Sharon Worcester

SAN DIEGO – The potential rituximab biosimilar drug PF-05280586 showed efficacy, safety, immunogenicity, pharmacokinetics, and pharmacodynamics similar to those of rituximab at up to 26 weeks in a randomized phase 3 study of treatment-naive patients with CD20-positive low tumor burden follicular lymphoma (LTB-FL).

Sharon Worcester/MDedge News

The primary endpoint of overall response rate at 26 weeks was 75.5% in 196 patients randomized to receive PF-05280586, and 70.7% in 198 patients who received a rituximab reference product sourced from the European Union (MabThera; rituximab‑EU), Jeff Sharman, MD, reported at the annual meeting of the American Society of Hematology.

“This resulted in a difference between the two arms of 4.66%,” said Dr. Sharman of Willamette Valley Cancer Institute and Research Center, Springfield, Ore.

The 95% confidence interval for this difference ... was entirely contained within the prespecified equivalence margin, he said.

“Depth of response was a key secondary endpoint, and rates of complete response were 29.3% and 30.4%, respectively,” he said, noting that rates of partial response, stable response, and progressive disease were also similar between the two study arms.

Estimated 1-year progression-free survival (PFS) rates were also highly similar at 76.4% and 81.2% in the PF-05280586 and rituximab-EU arms.


Rapid depletion in CD19-positive B-cell counts was observed in both groups after initial dosing, with recovery by week 39 and a sustained increase until the end of week 52.

Treatment-emergent adverse events (TEAEs) occurred in 78.6% vs. 72.1% of patients in the PF‑05280586 vs. rituximab‑EU arms, respectively, and the rates of serious adverse events and grade 3 events were similar in the groups, as were rates of infusion interruptions or infusion-related reactions (IRRs), Dr. Sharman said.

IRRs occurred in about 25% of patients in each arm, and most were grade 1 or 2. Grade 3 IRRs occurred in 2.6% vs. 0.5% of patients in the groups, respectively, and no grade 4 IRRs occurred.

Rates of anti-drug antibodies were also similar in the two groups, as were serum drug concentrations – regardless of anti-drug antibody status, he noted.

Study subjects were adults with a mean age of 60 years and histologically confirmed CD20-positive grade 1-3a follicular lymphoma with no prior rituximab or system therapy for B-cell non-Hodgkin lymphoma (NHL). They had Ann Arbor disease stages II (26.9%), III (44.2%) or IV (28.9%), ECOG performance status of 0-1, and at least 1 measurable disease lesion identifiable on imaging.

Risk level as assessed by the Follicular Lymphoma International Prognostic Index–2 was low in 28.4%, medium in 66%, and high in 5.6% of patients.

Treatment with each agent was given at intravenous doses of 375 mg/m² weekly for 4 weeks at days 1, 8, 15, and 22.

PF-05280586 is being developed by Pfizer, and in this 52-week double-blind study – the largest study to date of the early use of the potential rituximab biosimilar in patients with previously untreated CD20-positive LTB-FL – the primary endpoint was met, demonstrating its therapeutic equivalence with rituximab-EU for overall response rate at week 26, Dr. Sharman said.

“These results therefore confirm the biosimilarity of PF-05280586 with rituximab-EU,” he concluded.

Of note, the reporting of these findings comes on the heels of the first Food and Drug Administration approval of a biosimilar rituximab product for the treatment of NHL; Celltrion’s product Truxima (formerly CT-P10), a biosimilar of Genentech’s Rituxan (rituximab), was approved Nov. 28 to treat adults with CD20-positive, B-cell NHL, either as a single agent or in combination with chemotherapy.

The PF-0528056 study was sponsored by Pfizer. Dr. Sharman has been a consultant for, and/or received research funding and honoraria from Acerta, Pharmacyclics (an AbbVie Company), Pfizer, TG Therapeutics, Abbvie, and Genentech.

SOURCE: Sharman J et al. ASH 2018: Abstract 394.

SAN DIEGO – The potential rituximab biosimilar drug PF-05280586 showed efficacy, safety, immunogenicity, pharmacokinetics, and pharmacodynamics similar to those of rituximab at up to 26 weeks in a randomized phase 3 study of treatment-naive patients with CD20-positive low tumor burden follicular lymphoma (LTB-FL).

Sharon Worcester/MDedge News

The primary endpoint of overall response rate at 26 weeks was 75.5% in 196 patients randomized to receive PF-05280586, and 70.7% in 198 patients who received a rituximab reference product sourced from the European Union (MabThera; rituximab‑EU), Jeff Sharman, MD, reported at the annual meeting of the American Society of Hematology.

“This resulted in a difference between the two arms of 4.66%,” said Dr. Sharman of Willamette Valley Cancer Institute and Research Center, Springfield, Ore.

The 95% confidence interval for this difference ... was entirely contained within the prespecified equivalence margin, he said.

“Depth of response was a key secondary endpoint, and rates of complete response were 29.3% and 30.4%, respectively,” he said, noting that rates of partial response, stable response, and progressive disease were also similar between the two study arms.

Estimated 1-year progression-free survival (PFS) rates were also highly similar at 76.4% and 81.2% in the PF-05280586 and rituximab-EU arms.


Rapid depletion in CD19-positive B-cell counts was observed in both groups after initial dosing, with recovery by week 39 and a sustained increase until the end of week 52.

Treatment-emergent adverse events (TEAEs) occurred in 78.6% vs. 72.1% of patients in the PF‑05280586 vs. rituximab‑EU arms, respectively, and the rates of serious adverse events and grade 3 events were similar in the groups, as were rates of infusion interruptions or infusion-related reactions (IRRs), Dr. Sharman said.

IRRs occurred in about 25% of patients in each arm, and most were grade 1 or 2. Grade 3 IRRs occurred in 2.6% vs. 0.5% of patients in the groups, respectively, and no grade 4 IRRs occurred.

Rates of anti-drug antibodies were also similar in the two groups, as were serum drug concentrations – regardless of anti-drug antibody status, he noted.

Study subjects were adults with a mean age of 60 years and histologically confirmed CD20-positive grade 1-3a follicular lymphoma with no prior rituximab or system therapy for B-cell non-Hodgkin lymphoma (NHL). They had Ann Arbor disease stages II (26.9%), III (44.2%) or IV (28.9%), ECOG performance status of 0-1, and at least 1 measurable disease lesion identifiable on imaging.

Risk level as assessed by the Follicular Lymphoma International Prognostic Index–2 was low in 28.4%, medium in 66%, and high in 5.6% of patients.

Treatment with each agent was given at intravenous doses of 375 mg/m² weekly for 4 weeks at days 1, 8, 15, and 22.

PF-05280586 is being developed by Pfizer, and in this 52-week double-blind study – the largest study to date of the early use of the potential rituximab biosimilar in patients with previously untreated CD20-positive LTB-FL – the primary endpoint was met, demonstrating its therapeutic equivalence with rituximab-EU for overall response rate at week 26, Dr. Sharman said.

“These results therefore confirm the biosimilarity of PF-05280586 with rituximab-EU,” he concluded.

Of note, the reporting of these findings comes on the heels of the first Food and Drug Administration approval of a biosimilar rituximab product for the treatment of NHL; Celltrion’s product Truxima (formerly CT-P10), a biosimilar of Genentech’s Rituxan (rituximab), was approved Nov. 28 to treat adults with CD20-positive, B-cell NHL, either as a single agent or in combination with chemotherapy.

The PF-0528056 study was sponsored by Pfizer. Dr. Sharman has been a consultant for, and/or received research funding and honoraria from Acerta, Pharmacyclics (an AbbVie Company), Pfizer, TG Therapeutics, Abbvie, and Genentech.

SOURCE: Sharman J et al. ASH 2018: Abstract 394.

SAN DIEGO – The potential rituximab biosimilar drug PF-05280586 showed efficacy, safety, immunogenicity, pharmacokinetics, and pharmacodynamics similar to those of rituximab at up to 26 weeks in a randomized phase 3 study of treatment-naive patients with CD20-positive low tumor burden follicular lymphoma (LTB-FL).

Sharon Worcester/MDedge News

The primary endpoint of overall response rate at 26 weeks was 75.5% in 196 patients randomized to receive PF-05280586, and 70.7% in 198 patients who received a rituximab reference product sourced from the European Union (MabThera; rituximab‑EU), Jeff Sharman, MD, reported at the annual meeting of the American Society of Hematology.

“This resulted in a difference between the two arms of 4.66%,” said Dr. Sharman of Willamette Valley Cancer Institute and Research Center, Springfield, Ore.

The 95% confidence interval for this difference ... was entirely contained within the prespecified equivalence margin, he said.

“Depth of response was a key secondary endpoint, and rates of complete response were 29.3% and 30.4%, respectively,” he said, noting that rates of partial response, stable response, and progressive disease were also similar between the two study arms.

Estimated 1-year progression-free survival (PFS) rates were also highly similar at 76.4% and 81.2% in the PF-05280586 and rituximab-EU arms.


Rapid depletion in CD19-positive B-cell counts was observed in both groups after initial dosing, with recovery by week 39 and a sustained increase until the end of week 52.

Treatment-emergent adverse events (TEAEs) occurred in 78.6% vs. 72.1% of patients in the PF‑05280586 vs. rituximab‑EU arms, respectively, and the rates of serious adverse events and grade 3 events were similar in the groups, as were rates of infusion interruptions or infusion-related reactions (IRRs), Dr. Sharman said.

IRRs occurred in about 25% of patients in each arm, and most were grade 1 or 2. Grade 3 IRRs occurred in 2.6% vs. 0.5% of patients in the groups, respectively, and no grade 4 IRRs occurred.

Rates of anti-drug antibodies were also similar in the two groups, as were serum drug concentrations – regardless of anti-drug antibody status, he noted.

Study subjects were adults with a mean age of 60 years and histologically confirmed CD20-positive grade 1-3a follicular lymphoma with no prior rituximab or system therapy for B-cell non-Hodgkin lymphoma (NHL). They had Ann Arbor disease stages II (26.9%), III (44.2%) or IV (28.9%), ECOG performance status of 0-1, and at least 1 measurable disease lesion identifiable on imaging.

Risk level as assessed by the Follicular Lymphoma International Prognostic Index–2 was low in 28.4%, medium in 66%, and high in 5.6% of patients.

Treatment with each agent was given at intravenous doses of 375 mg/m² weekly for 4 weeks at days 1, 8, 15, and 22.

PF-05280586 is being developed by Pfizer, and in this 52-week double-blind study – the largest study to date of the early use of the potential rituximab biosimilar in patients with previously untreated CD20-positive LTB-FL – the primary endpoint was met, demonstrating its therapeutic equivalence with rituximab-EU for overall response rate at week 26, Dr. Sharman said.

“These results therefore confirm the biosimilarity of PF-05280586 with rituximab-EU,” he concluded.

Of note, the reporting of these findings comes on the heels of the first Food and Drug Administration approval of a biosimilar rituximab product for the treatment of NHL; Celltrion’s product Truxima (formerly CT-P10), a biosimilar of Genentech’s Rituxan (rituximab), was approved Nov. 28 to treat adults with CD20-positive, B-cell NHL, either as a single agent or in combination with chemotherapy.

The PF-0528056 study was sponsored by Pfizer. Dr. Sharman has been a consultant for, and/or received research funding and honoraria from Acerta, Pharmacyclics (an AbbVie Company), Pfizer, TG Therapeutics, Abbvie, and Genentech.

SOURCE: Sharman J et al. ASH 2018: Abstract 394.

SAN DIEGO – Therapeutic expression of factor IX remains stable with no late toxicities occurring at up to 8.6 years after a single infusion of a novel gene therapy in patients with severe hemophilia B, according to interim follow-up data from a phase 1/2 dose-escalation study.

The therapy – a self-complementary adeno-associated virus vector containing a codon-optimized factor IX gene, under control of a synthetic liver specific promoter and pseudotyped with serotype 8 capsid (scAAV2/8-LP1-hFIXco) – was previously shown to result in a dose-dependent increase in plasma factor IX levels in all 10 patients enrolled in the study, and an earlier update showed stable factor IX activity for at least 3 years, Ulrike M. Reiss, MD, reported at the annual meeting of the American Society of Hematology.

However, declining factor IX expression over time remains a concern, because AAV-mediated transgene expression is mediated mainly by episomally retained viral genomes, which may be lost with natural turnover of hepatocytes, noted Dr. Reiss, director of the clinical hematology division and the Hemophilia Treatment Center at St. Jude Children’s Research Hospital in Memphis.

At the “halfway mark,” with a median follow-up of 6.7 years in 10 patients aged 18-64 years who were treated with doses of either 2 x 10¹¹, 6 x 10¹¹, or 2 x 10¹² vector genomes per kg (in 2, 2, and 6 patients, respectively), “factor IX expression has been persistent and stable in all participants after vector infusion,” she said.

“Factor IX expression was vector-dose dependent, achieving average levels of 1.9%-2.3% at the lower doses, and 5.1% at the high vector dose. All patients converted from having severe hemophilia to mild-moderate hemophilia,” she added.

The single significant adverse event observed during annual follow-up evaluations in the patients was a vector-related, immune-mediated liver inflammation occurring within 2-3 months of infusion in four of the six high-dose participants.

“There was complete resolution in all cases after a short course of corticosteroids over 8-12 weeks, including the taper. There were no late sequelae or any recurrence of transaminitis over time,” Dr. Reiss said. “We did not observe any new factor IX inhibitor or any late toxicity in any of these participants.”

Additionally, a comparison of average data across 3 years prior to gene therapy with the average data at 6.7 years after gene therapy showed that the annualized bleed rate decreased by 82% in the 10 participants and factor IX use decreased by 66%. In the high-dose group, the bleed rate decreased from 21 bleeds to 2 bleeds per year, and vector consumption was markedly reduced to a mean of 500 IU/kg per year from a mean of more than 2800 IU/kg per year. “Only one of the six patients in the high-dose group currently continues on prophylaxis treatment, whereas three in the low- and mid-dose groups are currently on prophylaxis,” she said. “In all [patients], the interval between prophylactic infusions has lengthened.”

Of note, Dr. Reiss and her colleagues explored the ability of using a modified, empty capsid-reduced vector preparation of the gene therapy to prevent the transaminitis seen in the 2-3 months after infusion. A new clinical preparation of scAAV2/8-LP1-hFIXco was manufactured with most of the empty particles removed by cesium chloride density centrifugation, but this approach provided no benefit in that regard.

“This further supports the observation that the anticapsid immune response is vector-dose dependent,” she said.

Additionally, the pattern of humoral response to AAV8 capsid was consistent with the primary immune response in participants.

“High IgG antibody titers have persisted for over 6 years; this finding is important because it will preclude these patients from any retreatment with the same vector or even potentially alternative AAV vectors of other serotypes with cross-reactive antigenicity,” she said.

Dr. Reiss reported having no relevant disclosures

[email protected]

SOURCE: Reiss UM et al. ASH 2018, Abstract 491.

SAN DIEGO – Therapeutic expression of factor IX remains stable with no late toxicities occurring at up to 8.6 years after a single infusion of a novel gene therapy in patients with severe hemophilia B, according to interim follow-up data from a phase 1/2 dose-escalation study.

The therapy – a self-complementary adeno-associated virus vector containing a codon-optimized factor IX gene, under control of a synthetic liver specific promoter and pseudotyped with serotype 8 capsid (scAAV2/8-LP1-hFIXco) – was previously shown to result in a dose-dependent increase in plasma factor IX levels in all 10 patients enrolled in the study, and an earlier update showed stable factor IX activity for at least 3 years, Ulrike M. Reiss, MD, reported at the annual meeting of the American Society of Hematology.

However, declining factor IX expression over time remains a concern, because AAV-mediated transgene expression is mediated mainly by episomally retained viral genomes, which may be lost with natural turnover of hepatocytes, noted Dr. Reiss, director of the clinical hematology division and the Hemophilia Treatment Center at St. Jude Children’s Research Hospital in Memphis.

At the “halfway mark,” with a median follow-up of 6.7 years in 10 patients aged 18-64 years who were treated with doses of either 2 x 10¹¹, 6 x 10¹¹, or 2 x 10¹² vector genomes per kg (in 2, 2, and 6 patients, respectively), “factor IX expression has been persistent and stable in all participants after vector infusion,” she said.

“Factor IX expression was vector-dose dependent, achieving average levels of 1.9%-2.3% at the lower doses, and 5.1% at the high vector dose. All patients converted from having severe hemophilia to mild-moderate hemophilia,” she added.

The single significant adverse event observed during annual follow-up evaluations in the patients was a vector-related, immune-mediated liver inflammation occurring within 2-3 months of infusion in four of the six high-dose participants.

“There was complete resolution in all cases after a short course of corticosteroids over 8-12 weeks, including the taper. There were no late sequelae or any recurrence of transaminitis over time,” Dr. Reiss said. “We did not observe any new factor IX inhibitor or any late toxicity in any of these participants.”

Additionally, a comparison of average data across 3 years prior to gene therapy with the average data at 6.7 years after gene therapy showed that the annualized bleed rate decreased by 82% in the 10 participants and factor IX use decreased by 66%. In the high-dose group, the bleed rate decreased from 21 bleeds to 2 bleeds per year, and vector consumption was markedly reduced to a mean of 500 IU/kg per year from a mean of more than 2800 IU/kg per year. “Only one of the six patients in the high-dose group currently continues on prophylaxis treatment, whereas three in the low- and mid-dose groups are currently on prophylaxis,” she said. “In all [patients], the interval between prophylactic infusions has lengthened.”

Of note, Dr. Reiss and her colleagues explored the ability of using a modified, empty capsid-reduced vector preparation of the gene therapy to prevent the transaminitis seen in the 2-3 months after infusion. A new clinical preparation of scAAV2/8-LP1-hFIXco was manufactured with most of the empty particles removed by cesium chloride density centrifugation, but this approach provided no benefit in that regard.

“This further supports the observation that the anticapsid immune response is vector-dose dependent,” she said.

Additionally, the pattern of humoral response to AAV8 capsid was consistent with the primary immune response in participants.

“High IgG antibody titers have persisted for over 6 years; this finding is important because it will preclude these patients from any retreatment with the same vector or even potentially alternative AAV vectors of other serotypes with cross-reactive antigenicity,” she said.

Dr. Reiss reported having no relevant disclosures

[email protected]

SOURCE: Reiss UM et al. ASH 2018, Abstract 491.

SAN DIEGO – Therapeutic expression of factor IX remains stable with no late toxicities occurring at up to 8.6 years after a single infusion of a novel gene therapy in patients with severe hemophilia B, according to interim follow-up data from a phase 1/2 dose-escalation study.

The therapy – a self-complementary adeno-associated virus vector containing a codon-optimized factor IX gene, under control of a synthetic liver specific promoter and pseudotyped with serotype 8 capsid (scAAV2/8-LP1-hFIXco) – was previously shown to result in a dose-dependent increase in plasma factor IX levels in all 10 patients enrolled in the study, and an earlier update showed stable factor IX activity for at least 3 years, Ulrike M. Reiss, MD, reported at the annual meeting of the American Society of Hematology.

However, declining factor IX expression over time remains a concern, because AAV-mediated transgene expression is mediated mainly by episomally retained viral genomes, which may be lost with natural turnover of hepatocytes, noted Dr. Reiss, director of the clinical hematology division and the Hemophilia Treatment Center at St. Jude Children’s Research Hospital in Memphis.

At the “halfway mark,” with a median follow-up of 6.7 years in 10 patients aged 18-64 years who were treated with doses of either 2 x 10¹¹, 6 x 10¹¹, or 2 x 10¹² vector genomes per kg (in 2, 2, and 6 patients, respectively), “factor IX expression has been persistent and stable in all participants after vector infusion,” she said.

“Factor IX expression was vector-dose dependent, achieving average levels of 1.9%-2.3% at the lower doses, and 5.1% at the high vector dose. All patients converted from having severe hemophilia to mild-moderate hemophilia,” she added.

The single significant adverse event observed during annual follow-up evaluations in the patients was a vector-related, immune-mediated liver inflammation occurring within 2-3 months of infusion in four of the six high-dose participants.

“There was complete resolution in all cases after a short course of corticosteroids over 8-12 weeks, including the taper. There were no late sequelae or any recurrence of transaminitis over time,” Dr. Reiss said. “We did not observe any new factor IX inhibitor or any late toxicity in any of these participants.”

Additionally, a comparison of average data across 3 years prior to gene therapy with the average data at 6.7 years after gene therapy showed that the annualized bleed rate decreased by 82% in the 10 participants and factor IX use decreased by 66%. In the high-dose group, the bleed rate decreased from 21 bleeds to 2 bleeds per year, and vector consumption was markedly reduced to a mean of 500 IU/kg per year from a mean of more than 2800 IU/kg per year. “Only one of the six patients in the high-dose group currently continues on prophylaxis treatment, whereas three in the low- and mid-dose groups are currently on prophylaxis,” she said. “In all [patients], the interval between prophylactic infusions has lengthened.”

Of note, Dr. Reiss and her colleagues explored the ability of using a modified, empty capsid-reduced vector preparation of the gene therapy to prevent the transaminitis seen in the 2-3 months after infusion. A new clinical preparation of scAAV2/8-LP1-hFIXco was manufactured with most of the empty particles removed by cesium chloride density centrifugation, but this approach provided no benefit in that regard.

“This further supports the observation that the anticapsid immune response is vector-dose dependent,” she said.

Additionally, the pattern of humoral response to AAV8 capsid was consistent with the primary immune response in participants.

“High IgG antibody titers have persisted for over 6 years; this finding is important because it will preclude these patients from any retreatment with the same vector or even potentially alternative AAV vectors of other serotypes with cross-reactive antigenicity,” she said.

Dr. Reiss reported having no relevant disclosures

[email protected]

SOURCE: Reiss UM et al. ASH 2018, Abstract 491.

CHICAGO – Nonwhite ethnicity and limb infection at diagnosis predict vascular events in patients with thromboangiitis obliterans (TAO), and the latter also predicts amputation, which occurs within 10 years of diagnosis in nearly a third of patients, according to findings from a large retrospective French cohort study.

Shidlovski/gettyimages

After a mean follow-up of 5.7 years, 58.9% of 224 patients with TAO – also known as Buerger’s disease – experienced a vascular event, 21.4% experienced at least one amputation, and 1.3% died, Alexandre Le Joncour, MD, reported at the annual meeting of the American College of Rheumatology.

The 5- and 15-year vascular event-free survival rates were 45% and 28%, respectively, and the 10- and 15-year amputation-free survival rates were 74%, and 66%, respectively, said Dr. Le Joncour of Sorbonne University, Paris.

Of note, no significant difference was seen in the vascular event-free survival rates based on tobacco use levels (more than 22 pack-years vs. 22 or fewer pack-years; HR, 1.2), he said.

Patient characteristics and clinical factors found to independently predict vascular events included nonwhite ethnicity (hazard ratio, 2.35; P = .005) and limb infection at diagnosis (HR, 3.29; P = .045). Limb infection at diagnosis also independently predicted amputation (HR, 12.1; P less than .001), he said.

“But there was no significant [association with amputation] in patients who had claudication, critical ischemia, or ischemic ulcers/necrosis,” he noted, adding that a comparison of white and nonwhite patients showed that the groups were similar with respect to epidemiologic and cardiovascular factors, clinical symptom distribution, and rates of addiction to tobacco, alcohol, and illicit drugs.

It was also clear that patients who quit using tobacco had a significantly lower risk of amputation than did those who continued using tobacco (P = .001), he said, explaining that 43 of the 48 patients who experienced amputation were current smokers, and 5 were ex-smokers at the time of amputation.

Dr. Le Joncour and his colleagues included TAO patients diagnosed between 1967 and 2016 at a median age of 36 years at the time of first symptoms, with a median of 12 months from symptom onset until diagnosis. About 76% were men, and about 83% were white. Patients with diabetes, atherosclerosis, arterial emboli, connective tissue disease, and/or thrombophilia were excluded.

Vascular events in this study were defined as “an acute worsening of the disease course requiring treatment modifications,” and included critical ischemia (35% of cases), ulcers/necrosis (33%), claudication worsening (16%), deep vein thrombosis (3%), superficial phlebitis (7%), limb infection (4%), and “other” events (2%).

Major amputation was defined as “an amputation involving the tibio-tarsian articulation for lower limbs and the metacarpophalangeal articulation for upper limbs,” he explained.

The median time to amputation was 4 years, and patients who experienced amputation had a median age of 39 years. Half of the 48 patients who experienced amputation had one amputation, nearly a third had two amputations, and 19% had three amputations. About two-thirds had minor amputations and a third had major amputations.

The findings provide important prognostic information regarding TAO, Dr. Le Joncour said, noting that long-term data on outcomes in TAO patients have been lacking.

“We found specific characteristics that identified those at highest risk for subsequent vascular complications, and these factors are not only important predictors of vascular complications or relapse, but may also serve to adjust more aggressive management and close follow-up of these patients,” he concluded.

Dr. Le Joncour reported having no disclosures.

[email protected]

SOURCE: Le Joncour A et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract 1885.

CHICAGO – Nonwhite ethnicity and limb infection at diagnosis predict vascular events in patients with thromboangiitis obliterans (TAO), and the latter also predicts amputation, which occurs within 10 years of diagnosis in nearly a third of patients, according to findings from a large retrospective French cohort study.

Shidlovski/gettyimages

After a mean follow-up of 5.7 years, 58.9% of 224 patients with TAO – also known as Buerger’s disease – experienced a vascular event, 21.4% experienced at least one amputation, and 1.3% died, Alexandre Le Joncour, MD, reported at the annual meeting of the American College of Rheumatology.

The 5- and 15-year vascular event-free survival rates were 45% and 28%, respectively, and the 10- and 15-year amputation-free survival rates were 74%, and 66%, respectively, said Dr. Le Joncour of Sorbonne University, Paris.

Of note, no significant difference was seen in the vascular event-free survival rates based on tobacco use levels (more than 22 pack-years vs. 22 or fewer pack-years; HR, 1.2), he said.

Patient characteristics and clinical factors found to independently predict vascular events included nonwhite ethnicity (hazard ratio, 2.35; P = .005) and limb infection at diagnosis (HR, 3.29; P = .045). Limb infection at diagnosis also independently predicted amputation (HR, 12.1; P less than .001), he said.

“But there was no significant [association with amputation] in patients who had claudication, critical ischemia, or ischemic ulcers/necrosis,” he noted, adding that a comparison of white and nonwhite patients showed that the groups were similar with respect to epidemiologic and cardiovascular factors, clinical symptom distribution, and rates of addiction to tobacco, alcohol, and illicit drugs.

It was also clear that patients who quit using tobacco had a significantly lower risk of amputation than did those who continued using tobacco (P = .001), he said, explaining that 43 of the 48 patients who experienced amputation were current smokers, and 5 were ex-smokers at the time of amputation.

Dr. Le Joncour and his colleagues included TAO patients diagnosed between 1967 and 2016 at a median age of 36 years at the time of first symptoms, with a median of 12 months from symptom onset until diagnosis. About 76% were men, and about 83% were white. Patients with diabetes, atherosclerosis, arterial emboli, connective tissue disease, and/or thrombophilia were excluded.

Vascular events in this study were defined as “an acute worsening of the disease course requiring treatment modifications,” and included critical ischemia (35% of cases), ulcers/necrosis (33%), claudication worsening (16%), deep vein thrombosis (3%), superficial phlebitis (7%), limb infection (4%), and “other” events (2%).

Major amputation was defined as “an amputation involving the tibio-tarsian articulation for lower limbs and the metacarpophalangeal articulation for upper limbs,” he explained.

The median time to amputation was 4 years, and patients who experienced amputation had a median age of 39 years. Half of the 48 patients who experienced amputation had one amputation, nearly a third had two amputations, and 19% had three amputations. About two-thirds had minor amputations and a third had major amputations.

The findings provide important prognostic information regarding TAO, Dr. Le Joncour said, noting that long-term data on outcomes in TAO patients have been lacking.

“We found specific characteristics that identified those at highest risk for subsequent vascular complications, and these factors are not only important predictors of vascular complications or relapse, but may also serve to adjust more aggressive management and close follow-up of these patients,” he concluded.

Dr. Le Joncour reported having no disclosures.

[email protected]

SOURCE: Le Joncour A et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract 1885.

CHICAGO – Nonwhite ethnicity and limb infection at diagnosis predict vascular events in patients with thromboangiitis obliterans (TAO), and the latter also predicts amputation, which occurs within 10 years of diagnosis in nearly a third of patients, according to findings from a large retrospective French cohort study.

Shidlovski/gettyimages

After a mean follow-up of 5.7 years, 58.9% of 224 patients with TAO – also known as Buerger’s disease – experienced a vascular event, 21.4% experienced at least one amputation, and 1.3% died, Alexandre Le Joncour, MD, reported at the annual meeting of the American College of Rheumatology.

The 5- and 15-year vascular event-free survival rates were 45% and 28%, respectively, and the 10- and 15-year amputation-free survival rates were 74%, and 66%, respectively, said Dr. Le Joncour of Sorbonne University, Paris.

Of note, no significant difference was seen in the vascular event-free survival rates based on tobacco use levels (more than 22 pack-years vs. 22 or fewer pack-years; HR, 1.2), he said.

Patient characteristics and clinical factors found to independently predict vascular events included nonwhite ethnicity (hazard ratio, 2.35; P = .005) and limb infection at diagnosis (HR, 3.29; P = .045). Limb infection at diagnosis also independently predicted amputation (HR, 12.1; P less than .001), he said.

“But there was no significant [association with amputation] in patients who had claudication, critical ischemia, or ischemic ulcers/necrosis,” he noted, adding that a comparison of white and nonwhite patients showed that the groups were similar with respect to epidemiologic and cardiovascular factors, clinical symptom distribution, and rates of addiction to tobacco, alcohol, and illicit drugs.

It was also clear that patients who quit using tobacco had a significantly lower risk of amputation than did those who continued using tobacco (P = .001), he said, explaining that 43 of the 48 patients who experienced amputation were current smokers, and 5 were ex-smokers at the time of amputation.

Dr. Le Joncour and his colleagues included TAO patients diagnosed between 1967 and 2016 at a median age of 36 years at the time of first symptoms, with a median of 12 months from symptom onset until diagnosis. About 76% were men, and about 83% were white. Patients with diabetes, atherosclerosis, arterial emboli, connective tissue disease, and/or thrombophilia were excluded.

Vascular events in this study were defined as “an acute worsening of the disease course requiring treatment modifications,” and included critical ischemia (35% of cases), ulcers/necrosis (33%), claudication worsening (16%), deep vein thrombosis (3%), superficial phlebitis (7%), limb infection (4%), and “other” events (2%).

Major amputation was defined as “an amputation involving the tibio-tarsian articulation for lower limbs and the metacarpophalangeal articulation for upper limbs,” he explained.

The median time to amputation was 4 years, and patients who experienced amputation had a median age of 39 years. Half of the 48 patients who experienced amputation had one amputation, nearly a third had two amputations, and 19% had three amputations. About two-thirds had minor amputations and a third had major amputations.

The findings provide important prognostic information regarding TAO, Dr. Le Joncour said, noting that long-term data on outcomes in TAO patients have been lacking.

“We found specific characteristics that identified those at highest risk for subsequent vascular complications, and these factors are not only important predictors of vascular complications or relapse, but may also serve to adjust more aggressive management and close follow-up of these patients,” he concluded.

Dr. Le Joncour reported having no disclosures.

[email protected]

SOURCE: Le Joncour A et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract 1885.

Photo by Jen Smith

SAN DIEGO—Pediatric patients with mixed phenotype acute leukemia (MPAL) can achieve minimal residual disease (MRD) negativity with acute lymphoblastic leukemia (ALL)-directed chemotherapy, according to new research.

In a retrospective study, most pediatric MPAL patients who received ALL-directed chemotherapy achieved an MRD-negative complete response (CR).

Ninety-three percent of patients achieved a CR at the end of induction with an ALL regimen, 70% were MRD-negative at the end of induction, and 86% were MRD-negative at the end of induction or consolidation.

Etan Orgel, MD, of the University of Southern California, Los Angeles, presented these findings at the ASH 2018 Annual Meeting (abstract 558*).

The study included 94 patients aged 1-21 years who met World Health Organization MPAL criteria and were treated between 2008 and 2016 at one of six U.S. institutions.

Most patients had B/Myeloid phenotype (89%, n=84), 10% (n=9) had T/Myeloid, and 1% (n=1) had B/T phenotype.

Eighty-seven patients (93%) received ALL induction, and 83 (89%) continued on ALL therapy after induction.

Ninety-three percent (81/87) of patients treated with an ALL induction regimen had a CR at the end of induction. One patient died during induction, and six had induction failures, defined as either disease progression (n=2) or MRD of 5% or greater (n=4).

The MRD-negative rates, defined as MRD less than 0.01%, were 70% (59/84) at the end of induction and 86% (68/79) at the end of induction or consolidation.

Twelve of 14 patients (86%) who were MRD-positive at the end of induction and continued on ALL therapy achieved MRD negativity at the end of consolidation.

Survival

The researchers assessed 5-year survival in patients who received an ALL regimen but did not go on to transplant.

In these patients, the 5-year event-free survival (EFS) was 75%, and the 5-year overall survival (OS) was 89%, “thus demonstrating that, for a majority of patients, transplant in first remission may not be necessary,” Dr. Orgel said.

“[T]his is very different from the approach used at many adult centers and many of the adult recommendations,” he added.

The 5-year EFS rate was 80% in patients who were MRD-negative at the end of induction and 52% in patients who were MRD-positive at the end of induction. Five-year OS rates were 91% and 84%, respectively.

The 5-year EFS rate was 77% in patients who were MRD-negative at the end of consolidation and was unavailable in the three patients who were MRD-positive. The 5-year OS rates were 89% and not available, respectively.

In a multivariable analysis, MRD was the strongest predictor of EFS (hazard ratio [HR]=3.5) and OS (HR=4.6).

There was a trend toward earlier failure and worse OS (HR=4.49, P=0.074) for T-lineage-containing MPAL.

“That indicates that this might be a group that needs careful scrutiny of which form of ALL therapy they receive,” Dr. Orgel said.

In closing, he said this research suggests that ALL therapy without transplant may be sufficient to treat most patients with pediatric MPAL. However, he noted that clinical trials are necessary to prospectively validate MRD thresholds at end of induction and consolidation and to establish the threshold for favorable survival.

“Future research should explore either intensification of therapy or different therapies for patients with persistent MRD,” Dr. Orgel said.

He disclosed no conflicts of interest. 

* Data in the presentation differ from the abstract.

Photo by Jen Smith

SAN DIEGO—Pediatric patients with mixed phenotype acute leukemia (MPAL) can achieve minimal residual disease (MRD) negativity with acute lymphoblastic leukemia (ALL)-directed chemotherapy, according to new research.

In a retrospective study, most pediatric MPAL patients who received ALL-directed chemotherapy achieved an MRD-negative complete response (CR).

Ninety-three percent of patients achieved a CR at the end of induction with an ALL regimen, 70% were MRD-negative at the end of induction, and 86% were MRD-negative at the end of induction or consolidation.

Etan Orgel, MD, of the University of Southern California, Los Angeles, presented these findings at the ASH 2018 Annual Meeting (abstract 558*).

The study included 94 patients aged 1-21 years who met World Health Organization MPAL criteria and were treated between 2008 and 2016 at one of six U.S. institutions.

Most patients had B/Myeloid phenotype (89%, n=84), 10% (n=9) had T/Myeloid, and 1% (n=1) had B/T phenotype.

Eighty-seven patients (93%) received ALL induction, and 83 (89%) continued on ALL therapy after induction.

Ninety-three percent (81/87) of patients treated with an ALL induction regimen had a CR at the end of induction. One patient died during induction, and six had induction failures, defined as either disease progression (n=2) or MRD of 5% or greater (n=4).

The MRD-negative rates, defined as MRD less than 0.01%, were 70% (59/84) at the end of induction and 86% (68/79) at the end of induction or consolidation.

Twelve of 14 patients (86%) who were MRD-positive at the end of induction and continued on ALL therapy achieved MRD negativity at the end of consolidation.

Survival

The researchers assessed 5-year survival in patients who received an ALL regimen but did not go on to transplant.

In these patients, the 5-year event-free survival (EFS) was 75%, and the 5-year overall survival (OS) was 89%, “thus demonstrating that, for a majority of patients, transplant in first remission may not be necessary,” Dr. Orgel said.

“[T]his is very different from the approach used at many adult centers and many of the adult recommendations,” he added.

The 5-year EFS rate was 80% in patients who were MRD-negative at the end of induction and 52% in patients who were MRD-positive at the end of induction. Five-year OS rates were 91% and 84%, respectively.

The 5-year EFS rate was 77% in patients who were MRD-negative at the end of consolidation and was unavailable in the three patients who were MRD-positive. The 5-year OS rates were 89% and not available, respectively.

In a multivariable analysis, MRD was the strongest predictor of EFS (hazard ratio [HR]=3.5) and OS (HR=4.6).

There was a trend toward earlier failure and worse OS (HR=4.49, P=0.074) for T-lineage-containing MPAL.

“That indicates that this might be a group that needs careful scrutiny of which form of ALL therapy they receive,” Dr. Orgel said.

In closing, he said this research suggests that ALL therapy without transplant may be sufficient to treat most patients with pediatric MPAL. However, he noted that clinical trials are necessary to prospectively validate MRD thresholds at end of induction and consolidation and to establish the threshold for favorable survival.

“Future research should explore either intensification of therapy or different therapies for patients with persistent MRD,” Dr. Orgel said.

He disclosed no conflicts of interest. 

* Data in the presentation differ from the abstract.

Photo by Jen Smith

SAN DIEGO—Pediatric patients with mixed phenotype acute leukemia (MPAL) can achieve minimal residual disease (MRD) negativity with acute lymphoblastic leukemia (ALL)-directed chemotherapy, according to new research.

In a retrospective study, most pediatric MPAL patients who received ALL-directed chemotherapy achieved an MRD-negative complete response (CR).

Ninety-three percent of patients achieved a CR at the end of induction with an ALL regimen, 70% were MRD-negative at the end of induction, and 86% were MRD-negative at the end of induction or consolidation.

Etan Orgel, MD, of the University of Southern California, Los Angeles, presented these findings at the ASH 2018 Annual Meeting (abstract 558*).

The study included 94 patients aged 1-21 years who met World Health Organization MPAL criteria and were treated between 2008 and 2016 at one of six U.S. institutions.

Most patients had B/Myeloid phenotype (89%, n=84), 10% (n=9) had T/Myeloid, and 1% (n=1) had B/T phenotype.

Eighty-seven patients (93%) received ALL induction, and 83 (89%) continued on ALL therapy after induction.

Ninety-three percent (81/87) of patients treated with an ALL induction regimen had a CR at the end of induction. One patient died during induction, and six had induction failures, defined as either disease progression (n=2) or MRD of 5% or greater (n=4).

The MRD-negative rates, defined as MRD less than 0.01%, were 70% (59/84) at the end of induction and 86% (68/79) at the end of induction or consolidation.

Twelve of 14 patients (86%) who were MRD-positive at the end of induction and continued on ALL therapy achieved MRD negativity at the end of consolidation.

Survival

The researchers assessed 5-year survival in patients who received an ALL regimen but did not go on to transplant.

In these patients, the 5-year event-free survival (EFS) was 75%, and the 5-year overall survival (OS) was 89%, “thus demonstrating that, for a majority of patients, transplant in first remission may not be necessary,” Dr. Orgel said.

“[T]his is very different from the approach used at many adult centers and many of the adult recommendations,” he added.

The 5-year EFS rate was 80% in patients who were MRD-negative at the end of induction and 52% in patients who were MRD-positive at the end of induction. Five-year OS rates were 91% and 84%, respectively.

The 5-year EFS rate was 77% in patients who were MRD-negative at the end of consolidation and was unavailable in the three patients who were MRD-positive. The 5-year OS rates were 89% and not available, respectively.

In a multivariable analysis, MRD was the strongest predictor of EFS (hazard ratio [HR]=3.5) and OS (HR=4.6).

There was a trend toward earlier failure and worse OS (HR=4.49, P=0.074) for T-lineage-containing MPAL.

“That indicates that this might be a group that needs careful scrutiny of which form of ALL therapy they receive,” Dr. Orgel said.

In closing, he said this research suggests that ALL therapy without transplant may be sufficient to treat most patients with pediatric MPAL. However, he noted that clinical trials are necessary to prospectively validate MRD thresholds at end of induction and consolidation and to establish the threshold for favorable survival.

“Future research should explore either intensification of therapy or different therapies for patients with persistent MRD,” Dr. Orgel said.

He disclosed no conflicts of interest. 

* Data in the presentation differ from the abstract.

SAN DIEGO – A newly developed personalized model that “harnesses the power of artificial intelligence” to predict overall survival and transformation to acute myeloid leukemia (AML) in patients with myelodysplastic syndromes outperforms both the original and revised International Prognostic Scoring Systems (IPSS, IPSS-R), according to Aziz Nazha, MD.

The machine learning model, which was built using clinical and genomic data derived from myelodysplastic syndrome (MDS) patients diagnosed according to 2008 World Health Organization criteria, incorporates information beyond that included in the IPSS and IPSS-R, and provides patient-specific survival probabilities at different time points, Dr. Nazha of Cleveland Clinic reported during a press briefing at the annual meeting of the American Society of Hematology.

The model was developed in a combined training cohort of 1,471 patients from the Cleveland Clinic and Munich Leukemia Laboratory and was validated in a separate cohort of 831 patients from the Moffitt Cancer Center in Tampa, Fla.

The concordance index – a measure for comparing the accuracy of the various models – was 0.80 for overall survival (OS), and 0.78 for AML transformation vs. 0.66 and 0.73, respectively, for IPSS, and 0.67 and 0.73, respectively, for IPSS-R, Dr. Nazha said. The new “geno-clinical” model also outperformed mutations-only analysis, mutations plus cytogenetics analysis, and mutations plus cytogenetics plus age analyses for both OS and AML transformation.

Adding mutational variant allelic frequency did not significantly improve prediction accuracy, he noted.

Dr. Nazha and his colleagues are developing a web application tool that can be used to run the trained model to calculate patient-specific, time-specific OS and AML transformation probabilities. He discussed the new model and its implications for personalized prognosis and treatment in this video interview.

Improved risk assessment helps patients understand their disease and “establish expectations about their journey with their disease,” and it is also extremely important for treating physicians, he said.

“All of our consensus guidelines and treatment recommendations are based on risk,” he explained, noting that the approach varies greatly for higher- and lower-risk patients.

This model represents a potential new focus on “personalized prediction” in addition to the increasing focus on personalized treatment and takes into account the heterogeneous outcomes seen in patients with MDS, he said.

Dr. Nazha reported consultancy for Karyopharma and Tolero, and data-monitoring committee membership for MEI.

[email protected]

SOURCE: Nazha A et al. ASH 2018, Abstract 793.

SAN DIEGO – A newly developed personalized model that “harnesses the power of artificial intelligence” to predict overall survival and transformation to acute myeloid leukemia (AML) in patients with myelodysplastic syndromes outperforms both the original and revised International Prognostic Scoring Systems (IPSS, IPSS-R), according to Aziz Nazha, MD.

The machine learning model, which was built using clinical and genomic data derived from myelodysplastic syndrome (MDS) patients diagnosed according to 2008 World Health Organization criteria, incorporates information beyond that included in the IPSS and IPSS-R, and provides patient-specific survival probabilities at different time points, Dr. Nazha of Cleveland Clinic reported during a press briefing at the annual meeting of the American Society of Hematology.

The model was developed in a combined training cohort of 1,471 patients from the Cleveland Clinic and Munich Leukemia Laboratory and was validated in a separate cohort of 831 patients from the Moffitt Cancer Center in Tampa, Fla.

The concordance index – a measure for comparing the accuracy of the various models – was 0.80 for overall survival (OS), and 0.78 for AML transformation vs. 0.66 and 0.73, respectively, for IPSS, and 0.67 and 0.73, respectively, for IPSS-R, Dr. Nazha said. The new “geno-clinical” model also outperformed mutations-only analysis, mutations plus cytogenetics analysis, and mutations plus cytogenetics plus age analyses for both OS and AML transformation.

Adding mutational variant allelic frequency did not significantly improve prediction accuracy, he noted.

Dr. Nazha and his colleagues are developing a web application tool that can be used to run the trained model to calculate patient-specific, time-specific OS and AML transformation probabilities. He discussed the new model and its implications for personalized prognosis and treatment in this video interview.

Improved risk assessment helps patients understand their disease and “establish expectations about their journey with their disease,” and it is also extremely important for treating physicians, he said.

“All of our consensus guidelines and treatment recommendations are based on risk,” he explained, noting that the approach varies greatly for higher- and lower-risk patients.

This model represents a potential new focus on “personalized prediction” in addition to the increasing focus on personalized treatment and takes into account the heterogeneous outcomes seen in patients with MDS, he said.

Dr. Nazha reported consultancy for Karyopharma and Tolero, and data-monitoring committee membership for MEI.

[email protected]

SOURCE: Nazha A et al. ASH 2018, Abstract 793.

SAN DIEGO – A newly developed personalized model that “harnesses the power of artificial intelligence” to predict overall survival and transformation to acute myeloid leukemia (AML) in patients with myelodysplastic syndromes outperforms both the original and revised International Prognostic Scoring Systems (IPSS, IPSS-R), according to Aziz Nazha, MD.

The machine learning model, which was built using clinical and genomic data derived from myelodysplastic syndrome (MDS) patients diagnosed according to 2008 World Health Organization criteria, incorporates information beyond that included in the IPSS and IPSS-R, and provides patient-specific survival probabilities at different time points, Dr. Nazha of Cleveland Clinic reported during a press briefing at the annual meeting of the American Society of Hematology.

The model was developed in a combined training cohort of 1,471 patients from the Cleveland Clinic and Munich Leukemia Laboratory and was validated in a separate cohort of 831 patients from the Moffitt Cancer Center in Tampa, Fla.

The concordance index – a measure for comparing the accuracy of the various models – was 0.80 for overall survival (OS), and 0.78 for AML transformation vs. 0.66 and 0.73, respectively, for IPSS, and 0.67 and 0.73, respectively, for IPSS-R, Dr. Nazha said. The new “geno-clinical” model also outperformed mutations-only analysis, mutations plus cytogenetics analysis, and mutations plus cytogenetics plus age analyses for both OS and AML transformation.

Adding mutational variant allelic frequency did not significantly improve prediction accuracy, he noted.

Dr. Nazha and his colleagues are developing a web application tool that can be used to run the trained model to calculate patient-specific, time-specific OS and AML transformation probabilities. He discussed the new model and its implications for personalized prognosis and treatment in this video interview.

Improved risk assessment helps patients understand their disease and “establish expectations about their journey with their disease,” and it is also extremely important for treating physicians, he said.

“All of our consensus guidelines and treatment recommendations are based on risk,” he explained, noting that the approach varies greatly for higher- and lower-risk patients.

This model represents a potential new focus on “personalized prediction” in addition to the increasing focus on personalized treatment and takes into account the heterogeneous outcomes seen in patients with MDS, he said.

Dr. Nazha reported consultancy for Karyopharma and Tolero, and data-monitoring committee membership for MEI.

[email protected]

SOURCE: Nazha A et al. ASH 2018, Abstract 793.

SAN DIEGO – Ibrutinib alone or in combination with rituximab resulted in superior progression-free survival (PFS) when compared with bendamustine plus rituximab in the randomized, phase 3 Alliance A041202 trial of older patients with previously untreated chronic lymphocytic leukemia (CLL).

Sharon Worcester/MDedge News

[email protected]

SOURCE: Woyach JA et al. ASH 2018, Abstract 6.

SAN DIEGO – Ibrutinib alone or in combination with rituximab resulted in superior progression-free survival (PFS) when compared with bendamustine plus rituximab in the randomized, phase 3 Alliance A041202 trial of older patients with previously untreated chronic lymphocytic leukemia (CLL).

Sharon Worcester/MDedge News

[email protected]

SOURCE: Woyach JA et al. ASH 2018, Abstract 6.

SAN DIEGO – Ibrutinib alone or in combination with rituximab resulted in superior progression-free survival (PFS) when compared with bendamustine plus rituximab in the randomized, phase 3 Alliance A041202 trial of older patients with previously untreated chronic lymphocytic leukemia (CLL).

Sharon Worcester/MDedge News

[email protected]

SOURCE: Woyach JA et al. ASH 2018, Abstract 6.

SAN DIEGO – A novel myeloablative regimen along with familial haploidentical stem cell transplantation was well tolerated and cured 90% of 19 young patients with high-risk sickle cell disease who underwent the procedure, according to Mitchell S. Cairo, MD.

The approach involved parental donors who were partial matches (as opposed to human leukocyte antigen [HLA]–matched sibling donors), CD34 enrichment, and mononuclear cell add-back (2 x 10⁵ CD3/kg). The treatment resulted in a low cumulative incidence of acute and chronic graft-versus-host disease (6.2% and 6.7%, respectively) and stable to improved pulmonary and cardiac function. Patients also experienced significantly improved neurocognition and health-related quality of life at 2-year follow-up, Dr. Cairo of New York Medical College, Valhalla, reported at the annual meeting of the American Society of Hematology.

In a video interview, Dr. Cairo described the study, the potential benefits of familial haploidentical transplantation, and future directions.

“We have a 1-year 90% survival rate, and ... with a median follow-up now of 3 years with this approach, no patient has signs or symptoms of sickle cell disease,” he said. While the standard of care is “still to use an HLA-matched sibling donor that doesn’t have sickle cell disease,” this novel approach could benefit the five of six patients who don’t have such a donor.

The risks appear similar with the two approaches, but “more numbers will be needed to confirm this preliminary finding,” he said.

A second Food and Drug Administration–supported study with patients aged up to age 35 years (vs. 21 years in the current study) and with lower doses of the conditioning regimen to potentially reduce the risk of late adverse effects is underway, he said.

This study was supported by an FDA grant. Dr. Cairo reported receiving research funding from Janssen.

[email protected]

SAN DIEGO – A novel myeloablative regimen along with familial haploidentical stem cell transplantation was well tolerated and cured 90% of 19 young patients with high-risk sickle cell disease who underwent the procedure, according to Mitchell S. Cairo, MD.

The approach involved parental donors who were partial matches (as opposed to human leukocyte antigen [HLA]–matched sibling donors), CD34 enrichment, and mononuclear cell add-back (2 x 10⁵ CD3/kg). The treatment resulted in a low cumulative incidence of acute and chronic graft-versus-host disease (6.2% and 6.7%, respectively) and stable to improved pulmonary and cardiac function. Patients also experienced significantly improved neurocognition and health-related quality of life at 2-year follow-up, Dr. Cairo of New York Medical College, Valhalla, reported at the annual meeting of the American Society of Hematology.

In a video interview, Dr. Cairo described the study, the potential benefits of familial haploidentical transplantation, and future directions.

“We have a 1-year 90% survival rate, and ... with a median follow-up now of 3 years with this approach, no patient has signs or symptoms of sickle cell disease,” he said. While the standard of care is “still to use an HLA-matched sibling donor that doesn’t have sickle cell disease,” this novel approach could benefit the five of six patients who don’t have such a donor.

The risks appear similar with the two approaches, but “more numbers will be needed to confirm this preliminary finding,” he said.

A second Food and Drug Administration–supported study with patients aged up to age 35 years (vs. 21 years in the current study) and with lower doses of the conditioning regimen to potentially reduce the risk of late adverse effects is underway, he said.

This study was supported by an FDA grant. Dr. Cairo reported receiving research funding from Janssen.

[email protected]

SAN DIEGO – A novel myeloablative regimen along with familial haploidentical stem cell transplantation was well tolerated and cured 90% of 19 young patients with high-risk sickle cell disease who underwent the procedure, according to Mitchell S. Cairo, MD.

The approach involved parental donors who were partial matches (as opposed to human leukocyte antigen [HLA]–matched sibling donors), CD34 enrichment, and mononuclear cell add-back (2 x 10⁵ CD3/kg). The treatment resulted in a low cumulative incidence of acute and chronic graft-versus-host disease (6.2% and 6.7%, respectively) and stable to improved pulmonary and cardiac function. Patients also experienced significantly improved neurocognition and health-related quality of life at 2-year follow-up, Dr. Cairo of New York Medical College, Valhalla, reported at the annual meeting of the American Society of Hematology.

In a video interview, Dr. Cairo described the study, the potential benefits of familial haploidentical transplantation, and future directions.

“We have a 1-year 90% survival rate, and ... with a median follow-up now of 3 years with this approach, no patient has signs or symptoms of sickle cell disease,” he said. While the standard of care is “still to use an HLA-matched sibling donor that doesn’t have sickle cell disease,” this novel approach could benefit the five of six patients who don’t have such a donor.

The risks appear similar with the two approaches, but “more numbers will be needed to confirm this preliminary finding,” he said.

A second Food and Drug Administration–supported study with patients aged up to age 35 years (vs. 21 years in the current study) and with lower doses of the conditioning regimen to potentially reduce the risk of late adverse effects is underway, he said.

This study was supported by an FDA grant. Dr. Cairo reported receiving research funding from Janssen.

[email protected]

CHICAGO – Apremilast was effective and well tolerated for up to 28 weeks for the treatment of oral ulcers in patients with active Behçet’s disease, based on findings from the randomized, placebo-controlled, phase 3 RELIEF trial.

At baseline, mean oral ulcer counts were 4.2 in 104 patients randomized to receive the oral phosphodiesterase-4 inhibitor and 3.9 in 103 patients in the placebo group. Mean visual analog scale (VAS) pain scores were 61.2 and 60.8 in the two groups, respectively.

The primary study endpoint of area under the curve for total number of oral ulcers over a 12-week period (AUC_Wk0-12) – a measure that reflects the number of oral ulcers that occur over time and also accounts for the recurring-remitting course of oral ulcers – was achieved. AUC_Wk0-12 was significantly lower in the apremilast group than in the placebo group (129.54 vs. 222.14, respectively; P less than .0001), Gulen Hatemi, MD, reported at the annual meeting of the American College of Rheumatology.

From baseline to week 12, apremilast treatment also resulted in a significantly lower number of oral ulcers (mean of 1.1 vs. 2.0 for placebo at 12 weeks) and significantly reduced pain from oral ulcers at every visit from week 1 through week 12 of the study, compared with placebo (mean VAS score change from baseline, –40.7 vs. –15.9), said Dr. Hatemi, a professor of medicine at Istanbul University.

“The [12-week] complete response rate ... was 53% in the apremilast group and 22.3% in the placebo group. The [12-week] partial response rate ...was 76% in the apremilast group and 48% in the placebo group,” she said, adding that the efficacy of apremilast was sustained with continued treatment through 28 weeks.

Study participants were adults (mean age, 40 years) with active Behçet’s disease and three or more oral ulcers at randomization or two or more at screening and at randomization. All had been previously treated with at least one nonbiologic medication for oral ulcers and were allowed to have received previous biologic therapies for other disease manifestations. Those with active major organ involvement were excluded.

Treatment included a 30-mg dose of apremilast twice daily for 12 weeks or placebo. After 12 weeks, all patients received apremilast through at least 28 weeks of the 64-week study.

At the 28-week analysis, patients who were initially randomized to placebo and who switched to apremilast after week 12 had benefits comparable with those seen in those randomized to apremilast at the start of the study. A complete response was seen in 59% and 62% of patients in the groups, respectively, and a partial response was seen in 90% and 85%, respectively. Additionally, the mean change in the VAS score for oral ulcer pain in the groups at that time was –40.6 and –41.9, Dr. Hatemi said.

Apremilast was well tolerated in this study; the incidence of adverse events was comparable in the treatment and placebo groups during the 12-week placebo-controlled phase of the study – 78.8% and 71.8%, respectively. The most common events were diarrhea, nausea, headache, and upper respiratory tract infection, she said.

“These were generally mild to moderate, and only two patients had to discontinue the study due to gastrointestinal adverse events,” she said, noting that no new safety signals were observed.

Behçet’s disease is a chronic, relapsing, multisystem inflammatory disorder characterized by recurrent oral ulcers that can be disabling and have a substantial effect on quality of life. These findings, which include efficacy data up to 28 weeks and safety data for at least 100 patients exposed to apremilast for at least 1 year, demonstrate the efficacy of apremilast for the treatment oral ulcers in patients with Behçet’s disease, she said, noting that “the safety findings were consistent with the known safety profile of apremilast.”

The RELIEF study was supported by Celgene. Dr. Hatemi reported receiving grant/research support from Celgene and serving as a speaker for AbbVie, Mustafa Nevzet Pharmaceuticals, and UCB.

[email protected]

SOURCE: Hatemi G et al. Arthritis Rheumatol. 2018;70(Suppl 10), Abstract 2789.

CHICAGO – Apremilast was effective and well tolerated for up to 28 weeks for the treatment of oral ulcers in patients with active Behçet’s disease, based on findings from the randomized, placebo-controlled, phase 3 RELIEF trial.

At baseline, mean oral ulcer counts were 4.2 in 104 patients randomized to receive the oral phosphodiesterase-4 inhibitor and 3.9 in 103 patients in the placebo group. Mean visual analog scale (VAS) pain scores were 61.2 and 60.8 in the two groups, respectively.

The primary study endpoint of area under the curve for total number of oral ulcers over a 12-week period (AUC_Wk0-12) – a measure that reflects the number of oral ulcers that occur over time and also accounts for the recurring-remitting course of oral ulcers – was achieved. AUC_Wk0-12 was significantly lower in the apremilast group than in the placebo group (129.54 vs. 222.14, respectively; P less than .0001), Gulen Hatemi, MD, reported at the annual meeting of the American College of Rheumatology.

From baseline to week 12, apremilast treatment also resulted in a significantly lower number of oral ulcers (mean of 1.1 vs. 2.0 for placebo at 12 weeks) and significantly reduced pain from oral ulcers at every visit from week 1 through week 12 of the study, compared with placebo (mean VAS score change from baseline, –40.7 vs. –15.9), said Dr. Hatemi, a professor of medicine at Istanbul University.

“The [12-week] complete response rate ... was 53% in the apremilast group and 22.3% in the placebo group. The [12-week] partial response rate ...was 76% in the apremilast group and 48% in the placebo group,” she said, adding that the efficacy of apremilast was sustained with continued treatment through 28 weeks.

Study participants were adults (mean age, 40 years) with active Behçet’s disease and three or more oral ulcers at randomization or two or more at screening and at randomization. All had been previously treated with at least one nonbiologic medication for oral ulcers and were allowed to have received previous biologic therapies for other disease manifestations. Those with active major organ involvement were excluded.

Treatment included a 30-mg dose of apremilast twice daily for 12 weeks or placebo. After 12 weeks, all patients received apremilast through at least 28 weeks of the 64-week study.

At the 28-week analysis, patients who were initially randomized to placebo and who switched to apremilast after week 12 had benefits comparable with those seen in those randomized to apremilast at the start of the study. A complete response was seen in 59% and 62% of patients in the groups, respectively, and a partial response was seen in 90% and 85%, respectively. Additionally, the mean change in the VAS score for oral ulcer pain in the groups at that time was –40.6 and –41.9, Dr. Hatemi said.

Apremilast was well tolerated in this study; the incidence of adverse events was comparable in the treatment and placebo groups during the 12-week placebo-controlled phase of the study – 78.8% and 71.8%, respectively. The most common events were diarrhea, nausea, headache, and upper respiratory tract infection, she said.

“These were generally mild to moderate, and only two patients had to discontinue the study due to gastrointestinal adverse events,” she said, noting that no new safety signals were observed.

Behçet’s disease is a chronic, relapsing, multisystem inflammatory disorder characterized by recurrent oral ulcers that can be disabling and have a substantial effect on quality of life. These findings, which include efficacy data up to 28 weeks and safety data for at least 100 patients exposed to apremilast for at least 1 year, demonstrate the efficacy of apremilast for the treatment oral ulcers in patients with Behçet’s disease, she said, noting that “the safety findings were consistent with the known safety profile of apremilast.”

The RELIEF study was supported by Celgene. Dr. Hatemi reported receiving grant/research support from Celgene and serving as a speaker for AbbVie, Mustafa Nevzet Pharmaceuticals, and UCB.

[email protected]

SOURCE: Hatemi G et al. Arthritis Rheumatol. 2018;70(Suppl 10), Abstract 2789.

CHICAGO – Apremilast was effective and well tolerated for up to 28 weeks for the treatment of oral ulcers in patients with active Behçet’s disease, based on findings from the randomized, placebo-controlled, phase 3 RELIEF trial.

At baseline, mean oral ulcer counts were 4.2 in 104 patients randomized to receive the oral phosphodiesterase-4 inhibitor and 3.9 in 103 patients in the placebo group. Mean visual analog scale (VAS) pain scores were 61.2 and 60.8 in the two groups, respectively.

The primary study endpoint of area under the curve for total number of oral ulcers over a 12-week period (AUC_Wk0-12) – a measure that reflects the number of oral ulcers that occur over time and also accounts for the recurring-remitting course of oral ulcers – was achieved. AUC_Wk0-12 was significantly lower in the apremilast group than in the placebo group (129.54 vs. 222.14, respectively; P less than .0001), Gulen Hatemi, MD, reported at the annual meeting of the American College of Rheumatology.

From baseline to week 12, apremilast treatment also resulted in a significantly lower number of oral ulcers (mean of 1.1 vs. 2.0 for placebo at 12 weeks) and significantly reduced pain from oral ulcers at every visit from week 1 through week 12 of the study, compared with placebo (mean VAS score change from baseline, –40.7 vs. –15.9), said Dr. Hatemi, a professor of medicine at Istanbul University.

“The [12-week] complete response rate ... was 53% in the apremilast group and 22.3% in the placebo group. The [12-week] partial response rate ...was 76% in the apremilast group and 48% in the placebo group,” she said, adding that the efficacy of apremilast was sustained with continued treatment through 28 weeks.

Study participants were adults (mean age, 40 years) with active Behçet’s disease and three or more oral ulcers at randomization or two or more at screening and at randomization. All had been previously treated with at least one nonbiologic medication for oral ulcers and were allowed to have received previous biologic therapies for other disease manifestations. Those with active major organ involvement were excluded.

Treatment included a 30-mg dose of apremilast twice daily for 12 weeks or placebo. After 12 weeks, all patients received apremilast through at least 28 weeks of the 64-week study.

At the 28-week analysis, patients who were initially randomized to placebo and who switched to apremilast after week 12 had benefits comparable with those seen in those randomized to apremilast at the start of the study. A complete response was seen in 59% and 62% of patients in the groups, respectively, and a partial response was seen in 90% and 85%, respectively. Additionally, the mean change in the VAS score for oral ulcer pain in the groups at that time was –40.6 and –41.9, Dr. Hatemi said.

Apremilast was well tolerated in this study; the incidence of adverse events was comparable in the treatment and placebo groups during the 12-week placebo-controlled phase of the study – 78.8% and 71.8%, respectively. The most common events were diarrhea, nausea, headache, and upper respiratory tract infection, she said.

“These were generally mild to moderate, and only two patients had to discontinue the study due to gastrointestinal adverse events,” she said, noting that no new safety signals were observed.

Behçet’s disease is a chronic, relapsing, multisystem inflammatory disorder characterized by recurrent oral ulcers that can be disabling and have a substantial effect on quality of life. These findings, which include efficacy data up to 28 weeks and safety data for at least 100 patients exposed to apremilast for at least 1 year, demonstrate the efficacy of apremilast for the treatment oral ulcers in patients with Behçet’s disease, she said, noting that “the safety findings were consistent with the known safety profile of apremilast.”

The RELIEF study was supported by Celgene. Dr. Hatemi reported receiving grant/research support from Celgene and serving as a speaker for AbbVie, Mustafa Nevzet Pharmaceuticals, and UCB.

[email protected]

SOURCE: Hatemi G et al. Arthritis Rheumatol. 2018;70(Suppl 10), Abstract 2789.

WASHINGTON – Positron emission tomography (PET) using the CD8-tracer ⁸⁹Zr-IAB22M2C was safe and provided detailed whole-body information on the biodistribution of CD8 T-cells in advanced solid tumors and reference tissue in an open-label, phase 1, first-in-human study.

The findings demonstrate the ability of the tracer–an anti-CD8 zirconium-labeled minibody–to noninvasively detect CD8 distribution in patients with metastatic solid tumors, potentially providing more information – and more quickly – than is possible with a single biopsy, Michael S. Gordon, MD, reported during a late-breaking abstract session at the annual meeting of the Society for Immunotherapy of Cancer.

During a dose escalation period (stage 1) of the study, six patients received 3 mCi of ⁸⁹Zr-IAB22M2C once intravenously followed by serial PET scans over a period of 5-7 days. The patients received increasing protein doses of 0.2 through 10 mg to establish safety and determine a “recommended protein dose and scanning parameters for subsequent trials,” explained Dr. Gordon of HonorHealth Research Institute, Scottsdale, Ariz.

Stage 1 was followed by a dose expansion period (stage 2) in which an additional nine subjects were scanned to better delineate the recommended phase 2 study dose, he said.

All patients were monitored for drug-related adverse events and evaluated with blood chemistry, hematology, cytokine assay, and anti-drug antibodies. Biodistribution, radiodosimetry and semi-quantitative evaluation of CD8-tracer uptake were performed in all patients.

“We saw rapid clearance with excretion through the hepatobiliary mechanism, uptake in T-cell rich tissues, and no uptake in background normal tissues – so no uptake in muscle, heart, brain, or lungs,” he said, adding that “tumor uptake was variable and was clearly seen in 10 out of 15 patients.

“The protein dose that was considered to have favorable biodistribution was the range between 0.5 and 1.5, and based upon the analysis, the most favorable imaging time point ... was deemed to be 24 hours,” he said, noting that changes could be seen in as early as 6 hours.

SOURCE: Gordon M et al., SITC 2018: Abstract LB49.

WASHINGTON – Positron emission tomography (PET) using the CD8-tracer ⁸⁹Zr-IAB22M2C was safe and provided detailed whole-body information on the biodistribution of CD8 T-cells in advanced solid tumors and reference tissue in an open-label, phase 1, first-in-human study.

The findings demonstrate the ability of the tracer–an anti-CD8 zirconium-labeled minibody–to noninvasively detect CD8 distribution in patients with metastatic solid tumors, potentially providing more information – and more quickly – than is possible with a single biopsy, Michael S. Gordon, MD, reported during a late-breaking abstract session at the annual meeting of the Society for Immunotherapy of Cancer.

During a dose escalation period (stage 1) of the study, six patients received 3 mCi of ⁸⁹Zr-IAB22M2C once intravenously followed by serial PET scans over a period of 5-7 days. The patients received increasing protein doses of 0.2 through 10 mg to establish safety and determine a “recommended protein dose and scanning parameters for subsequent trials,” explained Dr. Gordon of HonorHealth Research Institute, Scottsdale, Ariz.

Stage 1 was followed by a dose expansion period (stage 2) in which an additional nine subjects were scanned to better delineate the recommended phase 2 study dose, he said.

All patients were monitored for drug-related adverse events and evaluated with blood chemistry, hematology, cytokine assay, and anti-drug antibodies. Biodistribution, radiodosimetry and semi-quantitative evaluation of CD8-tracer uptake were performed in all patients.

“We saw rapid clearance with excretion through the hepatobiliary mechanism, uptake in T-cell rich tissues, and no uptake in background normal tissues – so no uptake in muscle, heart, brain, or lungs,” he said, adding that “tumor uptake was variable and was clearly seen in 10 out of 15 patients.

“The protein dose that was considered to have favorable biodistribution was the range between 0.5 and 1.5, and based upon the analysis, the most favorable imaging time point ... was deemed to be 24 hours,” he said, noting that changes could be seen in as early as 6 hours.

SOURCE: Gordon M et al., SITC 2018: Abstract LB49.

WASHINGTON – Positron emission tomography (PET) using the CD8-tracer ⁸⁹Zr-IAB22M2C was safe and provided detailed whole-body information on the biodistribution of CD8 T-cells in advanced solid tumors and reference tissue in an open-label, phase 1, first-in-human study.

The findings demonstrate the ability of the tracer–an anti-CD8 zirconium-labeled minibody–to noninvasively detect CD8 distribution in patients with metastatic solid tumors, potentially providing more information – and more quickly – than is possible with a single biopsy, Michael S. Gordon, MD, reported during a late-breaking abstract session at the annual meeting of the Society for Immunotherapy of Cancer.

During a dose escalation period (stage 1) of the study, six patients received 3 mCi of ⁸⁹Zr-IAB22M2C once intravenously followed by serial PET scans over a period of 5-7 days. The patients received increasing protein doses of 0.2 through 10 mg to establish safety and determine a “recommended protein dose and scanning parameters for subsequent trials,” explained Dr. Gordon of HonorHealth Research Institute, Scottsdale, Ariz.

Stage 1 was followed by a dose expansion period (stage 2) in which an additional nine subjects were scanned to better delineate the recommended phase 2 study dose, he said.

All patients were monitored for drug-related adverse events and evaluated with blood chemistry, hematology, cytokine assay, and anti-drug antibodies. Biodistribution, radiodosimetry and semi-quantitative evaluation of CD8-tracer uptake were performed in all patients.

“We saw rapid clearance with excretion through the hepatobiliary mechanism, uptake in T-cell rich tissues, and no uptake in background normal tissues – so no uptake in muscle, heart, brain, or lungs,” he said, adding that “tumor uptake was variable and was clearly seen in 10 out of 15 patients.

“The protein dose that was considered to have favorable biodistribution was the range between 0.5 and 1.5, and based upon the analysis, the most favorable imaging time point ... was deemed to be 24 hours,” he said, noting that changes could be seen in as early as 6 hours.

SOURCE: Gordon M et al., SITC 2018: Abstract LB49.

CHICAGO – Recent randomized, placebo-controlled, phase 3 trials of tocilizumab, abatacept, and riociguat for the treatment of systemic sclerosis each failed to reach its primary endpoint of change from baseline in modified Rodnan Skin Score (mRSS).

Still, findings with respect to secondary endpoints and certain exploratory outcomes suggest each of the agents holds some promise in the systemic sclerosis (SSc) arena, according to the data presented at the annual meeting of the American College of Rheumatology.
 

Tocilizumab (Actemra)

In the double-blind portion of the phase 3 focuSSced trial of 212 patients with SSc, numerical improvement was observed for the primary endpoint of mean change in mRSS from baseline to week 48 with tocilizumab versus placebo (–6.14 vs. –4.41 points, respectively). The change in the treatment group was comparable with what was seen in the phase 2 faSScinate trial, but the decline in mRSS in the placebo group was much greater in phase 3 than in phase 2, and so the difference between the groups in the current study failed to reach statistical significance (P = .098), reported Dinesh Khanna, MBBS, a professor of medicine and director of the scleroderma program at the University of Michigan, Ann Arbor.

The interleukin-6 (IL-6) receptor–alpha antibody was previously shown in the faSScinate trial to lead to numeric improvements in skin thickening as measured by the mRSS, as well as to clinically meaningful lung function preservation as measured by percent predicted forced vital capacity (FVC).

In the current phase 3 study, key secondary end points also appeared to favor tocilizumab, but since the primary endpoint for mRSS was not met, all other P values cannot be considered statistically significant despite the strength of the evidence and were reported for informational purposes only, he noted.

The median cumulative distribution of change from baseline to week 48 in percent predicted FVC with tocilizumab versus placebo was –0.6 vs. –3.9, respectively (descriptive P = .0015), and the mean change from baseline in FVC at week 48 was –24 mL vs. –190 mL (difference of 167 mL in favor of tocilizumab; descriptive P = .0001).

Time to treatment failure also favored tocilizumab, he said (hazard ratio, 0.63; descriptive P = .082), he said.

Patients were randomly assigned to receive either weekly 162-mg injections of subcutaneous tocilizumab or placebo for 48 weeks. Escape therapy was allowed beginning at week 16 if patients experienced declines in FVC or beginning at week 24 if they experienced worsened mRSS or worsened SSc complications, Dr. Khanna said.

“The key part is that no immunotherapy was allowed. ... So it’s a true randomized, placebo-controlled trial,” he said.

Most (81%) of the patients were women, and they had a mean age of 48 years, mean SSc duration of 23 months, mean mRSS of 20.4 units on a 0-51 scale, and a normal mean percent predicted FVC of 82.1%.

“HAQ-DI showed moderate disability of 1.2,” he noted.

Safety in the study was consistent with that seen in prior tocilizumab studies; no new safety signals were identified. Serious adverse events occurred in 13% and 17% of tocilizumab and placebo group patients , respectively, and serious infections were reported by 7% and 2%.

Although clinically meaningful and consistent differences in FVC favoring tocilizumab were shown in this study, the primary endpoint was not met, Dr. Khanna said.

“There were no statistically significant differences, largely driven by unexpected improvement in the placebo group, which was different than what we found in [the faSScinate] trial,” he said, noting, however, that the FVC findings in the current study were clinically meaningful.

Also, in a separate presentation at the meeting, he explained that the differences favoring tocilizumab were statistically significant when patient-level data from the trial were analyzed based on the ACR Composite Response Index in Systemic Sclerosis (CRISS). Those findings provide validation of the novel outcomes measure, he said.

 

Abatacept (Orencia)

Dr. Khanna also reported results of the 12-month, double-blind, randomized, placebo-controlled phase 2 ASSET trial of abatacept, which showed no significant difference in mRSS in patients with early diffuse cutaneous SSc (dfSSc) who were treated with 125 mg of the recombinant fusion protein weekly and those who received placebo. However, certain secondary outcomes favored abatacept. No concomitant immunotherapy was allowed.

The adjusted mean decrease in the mRSS among patients who completed the 12-month treatment period was –6.24 vs. –4.49 in 34 patients in the abatacept group and 35 in the placebo group, respectively (P = .28).

The secondary outcome measures of mean change in Health Assessment Questionnaire Disability Index (HAQ-DI), patients global assessment, physician global assessment, and ACR CRISS scores were statistically significant or showed numerical results favoring abatacept over placebo: mean decrease in HAQ-DI, –0.17 vs. –0.11 (P = .05), respectively; mean change in physician global assessment scores, –1.30 vs. –0.35 (P = .03); median ACR CRISS index, 0.68 vs. 0.01 (P = .03), decline in percent predicted FVC of 4.13% and 1.34% (P = .11).

Escape therapy was allowed at 6 months for worsening SSc, but it did not change the outcomes trajectory, he said. A larger proportion of placebo vs. abatacept subjects required escape immunosuppressive therapy (36% vs. 16%; P = .03).

Patients were enrolled between 2014 and 2018 at 27 U.S., Canadian, and U.K. sites. At baseline, participants had a mean age of 49 years, 75% were women, and mean disease duration was very short at 1.59 years, with 60% having disease duration of 18 months or less. The mean baseline mRSS was 22.4, mean percent predicted FVC was 85.3%, and mean HAQ-DI was 1.0.

Compliance with both treatments was greater than 98%. Abatacept was well tolerated with comparable adverse events (AEs), serious AEs, and AEs of special interest such as infections and malignancies between treatments, Dr. Khanna said, noting that two deaths occurred in the abatacept group (caused by scleroderma renal crisis in both cases at days 11 and 46) and one occurred in a placebo group patient who experienced sudden cardiac arrest at day 310.

Of note, mRSS showed large variability, despite recruiting an early dcSSc population, Dr. Khanna said.

The finding with respect to the primary outcome is consistent with other recent trials because of improvement in mRSS that’s part of the natural history of the disease, including the tocilizumab findings that he reported at the meeting. The findings with respect to secondary endpoints and safety show promise.

“Stay tuned for robust ongoing work on the relationship between clinical changes and ongoing mechanistic work,” he said.
 

Riociguat (Adempas)

Similarly, in the randomized, placebo-controlled phase 2b RISE-SSc study comparing riociguat and placebo for early dcSSc, the primary efficacy endpoint of mean change in mRSS did not reach statistical significance, but exploratory data suggested that the soluble guanylate cyclase stimulator prevented disease progression in patients with early dcSSc, reported Oliver Distler, MD, head of the connective tissue diseases program at University Hospital Zurich (Switzerland).

The mean mRSS at baseline was comparable in 60 patients randomized to receive riociguat and 61 in the placebo group (16.8 and 16.71, respectively). These mean values at week 52 dropped to 14.63 vs. 15.73, respectively (P = .08).

“So it was close, but it didn’t reach significance,” he said.

The difference in the mRSS progression rate, however, suggested significant effects favoring riociguat (descriptive P = .02), he said.

Further, mean change from baseline to week 52 in percent predicted FVC was not different overall between the groups, but a large difference favoring riociguat was seen among patients with scleroderma interstitial lung disease at baseline (mean change of –2.7 vs. –8.9), he said.

No differences were seen between the groups in HAQ-DI or patient and physician global assessment. The proportion of patients with probability of improvement at 52 weeks as measured using ACR CRISS was also the same at 18% in both treatment arms, he noted, ”but the CRISS is designed more for assessing disease regression than for assessing prevention of progression.”

Treatment was, however, well tolerated. At week 52, fewer serious adverse events occurred with riociguat group than in the placebo group (15% vs. 25%, respectively), and no new safety signals were observed, he said.

Riociguat has previously shown antifibrotic effects in animal models and efficacy in patients with pulmonary arterial hypertension associated with connective tissue disease, so it was hypothesized that patients with dcSSc might benefit from riociguat therapy, Dr. Distler explained.

Study subjects had very early dcSSc (duration of 18 months or less; mean of 9 months), mRSS of 10-22 units, FVC of 45% predicted or greater, and diffusion capacity of the lung for carbon monoxide of at least 40% of predicted at screening.

Riociguat was given at an individually adjusted dose between 0.5 mg and 2.5 mg three times daily.

The findings demonstrate a numeric decrease in mRSS over time with riociguat versus placebo and a prevention of progression with riociguat; the failure to reach the primary endpoint may be related to the small study size and the higher than expected regression rate in the placebo group, Dr. Distler said.

Dr. Khanna is a consultant to Roche/Genentech and Bayer, which markets riociguat, and other companies. He has received research grants from Bayer, Bristol-Myers Squibb (which markets abatacept), and Pfizer. The ASSET trial he presented was sponsored by an National Institutes of Health/National Institute of Allergy and Infectious Diseases Clinical ACE grant and an investigator-initiated grant by Bristol-Myers Squibb. Dr. Distler has a consultancy relationship and/or has received research funding from Bayer, Roche/Genentech, and other companies. In addition, he has a patent on mir-29 for the treatment of systemic sclerosis.

[email protected]

SOURCES: Khanna D et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract 898 and Abstract 900; Distler O et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract 903.

CHICAGO – Recent randomized, placebo-controlled, phase 3 trials of tocilizumab, abatacept, and riociguat for the treatment of systemic sclerosis each failed to reach its primary endpoint of change from baseline in modified Rodnan Skin Score (mRSS).

Still, findings with respect to secondary endpoints and certain exploratory outcomes suggest each of the agents holds some promise in the systemic sclerosis (SSc) arena, according to the data presented at the annual meeting of the American College of Rheumatology.
 

Tocilizumab (Actemra)

In the double-blind portion of the phase 3 focuSSced trial of 212 patients with SSc, numerical improvement was observed for the primary endpoint of mean change in mRSS from baseline to week 48 with tocilizumab versus placebo (–6.14 vs. –4.41 points, respectively). The change in the treatment group was comparable with what was seen in the phase 2 faSScinate trial, but the decline in mRSS in the placebo group was much greater in phase 3 than in phase 2, and so the difference between the groups in the current study failed to reach statistical significance (P = .098), reported Dinesh Khanna, MBBS, a professor of medicine and director of the scleroderma program at the University of Michigan, Ann Arbor.

The interleukin-6 (IL-6) receptor–alpha antibody was previously shown in the faSScinate trial to lead to numeric improvements in skin thickening as measured by the mRSS, as well as to clinically meaningful lung function preservation as measured by percent predicted forced vital capacity (FVC).

In the current phase 3 study, key secondary end points also appeared to favor tocilizumab, but since the primary endpoint for mRSS was not met, all other P values cannot be considered statistically significant despite the strength of the evidence and were reported for informational purposes only, he noted.

The median cumulative distribution of change from baseline to week 48 in percent predicted FVC with tocilizumab versus placebo was –0.6 vs. –3.9, respectively (descriptive P = .0015), and the mean change from baseline in FVC at week 48 was –24 mL vs. –190 mL (difference of 167 mL in favor of tocilizumab; descriptive P = .0001).

Time to treatment failure also favored tocilizumab, he said (hazard ratio, 0.63; descriptive P = .082), he said.

Patients were randomly assigned to receive either weekly 162-mg injections of subcutaneous tocilizumab or placebo for 48 weeks. Escape therapy was allowed beginning at week 16 if patients experienced declines in FVC or beginning at week 24 if they experienced worsened mRSS or worsened SSc complications, Dr. Khanna said.

“The key part is that no immunotherapy was allowed. ... So it’s a true randomized, placebo-controlled trial,” he said.

Most (81%) of the patients were women, and they had a mean age of 48 years, mean SSc duration of 23 months, mean mRSS of 20.4 units on a 0-51 scale, and a normal mean percent predicted FVC of 82.1%.

“HAQ-DI showed moderate disability of 1.2,” he noted.

Safety in the study was consistent with that seen in prior tocilizumab studies; no new safety signals were identified. Serious adverse events occurred in 13% and 17% of tocilizumab and placebo group patients , respectively, and serious infections were reported by 7% and 2%.

Although clinically meaningful and consistent differences in FVC favoring tocilizumab were shown in this study, the primary endpoint was not met, Dr. Khanna said.

“There were no statistically significant differences, largely driven by unexpected improvement in the placebo group, which was different than what we found in [the faSScinate] trial,” he said, noting, however, that the FVC findings in the current study were clinically meaningful.

Also, in a separate presentation at the meeting, he explained that the differences favoring tocilizumab were statistically significant when patient-level data from the trial were analyzed based on the ACR Composite Response Index in Systemic Sclerosis (CRISS). Those findings provide validation of the novel outcomes measure, he said.

 

Abatacept (Orencia)

Dr. Khanna also reported results of the 12-month, double-blind, randomized, placebo-controlled phase 2 ASSET trial of abatacept, which showed no significant difference in mRSS in patients with early diffuse cutaneous SSc (dfSSc) who were treated with 125 mg of the recombinant fusion protein weekly and those who received placebo. However, certain secondary outcomes favored abatacept. No concomitant immunotherapy was allowed.

The adjusted mean decrease in the mRSS among patients who completed the 12-month treatment period was –6.24 vs. –4.49 in 34 patients in the abatacept group and 35 in the placebo group, respectively (P = .28).

The secondary outcome measures of mean change in Health Assessment Questionnaire Disability Index (HAQ-DI), patients global assessment, physician global assessment, and ACR CRISS scores were statistically significant or showed numerical results favoring abatacept over placebo: mean decrease in HAQ-DI, –0.17 vs. –0.11 (P = .05), respectively; mean change in physician global assessment scores, –1.30 vs. –0.35 (P = .03); median ACR CRISS index, 0.68 vs. 0.01 (P = .03), decline in percent predicted FVC of 4.13% and 1.34% (P = .11).

Escape therapy was allowed at 6 months for worsening SSc, but it did not change the outcomes trajectory, he said. A larger proportion of placebo vs. abatacept subjects required escape immunosuppressive therapy (36% vs. 16%; P = .03).

Patients were enrolled between 2014 and 2018 at 27 U.S., Canadian, and U.K. sites. At baseline, participants had a mean age of 49 years, 75% were women, and mean disease duration was very short at 1.59 years, with 60% having disease duration of 18 months or less. The mean baseline mRSS was 22.4, mean percent predicted FVC was 85.3%, and mean HAQ-DI was 1.0.

Compliance with both treatments was greater than 98%. Abatacept was well tolerated with comparable adverse events (AEs), serious AEs, and AEs of special interest such as infections and malignancies between treatments, Dr. Khanna said, noting that two deaths occurred in the abatacept group (caused by scleroderma renal crisis in both cases at days 11 and 46) and one occurred in a placebo group patient who experienced sudden cardiac arrest at day 310.

Of note, mRSS showed large variability, despite recruiting an early dcSSc population, Dr. Khanna said.

The finding with respect to the primary outcome is consistent with other recent trials because of improvement in mRSS that’s part of the natural history of the disease, including the tocilizumab findings that he reported at the meeting. The findings with respect to secondary endpoints and safety show promise.

“Stay tuned for robust ongoing work on the relationship between clinical changes and ongoing mechanistic work,” he said.
 

Riociguat (Adempas)

Similarly, in the randomized, placebo-controlled phase 2b RISE-SSc study comparing riociguat and placebo for early dcSSc, the primary efficacy endpoint of mean change in mRSS did not reach statistical significance, but exploratory data suggested that the soluble guanylate cyclase stimulator prevented disease progression in patients with early dcSSc, reported Oliver Distler, MD, head of the connective tissue diseases program at University Hospital Zurich (Switzerland).

The mean mRSS at baseline was comparable in 60 patients randomized to receive riociguat and 61 in the placebo group (16.8 and 16.71, respectively). These mean values at week 52 dropped to 14.63 vs. 15.73, respectively (P = .08).

“So it was close, but it didn’t reach significance,” he said.

The difference in the mRSS progression rate, however, suggested significant effects favoring riociguat (descriptive P = .02), he said.

Further, mean change from baseline to week 52 in percent predicted FVC was not different overall between the groups, but a large difference favoring riociguat was seen among patients with scleroderma interstitial lung disease at baseline (mean change of –2.7 vs. –8.9), he said.

No differences were seen between the groups in HAQ-DI or patient and physician global assessment. The proportion of patients with probability of improvement at 52 weeks as measured using ACR CRISS was also the same at 18% in both treatment arms, he noted, ”but the CRISS is designed more for assessing disease regression than for assessing prevention of progression.”

Treatment was, however, well tolerated. At week 52, fewer serious adverse events occurred with riociguat group than in the placebo group (15% vs. 25%, respectively), and no new safety signals were observed, he said.

Riociguat has previously shown antifibrotic effects in animal models and efficacy in patients with pulmonary arterial hypertension associated with connective tissue disease, so it was hypothesized that patients with dcSSc might benefit from riociguat therapy, Dr. Distler explained.

Study subjects had very early dcSSc (duration of 18 months or less; mean of 9 months), mRSS of 10-22 units, FVC of 45% predicted or greater, and diffusion capacity of the lung for carbon monoxide of at least 40% of predicted at screening.

Riociguat was given at an individually adjusted dose between 0.5 mg and 2.5 mg three times daily.

The findings demonstrate a numeric decrease in mRSS over time with riociguat versus placebo and a prevention of progression with riociguat; the failure to reach the primary endpoint may be related to the small study size and the higher than expected regression rate in the placebo group, Dr. Distler said.

Dr. Khanna is a consultant to Roche/Genentech and Bayer, which markets riociguat, and other companies. He has received research grants from Bayer, Bristol-Myers Squibb (which markets abatacept), and Pfizer. The ASSET trial he presented was sponsored by an National Institutes of Health/National Institute of Allergy and Infectious Diseases Clinical ACE grant and an investigator-initiated grant by Bristol-Myers Squibb. Dr. Distler has a consultancy relationship and/or has received research funding from Bayer, Roche/Genentech, and other companies. In addition, he has a patent on mir-29 for the treatment of systemic sclerosis.

[email protected]

SOURCES: Khanna D et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract 898 and Abstract 900; Distler O et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract 903.

CHICAGO – Recent randomized, placebo-controlled, phase 3 trials of tocilizumab, abatacept, and riociguat for the treatment of systemic sclerosis each failed to reach its primary endpoint of change from baseline in modified Rodnan Skin Score (mRSS).

Still, findings with respect to secondary endpoints and certain exploratory outcomes suggest each of the agents holds some promise in the systemic sclerosis (SSc) arena, according to the data presented at the annual meeting of the American College of Rheumatology.
 

Tocilizumab (Actemra)

In the double-blind portion of the phase 3 focuSSced trial of 212 patients with SSc, numerical improvement was observed for the primary endpoint of mean change in mRSS from baseline to week 48 with tocilizumab versus placebo (–6.14 vs. –4.41 points, respectively). The change in the treatment group was comparable with what was seen in the phase 2 faSScinate trial, but the decline in mRSS in the placebo group was much greater in phase 3 than in phase 2, and so the difference between the groups in the current study failed to reach statistical significance (P = .098), reported Dinesh Khanna, MBBS, a professor of medicine and director of the scleroderma program at the University of Michigan, Ann Arbor.

The interleukin-6 (IL-6) receptor–alpha antibody was previously shown in the faSScinate trial to lead to numeric improvements in skin thickening as measured by the mRSS, as well as to clinically meaningful lung function preservation as measured by percent predicted forced vital capacity (FVC).

In the current phase 3 study, key secondary end points also appeared to favor tocilizumab, but since the primary endpoint for mRSS was not met, all other P values cannot be considered statistically significant despite the strength of the evidence and were reported for informational purposes only, he noted.

The median cumulative distribution of change from baseline to week 48 in percent predicted FVC with tocilizumab versus placebo was –0.6 vs. –3.9, respectively (descriptive P = .0015), and the mean change from baseline in FVC at week 48 was –24 mL vs. –190 mL (difference of 167 mL in favor of tocilizumab; descriptive P = .0001).

Time to treatment failure also favored tocilizumab, he said (hazard ratio, 0.63; descriptive P = .082), he said.

Patients were randomly assigned to receive either weekly 162-mg injections of subcutaneous tocilizumab or placebo for 48 weeks. Escape therapy was allowed beginning at week 16 if patients experienced declines in FVC or beginning at week 24 if they experienced worsened mRSS or worsened SSc complications, Dr. Khanna said.

“The key part is that no immunotherapy was allowed. ... So it’s a true randomized, placebo-controlled trial,” he said.

Most (81%) of the patients were women, and they had a mean age of 48 years, mean SSc duration of 23 months, mean mRSS of 20.4 units on a 0-51 scale, and a normal mean percent predicted FVC of 82.1%.

“HAQ-DI showed moderate disability of 1.2,” he noted.

Safety in the study was consistent with that seen in prior tocilizumab studies; no new safety signals were identified. Serious adverse events occurred in 13% and 17% of tocilizumab and placebo group patients , respectively, and serious infections were reported by 7% and 2%.

Although clinically meaningful and consistent differences in FVC favoring tocilizumab were shown in this study, the primary endpoint was not met, Dr. Khanna said.

“There were no statistically significant differences, largely driven by unexpected improvement in the placebo group, which was different than what we found in [the faSScinate] trial,” he said, noting, however, that the FVC findings in the current study were clinically meaningful.

Also, in a separate presentation at the meeting, he explained that the differences favoring tocilizumab were statistically significant when patient-level data from the trial were analyzed based on the ACR Composite Response Index in Systemic Sclerosis (CRISS). Those findings provide validation of the novel outcomes measure, he said.

 

Abatacept (Orencia)

Dr. Khanna also reported results of the 12-month, double-blind, randomized, placebo-controlled phase 2 ASSET trial of abatacept, which showed no significant difference in mRSS in patients with early diffuse cutaneous SSc (dfSSc) who were treated with 125 mg of the recombinant fusion protein weekly and those who received placebo. However, certain secondary outcomes favored abatacept. No concomitant immunotherapy was allowed.

The adjusted mean decrease in the mRSS among patients who completed the 12-month treatment period was –6.24 vs. –4.49 in 34 patients in the abatacept group and 35 in the placebo group, respectively (P = .28).

The secondary outcome measures of mean change in Health Assessment Questionnaire Disability Index (HAQ-DI), patients global assessment, physician global assessment, and ACR CRISS scores were statistically significant or showed numerical results favoring abatacept over placebo: mean decrease in HAQ-DI, –0.17 vs. –0.11 (P = .05), respectively; mean change in physician global assessment scores, –1.30 vs. –0.35 (P = .03); median ACR CRISS index, 0.68 vs. 0.01 (P = .03), decline in percent predicted FVC of 4.13% and 1.34% (P = .11).

Escape therapy was allowed at 6 months for worsening SSc, but it did not change the outcomes trajectory, he said. A larger proportion of placebo vs. abatacept subjects required escape immunosuppressive therapy (36% vs. 16%; P = .03).

Patients were enrolled between 2014 and 2018 at 27 U.S., Canadian, and U.K. sites. At baseline, participants had a mean age of 49 years, 75% were women, and mean disease duration was very short at 1.59 years, with 60% having disease duration of 18 months or less. The mean baseline mRSS was 22.4, mean percent predicted FVC was 85.3%, and mean HAQ-DI was 1.0.

Compliance with both treatments was greater than 98%. Abatacept was well tolerated with comparable adverse events (AEs), serious AEs, and AEs of special interest such as infections and malignancies between treatments, Dr. Khanna said, noting that two deaths occurred in the abatacept group (caused by scleroderma renal crisis in both cases at days 11 and 46) and one occurred in a placebo group patient who experienced sudden cardiac arrest at day 310.

Of note, mRSS showed large variability, despite recruiting an early dcSSc population, Dr. Khanna said.

The finding with respect to the primary outcome is consistent with other recent trials because of improvement in mRSS that’s part of the natural history of the disease, including the tocilizumab findings that he reported at the meeting. The findings with respect to secondary endpoints and safety show promise.

“Stay tuned for robust ongoing work on the relationship between clinical changes and ongoing mechanistic work,” he said.
 

Riociguat (Adempas)

Similarly, in the randomized, placebo-controlled phase 2b RISE-SSc study comparing riociguat and placebo for early dcSSc, the primary efficacy endpoint of mean change in mRSS did not reach statistical significance, but exploratory data suggested that the soluble guanylate cyclase stimulator prevented disease progression in patients with early dcSSc, reported Oliver Distler, MD, head of the connective tissue diseases program at University Hospital Zurich (Switzerland).

The mean mRSS at baseline was comparable in 60 patients randomized to receive riociguat and 61 in the placebo group (16.8 and 16.71, respectively). These mean values at week 52 dropped to 14.63 vs. 15.73, respectively (P = .08).

“So it was close, but it didn’t reach significance,” he said.

The difference in the mRSS progression rate, however, suggested significant effects favoring riociguat (descriptive P = .02), he said.

Further, mean change from baseline to week 52 in percent predicted FVC was not different overall between the groups, but a large difference favoring riociguat was seen among patients with scleroderma interstitial lung disease at baseline (mean change of –2.7 vs. –8.9), he said.

No differences were seen between the groups in HAQ-DI or patient and physician global assessment. The proportion of patients with probability of improvement at 52 weeks as measured using ACR CRISS was also the same at 18% in both treatment arms, he noted, ”but the CRISS is designed more for assessing disease regression than for assessing prevention of progression.”

Treatment was, however, well tolerated. At week 52, fewer serious adverse events occurred with riociguat group than in the placebo group (15% vs. 25%, respectively), and no new safety signals were observed, he said.

Riociguat has previously shown antifibrotic effects in animal models and efficacy in patients with pulmonary arterial hypertension associated with connective tissue disease, so it was hypothesized that patients with dcSSc might benefit from riociguat therapy, Dr. Distler explained.

Study subjects had very early dcSSc (duration of 18 months or less; mean of 9 months), mRSS of 10-22 units, FVC of 45% predicted or greater, and diffusion capacity of the lung for carbon monoxide of at least 40% of predicted at screening.

Riociguat was given at an individually adjusted dose between 0.5 mg and 2.5 mg three times daily.

The findings demonstrate a numeric decrease in mRSS over time with riociguat versus placebo and a prevention of progression with riociguat; the failure to reach the primary endpoint may be related to the small study size and the higher than expected regression rate in the placebo group, Dr. Distler said.

Dr. Khanna is a consultant to Roche/Genentech and Bayer, which markets riociguat, and other companies. He has received research grants from Bayer, Bristol-Myers Squibb (which markets abatacept), and Pfizer. The ASSET trial he presented was sponsored by an National Institutes of Health/National Institute of Allergy and Infectious Diseases Clinical ACE grant and an investigator-initiated grant by Bristol-Myers Squibb. Dr. Distler has a consultancy relationship and/or has received research funding from Bayer, Roche/Genentech, and other companies. In addition, he has a patent on mir-29 for the treatment of systemic sclerosis.

[email protected]

SOURCES: Khanna D et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract 898 and Abstract 900; Distler O et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract 903.