Treatment of Hemolytic Uremic Syndrome With Eculizumab
Treatment of Hemolytic Uremic Syndrome With Eculizumab
In 2009, Gruppo and Rother reported the first use of eculizumab in a patient with congenital aHUS. The patient, an 18-month-old boy, first developed symptoms within 8 hours of birth. He was treated during the initial presentation and three subsequent relapses with exchange transfusions, plasma infusions, and plasmapheresis. Eculizumab was initiated on day 35 of his fourth relapse, with a dose of 300 mg given intravenously weekly for 3 weeks followed by 600 mg every 2 weeks. Hematologic parameters and renal function began to improve within 2 days, and full remission was noted within 10 days. At the time of the case report, the patient had remained on therapy and in remission for 4 months.
Since that initial publication, several authors have provided additional cases supporting the utility of eculizumab in aHUS. In 2011, Lapeyraque and colleagues described the use of eculizumab in a 7-year-old girl with aHUS associated with two factor H mutations (S119L and V1197A). She was initially diagnosed at 7 months of age and managed with plasma exchange. Later recurrences were also treated with plasma infusions. Eculizumab was started in response to a severe exacerbation with hypertension and acute kidney failure. She was treated with 600 mg weekly for three doses and then 600 mg every 2 weeks. Plasma infusions were no longer needed after beginning eculizumab. Her hypertension resolved, platelet count normalized, and renal function returned to baseline within one week. At the time of the report, she had remained on therapy and in remission for 12 months.
Tschumi and colleagues published a similar case in a 9-year-old girl with aHUS associated with heterozygous factor H mutation. After starting eculizumab at a dose of 600 mg every 2 weeks, the patient no longer required plasma exchanges. A renal biopsy performed 2 months after starting therapy demonstrated no evidence of TMA. She had remained in remission for more than 24 months at the time of the report.
Eculizumab has also been used in the management of children with aHUS who have undergone renal transplantation. It has been estimated that aHUS progresses to end-stage renal failure in 50% of patients. In patients with factor H mutation, the risk of renal allograft rejection within 2 years is as high as 80%. In 2010, Davin and colleagues described the use of eculizumab in a 17-year-old girl who had undergone three kidney transplants. Ten months after transplantation she developed worsening renal function and severe allergic reactions to her routine plasma infusions. Eculizumab was started at a dose of 900 mg weekly for 4 weeks followed by 1,200 mg every 2 weeks. Six months later, the authors reported that her serum creatinine had stabilized at 1.36 mg/dL and her platelet count had normalized. An additional case has been published describing a 15-year-old boy with recurrent aHUS after three kidney transplantations who was successfully treated with eculizumab 2 months post-transplant with return of renal function 3 weeks after starting therapy.
Zimmerhackl and coworkers described prophylactic use of eculizumab in a 10-year-old boy after kidney transplantation. The patient had been diagnosed with aHUS at 4 years of age. Plasma exchange was done on a daily basis for the first 9 days post-transplant. On day 10, eculizumab was started at a dose of 600 mg every 2 weeks. One year later, the authors reported no evidence of active disease, no signs of graft rejection, and no need for plasma infusions. Weitz and colleagues gave prophylactic eculizumab to a 7-year-old boy with aHUS starting 3 weeks prior to transplantation. He received an initial dose of 600 mg, followed by 300 mg one week later. Maintenance therapy with 300 mg was started on week 3 and continued every 2 weeks. An additional 600 mg dose was given before and after surgery to minimize complement activation. In spite of difficulty in maintaining complete complement blockade, there had been no need for plasmapheresis and no evidence of TMA 7 months after transplantation.
In addition to these case reports, eculizumab has been studied in larger numbers of patients as part of the FDA approval process. Eculizumab was evaluated under the FDA's priority review and accelerated approval programs, an expedited process for drugs offering a major advancement in treatment. The manufacturer submitted the results of two prospective Phase II trials and a retrospective study. In the first study, 17 adolescents and adults with aHUS were enrolled if signs of TMA persisted after at least four episodes of plasmapheresis or plasma exchange. All patients received the standard adult dosing regimen (detailed in the Availability and Dosing Recommendations section) for at least 26 weeks.
Treatment with eculizumab reduced signs of complement-mediated TMA. Mean platelet count increased from 109 ± 32 x10/L at baseline to 169 ± 72 x10/L at the end of one week and 210 ± 68 x10/L at 26 weeks. Seventy-six percent of patients experienced normalization of hematologic indices, defined as maintenance of normal platelet counts and lactate dehydrogenase (LDH) levels for at least 4 weeks. The median duration of normalization was 37% (range 25% to 62%). Renal function also improved, with a median increase in glomerular filtration rate of 20 mL/min/1.73 m at 26 weeks (range -1 to 98 mL/min/1.73 m). Four of the five patients who required dialysis were able to discontinue it. Only one patient progressed to requiring dialysis while receiving eculizumab.
The second prospective study enrolled 20 patients (ages 13 to 63 years) who required plasmapheresis or exchange but did not have ongoing TMA symptoms. At 26 weeks, 90% of patients experienced normalization of hematologic indices. The median duration of normalization was 38% (range 22% to 52%). Renal function also improved, with a median increase in glomerular filtration rate of 5 mL/min/1.73 m (range -1 to 20 mL/min/1.73 m). No new patients required dialysis.
Results from the 19 children (ages 2 months to 17 years) in the retrospective study were similar to those in the prospective studies. Platelet count normalized in 89% of the children, with hematologic normalization occurring in 42%. Forty-seven percent experienced an improvement in estimated glomerular filtration rate > 15 mL/min/1.73 m. No new patients required dialysis while receiving eculizumab. The manufacturer continues to collect data on patients treated with eculizumab to confirm the results of these three studies.
In the June 30, 2011 issue of The New England Journal of Medicine, Lapeyraque and colleagues described the use of eculizumab in three 3-year-old patients with STEC-HUS. The first two patients had undergone plasma exchange but progressed to central nervous system involvement and acute kidney failure requiring hemodialysis. The third patient presented with a similar course. Eculizumab was given at weekly intervals (three doses for patients 1 and 3; four doses for patient 2). All experienced improvement within 24 hours, with normalization of platelet counts and LDH values within 5 days. Dialysis was discontinued between 3 and 16 days after beginning treatment, with a full return of renal function. The authors hypothesize that the shiga toxin may have a direct activating effect on complement which is blocked by eculizumab.
At the time of publication of this case report, an outbreak of STEC-HUS was occurring in Germany that eventually affected nearly 900 children and adults. Physicians involved in caring for patients during the outbreak contacted Alexion Pharmaceuticals, the manufacturer of eculizumab. Working in conjunction with the German government, Alexion made the drug available on a compassionate-use basis. Many of the adult patients were treated, but because of the relative lack of experience with the drug in children, it was reserved for the most serious cases. No specific information has been made available about the efficacy of the drug in these patients, but only one child died during the outbreak. The manufacturer also has an ongoing open-label clinical trial to study the effects of eculizumab in patients with STEC-HUS who are 2 months of age or older.
Clinical Studies
Eculizumab Use in aHUS
In 2009, Gruppo and Rother reported the first use of eculizumab in a patient with congenital aHUS. The patient, an 18-month-old boy, first developed symptoms within 8 hours of birth. He was treated during the initial presentation and three subsequent relapses with exchange transfusions, plasma infusions, and plasmapheresis. Eculizumab was initiated on day 35 of his fourth relapse, with a dose of 300 mg given intravenously weekly for 3 weeks followed by 600 mg every 2 weeks. Hematologic parameters and renal function began to improve within 2 days, and full remission was noted within 10 days. At the time of the case report, the patient had remained on therapy and in remission for 4 months.
Since that initial publication, several authors have provided additional cases supporting the utility of eculizumab in aHUS. In 2011, Lapeyraque and colleagues described the use of eculizumab in a 7-year-old girl with aHUS associated with two factor H mutations (S119L and V1197A). She was initially diagnosed at 7 months of age and managed with plasma exchange. Later recurrences were also treated with plasma infusions. Eculizumab was started in response to a severe exacerbation with hypertension and acute kidney failure. She was treated with 600 mg weekly for three doses and then 600 mg every 2 weeks. Plasma infusions were no longer needed after beginning eculizumab. Her hypertension resolved, platelet count normalized, and renal function returned to baseline within one week. At the time of the report, she had remained on therapy and in remission for 12 months.
Tschumi and colleagues published a similar case in a 9-year-old girl with aHUS associated with heterozygous factor H mutation. After starting eculizumab at a dose of 600 mg every 2 weeks, the patient no longer required plasma exchanges. A renal biopsy performed 2 months after starting therapy demonstrated no evidence of TMA. She had remained in remission for more than 24 months at the time of the report.
Eculizumab has also been used in the management of children with aHUS who have undergone renal transplantation. It has been estimated that aHUS progresses to end-stage renal failure in 50% of patients. In patients with factor H mutation, the risk of renal allograft rejection within 2 years is as high as 80%. In 2010, Davin and colleagues described the use of eculizumab in a 17-year-old girl who had undergone three kidney transplants. Ten months after transplantation she developed worsening renal function and severe allergic reactions to her routine plasma infusions. Eculizumab was started at a dose of 900 mg weekly for 4 weeks followed by 1,200 mg every 2 weeks. Six months later, the authors reported that her serum creatinine had stabilized at 1.36 mg/dL and her platelet count had normalized. An additional case has been published describing a 15-year-old boy with recurrent aHUS after three kidney transplantations who was successfully treated with eculizumab 2 months post-transplant with return of renal function 3 weeks after starting therapy.
Zimmerhackl and coworkers described prophylactic use of eculizumab in a 10-year-old boy after kidney transplantation. The patient had been diagnosed with aHUS at 4 years of age. Plasma exchange was done on a daily basis for the first 9 days post-transplant. On day 10, eculizumab was started at a dose of 600 mg every 2 weeks. One year later, the authors reported no evidence of active disease, no signs of graft rejection, and no need for plasma infusions. Weitz and colleagues gave prophylactic eculizumab to a 7-year-old boy with aHUS starting 3 weeks prior to transplantation. He received an initial dose of 600 mg, followed by 300 mg one week later. Maintenance therapy with 300 mg was started on week 3 and continued every 2 weeks. An additional 600 mg dose was given before and after surgery to minimize complement activation. In spite of difficulty in maintaining complete complement blockade, there had been no need for plasmapheresis and no evidence of TMA 7 months after transplantation.
In addition to these case reports, eculizumab has been studied in larger numbers of patients as part of the FDA approval process. Eculizumab was evaluated under the FDA's priority review and accelerated approval programs, an expedited process for drugs offering a major advancement in treatment. The manufacturer submitted the results of two prospective Phase II trials and a retrospective study. In the first study, 17 adolescents and adults with aHUS were enrolled if signs of TMA persisted after at least four episodes of plasmapheresis or plasma exchange. All patients received the standard adult dosing regimen (detailed in the Availability and Dosing Recommendations section) for at least 26 weeks.
Treatment with eculizumab reduced signs of complement-mediated TMA. Mean platelet count increased from 109 ± 32 x10/L at baseline to 169 ± 72 x10/L at the end of one week and 210 ± 68 x10/L at 26 weeks. Seventy-six percent of patients experienced normalization of hematologic indices, defined as maintenance of normal platelet counts and lactate dehydrogenase (LDH) levels for at least 4 weeks. The median duration of normalization was 37% (range 25% to 62%). Renal function also improved, with a median increase in glomerular filtration rate of 20 mL/min/1.73 m at 26 weeks (range -1 to 98 mL/min/1.73 m). Four of the five patients who required dialysis were able to discontinue it. Only one patient progressed to requiring dialysis while receiving eculizumab.
The second prospective study enrolled 20 patients (ages 13 to 63 years) who required plasmapheresis or exchange but did not have ongoing TMA symptoms. At 26 weeks, 90% of patients experienced normalization of hematologic indices. The median duration of normalization was 38% (range 22% to 52%). Renal function also improved, with a median increase in glomerular filtration rate of 5 mL/min/1.73 m (range -1 to 20 mL/min/1.73 m). No new patients required dialysis.
Results from the 19 children (ages 2 months to 17 years) in the retrospective study were similar to those in the prospective studies. Platelet count normalized in 89% of the children, with hematologic normalization occurring in 42%. Forty-seven percent experienced an improvement in estimated glomerular filtration rate > 15 mL/min/1.73 m. No new patients required dialysis while receiving eculizumab. The manufacturer continues to collect data on patients treated with eculizumab to confirm the results of these three studies.
Eculizumab Use in STEC-HUS
In the June 30, 2011 issue of The New England Journal of Medicine, Lapeyraque and colleagues described the use of eculizumab in three 3-year-old patients with STEC-HUS. The first two patients had undergone plasma exchange but progressed to central nervous system involvement and acute kidney failure requiring hemodialysis. The third patient presented with a similar course. Eculizumab was given at weekly intervals (three doses for patients 1 and 3; four doses for patient 2). All experienced improvement within 24 hours, with normalization of platelet counts and LDH values within 5 days. Dialysis was discontinued between 3 and 16 days after beginning treatment, with a full return of renal function. The authors hypothesize that the shiga toxin may have a direct activating effect on complement which is blocked by eculizumab.
At the time of publication of this case report, an outbreak of STEC-HUS was occurring in Germany that eventually affected nearly 900 children and adults. Physicians involved in caring for patients during the outbreak contacted Alexion Pharmaceuticals, the manufacturer of eculizumab. Working in conjunction with the German government, Alexion made the drug available on a compassionate-use basis. Many of the adult patients were treated, but because of the relative lack of experience with the drug in children, it was reserved for the most serious cases. No specific information has been made available about the efficacy of the drug in these patients, but only one child died during the outbreak. The manufacturer also has an ongoing open-label clinical trial to study the effects of eculizumab in patients with STEC-HUS who are 2 months of age or older.
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