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      A Case of Gemcitabine-Induced Thrombotic Microangiopathy Treated With Ravulizumab in a Patient With Stage IV Pancreatic Cancer

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          Abstract

          A 47-year-old male with stage IV pancreatic cancer developed gemcitabine-induced thrombotic microangiopathy (GiTMA) after treatment with gemcitabine and nab-paclitaxel. GiTMA is a rare and life-threatening complication with an incidence ranging from 0.015% to 1.4% and reported mortality rate ranging from 50% to 90%. Clinically, GiTMA manifests as microangiopathic hemolytic anemia, thrombocytopenia, and renal failure. Early identification of GiTMA is essential to initiate early treatment and improve survival. Treatment of GiTMA includes discontinuation of gemcitabine, along with initiation of steroids, therapeutic plasma exchange (TPE), rituximab, and eculizumab. To our knowledge, this is the first case of GiTMA treated with ravulizumab, a long-acting complement inhibitor. Given the increasing number of patients treated with gemcitabine and seriousness of this complication, it is important for physicians to be aware of this disease entity and maintain a high index of suspicion when evaluating patients with microangiopathic hemolytic anemia, thrombocytopenia, and renal failure.

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          Most cited references 20

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          Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome.

          Atypical hemolytic-uremic syndrome is a genetic, life-threatening, chronic disease of complement-mediated thrombotic microangiopathy. Plasma exchange or infusion may transiently maintain normal levels of hematologic measures but does not treat the underlying systemic disease. We conducted two prospective phase 2 trials in which patients with atypical hemolytic-uremic syndrome who were 12 years of age or older received eculizumab for 26 weeks and during long-term extension phases. Patients with low platelet counts and renal damage (in trial 1) and those with renal damage but no decrease in the platelet count of more than 25% for at least 8 weeks during plasma exchange or infusion (in trial 2) were recruited. The primary end points included a change in the platelet count (in trial 1) and thrombotic microangiopathy event-free status (no decrease in the platelet count of >25%, no plasma exchange or infusion, and no initiation of dialysis) (in trial 2). A total of 37 patients (17 in trial 1 and 20 in trial 2) received eculizumab for a median of 64 and 62 weeks, respectively. Eculizumab resulted in increases in the platelet count; in trial 1, the mean increase in the count from baseline to week 26 was 73×10(9) per liter (P<0.001). In trial 2, 80% of the patients had thrombotic microangiopathy event-free status. Eculizumab was associated with significant improvement in all secondary end points, with continuous, time-dependent increases in the estimated glomerular filtration rate (GFR). In trial 1, dialysis was discontinued in 4 of 5 patients. Earlier intervention with eculizumab was associated with significantly greater improvement in the estimated GFR. Eculizumab was also associated with improvement in health-related quality of life. No cumulative toxicity of therapy or serious infection-related adverse events, including meningococcal infections, were observed through the extension period. Eculizumab inhibited complement-mediated thrombotic microangiopathy and was associated with significant time-dependent improvement in renal function in patients with atypical hemolytic-uremic syndrome. (Funded by Alexion Pharmaceuticals; C08-002 ClinicalTrials.gov numbers, NCT00844545 [adults] and NCT00844844 [adolescents]; C08-003 ClinicalTrials.gov numbers, NCT00838513 [adults] and NCT00844428 [adolescents]).
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            Gemcitabine nephrotoxicity and hemolytic uremic syndrome: report of 29 cases from a single institution.

            Gemcitabine is used in a variety of advanced malignancies. Hemolytic uremic syndrome has been reported as a side effect. we reviewed medical records of 29 patients with gemcitabine nephrotoxicity. The median cumulative dose of gemcitabine was 22 g/m2 (4 - 81) given over 7.5 months (2 - 34). Prior chemotherapy with mitomycin had been given to 9 patients, and in 4 the hemolytic uremic syndrome was particularly severe and appeared shortly after gemcitabine initiation. All patients had renal insufficiency. Microhematuria and proteinuria were present in 27 patients and red blood cell casts were seen in 8. Renal biopsies in 4 patients showed thrombotic microangiopathy. Worsening or new-onset hypertension was seen in 26 patients. Edema, shortness of breath and congestive heart failure were present in 21, 15 and 7 patients, respectively. All had anemia, thrombocytopenia and elevated serum lactate dehydrogenase. Haptoglobin was low in 23 of the 26 patients who had it measured. Schistocytes were present in 21 of the 24 patients who had blood smear reviewed. Gemcitabine was discontinued once hemolytic uremic syndrome was recognized. Full or partial recovery of renal function occurred in 19 patients. 7 patients progressed to end-stage renal disease and 3 patients developed chronic renal failure. Gemcitabine nephrotoxicity presents as new-onset renal disease with associated hypertension, thrombocytopenia and microangiopathic hemolytic anemia. Prior chemotherapy with mitomycin, especially when given in close proximity, may be synergistic. A high index of suspicion is essential to make an early diagnosis. Stopping gemcitabine improves the outcome.
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              A review of hemolytic uremic syndrome in patients treated with gemcitabine therapy.

              Hemolytic uremic syndrome (HUS) is a rare condition that occasionally is reported in cancer patients. Recently it has been observed that gemcitabine rarely may be associated with this condition. The manufacturer's safety database and literature were reviewed for any report regarding gemcitabine associated with renal and hematologic abnormalities. Descriptive analysis was used to examine each case for an association between gemcitabine therapy and HUS and to identify its incidence and risk factors. Through December 31, 1997, 12 cases were identified that fit either the clinical (uremia, microangiopathic hemolytic anemia, and thrombocytopenia) or pathologic (renal biopsy) criteria for HUS. There were 7 males (58%) and 5 females (42%) with a median age of 55.5 years (range, 37-73 years). The median duration of gemcitabine therapy was 5.8 months (range, 3.8-13.1 months). Six patients died, five improved, and one patient's outcome was unknown. Among the six deaths, three patients died of cancer progression, one patient died of an unrelated myocardial infarction, and two patients died of HUS or HUS-related complications. For the five patients who improved, treatment was comprised of dialysis, plasmapheresis, splenectomy, or a combination. Attempts to correlate patient demographics, primary malignancy, and cumulative gemcitabine dose failed to identify consistent risk factors in predisposing patients to HUS. Confounding factors were common, including mitomycin-C and/or 5-fluorouracil exposure, advanced stage tumors, or preexisting renal dysfunction. Based on a patient exposure of 78,800, a crude overall incidence rate of 0.015% (range, 0.008-0.078%) was determined, showing that HUS associated with gemcitabine treatment appears to be rare. Nonetheless, as with other cancer treatments, clinicians should weigh the appropriate risk/benefit ratio in using gemcitabine to treat their patients.
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                Author and article information

                Journal
                Cureus
                Cureus
                2168-8184
                Cureus
                Cureus (Palo Alto (CA) )
                2168-8184
                31 January 2021
                January 2021
                : 13
                : 1
                Affiliations
                [1 ] Internal Medicine, Northwell Health, Staten Island, USA
                [2 ] Hematology and Oncology, State University of New York (SUNY) Downstate Health Sciences University, Brooklyn, USA
                [3 ] Pathology, State University of New York (SUNY) Downstate Health Sciences University, Brooklyn, USA
                Author notes
                Article
                10.7759/cureus.13031
                7931775
                Copyright © 2021, MacDougall et al.

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Categories
                Oncology
                Hematology

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