High dose carfilzomib proteasome inhibition induces anemia by oxidative hemolysis: A case series of 8 patients from a single centre
Authors: Rajeev Rajagopal, Rory Bennett, James Liang, Gordon Royle
Journal: American Journal of Hematology (2019)

In this correspondence we posit our novel finding of oxidative hemolysis as the main mechanism of anemia induced by carfilzomib therapy in myeloma. Anemia is seen in at least one third of treated patients1, 2, 5; higher doses of carfilzomib are associated with an increased incidence of anemia. We report largely well compensated oxidative hemolysis associated with the use of higher doses of carfilzomib (56 mg/m2) in a case series of eight patients and subsequently recommend consideration of dose reduction in those developing symptomatic anemia, and screening for G6PD deficiency prior to commencing carfilzomib treatment. Carfilzomib, a second generation proteasome inhibitor, is increasingly used in patients with myeloma and used in various doses.1-3 Higher doses of carfilzomib are more effective but also result in an increased incidence of side effects, including anemia.4 A rare case of thrombotic microangiopathic anemia has been reported,6 but no main mechanism for carfilzomib-induced anemia has been identified. In our centre, we have used carfilzomib for relapsed/refractory myeloma patients at a dose of 27 mg/m2; anemia has not been an issue for the majority of these patients. In 2018, we treated 10 myeloma patients with three different carfilzomib-based treatment protocols with dosing at 56 mg/m2. Nine of these patients had newly diagnosed myeloma and the remaining patient received treatment for relapsed disease. During the treatment period at our centre, we noted a pattern of progressive anemia, and blood film features of oxidative hemolysis. We therefore reviewed the 10 patients with respect to oxidative hemolytic anemia, including peripheral blood parameters, reticulocyte count, biochemical markers of hemolysis, G6PD screens, and incubated Heinz body preparations. Their treatment histories were also reviewed. Of the 10 patients investigated, eight developed anemia gradually over a period of 2 to 3 months after starting carfilzomib treatment, with a blood film diagnostic of oxidant hemolysis. Full blood counts revealed progressive macrocytic anemia with reticulocytosis and positive biochemical markers of hemolysis. Blood film examination revealed bite cells, and Heinz body preparations were positive in each of these eight patients. None of the patients had blood film features of microangiopathic hemolytic anemia and all had negative direct antiglobulin tests. All patients had normal G6PD levels. The details of the blood investigations are summarized in Table 1. The anemia was mild and well compensated in the vast majority of patients, but two patients required red cell transfusions. The dose of carfilzomib was also reduced to 36 mg/m2 for patient #1. This allowed gradual improvement of hemoglobin and partial normalization of mean cell volume over the following cycles of treatment. Other patients were able to continue the same dose of carfilzomib. The blood features described persisted throughout the duration of their treatment. None of the patients had any other cause for the changes identified. Two patients who did not receive trimethoprim-sulfamethoxazole PJP prophylaxis still developed oxidative hemolysis with comparable severity, and patient #1 had received the same prophylaxis during previous treatment without any issues. We have not observed oxidative hemolysis in many other patients treated with trimethoprim-sulfamethoxazole. This case series outlines the novel finding of oxidative hemolytic anemia in eight patients receiving 56 mg/m2 carfilzomib-based therapy in three different treatment schemes, in the absence of other causes including supportive medications and G6PD deficiency. We believe this is the main mechanism of carfilzomib-induced anemia. While we observed mostly well compensated anemia, we recommend consideration of dose reduction of carfilzomib in severe and/or symptomatic cases. We now routinely screen our patients for G6PD deficiency prior to commencing high dose carfilzomib, an especially important consideration for high prevalence areas. Similarly, scrutinization of the medication history for other sources of oxidative stress should be performed routinely prior to treatment.