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Sharon Worcester is an award-winning medical journalist for MDedge News. She has been with the company since 1996, first as the Southeast Bureau Chief (1996-2009) when the company was known as International Medical News Group, then as a freelance writer (2010-2015) before returning as a reporter in 2015. She previously worked as a daily newspaper reporter covering health and local government. Sharon currently reports primarily on oncology and hematology. She has a BA from Eckerd College and an MA in Mass Communication/Print Journalism from the University of Florida. Connect with her via LinkedIn and follow her on twitter @SW_MedReporter.
Factor IX expression stable at up to 8 years with gene therapy
SAN DIEGO – 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
SOURCE: Reiss UM et al. ASH 2018, Abstract 491.
SAN DIEGO – 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
SOURCE: Reiss UM et al. ASH 2018, Abstract 491.
SAN DIEGO – 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
SOURCE: Reiss UM et al. ASH 2018, Abstract 491.
REPORTING FROM ASH 2018
Key clinical point: With a median follow-up of 6.7 years in 10 patients aged 18-64 years who were treated with scAAV2/8-LP1-hFIX–comediated gene therapy, factor IX expression has been persistent and stable.
Major finding: Factor IX expression averaged 1.9%-2.3% at the lower doses, and 5.1% at the high dose at up to 8.6 years.
Study details: An interim follow-up data for 10 patients in a phase 1/2 study.
Disclosures: Dr. Reiss reported having no disclosures.
Source: Reiss UM et al. ASH 2018, Abstract 491.
Large cohort study IDs prognostic factors in thromboangiitis obliterans
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.
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.
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.
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.
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.
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.
SOURCE: Le Joncour A et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract 1885.
REPORTING FROM THE ACR ANNUAL MEETING
Key clinical point: Nonwhite ethnicity and limb infection predict poor prognosis in TAO.
Major finding: Ethnicity predicts vascular events (HR, 2.35); limb infection at diagnosis predicts vascular events and amputation (HR, 3.29 and 12.1, respectively).
Study details: A retrospective cohort study of 224 patients.
Disclosures: Dr. Le Joncour reported having no disclosures.
Source: Le Joncour A et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract 1885.
ALL regimens clear disease in kids with MPAL
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—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—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.
Model bests IPSS-R for predicting survival, risk for AML in myelodysplastic syndrome
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.
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.
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.
SOURCE: Nazha A et al. ASH 2018, Abstract 793.
REPORTING FROM ASH 2018
Ibrutinib outperforms bendamustine and rituximab in older CLL patients
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).
“There was no difference in progression-free survival between ibrutinib and ibrutinib plus rituximab,” said Dr. Woyach of the Ohio State University, Columbus.
Median PFS in this study was 43 months in the BR arm, and was not reached in either of the ibrutinib-containing arms, she said. No significant differences in overall survival (OS) were seen among the treatment arms, which may have been because of short follow-up and the fact that patients in the BR arm were allowed to cross over to ibrutinib if they progressed on treatment.
Participants in the international, multicenter trial – a project of the National Cancer Institute National Clinical Trials Network – were 547 adults aged 65 years or older (median, 71 years) with previously untreated, symptomatic CLL. They were enrolled from 219 sites across the United States and Canada between Dec. 9, 2013, and May 16, 2016.
The three arms were well matched with respect to baseline characteristics except for a slightly higher number of patients with complex karyotypes in the IR arm, Dr. Woyach said.
Treatment in the BR arm included bendamustine 90 mg/m2 on days 1 and 2 of each 28-day cycle plus rituximab at a dose of 375 mg/m2 on day 0 of cycle 1 then 500 mg/m2 on day 1 of cycles 2-6. Patients in the ibrutinib arms received 420 mg daily until disease progression either with or without rituximab at 375 mg/m2 weekly for 4 weeks starting at cycle 2 day 1 and then given on day 1 of cycles 3-6.
Grade 3-5 treatment-emergent hematologic adverse events (AEs) occurred in 61%, 41%, and 38% of patients in the BR, ibrutinib, and IR arms, respectively. Neutropenia and thrombocytopenia occurred more often in the BR than in the ibrutinib arms. Nonhematologic AEs occurred in 63%, 74%, and 74%, respectively, with an overall greater incidence in the ibrutinib arms. Infections and sudden deaths were numerically but not significantly higher in the ibrutinib arms.
“We undertook this study to determine the most effective therapy for older patients with CLL,” Dr. Woyach said, explaining that while older patients make up the majority of patients with CLL, they are typically underrepresented in trials.
At the start of the study, BR was widely used and the Bruton’s tyrosine kinase inhibitor ibrutinib was “just entering the clinic,” she noted.
“Despite now-widespread use in the [front-line setting] following FDA approval for this indication in 2016, the efficacy of ibrutinib versus standard chemoimmunotherapy has not previously been investigated,” she said.
Since adding rituximab has been shown to improve PFS and OS when added to chemotherapy in CLL, she and her colleagues also looked at whether this was the case with ibrutinib as well.
“This is the only phase 3 trial designed to answer this question,” she noted, adding that the findings justify the use of ibrutinib as a standard-of-care treatment for CLL patients aged 65 years and older.
David P. Steensma, MD, of Dana-Farber Cancer Institute in Boston, who moderated the press briefing, agreed. “I think this really does indicate that ibrutinib as front-line therapy, which many clinicians have been doing, is a very reasonable practice.”
Dr. Woyach added, however, that while ibrutinib represents a major therapeutic advance, its cost and its toxicities in older patients are a concern that warrant close monitoring and development of strategies to reduce the need for long-term continuous treatment.
Additional phase 3 studies set to open soon will compare ibrutinib in combination with venetoclax and obinutuzumab with standard ibrutinib
Dr. Woyach reported having no disclosures. Dr. Steensma reported receiving research funding from, and/or serving as a consultant, board member, or adviser for Takeda Pharmaceutical, Syros Pharmaceuticals, Otsuka Pharmaceutical, Onconova Therapeutics, Novartis, Kura Oncology, Janssen, H3 Biosciences, Celgene, Amphivena Therapeutics, and Acceleron Pharma.
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).
“There was no difference in progression-free survival between ibrutinib and ibrutinib plus rituximab,” said Dr. Woyach of the Ohio State University, Columbus.
Median PFS in this study was 43 months in the BR arm, and was not reached in either of the ibrutinib-containing arms, she said. No significant differences in overall survival (OS) were seen among the treatment arms, which may have been because of short follow-up and the fact that patients in the BR arm were allowed to cross over to ibrutinib if they progressed on treatment.
Participants in the international, multicenter trial – a project of the National Cancer Institute National Clinical Trials Network – were 547 adults aged 65 years or older (median, 71 years) with previously untreated, symptomatic CLL. They were enrolled from 219 sites across the United States and Canada between Dec. 9, 2013, and May 16, 2016.
The three arms were well matched with respect to baseline characteristics except for a slightly higher number of patients with complex karyotypes in the IR arm, Dr. Woyach said.
Treatment in the BR arm included bendamustine 90 mg/m2 on days 1 and 2 of each 28-day cycle plus rituximab at a dose of 375 mg/m2 on day 0 of cycle 1 then 500 mg/m2 on day 1 of cycles 2-6. Patients in the ibrutinib arms received 420 mg daily until disease progression either with or without rituximab at 375 mg/m2 weekly for 4 weeks starting at cycle 2 day 1 and then given on day 1 of cycles 3-6.
Grade 3-5 treatment-emergent hematologic adverse events (AEs) occurred in 61%, 41%, and 38% of patients in the BR, ibrutinib, and IR arms, respectively. Neutropenia and thrombocytopenia occurred more often in the BR than in the ibrutinib arms. Nonhematologic AEs occurred in 63%, 74%, and 74%, respectively, with an overall greater incidence in the ibrutinib arms. Infections and sudden deaths were numerically but not significantly higher in the ibrutinib arms.
“We undertook this study to determine the most effective therapy for older patients with CLL,” Dr. Woyach said, explaining that while older patients make up the majority of patients with CLL, they are typically underrepresented in trials.
At the start of the study, BR was widely used and the Bruton’s tyrosine kinase inhibitor ibrutinib was “just entering the clinic,” she noted.
“Despite now-widespread use in the [front-line setting] following FDA approval for this indication in 2016, the efficacy of ibrutinib versus standard chemoimmunotherapy has not previously been investigated,” she said.
Since adding rituximab has been shown to improve PFS and OS when added to chemotherapy in CLL, she and her colleagues also looked at whether this was the case with ibrutinib as well.
“This is the only phase 3 trial designed to answer this question,” she noted, adding that the findings justify the use of ibrutinib as a standard-of-care treatment for CLL patients aged 65 years and older.
David P. Steensma, MD, of Dana-Farber Cancer Institute in Boston, who moderated the press briefing, agreed. “I think this really does indicate that ibrutinib as front-line therapy, which many clinicians have been doing, is a very reasonable practice.”
Dr. Woyach added, however, that while ibrutinib represents a major therapeutic advance, its cost and its toxicities in older patients are a concern that warrant close monitoring and development of strategies to reduce the need for long-term continuous treatment.
Additional phase 3 studies set to open soon will compare ibrutinib in combination with venetoclax and obinutuzumab with standard ibrutinib
Dr. Woyach reported having no disclosures. Dr. Steensma reported receiving research funding from, and/or serving as a consultant, board member, or adviser for Takeda Pharmaceutical, Syros Pharmaceuticals, Otsuka Pharmaceutical, Onconova Therapeutics, Novartis, Kura Oncology, Janssen, H3 Biosciences, Celgene, Amphivena Therapeutics, and Acceleron Pharma.
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).
“There was no difference in progression-free survival between ibrutinib and ibrutinib plus rituximab,” said Dr. Woyach of the Ohio State University, Columbus.
Median PFS in this study was 43 months in the BR arm, and was not reached in either of the ibrutinib-containing arms, she said. No significant differences in overall survival (OS) were seen among the treatment arms, which may have been because of short follow-up and the fact that patients in the BR arm were allowed to cross over to ibrutinib if they progressed on treatment.
Participants in the international, multicenter trial – a project of the National Cancer Institute National Clinical Trials Network – were 547 adults aged 65 years or older (median, 71 years) with previously untreated, symptomatic CLL. They were enrolled from 219 sites across the United States and Canada between Dec. 9, 2013, and May 16, 2016.
The three arms were well matched with respect to baseline characteristics except for a slightly higher number of patients with complex karyotypes in the IR arm, Dr. Woyach said.
Treatment in the BR arm included bendamustine 90 mg/m2 on days 1 and 2 of each 28-day cycle plus rituximab at a dose of 375 mg/m2 on day 0 of cycle 1 then 500 mg/m2 on day 1 of cycles 2-6. Patients in the ibrutinib arms received 420 mg daily until disease progression either with or without rituximab at 375 mg/m2 weekly for 4 weeks starting at cycle 2 day 1 and then given on day 1 of cycles 3-6.
Grade 3-5 treatment-emergent hematologic adverse events (AEs) occurred in 61%, 41%, and 38% of patients in the BR, ibrutinib, and IR arms, respectively. Neutropenia and thrombocytopenia occurred more often in the BR than in the ibrutinib arms. Nonhematologic AEs occurred in 63%, 74%, and 74%, respectively, with an overall greater incidence in the ibrutinib arms. Infections and sudden deaths were numerically but not significantly higher in the ibrutinib arms.
“We undertook this study to determine the most effective therapy for older patients with CLL,” Dr. Woyach said, explaining that while older patients make up the majority of patients with CLL, they are typically underrepresented in trials.
At the start of the study, BR was widely used and the Bruton’s tyrosine kinase inhibitor ibrutinib was “just entering the clinic,” she noted.
“Despite now-widespread use in the [front-line setting] following FDA approval for this indication in 2016, the efficacy of ibrutinib versus standard chemoimmunotherapy has not previously been investigated,” she said.
Since adding rituximab has been shown to improve PFS and OS when added to chemotherapy in CLL, she and her colleagues also looked at whether this was the case with ibrutinib as well.
“This is the only phase 3 trial designed to answer this question,” she noted, adding that the findings justify the use of ibrutinib as a standard-of-care treatment for CLL patients aged 65 years and older.
David P. Steensma, MD, of Dana-Farber Cancer Institute in Boston, who moderated the press briefing, agreed. “I think this really does indicate that ibrutinib as front-line therapy, which many clinicians have been doing, is a very reasonable practice.”
Dr. Woyach added, however, that while ibrutinib represents a major therapeutic advance, its cost and its toxicities in older patients are a concern that warrant close monitoring and development of strategies to reduce the need for long-term continuous treatment.
Additional phase 3 studies set to open soon will compare ibrutinib in combination with venetoclax and obinutuzumab with standard ibrutinib
Dr. Woyach reported having no disclosures. Dr. Steensma reported receiving research funding from, and/or serving as a consultant, board member, or adviser for Takeda Pharmaceutical, Syros Pharmaceuticals, Otsuka Pharmaceutical, Onconova Therapeutics, Novartis, Kura Oncology, Janssen, H3 Biosciences, Celgene, Amphivena Therapeutics, and Acceleron Pharma.
SOURCE: Woyach JA et al. ASH 2018, Abstract 6.
REPORTING FROM ASH 2018
Key clinical point: In chronic lymphocytic leukemia patients aged 65 years and older, progression-free survival is better with ibrutinib than with bendamustine and rituximab.
Major finding: The 2-year progression-free survival was 74%, 87%, and 88% with bendamustine and rituximab, ibrutinib, and ibrutinib and rituximab, respectively.
Study details: A randomized, phase 3 study of 547 previously untreated patients with CLL.
Disclosures: Dr. Woyach reported having no disclosures. Dr. Steensma reported receiving research funding from, and/or serving as a consultant, board member, or adviser for Takeda Pharmaceutical, Syros Pharmaceuticals, Otsuka Pharmaceutical, Onconova Therapeutics, Novartis, Kura Oncology, Janssen, H3 Biosciences, Celgene, Amphivena Therapeutics, and Acceleron Pharma.
Source: Woyach JA et al. ASH 2018, Abstract 6.
Novel conditioning and familial haploidentical SCT well tolerated, cured 90% of patients
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.
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.
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.
REPORTING FROM ASH 2018
RELIEF: In Behçet’s, apremilast improves oral ulcers for up to 28 weeks
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 (AUCWk0-12) – 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. AUCWk0-12 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.
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 (AUCWk0-12) – 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. AUCWk0-12 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.
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 (AUCWk0-12) – 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. AUCWk0-12 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.
SOURCE: Hatemi G et al. Arthritis Rheumatol. 2018;70(Suppl 10), Abstract 2789.
REPORTING FROM THE ACR ANNUAL MEETING
Key clinical point: Apremilast is safe and effective for treating oral ulcers in patients with Behçet’s disease.
Major finding: The AUCWk0-12 was significantly lower with apremilast (129.54) versus placebo (222.14).
Study details: A randomized, placebo-controlled, phase 3 study of 207 patients.
Disclosures: 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.
Source: Hatemi G et al. Arthritis Rheumatol. 2018;70(Suppl 10), Abstract 2789
A novel tracer shows promise for detecting CD8 T-cells in advanced solid tumors
WASHINGTON – 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.
The estimated mean effective radiation dose was 2.4 rem/mCi, “which is consistent with other zirconium-labeled antibody or minibody technologies,” Dr. Gordon said.
Study subjects ranged in age from 31 to 82 years and included nine men and six women with solid tumor malignancies who were eligible to receive checkpoint inhibitor therapy. Their primary cancer types were melanoma (eight patients), non–small-cell lung cancer (six patients), and hepatocellular carcinoma (one patient).
Two patients had received no prior treatment, three had discontinued prior checkpoint inhibitor therapy, and 10 were on immunotherapy.
No drug-related adverse events occurred during the course of the study, although one patient had a transient increase in anti-drug antibodies, Dr. Gordon said.
“Immunotherapy, and specifically checkpoint inhibitors (CPIs), have transformed the landscape of cancer care. Antitumor activity of CPIs is mediated by the CD8-positive T-cell cytotoxic effects, with preclinical and translational clinical studies demonstrating the importance of activated CD8-positive cells within the tumor microenvironment,” he explained, adding that currently available technology is limited in its ability to continually assess the presence of and change in the CD8 infiltrate; one biopsy may fail to capture the immunologic heterogeneity that exists among various tumors in an individual patient.
“As CPI therapy moves into front-line and earlier settings, the ability to have a noninvasive technology to assess whole body and intratumoral changes in CD8 trafficking or expansion in response to therapy is viewed as being crucial,” he said.
A phase 2 study to look closer at the potential for PET + 89Zr-IAB22M2C to fulfill that role will begin soon. The study will focus on correlating imaging with synchronous biopsies before and after primary immunotherapy to look for any predictive potential for this technology, he said.
This study was supported by ImaginAb and Parker Institute for Cancer Immunotherapy. Dr. Gordon reported having no disclosures.
SOURCE: Gordon M et al., SITC 2018: Abstract LB49.
WASHINGTON – 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.
The estimated mean effective radiation dose was 2.4 rem/mCi, “which is consistent with other zirconium-labeled antibody or minibody technologies,” Dr. Gordon said.
Study subjects ranged in age from 31 to 82 years and included nine men and six women with solid tumor malignancies who were eligible to receive checkpoint inhibitor therapy. Their primary cancer types were melanoma (eight patients), non–small-cell lung cancer (six patients), and hepatocellular carcinoma (one patient).
Two patients had received no prior treatment, three had discontinued prior checkpoint inhibitor therapy, and 10 were on immunotherapy.
No drug-related adverse events occurred during the course of the study, although one patient had a transient increase in anti-drug antibodies, Dr. Gordon said.
“Immunotherapy, and specifically checkpoint inhibitors (CPIs), have transformed the landscape of cancer care. Antitumor activity of CPIs is mediated by the CD8-positive T-cell cytotoxic effects, with preclinical and translational clinical studies demonstrating the importance of activated CD8-positive cells within the tumor microenvironment,” he explained, adding that currently available technology is limited in its ability to continually assess the presence of and change in the CD8 infiltrate; one biopsy may fail to capture the immunologic heterogeneity that exists among various tumors in an individual patient.
“As CPI therapy moves into front-line and earlier settings, the ability to have a noninvasive technology to assess whole body and intratumoral changes in CD8 trafficking or expansion in response to therapy is viewed as being crucial,” he said.
A phase 2 study to look closer at the potential for PET + 89Zr-IAB22M2C to fulfill that role will begin soon. The study will focus on correlating imaging with synchronous biopsies before and after primary immunotherapy to look for any predictive potential for this technology, he said.
This study was supported by ImaginAb and Parker Institute for Cancer Immunotherapy. Dr. Gordon reported having no disclosures.
SOURCE: Gordon M et al., SITC 2018: Abstract LB49.
WASHINGTON – 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.
The estimated mean effective radiation dose was 2.4 rem/mCi, “which is consistent with other zirconium-labeled antibody or minibody technologies,” Dr. Gordon said.
Study subjects ranged in age from 31 to 82 years and included nine men and six women with solid tumor malignancies who were eligible to receive checkpoint inhibitor therapy. Their primary cancer types were melanoma (eight patients), non–small-cell lung cancer (six patients), and hepatocellular carcinoma (one patient).
Two patients had received no prior treatment, three had discontinued prior checkpoint inhibitor therapy, and 10 were on immunotherapy.
No drug-related adverse events occurred during the course of the study, although one patient had a transient increase in anti-drug antibodies, Dr. Gordon said.
“Immunotherapy, and specifically checkpoint inhibitors (CPIs), have transformed the landscape of cancer care. Antitumor activity of CPIs is mediated by the CD8-positive T-cell cytotoxic effects, with preclinical and translational clinical studies demonstrating the importance of activated CD8-positive cells within the tumor microenvironment,” he explained, adding that currently available technology is limited in its ability to continually assess the presence of and change in the CD8 infiltrate; one biopsy may fail to capture the immunologic heterogeneity that exists among various tumors in an individual patient.
“As CPI therapy moves into front-line and earlier settings, the ability to have a noninvasive technology to assess whole body and intratumoral changes in CD8 trafficking or expansion in response to therapy is viewed as being crucial,” he said.
A phase 2 study to look closer at the potential for PET + 89Zr-IAB22M2C to fulfill that role will begin soon. The study will focus on correlating imaging with synchronous biopsies before and after primary immunotherapy to look for any predictive potential for this technology, he said.
This study was supported by ImaginAb and Parker Institute for Cancer Immunotherapy. Dr. Gordon reported having no disclosures.
SOURCE: Gordon M et al., SITC 2018: Abstract LB49.
REPORTING FROM SITC 2018
Key clinical point: PET with CD8-tracer 89Zr-IAB22M2C is safe, provides detailed CD8 T-cell information.
Major finding: Tumor uptake of the CD8-tracer was seen in 10 of 15 subjects.
Study details: An open-label phase 1 study of 15 patients.
Disclosures: This study was supported by ImaginAb and Parker Institute for Cancer Immunotherapy. Dr. Gordon reported having no disclosures.
Source: Gordon M et al. SITC 2018: Abstract LB49.
Three drugs disappoint in SSc trials, but show some promise
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.
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.
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.
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.
REPORTING FROM THE ACR ANNUAL MEETING
ACR CRISS: A way forward for scleroderma treatment trials?
CHICAGO – At least three phase 3 randomized scleroderma treatment trials presented at the annual meeting of the American College of Rheumatology failed to meet modified Rodnan Skin Score–based primary endpoints, but a different story emerged when data from the trials were analyzed using the novel ACR Composite Response Index in Systemic Sclerosis (CRISS).
The differences highlight the limitations of individual outcome measures like the modified Rodnan Skin Score (mRSS) and underscore the need for new measures that capture the complexity of systemic sclerosis (SSc) and are more sensitive to changes in disease severity, according to Robert Spiera, MD, director of the vasculitis and scleroderma program at the Hospital for Special Surgery in New York.
Such measures are needed to better assess the effects of treatment interventions in scleroderma trials, Dr. Spiera said in an interview.
The ACR CRISS
Development of the ACR CRISS was led by Dinesh Khanna, MBBS, a professor of medicine and director of the scleroderma program at the University of Michigan, Ann Arbor. He and his colleagues described the measure in 2016 (Arthritis Rheumatol. 2016 Feb;68[2]:299-311. doi: 10.1002/art.39501).
Its use involves a two-step process of identifying any significant disease worsening or new end-organ damage, and then calculating the probability of patient improvement after 1 year of treatment on a 0- to 1-point scale based on changes from baseline in five variables: the mRSS, percent predicted forced vital capacity (FVC), patient and physician global assessments, and the Health Assessment Questionnaire Disability Index (HAQ-DI).
A CRISS score of 0.6 or higher indicates likelihood that a patient improved on treatment. Of note, subjects with significant worsening of renal or cardiopulmonary involvement are classified as not improved (score of 0), regardless of improvements in other core items.
To devise the CRISS, the investigators compiled 150 patient profiles with standardized clinical outcome elements using patients with diffuse cutaneous systemic sclerosis (dcSSc). The profiles were assessed by 40 scleroderma experts who rated patient improvement or lack thereof over 12 months.
Using the 79% of profiles for which a consensus was reached, the investigators “fit logistic regression models in which the binary outcome referred to whether the patient was improved or not, and the changes in the core set items from baseline to follow-up were entered as covariates,” they explained.
This led to the selection of the five measures included in the final version, which was found to have sensitivity of 0.982 and specificity of 0.931. When evaluated in a previously completed 1-year randomized controlled trial, the index differentiated the effect of methotrexate from the effect of placebo (P = .02), they reported.
Based on these findings, the ACR board of directors granted “provisional” endorsement of the CRISS for use in SSc clinical studies, signifying that it had been quantitatively validated using patient data, but had not undergone validation using an external data set.
New data presented at the 2018 ACR meeting will likely lead to full approval of the measure once the studies validating the measure are published, according to Dr. Spiera.
The focuSSced study of tocilizumab
For example, in the phase 3 focuSSced study comparing the interleukin-6 (IL-6) receptor–alpha antibody tocilizumab (Actemra) with placebo in patients with SSc, the primary endpoint of mean change from baseline in mRSS was not met (–6.14 vs. –4.41 points with tocilizumab vs. placebo, respectively; P = .098), Dr. Khanna said during a report of findings from the double-blind portion of the study.
However, when the CRISS was applied and its performance prospectively assessed as an exploratory outcome at week 48 in the focuSSced trial, the differences between the groups were statistically significant. Dr. Khanna reported those findings in a separate presentation at the meeting, noting that they marked the first prospective evaluation of the ACR CRISS in a phase 3 trial in SSc.
The CRISS was applied – using a blinded review of adverse events and serious adverse events to complete step 1 – in all patients who received study treatment, stratified by baseline IL-6 levels.
Of 104 patients in the tocilizumab arm and 106 in the placebo arm, 6 and 13 patients, respectively, had cardio-pulmonary-renal involvement and therefore received a score of 0.
Using the ACR CRISS as a continuous measure, scores favored tocilizumab over placebo at week 48 with a median increase of 0.89 vs. 0.25 points (P = .023), and using the binary form of CRISS, 51% vs. 37% of patients in the treatment and placebo arms achieved the score cutoff of 0.60 or higher at week 48 (P = .035), he said.
“The focuSSced study validates the ACR CRISS endpoint for the first time in an independent prospective clinical trial and highlights the importance of step 1 as an indicator of reduced organ progression during 48 weeks of treatment,” Dr. Khanna concluded.
The ASSET trial of abatacept
Dr. Khanna also reported results from the 12-month phase 2 ASSET trial comparing abatacept (Orencia) and placebo in early dcSSc.
Again, the change from baseline in mRSS – the primary endpoint of the study – did not differ significantly with treatment vs. placebo (–6.24 vs. –4.49; P = .28).
And again, as presented separately in a poster session at ACR, application of CRISS at 12 months – a secondary outcome measure in the trial – showed a significant difference between the groups.
The investigators prospectively performed step 1 of the CRISS using a case report form. Of 63 patients with complete data available for relevant outcomes at 12 months, 10 (5 in each group) had cardio-pulmonary-renal involvement and thus were given a score of 0.
Overall, there was evidence of significantly improved CRISS scores in the abatacept group vs. the placebo group (P = .03), he said.
Most of the individual CRISS variables, except HAQ-DI and patient global assessment, had statistically significant correlations with the CRISS, he noted, adding that “although the degree of correlation is high between the mRSS and CRISS, there is evidence that CRISS may be more sensitive to clinically meaningful treatment changes than the standard skin score endpoint.”
“This suggests further validation of CRISS as an independent primary endpoint for scleroderma clinical trials,” he concluded.
The phase 2b RISE-SSc study of riociguat
As in the focuSSced and ASSET studies, the primary efficacy endpoint of mean change from baseline in mRSS was not met in the randomized, double-blind, placebo-controlled RISE-SSc study evaluating the safety and efficacy of the soluble guanylate cyclase stimulator riociguat (Adempas) vs. placebo in 121 patients with early dcSSc, reported Oliver Distler, MD, a professor at University Hospital Zurich.
The mean change in mRSS at 52 weeks was 2.25 vs. 0.97 with riociguat vs. placebo, respectively (P = .08), although the difference in mRSS progression rate showed significant effects favoring riociguat (P = .02), he noted.
In this study, however, the proportion of patients with ACR CRISS probability of improvement (score of 0.60 or higher) at week 52 – a secondary study outcome – was the same at 18% in both arms, Dr. Distler said.
In a way, it’s helpful that the CRISS findings as well as the mRSS outcome in the RISE-SSc study were negative because it shows that “not everything comes up positive using the CRISS,” Dr. Spiera said.
An open-label extension trial of lenabasum
In the open-label extension of a phase 2 trial of lenabasum, Dr. Spiera and his colleagues also found the CRISS useful for assessing response in 36 patients. Lenabasum is a synthetic, nonimunosuppressive, selective cannabinoid receptor type 2 agonist that activates resolution of innate immune responses.
The agent continued to demonstrate acceptable safety and tolerability in dcSSc with no severe or serious adverse events or study discontinuations related to treatment during 12 months of open-label extension dosing, both from baseline and from the start of the extension, they reported in a poster at the ACR meeting. These assessments were based on ACR CRISS score, mRSS, physician global assessment, and multiple patient-reported outcomes.
The median CRISS score was 92% at week 52, and mRSS declined by a mean of 9.4 points (41.3% from baseline). More than a third of patients (35%) achieved a low mRSS of 10 or less.
The investigators noted, however, that definitive attribution of the findings to lenabasum is limited by the use of background therapy, the potential for spontaneous improvement in patients, and open-label dosing.
Evaluating immunosuppressive therapy in SSc
In another study presented at the ACR meeting, Boyang Zheng, MD, a second-year rheumatology fellow at McGill University in Montreal and his colleagues evaluated the effect of current immunosuppressive therapy on the ACR CRISS in 301 adult dcSSc patients without prior immunosuppression who were part of the Canadian Scleroderma Research Group (CSRG) registry.
Patients newly treated with methotrexate, azathioprine, mycophenolate and/or cyclophosphamide for at least 2 years (47 patients) were considered “exposed patients,” and untreated patients with at least the same follow-up duration were considered control subjects (254 patients).
Inverse probability of treatment weighting (IPTW) was performed to balance potential confounders in the two groups, including age, sex, disease duration, and CRISS variables, in an effort “to create a statistical cohort that would resemble a randomized, controlled trial,” Dr Zheng explained.
Prior to IPTW, treated patients trended towards more improvement after 1 year, but with “unimpressive absolute values.”
“But [after IPTW], when you look at overall CRISS at 1 year, more of the treated patients had actually improved – 23% vs. 11.8% in the untreated patients. After adjusting for age, sex, and disease duration, immunosuppression was associated with an almost twofold higher likelihood of improvement, although this was not statistically significant,” he said.
“Most importantly, after our balancing in the statistical cohort – so after balancing and adjusting for covariates ... immunosuppression use was still associated with a higher likelihood of improving [with an] odds ratio of 1.85 and P-value of 0.018,” he said.
The treated patients were sicker, and the CRISS was still able to capture individual patient improvement, he added.
Though limited by the observational design and the fact that “IPTW balancing cannot correct for all possible confounders,” the findings “provide novel evidence to support the use of immunosuppression in diffuse systemic sclerosis, and this reassures us in our current practice; it provides evidence that the CRISS seems to have better sensitivity to change than the mean of individual disease measures,” he said.
However, it also shows that “we have a long way to go to have better treatment for our patients,” he added, noting that only a minority (23%) of the patients in this study improved on the CRISS.
Moving forward in systemic sclerosis
Indeed, in order to move forward in developing better treatment for SSc, it is important to have the best possible means for assessing the effects of the potential new treatments, Dr. Spiera said.
“The mRSS is a good, reliable outcome measure in terms of intra- and inter-rater reliability, and we know it has meaning in the real world; in a patient with rapidly progressive skin thickening and a skin score that is getting higher and higher, we know they have worse prognosis in terms of function and even survival,” he said. “On the other hand, it’s just one piece of this very complicated story when you’re dealing with patients with systemic sclerosis, some of whom can have important internal organ involvement and not even have skin involvement.”
The main challenge with the skin score is how it performs in clinical trials when it comes to demonstrating whether a drug works, he added.
“This is particularly relevant in an era where our better understanding of the disease has led to candidate therapeutic agents that we have reason to think might work, but where clinical trials haven’t shown a significant difference between the groups using the skin score.”
Conversely, there have been studies in which skin scores improve, but the patient is doing terribly, he noted.
“That patient would not be [shown to be] doing well using the CRISS,” he said, explaining that the complex formula used to determine the CRISS score, which is “heavily weighted toward skin score,” allows for an overall score that is “greater than the sum of its parts.” That is, if a patient is improving in multiple domains indicating that the patient is responding to therapy, more credit is given for each of those parts.
“So my sense, and I think it’s the consensus in the community of clinical investigators, is that the skin score is not adequately sensitive to change in the context of a trial and doesn’t capture the disease holistically enough to be the optimal measure for scleroderma clinical trials,” he said. “We think the CRISS score works better in terms of capturing improvement in the course of a trial, and also in capturing other outcomes that are really, really important to patients and to their physicians, like disability or lung function.”
The hope is that, given the evidence, regulatory agencies will look favorably on the ACR CRISS as an outcome measure in clinical trials moving forward, and that understanding of its use and value will increase across the rheumatology community, he said.
Dr. Spiera has received research grants, consulting fees, and/or other payments from many companies involved in SSc treatments, including Roche/Genentech, which markets tocilizumab, and Corbus Pharmaceuticals, which is developing lenabasum.
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 NIH/NIAID 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. He also has a patent for a treatment for systemic sclerosis.
Dr. Zheng reported having no disclosures.
CHICAGO – At least three phase 3 randomized scleroderma treatment trials presented at the annual meeting of the American College of Rheumatology failed to meet modified Rodnan Skin Score–based primary endpoints, but a different story emerged when data from the trials were analyzed using the novel ACR Composite Response Index in Systemic Sclerosis (CRISS).
The differences highlight the limitations of individual outcome measures like the modified Rodnan Skin Score (mRSS) and underscore the need for new measures that capture the complexity of systemic sclerosis (SSc) and are more sensitive to changes in disease severity, according to Robert Spiera, MD, director of the vasculitis and scleroderma program at the Hospital for Special Surgery in New York.
Such measures are needed to better assess the effects of treatment interventions in scleroderma trials, Dr. Spiera said in an interview.
The ACR CRISS
Development of the ACR CRISS was led by Dinesh Khanna, MBBS, a professor of medicine and director of the scleroderma program at the University of Michigan, Ann Arbor. He and his colleagues described the measure in 2016 (Arthritis Rheumatol. 2016 Feb;68[2]:299-311. doi: 10.1002/art.39501).
Its use involves a two-step process of identifying any significant disease worsening or new end-organ damage, and then calculating the probability of patient improvement after 1 year of treatment on a 0- to 1-point scale based on changes from baseline in five variables: the mRSS, percent predicted forced vital capacity (FVC), patient and physician global assessments, and the Health Assessment Questionnaire Disability Index (HAQ-DI).
A CRISS score of 0.6 or higher indicates likelihood that a patient improved on treatment. Of note, subjects with significant worsening of renal or cardiopulmonary involvement are classified as not improved (score of 0), regardless of improvements in other core items.
To devise the CRISS, the investigators compiled 150 patient profiles with standardized clinical outcome elements using patients with diffuse cutaneous systemic sclerosis (dcSSc). The profiles were assessed by 40 scleroderma experts who rated patient improvement or lack thereof over 12 months.
Using the 79% of profiles for which a consensus was reached, the investigators “fit logistic regression models in which the binary outcome referred to whether the patient was improved or not, and the changes in the core set items from baseline to follow-up were entered as covariates,” they explained.
This led to the selection of the five measures included in the final version, which was found to have sensitivity of 0.982 and specificity of 0.931. When evaluated in a previously completed 1-year randomized controlled trial, the index differentiated the effect of methotrexate from the effect of placebo (P = .02), they reported.
Based on these findings, the ACR board of directors granted “provisional” endorsement of the CRISS for use in SSc clinical studies, signifying that it had been quantitatively validated using patient data, but had not undergone validation using an external data set.
New data presented at the 2018 ACR meeting will likely lead to full approval of the measure once the studies validating the measure are published, according to Dr. Spiera.
The focuSSced study of tocilizumab
For example, in the phase 3 focuSSced study comparing the interleukin-6 (IL-6) receptor–alpha antibody tocilizumab (Actemra) with placebo in patients with SSc, the primary endpoint of mean change from baseline in mRSS was not met (–6.14 vs. –4.41 points with tocilizumab vs. placebo, respectively; P = .098), Dr. Khanna said during a report of findings from the double-blind portion of the study.
However, when the CRISS was applied and its performance prospectively assessed as an exploratory outcome at week 48 in the focuSSced trial, the differences between the groups were statistically significant. Dr. Khanna reported those findings in a separate presentation at the meeting, noting that they marked the first prospective evaluation of the ACR CRISS in a phase 3 trial in SSc.
The CRISS was applied – using a blinded review of adverse events and serious adverse events to complete step 1 – in all patients who received study treatment, stratified by baseline IL-6 levels.
Of 104 patients in the tocilizumab arm and 106 in the placebo arm, 6 and 13 patients, respectively, had cardio-pulmonary-renal involvement and therefore received a score of 0.
Using the ACR CRISS as a continuous measure, scores favored tocilizumab over placebo at week 48 with a median increase of 0.89 vs. 0.25 points (P = .023), and using the binary form of CRISS, 51% vs. 37% of patients in the treatment and placebo arms achieved the score cutoff of 0.60 or higher at week 48 (P = .035), he said.
“The focuSSced study validates the ACR CRISS endpoint for the first time in an independent prospective clinical trial and highlights the importance of step 1 as an indicator of reduced organ progression during 48 weeks of treatment,” Dr. Khanna concluded.
The ASSET trial of abatacept
Dr. Khanna also reported results from the 12-month phase 2 ASSET trial comparing abatacept (Orencia) and placebo in early dcSSc.
Again, the change from baseline in mRSS – the primary endpoint of the study – did not differ significantly with treatment vs. placebo (–6.24 vs. –4.49; P = .28).
And again, as presented separately in a poster session at ACR, application of CRISS at 12 months – a secondary outcome measure in the trial – showed a significant difference between the groups.
The investigators prospectively performed step 1 of the CRISS using a case report form. Of 63 patients with complete data available for relevant outcomes at 12 months, 10 (5 in each group) had cardio-pulmonary-renal involvement and thus were given a score of 0.
Overall, there was evidence of significantly improved CRISS scores in the abatacept group vs. the placebo group (P = .03), he said.
Most of the individual CRISS variables, except HAQ-DI and patient global assessment, had statistically significant correlations with the CRISS, he noted, adding that “although the degree of correlation is high between the mRSS and CRISS, there is evidence that CRISS may be more sensitive to clinically meaningful treatment changes than the standard skin score endpoint.”
“This suggests further validation of CRISS as an independent primary endpoint for scleroderma clinical trials,” he concluded.
The phase 2b RISE-SSc study of riociguat
As in the focuSSced and ASSET studies, the primary efficacy endpoint of mean change from baseline in mRSS was not met in the randomized, double-blind, placebo-controlled RISE-SSc study evaluating the safety and efficacy of the soluble guanylate cyclase stimulator riociguat (Adempas) vs. placebo in 121 patients with early dcSSc, reported Oliver Distler, MD, a professor at University Hospital Zurich.
The mean change in mRSS at 52 weeks was 2.25 vs. 0.97 with riociguat vs. placebo, respectively (P = .08), although the difference in mRSS progression rate showed significant effects favoring riociguat (P = .02), he noted.
In this study, however, the proportion of patients with ACR CRISS probability of improvement (score of 0.60 or higher) at week 52 – a secondary study outcome – was the same at 18% in both arms, Dr. Distler said.
In a way, it’s helpful that the CRISS findings as well as the mRSS outcome in the RISE-SSc study were negative because it shows that “not everything comes up positive using the CRISS,” Dr. Spiera said.
An open-label extension trial of lenabasum
In the open-label extension of a phase 2 trial of lenabasum, Dr. Spiera and his colleagues also found the CRISS useful for assessing response in 36 patients. Lenabasum is a synthetic, nonimunosuppressive, selective cannabinoid receptor type 2 agonist that activates resolution of innate immune responses.
The agent continued to demonstrate acceptable safety and tolerability in dcSSc with no severe or serious adverse events or study discontinuations related to treatment during 12 months of open-label extension dosing, both from baseline and from the start of the extension, they reported in a poster at the ACR meeting. These assessments were based on ACR CRISS score, mRSS, physician global assessment, and multiple patient-reported outcomes.
The median CRISS score was 92% at week 52, and mRSS declined by a mean of 9.4 points (41.3% from baseline). More than a third of patients (35%) achieved a low mRSS of 10 or less.
The investigators noted, however, that definitive attribution of the findings to lenabasum is limited by the use of background therapy, the potential for spontaneous improvement in patients, and open-label dosing.
Evaluating immunosuppressive therapy in SSc
In another study presented at the ACR meeting, Boyang Zheng, MD, a second-year rheumatology fellow at McGill University in Montreal and his colleagues evaluated the effect of current immunosuppressive therapy on the ACR CRISS in 301 adult dcSSc patients without prior immunosuppression who were part of the Canadian Scleroderma Research Group (CSRG) registry.
Patients newly treated with methotrexate, azathioprine, mycophenolate and/or cyclophosphamide for at least 2 years (47 patients) were considered “exposed patients,” and untreated patients with at least the same follow-up duration were considered control subjects (254 patients).
Inverse probability of treatment weighting (IPTW) was performed to balance potential confounders in the two groups, including age, sex, disease duration, and CRISS variables, in an effort “to create a statistical cohort that would resemble a randomized, controlled trial,” Dr Zheng explained.
Prior to IPTW, treated patients trended towards more improvement after 1 year, but with “unimpressive absolute values.”
“But [after IPTW], when you look at overall CRISS at 1 year, more of the treated patients had actually improved – 23% vs. 11.8% in the untreated patients. After adjusting for age, sex, and disease duration, immunosuppression was associated with an almost twofold higher likelihood of improvement, although this was not statistically significant,” he said.
“Most importantly, after our balancing in the statistical cohort – so after balancing and adjusting for covariates ... immunosuppression use was still associated with a higher likelihood of improving [with an] odds ratio of 1.85 and P-value of 0.018,” he said.
The treated patients were sicker, and the CRISS was still able to capture individual patient improvement, he added.
Though limited by the observational design and the fact that “IPTW balancing cannot correct for all possible confounders,” the findings “provide novel evidence to support the use of immunosuppression in diffuse systemic sclerosis, and this reassures us in our current practice; it provides evidence that the CRISS seems to have better sensitivity to change than the mean of individual disease measures,” he said.
However, it also shows that “we have a long way to go to have better treatment for our patients,” he added, noting that only a minority (23%) of the patients in this study improved on the CRISS.
Moving forward in systemic sclerosis
Indeed, in order to move forward in developing better treatment for SSc, it is important to have the best possible means for assessing the effects of the potential new treatments, Dr. Spiera said.
“The mRSS is a good, reliable outcome measure in terms of intra- and inter-rater reliability, and we know it has meaning in the real world; in a patient with rapidly progressive skin thickening and a skin score that is getting higher and higher, we know they have worse prognosis in terms of function and even survival,” he said. “On the other hand, it’s just one piece of this very complicated story when you’re dealing with patients with systemic sclerosis, some of whom can have important internal organ involvement and not even have skin involvement.”
The main challenge with the skin score is how it performs in clinical trials when it comes to demonstrating whether a drug works, he added.
“This is particularly relevant in an era where our better understanding of the disease has led to candidate therapeutic agents that we have reason to think might work, but where clinical trials haven’t shown a significant difference between the groups using the skin score.”
Conversely, there have been studies in which skin scores improve, but the patient is doing terribly, he noted.
“That patient would not be [shown to be] doing well using the CRISS,” he said, explaining that the complex formula used to determine the CRISS score, which is “heavily weighted toward skin score,” allows for an overall score that is “greater than the sum of its parts.” That is, if a patient is improving in multiple domains indicating that the patient is responding to therapy, more credit is given for each of those parts.
“So my sense, and I think it’s the consensus in the community of clinical investigators, is that the skin score is not adequately sensitive to change in the context of a trial and doesn’t capture the disease holistically enough to be the optimal measure for scleroderma clinical trials,” he said. “We think the CRISS score works better in terms of capturing improvement in the course of a trial, and also in capturing other outcomes that are really, really important to patients and to their physicians, like disability or lung function.”
The hope is that, given the evidence, regulatory agencies will look favorably on the ACR CRISS as an outcome measure in clinical trials moving forward, and that understanding of its use and value will increase across the rheumatology community, he said.
Dr. Spiera has received research grants, consulting fees, and/or other payments from many companies involved in SSc treatments, including Roche/Genentech, which markets tocilizumab, and Corbus Pharmaceuticals, which is developing lenabasum.
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 NIH/NIAID 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. He also has a patent for a treatment for systemic sclerosis.
Dr. Zheng reported having no disclosures.
CHICAGO – At least three phase 3 randomized scleroderma treatment trials presented at the annual meeting of the American College of Rheumatology failed to meet modified Rodnan Skin Score–based primary endpoints, but a different story emerged when data from the trials were analyzed using the novel ACR Composite Response Index in Systemic Sclerosis (CRISS).
The differences highlight the limitations of individual outcome measures like the modified Rodnan Skin Score (mRSS) and underscore the need for new measures that capture the complexity of systemic sclerosis (SSc) and are more sensitive to changes in disease severity, according to Robert Spiera, MD, director of the vasculitis and scleroderma program at the Hospital for Special Surgery in New York.
Such measures are needed to better assess the effects of treatment interventions in scleroderma trials, Dr. Spiera said in an interview.
The ACR CRISS
Development of the ACR CRISS was led by Dinesh Khanna, MBBS, a professor of medicine and director of the scleroderma program at the University of Michigan, Ann Arbor. He and his colleagues described the measure in 2016 (Arthritis Rheumatol. 2016 Feb;68[2]:299-311. doi: 10.1002/art.39501).
Its use involves a two-step process of identifying any significant disease worsening or new end-organ damage, and then calculating the probability of patient improvement after 1 year of treatment on a 0- to 1-point scale based on changes from baseline in five variables: the mRSS, percent predicted forced vital capacity (FVC), patient and physician global assessments, and the Health Assessment Questionnaire Disability Index (HAQ-DI).
A CRISS score of 0.6 or higher indicates likelihood that a patient improved on treatment. Of note, subjects with significant worsening of renal or cardiopulmonary involvement are classified as not improved (score of 0), regardless of improvements in other core items.
To devise the CRISS, the investigators compiled 150 patient profiles with standardized clinical outcome elements using patients with diffuse cutaneous systemic sclerosis (dcSSc). The profiles were assessed by 40 scleroderma experts who rated patient improvement or lack thereof over 12 months.
Using the 79% of profiles for which a consensus was reached, the investigators “fit logistic regression models in which the binary outcome referred to whether the patient was improved or not, and the changes in the core set items from baseline to follow-up were entered as covariates,” they explained.
This led to the selection of the five measures included in the final version, which was found to have sensitivity of 0.982 and specificity of 0.931. When evaluated in a previously completed 1-year randomized controlled trial, the index differentiated the effect of methotrexate from the effect of placebo (P = .02), they reported.
Based on these findings, the ACR board of directors granted “provisional” endorsement of the CRISS for use in SSc clinical studies, signifying that it had been quantitatively validated using patient data, but had not undergone validation using an external data set.
New data presented at the 2018 ACR meeting will likely lead to full approval of the measure once the studies validating the measure are published, according to Dr. Spiera.
The focuSSced study of tocilizumab
For example, in the phase 3 focuSSced study comparing the interleukin-6 (IL-6) receptor–alpha antibody tocilizumab (Actemra) with placebo in patients with SSc, the primary endpoint of mean change from baseline in mRSS was not met (–6.14 vs. –4.41 points with tocilizumab vs. placebo, respectively; P = .098), Dr. Khanna said during a report of findings from the double-blind portion of the study.
However, when the CRISS was applied and its performance prospectively assessed as an exploratory outcome at week 48 in the focuSSced trial, the differences between the groups were statistically significant. Dr. Khanna reported those findings in a separate presentation at the meeting, noting that they marked the first prospective evaluation of the ACR CRISS in a phase 3 trial in SSc.
The CRISS was applied – using a blinded review of adverse events and serious adverse events to complete step 1 – in all patients who received study treatment, stratified by baseline IL-6 levels.
Of 104 patients in the tocilizumab arm and 106 in the placebo arm, 6 and 13 patients, respectively, had cardio-pulmonary-renal involvement and therefore received a score of 0.
Using the ACR CRISS as a continuous measure, scores favored tocilizumab over placebo at week 48 with a median increase of 0.89 vs. 0.25 points (P = .023), and using the binary form of CRISS, 51% vs. 37% of patients in the treatment and placebo arms achieved the score cutoff of 0.60 or higher at week 48 (P = .035), he said.
“The focuSSced study validates the ACR CRISS endpoint for the first time in an independent prospective clinical trial and highlights the importance of step 1 as an indicator of reduced organ progression during 48 weeks of treatment,” Dr. Khanna concluded.
The ASSET trial of abatacept
Dr. Khanna also reported results from the 12-month phase 2 ASSET trial comparing abatacept (Orencia) and placebo in early dcSSc.
Again, the change from baseline in mRSS – the primary endpoint of the study – did not differ significantly with treatment vs. placebo (–6.24 vs. –4.49; P = .28).
And again, as presented separately in a poster session at ACR, application of CRISS at 12 months – a secondary outcome measure in the trial – showed a significant difference between the groups.
The investigators prospectively performed step 1 of the CRISS using a case report form. Of 63 patients with complete data available for relevant outcomes at 12 months, 10 (5 in each group) had cardio-pulmonary-renal involvement and thus were given a score of 0.
Overall, there was evidence of significantly improved CRISS scores in the abatacept group vs. the placebo group (P = .03), he said.
Most of the individual CRISS variables, except HAQ-DI and patient global assessment, had statistically significant correlations with the CRISS, he noted, adding that “although the degree of correlation is high between the mRSS and CRISS, there is evidence that CRISS may be more sensitive to clinically meaningful treatment changes than the standard skin score endpoint.”
“This suggests further validation of CRISS as an independent primary endpoint for scleroderma clinical trials,” he concluded.
The phase 2b RISE-SSc study of riociguat
As in the focuSSced and ASSET studies, the primary efficacy endpoint of mean change from baseline in mRSS was not met in the randomized, double-blind, placebo-controlled RISE-SSc study evaluating the safety and efficacy of the soluble guanylate cyclase stimulator riociguat (Adempas) vs. placebo in 121 patients with early dcSSc, reported Oliver Distler, MD, a professor at University Hospital Zurich.
The mean change in mRSS at 52 weeks was 2.25 vs. 0.97 with riociguat vs. placebo, respectively (P = .08), although the difference in mRSS progression rate showed significant effects favoring riociguat (P = .02), he noted.
In this study, however, the proportion of patients with ACR CRISS probability of improvement (score of 0.60 or higher) at week 52 – a secondary study outcome – was the same at 18% in both arms, Dr. Distler said.
In a way, it’s helpful that the CRISS findings as well as the mRSS outcome in the RISE-SSc study were negative because it shows that “not everything comes up positive using the CRISS,” Dr. Spiera said.
An open-label extension trial of lenabasum
In the open-label extension of a phase 2 trial of lenabasum, Dr. Spiera and his colleagues also found the CRISS useful for assessing response in 36 patients. Lenabasum is a synthetic, nonimunosuppressive, selective cannabinoid receptor type 2 agonist that activates resolution of innate immune responses.
The agent continued to demonstrate acceptable safety and tolerability in dcSSc with no severe or serious adverse events or study discontinuations related to treatment during 12 months of open-label extension dosing, both from baseline and from the start of the extension, they reported in a poster at the ACR meeting. These assessments were based on ACR CRISS score, mRSS, physician global assessment, and multiple patient-reported outcomes.
The median CRISS score was 92% at week 52, and mRSS declined by a mean of 9.4 points (41.3% from baseline). More than a third of patients (35%) achieved a low mRSS of 10 or less.
The investigators noted, however, that definitive attribution of the findings to lenabasum is limited by the use of background therapy, the potential for spontaneous improvement in patients, and open-label dosing.
Evaluating immunosuppressive therapy in SSc
In another study presented at the ACR meeting, Boyang Zheng, MD, a second-year rheumatology fellow at McGill University in Montreal and his colleagues evaluated the effect of current immunosuppressive therapy on the ACR CRISS in 301 adult dcSSc patients without prior immunosuppression who were part of the Canadian Scleroderma Research Group (CSRG) registry.
Patients newly treated with methotrexate, azathioprine, mycophenolate and/or cyclophosphamide for at least 2 years (47 patients) were considered “exposed patients,” and untreated patients with at least the same follow-up duration were considered control subjects (254 patients).
Inverse probability of treatment weighting (IPTW) was performed to balance potential confounders in the two groups, including age, sex, disease duration, and CRISS variables, in an effort “to create a statistical cohort that would resemble a randomized, controlled trial,” Dr Zheng explained.
Prior to IPTW, treated patients trended towards more improvement after 1 year, but with “unimpressive absolute values.”
“But [after IPTW], when you look at overall CRISS at 1 year, more of the treated patients had actually improved – 23% vs. 11.8% in the untreated patients. After adjusting for age, sex, and disease duration, immunosuppression was associated with an almost twofold higher likelihood of improvement, although this was not statistically significant,” he said.
“Most importantly, after our balancing in the statistical cohort – so after balancing and adjusting for covariates ... immunosuppression use was still associated with a higher likelihood of improving [with an] odds ratio of 1.85 and P-value of 0.018,” he said.
The treated patients were sicker, and the CRISS was still able to capture individual patient improvement, he added.
Though limited by the observational design and the fact that “IPTW balancing cannot correct for all possible confounders,” the findings “provide novel evidence to support the use of immunosuppression in diffuse systemic sclerosis, and this reassures us in our current practice; it provides evidence that the CRISS seems to have better sensitivity to change than the mean of individual disease measures,” he said.
However, it also shows that “we have a long way to go to have better treatment for our patients,” he added, noting that only a minority (23%) of the patients in this study improved on the CRISS.
Moving forward in systemic sclerosis
Indeed, in order to move forward in developing better treatment for SSc, it is important to have the best possible means for assessing the effects of the potential new treatments, Dr. Spiera said.
“The mRSS is a good, reliable outcome measure in terms of intra- and inter-rater reliability, and we know it has meaning in the real world; in a patient with rapidly progressive skin thickening and a skin score that is getting higher and higher, we know they have worse prognosis in terms of function and even survival,” he said. “On the other hand, it’s just one piece of this very complicated story when you’re dealing with patients with systemic sclerosis, some of whom can have important internal organ involvement and not even have skin involvement.”
The main challenge with the skin score is how it performs in clinical trials when it comes to demonstrating whether a drug works, he added.
“This is particularly relevant in an era where our better understanding of the disease has led to candidate therapeutic agents that we have reason to think might work, but where clinical trials haven’t shown a significant difference between the groups using the skin score.”
Conversely, there have been studies in which skin scores improve, but the patient is doing terribly, he noted.
“That patient would not be [shown to be] doing well using the CRISS,” he said, explaining that the complex formula used to determine the CRISS score, which is “heavily weighted toward skin score,” allows for an overall score that is “greater than the sum of its parts.” That is, if a patient is improving in multiple domains indicating that the patient is responding to therapy, more credit is given for each of those parts.
“So my sense, and I think it’s the consensus in the community of clinical investigators, is that the skin score is not adequately sensitive to change in the context of a trial and doesn’t capture the disease holistically enough to be the optimal measure for scleroderma clinical trials,” he said. “We think the CRISS score works better in terms of capturing improvement in the course of a trial, and also in capturing other outcomes that are really, really important to patients and to their physicians, like disability or lung function.”
The hope is that, given the evidence, regulatory agencies will look favorably on the ACR CRISS as an outcome measure in clinical trials moving forward, and that understanding of its use and value will increase across the rheumatology community, he said.
Dr. Spiera has received research grants, consulting fees, and/or other payments from many companies involved in SSc treatments, including Roche/Genentech, which markets tocilizumab, and Corbus Pharmaceuticals, which is developing lenabasum.
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 NIH/NIAID 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. He also has a patent for a treatment for systemic sclerosis.
Dr. Zheng reported having no disclosures.
REPORTING FROM THE ACR ANNUAL MEETING