Sharon Worcester

SAN ANTONIO – The investigational selective PARP-1 and PARP-2 inhibitor veliparib failed to significantly improve progression-free or overall survival, compared with placebo, when added to carboplatin and paclitaxel in patients with BRCA1 or BRCA2 mutations and locally recurrent or metastatic breast cancer in the randomized phase II BROCADE study.

The potent, orally bioavailable drug did, however, show a trend toward improvement on these measures, as well as a significant improvement in overall response-rate findings that warrant further investigation in a phase III trial, Hyo Han, MD, said at the San Antonio Breast Cancer Symposium.

Patients were randomized to receive placebo (98 patients) or 120 mg veliparib twice daily on days 1-7 (95 patients) in addition to carboplatin and 175 mg/m² of paclitaxel every 3 weeks.

Median progression-free survival – the primary endpoint of the study – was 12.3 months in the placebo group and 14.1 months in the veliparib group (hazard ratio, 0.789), and overall survival was 25.9 and 28.3 months, respectively (HR, 0.750), said Dr. Han of Moffitt Cancer Center, Tampa, Fla.

The overall response rate was 61.3% vs. 77.8% in the groups, respectively.

Although the study did not meet its primary endpoint, the findings are encouraging as it was powered to detect only dramatic differences between the groups, Dr. Han said.

In a video interview, she discussed veliparib, its safety, the BROCADE findings – including data from a third study arm looking at veliparib in combination with temozolomide, and plans for evaluating veliparib in the ongoing phase III BROCADE3 trial.

sworcester@frontlinemedcom.com

SAN ANTONIO – The investigational selective PARP-1 and PARP-2 inhibitor veliparib failed to significantly improve progression-free or overall survival, compared with placebo, when added to carboplatin and paclitaxel in patients with BRCA1 or BRCA2 mutations and locally recurrent or metastatic breast cancer in the randomized phase II BROCADE study.

The potent, orally bioavailable drug did, however, show a trend toward improvement on these measures, as well as a significant improvement in overall response-rate findings that warrant further investigation in a phase III trial, Hyo Han, MD, said at the San Antonio Breast Cancer Symposium.

Patients were randomized to receive placebo (98 patients) or 120 mg veliparib twice daily on days 1-7 (95 patients) in addition to carboplatin and 175 mg/m² of paclitaxel every 3 weeks.

Median progression-free survival – the primary endpoint of the study – was 12.3 months in the placebo group and 14.1 months in the veliparib group (hazard ratio, 0.789), and overall survival was 25.9 and 28.3 months, respectively (HR, 0.750), said Dr. Han of Moffitt Cancer Center, Tampa, Fla.

The overall response rate was 61.3% vs. 77.8% in the groups, respectively.

Although the study did not meet its primary endpoint, the findings are encouraging as it was powered to detect only dramatic differences between the groups, Dr. Han said.

In a video interview, she discussed veliparib, its safety, the BROCADE findings – including data from a third study arm looking at veliparib in combination with temozolomide, and plans for evaluating veliparib in the ongoing phase III BROCADE3 trial.

sworcester@frontlinemedcom.com

SAN ANTONIO – The investigational selective PARP-1 and PARP-2 inhibitor veliparib failed to significantly improve progression-free or overall survival, compared with placebo, when added to carboplatin and paclitaxel in patients with BRCA1 or BRCA2 mutations and locally recurrent or metastatic breast cancer in the randomized phase II BROCADE study.

The potent, orally bioavailable drug did, however, show a trend toward improvement on these measures, as well as a significant improvement in overall response-rate findings that warrant further investigation in a phase III trial, Hyo Han, MD, said at the San Antonio Breast Cancer Symposium.

Patients were randomized to receive placebo (98 patients) or 120 mg veliparib twice daily on days 1-7 (95 patients) in addition to carboplatin and 175 mg/m² of paclitaxel every 3 weeks.

Median progression-free survival – the primary endpoint of the study – was 12.3 months in the placebo group and 14.1 months in the veliparib group (hazard ratio, 0.789), and overall survival was 25.9 and 28.3 months, respectively (HR, 0.750), said Dr. Han of Moffitt Cancer Center, Tampa, Fla.

The overall response rate was 61.3% vs. 77.8% in the groups, respectively.

Although the study did not meet its primary endpoint, the findings are encouraging as it was powered to detect only dramatic differences between the groups, Dr. Han said.

In a video interview, she discussed veliparib, its safety, the BROCADE findings – including data from a third study arm looking at veliparib in combination with temozolomide, and plans for evaluating veliparib in the ongoing phase III BROCADE3 trial.

sworcester@frontlinemedcom.com

WASHINGTON – A novel biologic treatment strategy involving subcutaneous low-dose interleukin-2 therapy for refractory systemic lupus erythematosus (SLE) showed promise in a single-center, combined phase I/IIa trial.

In 12 patients with active and refractory SLE – that is, patients with SLE disease activity index (SLEDAI) score of at least 6 who were on at least two different immunosuppressive therapies – low-dose IL-2 treatment led to an effective and cycle-dependent increase in the percentage of CD25hi cells among regulatory T cells (Treg). The increase was statistically significant (P less than .001), Jens Humrich, MD, and his colleagues reported in a late-breaking poster at the annual meeting of the American College of Rheumatology.

wildpixel/Thinkstock

sworcester@frontlinemedcom.com

WASHINGTON – A novel biologic treatment strategy involving subcutaneous low-dose interleukin-2 therapy for refractory systemic lupus erythematosus (SLE) showed promise in a single-center, combined phase I/IIa trial.

In 12 patients with active and refractory SLE – that is, patients with SLE disease activity index (SLEDAI) score of at least 6 who were on at least two different immunosuppressive therapies – low-dose IL-2 treatment led to an effective and cycle-dependent increase in the percentage of CD25hi cells among regulatory T cells (Treg). The increase was statistically significant (P less than .001), Jens Humrich, MD, and his colleagues reported in a late-breaking poster at the annual meeting of the American College of Rheumatology.

wildpixel/Thinkstock

sworcester@frontlinemedcom.com

WASHINGTON – A novel biologic treatment strategy involving subcutaneous low-dose interleukin-2 therapy for refractory systemic lupus erythematosus (SLE) showed promise in a single-center, combined phase I/IIa trial.

In 12 patients with active and refractory SLE – that is, patients with SLE disease activity index (SLEDAI) score of at least 6 who were on at least two different immunosuppressive therapies – low-dose IL-2 treatment led to an effective and cycle-dependent increase in the percentage of CD25hi cells among regulatory T cells (Treg). The increase was statistically significant (P less than .001), Jens Humrich, MD, and his colleagues reported in a late-breaking poster at the annual meeting of the American College of Rheumatology.

wildpixel/Thinkstock

sworcester@frontlinemedcom.com

WASHINGTON – Myeloablative autologous hematopoietic stem cell transplantation was superior to monthly intravenous cyclophosphamide in patients with severe scleroderma with internal organ involvement in the randomized, multicenter Scleroderma: Cyclophosphamide or Transplantation (SCOT) trial.

At both 54 and 48 months, a comparison of global rank composite scores favored myeloablation followed by CD34+-selected autologous hematopoietic stem cell transplantation (HSCT) over 12 monthly pulses of 750 mg/m² cyclophosphamide in the intention-to-treat population of 36 and 39 subjects with diffuse cutaneous systemic sclerosis and high-risk lung and/or renal involvement who were randomized to the groups, respectively (P = .013 at 54 months and P = .008 at 48 months). In subjects who actually underwent HSCT or received at least nine cyclophosphamide doses, the effect was even stronger (P = .004 at 54 months and P = .003 at 48 months), Keith M. Sullivan, MD, reported at the annual meeting of the American College of Rheumatology.

The global rank composite scores were derived based on a hierarchy of outcomes including – in rank order – death, event-free survival, forced vital capacity, scleroderma health assessment questionnaire score, and modified Rodnan skin score (mRSS); each patient was compared, based on the hierarchy, with every other patient in the study.

HSCT was superior overall and within each of the components of the score, Dr. Sullivan said.

The findings were supported by secondary analyses showing that at 54 months, event-free survival was 79% in the HSCT group vs. 50% in the cyclophosphamide group, and overall survival was 91% vs. 77% in the groups, respectively; the differences between the groups were statistically significant, said Dr. Sullivan of Duke University, Durham, N.C.

“In advanced scleroderma, that is a remarkable finding,” he said of the nearly 30-point difference in event-free survival rates between the groups.

Further, disease-modifying antirheumatic drugs were initiated by 54 months in 9% of the HSCT recipients vs. 44% of those in the cyclophosphamide group, he noted.

The rate of serious adverse events was similar in the two groups, although grade 3 or greater adverse events, including treatment-related cytopenias, were more common in the HSCT group, as was herpes zoster. Remarkably, most serious adverse events and adverse events occurred in the first 14 months, Dr. Sullivan noted.

Treatment-related mortality at 54 months was 3% in the HSCT group, and 0% in the cyclophosphamide group, he said.

Study subjects were adults aged 18-69 years with mean baseline modified Rodnan skin score of 30, mean baseline forced vital capacity of 74%, and mean diffusing capacity of the lung for carbon monoxide (DLCO) of 53% of predicted. All but two had lung involvement.

“So [there was] significant skin and pulmonary impairment,” he said.

There are, unquestionably, risks with transplant, but the SCOT findings support myeloablative autologous HSCT as a significant advance in the care of diffuse cutaneous systemic scleroderma with internal organ involvement, as this approach provided superior long-term outcomes, compared with 12 months of IV cyclophosphamide, he said, adding that the global rank composite score developed for this study was a useful measure of scleroderma outcomes.

“Therefore it would be prudent to consider early referral to the transplant center for consultation, which would allow patients, earlier in their disease – before the mRSS hit 30 and the DLCOs hit 50 – to make informed decisions,” he concluded.

The SCOT trial was funded by the National Institute of Allergy and Infectious Diseases. The authors reported having no disclosures.

sworcester@frontlinemedcom.com

WASHINGTON – Myeloablative autologous hematopoietic stem cell transplantation was superior to monthly intravenous cyclophosphamide in patients with severe scleroderma with internal organ involvement in the randomized, multicenter Scleroderma: Cyclophosphamide or Transplantation (SCOT) trial.

At both 54 and 48 months, a comparison of global rank composite scores favored myeloablation followed by CD34+-selected autologous hematopoietic stem cell transplantation (HSCT) over 12 monthly pulses of 750 mg/m² cyclophosphamide in the intention-to-treat population of 36 and 39 subjects with diffuse cutaneous systemic sclerosis and high-risk lung and/or renal involvement who were randomized to the groups, respectively (P = .013 at 54 months and P = .008 at 48 months). In subjects who actually underwent HSCT or received at least nine cyclophosphamide doses, the effect was even stronger (P = .004 at 54 months and P = .003 at 48 months), Keith M. Sullivan, MD, reported at the annual meeting of the American College of Rheumatology.

The global rank composite scores were derived based on a hierarchy of outcomes including – in rank order – death, event-free survival, forced vital capacity, scleroderma health assessment questionnaire score, and modified Rodnan skin score (mRSS); each patient was compared, based on the hierarchy, with every other patient in the study.

HSCT was superior overall and within each of the components of the score, Dr. Sullivan said.

The findings were supported by secondary analyses showing that at 54 months, event-free survival was 79% in the HSCT group vs. 50% in the cyclophosphamide group, and overall survival was 91% vs. 77% in the groups, respectively; the differences between the groups were statistically significant, said Dr. Sullivan of Duke University, Durham, N.C.

“In advanced scleroderma, that is a remarkable finding,” he said of the nearly 30-point difference in event-free survival rates between the groups.

Further, disease-modifying antirheumatic drugs were initiated by 54 months in 9% of the HSCT recipients vs. 44% of those in the cyclophosphamide group, he noted.

The rate of serious adverse events was similar in the two groups, although grade 3 or greater adverse events, including treatment-related cytopenias, were more common in the HSCT group, as was herpes zoster. Remarkably, most serious adverse events and adverse events occurred in the first 14 months, Dr. Sullivan noted.

Treatment-related mortality at 54 months was 3% in the HSCT group, and 0% in the cyclophosphamide group, he said.

Study subjects were adults aged 18-69 years with mean baseline modified Rodnan skin score of 30, mean baseline forced vital capacity of 74%, and mean diffusing capacity of the lung for carbon monoxide (DLCO) of 53% of predicted. All but two had lung involvement.

“So [there was] significant skin and pulmonary impairment,” he said.

There are, unquestionably, risks with transplant, but the SCOT findings support myeloablative autologous HSCT as a significant advance in the care of diffuse cutaneous systemic scleroderma with internal organ involvement, as this approach provided superior long-term outcomes, compared with 12 months of IV cyclophosphamide, he said, adding that the global rank composite score developed for this study was a useful measure of scleroderma outcomes.

“Therefore it would be prudent to consider early referral to the transplant center for consultation, which would allow patients, earlier in their disease – before the mRSS hit 30 and the DLCOs hit 50 – to make informed decisions,” he concluded.

The SCOT trial was funded by the National Institute of Allergy and Infectious Diseases. The authors reported having no disclosures.

sworcester@frontlinemedcom.com

WASHINGTON – Myeloablative autologous hematopoietic stem cell transplantation was superior to monthly intravenous cyclophosphamide in patients with severe scleroderma with internal organ involvement in the randomized, multicenter Scleroderma: Cyclophosphamide or Transplantation (SCOT) trial.

At both 54 and 48 months, a comparison of global rank composite scores favored myeloablation followed by CD34+-selected autologous hematopoietic stem cell transplantation (HSCT) over 12 monthly pulses of 750 mg/m² cyclophosphamide in the intention-to-treat population of 36 and 39 subjects with diffuse cutaneous systemic sclerosis and high-risk lung and/or renal involvement who were randomized to the groups, respectively (P = .013 at 54 months and P = .008 at 48 months). In subjects who actually underwent HSCT or received at least nine cyclophosphamide doses, the effect was even stronger (P = .004 at 54 months and P = .003 at 48 months), Keith M. Sullivan, MD, reported at the annual meeting of the American College of Rheumatology.

The global rank composite scores were derived based on a hierarchy of outcomes including – in rank order – death, event-free survival, forced vital capacity, scleroderma health assessment questionnaire score, and modified Rodnan skin score (mRSS); each patient was compared, based on the hierarchy, with every other patient in the study.

HSCT was superior overall and within each of the components of the score, Dr. Sullivan said.

The findings were supported by secondary analyses showing that at 54 months, event-free survival was 79% in the HSCT group vs. 50% in the cyclophosphamide group, and overall survival was 91% vs. 77% in the groups, respectively; the differences between the groups were statistically significant, said Dr. Sullivan of Duke University, Durham, N.C.

“In advanced scleroderma, that is a remarkable finding,” he said of the nearly 30-point difference in event-free survival rates between the groups.

Further, disease-modifying antirheumatic drugs were initiated by 54 months in 9% of the HSCT recipients vs. 44% of those in the cyclophosphamide group, he noted.

The rate of serious adverse events was similar in the two groups, although grade 3 or greater adverse events, including treatment-related cytopenias, were more common in the HSCT group, as was herpes zoster. Remarkably, most serious adverse events and adverse events occurred in the first 14 months, Dr. Sullivan noted.

Treatment-related mortality at 54 months was 3% in the HSCT group, and 0% in the cyclophosphamide group, he said.

Study subjects were adults aged 18-69 years with mean baseline modified Rodnan skin score of 30, mean baseline forced vital capacity of 74%, and mean diffusing capacity of the lung for carbon monoxide (DLCO) of 53% of predicted. All but two had lung involvement.

“So [there was] significant skin and pulmonary impairment,” he said.

There are, unquestionably, risks with transplant, but the SCOT findings support myeloablative autologous HSCT as a significant advance in the care of diffuse cutaneous systemic scleroderma with internal organ involvement, as this approach provided superior long-term outcomes, compared with 12 months of IV cyclophosphamide, he said, adding that the global rank composite score developed for this study was a useful measure of scleroderma outcomes.

“Therefore it would be prudent to consider early referral to the transplant center for consultation, which would allow patients, earlier in their disease – before the mRSS hit 30 and the DLCOs hit 50 – to make informed decisions,” he concluded.

The SCOT trial was funded by the National Institute of Allergy and Infectious Diseases. The authors reported having no disclosures.

sworcester@frontlinemedcom.com

WASHINGTON – The recombinant fusion protein atacicept, which targets B-cell stimulating factors BLyS and APRIL, had a favorable safety profile and showed some evidence of efficacy in systemic lupus erythematosus patients – particularly those with high disease activity and serologically active disease – in the randomized, phase IIb ADDRESS II study.

Although the primary endpoint of the study – percentage of patients achieving SLE responder index-4 (SRI-4) response at 24 weeks – was not met, a reduction in both disease activity and severe flares was observed in patients in the multicenter study who received atacicept vs. placebo, Joan T. Merrill, MD, of the Oklahoma Medical Research Foundation, Oklahoma City, reported in a late-breaking poster at the annual meeting of the American College of Rheumatology.

sworcester@frontlinemedcom.com

WASHINGTON – The recombinant fusion protein atacicept, which targets B-cell stimulating factors BLyS and APRIL, had a favorable safety profile and showed some evidence of efficacy in systemic lupus erythematosus patients – particularly those with high disease activity and serologically active disease – in the randomized, phase IIb ADDRESS II study.

Although the primary endpoint of the study – percentage of patients achieving SLE responder index-4 (SRI-4) response at 24 weeks – was not met, a reduction in both disease activity and severe flares was observed in patients in the multicenter study who received atacicept vs. placebo, Joan T. Merrill, MD, of the Oklahoma Medical Research Foundation, Oklahoma City, reported in a late-breaking poster at the annual meeting of the American College of Rheumatology.

sworcester@frontlinemedcom.com

WASHINGTON – The recombinant fusion protein atacicept, which targets B-cell stimulating factors BLyS and APRIL, had a favorable safety profile and showed some evidence of efficacy in systemic lupus erythematosus patients – particularly those with high disease activity and serologically active disease – in the randomized, phase IIb ADDRESS II study.

Although the primary endpoint of the study – percentage of patients achieving SLE responder index-4 (SRI-4) response at 24 weeks – was not met, a reduction in both disease activity and severe flares was observed in patients in the multicenter study who received atacicept vs. placebo, Joan T. Merrill, MD, of the Oklahoma Medical Research Foundation, Oklahoma City, reported in a late-breaking poster at the annual meeting of the American College of Rheumatology.

sworcester@frontlinemedcom.com

NEW YORK – Safety issues with idelalisib, a first-in-class PI3K delta inhibitor, are an important concern in patients with chronic lymphocytic leukemia – particularly those aged 65 years and younger, according to Steven Coutre, MD.

Findings from the second interim analysis of the pivotal trial for idelalisib as reported at the 2014 annual meeting of the American Society of Hematology (Sharman J., et al. Abstract 330) and a recent update from an open-label extension represent the longest reported follow-up of idelalisib-treated patients to date. Those analyses showed substantial progression-free and overall survival advantages with idelalisib plus rituximab vs. placebo plus rituximab (progression-free survival in the latest update was 19.4 vs. 7.3 months, respectively; hazard ratio 0.25), said Dr. Coutre, professor of medicine at Stanford (Calif.) University.

“Still, even with that report, the follow-up on that initial study was relatively short, and I think it really underreports some of the safety issues of the toxicities that we see,” he said at an international congress on hematologic malignancies.

To further investigate those safety issues, Dr. Coutre and his colleagues performed an integrated analysis of eight clinical trials, including the pivotal trial. That analysis found idelalisib to be efficacious, but significant toxicities were noted, “particularly in younger less heavily-pretreated patients. [Idelalisib] should not be used as frontline therapy ... and I don’t think it will be developed in the future as frontline therapy,” Dr. Coutre said.

“At least in the relapse setting, idelalisib plus rituximab is a choice for all of our patients, but it has to be a considered choice; you have to put it in the context of other therapies that the patients have available to them and make a decision based on your individual patient.”

In the analysis, Dr. Coutre and his colleagues found numerous adverse events occurring in 15% or more of idelalisib-treated patients. These included diarrhea/colitis – with median onset at 7.1 months – in 37% who received monotherapy and 40% who received combination therapy (grade 3 or greater diarrhea/colitis in 11% and 17%, respectively), and pneumonia in 13% and 18% of patients (grade 3 or greater in 11% and 14%, respectively), Dr. Coutre said.

Transaminitis – which was observed early in the studies, usually within the first 8 weeks of treatment – also was common, occurring in 50% and 47% of those with monotherapy and combination therapy, respectively (grade 3 or greater, 16% and 13%, respectively).

Pneumonitis occurred in about 3% of patients, and usually within the first 6 months of therapy.

“So that’s sort of where things were until earlier this year when we learned from several ongoing studies, very important studies in both previously treated patients with low-grade lymphomas and previously untreated patients, that there was a further problem – and that is a difference in mortality,” he said.

Patients in many of these studies, including all of those where it was being used for previously untreated patients, were taken off the drug because of this finding.

“As a result of further analysis of these studies, there’s a new safety label indication,” he said.

Of note, in another idelalisib study reported at ASH 2015 an age-related toxicity concern emerged.

“Idelalisib was used for previously untreated patients. But the distinction here is that for the first time it was being used in younger patients – patients under the age of 65,” he said, noting that severe transaminitis occurred in a significant number of the younger patients.

More than half (52%) of patients had grade 3 or greater hepatotoxicity and all 7 subjects aged 65 years and younger required systemic steroids for toxicities.

Age was found in the study to be a significant risk factor for early hepatotoxicity.

“We’re finally starting to understand the mechanisms behind this, or at least the likely mechanisms, and this seems to be immune mediated,” he said, adding, “you see a lymphocytic infiltrate on liver biopsies, you see a lymphocytic colitis in patients who receive idelalisib.”

Typically, toxicities in these patients can be managed with corticosteroids, but in some cases of severe toxicity even steroids seem to be insufficient, he said.

Further, rapid recurrence is often seen upon re-exposure to the drug, especially with respect to hepatotoxicity, he added.

Preclinical data from mouse models supports this mechanism.

“And importantly [those models] demonstrated a decrease in regulatory T cells in patients treated with idelalisib,” he said.

Dr. Coutre reported consulting for Abbvie, Celgene, Gilead, Janssen, and Pharmacyclics.

sworcester@frontlinemedcom.com

NEW YORK – Safety issues with idelalisib, a first-in-class PI3K delta inhibitor, are an important concern in patients with chronic lymphocytic leukemia – particularly those aged 65 years and younger, according to Steven Coutre, MD.

Findings from the second interim analysis of the pivotal trial for idelalisib as reported at the 2014 annual meeting of the American Society of Hematology (Sharman J., et al. Abstract 330) and a recent update from an open-label extension represent the longest reported follow-up of idelalisib-treated patients to date. Those analyses showed substantial progression-free and overall survival advantages with idelalisib plus rituximab vs. placebo plus rituximab (progression-free survival in the latest update was 19.4 vs. 7.3 months, respectively; hazard ratio 0.25), said Dr. Coutre, professor of medicine at Stanford (Calif.) University.

“Still, even with that report, the follow-up on that initial study was relatively short, and I think it really underreports some of the safety issues of the toxicities that we see,” he said at an international congress on hematologic malignancies.

To further investigate those safety issues, Dr. Coutre and his colleagues performed an integrated analysis of eight clinical trials, including the pivotal trial. That analysis found idelalisib to be efficacious, but significant toxicities were noted, “particularly in younger less heavily-pretreated patients. [Idelalisib] should not be used as frontline therapy ... and I don’t think it will be developed in the future as frontline therapy,” Dr. Coutre said.

“At least in the relapse setting, idelalisib plus rituximab is a choice for all of our patients, but it has to be a considered choice; you have to put it in the context of other therapies that the patients have available to them and make a decision based on your individual patient.”

In the analysis, Dr. Coutre and his colleagues found numerous adverse events occurring in 15% or more of idelalisib-treated patients. These included diarrhea/colitis – with median onset at 7.1 months – in 37% who received monotherapy and 40% who received combination therapy (grade 3 or greater diarrhea/colitis in 11% and 17%, respectively), and pneumonia in 13% and 18% of patients (grade 3 or greater in 11% and 14%, respectively), Dr. Coutre said.

Transaminitis – which was observed early in the studies, usually within the first 8 weeks of treatment – also was common, occurring in 50% and 47% of those with monotherapy and combination therapy, respectively (grade 3 or greater, 16% and 13%, respectively).

Pneumonitis occurred in about 3% of patients, and usually within the first 6 months of therapy.

“So that’s sort of where things were until earlier this year when we learned from several ongoing studies, very important studies in both previously treated patients with low-grade lymphomas and previously untreated patients, that there was a further problem – and that is a difference in mortality,” he said.

Patients in many of these studies, including all of those where it was being used for previously untreated patients, were taken off the drug because of this finding.

“As a result of further analysis of these studies, there’s a new safety label indication,” he said.

Of note, in another idelalisib study reported at ASH 2015 an age-related toxicity concern emerged.

“Idelalisib was used for previously untreated patients. But the distinction here is that for the first time it was being used in younger patients – patients under the age of 65,” he said, noting that severe transaminitis occurred in a significant number of the younger patients.

More than half (52%) of patients had grade 3 or greater hepatotoxicity and all 7 subjects aged 65 years and younger required systemic steroids for toxicities.

Age was found in the study to be a significant risk factor for early hepatotoxicity.

“We’re finally starting to understand the mechanisms behind this, or at least the likely mechanisms, and this seems to be immune mediated,” he said, adding, “you see a lymphocytic infiltrate on liver biopsies, you see a lymphocytic colitis in patients who receive idelalisib.”

Typically, toxicities in these patients can be managed with corticosteroids, but in some cases of severe toxicity even steroids seem to be insufficient, he said.

Further, rapid recurrence is often seen upon re-exposure to the drug, especially with respect to hepatotoxicity, he added.

Preclinical data from mouse models supports this mechanism.

“And importantly [those models] demonstrated a decrease in regulatory T cells in patients treated with idelalisib,” he said.

Dr. Coutre reported consulting for Abbvie, Celgene, Gilead, Janssen, and Pharmacyclics.

sworcester@frontlinemedcom.com

NEW YORK – Safety issues with idelalisib, a first-in-class PI3K delta inhibitor, are an important concern in patients with chronic lymphocytic leukemia – particularly those aged 65 years and younger, according to Steven Coutre, MD.

Findings from the second interim analysis of the pivotal trial for idelalisib as reported at the 2014 annual meeting of the American Society of Hematology (Sharman J., et al. Abstract 330) and a recent update from an open-label extension represent the longest reported follow-up of idelalisib-treated patients to date. Those analyses showed substantial progression-free and overall survival advantages with idelalisib plus rituximab vs. placebo plus rituximab (progression-free survival in the latest update was 19.4 vs. 7.3 months, respectively; hazard ratio 0.25), said Dr. Coutre, professor of medicine at Stanford (Calif.) University.

“Still, even with that report, the follow-up on that initial study was relatively short, and I think it really underreports some of the safety issues of the toxicities that we see,” he said at an international congress on hematologic malignancies.

To further investigate those safety issues, Dr. Coutre and his colleagues performed an integrated analysis of eight clinical trials, including the pivotal trial. That analysis found idelalisib to be efficacious, but significant toxicities were noted, “particularly in younger less heavily-pretreated patients. [Idelalisib] should not be used as frontline therapy ... and I don’t think it will be developed in the future as frontline therapy,” Dr. Coutre said.

“At least in the relapse setting, idelalisib plus rituximab is a choice for all of our patients, but it has to be a considered choice; you have to put it in the context of other therapies that the patients have available to them and make a decision based on your individual patient.”

In the analysis, Dr. Coutre and his colleagues found numerous adverse events occurring in 15% or more of idelalisib-treated patients. These included diarrhea/colitis – with median onset at 7.1 months – in 37% who received monotherapy and 40% who received combination therapy (grade 3 or greater diarrhea/colitis in 11% and 17%, respectively), and pneumonia in 13% and 18% of patients (grade 3 or greater in 11% and 14%, respectively), Dr. Coutre said.

Transaminitis – which was observed early in the studies, usually within the first 8 weeks of treatment – also was common, occurring in 50% and 47% of those with monotherapy and combination therapy, respectively (grade 3 or greater, 16% and 13%, respectively).

Pneumonitis occurred in about 3% of patients, and usually within the first 6 months of therapy.

“So that’s sort of where things were until earlier this year when we learned from several ongoing studies, very important studies in both previously treated patients with low-grade lymphomas and previously untreated patients, that there was a further problem – and that is a difference in mortality,” he said.

Patients in many of these studies, including all of those where it was being used for previously untreated patients, were taken off the drug because of this finding.

“As a result of further analysis of these studies, there’s a new safety label indication,” he said.

Of note, in another idelalisib study reported at ASH 2015 an age-related toxicity concern emerged.

“Idelalisib was used for previously untreated patients. But the distinction here is that for the first time it was being used in younger patients – patients under the age of 65,” he said, noting that severe transaminitis occurred in a significant number of the younger patients.

More than half (52%) of patients had grade 3 or greater hepatotoxicity and all 7 subjects aged 65 years and younger required systemic steroids for toxicities.

Age was found in the study to be a significant risk factor for early hepatotoxicity.

“We’re finally starting to understand the mechanisms behind this, or at least the likely mechanisms, and this seems to be immune mediated,” he said, adding, “you see a lymphocytic infiltrate on liver biopsies, you see a lymphocytic colitis in patients who receive idelalisib.”

Typically, toxicities in these patients can be managed with corticosteroids, but in some cases of severe toxicity even steroids seem to be insufficient, he said.

Further, rapid recurrence is often seen upon re-exposure to the drug, especially with respect to hepatotoxicity, he added.

Preclinical data from mouse models supports this mechanism.

“And importantly [those models] demonstrated a decrease in regulatory T cells in patients treated with idelalisib,” he said.

Dr. Coutre reported consulting for Abbvie, Celgene, Gilead, Janssen, and Pharmacyclics.

sworcester@frontlinemedcom.com

Philadelphia chromosome–like acute lymphoblastic leukemia, a high-risk subtype of childhood ALL, accounts for more than 24% of ALL in adults and is associated with poor outcome, according to gene-expression profiling in nearly 800 adults with B-cell ALL.

In the 798 subjects aged 21-86 years, Philadelphia chromosome–like (Ph-like) ALL accounted for 27.9% of ALL cases in those aged 21-39 years, 20.4% of cases in those aged 40-59 years, and 24% of cases in those aged 60-86 years. The overall 5-year event-free survival rate was inferior in those with Ph-like ALL vs. non–Ph-like ALL (22.5% vs. 49.3%), as was the 5-year overall survival (23.8% vs. 52.4%). Increasing age also was associated with inferior outcomes: 5-year event-free survival was 40.4%, 29.8%, and 18.9% in the age groups, respectively, and 5-year overall survival was 45.2%, 35.1%, and 28.4% in the groups, respectively, Kathryn G. Roberts, Ph.D., of St. Jude Children’s Research Hospital in Memphis and her colleagues reported online ahead of print (J Clin Oncol. 2016 Nov 21. doi: 10.1200/JCO.2016.69.0073).

sworcester@frontlinemedcom.com

Philadelphia chromosome–like acute lymphoblastic leukemia, a high-risk subtype of childhood ALL, accounts for more than 24% of ALL in adults and is associated with poor outcome, according to gene-expression profiling in nearly 800 adults with B-cell ALL.

In the 798 subjects aged 21-86 years, Philadelphia chromosome–like (Ph-like) ALL accounted for 27.9% of ALL cases in those aged 21-39 years, 20.4% of cases in those aged 40-59 years, and 24% of cases in those aged 60-86 years. The overall 5-year event-free survival rate was inferior in those with Ph-like ALL vs. non–Ph-like ALL (22.5% vs. 49.3%), as was the 5-year overall survival (23.8% vs. 52.4%). Increasing age also was associated with inferior outcomes: 5-year event-free survival was 40.4%, 29.8%, and 18.9% in the age groups, respectively, and 5-year overall survival was 45.2%, 35.1%, and 28.4% in the groups, respectively, Kathryn G. Roberts, Ph.D., of St. Jude Children’s Research Hospital in Memphis and her colleagues reported online ahead of print (J Clin Oncol. 2016 Nov 21. doi: 10.1200/JCO.2016.69.0073).

sworcester@frontlinemedcom.com

Philadelphia chromosome–like acute lymphoblastic leukemia, a high-risk subtype of childhood ALL, accounts for more than 24% of ALL in adults and is associated with poor outcome, according to gene-expression profiling in nearly 800 adults with B-cell ALL.

In the 798 subjects aged 21-86 years, Philadelphia chromosome–like (Ph-like) ALL accounted for 27.9% of ALL cases in those aged 21-39 years, 20.4% of cases in those aged 40-59 years, and 24% of cases in those aged 60-86 years. The overall 5-year event-free survival rate was inferior in those with Ph-like ALL vs. non–Ph-like ALL (22.5% vs. 49.3%), as was the 5-year overall survival (23.8% vs. 52.4%). Increasing age also was associated with inferior outcomes: 5-year event-free survival was 40.4%, 29.8%, and 18.9% in the age groups, respectively, and 5-year overall survival was 45.2%, 35.1%, and 28.4% in the groups, respectively, Kathryn G. Roberts, Ph.D., of St. Jude Children’s Research Hospital in Memphis and her colleagues reported online ahead of print (J Clin Oncol. 2016 Nov 21. doi: 10.1200/JCO.2016.69.0073).

sworcester@frontlinemedcom.com

WASHINGTON – The investigational calcineurin inhibitor voclosporin, given in addition to mycophenolate mofetil and low-dose steroids, was associated with rapid and complete remissions in lupus nephritis patients in the randomized, controlled AURA-LV study.

Aurinia Urinary Protein Reduction Active – Lupus With Voclosporin (AURA-LV) included 265 subjects in over 20 countries with active lupus nephritis. Trial participants received low-dose voclosporin (23.7 mg b.i.d.) or high-dose voclosporin (39.5 mg b.i.d.) in addition to mycophenolate mofetil (2 g/day) and low-dose steroids. Patients began on 20-25 mg of a steroid with a taper to 5 mg at week 8 and 2.5 mg at week 16-24.
 

Complete remission occurred at 24 weeks in 32.6% of 89 subjects who received 23.7 mg of voclosporin twice daily and standard of care therapy and in 19.3% of 88 control subjects who received placebo and standard of care therapy (odds ratio, 2.03), Mary Anne Dooley, MD, reported at the annual meeting of the American College of Rheumatology.

The complete remission rate was 27.3% in the 88 subjects who received the higher dose (39.5 mg b.i.d.) of voclosporin. The difference between the high-dose voclosporin group and the control group was not statistically significant.

The “very exciting findings” of this study – the first lupus nephritis study to meet its primary endpoint of complete remission – are important, because “partial remission is insufficient for our patients,” she said.

“Clinical trials over the past 10 years have really shown that we’re not reaching a large group of patients. ... more than 40% of patients are complete nonresponders at 6 months,” she said. While attainment of partial remission has improved, half of those who achieve partial remission have been shown to have a 50% increase in the risk of end-stage renal disease in 10 years.

Complete remission was defined as urine protein/creatinine ratio of no more than 0.5 mg/mg using first morning void with an estimated glomerular filtration rate of at least 60 mL/min without a decrease of 20% or more, sustained low-dose steroids (at or below 10 mg/day) and no use of rescue medications.

Partial remission was a composite of reduction in protein/creatinine ratio of at least 50%, no use of rescue medication, and stability of renal function. Both the low- and high-dose voclosporin groups had outcomes that were superior to standard-of-care therapy, with 69.7% partial remission with low-dose voclosporin, 65.9% partial remission with high-dose voclosporin, and 49.4% partial remission with placebo, said Dr. Dooley, a rheumatologist in Chapel Hill, N.C.

“Patients began responding literally within weeks [to voclosporin] ... and we saw significant responses by 7-8 weeks. This was during the time period when the steroids rapidly decreased,” she said, noting that the steroid dosing at baseline was a median of 25 mg vs. 2.5 mg at 16 weeks.

Study subjects met ACR criteria for lupus and had biopsy-proven lupus nephritis, including proliferative nephritis class III/IV or class V alone or in combination with proliferative disease. All were treated with 2 g/day of mycophenolate mofetil, and the steroid taper “was such that by 10 weeks, patients were down to 5 mg, and that by 24 weeks the median dose was 2.5 mg,” she said.

Adverse events, most commonly infection and gastrointestinal disorders, occurred in 90% of study subjects. Infections occurred in 56.2% of those in the low-dose group, 63.6% of those in the high-dose group, and 50% of controls. GI disorders occurred in 41.6%, 52.3%, and 36.4% of patients in the groups, respectively.

Serious adverse events were more common in the voclosporin groups, occurring in 25.8% and 25% of patients in the low- and high-dose groups, respectively, compared with 15.8% of patients in the control group.

Ten of the 13 deaths occurred in the low-dose voclosporin group (3 due to infection, 3 due to thromboembolism, and 4 due to “other” causes); 2 occurred in the high-dose voclosporin group (1 each due to infection and thromboembolism); and 1 death due to thromboembolism occurred in the control group. As most of the deaths were clustered in the low-dose arm, and 11 of the 13 deaths occurred in areas with “compromised access to standard of care,” the deaths were not considered to be directly related to voclosporin therapy.

Patients who died had “a statistically different clinical baseline picture with higher levels of proteinuria or difficulty with comorbid conditions and some signs of poor nutrition,” Dr. Dooley said.

The findings of the study will be used as the basis for planned subsequent studies of the use of voclosporin in lupus nephritis, she said.

Voclosporin is an analogue of cyclosporin A that may allow flat dosing and a potentially improved safety profile compared with other calcineurin inhibitors.

Aurinia Pharmaceuticals, the maker of voclosporin, announced in early November 2016 that the twice-daily 23.7 mg voclosporin dose will advance to a global 52-week double-blind, placebo-controlled phase III study in the second quarter of 2017. Voclosporin has already received fast track designation from the Food and Drug Administration.

Dr. Dooley reported a financial relationship with Aurinia, which sponsored the study.

sworcester@frontlinemedcom.com

WASHINGTON – The investigational calcineurin inhibitor voclosporin, given in addition to mycophenolate mofetil and low-dose steroids, was associated with rapid and complete remissions in lupus nephritis patients in the randomized, controlled AURA-LV study.

Aurinia Urinary Protein Reduction Active – Lupus With Voclosporin (AURA-LV) included 265 subjects in over 20 countries with active lupus nephritis. Trial participants received low-dose voclosporin (23.7 mg b.i.d.) or high-dose voclosporin (39.5 mg b.i.d.) in addition to mycophenolate mofetil (2 g/day) and low-dose steroids. Patients began on 20-25 mg of a steroid with a taper to 5 mg at week 8 and 2.5 mg at week 16-24.
 

Complete remission occurred at 24 weeks in 32.6% of 89 subjects who received 23.7 mg of voclosporin twice daily and standard of care therapy and in 19.3% of 88 control subjects who received placebo and standard of care therapy (odds ratio, 2.03), Mary Anne Dooley, MD, reported at the annual meeting of the American College of Rheumatology.

The complete remission rate was 27.3% in the 88 subjects who received the higher dose (39.5 mg b.i.d.) of voclosporin. The difference between the high-dose voclosporin group and the control group was not statistically significant.

The “very exciting findings” of this study – the first lupus nephritis study to meet its primary endpoint of complete remission – are important, because “partial remission is insufficient for our patients,” she said.

“Clinical trials over the past 10 years have really shown that we’re not reaching a large group of patients. ... more than 40% of patients are complete nonresponders at 6 months,” she said. While attainment of partial remission has improved, half of those who achieve partial remission have been shown to have a 50% increase in the risk of end-stage renal disease in 10 years.

Complete remission was defined as urine protein/creatinine ratio of no more than 0.5 mg/mg using first morning void with an estimated glomerular filtration rate of at least 60 mL/min without a decrease of 20% or more, sustained low-dose steroids (at or below 10 mg/day) and no use of rescue medications.

Partial remission was a composite of reduction in protein/creatinine ratio of at least 50%, no use of rescue medication, and stability of renal function. Both the low- and high-dose voclosporin groups had outcomes that were superior to standard-of-care therapy, with 69.7% partial remission with low-dose voclosporin, 65.9% partial remission with high-dose voclosporin, and 49.4% partial remission with placebo, said Dr. Dooley, a rheumatologist in Chapel Hill, N.C.

“Patients began responding literally within weeks [to voclosporin] ... and we saw significant responses by 7-8 weeks. This was during the time period when the steroids rapidly decreased,” she said, noting that the steroid dosing at baseline was a median of 25 mg vs. 2.5 mg at 16 weeks.

Study subjects met ACR criteria for lupus and had biopsy-proven lupus nephritis, including proliferative nephritis class III/IV or class V alone or in combination with proliferative disease. All were treated with 2 g/day of mycophenolate mofetil, and the steroid taper “was such that by 10 weeks, patients were down to 5 mg, and that by 24 weeks the median dose was 2.5 mg,” she said.

Adverse events, most commonly infection and gastrointestinal disorders, occurred in 90% of study subjects. Infections occurred in 56.2% of those in the low-dose group, 63.6% of those in the high-dose group, and 50% of controls. GI disorders occurred in 41.6%, 52.3%, and 36.4% of patients in the groups, respectively.

Serious adverse events were more common in the voclosporin groups, occurring in 25.8% and 25% of patients in the low- and high-dose groups, respectively, compared with 15.8% of patients in the control group.

Ten of the 13 deaths occurred in the low-dose voclosporin group (3 due to infection, 3 due to thromboembolism, and 4 due to “other” causes); 2 occurred in the high-dose voclosporin group (1 each due to infection and thromboembolism); and 1 death due to thromboembolism occurred in the control group. As most of the deaths were clustered in the low-dose arm, and 11 of the 13 deaths occurred in areas with “compromised access to standard of care,” the deaths were not considered to be directly related to voclosporin therapy.

Patients who died had “a statistically different clinical baseline picture with higher levels of proteinuria or difficulty with comorbid conditions and some signs of poor nutrition,” Dr. Dooley said.

The findings of the study will be used as the basis for planned subsequent studies of the use of voclosporin in lupus nephritis, she said.

Voclosporin is an analogue of cyclosporin A that may allow flat dosing and a potentially improved safety profile compared with other calcineurin inhibitors.

Aurinia Pharmaceuticals, the maker of voclosporin, announced in early November 2016 that the twice-daily 23.7 mg voclosporin dose will advance to a global 52-week double-blind, placebo-controlled phase III study in the second quarter of 2017. Voclosporin has already received fast track designation from the Food and Drug Administration.

Dr. Dooley reported a financial relationship with Aurinia, which sponsored the study.

sworcester@frontlinemedcom.com

WASHINGTON – The investigational calcineurin inhibitor voclosporin, given in addition to mycophenolate mofetil and low-dose steroids, was associated with rapid and complete remissions in lupus nephritis patients in the randomized, controlled AURA-LV study.

Aurinia Urinary Protein Reduction Active – Lupus With Voclosporin (AURA-LV) included 265 subjects in over 20 countries with active lupus nephritis. Trial participants received low-dose voclosporin (23.7 mg b.i.d.) or high-dose voclosporin (39.5 mg b.i.d.) in addition to mycophenolate mofetil (2 g/day) and low-dose steroids. Patients began on 20-25 mg of a steroid with a taper to 5 mg at week 8 and 2.5 mg at week 16-24.
 

Complete remission occurred at 24 weeks in 32.6% of 89 subjects who received 23.7 mg of voclosporin twice daily and standard of care therapy and in 19.3% of 88 control subjects who received placebo and standard of care therapy (odds ratio, 2.03), Mary Anne Dooley, MD, reported at the annual meeting of the American College of Rheumatology.

The complete remission rate was 27.3% in the 88 subjects who received the higher dose (39.5 mg b.i.d.) of voclosporin. The difference between the high-dose voclosporin group and the control group was not statistically significant.

The “very exciting findings” of this study – the first lupus nephritis study to meet its primary endpoint of complete remission – are important, because “partial remission is insufficient for our patients,” she said.

“Clinical trials over the past 10 years have really shown that we’re not reaching a large group of patients. ... more than 40% of patients are complete nonresponders at 6 months,” she said. While attainment of partial remission has improved, half of those who achieve partial remission have been shown to have a 50% increase in the risk of end-stage renal disease in 10 years.

Complete remission was defined as urine protein/creatinine ratio of no more than 0.5 mg/mg using first morning void with an estimated glomerular filtration rate of at least 60 mL/min without a decrease of 20% or more, sustained low-dose steroids (at or below 10 mg/day) and no use of rescue medications.

Partial remission was a composite of reduction in protein/creatinine ratio of at least 50%, no use of rescue medication, and stability of renal function. Both the low- and high-dose voclosporin groups had outcomes that were superior to standard-of-care therapy, with 69.7% partial remission with low-dose voclosporin, 65.9% partial remission with high-dose voclosporin, and 49.4% partial remission with placebo, said Dr. Dooley, a rheumatologist in Chapel Hill, N.C.

“Patients began responding literally within weeks [to voclosporin] ... and we saw significant responses by 7-8 weeks. This was during the time period when the steroids rapidly decreased,” she said, noting that the steroid dosing at baseline was a median of 25 mg vs. 2.5 mg at 16 weeks.

Study subjects met ACR criteria for lupus and had biopsy-proven lupus nephritis, including proliferative nephritis class III/IV or class V alone or in combination with proliferative disease. All were treated with 2 g/day of mycophenolate mofetil, and the steroid taper “was such that by 10 weeks, patients were down to 5 mg, and that by 24 weeks the median dose was 2.5 mg,” she said.

Adverse events, most commonly infection and gastrointestinal disorders, occurred in 90% of study subjects. Infections occurred in 56.2% of those in the low-dose group, 63.6% of those in the high-dose group, and 50% of controls. GI disorders occurred in 41.6%, 52.3%, and 36.4% of patients in the groups, respectively.

Serious adverse events were more common in the voclosporin groups, occurring in 25.8% and 25% of patients in the low- and high-dose groups, respectively, compared with 15.8% of patients in the control group.

Ten of the 13 deaths occurred in the low-dose voclosporin group (3 due to infection, 3 due to thromboembolism, and 4 due to “other” causes); 2 occurred in the high-dose voclosporin group (1 each due to infection and thromboembolism); and 1 death due to thromboembolism occurred in the control group. As most of the deaths were clustered in the low-dose arm, and 11 of the 13 deaths occurred in areas with “compromised access to standard of care,” the deaths were not considered to be directly related to voclosporin therapy.

Patients who died had “a statistically different clinical baseline picture with higher levels of proteinuria or difficulty with comorbid conditions and some signs of poor nutrition,” Dr. Dooley said.

The findings of the study will be used as the basis for planned subsequent studies of the use of voclosporin in lupus nephritis, she said.

Voclosporin is an analogue of cyclosporin A that may allow flat dosing and a potentially improved safety profile compared with other calcineurin inhibitors.

Aurinia Pharmaceuticals, the maker of voclosporin, announced in early November 2016 that the twice-daily 23.7 mg voclosporin dose will advance to a global 52-week double-blind, placebo-controlled phase III study in the second quarter of 2017. Voclosporin has already received fast track designation from the Food and Drug Administration.

Dr. Dooley reported a financial relationship with Aurinia, which sponsored the study.

sworcester@frontlinemedcom.com

WASHINGTON – The oral Janus kinase inhibitor tofacitinib is safe and effective in patients with active psoriatic arthritis and an inadequate response to tumor necrosis factor inhibitors, according to findings from the phase III OPAL Beyond trial.

Both the American College of Rheumatology 20% improvement criteria (ACR20) response rate and change from baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) scores at month 3 – the primary endpoints of the study – were superior with tofacitinib (Xeljanz) versus placebo in the 6-month, double-blind, randomized, multicenter trial, Dafna D. Gladman, MD, reported in a late-breaking poster at the annual meeting of the American College of Rheumatology.

WASHINGTON – The oral Janus kinase inhibitor tofacitinib is safe and effective in patients with active psoriatic arthritis and an inadequate response to tumor necrosis factor inhibitors, according to findings from the phase III OPAL Beyond trial.

Both the American College of Rheumatology 20% improvement criteria (ACR20) response rate and change from baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) scores at month 3 – the primary endpoints of the study – were superior with tofacitinib (Xeljanz) versus placebo in the 6-month, double-blind, randomized, multicenter trial, Dafna D. Gladman, MD, reported in a late-breaking poster at the annual meeting of the American College of Rheumatology.

WASHINGTON – The oral Janus kinase inhibitor tofacitinib is safe and effective in patients with active psoriatic arthritis and an inadequate response to tumor necrosis factor inhibitors, according to findings from the phase III OPAL Beyond trial.

Both the American College of Rheumatology 20% improvement criteria (ACR20) response rate and change from baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) scores at month 3 – the primary endpoints of the study – were superior with tofacitinib (Xeljanz) versus placebo in the 6-month, double-blind, randomized, multicenter trial, Dafna D. Gladman, MD, reported in a late-breaking poster at the annual meeting of the American College of Rheumatology.

WASHINGTON – The investigational anti-interleukin-23 monoclonal antibody guselkumab was safe and well tolerated, and demonstrated significant improvement on a variety of measures in patients with active psoriatic arthritis in a randomized, placebo-controlled phase IIa study.

The primary endpoint of ACR20 at 24 weeks was achieved in 58% of 100 patients randomized to receive treatment with guselkumab versus 18.4% of 49 patients who received placebo, Atul A. Deodhar, MD, reported in a late-breaking abstract presentation at the annual meeting of the American College of Rheumatology.

Mitchel L. Zoler/Frontline Medical News

sworcester@frontlinemedcom.com

WASHINGTON – The investigational anti-interleukin-23 monoclonal antibody guselkumab was safe and well tolerated, and demonstrated significant improvement on a variety of measures in patients with active psoriatic arthritis in a randomized, placebo-controlled phase IIa study.

The primary endpoint of ACR20 at 24 weeks was achieved in 58% of 100 patients randomized to receive treatment with guselkumab versus 18.4% of 49 patients who received placebo, Atul A. Deodhar, MD, reported in a late-breaking abstract presentation at the annual meeting of the American College of Rheumatology.

Mitchel L. Zoler/Frontline Medical News

sworcester@frontlinemedcom.com

WASHINGTON – The investigational anti-interleukin-23 monoclonal antibody guselkumab was safe and well tolerated, and demonstrated significant improvement on a variety of measures in patients with active psoriatic arthritis in a randomized, placebo-controlled phase IIa study.

The primary endpoint of ACR20 at 24 weeks was achieved in 58% of 100 patients randomized to receive treatment with guselkumab versus 18.4% of 49 patients who received placebo, Atul A. Deodhar, MD, reported in a late-breaking abstract presentation at the annual meeting of the American College of Rheumatology.

Mitchel L. Zoler/Frontline Medical News

sworcester@frontlinemedcom.com

WASHINGTON – Biologic agents should be stopped prior to elective total knee or hip arthroplasty in patients with rheumatic diseases, according to a draft guideline developed by the American College of Rheumatology and the American Association of Hip and Knee Surgeons.

The guideline, which address the perioperative management of antirheumatic medications in patients with rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, juvenile idiopathic arthritis (JIA), or lupus who are undergoing such surgery, is currently under review, Dr. Susan Goodman, MD, coprincipal investigator, reported at the annual meeting of the American College of Rheumatology.

The draft guideline was created because “guidance was needed for common clinical situations, even where data were sparse. We didn’t want to configure treatment mandates – that’s not what these are,” Dr. Goodman of Cornell University, New York, said.

The recommendations are conditional, she said, meaning that the benefits probably outweigh the harms, that the recommendations apply to most but not all patients, and that future research may lead to changes.

“They’re also preference sensitive,” she said, explaining that patients’ values and preferences should be carefully considered, as they might differ from those of the patient panel consulted during guideline development; the panel expressed greater concern about the risk of infection following surgery than about perioperative flares resulting from medication discontinuation.

Based on agreement by at least 80% of a voting panel which considered available evidence in the context of their clinical experience along with the input from the patient panel, the draft guideline states that:

• Current doses of methotrexate, leflunomide, hydroxychloroquine, and sulfasalazine should be continued in patients with rheumatic diseases undergoing elective hip and knee replacement. This recommendation is based on an extensive literature review that showed the infection rate is decreased in patients who continue these medications, Dr. Goodman said.

• All biologics should be withheld prior to surgery in patients with inflammatory arthritis, and surgery should be planned for the end of the dosing cycle. This matter wasn’t specifically addressed in the literature; however, numerous randomized controlled trials outside of the surgical setting demonstrate an increased risk of infection associated with their use, she noted.

“All of the biologic medications were found to be associated with an increased risk of infection,” she said. “Because of this and the level of importance patients place on minimizing infection risk, we’ve recommended that biologics be withheld prior to surgery.”

• Tofacitinib, which was considered in a separate oral, targeted therapy category, should be withheld for at least 7 days prior to surgery in patients with RA, spondyloarthritis, and JIA. Data from systematic reviews and meta-analyses showed an increased risk of infection with tofacitinib, although more research is needed in order to “firm up” this recommendation, Dr. Goodman said.

• In lupus patients, rituximab and belimumab should be withheld prior to surgery, and surgery should be planned for the end of the dosing period.

“Again, this was not answered in the literature. We depended on observational studies that we reviewed that did show that patients with severe active lupus were at much higher risk for adverse events. But since rituximab isn’t approved by the [Food and Drug Administration] for use in lupus, and belimumab isn’t approved for use in severe lupus – and those seem to be the high-risk patients – we thought withholding them was more prudent,” she said.

• Patients with severe lupus should continue on current doses of methotrexate, mycophenolic acid, azathioprine, mizoribine, cyclosporine, and tacrolimus through surgery. This recommendation is based on indirect data from experience in organ transplant patients.

• All medications should be discontinued in patients whose lupus is not severe.

“Our recommendation is to withhold for 7 days to 2-5 days after surgery in the absence of any wound healing complications or any other complications,” she said, noting that the literature does not directly address this; the recommendation is based on indirect evidence in patients with either active infection or who are at risk for infection.

“We thought that careful monitoring of the patient would permit us to identify flare and intervene quickly. … and that, for mild cases of lupus, the morbidity associated with infection might not be greater than the morbidity associated with the disease flare,” she said.

• Biologics should be restarted once surgical wounds show evidence of healing and there is no clinical evidence of infection. The literature does not directly address this; the recommendation is based on the rationale for use of these medications in patients with either active infection or risk for infection.

• Current daily doses of glucocorticoids, rather than supraphysiologic doses, should be continued in adults with RA, lupus, or inflammatory arthritis. A meta-analysis and systematic review of randomized controlled trial data and observational data showed no hemodynamic difference between daily doses and stress doses.

“In addition, there are abundant observational data demonstrating an increase in infection in patients on chronic steroids greater than 15 mg, and we thought that part of the optimization of the patient would be getting them on the lowest possible steroid dose,” she said, stressing that this refers only to adults receiving glucocorticoids for their rheumatic disease, and not to those with a history of JIA who may have received steroids during development, or to those receiving glucocorticoids for primary, adrenal, or hypothalamic disease.

According to Dr. Goodman, the time is right for the introduction of these recommendations, because the increased use of disease-modifying drugs and biologics means that most patients coming in for these surgeries will be taking these medications.

Further, despite the widespread use of the medications, the rate of total knee and hip arthroplasty surgeries among patients with rheumatic diseases is about the same as it was 20 or 30 years ago – and their risk for devastating complications, including infections, remains high, she said, noting that appropriate medication management provides an opportunity to mitigate risk.

Coprincipal investigator, Bryan Springer, MD, further emphasized the importance of the guideline, noting that the 5-year survival among rheumatic disease patients who develop certain perioperative complications is lower than for many common cancers, and that the literature offers little guidance on managing medications in the perioperative period.

“We now have a document that’s based on the available evidence, and also based on expert opinion, to help us manage these patients much more thoroughly in the perioperative period,” Dr. Springer, an orthopedic surgeon in Charlotte, N.C., said during a press briefing on the guideline.

Dr. Springer highlighted the value of the unique collaboration between the ACR and the AAHKS, calling the effort a win both for patients, and for “collaborative efforts, collaborative research, which we just really don’t do enough of,” he said. “I hope this is a huge step towards that direction.”

This guideline development process was funded by the ACR and AAHKS.

sworcester@frontlinemedcom.com

WASHINGTON – Biologic agents should be stopped prior to elective total knee or hip arthroplasty in patients with rheumatic diseases, according to a draft guideline developed by the American College of Rheumatology and the American Association of Hip and Knee Surgeons.

The guideline, which address the perioperative management of antirheumatic medications in patients with rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, juvenile idiopathic arthritis (JIA), or lupus who are undergoing such surgery, is currently under review, Dr. Susan Goodman, MD, coprincipal investigator, reported at the annual meeting of the American College of Rheumatology.

The draft guideline was created because “guidance was needed for common clinical situations, even where data were sparse. We didn’t want to configure treatment mandates – that’s not what these are,” Dr. Goodman of Cornell University, New York, said.

The recommendations are conditional, she said, meaning that the benefits probably outweigh the harms, that the recommendations apply to most but not all patients, and that future research may lead to changes.

“They’re also preference sensitive,” she said, explaining that patients’ values and preferences should be carefully considered, as they might differ from those of the patient panel consulted during guideline development; the panel expressed greater concern about the risk of infection following surgery than about perioperative flares resulting from medication discontinuation.

Based on agreement by at least 80% of a voting panel which considered available evidence in the context of their clinical experience along with the input from the patient panel, the draft guideline states that:

• Current doses of methotrexate, leflunomide, hydroxychloroquine, and sulfasalazine should be continued in patients with rheumatic diseases undergoing elective hip and knee replacement. This recommendation is based on an extensive literature review that showed the infection rate is decreased in patients who continue these medications, Dr. Goodman said.

• All biologics should be withheld prior to surgery in patients with inflammatory arthritis, and surgery should be planned for the end of the dosing cycle. This matter wasn’t specifically addressed in the literature; however, numerous randomized controlled trials outside of the surgical setting demonstrate an increased risk of infection associated with their use, she noted.

“All of the biologic medications were found to be associated with an increased risk of infection,” she said. “Because of this and the level of importance patients place on minimizing infection risk, we’ve recommended that biologics be withheld prior to surgery.”

• Tofacitinib, which was considered in a separate oral, targeted therapy category, should be withheld for at least 7 days prior to surgery in patients with RA, spondyloarthritis, and JIA. Data from systematic reviews and meta-analyses showed an increased risk of infection with tofacitinib, although more research is needed in order to “firm up” this recommendation, Dr. Goodman said.

• In lupus patients, rituximab and belimumab should be withheld prior to surgery, and surgery should be planned for the end of the dosing period.

“Again, this was not answered in the literature. We depended on observational studies that we reviewed that did show that patients with severe active lupus were at much higher risk for adverse events. But since rituximab isn’t approved by the [Food and Drug Administration] for use in lupus, and belimumab isn’t approved for use in severe lupus – and those seem to be the high-risk patients – we thought withholding them was more prudent,” she said.

• Patients with severe lupus should continue on current doses of methotrexate, mycophenolic acid, azathioprine, mizoribine, cyclosporine, and tacrolimus through surgery. This recommendation is based on indirect data from experience in organ transplant patients.

• All medications should be discontinued in patients whose lupus is not severe.

“Our recommendation is to withhold for 7 days to 2-5 days after surgery in the absence of any wound healing complications or any other complications,” she said, noting that the literature does not directly address this; the recommendation is based on indirect evidence in patients with either active infection or who are at risk for infection.

“We thought that careful monitoring of the patient would permit us to identify flare and intervene quickly. … and that, for mild cases of lupus, the morbidity associated with infection might not be greater than the morbidity associated with the disease flare,” she said.

• Biologics should be restarted once surgical wounds show evidence of healing and there is no clinical evidence of infection. The literature does not directly address this; the recommendation is based on the rationale for use of these medications in patients with either active infection or risk for infection.

• Current daily doses of glucocorticoids, rather than supraphysiologic doses, should be continued in adults with RA, lupus, or inflammatory arthritis. A meta-analysis and systematic review of randomized controlled trial data and observational data showed no hemodynamic difference between daily doses and stress doses.

“In addition, there are abundant observational data demonstrating an increase in infection in patients on chronic steroids greater than 15 mg, and we thought that part of the optimization of the patient would be getting them on the lowest possible steroid dose,” she said, stressing that this refers only to adults receiving glucocorticoids for their rheumatic disease, and not to those with a history of JIA who may have received steroids during development, or to those receiving glucocorticoids for primary, adrenal, or hypothalamic disease.

According to Dr. Goodman, the time is right for the introduction of these recommendations, because the increased use of disease-modifying drugs and biologics means that most patients coming in for these surgeries will be taking these medications.

Further, despite the widespread use of the medications, the rate of total knee and hip arthroplasty surgeries among patients with rheumatic diseases is about the same as it was 20 or 30 years ago – and their risk for devastating complications, including infections, remains high, she said, noting that appropriate medication management provides an opportunity to mitigate risk.

Coprincipal investigator, Bryan Springer, MD, further emphasized the importance of the guideline, noting that the 5-year survival among rheumatic disease patients who develop certain perioperative complications is lower than for many common cancers, and that the literature offers little guidance on managing medications in the perioperative period.

“We now have a document that’s based on the available evidence, and also based on expert opinion, to help us manage these patients much more thoroughly in the perioperative period,” Dr. Springer, an orthopedic surgeon in Charlotte, N.C., said during a press briefing on the guideline.

Dr. Springer highlighted the value of the unique collaboration between the ACR and the AAHKS, calling the effort a win both for patients, and for “collaborative efforts, collaborative research, which we just really don’t do enough of,” he said. “I hope this is a huge step towards that direction.”

This guideline development process was funded by the ACR and AAHKS.

sworcester@frontlinemedcom.com

WASHINGTON – Biologic agents should be stopped prior to elective total knee or hip arthroplasty in patients with rheumatic diseases, according to a draft guideline developed by the American College of Rheumatology and the American Association of Hip and Knee Surgeons.

The guideline, which address the perioperative management of antirheumatic medications in patients with rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, juvenile idiopathic arthritis (JIA), or lupus who are undergoing such surgery, is currently under review, Dr. Susan Goodman, MD, coprincipal investigator, reported at the annual meeting of the American College of Rheumatology.

The draft guideline was created because “guidance was needed for common clinical situations, even where data were sparse. We didn’t want to configure treatment mandates – that’s not what these are,” Dr. Goodman of Cornell University, New York, said.

The recommendations are conditional, she said, meaning that the benefits probably outweigh the harms, that the recommendations apply to most but not all patients, and that future research may lead to changes.

“They’re also preference sensitive,” she said, explaining that patients’ values and preferences should be carefully considered, as they might differ from those of the patient panel consulted during guideline development; the panel expressed greater concern about the risk of infection following surgery than about perioperative flares resulting from medication discontinuation.

Based on agreement by at least 80% of a voting panel which considered available evidence in the context of their clinical experience along with the input from the patient panel, the draft guideline states that:

• Current doses of methotrexate, leflunomide, hydroxychloroquine, and sulfasalazine should be continued in patients with rheumatic diseases undergoing elective hip and knee replacement. This recommendation is based on an extensive literature review that showed the infection rate is decreased in patients who continue these medications, Dr. Goodman said.

• All biologics should be withheld prior to surgery in patients with inflammatory arthritis, and surgery should be planned for the end of the dosing cycle. This matter wasn’t specifically addressed in the literature; however, numerous randomized controlled trials outside of the surgical setting demonstrate an increased risk of infection associated with their use, she noted.

“All of the biologic medications were found to be associated with an increased risk of infection,” she said. “Because of this and the level of importance patients place on minimizing infection risk, we’ve recommended that biologics be withheld prior to surgery.”

• Tofacitinib, which was considered in a separate oral, targeted therapy category, should be withheld for at least 7 days prior to surgery in patients with RA, spondyloarthritis, and JIA. Data from systematic reviews and meta-analyses showed an increased risk of infection with tofacitinib, although more research is needed in order to “firm up” this recommendation, Dr. Goodman said.

• In lupus patients, rituximab and belimumab should be withheld prior to surgery, and surgery should be planned for the end of the dosing period.

“Again, this was not answered in the literature. We depended on observational studies that we reviewed that did show that patients with severe active lupus were at much higher risk for adverse events. But since rituximab isn’t approved by the [Food and Drug Administration] for use in lupus, and belimumab isn’t approved for use in severe lupus – and those seem to be the high-risk patients – we thought withholding them was more prudent,” she said.

• Patients with severe lupus should continue on current doses of methotrexate, mycophenolic acid, azathioprine, mizoribine, cyclosporine, and tacrolimus through surgery. This recommendation is based on indirect data from experience in organ transplant patients.

• All medications should be discontinued in patients whose lupus is not severe.

“Our recommendation is to withhold for 7 days to 2-5 days after surgery in the absence of any wound healing complications or any other complications,” she said, noting that the literature does not directly address this; the recommendation is based on indirect evidence in patients with either active infection or who are at risk for infection.

“We thought that careful monitoring of the patient would permit us to identify flare and intervene quickly. … and that, for mild cases of lupus, the morbidity associated with infection might not be greater than the morbidity associated with the disease flare,” she said.

• Biologics should be restarted once surgical wounds show evidence of healing and there is no clinical evidence of infection. The literature does not directly address this; the recommendation is based on the rationale for use of these medications in patients with either active infection or risk for infection.

• Current daily doses of glucocorticoids, rather than supraphysiologic doses, should be continued in adults with RA, lupus, or inflammatory arthritis. A meta-analysis and systematic review of randomized controlled trial data and observational data showed no hemodynamic difference between daily doses and stress doses.

“In addition, there are abundant observational data demonstrating an increase in infection in patients on chronic steroids greater than 15 mg, and we thought that part of the optimization of the patient would be getting them on the lowest possible steroid dose,” she said, stressing that this refers only to adults receiving glucocorticoids for their rheumatic disease, and not to those with a history of JIA who may have received steroids during development, or to those receiving glucocorticoids for primary, adrenal, or hypothalamic disease.

According to Dr. Goodman, the time is right for the introduction of these recommendations, because the increased use of disease-modifying drugs and biologics means that most patients coming in for these surgeries will be taking these medications.

Further, despite the widespread use of the medications, the rate of total knee and hip arthroplasty surgeries among patients with rheumatic diseases is about the same as it was 20 or 30 years ago – and their risk for devastating complications, including infections, remains high, she said, noting that appropriate medication management provides an opportunity to mitigate risk.

Coprincipal investigator, Bryan Springer, MD, further emphasized the importance of the guideline, noting that the 5-year survival among rheumatic disease patients who develop certain perioperative complications is lower than for many common cancers, and that the literature offers little guidance on managing medications in the perioperative period.

“We now have a document that’s based on the available evidence, and also based on expert opinion, to help us manage these patients much more thoroughly in the perioperative period,” Dr. Springer, an orthopedic surgeon in Charlotte, N.C., said during a press briefing on the guideline.

Dr. Springer highlighted the value of the unique collaboration between the ACR and the AAHKS, calling the effort a win both for patients, and for “collaborative efforts, collaborative research, which we just really don’t do enough of,” he said. “I hope this is a huge step towards that direction.”

This guideline development process was funded by the ACR and AAHKS.

sworcester@frontlinemedcom.com