstrated manageable toxicity and promising preliminary efficacy in patients with advanced, untreated DLBCL.
So with the phase 3 GOYA trial, researchers wanted to compare G-CHOP to R-CHOP in DLBCL. The trial enrolled 1418 patients (median age 62) with previously untreated DLBCL.
Patients from 207 centers around the world were randomized to receive eight 21-day cycles of obinutuzumab at 1000 mg intravenously on days 1, 8, and 15 in cycle 1 and day 1 in cycles 2 to 8 (n=706) or rituximab at 375 mg/m2 intravenously on day 1 (n=712) in combination with 6 or 8 cycles of CHOP. Preplanned radiotherapy was allowed for bulky or extranodal disease.
Dr Vitolo said baseline characteristics were well balanced between the 2 treatment arms. Cell-of-origin distribution, as assessed by gene-expression profiling, was similar in both arms.
Virtually all (88%) of the patients received more than 90% of the planned cumulative dose of chemotherapy. Antibody dose delays were more common in the G-CHOP arm.
Efficacy
The median follow-up was 29 months.
For the primary endpoint of investigator-assessed PFS, there was no significant difference between the G-CHOP and R-CHOP arms. The 3-year PFS was 69.6% for G-CHOP and 66.9% for R-CHOP (hazard ratio [HR]=0.92, P=0.3868).
There were no clinically meaningful differences observed between the treatment arms in terms of secondary endpoints, including OS, end-of-treatment overall response rate, and complete response rate, with or without PET scanning.
At the end of treatment, the overall response rates, according to CT and PET, were 77.9% in the R-CHOP arm and 77.4% in the G-CHOP arm. The complete response rates were 59.5% and 56.7%, respectively.
The 3-year OS rate was 81.4% in the R-CHOP arm and 81.2% in the G-CHOP arm (HR=1.00, P=0.9982).
In a pre-specified subgroup analysis of investigator-assessed PFS, there was a slight trend toward improved PFS in favor of G-CHOP for patients with GCB DLBCL, with a 3-year PFS of 79% vs 70% for R-CHOP (HR=0.72).
Safety
No new safety signals were identified. Grade 3 or higher AEs and serious AEs were more common in the G-CHOP arm than the R-CHOP arm. The incidence of grade 3-5 AEs was 73.7% and 64.7%, respectively. The incidence of serious AEs was 42.6% and 37.6%, respectively.
Certain grade 3-5 AEs were more common with G-CHOP than R-CHOP, including neutropenia (46.2% vs 38.1%), infusion-related reactions (2.8% vs 0.6%), infections (19.2% vs 15.5%), and thrombocytopenia 4.4% vs 1.4%).
AEs resulting in withdrawal from treatment and AEs with fatal outcomes were slightly more common with G-CHOP than with R-CHOP. AEs leading to withdrawal occurred in 11.9% and 8.5% of patients, respectively.
Fatal AEs (listed by preferred term) in the G-CHOP arm included septic shock (n=6, 0.9%), pneumonia (n=5, 0.7%), death (n=3, 0.4%), pulmonary embolism (n=2, 1.3%), and cerebrovascular accident (n=2, 0.3%).
Fatal AEs in the R-CHOP arm included pneumonia (n=6, 0.9%), sepsis (n=3, 0.4%), cerebrovascular accident (n=2, 0.3%), and death (n=2, 0.3%).
Combined checkpoint blockade promising in HL
© Todd Buchanan 2016
SAN DIEGO—Immune checkpoint blockade with nivolumab plus ipilimumab has shown promise in treating hematologic malignancies, particularly classical Hodgkin lymphoma (HL), based on results of the combination cohort of the phase 1 CheckMate 039 study.
Thirty-one heavily pre-treated HL patients achieved an overall response rate (ORR) of 74%, including 6 complete responses.
And in transplant-naïve HL patients, the combination produced an ORR of 67%.
“Most in the room would be familiar with the excellent results that we have seen with monotherapy with nivolumab,” Stephen Ansell, MD, PhD, of the Mayo Clinic in Rochester, Minnesota, said at the 2016 ASH Annual Meeting.
“In classical Hodgkin lymphoma, we’ve seen meaningful and clinically quite stellar results and durable responses.”
“Our plan was, as part of this trial [CheckMate 039], to then move to see whether adding a further checkpoint, ipilimumab, could enhance the results seen with nivolumab.”
Dr Ansell presented the findings for the checkpoint combination as abstract 183. He disclosed research funding from Bristol-Myers Squibb, the company that funded the study.
Checkpoint inhibitors
Nivolumab and ipilimumab are both fully human monoclonal antibodies, but ipilimumab “works in a slightly different fashion from nivolumab,” Dr Ansell said.
Nivolumab targets the programmed death receptor-1 (PD-1) and disrupts PD-1 pathway signaling and restores anti-tumor T-cell function.
Ipilimumab targets cytotoxic T-lymphocyte antigen 4 (CTLA-4) and induces anti-tumor immunity.
The combination has shown superior efficacy, compared to either agent alone, in preclinical studies and a phase 1 trial of patients with advanced melanoma.
So the investigators added a combination cohort to CheckMate 039.
Combination cohort study design
Patients were eligible to enroll if they had relapsed or refractory HL, B-cell non-Hodgkin lymphoma (NHL, including follicular or diffuse large B-cell lymphoma), T-cell NHL (including cutaneous or peripheral T-cell lymphoma), or multiple myeloma (MM).
Patients could not have had prior organ or allogeneic stem cell transplant and no prior immune checkpoint blockade therapy.
Treatment consisted of nivolumab at 3 mg/kg IV plus ipilimumab at 1 mg/kg IV every 3 weeks for 4 doses. The combination phase was followed by nivolumab monotherapy at the same dose every 2 weeks for 2 years.
The primary endpoint was safety and tolerability. Secondary endpoints included investigator-assessed best overall response, duration of response, progression-free survival (PFS), and biomarker analyses.
Patient characteristics
The investigators enrolled 31 HL, 15 B-cell NHL, 11 T-cell NHL, and 7 MM patients. Most patients, Dr Ansell noted, were heavily pretreated.
HL patients were 42% male, 52% had an ECOG status of 1, and they had a median of 4 (range, 2 to 10) prior systemic therapies. Forty-two percent had prior autologous stem cell transplant (ASCT).
“Interestingly, in the Hodgkin cohort, a number of patients had not proceeded to an autologous transplant, but predominantly because these were chemo-refractory or chemo-resistant patients not eligible for a transplant,” Dr Ansell pointed out.
Of the HL patients, 18 were transplant-naïve, 13 were chemo-resistant, 3 were ineligible for ASCT, and 2 declined the procedure.
B-cell NHL patients were 73% male, and 80% had an ECOG status of 1. They had a median of 3 (range, 1 to 16) prior systemic therapies. Seven percent had a prior ASCT.
T-cell NHL patients were 55% male, 73% had an ECOG status of 1, and they had a median of 4 (range, 1 to 11) prior systemic therapies. None had a prior ASCT.
MM patients were 86% male, 71% had an ECOG status of 1, and they had a median of 5 (range, 2 to 20) prior systemic therapies. More than half had a prior ASCT.
Patient disposition
With follow-up approaching a year, more patients with HL are still on treatment (39%) compared with B-cell NHL (13%), T-cell NHL (18%), and MM (0%) patients.
“Of note, however, is that the reasons for going off treatment were predominantly disease progression,” Dr Ansell said.
“The vast majority of patients who came off treatment came off treatment because their disease progressed, and the numbers that came off because of toxicity were relatively low.”
Seven HL patients went off treatment due to disease progression and 2 due to study drug toxicity.
Eleven B-cell NHL patients went off treatment due to disease progression and 2 withdrew due to unrelated adverse events (AEs).
Five T-cell NHL patients went off treatment due to disease progression and 2 due to study drug toxicity.
And 4 MM patients withdrew due to disease progression, 1 due to study drug toxicity, and 1 due to AEs unrelated to the study drug.
About two-thirds of HL patients, over 90% of B-cell NHL patients, about 80% of T-cell NHL patients, and about 70% of MM patients received 90% or more of the intended dose of each drug.
Safety
One patient with primary mediastinal B-cell lymphoma was included in the safety analysis, for a total of 65 patients treated.
“The majority of patients had some degree of adverse event,” Dr Ansell explained. “But if one looks at the grade 3 and 4 adverse events, those were seen in a more modest number of patients, in a minority of patients. And most importantly, if one looks at the adverse events that led to discontinuation, one can see that this was in a significant minority of patients.”
Five patients discontinued due to treatment-related AEs, which were pneumonitis (n=3), pneumonia and pneumonitis (n=1), and diabetic ketoacidosis (n=1).
Overall, 51 patients (78%) experienced an AE; 19 (29%) had a grade 3–4 AE, 14 (22%) had a serious AE, and 5 (8%) discontinued due to an AE.
Of 31 HL patients, 28 (90%) had an AE, 8 (26%) had a grade 3–4 AE, 6 (19%) had a serious AE, and 2 (6%) discontinued due to an AE.
All 11 T-cell NHL patients experienced an AE, 5 patients (45%) a grade 3-4 AE, 4 patients (36%) had a serious AE, and 2 patients (18%) discontinued because of an AE.
About half of B-cell NHL and MM patients experienced an AE, with 1 MM patient discontinuing as a result of it and no B-cell NHL patient discontinuing due to an AE.
“I would highlight that most of the adverse events were, as expected, immunological in nature . . . . ,” Dr Ansell said. “A very modest number of patients had grade 3 and 4 toxicities.”
The most common drug-related AEs of any grade were fatigue (n=17; 26%), pyrexia (n=15; 23%), rash (n=7; 11%), diarrhea (n=12; 18%), and nausea, pneumonitis, cough, and infusion-related reactions, with 9 patients each (14%).
Efficacy
Twenty-three HL patients (74%) achieved an overall response, including 6 patients (19%) with a complete response and 17 (55%) with a partial response. Three patients (10%) had stable disease, and 3 (10%) had relapsed or progressive disease. Response was not reported for 2 patients (6%).
“Most of these responses are durable, and, very encouraging, you can see patients out approaching a year continuing on therapy,” Dr Ansell said.
The ORR in the 18 transplant-naive patients was 67% (n=67).
The median duration of response for HL patients was not reached and ranged from 0.0 to 13.4 months.
B-cell NHL patients had an ORR of 20% (n=3). There were no complete responses and 3 (20%) partial responses. One patient (7%) had stable disease, and 8 (53%) had relapsed or progressive disase. The median duration of partial response was not reached and ranged from 11.0 to 12.7 months.
T-cell NHL patients had an ORR of 9% (n=1). There were no complete responses and 1 (9%) partial response. Four patients (36%) had stable disease, and 3 (27%) had relapsed or progressive disease. The median duration of partial response was not reached and was 3.9 months.
Except for 1 patient with stable disease, MM patients did not respond to therapy.
Biomarker analysis
All 19 HL patients with a known PD-L1 status at baseline saw their tumor burden decrease to below baseline levels. This may be because HL is characterized by high PD-L1 expression and high responsiveness to checkpoint blockade.
Patients with NHL, on the other hand, have a diverse group of tumors characterized by variable PD-L1 expression. Eight of 13 patients with known expression saw their tumor burden decrease with treatment to below baseline.
Encouraged by the results, the investigators believe further investigation of the combination is in order, as the combination, with limited follow-up, achieved a high and durable ORR in HL patients, including those who were transplant-naïve.
© Todd Buchanan 2016
SAN DIEGO—Immune checkpoint blockade with nivolumab plus ipilimumab has shown promise in treating hematologic malignancies, particularly classical Hodgkin lymphoma (HL), based on results of the combination cohort of the phase 1 CheckMate 039 study.
Thirty-one heavily pre-treated HL patients achieved an overall response rate (ORR) of 74%, including 6 complete responses.
And in transplant-naïve HL patients, the combination produced an ORR of 67%.
“Most in the room would be familiar with the excellent results that we have seen with monotherapy with nivolumab,” Stephen Ansell, MD, PhD, of the Mayo Clinic in Rochester, Minnesota, said at the 2016 ASH Annual Meeting.
“In classical Hodgkin lymphoma, we’ve seen meaningful and clinically quite stellar results and durable responses.”
“Our plan was, as part of this trial [CheckMate 039], to then move to see whether adding a further checkpoint, ipilimumab, could enhance the results seen with nivolumab.”
Dr Ansell presented the findings for the checkpoint combination as abstract 183. He disclosed research funding from Bristol-Myers Squibb, the company that funded the study.
Checkpoint inhibitors
Nivolumab and ipilimumab are both fully human monoclonal antibodies, but ipilimumab “works in a slightly different fashion from nivolumab,” Dr Ansell said.
Nivolumab targets the programmed death receptor-1 (PD-1) and disrupts PD-1 pathway signaling and restores anti-tumor T-cell function.
Ipilimumab targets cytotoxic T-lymphocyte antigen 4 (CTLA-4) and induces anti-tumor immunity.
The combination has shown superior efficacy, compared to either agent alone, in preclinical studies and a phase 1 trial of patients with advanced melanoma.
So the investigators added a combination cohort to CheckMate 039.
Combination cohort study design
Patients were eligible to enroll if they had relapsed or refractory HL, B-cell non-Hodgkin lymphoma (NHL, including follicular or diffuse large B-cell lymphoma), T-cell NHL (including cutaneous or peripheral T-cell lymphoma), or multiple myeloma (MM).
Patients could not have had prior organ or allogeneic stem cell transplant and no prior immune checkpoint blockade therapy.
Treatment consisted of nivolumab at 3 mg/kg IV plus ipilimumab at 1 mg/kg IV every 3 weeks for 4 doses. The combination phase was followed by nivolumab monotherapy at the same dose every 2 weeks for 2 years.
The primary endpoint was safety and tolerability. Secondary endpoints included investigator-assessed best overall response, duration of response, progression-free survival (PFS), and biomarker analyses.
Patient characteristics
The investigators enrolled 31 HL, 15 B-cell NHL, 11 T-cell NHL, and 7 MM patients. Most patients, Dr Ansell noted, were heavily pretreated.
HL patients were 42% male, 52% had an ECOG status of 1, and they had a median of 4 (range, 2 to 10) prior systemic therapies. Forty-two percent had prior autologous stem cell transplant (ASCT).
“Interestingly, in the Hodgkin cohort, a number of patients had not proceeded to an autologous transplant, but predominantly because these were chemo-refractory or chemo-resistant patients not eligible for a transplant,” Dr Ansell pointed out.
Of the HL patients, 18 were transplant-naïve, 13 were chemo-resistant, 3 were ineligible for ASCT, and 2 declined the procedure.
B-cell NHL patients were 73% male, and 80% had an ECOG status of 1. They had a median of 3 (range, 1 to 16) prior systemic therapies. Seven percent had a prior ASCT.
T-cell NHL patients were 55% male, 73% had an ECOG status of 1, and they had a median of 4 (range, 1 to 11) prior systemic therapies. None had a prior ASCT.
MM patients were 86% male, 71% had an ECOG status of 1, and they had a median of 5 (range, 2 to 20) prior systemic therapies. More than half had a prior ASCT.
Patient disposition
With follow-up approaching a year, more patients with HL are still on treatment (39%) compared with B-cell NHL (13%), T-cell NHL (18%), and MM (0%) patients.
“Of note, however, is that the reasons for going off treatment were predominantly disease progression,” Dr Ansell said.
“The vast majority of patients who came off treatment came off treatment because their disease progressed, and the numbers that came off because of toxicity were relatively low.”
Seven HL patients went off treatment due to disease progression and 2 due to study drug toxicity.
Eleven B-cell NHL patients went off treatment due to disease progression and 2 withdrew due to unrelated adverse events (AEs).
Five T-cell NHL patients went off treatment due to disease progression and 2 due to study drug toxicity.
And 4 MM patients withdrew due to disease progression, 1 due to study drug toxicity, and 1 due to AEs unrelated to the study drug.
About two-thirds of HL patients, over 90% of B-cell NHL patients, about 80% of T-cell NHL patients, and about 70% of MM patients received 90% or more of the intended dose of each drug.
Safety
One patient with primary mediastinal B-cell lymphoma was included in the safety analysis, for a total of 65 patients treated.
“The majority of patients had some degree of adverse event,” Dr Ansell explained. “But if one looks at the grade 3 and 4 adverse events, those were seen in a more modest number of patients, in a minority of patients. And most importantly, if one looks at the adverse events that led to discontinuation, one can see that this was in a significant minority of patients.”
Five patients discontinued due to treatment-related AEs, which were pneumonitis (n=3), pneumonia and pneumonitis (n=1), and diabetic ketoacidosis (n=1).
Overall, 51 patients (78%) experienced an AE; 19 (29%) had a grade 3–4 AE, 14 (22%) had a serious AE, and 5 (8%) discontinued due to an AE.
Of 31 HL patients, 28 (90%) had an AE, 8 (26%) had a grade 3–4 AE, 6 (19%) had a serious AE, and 2 (6%) discontinued due to an AE.
All 11 T-cell NHL patients experienced an AE, 5 patients (45%) a grade 3-4 AE, 4 patients (36%) had a serious AE, and 2 patients (18%) discontinued because of an AE.
About half of B-cell NHL and MM patients experienced an AE, with 1 MM patient discontinuing as a result of it and no B-cell NHL patient discontinuing due to an AE.
“I would highlight that most of the adverse events were, as expected, immunological in nature . . . . ,” Dr Ansell said. “A very modest number of patients had grade 3 and 4 toxicities.”
The most common drug-related AEs of any grade were fatigue (n=17; 26%), pyrexia (n=15; 23%), rash (n=7; 11%), diarrhea (n=12; 18%), and nausea, pneumonitis, cough, and infusion-related reactions, with 9 patients each (14%).
Efficacy
Twenty-three HL patients (74%) achieved an overall response, including 6 patients (19%) with a complete response and 17 (55%) with a partial response. Three patients (10%) had stable disease, and 3 (10%) had relapsed or progressive disease. Response was not reported for 2 patients (6%).
“Most of these responses are durable, and, very encouraging, you can see patients out approaching a year continuing on therapy,” Dr Ansell said.
The ORR in the 18 transplant-naive patients was 67% (n=67).
The median duration of response for HL patients was not reached and ranged from 0.0 to 13.4 months.
B-cell NHL patients had an ORR of 20% (n=3). There were no complete responses and 3 (20%) partial responses. One patient (7%) had stable disease, and 8 (53%) had relapsed or progressive disase. The median duration of partial response was not reached and ranged from 11.0 to 12.7 months.
T-cell NHL patients had an ORR of 9% (n=1). There were no complete responses and 1 (9%) partial response. Four patients (36%) had stable disease, and 3 (27%) had relapsed or progressive disease. The median duration of partial response was not reached and was 3.9 months.
Except for 1 patient with stable disease, MM patients did not respond to therapy.
Biomarker analysis
All 19 HL patients with a known PD-L1 status at baseline saw their tumor burden decrease to below baseline levels. This may be because HL is characterized by high PD-L1 expression and high responsiveness to checkpoint blockade.
Patients with NHL, on the other hand, have a diverse group of tumors characterized by variable PD-L1 expression. Eight of 13 patients with known expression saw their tumor burden decrease with treatment to below baseline.
Encouraged by the results, the investigators believe further investigation of the combination is in order, as the combination, with limited follow-up, achieved a high and durable ORR in HL patients, including those who were transplant-naïve.
© Todd Buchanan 2016
SAN DIEGO—Immune checkpoint blockade with nivolumab plus ipilimumab has shown promise in treating hematologic malignancies, particularly classical Hodgkin lymphoma (HL), based on results of the combination cohort of the phase 1 CheckMate 039 study.
Thirty-one heavily pre-treated HL patients achieved an overall response rate (ORR) of 74%, including 6 complete responses.
And in transplant-naïve HL patients, the combination produced an ORR of 67%.
“Most in the room would be familiar with the excellent results that we have seen with monotherapy with nivolumab,” Stephen Ansell, MD, PhD, of the Mayo Clinic in Rochester, Minnesota, said at the 2016 ASH Annual Meeting.
“In classical Hodgkin lymphoma, we’ve seen meaningful and clinically quite stellar results and durable responses.”
“Our plan was, as part of this trial [CheckMate 039], to then move to see whether adding a further checkpoint, ipilimumab, could enhance the results seen with nivolumab.”
Dr Ansell presented the findings for the checkpoint combination as abstract 183. He disclosed research funding from Bristol-Myers Squibb, the company that funded the study.
Checkpoint inhibitors
Nivolumab and ipilimumab are both fully human monoclonal antibodies, but ipilimumab “works in a slightly different fashion from nivolumab,” Dr Ansell said.
Nivolumab targets the programmed death receptor-1 (PD-1) and disrupts PD-1 pathway signaling and restores anti-tumor T-cell function.
Ipilimumab targets cytotoxic T-lymphocyte antigen 4 (CTLA-4) and induces anti-tumor immunity.
The combination has shown superior efficacy, compared to either agent alone, in preclinical studies and a phase 1 trial of patients with advanced melanoma.
So the investigators added a combination cohort to CheckMate 039.
Combination cohort study design
Patients were eligible to enroll if they had relapsed or refractory HL, B-cell non-Hodgkin lymphoma (NHL, including follicular or diffuse large B-cell lymphoma), T-cell NHL (including cutaneous or peripheral T-cell lymphoma), or multiple myeloma (MM).
Patients could not have had prior organ or allogeneic stem cell transplant and no prior immune checkpoint blockade therapy.
Treatment consisted of nivolumab at 3 mg/kg IV plus ipilimumab at 1 mg/kg IV every 3 weeks for 4 doses. The combination phase was followed by nivolumab monotherapy at the same dose every 2 weeks for 2 years.
The primary endpoint was safety and tolerability. Secondary endpoints included investigator-assessed best overall response, duration of response, progression-free survival (PFS), and biomarker analyses.
Patient characteristics
The investigators enrolled 31 HL, 15 B-cell NHL, 11 T-cell NHL, and 7 MM patients. Most patients, Dr Ansell noted, were heavily pretreated.
HL patients were 42% male, 52% had an ECOG status of 1, and they had a median of 4 (range, 2 to 10) prior systemic therapies. Forty-two percent had prior autologous stem cell transplant (ASCT).
“Interestingly, in the Hodgkin cohort, a number of patients had not proceeded to an autologous transplant, but predominantly because these were chemo-refractory or chemo-resistant patients not eligible for a transplant,” Dr Ansell pointed out.
Of the HL patients, 18 were transplant-naïve, 13 were chemo-resistant, 3 were ineligible for ASCT, and 2 declined the procedure.
B-cell NHL patients were 73% male, and 80% had an ECOG status of 1. They had a median of 3 (range, 1 to 16) prior systemic therapies. Seven percent had a prior ASCT.
T-cell NHL patients were 55% male, 73% had an ECOG status of 1, and they had a median of 4 (range, 1 to 11) prior systemic therapies. None had a prior ASCT.
MM patients were 86% male, 71% had an ECOG status of 1, and they had a median of 5 (range, 2 to 20) prior systemic therapies. More than half had a prior ASCT.
Patient disposition
With follow-up approaching a year, more patients with HL are still on treatment (39%) compared with B-cell NHL (13%), T-cell NHL (18%), and MM (0%) patients.
“Of note, however, is that the reasons for going off treatment were predominantly disease progression,” Dr Ansell said.
“The vast majority of patients who came off treatment came off treatment because their disease progressed, and the numbers that came off because of toxicity were relatively low.”
Seven HL patients went off treatment due to disease progression and 2 due to study drug toxicity.
Eleven B-cell NHL patients went off treatment due to disease progression and 2 withdrew due to unrelated adverse events (AEs).
Five T-cell NHL patients went off treatment due to disease progression and 2 due to study drug toxicity.
And 4 MM patients withdrew due to disease progression, 1 due to study drug toxicity, and 1 due to AEs unrelated to the study drug.
About two-thirds of HL patients, over 90% of B-cell NHL patients, about 80% of T-cell NHL patients, and about 70% of MM patients received 90% or more of the intended dose of each drug.
Safety
One patient with primary mediastinal B-cell lymphoma was included in the safety analysis, for a total of 65 patients treated.
“The majority of patients had some degree of adverse event,” Dr Ansell explained. “But if one looks at the grade 3 and 4 adverse events, those were seen in a more modest number of patients, in a minority of patients. And most importantly, if one looks at the adverse events that led to discontinuation, one can see that this was in a significant minority of patients.”
Five patients discontinued due to treatment-related AEs, which were pneumonitis (n=3), pneumonia and pneumonitis (n=1), and diabetic ketoacidosis (n=1).
Overall, 51 patients (78%) experienced an AE; 19 (29%) had a grade 3–4 AE, 14 (22%) had a serious AE, and 5 (8%) discontinued due to an AE.
Of 31 HL patients, 28 (90%) had an AE, 8 (26%) had a grade 3–4 AE, 6 (19%) had a serious AE, and 2 (6%) discontinued due to an AE.
All 11 T-cell NHL patients experienced an AE, 5 patients (45%) a grade 3-4 AE, 4 patients (36%) had a serious AE, and 2 patients (18%) discontinued because of an AE.
About half of B-cell NHL and MM patients experienced an AE, with 1 MM patient discontinuing as a result of it and no B-cell NHL patient discontinuing due to an AE.
“I would highlight that most of the adverse events were, as expected, immunological in nature . . . . ,” Dr Ansell said. “A very modest number of patients had grade 3 and 4 toxicities.”
The most common drug-related AEs of any grade were fatigue (n=17; 26%), pyrexia (n=15; 23%), rash (n=7; 11%), diarrhea (n=12; 18%), and nausea, pneumonitis, cough, and infusion-related reactions, with 9 patients each (14%).
Efficacy
Twenty-three HL patients (74%) achieved an overall response, including 6 patients (19%) with a complete response and 17 (55%) with a partial response. Three patients (10%) had stable disease, and 3 (10%) had relapsed or progressive disease. Response was not reported for 2 patients (6%).
“Most of these responses are durable, and, very encouraging, you can see patients out approaching a year continuing on therapy,” Dr Ansell said.
The ORR in the 18 transplant-naive patients was 67% (n=67).
The median duration of response for HL patients was not reached and ranged from 0.0 to 13.4 months.
B-cell NHL patients had an ORR of 20% (n=3). There were no complete responses and 3 (20%) partial responses. One patient (7%) had stable disease, and 8 (53%) had relapsed or progressive disase. The median duration of partial response was not reached and ranged from 11.0 to 12.7 months.
T-cell NHL patients had an ORR of 9% (n=1). There were no complete responses and 1 (9%) partial response. Four patients (36%) had stable disease, and 3 (27%) had relapsed or progressive disease. The median duration of partial response was not reached and was 3.9 months.
Except for 1 patient with stable disease, MM patients did not respond to therapy.
Biomarker analysis
All 19 HL patients with a known PD-L1 status at baseline saw their tumor burden decrease to below baseline levels. This may be because HL is characterized by high PD-L1 expression and high responsiveness to checkpoint blockade.
Patients with NHL, on the other hand, have a diverse group of tumors characterized by variable PD-L1 expression. Eight of 13 patients with known expression saw their tumor burden decrease with treatment to below baseline.
Encouraged by the results, the investigators believe further investigation of the combination is in order, as the combination, with limited follow-up, achieved a high and durable ORR in HL patients, including those who were transplant-naïve.
Drug granted fast track designation for PNH
The US Food and Drug Administration (FDA) has granted fast track designation for the complement C3 inhibitor APL-2.
The designation applies to APL-2 in the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH) who continue to experience hemolysis and require red blood cell transfusions despite receiving therapy with eculizumab.
APL-2 is also being developed as a treatment for PNH patients not previously treated with eculizumab.
The company developing APL-2 is Apellis Pharmaceuticals, Inc.
APL-2 is a synthetic cyclic peptide conjugated to a polyethylene glycol polymer that binds specifically to C3 and C3b, blocking all 3 pathways of complement activation (classical, lectin, and alternative).
According to Apellis, this comprehensive inhibition of complement-mediated pathology may have the potential to control symptoms and modify underlying disease in patients with PNH.
Results from a pair of phase 1 studies of APL-2 in healthy volunteers were recently presented at the 2016 ASH Annual Meeting (abstract 1251).
Now, Apellis is evaluating APL-2 in a pair of phase 1b clinical trials of patients with PNH.
In PADDOCK (NCT02588833), researchers are assessing the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of multiple doses of APL-2 administered by daily subcutaneous injection in patients with PNH who have not received the standard of care in the past.
In PHAROAH (NCT02264639), researchers are assessing the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple doses of APL-2 administered by subcutaneous injection as an add-on to the standard of care in patients with PNH.
About fast track designation
The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.
Through the FDA’s fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the biologic license application or new drug application on a rolling basis as data become available.
Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.
The US Food and Drug Administration (FDA) has granted fast track designation for the complement C3 inhibitor APL-2.
The designation applies to APL-2 in the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH) who continue to experience hemolysis and require red blood cell transfusions despite receiving therapy with eculizumab.
APL-2 is also being developed as a treatment for PNH patients not previously treated with eculizumab.
The company developing APL-2 is Apellis Pharmaceuticals, Inc.
APL-2 is a synthetic cyclic peptide conjugated to a polyethylene glycol polymer that binds specifically to C3 and C3b, blocking all 3 pathways of complement activation (classical, lectin, and alternative).
According to Apellis, this comprehensive inhibition of complement-mediated pathology may have the potential to control symptoms and modify underlying disease in patients with PNH.
Results from a pair of phase 1 studies of APL-2 in healthy volunteers were recently presented at the 2016 ASH Annual Meeting (abstract 1251).
Now, Apellis is evaluating APL-2 in a pair of phase 1b clinical trials of patients with PNH.
In PADDOCK (NCT02588833), researchers are assessing the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of multiple doses of APL-2 administered by daily subcutaneous injection in patients with PNH who have not received the standard of care in the past.
In PHAROAH (NCT02264639), researchers are assessing the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple doses of APL-2 administered by subcutaneous injection as an add-on to the standard of care in patients with PNH.
About fast track designation
The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.
Through the FDA’s fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the biologic license application or new drug application on a rolling basis as data become available.
Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.
The US Food and Drug Administration (FDA) has granted fast track designation for the complement C3 inhibitor APL-2.
The designation applies to APL-2 in the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH) who continue to experience hemolysis and require red blood cell transfusions despite receiving therapy with eculizumab.
APL-2 is also being developed as a treatment for PNH patients not previously treated with eculizumab.
The company developing APL-2 is Apellis Pharmaceuticals, Inc.
APL-2 is a synthetic cyclic peptide conjugated to a polyethylene glycol polymer that binds specifically to C3 and C3b, blocking all 3 pathways of complement activation (classical, lectin, and alternative).
According to Apellis, this comprehensive inhibition of complement-mediated pathology may have the potential to control symptoms and modify underlying disease in patients with PNH.
Results from a pair of phase 1 studies of APL-2 in healthy volunteers were recently presented at the 2016 ASH Annual Meeting (abstract 1251).
Now, Apellis is evaluating APL-2 in a pair of phase 1b clinical trials of patients with PNH.
In PADDOCK (NCT02588833), researchers are assessing the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of multiple doses of APL-2 administered by daily subcutaneous injection in patients with PNH who have not received the standard of care in the past.
In PHAROAH (NCT02264639), researchers are assessing the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple doses of APL-2 administered by subcutaneous injection as an add-on to the standard of care in patients with PNH.
About fast track designation
The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.
Through the FDA’s fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the biologic license application or new drug application on a rolling basis as data become available.
Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.
Malodorous, itchy feet
This patient was suffering from pitted keratolysis and interdigital tinea pedis. Pitted keratolysis is caused by the bacterium Kytococcus sedentarius. Like tinea pedis, moist and sweaty feet provide a great environment for growth of this organism. The patient admitted to having sweaty feet—especially while playing soccer for hours. He also didn’t use shower shoes in the gym shower.
In pitted keratolysis, the bacteria live on the dead cells of the stratum corneum of the sole and form visible pits. In interdigital tinea pedis, the skin between the toes is white in appearance.
The FP recommended that the patient wear shower shoes and change his socks during the day if they become sweaty. He also prescribed topical 2% erythromycin solution to apply twice daily to the area with visible pits. In addition, the FP recommended that the patient buy over-the-counter topical terbinafine cream and apply it between the toes once or twice daily—especially after drying his feet well after a shower. A month later, both infections were clear.
Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Usatine R, Reppa R. Tinea pedis. In: Usatine R, Smith M, Mayeaux EJ, et al, eds. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill; 2013:799-804.
To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/
You can now get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com
This patient was suffering from pitted keratolysis and interdigital tinea pedis. Pitted keratolysis is caused by the bacterium Kytococcus sedentarius. Like tinea pedis, moist and sweaty feet provide a great environment for growth of this organism. The patient admitted to having sweaty feet—especially while playing soccer for hours. He also didn’t use shower shoes in the gym shower.
In pitted keratolysis, the bacteria live on the dead cells of the stratum corneum of the sole and form visible pits. In interdigital tinea pedis, the skin between the toes is white in appearance.
The FP recommended that the patient wear shower shoes and change his socks during the day if they become sweaty. He also prescribed topical 2% erythromycin solution to apply twice daily to the area with visible pits. In addition, the FP recommended that the patient buy over-the-counter topical terbinafine cream and apply it between the toes once or twice daily—especially after drying his feet well after a shower. A month later, both infections were clear.
Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Usatine R, Reppa R. Tinea pedis. In: Usatine R, Smith M, Mayeaux EJ, et al, eds. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill; 2013:799-804.
To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/
You can now get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com
This patient was suffering from pitted keratolysis and interdigital tinea pedis. Pitted keratolysis is caused by the bacterium Kytococcus sedentarius. Like tinea pedis, moist and sweaty feet provide a great environment for growth of this organism. The patient admitted to having sweaty feet—especially while playing soccer for hours. He also didn’t use shower shoes in the gym shower.
In pitted keratolysis, the bacteria live on the dead cells of the stratum corneum of the sole and form visible pits. In interdigital tinea pedis, the skin between the toes is white in appearance.
The FP recommended that the patient wear shower shoes and change his socks during the day if they become sweaty. He also prescribed topical 2% erythromycin solution to apply twice daily to the area with visible pits. In addition, the FP recommended that the patient buy over-the-counter topical terbinafine cream and apply it between the toes once or twice daily—especially after drying his feet well after a shower. A month later, both infections were clear.
Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Usatine R, Reppa R. Tinea pedis. In: Usatine R, Smith M, Mayeaux EJ, et al, eds. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill; 2013:799-804.
To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/
You can now get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com
Pain after hernia repair shows improvement at 6 months
Patients who have undergone open ventral abdominal hernia repair see significant improvements in some self-reported pain measures at 6 or more months after surgery, according to results from a new study.
The investigators, led by Eugene Park, MD, of Northwestern University, Chicago, suggested that the timing of the improvements may have to do with the mesh used in the surgeries.
For their research, published in the January issue of The American Journal of Surgery (2017;213:58-63), Dr. Park and his colleagues recruited 77 patients scheduled for midline incisional ventral hernia repair between 2010 and 2013 (mean age, 54 years; 45% female), who completed detailed pain surveys before surgery and during all postoperative visits; 38 patients completed surveys at least 6 months after surgery. All surgeries were performed by one of the study authors, Gregory A. Dumanian, MD, also of Northwestern.
The investigators used pain surveys from the Patient-Reported Outcomes Measurement Information System (PROMIS), which was developed under the National Institutes of Health. The investigators called the PROMIS surveys, which are computer based, a “rigorous and reliable tool” to measure patient feedback in clinical research and healthcare settings. PROMIS is designed to measure, among other things, how pain impacts a patient’s behavior and interferes with his or her everyday functioning.
Dr. Park and his colleagues reported that the patients with at least 6 months of follow-up saw significant improvement in measures of pain interference (P less than 0.05), though not in pain behavior.
The researchers wrote in their analysis that the mesh used in securing the hernia repair – all patients in the study were treated with some type of mesh – might be why pain scores were seen to improve significantly at around 6 months.
“The changes noted in pain interference at the 4- to 8-month time frame may represent a physiologic change as the mesh solidly integrates and begins to contribute to a patient’s increasing ability to perform tasks.”
The mesh used in the study, the researchers also noted, was narrower than that generally reported for hernia repairs of this type.
Dr. Park and his colleagues described as limitations of their study the relatively small number of patients completing long-term follow-up. Also, the investigators noted, the PROMIS pain interference and pain behavior surveys “were not designed specifically with ventral hernia patients in mind, which may limit the scope of hernia-related symptoms covered” and that data on patients’ use of pain medications was not recorded.
The study authors reported no outside funding or conflicts of interest related to their findings.
Patients who have undergone open ventral abdominal hernia repair see significant improvements in some self-reported pain measures at 6 or more months after surgery, according to results from a new study.
The investigators, led by Eugene Park, MD, of Northwestern University, Chicago, suggested that the timing of the improvements may have to do with the mesh used in the surgeries.
For their research, published in the January issue of The American Journal of Surgery (2017;213:58-63), Dr. Park and his colleagues recruited 77 patients scheduled for midline incisional ventral hernia repair between 2010 and 2013 (mean age, 54 years; 45% female), who completed detailed pain surveys before surgery and during all postoperative visits; 38 patients completed surveys at least 6 months after surgery. All surgeries were performed by one of the study authors, Gregory A. Dumanian, MD, also of Northwestern.
The investigators used pain surveys from the Patient-Reported Outcomes Measurement Information System (PROMIS), which was developed under the National Institutes of Health. The investigators called the PROMIS surveys, which are computer based, a “rigorous and reliable tool” to measure patient feedback in clinical research and healthcare settings. PROMIS is designed to measure, among other things, how pain impacts a patient’s behavior and interferes with his or her everyday functioning.
Dr. Park and his colleagues reported that the patients with at least 6 months of follow-up saw significant improvement in measures of pain interference (P less than 0.05), though not in pain behavior.
The researchers wrote in their analysis that the mesh used in securing the hernia repair – all patients in the study were treated with some type of mesh – might be why pain scores were seen to improve significantly at around 6 months.
“The changes noted in pain interference at the 4- to 8-month time frame may represent a physiologic change as the mesh solidly integrates and begins to contribute to a patient’s increasing ability to perform tasks.”
The mesh used in the study, the researchers also noted, was narrower than that generally reported for hernia repairs of this type.
Dr. Park and his colleagues described as limitations of their study the relatively small number of patients completing long-term follow-up. Also, the investigators noted, the PROMIS pain interference and pain behavior surveys “were not designed specifically with ventral hernia patients in mind, which may limit the scope of hernia-related symptoms covered” and that data on patients’ use of pain medications was not recorded.
The study authors reported no outside funding or conflicts of interest related to their findings.
Patients who have undergone open ventral abdominal hernia repair see significant improvements in some self-reported pain measures at 6 or more months after surgery, according to results from a new study.
The investigators, led by Eugene Park, MD, of Northwestern University, Chicago, suggested that the timing of the improvements may have to do with the mesh used in the surgeries.
For their research, published in the January issue of The American Journal of Surgery (2017;213:58-63), Dr. Park and his colleagues recruited 77 patients scheduled for midline incisional ventral hernia repair between 2010 and 2013 (mean age, 54 years; 45% female), who completed detailed pain surveys before surgery and during all postoperative visits; 38 patients completed surveys at least 6 months after surgery. All surgeries were performed by one of the study authors, Gregory A. Dumanian, MD, also of Northwestern.
The investigators used pain surveys from the Patient-Reported Outcomes Measurement Information System (PROMIS), which was developed under the National Institutes of Health. The investigators called the PROMIS surveys, which are computer based, a “rigorous and reliable tool” to measure patient feedback in clinical research and healthcare settings. PROMIS is designed to measure, among other things, how pain impacts a patient’s behavior and interferes with his or her everyday functioning.
Dr. Park and his colleagues reported that the patients with at least 6 months of follow-up saw significant improvement in measures of pain interference (P less than 0.05), though not in pain behavior.
The researchers wrote in their analysis that the mesh used in securing the hernia repair – all patients in the study were treated with some type of mesh – might be why pain scores were seen to improve significantly at around 6 months.
“The changes noted in pain interference at the 4- to 8-month time frame may represent a physiologic change as the mesh solidly integrates and begins to contribute to a patient’s increasing ability to perform tasks.”
The mesh used in the study, the researchers also noted, was narrower than that generally reported for hernia repairs of this type.
Dr. Park and his colleagues described as limitations of their study the relatively small number of patients completing long-term follow-up. Also, the investigators noted, the PROMIS pain interference and pain behavior surveys “were not designed specifically with ventral hernia patients in mind, which may limit the scope of hernia-related symptoms covered” and that data on patients’ use of pain medications was not recorded.
The study authors reported no outside funding or conflicts of interest related to their findings.
Key clinical point: People undergoing open ventral hernia repair saw significant improvements in self-reported pain starting at about 6 months after their procedures.
Major finding: Reported reductions of pain interference were significant among patients with 6 or more months’ follow-up (P less than .05).
Data source: 77 patients undergoing open ventral hernia repairs who completed validated pain questionnaires pre- and post-surgery; of these, 38 had follow-up of 6 months or longer.
Disclosures: None.
ACOG supports delayed umbilical cord clamping for term infants
The American College of Obstetricians and Gynecologists recommends that umbilical cord clamping be delayed for at least 30-60 seconds after birth in vigorous preterm and term infants.
Since early studies suggested that up to 90% of the blood transfer from the placenta to the newborn after birth happens with an infant’s first few breaths, it has become common practice to clamp the cord within 15-20 seconds after birth.
In 2012, the ACOG Committee on Obstetric Practice recommended use of delayed umbilical cord clamping in preterm infants, but found a lack of evidence in term infants. “However, more recent randomized controlled trials of term and preterm infants as well as physiologic studies of blood volume, oxygenation, and arterial pressure have evaluated the effects of immediate versus delayed umbilical cord clamping (usually defined as cord clamping at least 30-60 seconds after birth),” wrote the members of the College’s Committee on Obstetric Practice in an updated opinion released on Dec. 21.
These studies showed that around 80 mL of blood is transferred from the placenta within 1 minute of birth, which appears to be facilitated by the newborn’s initial breaths. This initial transfer of blood supplies significant quantities of iron – 40-50 mg/kg of body weight - and is associated with a lower risk of iron deficiency during the first year of life (Obstet Gynecol. 2017;129:e5-10).
The committee cited a 2012 systematic review of the data on preterm infants that found a 39% reduction in the number of infants requiring transfusion for anemia when delayed umbilical cord clamping – defined as a delay of 30-180 seconds – was used, compared with immediate clamping. The review also noted a 41% reduction in the incidence of intraventricular hemorrhage and 38% reduction in necrotizing enterocolitis, compared with immediate umbilical cord clamping.
Similarly in term infants, those who had their umbilical cord clamped early showed significantly lower hemoglobin concentrations at birth and were more likely to have iron deficiency at 3-6 months of age, compared with term infants who had delayed clamping.
The committee did note that preterm infants who experienced delayed cord clamping showed higher peak bilirubin levels, compared with early clamping. In term infants, delayed cord clamping was associated with a small increase in the incidence of jaundice requiring phototherapy, although there were no significant differences in the rates of polycythemia or jaundice overall.
“Consequently, obstetrician-gynecologists and other obstetric care providers adopting delayed cord clamping in term infants should ensure that mechanisms are in place to monitor for and treat neonatal jaundice,” the committee members wrote.
With regards to maternal outcomes, there had been concerns that delayed umbilical cord clamping could increase the risk of maternal hemorrhage. But a review of five trials including more than 2,200 women found no sign of an increase in adverse events such as postpartum hemorrhage, increased blood loss at delivery, blood transfusions, or reduced postpartum hemoglobin levels.
“However, when there is increased risk of hemorrhage (e.g., placenta previa or placental abruption), the benefits of delayed umbilical cord clamping need to be balanced with the need for timely hemodynamic stabilization of the woman,” the authors wrote.
The committee found that skin-to-skin care could still take place with delayed umbilical cord clamping, as gravity was not necessary to facilitate the flow of blood from the placenta to the newborn. They also advised that early care of the newborn could still be carried out, including drying and stimulating for the first breath.
Delayed umbilical cord clamping should also not interfere with active management of the third stage of labor, including the use of uterotonic agents after delivery.
The authors reported having no conflicts of interest.
The American College of Obstetricians and Gynecologists recommends that umbilical cord clamping be delayed for at least 30-60 seconds after birth in vigorous preterm and term infants.
Since early studies suggested that up to 90% of the blood transfer from the placenta to the newborn after birth happens with an infant’s first few breaths, it has become common practice to clamp the cord within 15-20 seconds after birth.
In 2012, the ACOG Committee on Obstetric Practice recommended use of delayed umbilical cord clamping in preterm infants, but found a lack of evidence in term infants. “However, more recent randomized controlled trials of term and preterm infants as well as physiologic studies of blood volume, oxygenation, and arterial pressure have evaluated the effects of immediate versus delayed umbilical cord clamping (usually defined as cord clamping at least 30-60 seconds after birth),” wrote the members of the College’s Committee on Obstetric Practice in an updated opinion released on Dec. 21.
These studies showed that around 80 mL of blood is transferred from the placenta within 1 minute of birth, which appears to be facilitated by the newborn’s initial breaths. This initial transfer of blood supplies significant quantities of iron – 40-50 mg/kg of body weight - and is associated with a lower risk of iron deficiency during the first year of life (Obstet Gynecol. 2017;129:e5-10).
The committee cited a 2012 systematic review of the data on preterm infants that found a 39% reduction in the number of infants requiring transfusion for anemia when delayed umbilical cord clamping – defined as a delay of 30-180 seconds – was used, compared with immediate clamping. The review also noted a 41% reduction in the incidence of intraventricular hemorrhage and 38% reduction in necrotizing enterocolitis, compared with immediate umbilical cord clamping.
Similarly in term infants, those who had their umbilical cord clamped early showed significantly lower hemoglobin concentrations at birth and were more likely to have iron deficiency at 3-6 months of age, compared with term infants who had delayed clamping.
The committee did note that preterm infants who experienced delayed cord clamping showed higher peak bilirubin levels, compared with early clamping. In term infants, delayed cord clamping was associated with a small increase in the incidence of jaundice requiring phototherapy, although there were no significant differences in the rates of polycythemia or jaundice overall.
“Consequently, obstetrician-gynecologists and other obstetric care providers adopting delayed cord clamping in term infants should ensure that mechanisms are in place to monitor for and treat neonatal jaundice,” the committee members wrote.
With regards to maternal outcomes, there had been concerns that delayed umbilical cord clamping could increase the risk of maternal hemorrhage. But a review of five trials including more than 2,200 women found no sign of an increase in adverse events such as postpartum hemorrhage, increased blood loss at delivery, blood transfusions, or reduced postpartum hemoglobin levels.
“However, when there is increased risk of hemorrhage (e.g., placenta previa or placental abruption), the benefits of delayed umbilical cord clamping need to be balanced with the need for timely hemodynamic stabilization of the woman,” the authors wrote.
The committee found that skin-to-skin care could still take place with delayed umbilical cord clamping, as gravity was not necessary to facilitate the flow of blood from the placenta to the newborn. They also advised that early care of the newborn could still be carried out, including drying and stimulating for the first breath.
Delayed umbilical cord clamping should also not interfere with active management of the third stage of labor, including the use of uterotonic agents after delivery.
The authors reported having no conflicts of interest.
The American College of Obstetricians and Gynecologists recommends that umbilical cord clamping be delayed for at least 30-60 seconds after birth in vigorous preterm and term infants.
Since early studies suggested that up to 90% of the blood transfer from the placenta to the newborn after birth happens with an infant’s first few breaths, it has become common practice to clamp the cord within 15-20 seconds after birth.
In 2012, the ACOG Committee on Obstetric Practice recommended use of delayed umbilical cord clamping in preterm infants, but found a lack of evidence in term infants. “However, more recent randomized controlled trials of term and preterm infants as well as physiologic studies of blood volume, oxygenation, and arterial pressure have evaluated the effects of immediate versus delayed umbilical cord clamping (usually defined as cord clamping at least 30-60 seconds after birth),” wrote the members of the College’s Committee on Obstetric Practice in an updated opinion released on Dec. 21.
These studies showed that around 80 mL of blood is transferred from the placenta within 1 minute of birth, which appears to be facilitated by the newborn’s initial breaths. This initial transfer of blood supplies significant quantities of iron – 40-50 mg/kg of body weight - and is associated with a lower risk of iron deficiency during the first year of life (Obstet Gynecol. 2017;129:e5-10).
The committee cited a 2012 systematic review of the data on preterm infants that found a 39% reduction in the number of infants requiring transfusion for anemia when delayed umbilical cord clamping – defined as a delay of 30-180 seconds – was used, compared with immediate clamping. The review also noted a 41% reduction in the incidence of intraventricular hemorrhage and 38% reduction in necrotizing enterocolitis, compared with immediate umbilical cord clamping.
Similarly in term infants, those who had their umbilical cord clamped early showed significantly lower hemoglobin concentrations at birth and were more likely to have iron deficiency at 3-6 months of age, compared with term infants who had delayed clamping.
The committee did note that preterm infants who experienced delayed cord clamping showed higher peak bilirubin levels, compared with early clamping. In term infants, delayed cord clamping was associated with a small increase in the incidence of jaundice requiring phototherapy, although there were no significant differences in the rates of polycythemia or jaundice overall.
“Consequently, obstetrician-gynecologists and other obstetric care providers adopting delayed cord clamping in term infants should ensure that mechanisms are in place to monitor for and treat neonatal jaundice,” the committee members wrote.
With regards to maternal outcomes, there had been concerns that delayed umbilical cord clamping could increase the risk of maternal hemorrhage. But a review of five trials including more than 2,200 women found no sign of an increase in adverse events such as postpartum hemorrhage, increased blood loss at delivery, blood transfusions, or reduced postpartum hemoglobin levels.
“However, when there is increased risk of hemorrhage (e.g., placenta previa or placental abruption), the benefits of delayed umbilical cord clamping need to be balanced with the need for timely hemodynamic stabilization of the woman,” the authors wrote.
The committee found that skin-to-skin care could still take place with delayed umbilical cord clamping, as gravity was not necessary to facilitate the flow of blood from the placenta to the newborn. They also advised that early care of the newborn could still be carried out, including drying and stimulating for the first breath.
Delayed umbilical cord clamping should also not interfere with active management of the third stage of labor, including the use of uterotonic agents after delivery.
The authors reported having no conflicts of interest.
Shorter-course antimicrobials do not reduce antimicrobial resistance in AOM
A shorter duration of antimicrobial therapy for acute otitis media (AOM) in children is associated with higher rates of clinical failure and higher symptom scores but without any associated reduction in the rates of antimicrobial resistance or adverse events.
Alejandro Hoberman, MD, of the Children’s Hospital of Pittsburgh at the University of Pittsburgh Medical Center, and his coauthors report the results of a study in which 520 children aged 6-23 months were randomized to either 10 days of amoxicillin-clavulanate therapy, or 5 days of therapy followed by 5 days of placebo.
The children who received the full 10-day course also had lower mean symptom scores in the 6-14 days after initiation of therapy, compared with those who received 5 days of treatment (1.34 vs. 1.61; P = 0.07), while the number of children whose symptom scores decreased by 50% from baseline to the end of treatment was significantly lower in the 5-day group.
However, there were no significant differences between the two groups in the rate of nasopharyngeal colonization pathogens not susceptible to penicillin: 47% in the 10-day group, compared with 44% in the 5-day group (N Engl J Med. 2016 Dec 22;375[25]:2446-56).
Similarly, the rates of recurrence and adverse events were not significantly different between the two groups.
A shorter duration of treatment has been considered as a strategy for reducing the risk of antimicrobial resistance, but clinical trials so far have showed either modest difference favoring the standard duration of treatment, or no difference at all.
“The outcome differences we found were larger than the differences that have been reported previously, mainly because the rates of clinical failure among children who received reduced duration treatment were higher in our trial than in previous trials,” Dr. Hoberman and his associates wrote.
The researchers did note that clinical failure rates were higher among children with greater exposure to other children, and those with infection in both ears rather than a single ear.
The study was supported by the National Institute of Allergy and Infectious Diseases and the National Institutes of Health. Dr. Hoberman and Dr. Judith M. Martin declared consulting fees from Genocea Biosciences, and Dr. Hoberman declared grant support from Ricoh Innovations and holding pending patents for a reduced clavulanate concentration version of amoxicillin–clavulanate potassium, and a method and device for aiding in the diagnosis of otitis media. No other conflicts of interest were declared.
The study of acute otitis media is challenging owing to antibiotic pharmacokinetics, age of the patients, variation in regional pathogens, polymicrobial infection, viral cofactors, antibiotic resistance, status of patients with regard to receipt of PCV7 or PCV13, and a high rate of spontaneous resolution.
The study was not designed to address outcomes in older children, children with less severe acute otitis media or with acute otitis media in one ear, or children with additional risk factors such as cleft palate or trisomy 21. In addition, there is a paucity of studies from resource-poor and low income countries.
But for now, 10 days of amoxicillin-clavulanate for children younger than 2 years of age who have a definite diagnosis of acute otitis media seems to be a reasonable option.
Margaret A. Kenna, MD, MPH, is from the department of otolaryngology and communication enhancement at the Boston Children’s Hospital. These comments are excerpted from an accompanying editorial (N Engl J Med. 2016 Dec 22;375[25]:2492-93). Dr. Kenna declared a grant from Agilis outside the submitted work.
The study of acute otitis media is challenging owing to antibiotic pharmacokinetics, age of the patients, variation in regional pathogens, polymicrobial infection, viral cofactors, antibiotic resistance, status of patients with regard to receipt of PCV7 or PCV13, and a high rate of spontaneous resolution.
The study was not designed to address outcomes in older children, children with less severe acute otitis media or with acute otitis media in one ear, or children with additional risk factors such as cleft palate or trisomy 21. In addition, there is a paucity of studies from resource-poor and low income countries.
But for now, 10 days of amoxicillin-clavulanate for children younger than 2 years of age who have a definite diagnosis of acute otitis media seems to be a reasonable option.
Margaret A. Kenna, MD, MPH, is from the department of otolaryngology and communication enhancement at the Boston Children’s Hospital. These comments are excerpted from an accompanying editorial (N Engl J Med. 2016 Dec 22;375[25]:2492-93). Dr. Kenna declared a grant from Agilis outside the submitted work.
The study of acute otitis media is challenging owing to antibiotic pharmacokinetics, age of the patients, variation in regional pathogens, polymicrobial infection, viral cofactors, antibiotic resistance, status of patients with regard to receipt of PCV7 or PCV13, and a high rate of spontaneous resolution.
The study was not designed to address outcomes in older children, children with less severe acute otitis media or with acute otitis media in one ear, or children with additional risk factors such as cleft palate or trisomy 21. In addition, there is a paucity of studies from resource-poor and low income countries.
But for now, 10 days of amoxicillin-clavulanate for children younger than 2 years of age who have a definite diagnosis of acute otitis media seems to be a reasonable option.
Margaret A. Kenna, MD, MPH, is from the department of otolaryngology and communication enhancement at the Boston Children’s Hospital. These comments are excerpted from an accompanying editorial (N Engl J Med. 2016 Dec 22;375[25]:2492-93). Dr. Kenna declared a grant from Agilis outside the submitted work.
A shorter duration of antimicrobial therapy for acute otitis media (AOM) in children is associated with higher rates of clinical failure and higher symptom scores but without any associated reduction in the rates of antimicrobial resistance or adverse events.
Alejandro Hoberman, MD, of the Children’s Hospital of Pittsburgh at the University of Pittsburgh Medical Center, and his coauthors report the results of a study in which 520 children aged 6-23 months were randomized to either 10 days of amoxicillin-clavulanate therapy, or 5 days of therapy followed by 5 days of placebo.
The children who received the full 10-day course also had lower mean symptom scores in the 6-14 days after initiation of therapy, compared with those who received 5 days of treatment (1.34 vs. 1.61; P = 0.07), while the number of children whose symptom scores decreased by 50% from baseline to the end of treatment was significantly lower in the 5-day group.
However, there were no significant differences between the two groups in the rate of nasopharyngeal colonization pathogens not susceptible to penicillin: 47% in the 10-day group, compared with 44% in the 5-day group (N Engl J Med. 2016 Dec 22;375[25]:2446-56).
Similarly, the rates of recurrence and adverse events were not significantly different between the two groups.
A shorter duration of treatment has been considered as a strategy for reducing the risk of antimicrobial resistance, but clinical trials so far have showed either modest difference favoring the standard duration of treatment, or no difference at all.
“The outcome differences we found were larger than the differences that have been reported previously, mainly because the rates of clinical failure among children who received reduced duration treatment were higher in our trial than in previous trials,” Dr. Hoberman and his associates wrote.
The researchers did note that clinical failure rates were higher among children with greater exposure to other children, and those with infection in both ears rather than a single ear.
The study was supported by the National Institute of Allergy and Infectious Diseases and the National Institutes of Health. Dr. Hoberman and Dr. Judith M. Martin declared consulting fees from Genocea Biosciences, and Dr. Hoberman declared grant support from Ricoh Innovations and holding pending patents for a reduced clavulanate concentration version of amoxicillin–clavulanate potassium, and a method and device for aiding in the diagnosis of otitis media. No other conflicts of interest were declared.
A shorter duration of antimicrobial therapy for acute otitis media (AOM) in children is associated with higher rates of clinical failure and higher symptom scores but without any associated reduction in the rates of antimicrobial resistance or adverse events.
Alejandro Hoberman, MD, of the Children’s Hospital of Pittsburgh at the University of Pittsburgh Medical Center, and his coauthors report the results of a study in which 520 children aged 6-23 months were randomized to either 10 days of amoxicillin-clavulanate therapy, or 5 days of therapy followed by 5 days of placebo.
The children who received the full 10-day course also had lower mean symptom scores in the 6-14 days after initiation of therapy, compared with those who received 5 days of treatment (1.34 vs. 1.61; P = 0.07), while the number of children whose symptom scores decreased by 50% from baseline to the end of treatment was significantly lower in the 5-day group.
However, there were no significant differences between the two groups in the rate of nasopharyngeal colonization pathogens not susceptible to penicillin: 47% in the 10-day group, compared with 44% in the 5-day group (N Engl J Med. 2016 Dec 22;375[25]:2446-56).
Similarly, the rates of recurrence and adverse events were not significantly different between the two groups.
A shorter duration of treatment has been considered as a strategy for reducing the risk of antimicrobial resistance, but clinical trials so far have showed either modest difference favoring the standard duration of treatment, or no difference at all.
“The outcome differences we found were larger than the differences that have been reported previously, mainly because the rates of clinical failure among children who received reduced duration treatment were higher in our trial than in previous trials,” Dr. Hoberman and his associates wrote.
The researchers did note that clinical failure rates were higher among children with greater exposure to other children, and those with infection in both ears rather than a single ear.
The study was supported by the National Institute of Allergy and Infectious Diseases and the National Institutes of Health. Dr. Hoberman and Dr. Judith M. Martin declared consulting fees from Genocea Biosciences, and Dr. Hoberman declared grant support from Ricoh Innovations and holding pending patents for a reduced clavulanate concentration version of amoxicillin–clavulanate potassium, and a method and device for aiding in the diagnosis of otitis media. No other conflicts of interest were declared.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point: A shorter duration of antimicrobial therapy for acute otitis media (AOM) in children is associated with higher rates of clinical failure without a reduction in the rates of antimicrobial resistance.
Major finding: Children who received 5 days of antimicrobial experienced clinical failure rates of 35%, compared with 16% in those who received a full 10-day course.
Data source: Randomized controlled trial in 520 children aged 6-23 months with AOM.
Disclosures: The study was supported by the National Institute of Allergy and Infectious Diseases and the National Institutes of Health. Dr. Hoberman and Dr. Judith M. Martin declared consulting fees from Genocea Biosciences, and Dr. Hoberman declared grant support from Ricoh Innovations and holding pending patents for a reduced clavulanate concentration version of amoxicillin–clavulanate potassium, and a method and device for aiding in the diagnosis of otitis media. No other conflicts of interest were declared.
Coronary revascularization appropriate use criteria updated
For ST segment–elevation myocardial infarction (STEMI) patients presenting between 12 and 24 hours from symptom onset but with no signs of clinical instability, coronary revascularization “may be appropriate,” according to a new report. At the same time, for STEMI patients initially treated with fibrinolysis, revascularization was rated as “appropriate therapy” in the setting of suspected failed fibrinolytic therapy or in stable and asymptomatic patients from 3 to 24 hours after fibrinolysis.
Those are two conclusions contained in a revision of the appropriate use criteria (AUC) for coronary revascularization published on Dec. 21 (J Am Coll Cardiol. doi: 10.1016/j.jacc.2016.10.034).
“This update provides a reassessment of clinical scenarios that the writing group felt to be affected by significant changes in the medical literature or gaps from prior criteria,” Manesh R. Patel, MD, chief of the division of cardiology and codirector of the Duke Heart Center at Duke University, Durham, N.C., and chair of the seven-member writing committee for the document, said in a prepared statement. “The primary objective of the appropriate use criteria is to provide a framework for the assessment of practice patterns that will hopefully improve physician decision making and ultimately lead to better patient outcomes.”
The 22-page document contains 17 clinical scenarios that were scored by a separate committee of 17 experts to indicate whether revascularization in patients with acute coronary syndromes is appropriate, may be appropriate, or is rarely appropriate for the clinical scenario presented. Step-by-step flow charts are included to help use the criteria. “Since publication of the 2012 AUC document (J Am Coll Cardiol. 2012;59:857-81), new guidelines for [STEMI] and non–ST segment elevation myocardial infarction (NSTEMI)/unstable angina have been published with additional focused updates of the [stable ischemic heart disease] guideline and a combined focused update of the percutaneous coronary intervention (PCI) and STEMI guideline,” the writing committee noted. “New clinical trials have been published extending the knowledge and evidence around coronary revascularization, including trials that challenge earlier recommendations about the timing of nonculprit vessel PCI in the setting of STEMI. Additional studies related to coronary artery bypass graft surgery, medical therapy, and diagnostic technologies such as fractional flow reserve (FFR) have emerged as well as analyses from the National Cardiovascular Data Registry (NCDR) on the existing AUC that provide insights into practice patterns, clinical scenarios, and patient features not previously addressed.”
Conclusions in the document include those for nonculprit artery revascularization during the index hospitalization after primary PCI or fibrinolysis. This was rated as “appropriate and reasonable” for patients with one or more severe stenoses and spontaneous or easily provoked ischemia or for asymptomatic patients with ischemic findings on noninvasive testing. Meanwhile, in the presence of an intermediate-severity nonculprit artery stenosis, revascularization was rated as “appropriate therapy” in cases where the fractional flow reserve is at or below 0.80. For patients who are stable and asymptomatic after primary PCI, revascularization was rated as “may be appropriate” for one or more severe stenoses even in the absence of further testing.
The only “rarely appropriate” rating in patients with acute coronary syndromes occurred for asymptomatic patients with intermediate-severity nonculprit artery stenoses in the absence of any additional testing to demonstrate the functional significance of the stenosis.
“As in prior versions of the AUC, these revascularization ratings should be used to reinforce existing management strategies and identify patient populations that need more information to identify the most effective treatments,” the authors concluded. Dr. Patel reported having no financial disclosures.
For ST segment–elevation myocardial infarction (STEMI) patients presenting between 12 and 24 hours from symptom onset but with no signs of clinical instability, coronary revascularization “may be appropriate,” according to a new report. At the same time, for STEMI patients initially treated with fibrinolysis, revascularization was rated as “appropriate therapy” in the setting of suspected failed fibrinolytic therapy or in stable and asymptomatic patients from 3 to 24 hours after fibrinolysis.
Those are two conclusions contained in a revision of the appropriate use criteria (AUC) for coronary revascularization published on Dec. 21 (J Am Coll Cardiol. doi: 10.1016/j.jacc.2016.10.034).
“This update provides a reassessment of clinical scenarios that the writing group felt to be affected by significant changes in the medical literature or gaps from prior criteria,” Manesh R. Patel, MD, chief of the division of cardiology and codirector of the Duke Heart Center at Duke University, Durham, N.C., and chair of the seven-member writing committee for the document, said in a prepared statement. “The primary objective of the appropriate use criteria is to provide a framework for the assessment of practice patterns that will hopefully improve physician decision making and ultimately lead to better patient outcomes.”
The 22-page document contains 17 clinical scenarios that were scored by a separate committee of 17 experts to indicate whether revascularization in patients with acute coronary syndromes is appropriate, may be appropriate, or is rarely appropriate for the clinical scenario presented. Step-by-step flow charts are included to help use the criteria. “Since publication of the 2012 AUC document (J Am Coll Cardiol. 2012;59:857-81), new guidelines for [STEMI] and non–ST segment elevation myocardial infarction (NSTEMI)/unstable angina have been published with additional focused updates of the [stable ischemic heart disease] guideline and a combined focused update of the percutaneous coronary intervention (PCI) and STEMI guideline,” the writing committee noted. “New clinical trials have been published extending the knowledge and evidence around coronary revascularization, including trials that challenge earlier recommendations about the timing of nonculprit vessel PCI in the setting of STEMI. Additional studies related to coronary artery bypass graft surgery, medical therapy, and diagnostic technologies such as fractional flow reserve (FFR) have emerged as well as analyses from the National Cardiovascular Data Registry (NCDR) on the existing AUC that provide insights into practice patterns, clinical scenarios, and patient features not previously addressed.”
Conclusions in the document include those for nonculprit artery revascularization during the index hospitalization after primary PCI or fibrinolysis. This was rated as “appropriate and reasonable” for patients with one or more severe stenoses and spontaneous or easily provoked ischemia or for asymptomatic patients with ischemic findings on noninvasive testing. Meanwhile, in the presence of an intermediate-severity nonculprit artery stenosis, revascularization was rated as “appropriate therapy” in cases where the fractional flow reserve is at or below 0.80. For patients who are stable and asymptomatic after primary PCI, revascularization was rated as “may be appropriate” for one or more severe stenoses even in the absence of further testing.
The only “rarely appropriate” rating in patients with acute coronary syndromes occurred for asymptomatic patients with intermediate-severity nonculprit artery stenoses in the absence of any additional testing to demonstrate the functional significance of the stenosis.
“As in prior versions of the AUC, these revascularization ratings should be used to reinforce existing management strategies and identify patient populations that need more information to identify the most effective treatments,” the authors concluded. Dr. Patel reported having no financial disclosures.
For ST segment–elevation myocardial infarction (STEMI) patients presenting between 12 and 24 hours from symptom onset but with no signs of clinical instability, coronary revascularization “may be appropriate,” according to a new report. At the same time, for STEMI patients initially treated with fibrinolysis, revascularization was rated as “appropriate therapy” in the setting of suspected failed fibrinolytic therapy or in stable and asymptomatic patients from 3 to 24 hours after fibrinolysis.
Those are two conclusions contained in a revision of the appropriate use criteria (AUC) for coronary revascularization published on Dec. 21 (J Am Coll Cardiol. doi: 10.1016/j.jacc.2016.10.034).
“This update provides a reassessment of clinical scenarios that the writing group felt to be affected by significant changes in the medical literature or gaps from prior criteria,” Manesh R. Patel, MD, chief of the division of cardiology and codirector of the Duke Heart Center at Duke University, Durham, N.C., and chair of the seven-member writing committee for the document, said in a prepared statement. “The primary objective of the appropriate use criteria is to provide a framework for the assessment of practice patterns that will hopefully improve physician decision making and ultimately lead to better patient outcomes.”
The 22-page document contains 17 clinical scenarios that were scored by a separate committee of 17 experts to indicate whether revascularization in patients with acute coronary syndromes is appropriate, may be appropriate, or is rarely appropriate for the clinical scenario presented. Step-by-step flow charts are included to help use the criteria. “Since publication of the 2012 AUC document (J Am Coll Cardiol. 2012;59:857-81), new guidelines for [STEMI] and non–ST segment elevation myocardial infarction (NSTEMI)/unstable angina have been published with additional focused updates of the [stable ischemic heart disease] guideline and a combined focused update of the percutaneous coronary intervention (PCI) and STEMI guideline,” the writing committee noted. “New clinical trials have been published extending the knowledge and evidence around coronary revascularization, including trials that challenge earlier recommendations about the timing of nonculprit vessel PCI in the setting of STEMI. Additional studies related to coronary artery bypass graft surgery, medical therapy, and diagnostic technologies such as fractional flow reserve (FFR) have emerged as well as analyses from the National Cardiovascular Data Registry (NCDR) on the existing AUC that provide insights into practice patterns, clinical scenarios, and patient features not previously addressed.”
Conclusions in the document include those for nonculprit artery revascularization during the index hospitalization after primary PCI or fibrinolysis. This was rated as “appropriate and reasonable” for patients with one or more severe stenoses and spontaneous or easily provoked ischemia or for asymptomatic patients with ischemic findings on noninvasive testing. Meanwhile, in the presence of an intermediate-severity nonculprit artery stenosis, revascularization was rated as “appropriate therapy” in cases where the fractional flow reserve is at or below 0.80. For patients who are stable and asymptomatic after primary PCI, revascularization was rated as “may be appropriate” for one or more severe stenoses even in the absence of further testing.
The only “rarely appropriate” rating in patients with acute coronary syndromes occurred for asymptomatic patients with intermediate-severity nonculprit artery stenoses in the absence of any additional testing to demonstrate the functional significance of the stenosis.
“As in prior versions of the AUC, these revascularization ratings should be used to reinforce existing management strategies and identify patient populations that need more information to identify the most effective treatments,” the authors concluded. Dr. Patel reported having no financial disclosures.
FROM THE JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
Initial suboptimal responders to secukinumab usually bloom later
VIENNA – When the occasional patient on secukinumab for moderate to severe psoriasis fails to achieve a PASI 75 response initially, don’t despair: Continuing treatment with the biologic usually gets them over that bar, Christopher E. Griffiths, MD, reported at the annual congress of the European Academy of Dermatology and Venereology.
A new secondary pooled analysis of four phase III, 52-week, pivotal clinical trials of secukinumab (Cosentyx) indicates that more than three-quarters of initial suboptimal responders will go on to achieve a PASI 75 response. Moreover, more than one-third will have a PASI 90 response by week 16, which is sustained through week 52. And almost one in five slow responders will have a PASI 100 response – clear skin – at week 52, according to Dr. Griffiths, professor of dermatology at the University of Manchester, England.
He presented a secondary analysis of four phase III studies: ERASURE (Efficacy of Response and Safety of Two Fixed Secukinumab Regimens in Psoriasis), FEATURE (First Study of Secukinumab in Pre-filled Syringes in Subjects With Chronic Plaque-type Psoriasis: Response at 12 Weeks), FIXTURE (Full Year Investigative Examination of Secukinumab vs. Etanercept Using Two Dosing Regimens to Determine Efficacy in Psoriasis), and JUNCTURE (Judging the Efficacy of Secukinumab in Patients With Psoriasis Using AutoiNjector: a Clinical Trial Evaluating Treatment Results). The analysis was conducted to provide additional perspective on the product labeling statement that treatment discontinuation should be considered in patients who haven’t responded to secukinumab by week 16.
The four studies featured a total of 2,405 patients with moderate to severe psoriasis on secukinumab at the approved dosing schedule.
The key findings: At week 12 – the primary endpoint in the four trials – only 5.2% of patients on secukinumab had not achieved a PASI 75 response. Yet just 4 weeks later, at week 16, 56% of this group had managed to get there. Seventy-seven percent of early non- or partial responders achieved a PASI 75 response at some point during weeks 13-52, and 55% had a PASI 75 response at 52 weeks.
Thirty-five percent of early poor responders achieved PASI 90 at 16 weeks and 37% at 52 weeks. Twelve percent of patients who didn’t get to PASI 75 at 12 weeks had a PASI 100 response by 16 weeks, and nearly 18% did by week 52.
This analysis was supported by secukinumab manufacturer Novartis. Dr. Griffiths reported receiving research funds from and serving as a consultant to Novartis and numerous other pharmaceutical companies.
VIENNA – When the occasional patient on secukinumab for moderate to severe psoriasis fails to achieve a PASI 75 response initially, don’t despair: Continuing treatment with the biologic usually gets them over that bar, Christopher E. Griffiths, MD, reported at the annual congress of the European Academy of Dermatology and Venereology.
A new secondary pooled analysis of four phase III, 52-week, pivotal clinical trials of secukinumab (Cosentyx) indicates that more than three-quarters of initial suboptimal responders will go on to achieve a PASI 75 response. Moreover, more than one-third will have a PASI 90 response by week 16, which is sustained through week 52. And almost one in five slow responders will have a PASI 100 response – clear skin – at week 52, according to Dr. Griffiths, professor of dermatology at the University of Manchester, England.
He presented a secondary analysis of four phase III studies: ERASURE (Efficacy of Response and Safety of Two Fixed Secukinumab Regimens in Psoriasis), FEATURE (First Study of Secukinumab in Pre-filled Syringes in Subjects With Chronic Plaque-type Psoriasis: Response at 12 Weeks), FIXTURE (Full Year Investigative Examination of Secukinumab vs. Etanercept Using Two Dosing Regimens to Determine Efficacy in Psoriasis), and JUNCTURE (Judging the Efficacy of Secukinumab in Patients With Psoriasis Using AutoiNjector: a Clinical Trial Evaluating Treatment Results). The analysis was conducted to provide additional perspective on the product labeling statement that treatment discontinuation should be considered in patients who haven’t responded to secukinumab by week 16.
The four studies featured a total of 2,405 patients with moderate to severe psoriasis on secukinumab at the approved dosing schedule.
The key findings: At week 12 – the primary endpoint in the four trials – only 5.2% of patients on secukinumab had not achieved a PASI 75 response. Yet just 4 weeks later, at week 16, 56% of this group had managed to get there. Seventy-seven percent of early non- or partial responders achieved a PASI 75 response at some point during weeks 13-52, and 55% had a PASI 75 response at 52 weeks.
Thirty-five percent of early poor responders achieved PASI 90 at 16 weeks and 37% at 52 weeks. Twelve percent of patients who didn’t get to PASI 75 at 12 weeks had a PASI 100 response by 16 weeks, and nearly 18% did by week 52.
This analysis was supported by secukinumab manufacturer Novartis. Dr. Griffiths reported receiving research funds from and serving as a consultant to Novartis and numerous other pharmaceutical companies.
VIENNA – When the occasional patient on secukinumab for moderate to severe psoriasis fails to achieve a PASI 75 response initially, don’t despair: Continuing treatment with the biologic usually gets them over that bar, Christopher E. Griffiths, MD, reported at the annual congress of the European Academy of Dermatology and Venereology.
A new secondary pooled analysis of four phase III, 52-week, pivotal clinical trials of secukinumab (Cosentyx) indicates that more than three-quarters of initial suboptimal responders will go on to achieve a PASI 75 response. Moreover, more than one-third will have a PASI 90 response by week 16, which is sustained through week 52. And almost one in five slow responders will have a PASI 100 response – clear skin – at week 52, according to Dr. Griffiths, professor of dermatology at the University of Manchester, England.
He presented a secondary analysis of four phase III studies: ERASURE (Efficacy of Response and Safety of Two Fixed Secukinumab Regimens in Psoriasis), FEATURE (First Study of Secukinumab in Pre-filled Syringes in Subjects With Chronic Plaque-type Psoriasis: Response at 12 Weeks), FIXTURE (Full Year Investigative Examination of Secukinumab vs. Etanercept Using Two Dosing Regimens to Determine Efficacy in Psoriasis), and JUNCTURE (Judging the Efficacy of Secukinumab in Patients With Psoriasis Using AutoiNjector: a Clinical Trial Evaluating Treatment Results). The analysis was conducted to provide additional perspective on the product labeling statement that treatment discontinuation should be considered in patients who haven’t responded to secukinumab by week 16.
The four studies featured a total of 2,405 patients with moderate to severe psoriasis on secukinumab at the approved dosing schedule.
The key findings: At week 12 – the primary endpoint in the four trials – only 5.2% of patients on secukinumab had not achieved a PASI 75 response. Yet just 4 weeks later, at week 16, 56% of this group had managed to get there. Seventy-seven percent of early non- or partial responders achieved a PASI 75 response at some point during weeks 13-52, and 55% had a PASI 75 response at 52 weeks.
Thirty-five percent of early poor responders achieved PASI 90 at 16 weeks and 37% at 52 weeks. Twelve percent of patients who didn’t get to PASI 75 at 12 weeks had a PASI 100 response by 16 weeks, and nearly 18% did by week 52.
This analysis was supported by secukinumab manufacturer Novartis. Dr. Griffiths reported receiving research funds from and serving as a consultant to Novartis and numerous other pharmaceutical companies.
AT THE EADV CONGRESS
Key clinical point:
Major finding: Most psoriasis patients who don’t achieve a PASI 75 response by week 12 on secukinumab will do so by week 16 and will maintain that response through week 52.
Data source: A pooled secondary analysis of PASI response rates in four phase III randomized clinical trials of secukinumab featuring 2,405 patients with moderate to severe psoriasis who were on the biologic for 52 weeks, including the 119 who did not achieve a PASI 75 response by week 12.
Disclosures: This analysis of four phase III clinical trials was sponsored by Novartis, as were the trials. The presenter reported receiving research funding from and serving as a consultant to Novartis and other pharmaceutical companies.
Systemic inflammation expands clinical challenge in IBD
ORLANDO – Prescribing optimal therapy for a patient with inflammatory bowel disease can be challenging under ordinary circumstances, but add an extra-intestinal manifestation and the complexity grows greater still. Until more evidence-based findings emerge to help guide and individualize systemic or combination therapy, one of the advantages of biologics – their ability to target the intestine – can be a drawback when patients present with other manifestations.
To highlight the challenges and propose management strategies, Corey A. Siegel, MD, presented the case of a 45-year-old man seeking care 8 years after a diagnosis of ileocolonic Crohn’s disease. Seven years earlier, after the patient failed 5-aminosalicylic acid medication and prednisone therapy, clinicians prescribed infliximab (Remicade, Janssen) monotherapy. He experienced a “great response,” Dr. Siegel said at the Advances in Inflammatory Bowel Diseases meeting.
“Unfortunately, he had a real-life delayed hypersensitivity reaction 2 years ago with no drug present at trough and good antibodies, equal to 12 on a drug tolerant assay,” added Dr. Siegel, director of the Inflammatory Bowel Disease Center at Dartmouth-Hitchcock Medical Center in Lebanon, N.H., and moderator of a case discussion panel session. So physicians initiated combination therapy with adalimumab (Humira, AbbVie) and methotrexate, but the patient “never felt as good as he did on infliximab, even with weekly dosing.”
A colonoscopy 9 months ago revealed mild to mildly active ileal and ascending colon disease. “So he still has residual disease present, even with weekly dosing of adalimumab,” Dr. Siegel explained. At the time, clinicians prescribed vedolizumab (Entyvio, Takeda) and the patient reported IBD symptom improvement. “He was doing better but not fantastic, and now his joints were bothering him, and they never bothered him before.” The man reported joint pain in his hands, knees, and hips. A more recent, follow-up colonoscopy revealed improvement, although mildly active disease was still present.
Do we need to dose-optimize vedolizumab or is it time to move on here? Dr. Siegel asked an expert panel: Bruce E. Sands, MD, David T. Rubin, MD, and Gary L. Lichtenstein, MD.
Instead of considering a third anti–tumor necrosis factor (anti-TNF) agent when the patient has already not responded fully to others in that class, Dr. Sands suggested ustekinumab (Stelara, Janssen). “It could be that ustekinumab would be a better choice versus dose escalation of vedolizumab, unless you add something to the dose-escalated vedolizumab to treat the arthralgias like celecoxib.”
Next, Dr. Siegel asked if the arthralgias are truly extra-intestinal manifestations of inflammatory bowel disease “or is it what my patients are telling me – what they see all over the Internet – that vedolizumab causes arthralgias or arthropathies?
“That is an important question,” said Dr. Rubin, section chief of gastroenterology, hepatology, and nutrition at the University of Chicago. “My question back to you is when did the joint pain start – right after vedolizumab was initiated? Right after steroids were tapered? Or after the patient was on stable dosing for some time?”
The arthralgias seemed to start right after the patient started vedolizumab, Dr. Siegel said. But when clinicians inquired a little further, the patient reported “it was when he came off the adalimumab that things really started.”
It could be that systemically active infliximab and adalimumab with methotrexate were essentially covering up an extra-intestinal manifestation that was later uncovered with the selective mechanism of vedolizumab, Dr. Rubin said. “If that’s true, I don’t think I would give him more vedolizumab to treat his joint pain – that certainly wouldn’t do it. I would make sure his disease is responding from mucosal view, then I would add methotrexate or even consider sulfasalazine.”
A meeting attendee said that the patient did very well with infliximab, and asked “can we ever go back?”
“Probably not easily,” Dr. Sands said. “For someone with a bona fide delayed hypersensitivity reaction – I wouldn’t go there, and I wouldn’t think that you could.”
Another attendee asked if there is a role for adding another biologic to vedolizumab. “We hope to initiate a study soon looking at combination of biologics, such as vedolizumab with adalimumab, with and without an immunomodulator, Dr. Sands replied. They cover somewhat different targets – so it’s sort of a ‘belts and suspenders approach’ … but there are no data whatsoever [yet].”
Dr. Siegel wrapped up the case discussion with the patient’s outcomes. “We did move him on to ustekinumab. He felt better and his arthralgias went away.”
The meeting was sponsored by the Crohn’s & Colitis Foundation of America.
Dr. Siegel and Dr. Rubin disclosed ties with AbbVie, Janssen, and Takeda. Dr. Sands disclosed ties with AbbVie, Janssen Biotech, and Takeda. Dr. Lichtenstein disclosed ties with AbbVie, Janssen Orthobiotech, and Takeda.
ORLANDO – Prescribing optimal therapy for a patient with inflammatory bowel disease can be challenging under ordinary circumstances, but add an extra-intestinal manifestation and the complexity grows greater still. Until more evidence-based findings emerge to help guide and individualize systemic or combination therapy, one of the advantages of biologics – their ability to target the intestine – can be a drawback when patients present with other manifestations.
To highlight the challenges and propose management strategies, Corey A. Siegel, MD, presented the case of a 45-year-old man seeking care 8 years after a diagnosis of ileocolonic Crohn’s disease. Seven years earlier, after the patient failed 5-aminosalicylic acid medication and prednisone therapy, clinicians prescribed infliximab (Remicade, Janssen) monotherapy. He experienced a “great response,” Dr. Siegel said at the Advances in Inflammatory Bowel Diseases meeting.
“Unfortunately, he had a real-life delayed hypersensitivity reaction 2 years ago with no drug present at trough and good antibodies, equal to 12 on a drug tolerant assay,” added Dr. Siegel, director of the Inflammatory Bowel Disease Center at Dartmouth-Hitchcock Medical Center in Lebanon, N.H., and moderator of a case discussion panel session. So physicians initiated combination therapy with adalimumab (Humira, AbbVie) and methotrexate, but the patient “never felt as good as he did on infliximab, even with weekly dosing.”
A colonoscopy 9 months ago revealed mild to mildly active ileal and ascending colon disease. “So he still has residual disease present, even with weekly dosing of adalimumab,” Dr. Siegel explained. At the time, clinicians prescribed vedolizumab (Entyvio, Takeda) and the patient reported IBD symptom improvement. “He was doing better but not fantastic, and now his joints were bothering him, and they never bothered him before.” The man reported joint pain in his hands, knees, and hips. A more recent, follow-up colonoscopy revealed improvement, although mildly active disease was still present.
Do we need to dose-optimize vedolizumab or is it time to move on here? Dr. Siegel asked an expert panel: Bruce E. Sands, MD, David T. Rubin, MD, and Gary L. Lichtenstein, MD.
Instead of considering a third anti–tumor necrosis factor (anti-TNF) agent when the patient has already not responded fully to others in that class, Dr. Sands suggested ustekinumab (Stelara, Janssen). “It could be that ustekinumab would be a better choice versus dose escalation of vedolizumab, unless you add something to the dose-escalated vedolizumab to treat the arthralgias like celecoxib.”
Next, Dr. Siegel asked if the arthralgias are truly extra-intestinal manifestations of inflammatory bowel disease “or is it what my patients are telling me – what they see all over the Internet – that vedolizumab causes arthralgias or arthropathies?
“That is an important question,” said Dr. Rubin, section chief of gastroenterology, hepatology, and nutrition at the University of Chicago. “My question back to you is when did the joint pain start – right after vedolizumab was initiated? Right after steroids were tapered? Or after the patient was on stable dosing for some time?”
The arthralgias seemed to start right after the patient started vedolizumab, Dr. Siegel said. But when clinicians inquired a little further, the patient reported “it was when he came off the adalimumab that things really started.”
It could be that systemically active infliximab and adalimumab with methotrexate were essentially covering up an extra-intestinal manifestation that was later uncovered with the selective mechanism of vedolizumab, Dr. Rubin said. “If that’s true, I don’t think I would give him more vedolizumab to treat his joint pain – that certainly wouldn’t do it. I would make sure his disease is responding from mucosal view, then I would add methotrexate or even consider sulfasalazine.”
A meeting attendee said that the patient did very well with infliximab, and asked “can we ever go back?”
“Probably not easily,” Dr. Sands said. “For someone with a bona fide delayed hypersensitivity reaction – I wouldn’t go there, and I wouldn’t think that you could.”
Another attendee asked if there is a role for adding another biologic to vedolizumab. “We hope to initiate a study soon looking at combination of biologics, such as vedolizumab with adalimumab, with and without an immunomodulator, Dr. Sands replied. They cover somewhat different targets – so it’s sort of a ‘belts and suspenders approach’ … but there are no data whatsoever [yet].”
Dr. Siegel wrapped up the case discussion with the patient’s outcomes. “We did move him on to ustekinumab. He felt better and his arthralgias went away.”
The meeting was sponsored by the Crohn’s & Colitis Foundation of America.
Dr. Siegel and Dr. Rubin disclosed ties with AbbVie, Janssen, and Takeda. Dr. Sands disclosed ties with AbbVie, Janssen Biotech, and Takeda. Dr. Lichtenstein disclosed ties with AbbVie, Janssen Orthobiotech, and Takeda.
ORLANDO – Prescribing optimal therapy for a patient with inflammatory bowel disease can be challenging under ordinary circumstances, but add an extra-intestinal manifestation and the complexity grows greater still. Until more evidence-based findings emerge to help guide and individualize systemic or combination therapy, one of the advantages of biologics – their ability to target the intestine – can be a drawback when patients present with other manifestations.
To highlight the challenges and propose management strategies, Corey A. Siegel, MD, presented the case of a 45-year-old man seeking care 8 years after a diagnosis of ileocolonic Crohn’s disease. Seven years earlier, after the patient failed 5-aminosalicylic acid medication and prednisone therapy, clinicians prescribed infliximab (Remicade, Janssen) monotherapy. He experienced a “great response,” Dr. Siegel said at the Advances in Inflammatory Bowel Diseases meeting.
“Unfortunately, he had a real-life delayed hypersensitivity reaction 2 years ago with no drug present at trough and good antibodies, equal to 12 on a drug tolerant assay,” added Dr. Siegel, director of the Inflammatory Bowel Disease Center at Dartmouth-Hitchcock Medical Center in Lebanon, N.H., and moderator of a case discussion panel session. So physicians initiated combination therapy with adalimumab (Humira, AbbVie) and methotrexate, but the patient “never felt as good as he did on infliximab, even with weekly dosing.”
A colonoscopy 9 months ago revealed mild to mildly active ileal and ascending colon disease. “So he still has residual disease present, even with weekly dosing of adalimumab,” Dr. Siegel explained. At the time, clinicians prescribed vedolizumab (Entyvio, Takeda) and the patient reported IBD symptom improvement. “He was doing better but not fantastic, and now his joints were bothering him, and they never bothered him before.” The man reported joint pain in his hands, knees, and hips. A more recent, follow-up colonoscopy revealed improvement, although mildly active disease was still present.
Do we need to dose-optimize vedolizumab or is it time to move on here? Dr. Siegel asked an expert panel: Bruce E. Sands, MD, David T. Rubin, MD, and Gary L. Lichtenstein, MD.
Instead of considering a third anti–tumor necrosis factor (anti-TNF) agent when the patient has already not responded fully to others in that class, Dr. Sands suggested ustekinumab (Stelara, Janssen). “It could be that ustekinumab would be a better choice versus dose escalation of vedolizumab, unless you add something to the dose-escalated vedolizumab to treat the arthralgias like celecoxib.”
Next, Dr. Siegel asked if the arthralgias are truly extra-intestinal manifestations of inflammatory bowel disease “or is it what my patients are telling me – what they see all over the Internet – that vedolizumab causes arthralgias or arthropathies?
“That is an important question,” said Dr. Rubin, section chief of gastroenterology, hepatology, and nutrition at the University of Chicago. “My question back to you is when did the joint pain start – right after vedolizumab was initiated? Right after steroids were tapered? Or after the patient was on stable dosing for some time?”
The arthralgias seemed to start right after the patient started vedolizumab, Dr. Siegel said. But when clinicians inquired a little further, the patient reported “it was when he came off the adalimumab that things really started.”
It could be that systemically active infliximab and adalimumab with methotrexate were essentially covering up an extra-intestinal manifestation that was later uncovered with the selective mechanism of vedolizumab, Dr. Rubin said. “If that’s true, I don’t think I would give him more vedolizumab to treat his joint pain – that certainly wouldn’t do it. I would make sure his disease is responding from mucosal view, then I would add methotrexate or even consider sulfasalazine.”
A meeting attendee said that the patient did very well with infliximab, and asked “can we ever go back?”
“Probably not easily,” Dr. Sands said. “For someone with a bona fide delayed hypersensitivity reaction – I wouldn’t go there, and I wouldn’t think that you could.”
Another attendee asked if there is a role for adding another biologic to vedolizumab. “We hope to initiate a study soon looking at combination of biologics, such as vedolizumab with adalimumab, with and without an immunomodulator, Dr. Sands replied. They cover somewhat different targets – so it’s sort of a ‘belts and suspenders approach’ … but there are no data whatsoever [yet].”
Dr. Siegel wrapped up the case discussion with the patient’s outcomes. “We did move him on to ustekinumab. He felt better and his arthralgias went away.”
The meeting was sponsored by the Crohn’s & Colitis Foundation of America.
Dr. Siegel and Dr. Rubin disclosed ties with AbbVie, Janssen, and Takeda. Dr. Sands disclosed ties with AbbVie, Janssen Biotech, and Takeda. Dr. Lichtenstein disclosed ties with AbbVie, Janssen Orthobiotech, and Takeda.
AT AIBD 2016
Key clinical point: Extra-intestinal manifestations of inflammatory bowel disease can leave gastroenterologists wondering about the best approach to treatment.
Major finding: Less gut-specific drug action may actually be better for these patients.
Data source: Panel discussion of challenging cases at AIBD 2016.
Disclosures: Dr. Siegel and Dr. Rubin disclosed ties with AbbVie, Janssen, and Takeda. Dr. Sands disclosed ties with AbbVie, Janssen Biotech, and Takeda. Dr. Lichtenstein disclosed ties with AbbVie, Janssen Orthobiotech, and Takeda.