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  • Clofarabine associated capillary leak syndrome attributed to

    2019-05-10

    Clofarabine-associated capillary leak syndrome, attributed to cytokine release, is characterized by hypotension, tachycardia, and tachypnea, and can be fatal. Alternatively, Type I hypersensitivity to clofarabine can occur in up to 5% of patients, and is also a contraindication to further therapy per product labeling [4]. In practice, reactions to clofarabine often result in discontinuation of a therapy which may otherwise provide complete responses in patients treated for AML. However, attempts at clofarabine desensitization have not been previously described in the literature.
    Case report Here we report successful clofarabine desensitization in a 76-year-old male patient with AML. His comorbidities include Type II diabetes, hypertension, and a history of acute illness induced cardiomyopathy that has resolved. The patient was diagnosed with AML in 2012. After no response to azacitidine therapy in 9/2012 he was treated with clofarabine 20mg/m2 Days 1–5+ cytarabine 20mg subcutaneously twice daily Days 1–10 based on the Faderl Cancer 2012 study [5] in the hopes of achieving a complete remission and moving on to stem cell transplantation. He achieved his first complete response (CR1). However, he developed cardiomyopathy with a drop in ejection fraction to 20% and thus was no longer eligible to proceed with stem cell transplant. His age of greater than 70 precluded standard high dose cytarabine consolidation, thus “maintenance” therapy to prolong his initial remission was discussed. Based on small series suggesting successful azacitidine maintenance post CR [6], he was treated with azacitidine Days 1–5 of a 28 day Spadin cost off study through 9/2014. He did well until 9/2014 at which time a surveillance bone marrow revealed his first relapse with low volume disease of <10% blasts. Attempts at increasing the schedule of azacitidine to the standard 7-day schedule every 28 days were not successful in regaining remission. Subsequently, given a 2 year remission from his first round of clofarabine + cytarabine induction + azacitidine maintenance and ongoing good performance status he was re-induced with the same regimen in 11/2014. He achieved CR2 with the first induction of clofarabine Days 1–5 + cytarabine Days 1–10. With this treatment round, the entire Faderl approach was used, as described in the 2012 publication [5,7]. Per protocol, once complete remission is achieved, patients go on to receive two abbreviated courses of clofarabine Days 1–3 + cytarabine Days 1–7 consolidation. During his first clofarabine + cytarabine consolidation in January 2015 he only received 2 doses of the clofarabine due to an episode of hypotension and vomiting and the development of acute kidney injury (AKI) after the second dose. He completed all 7 days of the cytarabine. He then was readmitted in February 2015 for the second consolidation clofarabine + cytarabine per protocol. He unfortunately developed a severe reaction occurring after Day 1 of the two-hour clofarabine infusion including rigors, hypotension (systolic blood pressure between 70 and 80mmHg), six episodes of emesis, tachycardia leading to demand-related ischemia and mild troponin elevation, and low urine output resulting in AKI with a peak serum creatinine of 1.5mg/dL. Clofarabine therapy was discontinued as his reaction was felt to be consistent with a combination of components of both clofarabine-induced capillary leak syndrome and an allergic reaction. Cytarabine was held, and the first dose was administered two days later following recovery from the clofarabine reaction. He recovered from this episode without long term toxicity and remained in CR2. He then went on to decitabine maintenance, per the Faderl protocol, without the intermittent protocol defined clofarabine + cytarabine maintenance cycles. He continued to do well until counts dropped in 8/2016. Repeat bone marrow biopsy then documented AML relapse number 2. Upon discovery of this AML relapse in 8/2016, extensive discussion ensued. Given his excellent performance status, the lack of good clinical trial options that he was eligible for, and his prior prolonged remissions with clofarabine + cytarabine, the possibility of clofarabine desensitization was raised. After presenting the patient with the options, the decision was made to attempt re-induction therapy again with clofarabine + cytarabine. We designed a desensitization protocol for the administration of clofarabine, described in Table 1. The protocol was based on existing protocols for carboplatin desensitization at our institution. Pre-medications included ondansetron 16mg by mouth, ranitidine 50mg intravenously, acetaminophen 650mg by mouth, diphenhydramine 50mg by mouth, and dexamethasone 12mg by mouth. All nephrotoxic medications, or those likely to contribute to AKI, were held. Vital signs were obtained every 15min during infusion. During the last ten minutes of the first clofarabine infusion, the patient experienced mild rigors. Vital signs remained stable. He was given warm blankets and the rigors subsided. No medications were required to alleviate the mild reaction. All remaining doses of clofarabine were subsequently infused per standard rates without incident, and the patient was discharged from the hospital to home at the conclusion of chemotherapy. Four weeks later, the post-re-induction bone marrow biopsy showed no evidence of AML.