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according to three new case reports and series in Neurology.
The complications include acute coronary syndrome in one patient, hemophagocytic lymphohistiocytosis (HLH) in two patients, and acute acalculous cholecystitis in eight patients.
Postmarketing surveillance aims to identify rare and late adverse events that may not be discovered during clinical trials.
The cardiac arrest incident occurred in a 24-year old woman with spinal-onset relapsing-remitting multiple sclerosis (RRMS) during alemtuzumab infusion. She had experienced two clinical relapses and a significant increase in cerebral and spinal MRI lesion load, despite previous treatment with natalizumab (Tysabri). The only striking thing about her medical history was allergic asthma.
On the third day of treatment, she developed severe asymptomatic sinus bradycardia (HR, 38 beats per minute), which resolved with treatment, and clinicians continued the regimen. The following morning, she experienced acute coronary syndrome, which later resolved.
The authors recommend that clinicians treating RRMS patients with alemtuzumab consider a baseline preinfusion ECG and monitoring heart rate at least hourly while infusion is being carried out.
The HLH cases occurred in a man and a woman with RRMS, both in their 20s. The woman was switched from natalizumab to alemtuzumab because of a high anti-JC virus antibody index. Both cases presented in the time frame typical of secondary autoimmunity. The female patient had an acalculous gallbladder with thickened walls and pericholecystic fluid and responded to intravenous antibiotics, but 3 weeks later she developed thrombocytopenia, coagulopathy, and anemia with abnormal liver enzymes. Treatment failed and she succumbed to the condition.
The man received alemtuzumab as first-line therapy for RRMS during the Keratinocyte Growth Factor to Prevent Autoimmunity After Alemtuzumab Treatment of Multiple Sclerosis (CAM-THY) clinical trial. He received boluses of either placebo or palifermin (Kepivance) before and after each alemtuzumab dose in order to reduce secondary autoimmunity. At 30 months after his initial cycle of alemtuzumab, he was admitted to the hospital with HLH and also developed acquired factor VIII hemophilia. He responded positively to 4 months of corticosteroid treatment combined with two doses of rituximab (Rituxan) and ultimately returned to work. However, he experienced a relapse of acquired hemophilia during later doses of corticosteroids and rituximab.
A search of the Food and Drug Administration Adverse Event Reporting System (FAERS) revealed eight cases of acute acalculous cholecystitis (AAC) – four assessed as possibly caused by alemtuzumab, and four assessed as probable – that occurred in patients with RRMS. Seven of the cases involved presentation during treatment or soon afterward, which suggests that acute cytokine release syndrome (ACRS) may be the cause. The cases did not share all of the manifestations of typical ACRS, but the researchers noted that coadministration of methylprednisolone in the RRMS dosing schedule may have masked some of the features.
Unlike typical AAC, these cases occurred primarily in females (six of eight) and were not associated with concurrent critical illnesses. Other risk factors were not consistently present. Historically, AAC is associated with treatment of older male patients in the ICU. Three of the patients underwent surgical treatment, and five received conservative treatment of antibiotics or an unspecified treatment. Seven patients recovered. The outcome in the eighth patient was not reported.
Despite these good outcomes, the authors of the report note that longer-term outcomes in this AAC population are not yet understood.
The findings led to the addition of AAC to the Warnings and Precautions section of the alemtuzumab label in October 2017.
None of the reports received funding. Some of the authors had financial ties to the pharmaceutical industry.
SOURCES: Croteau D et al. Neurology. 2018 Mar 30. doi: 10.1212/WNL.0000000000005422. Saarela M et al. Neurology. 2018 Mar 30. doi: 10.1212/WNL.0000000000005420. Ferraro D et al. Neurology. 2018 Mar 30. doi: 10.1212/WNL.0000000000005417.
Clinical trials find most adverse events for a new drug, but postmarketing surveillance is essential to find rare events, even though they may underestimate the frequency of these events because of underreporting.
Other reports suggest the emergence of uncommon infectious complications associated with alemtuzumab, especially Listeria meningitis. Listeria infection can occur within days of alemtuzumab treatment, and the use of preventive sulfamethoxazole-trimethoprim treatment is now advocated in the United Kingdom.
Overall, these adverse events remind clinicians that they must balance the benefits of alemtuzumab, which is highly effective, against its potential risks.
Paolo A. Muraro, MD, PhD is a professor of neurology, neuroimmunology, and immunotherapy at Imperial College London. Neil J. Scolding MD, PhD, is director of the Bristol Institute of Clinical Neurosciences at the University of Bristol (England). Robert J. Fox, MD, is a neurologist at the Mellen Center for Multiple Sclerosis at the Cleveland Clinic in Ohio. All of the authors reported financial relationships with companies marketing MS drugs. Their comments are derived from an editorial accompanying the adverse event reports (Neurology. 2018 Mar 30. doi: 10.1212/WNL.0000000000005409).
Clinical trials find most adverse events for a new drug, but postmarketing surveillance is essential to find rare events, even though they may underestimate the frequency of these events because of underreporting.
Other reports suggest the emergence of uncommon infectious complications associated with alemtuzumab, especially Listeria meningitis. Listeria infection can occur within days of alemtuzumab treatment, and the use of preventive sulfamethoxazole-trimethoprim treatment is now advocated in the United Kingdom.
Overall, these adverse events remind clinicians that they must balance the benefits of alemtuzumab, which is highly effective, against its potential risks.
Paolo A. Muraro, MD, PhD is a professor of neurology, neuroimmunology, and immunotherapy at Imperial College London. Neil J. Scolding MD, PhD, is director of the Bristol Institute of Clinical Neurosciences at the University of Bristol (England). Robert J. Fox, MD, is a neurologist at the Mellen Center for Multiple Sclerosis at the Cleveland Clinic in Ohio. All of the authors reported financial relationships with companies marketing MS drugs. Their comments are derived from an editorial accompanying the adverse event reports (Neurology. 2018 Mar 30. doi: 10.1212/WNL.0000000000005409).
Clinical trials find most adverse events for a new drug, but postmarketing surveillance is essential to find rare events, even though they may underestimate the frequency of these events because of underreporting.
Other reports suggest the emergence of uncommon infectious complications associated with alemtuzumab, especially Listeria meningitis. Listeria infection can occur within days of alemtuzumab treatment, and the use of preventive sulfamethoxazole-trimethoprim treatment is now advocated in the United Kingdom.
Overall, these adverse events remind clinicians that they must balance the benefits of alemtuzumab, which is highly effective, against its potential risks.
Paolo A. Muraro, MD, PhD is a professor of neurology, neuroimmunology, and immunotherapy at Imperial College London. Neil J. Scolding MD, PhD, is director of the Bristol Institute of Clinical Neurosciences at the University of Bristol (England). Robert J. Fox, MD, is a neurologist at the Mellen Center for Multiple Sclerosis at the Cleveland Clinic in Ohio. All of the authors reported financial relationships with companies marketing MS drugs. Their comments are derived from an editorial accompanying the adverse event reports (Neurology. 2018 Mar 30. doi: 10.1212/WNL.0000000000005409).
according to three new case reports and series in Neurology.
The complications include acute coronary syndrome in one patient, hemophagocytic lymphohistiocytosis (HLH) in two patients, and acute acalculous cholecystitis in eight patients.
Postmarketing surveillance aims to identify rare and late adverse events that may not be discovered during clinical trials.
The cardiac arrest incident occurred in a 24-year old woman with spinal-onset relapsing-remitting multiple sclerosis (RRMS) during alemtuzumab infusion. She had experienced two clinical relapses and a significant increase in cerebral and spinal MRI lesion load, despite previous treatment with natalizumab (Tysabri). The only striking thing about her medical history was allergic asthma.
On the third day of treatment, she developed severe asymptomatic sinus bradycardia (HR, 38 beats per minute), which resolved with treatment, and clinicians continued the regimen. The following morning, she experienced acute coronary syndrome, which later resolved.
The authors recommend that clinicians treating RRMS patients with alemtuzumab consider a baseline preinfusion ECG and monitoring heart rate at least hourly while infusion is being carried out.
The HLH cases occurred in a man and a woman with RRMS, both in their 20s. The woman was switched from natalizumab to alemtuzumab because of a high anti-JC virus antibody index. Both cases presented in the time frame typical of secondary autoimmunity. The female patient had an acalculous gallbladder with thickened walls and pericholecystic fluid and responded to intravenous antibiotics, but 3 weeks later she developed thrombocytopenia, coagulopathy, and anemia with abnormal liver enzymes. Treatment failed and she succumbed to the condition.
The man received alemtuzumab as first-line therapy for RRMS during the Keratinocyte Growth Factor to Prevent Autoimmunity After Alemtuzumab Treatment of Multiple Sclerosis (CAM-THY) clinical trial. He received boluses of either placebo or palifermin (Kepivance) before and after each alemtuzumab dose in order to reduce secondary autoimmunity. At 30 months after his initial cycle of alemtuzumab, he was admitted to the hospital with HLH and also developed acquired factor VIII hemophilia. He responded positively to 4 months of corticosteroid treatment combined with two doses of rituximab (Rituxan) and ultimately returned to work. However, he experienced a relapse of acquired hemophilia during later doses of corticosteroids and rituximab.
A search of the Food and Drug Administration Adverse Event Reporting System (FAERS) revealed eight cases of acute acalculous cholecystitis (AAC) – four assessed as possibly caused by alemtuzumab, and four assessed as probable – that occurred in patients with RRMS. Seven of the cases involved presentation during treatment or soon afterward, which suggests that acute cytokine release syndrome (ACRS) may be the cause. The cases did not share all of the manifestations of typical ACRS, but the researchers noted that coadministration of methylprednisolone in the RRMS dosing schedule may have masked some of the features.
Unlike typical AAC, these cases occurred primarily in females (six of eight) and were not associated with concurrent critical illnesses. Other risk factors were not consistently present. Historically, AAC is associated with treatment of older male patients in the ICU. Three of the patients underwent surgical treatment, and five received conservative treatment of antibiotics or an unspecified treatment. Seven patients recovered. The outcome in the eighth patient was not reported.
Despite these good outcomes, the authors of the report note that longer-term outcomes in this AAC population are not yet understood.
The findings led to the addition of AAC to the Warnings and Precautions section of the alemtuzumab label in October 2017.
None of the reports received funding. Some of the authors had financial ties to the pharmaceutical industry.
SOURCES: Croteau D et al. Neurology. 2018 Mar 30. doi: 10.1212/WNL.0000000000005422. Saarela M et al. Neurology. 2018 Mar 30. doi: 10.1212/WNL.0000000000005420. Ferraro D et al. Neurology. 2018 Mar 30. doi: 10.1212/WNL.0000000000005417.
according to three new case reports and series in Neurology.
The complications include acute coronary syndrome in one patient, hemophagocytic lymphohistiocytosis (HLH) in two patients, and acute acalculous cholecystitis in eight patients.
Postmarketing surveillance aims to identify rare and late adverse events that may not be discovered during clinical trials.
The cardiac arrest incident occurred in a 24-year old woman with spinal-onset relapsing-remitting multiple sclerosis (RRMS) during alemtuzumab infusion. She had experienced two clinical relapses and a significant increase in cerebral and spinal MRI lesion load, despite previous treatment with natalizumab (Tysabri). The only striking thing about her medical history was allergic asthma.
On the third day of treatment, she developed severe asymptomatic sinus bradycardia (HR, 38 beats per minute), which resolved with treatment, and clinicians continued the regimen. The following morning, she experienced acute coronary syndrome, which later resolved.
The authors recommend that clinicians treating RRMS patients with alemtuzumab consider a baseline preinfusion ECG and monitoring heart rate at least hourly while infusion is being carried out.
The HLH cases occurred in a man and a woman with RRMS, both in their 20s. The woman was switched from natalizumab to alemtuzumab because of a high anti-JC virus antibody index. Both cases presented in the time frame typical of secondary autoimmunity. The female patient had an acalculous gallbladder with thickened walls and pericholecystic fluid and responded to intravenous antibiotics, but 3 weeks later she developed thrombocytopenia, coagulopathy, and anemia with abnormal liver enzymes. Treatment failed and she succumbed to the condition.
The man received alemtuzumab as first-line therapy for RRMS during the Keratinocyte Growth Factor to Prevent Autoimmunity After Alemtuzumab Treatment of Multiple Sclerosis (CAM-THY) clinical trial. He received boluses of either placebo or palifermin (Kepivance) before and after each alemtuzumab dose in order to reduce secondary autoimmunity. At 30 months after his initial cycle of alemtuzumab, he was admitted to the hospital with HLH and also developed acquired factor VIII hemophilia. He responded positively to 4 months of corticosteroid treatment combined with two doses of rituximab (Rituxan) and ultimately returned to work. However, he experienced a relapse of acquired hemophilia during later doses of corticosteroids and rituximab.
A search of the Food and Drug Administration Adverse Event Reporting System (FAERS) revealed eight cases of acute acalculous cholecystitis (AAC) – four assessed as possibly caused by alemtuzumab, and four assessed as probable – that occurred in patients with RRMS. Seven of the cases involved presentation during treatment or soon afterward, which suggests that acute cytokine release syndrome (ACRS) may be the cause. The cases did not share all of the manifestations of typical ACRS, but the researchers noted that coadministration of methylprednisolone in the RRMS dosing schedule may have masked some of the features.
Unlike typical AAC, these cases occurred primarily in females (six of eight) and were not associated with concurrent critical illnesses. Other risk factors were not consistently present. Historically, AAC is associated with treatment of older male patients in the ICU. Three of the patients underwent surgical treatment, and five received conservative treatment of antibiotics or an unspecified treatment. Seven patients recovered. The outcome in the eighth patient was not reported.
Despite these good outcomes, the authors of the report note that longer-term outcomes in this AAC population are not yet understood.
The findings led to the addition of AAC to the Warnings and Precautions section of the alemtuzumab label in October 2017.
None of the reports received funding. Some of the authors had financial ties to the pharmaceutical industry.
SOURCES: Croteau D et al. Neurology. 2018 Mar 30. doi: 10.1212/WNL.0000000000005422. Saarela M et al. Neurology. 2018 Mar 30. doi: 10.1212/WNL.0000000000005420. Ferraro D et al. Neurology. 2018 Mar 30. doi: 10.1212/WNL.0000000000005417.
FROM NEUROLOGY
Key clinical point: Rare events associated with alemtuzumab are emerging that were not uncovered during clinical trials.
Major finding: Eight cases of acute acalculous cholecystitis formed the basis for its addition to the Warnings and Precautions section of the alemtuzumab label in October 2017.
Study details: Case reports of acute coronary syndrome in one patient, hemophagocytic lymphohistiocytosis in two patients, and acute acalculous cholecystitis in eight patients.
Disclosures: None of the reports received funding. Some of the authors had financial ties to the pharmaceutical industry.
Sources: Croteau D et al. Neurology. 2018 Mar 30. doi: 10.1212/WNL.0000000000005422; Saarela M et al. Neurology. 2018 Mar 30. doi: 10.1212/WNL.0000000000005420; Ferraro D et al. Neurology. 2018 Mar 30. doi: 10.1212/WNL.0000000000005417.