High dose carfilzomib proteasome inhibition induces anemia by oxidative hemolysis: A case series of 8 patients from a single centre

Rajagopal, Rajeev; Bennett, Rory; Liang, James; Royle, Gordon

doi:10.1002/ajh.25504

Cited by 3 publications

(11 citation statements)

References 6 publications

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“…However, in most of our patients, the grade of hemolytic anemia seemed modest, as in the recent report. 12 This is in contrast to profound anemia in previously reported patients with CFZ-induced TMA. 7,[9][10][11] 4,[6][7][8][9][10][11] and ruled out thrombotic thrombocytopenic purpura (TTP).…”

Section: Discussionmentioning

confidence: 55%

“…12 Oxidative stress as a trigger of mostly well-compensated hemolysis during CFZ treatment was proposed previously. 12 The retrospective nature of our study precluded collection of desirable additional laboratory data, including evaluation of the possible presence of Heinz bodies in the red blood cells (found by the recent report). 12 Here, we hypothesize that hemolysis may be induced by a previously described suppressive effect of CFZ on phosphorylation of eukaryotic translation initiation factor 2-alpha (eIF2α) by eIF2α kinase 1 (EIF2AK1), also known as heme-regulated inhibitor kinase (HRI).…”

Section: Discussionmentioning

confidence: 84%

“…12 The retrospective nature of our study precluded collection of desirable additional laboratory data, including evaluation of the possible presence of Heinz bodies in the red blood cells (found by the recent report). 12 Here, we hypothesize that hemolysis may be induced by a previously described suppressive effect of CFZ on phosphorylation of eukaryotic translation initiation factor 2-alpha (eIF2α) by eIF2α kinase 1 (EIF2AK1), also known as heme-regulated inhibitor kinase (HRI). 16 Physiologically, intracellular heme depletion activates EIF2AK1, which shuts off protein synthesis and prevents excess of globin chains, protecting erythrocyte survival in states of iron deficiency.…”

Section: Discussionmentioning

confidence: 99%

“…To our knowledge, only one recent study of high-dose CFZ in mostly first-line myeloma treatment has reported similar findings, with 8 of 10 patients showing modest hemolysis (but the biochemical markers were not specified). 12 In the present investigation, we used Hp levels to demonstrate associations of hemolysis with the time courses of CFZ therapy. We found no other explanations for low Hp, such as liver failure or malnutrition.…”

Section: Discussionmentioning

confidence: 99%

“…[4][5][6][7][8][9][10][11] Recently, mostly well-compensated hemolysis was observed in 8 of 10 patients treated with CFZ in a single center. 12 The most sensitive and specific hemolysis parameter is a decreased plasma level of the heme scavenger protein haptoglobin (Hp). 13 Here, we aimed to explore the frequency with which hemolysis occurs based on Hp levels in patients receiving CFZ, and to identify patient and treatment characteristics associated with hemolysis occurrence.…”

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confidence: 99%

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Carfilzomib‐induced hemolysis is noticeably common but rarely shows features of thrombotic microangiopathy: A retrospective study

Kozlowski

Behnam

Uggla

et al. 2020

European J of Haematology

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Objective Hemolysis is a sporadically reported but potentially serious side effect of the proteasome inhibitor carfilzomib. We aimed to investigate the frequency of hemolysis in an unselected cohort. Methods We performed a retrospective, single‐center study of the incidence of hemolysis in patients treated with carfilzomib, based mainly on consecutive haptoglobin levels. The patients were diagnosed with myeloma (n = 20), AL amyloidosis (n = 3), and light‐chain deposition disease (n = 1). Carfilzomib treatment was applied after a median of 3 (range: 1‐7) therapy lines. Results Haptoglobin levels were normal/increased before, generally suppressed during, and normalized after treatment with carfilzomib. Very low haptoglobin (<0.1 g/L) implying the presence of hemolysis was observed in 16 of 24 (67%) patients during carfilzomib therapy. Hemolysis was mild in 11 of 16 (69%) affected patients, whereas 5 of 16 (31%) required transfusion. Severe hemolysis was explained by thrombotic microangiopathy (TMA) in one patient who died of the complication. Mechanisms were unclear in the remaining 15 patients. Conclusions Hemolysis was surprisingly common but mostly mild during carfilzomib treatment. However, the possibility of TMA should be kept in mind in this setting. Hypothetically, non‐TMA hemolysis could be attributed to the accumulation of globin chains due to the suppression of eukaryotic translation initiation inhibition by carfilzomib.

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Section: Discussionmentioning

confidence: 55%

Section: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Carfilzomib‐induced hemolysis is noticeably common but rarely shows features of thrombotic microangiopathy: A retrospective study

Kozlowski

Behnam

Uggla

et al. 2020

European J of Haematology

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Carfilzomib

2019

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Carfilzomib-Induced Thrombotic Microangiopathy Treated with Eculizumab: A Case Report and Rapid Literature Review

Pallotti

Queffeulou

Bellal

et al. 2022

Kidney and Dialysis

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Background: Thrombotic microangiopathies (TMAs) can be induced by drugs. Recent works have indicated proteasome inhibitors, including carfilzomib, as a possible new causative agent. Although the physiopathology and management of carfilzomib-induced TMA are still unknown, eculizumab seems to be efficient. Results: We report a clinical case of TMA during carfilzomib treatment for multiple myeloma, possibly triggered by a concomitant influenza infection, suggesting a multi-hit process. Histologic analysis of the kidney biopsy proved renal TMA. Eculizumab allowed rapid and long-lasting renal and hematologic recovery. We enriched our work with a systemic review of published cases of carfilzomib-induced TMA treated by eculizumab. Twelve patients were included, all of whom presented acute renal failure and nine of them required hemodialysis. Eculizumab led to TMA resolution in eleven patients and complete renal recovery with hemodialysis withdrawal for seven of them within a month. One patient died from multiple myeloma progression. Two patients presented inter-current viral infection. Soluble complement fragment Bb and C5b9s were found in two patients and genetic benign variant of Factor H (CFH3–CFH1) in four. Conclusion: Our results suggest that eculizumab is effective in carfilzomib-induced TMA, which could support its inclusion as a treatment option. Further studies are required to clarify its physiopathology, complement role, and management.

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High dose carfilzomib proteasome inhibition induces anemia by oxidative hemolysis: A case series of 8 patients from a single centre

Cited by 3 publications

References 6 publications

Carfilzomib‐induced hemolysis is noticeably common but rarely shows features of thrombotic microangiopathy: A retrospective study

Carfilzomib‐induced hemolysis is noticeably common but rarely shows features of thrombotic microangiopathy: A retrospective study

Carfilzomib

Carfilzomib-Induced Thrombotic Microangiopathy Treated with Eculizumab: A Case Report and Rapid Literature Review

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