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Low spinal cord volume linked to higher MS disability
BERLIN – Spinal cord volume deficits in patients with multiple sclerosis may contribute to clinical disability that appears out of proportion to lesion load on brain imaging, according to new research.
In a pool of 362 patients with mild to moderate MS-related disability but identical white matter lesion load identified by MRI, those with higher disability had significantly lower spinal cord volumes when compared against those with disability scores in the mild range (P less than .001).
Though brain MRI is a key tool used to track disease severity and progression in MS, some patients have relatively high disability but a low burden of white matter intracerebral lesions on MRI. Little is known about spinal cord volume in MS patients with pronounced dissociation between intracerebral lesion load and disability, Michaela Andelova, MD, said in an interview during a poster session at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
Dr. Andelova, of Charles University, Prague, said that she and her colleagues hypothesized that spinal cord volume would differ between patients who had varying levels of disability, despite identical white matter lesion load.
To test this, she and her colleagues looked at records of 1,245 patients with relapsing-remitting MS. They divided them into three groups by severity of clinical disability, and also by extent of cerebral T2 hyperintense lesion load. The investigators identified a group of patients (n = 53) whose total volume of T2-weighted hyperintense lesions was less than 3 mL, but whose Expanded Disability Status Scale (EDSS) scores were at least 3.5; this was the low lesion load/high disability (LLHD) group.
Dr. Andelova and her colleagues then identified another group of patients (n = 71) who had a volume of T2-weighted hyperintensities that was greater than 9 mL, but whose EDSS score was less than 1.5. This was the high lesion load/low disability (HLLD) group.
The remaining patients (n = 1,121), who did not have these paradoxical associations, were analyzed separately.
For all patients, mean upper cervical cord area (MUCCA) was also measured. Using images acquired by a 3 T MRI scanner, MUCCA was calculated as the mean sum of spinal cord area in 21 slices centered at the C3/4 intervertebral disk, using an in-house, semiautomated method.
“Despite higher disability, LLHD patients demonstrated significantly higher normalized total brain volume, higher normalized volumes of thalamus and callosum, and smaller lateral ventricles than [the] HLLD group,” wrote Dr. Andelova and her collaborators.
However, the LLHD patients had MUCCA values that were significantly lower than the other groups: The nonparadoxical group’s mean MUCCA was 84.02 mm2, while the HLLD group had a mean MUCCA of 85.75 mm2. This difference was not statistically significant. By contrast, the LLHD group’s mean MUCCA was significantly smaller, at 80.40 mm2 (P = .023 versus nonparadoxical patients, and P = .007 versus HLLD patients).
Looking at the data another way, Dr. Andelova and her colleagues compared 362 evenly divided patients with moderate disability (EDSS 3.5-6.5) with matched patients who had mild MS-related disability (EDSS less than 3) and identical cerebral lesion loads. They found that MUCCA was significantly smaller in the moderate disability group (78.86 versus 84.44 mm2; P less than .001).
In addition to having identical lesions loads, the mild and moderate disability groups didn’t differ significantly in normalized total brain volume or regional brain volumes. The group with moderate disability did have slightly less white matter volume (P = .039), Dr. Andelova pointed out.
All differences found between groups retained statistical significance even after adjustment for such potential confounders as age, sex, and duration of disease, Dr. Andelova said.
“Reduced spinal cord volume may explain part of the clinical-radiological paradox in patients who have high disability despite low intracranial lesion load,” Dr. Andelova and her collaborators wrote. “In line with this finding, relatively preserved spinal cord volume may be associated with functional reserve and less physical disability in patients with low disability despite high cerebral lesion load.”
Further work looking more precisely at cerebral lesion distribution and quantitative MRI investigation of lesion distribution is in the works for Dr. Andelova and her collaborators. They are hoping to see some association between various distribution patterns and accelerated spinal atrophy.
The research was supported by the Czech government. Dr. Andelova and several of her collaborators reported financial relationships with pharmaceutical companies.
SOURCE: Andelova M et al. Mult Scler. 2018;24(Suppl 2):211, Abstract P477.
BERLIN – Spinal cord volume deficits in patients with multiple sclerosis may contribute to clinical disability that appears out of proportion to lesion load on brain imaging, according to new research.
In a pool of 362 patients with mild to moderate MS-related disability but identical white matter lesion load identified by MRI, those with higher disability had significantly lower spinal cord volumes when compared against those with disability scores in the mild range (P less than .001).
Though brain MRI is a key tool used to track disease severity and progression in MS, some patients have relatively high disability but a low burden of white matter intracerebral lesions on MRI. Little is known about spinal cord volume in MS patients with pronounced dissociation between intracerebral lesion load and disability, Michaela Andelova, MD, said in an interview during a poster session at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
Dr. Andelova, of Charles University, Prague, said that she and her colleagues hypothesized that spinal cord volume would differ between patients who had varying levels of disability, despite identical white matter lesion load.
To test this, she and her colleagues looked at records of 1,245 patients with relapsing-remitting MS. They divided them into three groups by severity of clinical disability, and also by extent of cerebral T2 hyperintense lesion load. The investigators identified a group of patients (n = 53) whose total volume of T2-weighted hyperintense lesions was less than 3 mL, but whose Expanded Disability Status Scale (EDSS) scores were at least 3.5; this was the low lesion load/high disability (LLHD) group.
Dr. Andelova and her colleagues then identified another group of patients (n = 71) who had a volume of T2-weighted hyperintensities that was greater than 9 mL, but whose EDSS score was less than 1.5. This was the high lesion load/low disability (HLLD) group.
The remaining patients (n = 1,121), who did not have these paradoxical associations, were analyzed separately.
For all patients, mean upper cervical cord area (MUCCA) was also measured. Using images acquired by a 3 T MRI scanner, MUCCA was calculated as the mean sum of spinal cord area in 21 slices centered at the C3/4 intervertebral disk, using an in-house, semiautomated method.
“Despite higher disability, LLHD patients demonstrated significantly higher normalized total brain volume, higher normalized volumes of thalamus and callosum, and smaller lateral ventricles than [the] HLLD group,” wrote Dr. Andelova and her collaborators.
However, the LLHD patients had MUCCA values that were significantly lower than the other groups: The nonparadoxical group’s mean MUCCA was 84.02 mm2, while the HLLD group had a mean MUCCA of 85.75 mm2. This difference was not statistically significant. By contrast, the LLHD group’s mean MUCCA was significantly smaller, at 80.40 mm2 (P = .023 versus nonparadoxical patients, and P = .007 versus HLLD patients).
Looking at the data another way, Dr. Andelova and her colleagues compared 362 evenly divided patients with moderate disability (EDSS 3.5-6.5) with matched patients who had mild MS-related disability (EDSS less than 3) and identical cerebral lesion loads. They found that MUCCA was significantly smaller in the moderate disability group (78.86 versus 84.44 mm2; P less than .001).
In addition to having identical lesions loads, the mild and moderate disability groups didn’t differ significantly in normalized total brain volume or regional brain volumes. The group with moderate disability did have slightly less white matter volume (P = .039), Dr. Andelova pointed out.
All differences found between groups retained statistical significance even after adjustment for such potential confounders as age, sex, and duration of disease, Dr. Andelova said.
“Reduced spinal cord volume may explain part of the clinical-radiological paradox in patients who have high disability despite low intracranial lesion load,” Dr. Andelova and her collaborators wrote. “In line with this finding, relatively preserved spinal cord volume may be associated with functional reserve and less physical disability in patients with low disability despite high cerebral lesion load.”
Further work looking more precisely at cerebral lesion distribution and quantitative MRI investigation of lesion distribution is in the works for Dr. Andelova and her collaborators. They are hoping to see some association between various distribution patterns and accelerated spinal atrophy.
The research was supported by the Czech government. Dr. Andelova and several of her collaborators reported financial relationships with pharmaceutical companies.
SOURCE: Andelova M et al. Mult Scler. 2018;24(Suppl 2):211, Abstract P477.
BERLIN – Spinal cord volume deficits in patients with multiple sclerosis may contribute to clinical disability that appears out of proportion to lesion load on brain imaging, according to new research.
In a pool of 362 patients with mild to moderate MS-related disability but identical white matter lesion load identified by MRI, those with higher disability had significantly lower spinal cord volumes when compared against those with disability scores in the mild range (P less than .001).
Though brain MRI is a key tool used to track disease severity and progression in MS, some patients have relatively high disability but a low burden of white matter intracerebral lesions on MRI. Little is known about spinal cord volume in MS patients with pronounced dissociation between intracerebral lesion load and disability, Michaela Andelova, MD, said in an interview during a poster session at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
Dr. Andelova, of Charles University, Prague, said that she and her colleagues hypothesized that spinal cord volume would differ between patients who had varying levels of disability, despite identical white matter lesion load.
To test this, she and her colleagues looked at records of 1,245 patients with relapsing-remitting MS. They divided them into three groups by severity of clinical disability, and also by extent of cerebral T2 hyperintense lesion load. The investigators identified a group of patients (n = 53) whose total volume of T2-weighted hyperintense lesions was less than 3 mL, but whose Expanded Disability Status Scale (EDSS) scores were at least 3.5; this was the low lesion load/high disability (LLHD) group.
Dr. Andelova and her colleagues then identified another group of patients (n = 71) who had a volume of T2-weighted hyperintensities that was greater than 9 mL, but whose EDSS score was less than 1.5. This was the high lesion load/low disability (HLLD) group.
The remaining patients (n = 1,121), who did not have these paradoxical associations, were analyzed separately.
For all patients, mean upper cervical cord area (MUCCA) was also measured. Using images acquired by a 3 T MRI scanner, MUCCA was calculated as the mean sum of spinal cord area in 21 slices centered at the C3/4 intervertebral disk, using an in-house, semiautomated method.
“Despite higher disability, LLHD patients demonstrated significantly higher normalized total brain volume, higher normalized volumes of thalamus and callosum, and smaller lateral ventricles than [the] HLLD group,” wrote Dr. Andelova and her collaborators.
However, the LLHD patients had MUCCA values that were significantly lower than the other groups: The nonparadoxical group’s mean MUCCA was 84.02 mm2, while the HLLD group had a mean MUCCA of 85.75 mm2. This difference was not statistically significant. By contrast, the LLHD group’s mean MUCCA was significantly smaller, at 80.40 mm2 (P = .023 versus nonparadoxical patients, and P = .007 versus HLLD patients).
Looking at the data another way, Dr. Andelova and her colleagues compared 362 evenly divided patients with moderate disability (EDSS 3.5-6.5) with matched patients who had mild MS-related disability (EDSS less than 3) and identical cerebral lesion loads. They found that MUCCA was significantly smaller in the moderate disability group (78.86 versus 84.44 mm2; P less than .001).
In addition to having identical lesions loads, the mild and moderate disability groups didn’t differ significantly in normalized total brain volume or regional brain volumes. The group with moderate disability did have slightly less white matter volume (P = .039), Dr. Andelova pointed out.
All differences found between groups retained statistical significance even after adjustment for such potential confounders as age, sex, and duration of disease, Dr. Andelova said.
“Reduced spinal cord volume may explain part of the clinical-radiological paradox in patients who have high disability despite low intracranial lesion load,” Dr. Andelova and her collaborators wrote. “In line with this finding, relatively preserved spinal cord volume may be associated with functional reserve and less physical disability in patients with low disability despite high cerebral lesion load.”
Further work looking more precisely at cerebral lesion distribution and quantitative MRI investigation of lesion distribution is in the works for Dr. Andelova and her collaborators. They are hoping to see some association between various distribution patterns and accelerated spinal atrophy.
The research was supported by the Czech government. Dr. Andelova and several of her collaborators reported financial relationships with pharmaceutical companies.
SOURCE: Andelova M et al. Mult Scler. 2018;24(Suppl 2):211, Abstract P477.
REPORTING FROM ECTRIMS 2018
Key clinical point:
Major finding: Moderate disability patients had lower spinal cord volumes than did those with mild disability but a similar intracerebral lesion load.
Study details: Retrospective study of 1,245 patients with relapsing-remitting MS.
Disclosures: The study was sponsored by a grant from the Czech government. Several authors, including Dr. Andelova, reported multiple financial relationships with pharmaceutical companies.
Source: Andelova M et al. Mult Scler. 2018;24(Suppl 2):211, Abstract P477.
Relapsing-remitting MS best treated within 6 months of onset
BERLIN – according to real-world data from the Big Multiple Sclerosis Data Network.
Receiving disease-modifying treatments (DMTs) within 6 months of diagnosis was associated with a 28% reduction in the risk of reaching an Expanded Disability Status Scale score of 3.0 or more for the first time at 12 months versus receiving treatment after 6 months (hazard ratio, 0.72; 95% confidence interval, 0.59-0.90; P = .003).
Results were not significant, looking at all the other periods tested at 6-month intervals from 1 year up to 5 years after diagnosis. HRs (95% CIs) comparing a first DMT given at 1 year, 1.5 years, 2 years, 2.5 years, 3 years, 3.5 years, 4 years, 4.5 years, and 5 years were a respective 0.90 (0.78-1.03), 0.89 (0.79-1.01), 0.99 (0.88-1.11), 0.95 (0.85-1.06), 1.01 (0.90-1.12), 0.97 (0.86-1.09), 1.09 (0.96-1.22), 1.11 (0.98-1.25), and 1.06 (0.93-1.20).
“To date, these data represent the largest RRMS cohort with the longest follow-up ever analyzed to determine the long-term effectiveness of the early start of DMTs,” said Pietro Iaffaldano, MD, at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
“This study also provides evidence that data sharing from MS registries and databases is feasible,” noted Dr. Iaffaldano, who is assistant professor of neurology at the University of Bari (Italy). Such an approach can provide enough statistical power to detect the impact of treatment on disability outcomes in the long term, he suggested.
For the study, a cohort of 11,934 patients was obtained by screening more than 149,636 patients from five large registries and databases of MS patients – the Italian MS Registry, the Swedish MS Registry, the Danish MS Registry, OFSEP (Observatoire Français de al Sclérose en Plaques), and MSBase. Patients were included in the current analysis if they had at least 10 years of follow-up, had at least three EDSS evaluations, and at least one DMT prescription.
“It is well known that randomized, controlled trials support the early start of treatment in MS, but open-label extensions of the same trials reported inconsistent results about the long-term benefit on disability accumulation,” Dr. Iaffaldano explained. Further, recent observational studies have suggested that initiating DMTs early might not only delay the accumulation of disability but perhaps also death.
The aim of the research was thus to look at what effect the time interval from disease onset to the first administration of a DMT might have on long-term disability accumulation, as measured by the EDSS, in patients with RRMS.
The population of patients studied was mostly (71%) female, with a median age of 27 years at disease onset. The number of relapses prior to starting a DMT was two and the baseline EDSS was 2.0. In almost all (98.9%) cases, DMT was used as first-line treatment (second line in 1.1% of cases). The median follow-up was 13.2 years and cumulative DMT exposure was 10.5 years.
The work was supported by Biogen International on the basis of a sponsored research agreement with the Big Multiple Sclerosis Data Network. Dr. Iaffaldano has served on scientific advisory boards for and received funding for travel and/or speaker honoraria from Biogen and other companies that market DMTs for MS. Several study authors are employees of Biogen, and other study authors also reported financial ties to Biogen and other pharmaceutical companies.
SOURCE: Iaffaldano P et al. Mult Scler. 2018;24(Suppl 2):71-2, Abstract 204.
BERLIN – according to real-world data from the Big Multiple Sclerosis Data Network.
Receiving disease-modifying treatments (DMTs) within 6 months of diagnosis was associated with a 28% reduction in the risk of reaching an Expanded Disability Status Scale score of 3.0 or more for the first time at 12 months versus receiving treatment after 6 months (hazard ratio, 0.72; 95% confidence interval, 0.59-0.90; P = .003).
Results were not significant, looking at all the other periods tested at 6-month intervals from 1 year up to 5 years after diagnosis. HRs (95% CIs) comparing a first DMT given at 1 year, 1.5 years, 2 years, 2.5 years, 3 years, 3.5 years, 4 years, 4.5 years, and 5 years were a respective 0.90 (0.78-1.03), 0.89 (0.79-1.01), 0.99 (0.88-1.11), 0.95 (0.85-1.06), 1.01 (0.90-1.12), 0.97 (0.86-1.09), 1.09 (0.96-1.22), 1.11 (0.98-1.25), and 1.06 (0.93-1.20).
“To date, these data represent the largest RRMS cohort with the longest follow-up ever analyzed to determine the long-term effectiveness of the early start of DMTs,” said Pietro Iaffaldano, MD, at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
“This study also provides evidence that data sharing from MS registries and databases is feasible,” noted Dr. Iaffaldano, who is assistant professor of neurology at the University of Bari (Italy). Such an approach can provide enough statistical power to detect the impact of treatment on disability outcomes in the long term, he suggested.
For the study, a cohort of 11,934 patients was obtained by screening more than 149,636 patients from five large registries and databases of MS patients – the Italian MS Registry, the Swedish MS Registry, the Danish MS Registry, OFSEP (Observatoire Français de al Sclérose en Plaques), and MSBase. Patients were included in the current analysis if they had at least 10 years of follow-up, had at least three EDSS evaluations, and at least one DMT prescription.
“It is well known that randomized, controlled trials support the early start of treatment in MS, but open-label extensions of the same trials reported inconsistent results about the long-term benefit on disability accumulation,” Dr. Iaffaldano explained. Further, recent observational studies have suggested that initiating DMTs early might not only delay the accumulation of disability but perhaps also death.
The aim of the research was thus to look at what effect the time interval from disease onset to the first administration of a DMT might have on long-term disability accumulation, as measured by the EDSS, in patients with RRMS.
The population of patients studied was mostly (71%) female, with a median age of 27 years at disease onset. The number of relapses prior to starting a DMT was two and the baseline EDSS was 2.0. In almost all (98.9%) cases, DMT was used as first-line treatment (second line in 1.1% of cases). The median follow-up was 13.2 years and cumulative DMT exposure was 10.5 years.
The work was supported by Biogen International on the basis of a sponsored research agreement with the Big Multiple Sclerosis Data Network. Dr. Iaffaldano has served on scientific advisory boards for and received funding for travel and/or speaker honoraria from Biogen and other companies that market DMTs for MS. Several study authors are employees of Biogen, and other study authors also reported financial ties to Biogen and other pharmaceutical companies.
SOURCE: Iaffaldano P et al. Mult Scler. 2018;24(Suppl 2):71-2, Abstract 204.
BERLIN – according to real-world data from the Big Multiple Sclerosis Data Network.
Receiving disease-modifying treatments (DMTs) within 6 months of diagnosis was associated with a 28% reduction in the risk of reaching an Expanded Disability Status Scale score of 3.0 or more for the first time at 12 months versus receiving treatment after 6 months (hazard ratio, 0.72; 95% confidence interval, 0.59-0.90; P = .003).
Results were not significant, looking at all the other periods tested at 6-month intervals from 1 year up to 5 years after diagnosis. HRs (95% CIs) comparing a first DMT given at 1 year, 1.5 years, 2 years, 2.5 years, 3 years, 3.5 years, 4 years, 4.5 years, and 5 years were a respective 0.90 (0.78-1.03), 0.89 (0.79-1.01), 0.99 (0.88-1.11), 0.95 (0.85-1.06), 1.01 (0.90-1.12), 0.97 (0.86-1.09), 1.09 (0.96-1.22), 1.11 (0.98-1.25), and 1.06 (0.93-1.20).
“To date, these data represent the largest RRMS cohort with the longest follow-up ever analyzed to determine the long-term effectiveness of the early start of DMTs,” said Pietro Iaffaldano, MD, at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
“This study also provides evidence that data sharing from MS registries and databases is feasible,” noted Dr. Iaffaldano, who is assistant professor of neurology at the University of Bari (Italy). Such an approach can provide enough statistical power to detect the impact of treatment on disability outcomes in the long term, he suggested.
For the study, a cohort of 11,934 patients was obtained by screening more than 149,636 patients from five large registries and databases of MS patients – the Italian MS Registry, the Swedish MS Registry, the Danish MS Registry, OFSEP (Observatoire Français de al Sclérose en Plaques), and MSBase. Patients were included in the current analysis if they had at least 10 years of follow-up, had at least three EDSS evaluations, and at least one DMT prescription.
“It is well known that randomized, controlled trials support the early start of treatment in MS, but open-label extensions of the same trials reported inconsistent results about the long-term benefit on disability accumulation,” Dr. Iaffaldano explained. Further, recent observational studies have suggested that initiating DMTs early might not only delay the accumulation of disability but perhaps also death.
The aim of the research was thus to look at what effect the time interval from disease onset to the first administration of a DMT might have on long-term disability accumulation, as measured by the EDSS, in patients with RRMS.
The population of patients studied was mostly (71%) female, with a median age of 27 years at disease onset. The number of relapses prior to starting a DMT was two and the baseline EDSS was 2.0. In almost all (98.9%) cases, DMT was used as first-line treatment (second line in 1.1% of cases). The median follow-up was 13.2 years and cumulative DMT exposure was 10.5 years.
The work was supported by Biogen International on the basis of a sponsored research agreement with the Big Multiple Sclerosis Data Network. Dr. Iaffaldano has served on scientific advisory boards for and received funding for travel and/or speaker honoraria from Biogen and other companies that market DMTs for MS. Several study authors are employees of Biogen, and other study authors also reported financial ties to Biogen and other pharmaceutical companies.
SOURCE: Iaffaldano P et al. Mult Scler. 2018;24(Suppl 2):71-2, Abstract 204.
REPORTING FROM ECTRIMS 2018
Key clinical point: Less disease progression occurs if disease-modifying treatments (DMTs) are given early in relapsing-remitting multiple sclerosis (RRMS).
Major finding: DMTs within 6 months vs. later decreased the risk of confirmed first disability progression at 12 months by 28% (P = .003).
Study details: 11,934 patients with RRMS with at least 10 years’ follow-up, three or more Expanded Disability Status Scale evaluations, and at least one DMT prescription.
Disclosures: The work was supported by Biogen International on the basis of a sponsored research agreement with the Big Multiple Sclerosis Data Network. Dr. Iaffaldano has served on scientific advisory boards for and received funding for travel and/or speaker honoraria from Biogen and other companies that market DMTs for MS. Several study authors are employees of Biogen, and other study authors also reported financial ties to Biogen and other pharmaceutical companies.
Source: Iaffaldano P et al. Mult Scler. 2018;24(Suppl 2):71-2, Abstract 204.
Entospletinib falls short in relapsed/refractory DLBCL
Entospletinib, a selective inhibitor of spleen tyrosine kinase (Syk), showed a dismal rate of progression-free survival and a high rate of adverse events in a cohort of previously treated patients with diffuse large B-cell lymphoma (DLBCL).
Entospletinib was evaluated in an open-label, single-agent, phase 2 trial (NCT01799889) with five relapsed/refractory patient cohorts: chronic lymphocytic leukemia (CLL), follicular lymphoma, other indolent non-Hodgkin lymphomas, mantle cell lymphoma, and DLBCL.
John M. Burke, MD, of Rocky Mountain Cancer Centers in Aurora, Colo., and his colleagues reported on the current analysis, which looked specifically at the 43 patients in the trial with previously treated DLBCL. Patients received at least one starting dose of 800 mg of entospletinib orally twice daily. The findings were published in Clinical Lymphoma, Myeloma & Leukemia.
In a previous report on the relapsed/refractory CLL cohort, the investigational agent demonstrated clinical activity with acceptable toxicity (Blood. 2015 Apr 9;125[15]:2336-43).
In the current report, the rate of progression-free survival (PFS) at 16 weeks was 3.6% and the median PFS was 1.5 months. None of the patients in the study achieved a complete or partial response to treatment, and just five patients had stable disease.
All patients in the study eventually discontinued treatment and the median treatment duration was 1 month.
“The lack of activity of Syk inhibition in patients with relapsed DLBCL is in contrast to what would have been expected from preclinical data,” the investigators wrote. “Although it is unclear why entospletinib monotherapy lacked activity in the present study, it is possible that resistance to Syk inhibition played a role. Potential mechanisms of resistance of DLBCL to Syk inhibition include transcriptional upregulation of Syk mediated by FOXO1 and PTEN depletion.”
The investigators said that Syk inhibition in combination with BCL2 inhibitors could potentially overcome this resistance. Another approach, they suggested, would be to offer entospletinib in combination with Janus kinase (JAK) 1/3 inhibition.
“Based on results of the preclinical data, the efficacy of entospletinib in combination will be evaluated in future clinical trials,” the investigators wrote.
The rate of adverse events was high in the DLBCL cohort. Forty-two patients (98%) experienced an adverse event and nearly three-quarters experienced a grade 3 event. Overall, 30% of the grade 3 adverse events were related to treatment. More than 40% of patients interrupted treatment because of adverse events, and 19% discontinued. Four patients experienced an adverse event that led to death.
While the lack of clinical activity may have surprised investigators, the safety profile was in line with other patient cohorts in the phase 2 study. In the CLL and indolent non-Hodgkin lymphoma cohorts, the rates of treatment interruption were 45% and 54%, respectively.
The study was supported by Gilead Sciences. Dr. Burke reported relationships with Gilead and other companies.
SOURCE: Burke JM et al. Clin Lymphoma Myeloma Leuk. 2018 Aug;18(8):e327-e331.
Entospletinib, a selective inhibitor of spleen tyrosine kinase (Syk), showed a dismal rate of progression-free survival and a high rate of adverse events in a cohort of previously treated patients with diffuse large B-cell lymphoma (DLBCL).
Entospletinib was evaluated in an open-label, single-agent, phase 2 trial (NCT01799889) with five relapsed/refractory patient cohorts: chronic lymphocytic leukemia (CLL), follicular lymphoma, other indolent non-Hodgkin lymphomas, mantle cell lymphoma, and DLBCL.
John M. Burke, MD, of Rocky Mountain Cancer Centers in Aurora, Colo., and his colleagues reported on the current analysis, which looked specifically at the 43 patients in the trial with previously treated DLBCL. Patients received at least one starting dose of 800 mg of entospletinib orally twice daily. The findings were published in Clinical Lymphoma, Myeloma & Leukemia.
In a previous report on the relapsed/refractory CLL cohort, the investigational agent demonstrated clinical activity with acceptable toxicity (Blood. 2015 Apr 9;125[15]:2336-43).
In the current report, the rate of progression-free survival (PFS) at 16 weeks was 3.6% and the median PFS was 1.5 months. None of the patients in the study achieved a complete or partial response to treatment, and just five patients had stable disease.
All patients in the study eventually discontinued treatment and the median treatment duration was 1 month.
“The lack of activity of Syk inhibition in patients with relapsed DLBCL is in contrast to what would have been expected from preclinical data,” the investigators wrote. “Although it is unclear why entospletinib monotherapy lacked activity in the present study, it is possible that resistance to Syk inhibition played a role. Potential mechanisms of resistance of DLBCL to Syk inhibition include transcriptional upregulation of Syk mediated by FOXO1 and PTEN depletion.”
The investigators said that Syk inhibition in combination with BCL2 inhibitors could potentially overcome this resistance. Another approach, they suggested, would be to offer entospletinib in combination with Janus kinase (JAK) 1/3 inhibition.
“Based on results of the preclinical data, the efficacy of entospletinib in combination will be evaluated in future clinical trials,” the investigators wrote.
The rate of adverse events was high in the DLBCL cohort. Forty-two patients (98%) experienced an adverse event and nearly three-quarters experienced a grade 3 event. Overall, 30% of the grade 3 adverse events were related to treatment. More than 40% of patients interrupted treatment because of adverse events, and 19% discontinued. Four patients experienced an adverse event that led to death.
While the lack of clinical activity may have surprised investigators, the safety profile was in line with other patient cohorts in the phase 2 study. In the CLL and indolent non-Hodgkin lymphoma cohorts, the rates of treatment interruption were 45% and 54%, respectively.
The study was supported by Gilead Sciences. Dr. Burke reported relationships with Gilead and other companies.
SOURCE: Burke JM et al. Clin Lymphoma Myeloma Leuk. 2018 Aug;18(8):e327-e331.
Entospletinib, a selective inhibitor of spleen tyrosine kinase (Syk), showed a dismal rate of progression-free survival and a high rate of adverse events in a cohort of previously treated patients with diffuse large B-cell lymphoma (DLBCL).
Entospletinib was evaluated in an open-label, single-agent, phase 2 trial (NCT01799889) with five relapsed/refractory patient cohorts: chronic lymphocytic leukemia (CLL), follicular lymphoma, other indolent non-Hodgkin lymphomas, mantle cell lymphoma, and DLBCL.
John M. Burke, MD, of Rocky Mountain Cancer Centers in Aurora, Colo., and his colleagues reported on the current analysis, which looked specifically at the 43 patients in the trial with previously treated DLBCL. Patients received at least one starting dose of 800 mg of entospletinib orally twice daily. The findings were published in Clinical Lymphoma, Myeloma & Leukemia.
In a previous report on the relapsed/refractory CLL cohort, the investigational agent demonstrated clinical activity with acceptable toxicity (Blood. 2015 Apr 9;125[15]:2336-43).
In the current report, the rate of progression-free survival (PFS) at 16 weeks was 3.6% and the median PFS was 1.5 months. None of the patients in the study achieved a complete or partial response to treatment, and just five patients had stable disease.
All patients in the study eventually discontinued treatment and the median treatment duration was 1 month.
“The lack of activity of Syk inhibition in patients with relapsed DLBCL is in contrast to what would have been expected from preclinical data,” the investigators wrote. “Although it is unclear why entospletinib monotherapy lacked activity in the present study, it is possible that resistance to Syk inhibition played a role. Potential mechanisms of resistance of DLBCL to Syk inhibition include transcriptional upregulation of Syk mediated by FOXO1 and PTEN depletion.”
The investigators said that Syk inhibition in combination with BCL2 inhibitors could potentially overcome this resistance. Another approach, they suggested, would be to offer entospletinib in combination with Janus kinase (JAK) 1/3 inhibition.
“Based on results of the preclinical data, the efficacy of entospletinib in combination will be evaluated in future clinical trials,” the investigators wrote.
The rate of adverse events was high in the DLBCL cohort. Forty-two patients (98%) experienced an adverse event and nearly three-quarters experienced a grade 3 event. Overall, 30% of the grade 3 adverse events were related to treatment. More than 40% of patients interrupted treatment because of adverse events, and 19% discontinued. Four patients experienced an adverse event that led to death.
While the lack of clinical activity may have surprised investigators, the safety profile was in line with other patient cohorts in the phase 2 study. In the CLL and indolent non-Hodgkin lymphoma cohorts, the rates of treatment interruption were 45% and 54%, respectively.
The study was supported by Gilead Sciences. Dr. Burke reported relationships with Gilead and other companies.
SOURCE: Burke JM et al. Clin Lymphoma Myeloma Leuk. 2018 Aug;18(8):e327-e331.
FROM CLINICAL LYMPHOMA, MYELOMA & LEUKEMIA
Key clinical point:
Major finding: The rate of progression-free survival at 16 weeks was 3.6% with a median PFS of 1.5 months.
Study details: An analysis of 43 relapsed/refractory DLBCL patients who received single-agent entospletinib.
Disclosures: The study was supported by Gilead Sciences. Dr. Burke reported relationships with Gilead and other companies.
Source: Burke JM et al. Clin Lymphoma Myeloma Leuk. 2018 Aug;18(8):e327-e331.
Mood disorders worsen multiple sclerosis disability
BERLIN – Depression and bipolar disorder are major risk factors for worsening disability in people with multiple sclerosis, according to the results of a large Swedish registry-based study.
The presence of depression increased the risk of having a sustained Expanded Disability Status Scale (EDSS) score of 3.0 by 54% and 4.0 by 87%, and it doubled the risk of an EDSS of 6.0.
Selective serotonin reuptake inhibitor treatment also upped the risk of greater disability, with patients exposed to SSRIs having a 40% increased risk of a sustained EDSS of 3.0, a 97% chance of having a sustained EDSS of 4.0, and 2.2-fold increased risk of a sustained EDSS of 6.0.
“We know that mood disorders are highly prevalent in people with multiple sclerosis,” Stefanie Binzer, MD, said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis. She gave her presentation at the meeting on Oct. 10, which was World Mental Health Day.
The presence of mood disorders is associated with reduced quality of life, said Dr. Binzer of the department of clinical neuroscience at the Karolinska Institute in Stockholm. Furthermore, depression is the major risk factor for suicidality in patients with MS. However, before this study the effect of having a comorbid mood disorder on MS patients’ disability levels had not been established.
The investigators analyzed data from 5,875 patients in the Swedish MS registry between 2001 and 2014. By matching these patients to records in the Swedish National Patient Registry and the Swedish National Prescribed Drug Registry, they found that 8.5% (n = 502) had an International Classification of Diseases, 10th revision (ICD-10), code for depression. Of these, 261 had received a diagnosis of depression before their diagnosis of MS.
Of 3,817 patients with MS onset between 2005 and 2014, 27.4% (n = 1,048) had collected at least one prescription for an SSRI.
“What we found was that MS patients with either an ICD code for depression or having been exposed to SSRIs had a significantly increased risk of reaching EDSS 3.0,” Dr. Binzer reported. The age at which patients reached these milestones were younger in both groups when compared with MS patients without depression, she observed.
“The difference between the groups [MS with and MS without depression] seemed to increased with EDSS,” Dr. Binzer said.
Although not statistically significant, there was a trend for patients with depression to be more likely to convert to secondary progressive MS, with a hazard ratio of 1.38 (95% confidence interval, 0.91-2.1).
“For a sensitivity analysis, we found that those who had depression prior to their first MS symptom, the median age when they reached EDSS 3.0 and 4.0 was reduced by 3 and 7 years, respectively,” Dr. Binzer said, adding that, unfortunately, there wasn’t enough power to look at the other endpoints.
In regard to bipolar disorder, 1.5% (n = 200) of 13,125 MS patients diagnosed between 1973 and 2014 were identified with this mood disorder. Its presence significantly increased the risk of MS patients reaching an EDSS score of 4.0 by 58% (95% CI, 1.1-2.28), but not EDSS 3.0 (HR = 1.34; 95% CI, 0.94-1.92) or 6.0 (HR = 1.16; 95% CI, 0.79-1.69). The latter could be due to smaller sample size, Dr. Binzer suggested.
The investigators’ analysis of the results stratified by sex, conducted because men tend to fare worse than women with MS and progress faster, showed that for both depression and bipolar disorder, men were at significantly higher risk of reaching sustained disability milestones. Indeed, compared with women, men with depression had a 61% increased risk and those with bipolar disorder a 31% increased risk of reaching an EDSS score of 6.0. They also had 51% and 32% increased risks of conversion to secondary progressive MS.
“We don’t know the mechanisms that underlie these associations,” Dr. Binzer noted. “Irrespective of the underlying mechanisms, [the study] clearly shows that it’s imperative that we recognize, early, mood disorders in MS patients, and manage them effectively in order to provide better care and hopefully reduce MS disability worsening.”
The research was funded by the Swedish Research Council and the Swedish Brain Foundation. Dr. Binzer has received speaker fees and travel grants from Biogen.
SOURCE: Binzer S et al. Mult Scler. 2018;24(Suppl 2):41. Abstract 99.
BERLIN – Depression and bipolar disorder are major risk factors for worsening disability in people with multiple sclerosis, according to the results of a large Swedish registry-based study.
The presence of depression increased the risk of having a sustained Expanded Disability Status Scale (EDSS) score of 3.0 by 54% and 4.0 by 87%, and it doubled the risk of an EDSS of 6.0.
Selective serotonin reuptake inhibitor treatment also upped the risk of greater disability, with patients exposed to SSRIs having a 40% increased risk of a sustained EDSS of 3.0, a 97% chance of having a sustained EDSS of 4.0, and 2.2-fold increased risk of a sustained EDSS of 6.0.
“We know that mood disorders are highly prevalent in people with multiple sclerosis,” Stefanie Binzer, MD, said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis. She gave her presentation at the meeting on Oct. 10, which was World Mental Health Day.
The presence of mood disorders is associated with reduced quality of life, said Dr. Binzer of the department of clinical neuroscience at the Karolinska Institute in Stockholm. Furthermore, depression is the major risk factor for suicidality in patients with MS. However, before this study the effect of having a comorbid mood disorder on MS patients’ disability levels had not been established.
The investigators analyzed data from 5,875 patients in the Swedish MS registry between 2001 and 2014. By matching these patients to records in the Swedish National Patient Registry and the Swedish National Prescribed Drug Registry, they found that 8.5% (n = 502) had an International Classification of Diseases, 10th revision (ICD-10), code for depression. Of these, 261 had received a diagnosis of depression before their diagnosis of MS.
Of 3,817 patients with MS onset between 2005 and 2014, 27.4% (n = 1,048) had collected at least one prescription for an SSRI.
“What we found was that MS patients with either an ICD code for depression or having been exposed to SSRIs had a significantly increased risk of reaching EDSS 3.0,” Dr. Binzer reported. The age at which patients reached these milestones were younger in both groups when compared with MS patients without depression, she observed.
“The difference between the groups [MS with and MS without depression] seemed to increased with EDSS,” Dr. Binzer said.
Although not statistically significant, there was a trend for patients with depression to be more likely to convert to secondary progressive MS, with a hazard ratio of 1.38 (95% confidence interval, 0.91-2.1).
“For a sensitivity analysis, we found that those who had depression prior to their first MS symptom, the median age when they reached EDSS 3.0 and 4.0 was reduced by 3 and 7 years, respectively,” Dr. Binzer said, adding that, unfortunately, there wasn’t enough power to look at the other endpoints.
In regard to bipolar disorder, 1.5% (n = 200) of 13,125 MS patients diagnosed between 1973 and 2014 were identified with this mood disorder. Its presence significantly increased the risk of MS patients reaching an EDSS score of 4.0 by 58% (95% CI, 1.1-2.28), but not EDSS 3.0 (HR = 1.34; 95% CI, 0.94-1.92) or 6.0 (HR = 1.16; 95% CI, 0.79-1.69). The latter could be due to smaller sample size, Dr. Binzer suggested.
The investigators’ analysis of the results stratified by sex, conducted because men tend to fare worse than women with MS and progress faster, showed that for both depression and bipolar disorder, men were at significantly higher risk of reaching sustained disability milestones. Indeed, compared with women, men with depression had a 61% increased risk and those with bipolar disorder a 31% increased risk of reaching an EDSS score of 6.0. They also had 51% and 32% increased risks of conversion to secondary progressive MS.
“We don’t know the mechanisms that underlie these associations,” Dr. Binzer noted. “Irrespective of the underlying mechanisms, [the study] clearly shows that it’s imperative that we recognize, early, mood disorders in MS patients, and manage them effectively in order to provide better care and hopefully reduce MS disability worsening.”
The research was funded by the Swedish Research Council and the Swedish Brain Foundation. Dr. Binzer has received speaker fees and travel grants from Biogen.
SOURCE: Binzer S et al. Mult Scler. 2018;24(Suppl 2):41. Abstract 99.
BERLIN – Depression and bipolar disorder are major risk factors for worsening disability in people with multiple sclerosis, according to the results of a large Swedish registry-based study.
The presence of depression increased the risk of having a sustained Expanded Disability Status Scale (EDSS) score of 3.0 by 54% and 4.0 by 87%, and it doubled the risk of an EDSS of 6.0.
Selective serotonin reuptake inhibitor treatment also upped the risk of greater disability, with patients exposed to SSRIs having a 40% increased risk of a sustained EDSS of 3.0, a 97% chance of having a sustained EDSS of 4.0, and 2.2-fold increased risk of a sustained EDSS of 6.0.
“We know that mood disorders are highly prevalent in people with multiple sclerosis,” Stefanie Binzer, MD, said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis. She gave her presentation at the meeting on Oct. 10, which was World Mental Health Day.
The presence of mood disorders is associated with reduced quality of life, said Dr. Binzer of the department of clinical neuroscience at the Karolinska Institute in Stockholm. Furthermore, depression is the major risk factor for suicidality in patients with MS. However, before this study the effect of having a comorbid mood disorder on MS patients’ disability levels had not been established.
The investigators analyzed data from 5,875 patients in the Swedish MS registry between 2001 and 2014. By matching these patients to records in the Swedish National Patient Registry and the Swedish National Prescribed Drug Registry, they found that 8.5% (n = 502) had an International Classification of Diseases, 10th revision (ICD-10), code for depression. Of these, 261 had received a diagnosis of depression before their diagnosis of MS.
Of 3,817 patients with MS onset between 2005 and 2014, 27.4% (n = 1,048) had collected at least one prescription for an SSRI.
“What we found was that MS patients with either an ICD code for depression or having been exposed to SSRIs had a significantly increased risk of reaching EDSS 3.0,” Dr. Binzer reported. The age at which patients reached these milestones were younger in both groups when compared with MS patients without depression, she observed.
“The difference between the groups [MS with and MS without depression] seemed to increased with EDSS,” Dr. Binzer said.
Although not statistically significant, there was a trend for patients with depression to be more likely to convert to secondary progressive MS, with a hazard ratio of 1.38 (95% confidence interval, 0.91-2.1).
“For a sensitivity analysis, we found that those who had depression prior to their first MS symptom, the median age when they reached EDSS 3.0 and 4.0 was reduced by 3 and 7 years, respectively,” Dr. Binzer said, adding that, unfortunately, there wasn’t enough power to look at the other endpoints.
In regard to bipolar disorder, 1.5% (n = 200) of 13,125 MS patients diagnosed between 1973 and 2014 were identified with this mood disorder. Its presence significantly increased the risk of MS patients reaching an EDSS score of 4.0 by 58% (95% CI, 1.1-2.28), but not EDSS 3.0 (HR = 1.34; 95% CI, 0.94-1.92) or 6.0 (HR = 1.16; 95% CI, 0.79-1.69). The latter could be due to smaller sample size, Dr. Binzer suggested.
The investigators’ analysis of the results stratified by sex, conducted because men tend to fare worse than women with MS and progress faster, showed that for both depression and bipolar disorder, men were at significantly higher risk of reaching sustained disability milestones. Indeed, compared with women, men with depression had a 61% increased risk and those with bipolar disorder a 31% increased risk of reaching an EDSS score of 6.0. They also had 51% and 32% increased risks of conversion to secondary progressive MS.
“We don’t know the mechanisms that underlie these associations,” Dr. Binzer noted. “Irrespective of the underlying mechanisms, [the study] clearly shows that it’s imperative that we recognize, early, mood disorders in MS patients, and manage them effectively in order to provide better care and hopefully reduce MS disability worsening.”
The research was funded by the Swedish Research Council and the Swedish Brain Foundation. Dr. Binzer has received speaker fees and travel grants from Biogen.
SOURCE: Binzer S et al. Mult Scler. 2018;24(Suppl 2):41. Abstract 99.
REPORTING FROM ECTRIMS 2018
Key clinical point:
Major finding: Depression and bipolar disorder increased the risk of reaching Expanded Disability Status Scale scores of 3.0, 4.0, and 6.0, particularly in men with MS.
Study details: Swedish registry study of nearly 6,000 individuals with confirmed MS, 8.5% of whom had depression and 1.5% of whom had bipolar disorder.
Disclosures: The research was funded by the Swedish Research Council and the Swedish Brain Foundation. Dr. Binzer has received speaker fees and travel grants from Biogen.
Source: Binzer S et al. Mult Scler. 2018;24(Suppl 2):41. Abstract 99.
Revamped MS criteria boost pediatric diagnoses
BERLIN –
The increased accuracy largely hinged on a positive finding of oligoclonal bands in cerebrospinal fluid – a diagnostic hallmark that was not included in the earlier criteria, Georgina Arrambide, MD, said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
“Application to children of the new diagnostic criteria is limited,” said Dr. Arrambide, of the University Hospital Vall d’Hebron Multiple Sclerosis Centre of Catalonia, Barcelona. “And there are still some uncertainties with regard to fluid biomarkers and how they predict or confirm a diagnosis of MS in children, and also their relationship to the disease evolution.”
The updated McDonald criteria are intended to boost early, definitive MS diagnosis, leading to earlier initiation of therapy. They are intended primarily for patients aged 11 years and older who present with a typical clinically isolated syndrome and high probability of MS (Lancet Neurol. 2018;17[2]:162-73).
Dr. Arrambide and her colleagues used the revamped criteria to reassess MS diagnoses in a prospective Spanish cohort of children who experienced an acute first demyelinating event and were diagnosed with the 2010 criteria. The Kids-METOMS-MOGBCN Study enrolls children aged younger than 18 years within 1 year of a first acute demyelinating episode. It includes demographic, clinical, and imaging data, as well as data on oligoclonal bands and antibodies against aquaporin-4 and myelin oligodendrocyte glycoprotein (MoG). Of these fluid biomarkers, only oligoclonal bands are included in the new McDonald criteria.
The 55 children in Dr. Arrambide’s analysis were followed for a mean of 16 months. They included 25 (45%) girls with an overall median age of 6 years at the first acute event. Oligoclonal bands were present in 56%, and both anti-MoG and anti–aquaporin-4 antibodies in 82%.
All children had abnormal brain MRI at baseline, with about 33% having gadolinium-enhancing brain lesions. Spinal cord MRI was abnormal in 50%, with 39% having gadolinium-enhancing lesions. According to the 2010 criteria, only three had a definitive MS diagnosis at baseline. The diagnosis was acute disseminated encephalomyelitis in 51%, clinically isolated syndrome in 31%, radiologically isolated syndrome in 2%, and nonencephalopathic disseminated encephalomyelitis in the remainder.
At baseline, three of those had a definitive MS diagnosis, displaying dissemination in both space and time as required by both the 2010 and 2017 criteria. The addition of oligoclonal band positivity added one more patient over the 2010 criteria, and assessing the cohort with the complete 2017 criteria added three more definitive diagnoses. This was a significant increase in definitive MS diagnoses when compared against the earlier criteria (70% vs. 30%).
Diagnoses changed in 10 other patients during follow-up. The single patient with radiologically isolated syndrome was definitively diagnosed with MS. Of the seven with clinically isolated syndrome, six were diagnosed with MS and one with a relapsing optic neuritis. Of the 28 with a nonencephalopathic encephalitis, 2 were diagnosed with optic neuritis.
The study also confirmed the benefit of adding oligoclonal bands as a diagnostic marker in children. Of those with an MS diagnosis at last follow-up, 71% were positive for the cerebrospinal fluid finding, compared with just 4% of those with a non-MS diagnosis. However, none of those children had anti-MoG antibodies, compared with 58% of those with a non-MS diagnosis. None of the patients were positive for anti–aquaporin-4, regardless of diagnosis.
That finding does not necessarily mean that the absence of anti-MoG antibodies can rule out an MS diagnosis in children, Dr. Arrambide cautioned. Nevertheless, the finding is a useful clinical marker during a diagnostic work-up.
“The presence of oligoclonal bands and the absence of MOG-IgG are both useful biomarkers when evaluating the risk of MS in children with a first demyelinating event,” she said.
She disclosed financial relationships with several pharmaceutical companies.
SOURCE: Arrambide G et al. ECTRIMS 2018, Abstract 64
BERLIN –
The increased accuracy largely hinged on a positive finding of oligoclonal bands in cerebrospinal fluid – a diagnostic hallmark that was not included in the earlier criteria, Georgina Arrambide, MD, said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
“Application to children of the new diagnostic criteria is limited,” said Dr. Arrambide, of the University Hospital Vall d’Hebron Multiple Sclerosis Centre of Catalonia, Barcelona. “And there are still some uncertainties with regard to fluid biomarkers and how they predict or confirm a diagnosis of MS in children, and also their relationship to the disease evolution.”
The updated McDonald criteria are intended to boost early, definitive MS diagnosis, leading to earlier initiation of therapy. They are intended primarily for patients aged 11 years and older who present with a typical clinically isolated syndrome and high probability of MS (Lancet Neurol. 2018;17[2]:162-73).
Dr. Arrambide and her colleagues used the revamped criteria to reassess MS diagnoses in a prospective Spanish cohort of children who experienced an acute first demyelinating event and were diagnosed with the 2010 criteria. The Kids-METOMS-MOGBCN Study enrolls children aged younger than 18 years within 1 year of a first acute demyelinating episode. It includes demographic, clinical, and imaging data, as well as data on oligoclonal bands and antibodies against aquaporin-4 and myelin oligodendrocyte glycoprotein (MoG). Of these fluid biomarkers, only oligoclonal bands are included in the new McDonald criteria.
The 55 children in Dr. Arrambide’s analysis were followed for a mean of 16 months. They included 25 (45%) girls with an overall median age of 6 years at the first acute event. Oligoclonal bands were present in 56%, and both anti-MoG and anti–aquaporin-4 antibodies in 82%.
All children had abnormal brain MRI at baseline, with about 33% having gadolinium-enhancing brain lesions. Spinal cord MRI was abnormal in 50%, with 39% having gadolinium-enhancing lesions. According to the 2010 criteria, only three had a definitive MS diagnosis at baseline. The diagnosis was acute disseminated encephalomyelitis in 51%, clinically isolated syndrome in 31%, radiologically isolated syndrome in 2%, and nonencephalopathic disseminated encephalomyelitis in the remainder.
At baseline, three of those had a definitive MS diagnosis, displaying dissemination in both space and time as required by both the 2010 and 2017 criteria. The addition of oligoclonal band positivity added one more patient over the 2010 criteria, and assessing the cohort with the complete 2017 criteria added three more definitive diagnoses. This was a significant increase in definitive MS diagnoses when compared against the earlier criteria (70% vs. 30%).
Diagnoses changed in 10 other patients during follow-up. The single patient with radiologically isolated syndrome was definitively diagnosed with MS. Of the seven with clinically isolated syndrome, six were diagnosed with MS and one with a relapsing optic neuritis. Of the 28 with a nonencephalopathic encephalitis, 2 were diagnosed with optic neuritis.
The study also confirmed the benefit of adding oligoclonal bands as a diagnostic marker in children. Of those with an MS diagnosis at last follow-up, 71% were positive for the cerebrospinal fluid finding, compared with just 4% of those with a non-MS diagnosis. However, none of those children had anti-MoG antibodies, compared with 58% of those with a non-MS diagnosis. None of the patients were positive for anti–aquaporin-4, regardless of diagnosis.
That finding does not necessarily mean that the absence of anti-MoG antibodies can rule out an MS diagnosis in children, Dr. Arrambide cautioned. Nevertheless, the finding is a useful clinical marker during a diagnostic work-up.
“The presence of oligoclonal bands and the absence of MOG-IgG are both useful biomarkers when evaluating the risk of MS in children with a first demyelinating event,” she said.
She disclosed financial relationships with several pharmaceutical companies.
SOURCE: Arrambide G et al. ECTRIMS 2018, Abstract 64
BERLIN –
The increased accuracy largely hinged on a positive finding of oligoclonal bands in cerebrospinal fluid – a diagnostic hallmark that was not included in the earlier criteria, Georgina Arrambide, MD, said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
“Application to children of the new diagnostic criteria is limited,” said Dr. Arrambide, of the University Hospital Vall d’Hebron Multiple Sclerosis Centre of Catalonia, Barcelona. “And there are still some uncertainties with regard to fluid biomarkers and how they predict or confirm a diagnosis of MS in children, and also their relationship to the disease evolution.”
The updated McDonald criteria are intended to boost early, definitive MS diagnosis, leading to earlier initiation of therapy. They are intended primarily for patients aged 11 years and older who present with a typical clinically isolated syndrome and high probability of MS (Lancet Neurol. 2018;17[2]:162-73).
Dr. Arrambide and her colleagues used the revamped criteria to reassess MS diagnoses in a prospective Spanish cohort of children who experienced an acute first demyelinating event and were diagnosed with the 2010 criteria. The Kids-METOMS-MOGBCN Study enrolls children aged younger than 18 years within 1 year of a first acute demyelinating episode. It includes demographic, clinical, and imaging data, as well as data on oligoclonal bands and antibodies against aquaporin-4 and myelin oligodendrocyte glycoprotein (MoG). Of these fluid biomarkers, only oligoclonal bands are included in the new McDonald criteria.
The 55 children in Dr. Arrambide’s analysis were followed for a mean of 16 months. They included 25 (45%) girls with an overall median age of 6 years at the first acute event. Oligoclonal bands were present in 56%, and both anti-MoG and anti–aquaporin-4 antibodies in 82%.
All children had abnormal brain MRI at baseline, with about 33% having gadolinium-enhancing brain lesions. Spinal cord MRI was abnormal in 50%, with 39% having gadolinium-enhancing lesions. According to the 2010 criteria, only three had a definitive MS diagnosis at baseline. The diagnosis was acute disseminated encephalomyelitis in 51%, clinically isolated syndrome in 31%, radiologically isolated syndrome in 2%, and nonencephalopathic disseminated encephalomyelitis in the remainder.
At baseline, three of those had a definitive MS diagnosis, displaying dissemination in both space and time as required by both the 2010 and 2017 criteria. The addition of oligoclonal band positivity added one more patient over the 2010 criteria, and assessing the cohort with the complete 2017 criteria added three more definitive diagnoses. This was a significant increase in definitive MS diagnoses when compared against the earlier criteria (70% vs. 30%).
Diagnoses changed in 10 other patients during follow-up. The single patient with radiologically isolated syndrome was definitively diagnosed with MS. Of the seven with clinically isolated syndrome, six were diagnosed with MS and one with a relapsing optic neuritis. Of the 28 with a nonencephalopathic encephalitis, 2 were diagnosed with optic neuritis.
The study also confirmed the benefit of adding oligoclonal bands as a diagnostic marker in children. Of those with an MS diagnosis at last follow-up, 71% were positive for the cerebrospinal fluid finding, compared with just 4% of those with a non-MS diagnosis. However, none of those children had anti-MoG antibodies, compared with 58% of those with a non-MS diagnosis. None of the patients were positive for anti–aquaporin-4, regardless of diagnosis.
That finding does not necessarily mean that the absence of anti-MoG antibodies can rule out an MS diagnosis in children, Dr. Arrambide cautioned. Nevertheless, the finding is a useful clinical marker during a diagnostic work-up.
“The presence of oligoclonal bands and the absence of MOG-IgG are both useful biomarkers when evaluating the risk of MS in children with a first demyelinating event,” she said.
She disclosed financial relationships with several pharmaceutical companies.
SOURCE: Arrambide G et al. ECTRIMS 2018, Abstract 64
REPORTING FROM ECTRIMS 2018
Key clinical point: The revised McDonald criteria increased definitive multiple sclerosis diagnoses in children.
Major finding: The 2017 criteria boosted pediatric diagnostic accuracy by 40%.
Study details: The prospective cohort study comprised 55 patients.
Disclosures: Dr. Arrambide disclosed relationships with several pharmaceutical companies.
Source: Arrambide G et al. ECTRIMS 2018, Abstract 64.
No elevated cancer risk with MS therapies in COMBAT-MS data
BERLIN – The risk of cancer – and breast cancer in particular – was not elevated above background levels in a large cohort of multiple sclerosis patients taking disease-modifying therapies.
Those findings from the large Nordic cohort study COMBAT-MS stand in contrast to previous work showing an elevated cancer risk for some monoclonal antibodies.
After statistical adjustment and use of rituximab (Rituxan) as the standard, the hazard ratio (HR) for any malignancy with fingolimod (Gilenya) was 1.74 (95% confidence interval, 0.92-3.28). For natalizumab (Tysabri), the malignancy HR was 1.06 (95% CI, 0.53-2.10), said Peter Alping, a PhD student in the department of clinical neuroscience at the Karolinska Institute, Stockholm.
Only limited data exist for real-world multiple sclerosis (MS) cohorts who have been exposed to novel disease-modifying therapies, said Mr. Alping, presenting the findings at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis. Rituximab has been studied in patients with rheumatoid arthritis, but the treatment regimens differ, as do patient characteristics, he noted. However, surveillance for risk of malignancy is important in these therapies, he said, “since modern disease-modifying therapies exert a more profound effect on the immune system, and we know that the immune system is vital in fighting and preventing cancers.”
The anti-CD20 monoclonal antibody ocrelizumab was studied in the ORATORIO trial. “There, they saw an imbalance in the numbers of breast cancers between the ocrelizumab and placebo groups,” said Mr. Alping, with raw data showing four breast cancers in the ocrelizumab population. However, this would translate to 26.1 cancers per 10,000 person-years, as opposed to the zero breast cancers seen in the placebo group (N Engl J Med. 2017;376:209-20).
“To what degree is cancer risk a concern with novel [disease-modifying therapy] use in MS?” Mr. Alping asked.
To answer the question, he and his colleagues from the Karolinska Institute sought to compare the risk of cancer in MS patients who were treated with rituximab, fingolimod, and natalizumab.
To do this, they conducted a nationwide cohort study using the Swedish MS registry, looking at treatment episodes between 2011 and 2016. In Sweden, the MS registry is also linked to the overall patient registry, as well as registries for cancer and prescription drug use. In addition, patient data are linked to national census data.
Mr. Alping and his colleagues looked at data for the first instance of use for an MS patient of rituximab, natalizumab, and/or fingolimod between the years 2011 and 2016. Then, they matched patient records from the general population by age, sex, and geographic location, enrolling the matched controls at the same time point as the MS match entered the study.
Patients treated with mitoxantrone, those who emigrated, and those who died during the study period were excluded from the study.
The statistical analysis, Mr. Alping said, used an ever-treated approach and didn’t attempt to weight exposure duration or dose. However, statistical adjustments were made for patient and control demographics and medical history, for any previous history of cancer, and for MS disease characteristics.
At baseline, 1,558 patients had been treated with fingolimod, 1,761 with natalizumab, and 3,012 with rituximab. A little less than one-third of the patients (26.3%-31.6%) were male, and the mean age was 35-43 years. Most patients (66%-86%) had undergone one or two previous therapies. The mean Expanded Disability Status Scale (EDSS) score was 2.20-2.88. Few patients (0.9%-1.7%) had any history of previous cancer.
Overall, the incidence of cancer in the MS cohort ranged from 23.09 per 10,000 person-years for rituximab ever-takers to 46.28 for those who had ever taken fingolimod. Among the general population, rates of any malignancy were 29.62 per 10,000 person-years.
Looking just at breast cancer, rates in the MS cohort ranged from 2.19 to 2.92/10,000 person-years. For the general population, the rate was 12.07/10,000 person-years.
However, using a Cox regression analysis employing MS-specific covariates and using rituximab as the reference, Mr. Alping and his colleagues calculated an inverse proportion-weighted hazard ratio for any malignancy under the various treatment conditions. Using this analysis, the HR for any cancer with fingolimod was 1.74 (95% CI, 0.92-3.28). For natalizumab, the malignancy HR was 1.06 (95% CI, 0.53-2.10).
Among just women taking rituximab, 2,274 therapy starts occurred, and one breast cancer was seen in 4,050 person-years. This yielded an incidence of 2.32 cancers per 10,000 person-years (95% CI, 0.06-12.9). This contrasts with the adjusted incidence rate in the general female population of 11.06 breast cancers per 10,000 person-years.
Looking at all the therapy episodes captured in the cohort study, there were 6,660 incidences of therapy initiation, and 52 malignancies were seen over 17,283 person-years, Mr. Alping said.
“For malignant cancer of any type, we found no increased risk for rituximab, compared to fingolimod and natalizumab,” Mr. Alping said, pointing to the wide confidence intervals in all the adjusted data. The incidence of breast cancer in women who have taken rituximab, he said, is “comparable to, or possibly lower than, that of the general female population, and lower than the incidence rate reported in the ORATORIO trial for ocrelizumab.
“The overall cancer risk and risk of breast cancer might not be major concerns short term when treating MS patients with rituximab relative to other disease-modifying therapies,” he said.
The study was partially funded by the Patient-Centered Outcomes Research Institute. Mr. Alping reported no conflicts of interest. One study author reported relationships with several pharmaceutical companies.
[email protected]
SOURCE: Alping P et al. Mult Scler. 2018;24(Suppl 2):36. Abstract 89.
BERLIN – The risk of cancer – and breast cancer in particular – was not elevated above background levels in a large cohort of multiple sclerosis patients taking disease-modifying therapies.
Those findings from the large Nordic cohort study COMBAT-MS stand in contrast to previous work showing an elevated cancer risk for some monoclonal antibodies.
After statistical adjustment and use of rituximab (Rituxan) as the standard, the hazard ratio (HR) for any malignancy with fingolimod (Gilenya) was 1.74 (95% confidence interval, 0.92-3.28). For natalizumab (Tysabri), the malignancy HR was 1.06 (95% CI, 0.53-2.10), said Peter Alping, a PhD student in the department of clinical neuroscience at the Karolinska Institute, Stockholm.
Only limited data exist for real-world multiple sclerosis (MS) cohorts who have been exposed to novel disease-modifying therapies, said Mr. Alping, presenting the findings at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis. Rituximab has been studied in patients with rheumatoid arthritis, but the treatment regimens differ, as do patient characteristics, he noted. However, surveillance for risk of malignancy is important in these therapies, he said, “since modern disease-modifying therapies exert a more profound effect on the immune system, and we know that the immune system is vital in fighting and preventing cancers.”
The anti-CD20 monoclonal antibody ocrelizumab was studied in the ORATORIO trial. “There, they saw an imbalance in the numbers of breast cancers between the ocrelizumab and placebo groups,” said Mr. Alping, with raw data showing four breast cancers in the ocrelizumab population. However, this would translate to 26.1 cancers per 10,000 person-years, as opposed to the zero breast cancers seen in the placebo group (N Engl J Med. 2017;376:209-20).
“To what degree is cancer risk a concern with novel [disease-modifying therapy] use in MS?” Mr. Alping asked.
To answer the question, he and his colleagues from the Karolinska Institute sought to compare the risk of cancer in MS patients who were treated with rituximab, fingolimod, and natalizumab.
To do this, they conducted a nationwide cohort study using the Swedish MS registry, looking at treatment episodes between 2011 and 2016. In Sweden, the MS registry is also linked to the overall patient registry, as well as registries for cancer and prescription drug use. In addition, patient data are linked to national census data.
Mr. Alping and his colleagues looked at data for the first instance of use for an MS patient of rituximab, natalizumab, and/or fingolimod between the years 2011 and 2016. Then, they matched patient records from the general population by age, sex, and geographic location, enrolling the matched controls at the same time point as the MS match entered the study.
Patients treated with mitoxantrone, those who emigrated, and those who died during the study period were excluded from the study.
The statistical analysis, Mr. Alping said, used an ever-treated approach and didn’t attempt to weight exposure duration or dose. However, statistical adjustments were made for patient and control demographics and medical history, for any previous history of cancer, and for MS disease characteristics.
At baseline, 1,558 patients had been treated with fingolimod, 1,761 with natalizumab, and 3,012 with rituximab. A little less than one-third of the patients (26.3%-31.6%) were male, and the mean age was 35-43 years. Most patients (66%-86%) had undergone one or two previous therapies. The mean Expanded Disability Status Scale (EDSS) score was 2.20-2.88. Few patients (0.9%-1.7%) had any history of previous cancer.
Overall, the incidence of cancer in the MS cohort ranged from 23.09 per 10,000 person-years for rituximab ever-takers to 46.28 for those who had ever taken fingolimod. Among the general population, rates of any malignancy were 29.62 per 10,000 person-years.
Looking just at breast cancer, rates in the MS cohort ranged from 2.19 to 2.92/10,000 person-years. For the general population, the rate was 12.07/10,000 person-years.
However, using a Cox regression analysis employing MS-specific covariates and using rituximab as the reference, Mr. Alping and his colleagues calculated an inverse proportion-weighted hazard ratio for any malignancy under the various treatment conditions. Using this analysis, the HR for any cancer with fingolimod was 1.74 (95% CI, 0.92-3.28). For natalizumab, the malignancy HR was 1.06 (95% CI, 0.53-2.10).
Among just women taking rituximab, 2,274 therapy starts occurred, and one breast cancer was seen in 4,050 person-years. This yielded an incidence of 2.32 cancers per 10,000 person-years (95% CI, 0.06-12.9). This contrasts with the adjusted incidence rate in the general female population of 11.06 breast cancers per 10,000 person-years.
Looking at all the therapy episodes captured in the cohort study, there were 6,660 incidences of therapy initiation, and 52 malignancies were seen over 17,283 person-years, Mr. Alping said.
“For malignant cancer of any type, we found no increased risk for rituximab, compared to fingolimod and natalizumab,” Mr. Alping said, pointing to the wide confidence intervals in all the adjusted data. The incidence of breast cancer in women who have taken rituximab, he said, is “comparable to, or possibly lower than, that of the general female population, and lower than the incidence rate reported in the ORATORIO trial for ocrelizumab.
“The overall cancer risk and risk of breast cancer might not be major concerns short term when treating MS patients with rituximab relative to other disease-modifying therapies,” he said.
The study was partially funded by the Patient-Centered Outcomes Research Institute. Mr. Alping reported no conflicts of interest. One study author reported relationships with several pharmaceutical companies.
[email protected]
SOURCE: Alping P et al. Mult Scler. 2018;24(Suppl 2):36. Abstract 89.
BERLIN – The risk of cancer – and breast cancer in particular – was not elevated above background levels in a large cohort of multiple sclerosis patients taking disease-modifying therapies.
Those findings from the large Nordic cohort study COMBAT-MS stand in contrast to previous work showing an elevated cancer risk for some monoclonal antibodies.
After statistical adjustment and use of rituximab (Rituxan) as the standard, the hazard ratio (HR) for any malignancy with fingolimod (Gilenya) was 1.74 (95% confidence interval, 0.92-3.28). For natalizumab (Tysabri), the malignancy HR was 1.06 (95% CI, 0.53-2.10), said Peter Alping, a PhD student in the department of clinical neuroscience at the Karolinska Institute, Stockholm.
Only limited data exist for real-world multiple sclerosis (MS) cohorts who have been exposed to novel disease-modifying therapies, said Mr. Alping, presenting the findings at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis. Rituximab has been studied in patients with rheumatoid arthritis, but the treatment regimens differ, as do patient characteristics, he noted. However, surveillance for risk of malignancy is important in these therapies, he said, “since modern disease-modifying therapies exert a more profound effect on the immune system, and we know that the immune system is vital in fighting and preventing cancers.”
The anti-CD20 monoclonal antibody ocrelizumab was studied in the ORATORIO trial. “There, they saw an imbalance in the numbers of breast cancers between the ocrelizumab and placebo groups,” said Mr. Alping, with raw data showing four breast cancers in the ocrelizumab population. However, this would translate to 26.1 cancers per 10,000 person-years, as opposed to the zero breast cancers seen in the placebo group (N Engl J Med. 2017;376:209-20).
“To what degree is cancer risk a concern with novel [disease-modifying therapy] use in MS?” Mr. Alping asked.
To answer the question, he and his colleagues from the Karolinska Institute sought to compare the risk of cancer in MS patients who were treated with rituximab, fingolimod, and natalizumab.
To do this, they conducted a nationwide cohort study using the Swedish MS registry, looking at treatment episodes between 2011 and 2016. In Sweden, the MS registry is also linked to the overall patient registry, as well as registries for cancer and prescription drug use. In addition, patient data are linked to national census data.
Mr. Alping and his colleagues looked at data for the first instance of use for an MS patient of rituximab, natalizumab, and/or fingolimod between the years 2011 and 2016. Then, they matched patient records from the general population by age, sex, and geographic location, enrolling the matched controls at the same time point as the MS match entered the study.
Patients treated with mitoxantrone, those who emigrated, and those who died during the study period were excluded from the study.
The statistical analysis, Mr. Alping said, used an ever-treated approach and didn’t attempt to weight exposure duration or dose. However, statistical adjustments were made for patient and control demographics and medical history, for any previous history of cancer, and for MS disease characteristics.
At baseline, 1,558 patients had been treated with fingolimod, 1,761 with natalizumab, and 3,012 with rituximab. A little less than one-third of the patients (26.3%-31.6%) were male, and the mean age was 35-43 years. Most patients (66%-86%) had undergone one or two previous therapies. The mean Expanded Disability Status Scale (EDSS) score was 2.20-2.88. Few patients (0.9%-1.7%) had any history of previous cancer.
Overall, the incidence of cancer in the MS cohort ranged from 23.09 per 10,000 person-years for rituximab ever-takers to 46.28 for those who had ever taken fingolimod. Among the general population, rates of any malignancy were 29.62 per 10,000 person-years.
Looking just at breast cancer, rates in the MS cohort ranged from 2.19 to 2.92/10,000 person-years. For the general population, the rate was 12.07/10,000 person-years.
However, using a Cox regression analysis employing MS-specific covariates and using rituximab as the reference, Mr. Alping and his colleagues calculated an inverse proportion-weighted hazard ratio for any malignancy under the various treatment conditions. Using this analysis, the HR for any cancer with fingolimod was 1.74 (95% CI, 0.92-3.28). For natalizumab, the malignancy HR was 1.06 (95% CI, 0.53-2.10).
Among just women taking rituximab, 2,274 therapy starts occurred, and one breast cancer was seen in 4,050 person-years. This yielded an incidence of 2.32 cancers per 10,000 person-years (95% CI, 0.06-12.9). This contrasts with the adjusted incidence rate in the general female population of 11.06 breast cancers per 10,000 person-years.
Looking at all the therapy episodes captured in the cohort study, there were 6,660 incidences of therapy initiation, and 52 malignancies were seen over 17,283 person-years, Mr. Alping said.
“For malignant cancer of any type, we found no increased risk for rituximab, compared to fingolimod and natalizumab,” Mr. Alping said, pointing to the wide confidence intervals in all the adjusted data. The incidence of breast cancer in women who have taken rituximab, he said, is “comparable to, or possibly lower than, that of the general female population, and lower than the incidence rate reported in the ORATORIO trial for ocrelizumab.
“The overall cancer risk and risk of breast cancer might not be major concerns short term when treating MS patients with rituximab relative to other disease-modifying therapies,” he said.
The study was partially funded by the Patient-Centered Outcomes Research Institute. Mr. Alping reported no conflicts of interest. One study author reported relationships with several pharmaceutical companies.
[email protected]
SOURCE: Alping P et al. Mult Scler. 2018;24(Suppl 2):36. Abstract 89.
REPORTING FROM ECTRIMS 2018
Key clinical point:
Major finding: The hazard ratios for fingolimod and natalizumab versus rituximab were 1.74 and 1.06, respectively, with confidence intervals crossing 1.
Study details: Case-matched observational cohort study of 6,331 DMT-taking patients with MS.
Disclosures: The study was sponsored in part by the Patient-Centered Outcomes Research Institute. Mr. Alping reported no disclosures; one study author reported financial relationships with multiple pharmaceutical companies.
Source: Alping P et al. Mult Scler. 2018;24(Suppl 2):36. Abstract 89.
Inhibitor receives orphan designation for PTCL
The U.S. Food and Drug Administration (FDA) has granted orphan drug designation to cerdulatinib for the treatment of peripheral T-cell lymphoma (PTCL).
Cerdulatinib is an oral Syk/JAK inhibitor being developed by Portola Pharmaceuticals, Inc.
Preclinical data have suggested an important role for Syk and JAK in PTCL tumor survival, and cerdulatinib is currently under evaluation in a phase 2a study of patients with PTCL and other non-Hodgkin lymphomas.
Results from this trial were presented at the 23rd Congress of the European Hematology Association (EHA) earlier this year.
At that time, the trial had enrolled 114 patients, 25 of them with PTCL. The patients received cerdulatinib at 25, 30, or 35 mg twice daily.
The objective response rate was 35% among the PTCL patients. All seven responders had a complete response, and 11 PTCL patients were still on cerdulatinib at the time of the presentation.
Grade 3 or higher adverse events observed in all evaluable patients included lipase increase (18%), neutropenia (17%), pneumonia/lung infection (11%), diarrhea (8%), fatigue (6%), amylase increase (5%), sepsis/septic shock (4%), hypertension (4%), anemia (4%), thrombocytopenia (4%), and hypophosphatemia (4%).
There were five deaths due to sepsis or septic shock (three of which were concomitant with pneumonia) that were considered related to cerdulatinib.
Three of the deaths occurred in patients with chronic lymphocytic leukemia, one in a patient with diffuse large B-cell lymphoma, and one in a patient with follicular lymphoma.
The deaths occurred early on in the trial, and researchers have since taken steps—dose reductions, monitoring, and antibiotic prophylaxis—to prevent additional deaths.
About orphan designation
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the United States.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
The U.S. Food and Drug Administration (FDA) has granted orphan drug designation to cerdulatinib for the treatment of peripheral T-cell lymphoma (PTCL).
Cerdulatinib is an oral Syk/JAK inhibitor being developed by Portola Pharmaceuticals, Inc.
Preclinical data have suggested an important role for Syk and JAK in PTCL tumor survival, and cerdulatinib is currently under evaluation in a phase 2a study of patients with PTCL and other non-Hodgkin lymphomas.
Results from this trial were presented at the 23rd Congress of the European Hematology Association (EHA) earlier this year.
At that time, the trial had enrolled 114 patients, 25 of them with PTCL. The patients received cerdulatinib at 25, 30, or 35 mg twice daily.
The objective response rate was 35% among the PTCL patients. All seven responders had a complete response, and 11 PTCL patients were still on cerdulatinib at the time of the presentation.
Grade 3 or higher adverse events observed in all evaluable patients included lipase increase (18%), neutropenia (17%), pneumonia/lung infection (11%), diarrhea (8%), fatigue (6%), amylase increase (5%), sepsis/septic shock (4%), hypertension (4%), anemia (4%), thrombocytopenia (4%), and hypophosphatemia (4%).
There were five deaths due to sepsis or septic shock (three of which were concomitant with pneumonia) that were considered related to cerdulatinib.
Three of the deaths occurred in patients with chronic lymphocytic leukemia, one in a patient with diffuse large B-cell lymphoma, and one in a patient with follicular lymphoma.
The deaths occurred early on in the trial, and researchers have since taken steps—dose reductions, monitoring, and antibiotic prophylaxis—to prevent additional deaths.
About orphan designation
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the United States.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
The U.S. Food and Drug Administration (FDA) has granted orphan drug designation to cerdulatinib for the treatment of peripheral T-cell lymphoma (PTCL).
Cerdulatinib is an oral Syk/JAK inhibitor being developed by Portola Pharmaceuticals, Inc.
Preclinical data have suggested an important role for Syk and JAK in PTCL tumor survival, and cerdulatinib is currently under evaluation in a phase 2a study of patients with PTCL and other non-Hodgkin lymphomas.
Results from this trial were presented at the 23rd Congress of the European Hematology Association (EHA) earlier this year.
At that time, the trial had enrolled 114 patients, 25 of them with PTCL. The patients received cerdulatinib at 25, 30, or 35 mg twice daily.
The objective response rate was 35% among the PTCL patients. All seven responders had a complete response, and 11 PTCL patients were still on cerdulatinib at the time of the presentation.
Grade 3 or higher adverse events observed in all evaluable patients included lipase increase (18%), neutropenia (17%), pneumonia/lung infection (11%), diarrhea (8%), fatigue (6%), amylase increase (5%), sepsis/septic shock (4%), hypertension (4%), anemia (4%), thrombocytopenia (4%), and hypophosphatemia (4%).
There were five deaths due to sepsis or septic shock (three of which were concomitant with pneumonia) that were considered related to cerdulatinib.
Three of the deaths occurred in patients with chronic lymphocytic leukemia, one in a patient with diffuse large B-cell lymphoma, and one in a patient with follicular lymphoma.
The deaths occurred early on in the trial, and researchers have since taken steps—dose reductions, monitoring, and antibiotic prophylaxis—to prevent additional deaths.
About orphan designation
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the United States.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
MCL treatment choices depend partly on age
CHICAGO – Treatment for mantle cell lymphoma (MCL) depends at least in part on patient age, with some important differences in those aged 65 years or younger versus those over age 65, according to Kristie A. Blum, MD.
“For the [younger] early-stage patients I’ll think about radiation and maybe observation, although I think [observation] is pretty uncommon,” Dr. Blum, acting hematology and medical oncology professor at Emory University in Atlanta, said at the American Society of Hematology Meeting on Hematologic Malignancies.
For advanced-stage patients, a number of options, including observation, can be considered, she said.
Observation
Observation is acceptable in highly selected advanced stage cases. In a 2009 study of 97 mantle cell patients, 31 were observed for more than 3 months before treatment was initiated (median time to treatment, 12 months), and at median follow-up of 55 months, overall survival (OS) was significantly better in the observation group (not reached vs. 64 months in treated patients), she said (J Clin Oncol. 2009 Mar 10;27[8]:1209-13).
Observed patients had better performance status and lower-risk standard International Prognostic Index scores, compared with treated patients, and the authors concluded that a “watch-and-wait” approach is acceptable in select patients.
“In addition, if you looked at their overall survival from the time of first treatment, there was no difference in the groups, suggesting you really weren’t hurting people by delaying their therapy,” Dr. Blum said.
In a more recent series of 440 favorable-risk MCL patients, 17% were observed for at least 3 months (median time to treatment, 35 months), 80% were observed for at least 12 months, and 13% were observed for 5 years.
Again, median OS was better for observed patients than for those treated initially, at 72 months vs. 52.5 months (Ann Oncol. 2017;28[10]:2489-95).
“So I do think there is a subset of patients that can safely be observed with mantle cell [lymphoma],” she said.
Transplant-based approaches
Transplant-based approaches in younger patients with advanced disease include the Nordic regimen plus autologous stem cell transplant (ASCT), R-CHOP/R-DHAP plus ASCT, and R-bendamustine/R-cytarabine – all with post-ASCT maintenance rituximab, Dr. Blum said.
Cytarabine-containing induction was established as the pretransplant standard of care by the 474-patient MCL Younger trial, which demonstrated significantly prolonged time to treatment failure (9.1 vs. 3.9 years), with alternating pretransplant R-CHOP/R-DHAP versus R-CHOP for six cycles, though this was associated with increased toxicity. (Lancet. 2016 Aug 6;388[10044]:565-75).
For example, grade 3-4 thrombocytopenia occurred in 73% vs. 9% of patients, she noted.
The Nordic MCL2 trial showed that an intensive regimen involving alternating Maxi-CHOP and AraC followed by transplant results in median OS of about 12 years and PFS of about 8 years.
“I do want to highlight, though, that again, the high-risk patients don’t do very well,” she said, noting that median PFS even with this intensive approach was only 2.5 years in those at high risk based on MCL International Prognostic Index (MIPI) score, compared with 12.7 years for patients with a low-risk MIPI score.
Newer induction regimens also show some promise and appear feasible in younger patients based on early data, she said, noting that the SWOG S1106 trial comparing R-bendamustine and R-HyperCVAD showed a minimal residual disease (MRD) negativity rate of 78% in the R-bendamustine group. Another study evaluating R-bendamustine followed by AraC showed a 96% complete remission and PFS at 13 months of 96%, with MRD-negativity of 93% (Br J Haematol. 2016 Apr;173[1]:89-95).
Transplant also is an option in advanced stage patients aged 66-70 years who are fit and willing, Dr. Blum said.
“I spend a long time talking to these patients about whether they want a transplant or not,” she said.
For induction in those patients who choose transplant, Dr. Blum said she prefers bendamustine-based regimens, “because these have been published in patients up to the age of 70.”
Transplant timing is usually at the first complete remission.
Data show that 5-year OS after such early ASCT in patients with no more than two prior lines of chemotherapy is about 60%, compared with about 44% with late ASCT. For reduced intensity conditioning allogeneic stem cell transplant in that study, the 5-year OS was 62% for early transplant and 31% for late transplant (J Clin Oncol. 2014 Feb 1;32[4]:273-81).
R-HyperCVAD
R-HyperCVAD is another option in younger patients, and is usually given for eight cycles, followed by transplant only in those who aren’t in complete remission, Dr. Blum said.
Median failure-free survival among patients aged 65 years and younger in one study of this regimen was 6.5 years and OS was 13.4 years. In those over age 65, median failure-free survival was about 3 years (Br J Haematol. 2016 Jan;172[1]:80-88).
The SWOG 0213 study looked at this in a multicenter fashion, she said, noting that 39% of patients – 48% of whom were aged 65 and older – could not complete all eight cycles.
“Again, there was a high rate of this sort of infectious toxicity,” she said.
Median PFS was about 5 years in this study as well, and OS was nearly 7 years. For those over age 65, median PFS was just 1.6 years.
“So I don’t typically recommend this for the 65- to 70-year-olds,” she said.
Older nontransplant candidates
When treating patients who are unfit for transplant, Dr. Blum pointed to the results of the StiL and BRIGHT studies, which both showed that R-bendamustine was noninferior to R-CHOP as first-line treatment.
In addition, recent data on combined bendamustine and cytarabine (R-BAC500) showed that in 57 patients with a median age of 71 years, 95% received at least four cycles, and 67% completed six cycles. CR was 91% , and 2-year OS and PFS were 86% and 81%, respectively.
However, grade 3-4 neutropenia and thrombocytopenia occurred in 49% and 52% of patients, respectively (Lancet Haematol. 2017 Jan 1;4[1]:e15-e23).
The bortezomib-containing regimen VR-CAP has also been shown to be of benefit for older MCL patients not eligible for transplant, she said.
Median PFS with VR-CAP in a study of 487 newly diagnosed MCL patients was about 25 months vs. 14 months with R-CHOP (N Engl J Med. 2015 Mar 5;372:944-53).
“R-lenalidomide has activity in the front-line setting as well,” Dr. Blum said, citing a multicenter phase 2 study of 38 patients with a mean age of 65 years. The intention-to-treat analysis showed an overall response rate of 87%, CR rate of 61%, and 2-year PFS of 85% (N Engl J Med. 2015;373:1835-44).
Maintenance therapy
As for maintenance therapy in younger patients, a phase 3 study of 299 patients showed that rituximab maintenance was associated with significantly better 4-year PFS (83% vs. 64% with observation), and 4-year OS (89% vs. 80% with observation), she said (N Engl J Med. 2017 Sep 28;377:1250-60).
“I do think that rituximab maintenance is the standard of care now, based on this study,” Dr. Blum said, adding that there is also a role for rituximab maintenance in older patients.
A European Mantle Cell Network study of patients aged 60 and older (median age of 70) showed an OS of 62% with R-CHOP vs. 47% with R-FC (rituximab, fludarabine, and cyclophosphamide), and – among those then randomized to maintenance rituximab or interferon alpha – 4-year PFS of 58% vs. 29%, respectively (N Engl J Med. 2012;367:520-31).
“Now I will tell you that most of these patients are getting bendamustine. We don’t really know the role for rituximab maintenance after bendamustine-based induction, but at this point I think it’s reasonable to consider adding it,” she said.
Dr. Blum is a consultant for Acerta, AstraZeneca, and Molecular Templates and has received research funding from Acerta, AstraZeneca, Celgene, Cephalon, Immunomedics, Janssen, Merck, Millennium, Molecular Templates, Novartis, Pharmacyclics, and Seattle Genetics.
CHICAGO – Treatment for mantle cell lymphoma (MCL) depends at least in part on patient age, with some important differences in those aged 65 years or younger versus those over age 65, according to Kristie A. Blum, MD.
“For the [younger] early-stage patients I’ll think about radiation and maybe observation, although I think [observation] is pretty uncommon,” Dr. Blum, acting hematology and medical oncology professor at Emory University in Atlanta, said at the American Society of Hematology Meeting on Hematologic Malignancies.
For advanced-stage patients, a number of options, including observation, can be considered, she said.
Observation
Observation is acceptable in highly selected advanced stage cases. In a 2009 study of 97 mantle cell patients, 31 were observed for more than 3 months before treatment was initiated (median time to treatment, 12 months), and at median follow-up of 55 months, overall survival (OS) was significantly better in the observation group (not reached vs. 64 months in treated patients), she said (J Clin Oncol. 2009 Mar 10;27[8]:1209-13).
Observed patients had better performance status and lower-risk standard International Prognostic Index scores, compared with treated patients, and the authors concluded that a “watch-and-wait” approach is acceptable in select patients.
“In addition, if you looked at their overall survival from the time of first treatment, there was no difference in the groups, suggesting you really weren’t hurting people by delaying their therapy,” Dr. Blum said.
In a more recent series of 440 favorable-risk MCL patients, 17% were observed for at least 3 months (median time to treatment, 35 months), 80% were observed for at least 12 months, and 13% were observed for 5 years.
Again, median OS was better for observed patients than for those treated initially, at 72 months vs. 52.5 months (Ann Oncol. 2017;28[10]:2489-95).
“So I do think there is a subset of patients that can safely be observed with mantle cell [lymphoma],” she said.
Transplant-based approaches
Transplant-based approaches in younger patients with advanced disease include the Nordic regimen plus autologous stem cell transplant (ASCT), R-CHOP/R-DHAP plus ASCT, and R-bendamustine/R-cytarabine – all with post-ASCT maintenance rituximab, Dr. Blum said.
Cytarabine-containing induction was established as the pretransplant standard of care by the 474-patient MCL Younger trial, which demonstrated significantly prolonged time to treatment failure (9.1 vs. 3.9 years), with alternating pretransplant R-CHOP/R-DHAP versus R-CHOP for six cycles, though this was associated with increased toxicity. (Lancet. 2016 Aug 6;388[10044]:565-75).
For example, grade 3-4 thrombocytopenia occurred in 73% vs. 9% of patients, she noted.
The Nordic MCL2 trial showed that an intensive regimen involving alternating Maxi-CHOP and AraC followed by transplant results in median OS of about 12 years and PFS of about 8 years.
“I do want to highlight, though, that again, the high-risk patients don’t do very well,” she said, noting that median PFS even with this intensive approach was only 2.5 years in those at high risk based on MCL International Prognostic Index (MIPI) score, compared with 12.7 years for patients with a low-risk MIPI score.
Newer induction regimens also show some promise and appear feasible in younger patients based on early data, she said, noting that the SWOG S1106 trial comparing R-bendamustine and R-HyperCVAD showed a minimal residual disease (MRD) negativity rate of 78% in the R-bendamustine group. Another study evaluating R-bendamustine followed by AraC showed a 96% complete remission and PFS at 13 months of 96%, with MRD-negativity of 93% (Br J Haematol. 2016 Apr;173[1]:89-95).
Transplant also is an option in advanced stage patients aged 66-70 years who are fit and willing, Dr. Blum said.
“I spend a long time talking to these patients about whether they want a transplant or not,” she said.
For induction in those patients who choose transplant, Dr. Blum said she prefers bendamustine-based regimens, “because these have been published in patients up to the age of 70.”
Transplant timing is usually at the first complete remission.
Data show that 5-year OS after such early ASCT in patients with no more than two prior lines of chemotherapy is about 60%, compared with about 44% with late ASCT. For reduced intensity conditioning allogeneic stem cell transplant in that study, the 5-year OS was 62% for early transplant and 31% for late transplant (J Clin Oncol. 2014 Feb 1;32[4]:273-81).
R-HyperCVAD
R-HyperCVAD is another option in younger patients, and is usually given for eight cycles, followed by transplant only in those who aren’t in complete remission, Dr. Blum said.
Median failure-free survival among patients aged 65 years and younger in one study of this regimen was 6.5 years and OS was 13.4 years. In those over age 65, median failure-free survival was about 3 years (Br J Haematol. 2016 Jan;172[1]:80-88).
The SWOG 0213 study looked at this in a multicenter fashion, she said, noting that 39% of patients – 48% of whom were aged 65 and older – could not complete all eight cycles.
“Again, there was a high rate of this sort of infectious toxicity,” she said.
Median PFS was about 5 years in this study as well, and OS was nearly 7 years. For those over age 65, median PFS was just 1.6 years.
“So I don’t typically recommend this for the 65- to 70-year-olds,” she said.
Older nontransplant candidates
When treating patients who are unfit for transplant, Dr. Blum pointed to the results of the StiL and BRIGHT studies, which both showed that R-bendamustine was noninferior to R-CHOP as first-line treatment.
In addition, recent data on combined bendamustine and cytarabine (R-BAC500) showed that in 57 patients with a median age of 71 years, 95% received at least four cycles, and 67% completed six cycles. CR was 91% , and 2-year OS and PFS were 86% and 81%, respectively.
However, grade 3-4 neutropenia and thrombocytopenia occurred in 49% and 52% of patients, respectively (Lancet Haematol. 2017 Jan 1;4[1]:e15-e23).
The bortezomib-containing regimen VR-CAP has also been shown to be of benefit for older MCL patients not eligible for transplant, she said.
Median PFS with VR-CAP in a study of 487 newly diagnosed MCL patients was about 25 months vs. 14 months with R-CHOP (N Engl J Med. 2015 Mar 5;372:944-53).
“R-lenalidomide has activity in the front-line setting as well,” Dr. Blum said, citing a multicenter phase 2 study of 38 patients with a mean age of 65 years. The intention-to-treat analysis showed an overall response rate of 87%, CR rate of 61%, and 2-year PFS of 85% (N Engl J Med. 2015;373:1835-44).
Maintenance therapy
As for maintenance therapy in younger patients, a phase 3 study of 299 patients showed that rituximab maintenance was associated with significantly better 4-year PFS (83% vs. 64% with observation), and 4-year OS (89% vs. 80% with observation), she said (N Engl J Med. 2017 Sep 28;377:1250-60).
“I do think that rituximab maintenance is the standard of care now, based on this study,” Dr. Blum said, adding that there is also a role for rituximab maintenance in older patients.
A European Mantle Cell Network study of patients aged 60 and older (median age of 70) showed an OS of 62% with R-CHOP vs. 47% with R-FC (rituximab, fludarabine, and cyclophosphamide), and – among those then randomized to maintenance rituximab or interferon alpha – 4-year PFS of 58% vs. 29%, respectively (N Engl J Med. 2012;367:520-31).
“Now I will tell you that most of these patients are getting bendamustine. We don’t really know the role for rituximab maintenance after bendamustine-based induction, but at this point I think it’s reasonable to consider adding it,” she said.
Dr. Blum is a consultant for Acerta, AstraZeneca, and Molecular Templates and has received research funding from Acerta, AstraZeneca, Celgene, Cephalon, Immunomedics, Janssen, Merck, Millennium, Molecular Templates, Novartis, Pharmacyclics, and Seattle Genetics.
CHICAGO – Treatment for mantle cell lymphoma (MCL) depends at least in part on patient age, with some important differences in those aged 65 years or younger versus those over age 65, according to Kristie A. Blum, MD.
“For the [younger] early-stage patients I’ll think about radiation and maybe observation, although I think [observation] is pretty uncommon,” Dr. Blum, acting hematology and medical oncology professor at Emory University in Atlanta, said at the American Society of Hematology Meeting on Hematologic Malignancies.
For advanced-stage patients, a number of options, including observation, can be considered, she said.
Observation
Observation is acceptable in highly selected advanced stage cases. In a 2009 study of 97 mantle cell patients, 31 were observed for more than 3 months before treatment was initiated (median time to treatment, 12 months), and at median follow-up of 55 months, overall survival (OS) was significantly better in the observation group (not reached vs. 64 months in treated patients), she said (J Clin Oncol. 2009 Mar 10;27[8]:1209-13).
Observed patients had better performance status and lower-risk standard International Prognostic Index scores, compared with treated patients, and the authors concluded that a “watch-and-wait” approach is acceptable in select patients.
“In addition, if you looked at their overall survival from the time of first treatment, there was no difference in the groups, suggesting you really weren’t hurting people by delaying their therapy,” Dr. Blum said.
In a more recent series of 440 favorable-risk MCL patients, 17% were observed for at least 3 months (median time to treatment, 35 months), 80% were observed for at least 12 months, and 13% were observed for 5 years.
Again, median OS was better for observed patients than for those treated initially, at 72 months vs. 52.5 months (Ann Oncol. 2017;28[10]:2489-95).
“So I do think there is a subset of patients that can safely be observed with mantle cell [lymphoma],” she said.
Transplant-based approaches
Transplant-based approaches in younger patients with advanced disease include the Nordic regimen plus autologous stem cell transplant (ASCT), R-CHOP/R-DHAP plus ASCT, and R-bendamustine/R-cytarabine – all with post-ASCT maintenance rituximab, Dr. Blum said.
Cytarabine-containing induction was established as the pretransplant standard of care by the 474-patient MCL Younger trial, which demonstrated significantly prolonged time to treatment failure (9.1 vs. 3.9 years), with alternating pretransplant R-CHOP/R-DHAP versus R-CHOP for six cycles, though this was associated with increased toxicity. (Lancet. 2016 Aug 6;388[10044]:565-75).
For example, grade 3-4 thrombocytopenia occurred in 73% vs. 9% of patients, she noted.
The Nordic MCL2 trial showed that an intensive regimen involving alternating Maxi-CHOP and AraC followed by transplant results in median OS of about 12 years and PFS of about 8 years.
“I do want to highlight, though, that again, the high-risk patients don’t do very well,” she said, noting that median PFS even with this intensive approach was only 2.5 years in those at high risk based on MCL International Prognostic Index (MIPI) score, compared with 12.7 years for patients with a low-risk MIPI score.
Newer induction regimens also show some promise and appear feasible in younger patients based on early data, she said, noting that the SWOG S1106 trial comparing R-bendamustine and R-HyperCVAD showed a minimal residual disease (MRD) negativity rate of 78% in the R-bendamustine group. Another study evaluating R-bendamustine followed by AraC showed a 96% complete remission and PFS at 13 months of 96%, with MRD-negativity of 93% (Br J Haematol. 2016 Apr;173[1]:89-95).
Transplant also is an option in advanced stage patients aged 66-70 years who are fit and willing, Dr. Blum said.
“I spend a long time talking to these patients about whether they want a transplant or not,” she said.
For induction in those patients who choose transplant, Dr. Blum said she prefers bendamustine-based regimens, “because these have been published in patients up to the age of 70.”
Transplant timing is usually at the first complete remission.
Data show that 5-year OS after such early ASCT in patients with no more than two prior lines of chemotherapy is about 60%, compared with about 44% with late ASCT. For reduced intensity conditioning allogeneic stem cell transplant in that study, the 5-year OS was 62% for early transplant and 31% for late transplant (J Clin Oncol. 2014 Feb 1;32[4]:273-81).
R-HyperCVAD
R-HyperCVAD is another option in younger patients, and is usually given for eight cycles, followed by transplant only in those who aren’t in complete remission, Dr. Blum said.
Median failure-free survival among patients aged 65 years and younger in one study of this regimen was 6.5 years and OS was 13.4 years. In those over age 65, median failure-free survival was about 3 years (Br J Haematol. 2016 Jan;172[1]:80-88).
The SWOG 0213 study looked at this in a multicenter fashion, she said, noting that 39% of patients – 48% of whom were aged 65 and older – could not complete all eight cycles.
“Again, there was a high rate of this sort of infectious toxicity,” she said.
Median PFS was about 5 years in this study as well, and OS was nearly 7 years. For those over age 65, median PFS was just 1.6 years.
“So I don’t typically recommend this for the 65- to 70-year-olds,” she said.
Older nontransplant candidates
When treating patients who are unfit for transplant, Dr. Blum pointed to the results of the StiL and BRIGHT studies, which both showed that R-bendamustine was noninferior to R-CHOP as first-line treatment.
In addition, recent data on combined bendamustine and cytarabine (R-BAC500) showed that in 57 patients with a median age of 71 years, 95% received at least four cycles, and 67% completed six cycles. CR was 91% , and 2-year OS and PFS were 86% and 81%, respectively.
However, grade 3-4 neutropenia and thrombocytopenia occurred in 49% and 52% of patients, respectively (Lancet Haematol. 2017 Jan 1;4[1]:e15-e23).
The bortezomib-containing regimen VR-CAP has also been shown to be of benefit for older MCL patients not eligible for transplant, she said.
Median PFS with VR-CAP in a study of 487 newly diagnosed MCL patients was about 25 months vs. 14 months with R-CHOP (N Engl J Med. 2015 Mar 5;372:944-53).
“R-lenalidomide has activity in the front-line setting as well,” Dr. Blum said, citing a multicenter phase 2 study of 38 patients with a mean age of 65 years. The intention-to-treat analysis showed an overall response rate of 87%, CR rate of 61%, and 2-year PFS of 85% (N Engl J Med. 2015;373:1835-44).
Maintenance therapy
As for maintenance therapy in younger patients, a phase 3 study of 299 patients showed that rituximab maintenance was associated with significantly better 4-year PFS (83% vs. 64% with observation), and 4-year OS (89% vs. 80% with observation), she said (N Engl J Med. 2017 Sep 28;377:1250-60).
“I do think that rituximab maintenance is the standard of care now, based on this study,” Dr. Blum said, adding that there is also a role for rituximab maintenance in older patients.
A European Mantle Cell Network study of patients aged 60 and older (median age of 70) showed an OS of 62% with R-CHOP vs. 47% with R-FC (rituximab, fludarabine, and cyclophosphamide), and – among those then randomized to maintenance rituximab or interferon alpha – 4-year PFS of 58% vs. 29%, respectively (N Engl J Med. 2012;367:520-31).
“Now I will tell you that most of these patients are getting bendamustine. We don’t really know the role for rituximab maintenance after bendamustine-based induction, but at this point I think it’s reasonable to consider adding it,” she said.
Dr. Blum is a consultant for Acerta, AstraZeneca, and Molecular Templates and has received research funding from Acerta, AstraZeneca, Celgene, Cephalon, Immunomedics, Janssen, Merck, Millennium, Molecular Templates, Novartis, Pharmacyclics, and Seattle Genetics.
EXPERT ANALYSIS FROM MHM 2018
Phase 1 NHL, ALL trials placed on clinical hold
Update: On October 12, 2018, Affimed N.V. received a notification from the U.S. Food and Drug Administration (FDA) saying the agency concurred with Affimed’s decision and formally placed the investigational new drug application for AFM11 on full clinical hold. Affimed said it will comply with the FDA and other global health authorities’ requests for information to resolve the clinical hold.
Affimed N.V. has placed trials of AFM11 on clinical hold and notified the global health authorities of its decision.
AFM11 is a CD19/CD3-targeting T-cell engager being evaluated in two phase 1 trials—one in patients with relapsed or refractory, CD19-positive B-cell non-Hodgkin lymphoma (NHL) and one in adults with relapsed or refractory B-precursor acute lymphoblastic leukemia (ALL).
Affimed initiated the clinical hold on these trials after serious adverse events occurred in three patients treated with AFM11.
This included a death in the ALL study and two life-threatening events in the NHL study.
The serious adverse events occurred in patients enrolled in the highest dose cohorts of each study.
A total of 33 patients have been treated in the two studies (NCT02848911 and NCT02106091), and preliminary signs of clinical activity have been observed in several patients.
Affimed said it will be working closely with the global health authorities, safety monitoring committees, and the studies’ clinical investigators to review the adverse events, assess all the data, and determine next steps for the AFM11 program.
Affimed intends to provide an update on AFM11 upon completing the evaluation.
Update: On October 12, 2018, Affimed N.V. received a notification from the U.S. Food and Drug Administration (FDA) saying the agency concurred with Affimed’s decision and formally placed the investigational new drug application for AFM11 on full clinical hold. Affimed said it will comply with the FDA and other global health authorities’ requests for information to resolve the clinical hold.
Affimed N.V. has placed trials of AFM11 on clinical hold and notified the global health authorities of its decision.
AFM11 is a CD19/CD3-targeting T-cell engager being evaluated in two phase 1 trials—one in patients with relapsed or refractory, CD19-positive B-cell non-Hodgkin lymphoma (NHL) and one in adults with relapsed or refractory B-precursor acute lymphoblastic leukemia (ALL).
Affimed initiated the clinical hold on these trials after serious adverse events occurred in three patients treated with AFM11.
This included a death in the ALL study and two life-threatening events in the NHL study.
The serious adverse events occurred in patients enrolled in the highest dose cohorts of each study.
A total of 33 patients have been treated in the two studies (NCT02848911 and NCT02106091), and preliminary signs of clinical activity have been observed in several patients.
Affimed said it will be working closely with the global health authorities, safety monitoring committees, and the studies’ clinical investigators to review the adverse events, assess all the data, and determine next steps for the AFM11 program.
Affimed intends to provide an update on AFM11 upon completing the evaluation.
Update: On October 12, 2018, Affimed N.V. received a notification from the U.S. Food and Drug Administration (FDA) saying the agency concurred with Affimed’s decision and formally placed the investigational new drug application for AFM11 on full clinical hold. Affimed said it will comply with the FDA and other global health authorities’ requests for information to resolve the clinical hold.
Affimed N.V. has placed trials of AFM11 on clinical hold and notified the global health authorities of its decision.
AFM11 is a CD19/CD3-targeting T-cell engager being evaluated in two phase 1 trials—one in patients with relapsed or refractory, CD19-positive B-cell non-Hodgkin lymphoma (NHL) and one in adults with relapsed or refractory B-precursor acute lymphoblastic leukemia (ALL).
Affimed initiated the clinical hold on these trials after serious adverse events occurred in three patients treated with AFM11.
This included a death in the ALL study and two life-threatening events in the NHL study.
The serious adverse events occurred in patients enrolled in the highest dose cohorts of each study.
A total of 33 patients have been treated in the two studies (NCT02848911 and NCT02106091), and preliminary signs of clinical activity have been observed in several patients.
Affimed said it will be working closely with the global health authorities, safety monitoring committees, and the studies’ clinical investigators to review the adverse events, assess all the data, and determine next steps for the AFM11 program.
Affimed intends to provide an update on AFM11 upon completing the evaluation.
ALTA-1L: Brigatinib beats crizotinib for PFS in ALK-positive NSCLC
TORONTO – in the first interim results from the multicenter, open-label, phase 3 ALTA-1L trial.
In fact, the primary endpoint of the study – blinded independent review committee–assessed progression-free survival (PFS) – was met at this first analysis. The next-generation ALK inhibitor brigatinib reduced the chance of progression or death by 51% as compared with crizotinib – the current first-line standard of care in this population, D. Ross Camidge, MD, reported at the World Conference on Lung Cancer.
“At a median follow-up of 9-11 months, 26% [of 137 patients] on the brigatinib arm and 46% [of 138 patients] on the crizotinib arm had experienced a PFS event. Median PFS was not reached for the brigatinib arm and was 9.8 months for the crizotinib arm; the hazard ratio for progression or death was 0.49 and highly statistically significant,” said Dr. Camidge, director of thoracic oncology and the Joyce Zeff Chair in Lung Cancer Research at the University of Colorado Cancer Center, Aurora, at the meeting sponsored by the International Association for the Study of Lung Cancer.
The findings were published simultaneously in the New England Journal of Medicine.
The 12-month PFS rate estimate was 67% for brigatinib and 43% for crizotinib, and the investigator-assessed hazard ratio for PFS was 0.45. Overall survival data are immature, Dr. Camidge added, noting that the PFS hazard ratios for those with versus those without prior chemotherapy were 0.35 and 0.55, respectively.
“PFS consistently favored brigatinib across all other subgroups,” he said. “Although the confidence intervals overlap, the effect size appears greater among those with baseline [CNS] disease than among those without [HR, 0.2 vs. 0.72].”
Data suggest that CNS progression among those with CNS disease at baseline tends to be an earlier event than either extra-CNS progression in general or CNS progression in those without baseline CNS disease. “Consequently, this first interim analysis may be preferentially emphasizing drug efficacy differences within the subgroup in whom the earlier progression events are occurring,” Dr. Camidge said.
As for overall objective responses, the rates were numerically higher with brigatinib versus crizotinib (70% vs. 60%), but were not statistically different in the two groups. “However, the median duration of confirmed responses was not reached for brigatinib and [was] 11.1 months with crizotinib, with the 12-month [probability] of sustained response being 75% for brigatinib and 41% for crizotinib,” he added.
Further, among those with measurable CNS lesions, brigatinib demonstrated a significantly higher intracranial response rate of 78% versus 29% (odds ratio, 10.42), and when those with nonmeasurable CNS disease were included in the intracranial response assessment, the odds ratio was 13.
Median intracranial PFS among those with CNS involvement at baseline was not reached in the brigatinib arm versus 5.6 months with crizotinib, for a highly statistically significant hazard ratio of 0.27. “Which, given that the median PFS for crizotinib in the overall population ... was 9.8 months, again emphasizes how CNS events in this subgroup tend to occur early,” he noted.
Study subjects had stage IIIB/IV ALK-positive non–small cell lung cancer (NSCLC) based on local ALK testing, Eastern Cooperative Oncology Group performance status of 0-2, no more than one prior systemic therapy for locally advanced/metastatic NSCLC, and no prior ALK inhibitor therapy, Dr. Camidge said, noting that asymptomatic, untreated brain metastases were allowed and crossover to the brigatinib arm was permitted for those with blinded independent review committee–assessed progression on crizotinib.
Those randomized to the brigatinib arm had a median age of 58 years and received 180 mg daily with a 7-day lead-in at 90 mg. Those randomized to the crizotinib group had a median age of 60 years and received 250 mg twice daily. Prior chemotherapy for advanced disease was received by 26% and 27% and brain metastasis was present in 29% and 30% of patients in the arms, respectively.
The most common treatment-emergent adverse events of grade 3 or higher in the brigatinib patients were laboratory abnormalities such as creatinine phosphokinase, lipase, and amylase increases, and the most common in the crizotinib group were gastrointestinal effects, transaminitis, bradycardia, peripheral edema, and vision disturbances.
Discontinuations caused by adverse events occurred in 12% and 9% of the brigatinib and crizotinib patients, respectively, he said. No clinical cases of pancreatitis occurred in either arm, there was no difference in the incidence of any grade myalgia or musculoskeletal pain between arms, and there was no grade 3 or greater myalgia or musculoskeletal pain reported.
Early-onset interstitial lung disease, however, “appears to be a unique side effect of brigatinib,” Dr. Camidge noted.
Although interstitial lung disease/pneumonitis occurred in both groups, onset at days 3-8 after treatment initiation occurred only with brigatinib, he said, adding that “it only occurred in 3% of cases – half the rate seen in the postcrizotinib setting.”
The PROFILE 1014 study established crizotinib as the standard first-line therapy for advanced ALK-rearranged NSCLC, showing superior PFS versus pemetrexed doublet chemotherapy (HR, 0.45), but median PFS with crizotinib in that trial was only 10.9 months, Dr. Camidge said.
The next-generation ALK inhibitor brigatinib, however, has demonstrated broad preclinical activity against ALK resistance mutations, has excellent CNS penetration, and is the only ALK inhibitor with marked activity against multiple epidermal growth factor receptor–mutant cell lines, he said. “It has already shown significant activity both within the CNS and extracranially in the postcrizotinib setting, where it has consistently demonstrated the longest reported median PFS [up to 16.7 months] of any licensed or experimental ALK inhibitor.”
The ALTA-1L study provides a head-to-head comparison of brigatinib and crizotinib in a real-world setting, and the findings demonstrate that “brigatinib represents a promising new treatment for inhibitor-naive, ALK-rearranged NSCLC,” he said.
In a press statement, Dr. Camidge further stated that, based on these findings, brigatinib is set to become a first-line treatment option for ALK-positive lung cancer, adding that, “even with only 9-11 months of follow-up, the efficacy of brigatinib is clearly superior to crizotinib. A lot of the initial difference is driven by an effect on brain metastases, which tend to be an earlier progression event. However, once differences in control of disease outside the brain have time to manifest, it is possible the PFS improvement may increase.”
Both Dr. Camidge and invited discussant Fiona Blackhall, PhD, noted that the tolerability of brigatinib may be “even better in the real world,” as most of the 29% of patients on the brigatinib arm with adverse event–related dose reductions had “paper toxicities” for which the clinical impact is not well understood.
The rate of dose reductions for adverse events with brigatinib was higher in ALTA-1L than that seen in earlier studies of the second-generation ALK inhibitor alectinib, said Dr. Blackhall, professor and chair in thoracic oncology at the University of Manchester (England).
“We need to be sure that these dose reductions are appropriate and not potentially compromising efficacy,” she added.
Dr. Blackhall also suggested that sequential use of crizotinib and other ALK inhibitors like brigatinib should be evaluated and that the potential impact of ALK inhibitor selection “on the spectrum and type of resistance mutations and mechanisms” should be considered.
“Brigatinib is a new first-line treatment option for patients with ALK-positive non–small cell lung cancer. ... But in the absence of direct comparison of next-generation ALK inhibitors, it is going to take some time before we can determine whether there is indeed – if there ever will be – a ‘best’ ALK inhibitor for our patients,” she said.
Dr. Camidge has received honoraria from Arrys/Kyn, AstraZeneca, Biothera, Celgene, Clovis Oncology, Daiichi Sankyo, G1 Therapeutics, Genoptix, Hansoh, Ignyta, Lycera, Mersana Therapeutics, Novartis, Orion, Revolution Medicines, Roche/Genentech, and Takeda, and has received research funding from ARIADTakeda. Dr. Blackhall reported research funding from Amgen, AstraZeneca, Novartis, and Pfizer, and has served has an advisory board member, consultant, or speaker for AbbVie, Boehringer Ingelheim, Cell Medica, Medivation, Merck, Regeneron, Roche, and Takeda.
SOURCE: Camidge DR et al. WCLC 2018, Abstract PL02.03.
TORONTO – in the first interim results from the multicenter, open-label, phase 3 ALTA-1L trial.
In fact, the primary endpoint of the study – blinded independent review committee–assessed progression-free survival (PFS) – was met at this first analysis. The next-generation ALK inhibitor brigatinib reduced the chance of progression or death by 51% as compared with crizotinib – the current first-line standard of care in this population, D. Ross Camidge, MD, reported at the World Conference on Lung Cancer.
“At a median follow-up of 9-11 months, 26% [of 137 patients] on the brigatinib arm and 46% [of 138 patients] on the crizotinib arm had experienced a PFS event. Median PFS was not reached for the brigatinib arm and was 9.8 months for the crizotinib arm; the hazard ratio for progression or death was 0.49 and highly statistically significant,” said Dr. Camidge, director of thoracic oncology and the Joyce Zeff Chair in Lung Cancer Research at the University of Colorado Cancer Center, Aurora, at the meeting sponsored by the International Association for the Study of Lung Cancer.
The findings were published simultaneously in the New England Journal of Medicine.
The 12-month PFS rate estimate was 67% for brigatinib and 43% for crizotinib, and the investigator-assessed hazard ratio for PFS was 0.45. Overall survival data are immature, Dr. Camidge added, noting that the PFS hazard ratios for those with versus those without prior chemotherapy were 0.35 and 0.55, respectively.
“PFS consistently favored brigatinib across all other subgroups,” he said. “Although the confidence intervals overlap, the effect size appears greater among those with baseline [CNS] disease than among those without [HR, 0.2 vs. 0.72].”
Data suggest that CNS progression among those with CNS disease at baseline tends to be an earlier event than either extra-CNS progression in general or CNS progression in those without baseline CNS disease. “Consequently, this first interim analysis may be preferentially emphasizing drug efficacy differences within the subgroup in whom the earlier progression events are occurring,” Dr. Camidge said.
As for overall objective responses, the rates were numerically higher with brigatinib versus crizotinib (70% vs. 60%), but were not statistically different in the two groups. “However, the median duration of confirmed responses was not reached for brigatinib and [was] 11.1 months with crizotinib, with the 12-month [probability] of sustained response being 75% for brigatinib and 41% for crizotinib,” he added.
Further, among those with measurable CNS lesions, brigatinib demonstrated a significantly higher intracranial response rate of 78% versus 29% (odds ratio, 10.42), and when those with nonmeasurable CNS disease were included in the intracranial response assessment, the odds ratio was 13.
Median intracranial PFS among those with CNS involvement at baseline was not reached in the brigatinib arm versus 5.6 months with crizotinib, for a highly statistically significant hazard ratio of 0.27. “Which, given that the median PFS for crizotinib in the overall population ... was 9.8 months, again emphasizes how CNS events in this subgroup tend to occur early,” he noted.
Study subjects had stage IIIB/IV ALK-positive non–small cell lung cancer (NSCLC) based on local ALK testing, Eastern Cooperative Oncology Group performance status of 0-2, no more than one prior systemic therapy for locally advanced/metastatic NSCLC, and no prior ALK inhibitor therapy, Dr. Camidge said, noting that asymptomatic, untreated brain metastases were allowed and crossover to the brigatinib arm was permitted for those with blinded independent review committee–assessed progression on crizotinib.
Those randomized to the brigatinib arm had a median age of 58 years and received 180 mg daily with a 7-day lead-in at 90 mg. Those randomized to the crizotinib group had a median age of 60 years and received 250 mg twice daily. Prior chemotherapy for advanced disease was received by 26% and 27% and brain metastasis was present in 29% and 30% of patients in the arms, respectively.
The most common treatment-emergent adverse events of grade 3 or higher in the brigatinib patients were laboratory abnormalities such as creatinine phosphokinase, lipase, and amylase increases, and the most common in the crizotinib group were gastrointestinal effects, transaminitis, bradycardia, peripheral edema, and vision disturbances.
Discontinuations caused by adverse events occurred in 12% and 9% of the brigatinib and crizotinib patients, respectively, he said. No clinical cases of pancreatitis occurred in either arm, there was no difference in the incidence of any grade myalgia or musculoskeletal pain between arms, and there was no grade 3 or greater myalgia or musculoskeletal pain reported.
Early-onset interstitial lung disease, however, “appears to be a unique side effect of brigatinib,” Dr. Camidge noted.
Although interstitial lung disease/pneumonitis occurred in both groups, onset at days 3-8 after treatment initiation occurred only with brigatinib, he said, adding that “it only occurred in 3% of cases – half the rate seen in the postcrizotinib setting.”
The PROFILE 1014 study established crizotinib as the standard first-line therapy for advanced ALK-rearranged NSCLC, showing superior PFS versus pemetrexed doublet chemotherapy (HR, 0.45), but median PFS with crizotinib in that trial was only 10.9 months, Dr. Camidge said.
The next-generation ALK inhibitor brigatinib, however, has demonstrated broad preclinical activity against ALK resistance mutations, has excellent CNS penetration, and is the only ALK inhibitor with marked activity against multiple epidermal growth factor receptor–mutant cell lines, he said. “It has already shown significant activity both within the CNS and extracranially in the postcrizotinib setting, where it has consistently demonstrated the longest reported median PFS [up to 16.7 months] of any licensed or experimental ALK inhibitor.”
The ALTA-1L study provides a head-to-head comparison of brigatinib and crizotinib in a real-world setting, and the findings demonstrate that “brigatinib represents a promising new treatment for inhibitor-naive, ALK-rearranged NSCLC,” he said.
In a press statement, Dr. Camidge further stated that, based on these findings, brigatinib is set to become a first-line treatment option for ALK-positive lung cancer, adding that, “even with only 9-11 months of follow-up, the efficacy of brigatinib is clearly superior to crizotinib. A lot of the initial difference is driven by an effect on brain metastases, which tend to be an earlier progression event. However, once differences in control of disease outside the brain have time to manifest, it is possible the PFS improvement may increase.”
Both Dr. Camidge and invited discussant Fiona Blackhall, PhD, noted that the tolerability of brigatinib may be “even better in the real world,” as most of the 29% of patients on the brigatinib arm with adverse event–related dose reductions had “paper toxicities” for which the clinical impact is not well understood.
The rate of dose reductions for adverse events with brigatinib was higher in ALTA-1L than that seen in earlier studies of the second-generation ALK inhibitor alectinib, said Dr. Blackhall, professor and chair in thoracic oncology at the University of Manchester (England).
“We need to be sure that these dose reductions are appropriate and not potentially compromising efficacy,” she added.
Dr. Blackhall also suggested that sequential use of crizotinib and other ALK inhibitors like brigatinib should be evaluated and that the potential impact of ALK inhibitor selection “on the spectrum and type of resistance mutations and mechanisms” should be considered.
“Brigatinib is a new first-line treatment option for patients with ALK-positive non–small cell lung cancer. ... But in the absence of direct comparison of next-generation ALK inhibitors, it is going to take some time before we can determine whether there is indeed – if there ever will be – a ‘best’ ALK inhibitor for our patients,” she said.
Dr. Camidge has received honoraria from Arrys/Kyn, AstraZeneca, Biothera, Celgene, Clovis Oncology, Daiichi Sankyo, G1 Therapeutics, Genoptix, Hansoh, Ignyta, Lycera, Mersana Therapeutics, Novartis, Orion, Revolution Medicines, Roche/Genentech, and Takeda, and has received research funding from ARIADTakeda. Dr. Blackhall reported research funding from Amgen, AstraZeneca, Novartis, and Pfizer, and has served has an advisory board member, consultant, or speaker for AbbVie, Boehringer Ingelheim, Cell Medica, Medivation, Merck, Regeneron, Roche, and Takeda.
SOURCE: Camidge DR et al. WCLC 2018, Abstract PL02.03.
TORONTO – in the first interim results from the multicenter, open-label, phase 3 ALTA-1L trial.
In fact, the primary endpoint of the study – blinded independent review committee–assessed progression-free survival (PFS) – was met at this first analysis. The next-generation ALK inhibitor brigatinib reduced the chance of progression or death by 51% as compared with crizotinib – the current first-line standard of care in this population, D. Ross Camidge, MD, reported at the World Conference on Lung Cancer.
“At a median follow-up of 9-11 months, 26% [of 137 patients] on the brigatinib arm and 46% [of 138 patients] on the crizotinib arm had experienced a PFS event. Median PFS was not reached for the brigatinib arm and was 9.8 months for the crizotinib arm; the hazard ratio for progression or death was 0.49 and highly statistically significant,” said Dr. Camidge, director of thoracic oncology and the Joyce Zeff Chair in Lung Cancer Research at the University of Colorado Cancer Center, Aurora, at the meeting sponsored by the International Association for the Study of Lung Cancer.
The findings were published simultaneously in the New England Journal of Medicine.
The 12-month PFS rate estimate was 67% for brigatinib and 43% for crizotinib, and the investigator-assessed hazard ratio for PFS was 0.45. Overall survival data are immature, Dr. Camidge added, noting that the PFS hazard ratios for those with versus those without prior chemotherapy were 0.35 and 0.55, respectively.
“PFS consistently favored brigatinib across all other subgroups,” he said. “Although the confidence intervals overlap, the effect size appears greater among those with baseline [CNS] disease than among those without [HR, 0.2 vs. 0.72].”
Data suggest that CNS progression among those with CNS disease at baseline tends to be an earlier event than either extra-CNS progression in general or CNS progression in those without baseline CNS disease. “Consequently, this first interim analysis may be preferentially emphasizing drug efficacy differences within the subgroup in whom the earlier progression events are occurring,” Dr. Camidge said.
As for overall objective responses, the rates were numerically higher with brigatinib versus crizotinib (70% vs. 60%), but were not statistically different in the two groups. “However, the median duration of confirmed responses was not reached for brigatinib and [was] 11.1 months with crizotinib, with the 12-month [probability] of sustained response being 75% for brigatinib and 41% for crizotinib,” he added.
Further, among those with measurable CNS lesions, brigatinib demonstrated a significantly higher intracranial response rate of 78% versus 29% (odds ratio, 10.42), and when those with nonmeasurable CNS disease were included in the intracranial response assessment, the odds ratio was 13.
Median intracranial PFS among those with CNS involvement at baseline was not reached in the brigatinib arm versus 5.6 months with crizotinib, for a highly statistically significant hazard ratio of 0.27. “Which, given that the median PFS for crizotinib in the overall population ... was 9.8 months, again emphasizes how CNS events in this subgroup tend to occur early,” he noted.
Study subjects had stage IIIB/IV ALK-positive non–small cell lung cancer (NSCLC) based on local ALK testing, Eastern Cooperative Oncology Group performance status of 0-2, no more than one prior systemic therapy for locally advanced/metastatic NSCLC, and no prior ALK inhibitor therapy, Dr. Camidge said, noting that asymptomatic, untreated brain metastases were allowed and crossover to the brigatinib arm was permitted for those with blinded independent review committee–assessed progression on crizotinib.
Those randomized to the brigatinib arm had a median age of 58 years and received 180 mg daily with a 7-day lead-in at 90 mg. Those randomized to the crizotinib group had a median age of 60 years and received 250 mg twice daily. Prior chemotherapy for advanced disease was received by 26% and 27% and brain metastasis was present in 29% and 30% of patients in the arms, respectively.
The most common treatment-emergent adverse events of grade 3 or higher in the brigatinib patients were laboratory abnormalities such as creatinine phosphokinase, lipase, and amylase increases, and the most common in the crizotinib group were gastrointestinal effects, transaminitis, bradycardia, peripheral edema, and vision disturbances.
Discontinuations caused by adverse events occurred in 12% and 9% of the brigatinib and crizotinib patients, respectively, he said. No clinical cases of pancreatitis occurred in either arm, there was no difference in the incidence of any grade myalgia or musculoskeletal pain between arms, and there was no grade 3 or greater myalgia or musculoskeletal pain reported.
Early-onset interstitial lung disease, however, “appears to be a unique side effect of brigatinib,” Dr. Camidge noted.
Although interstitial lung disease/pneumonitis occurred in both groups, onset at days 3-8 after treatment initiation occurred only with brigatinib, he said, adding that “it only occurred in 3% of cases – half the rate seen in the postcrizotinib setting.”
The PROFILE 1014 study established crizotinib as the standard first-line therapy for advanced ALK-rearranged NSCLC, showing superior PFS versus pemetrexed doublet chemotherapy (HR, 0.45), but median PFS with crizotinib in that trial was only 10.9 months, Dr. Camidge said.
The next-generation ALK inhibitor brigatinib, however, has demonstrated broad preclinical activity against ALK resistance mutations, has excellent CNS penetration, and is the only ALK inhibitor with marked activity against multiple epidermal growth factor receptor–mutant cell lines, he said. “It has already shown significant activity both within the CNS and extracranially in the postcrizotinib setting, where it has consistently demonstrated the longest reported median PFS [up to 16.7 months] of any licensed or experimental ALK inhibitor.”
The ALTA-1L study provides a head-to-head comparison of brigatinib and crizotinib in a real-world setting, and the findings demonstrate that “brigatinib represents a promising new treatment for inhibitor-naive, ALK-rearranged NSCLC,” he said.
In a press statement, Dr. Camidge further stated that, based on these findings, brigatinib is set to become a first-line treatment option for ALK-positive lung cancer, adding that, “even with only 9-11 months of follow-up, the efficacy of brigatinib is clearly superior to crizotinib. A lot of the initial difference is driven by an effect on brain metastases, which tend to be an earlier progression event. However, once differences in control of disease outside the brain have time to manifest, it is possible the PFS improvement may increase.”
Both Dr. Camidge and invited discussant Fiona Blackhall, PhD, noted that the tolerability of brigatinib may be “even better in the real world,” as most of the 29% of patients on the brigatinib arm with adverse event–related dose reductions had “paper toxicities” for which the clinical impact is not well understood.
The rate of dose reductions for adverse events with brigatinib was higher in ALTA-1L than that seen in earlier studies of the second-generation ALK inhibitor alectinib, said Dr. Blackhall, professor and chair in thoracic oncology at the University of Manchester (England).
“We need to be sure that these dose reductions are appropriate and not potentially compromising efficacy,” she added.
Dr. Blackhall also suggested that sequential use of crizotinib and other ALK inhibitors like brigatinib should be evaluated and that the potential impact of ALK inhibitor selection “on the spectrum and type of resistance mutations and mechanisms” should be considered.
“Brigatinib is a new first-line treatment option for patients with ALK-positive non–small cell lung cancer. ... But in the absence of direct comparison of next-generation ALK inhibitors, it is going to take some time before we can determine whether there is indeed – if there ever will be – a ‘best’ ALK inhibitor for our patients,” she said.
Dr. Camidge has received honoraria from Arrys/Kyn, AstraZeneca, Biothera, Celgene, Clovis Oncology, Daiichi Sankyo, G1 Therapeutics, Genoptix, Hansoh, Ignyta, Lycera, Mersana Therapeutics, Novartis, Orion, Revolution Medicines, Roche/Genentech, and Takeda, and has received research funding from ARIADTakeda. Dr. Blackhall reported research funding from Amgen, AstraZeneca, Novartis, and Pfizer, and has served has an advisory board member, consultant, or speaker for AbbVie, Boehringer Ingelheim, Cell Medica, Medivation, Merck, Regeneron, Roche, and Takeda.
SOURCE: Camidge DR et al. WCLC 2018, Abstract PL02.03.
REPORTING FROM WCLC 2018
Key clinical point: Brigatinib improves progression-free survival versus crizotinib in anaplastic lymphoma kinase–positive non–small cell lung cancer.
Major finding: Brigatinib reduced the chance of progression or death by 51% versus crizotinib.
Study details: The multicenter, open-label, phase 3 ALTA-1L trial of 275 patients.
Disclosures: Dr. Camidge has received honoraria from Arrys/Kyn, AstraZeneca, Biothera, Celgene, Clovis Oncology, Daiichi Sankyo, G1 Therapeutics, Genoptix, Hansoh, Ignyta, Lycera, Mersana Therapeutics, Novartis, Orion, Revolution Medicines, Roche/Genentech, and Takeda, and has received research funding from ARIAD/Takeda. Dr. Blackhall reported research funding from Amgen, AstraZeneca, Novartis, and Pfizer, and has served has an advisory board member, consultant, or speaker for AbbVie, Boehringer Ingelheim, Cell Medica, Medivation, Merck, Regeneron, Roche, and Takeda.
Source: Camidge DR et al. WCLC 2018, Abstract PL02.03.