The use of eculizumab in gemcitabine induced thrombotic microangiopathy

Abstract

BackgroundThrombotic microangiopathy (TMA) secondary to gemcitabine therapy (GiTMA) is a very rare pathology that carries a poor prognosis, with nearly half of the cases progressing to end stage renal disease. GiTMA is most commonly associated with adenocarcinomas, most notably pancreatic cancers. The mainstay of management is withdrawal of the offending drug and supportive care. Plasmapheresis has a limited role and hemodialysis may help in the management of fluid overload secondary to renal failure. Furthermore, a C5 inhibitor, eculizumab, has been successfully used in the treatment of GiTMA.Case presentationA 64-year-old Caucasian female with history of pancreatic adenocarcinoma on gemcitabine chemotherapy presented with signs and symptoms of fluid overload and was found to have abnormal kidney function. Her BP was 195/110 mmHg, serum creatinine 4.48 mg/dl, hemoglobin 8.2 g/dl, platelets 53 × 103/cmm, lactate dehydrogenase 540 IU/L, and was found to have schistocytes on blood film. A diagnosis of TMA secondary to gemcitabine therapy was suspected. Hemodialysis for volume overload and daily plasmapheresis were initiated. After six days of plasmapheresis, renal function did not improve. Further work up revealed ADAMTS 13 activity >15%, low C3, and stool culture and Shiga-toxin PCR were negative. Renal biopsy was consistent with TMA. Gemcitabine was discontinued, but renal function failed to improve and eculizumab therapy was considered due to suspicion of aHUS. Serum creatinine >2.26 mg/dl and a platelet count of >/= 30 × 109/L is highly suggestive of aHUS, while TTP is more likely when creatinine is <2.26 mg/dl and platelet count of <30 × 109/L. She received intravenous eculizumab for eight months, which resulted in significant improvement of renal function. Other markers of hemolysis, namely LDH and bilirubin, also rapidly improved following eculizumab therapy. Plasmapheresis and hemodialysis were discontinued after two and eight weeks of initiation respectively.ConclusionChemotherapy induced TMA is very rare and requires a high index of clinical suspicion for timely diagnosis. Discontinuation of the offending drug and supportive care is the main stay of treatment; however, eculizumab has been shown to be beneficial in GiTMA. Further research is required to validate this approach.

Atypical Hemolytic‐Uremic Syndrome: An Update on Pathophysiology, Diagnosis, and Treatment

“…Activity level < 50% indicates abnormal ADAMTS13 activity, 10–50% indicates low activity; severe deficiency (<5–10% activity) is highly indicative of TTP . Secondary HUS may be considered in presence of autoimmune diseases, malignancies, hemopoietic stem cell or solid organ transplantation, malignant hypertension or use of drugs such as calcineurin inhibitors (cyclosporine, tacrolimus), gemcitabine, mitomycin, interferon, quinine, and cocaine . The treatment of secondary HUS is withdrawal of offending drug or treating triggering condition .…”

“…Secondary HUS may be considered in presence of autoimmune diseases, malignancies, hemopoietic stem cell or solid organ transplantation, malignant hypertension or use of drugs such as calcineurin inhibitors (cyclosporine, tacrolimus), gemcitabine, mitomycin, interferon, quinine, and cocaine . The treatment of secondary HUS is withdrawal of offending drug or treating triggering condition . Regardless of evidence, empirical plasma therapy and in resistant cases, complement blockade drugs have also been used successfully prompting immediate necessity of large‐scale studies to investigate genetic mutations and dysregulation of alternative complement pathway .…”

“…The treatment of secondary HUS is withdrawal of offending drug or treating triggering condition . Regardless of evidence, empirical plasma therapy and in resistant cases, complement blockade drugs have also been used successfully prompting immediate necessity of large‐scale studies to investigate genetic mutations and dysregulation of alternative complement pathway .…”

“…In patients with CFH, CFI, C3, or CFB mutations, eculizumab is the preferred intervention for therapy of current illness as well prevention of recurrences . It is also efficacious in patients with post‐transplant disease recurrence, transplantation‐associated aHUS , pregnancy‐associated aHUS , and HUS secondary to chemotherapy . By preventing MAC formation, eculizumab inhibits the mechanism by which aHUS causes pathology, making this novel drug the treatment of choice for aHUS patients.…”

Thrombotic microangiopathy and liver toxicity due to a combination therapy of leflunomide and methotrexate: a case report

“…Rheumatologists and nephrologists should consider the possibility of this rare side effect. In addition, if a DITMA under leflunomide or methotrexate occurs, the use of therapeutic anti-complement strategies should be considered [9].…”