Eculizumab in chemotherapy-induced thrombotic microangiopathy

Schulte-Kemna, Lena; Reister, Barbara; Bettac, Lucas; Ludwig, Ulla; Fürst, Daniel E.; Mytilineos, Joannis; Bergmann, Carsten; Erp, R. van; Schröppel, Bernd

doi:10.5414/cncs109836

Cited by 8 publications

(8 citation statements)

References 43 publications

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“…Among these, eculizumab (Soliris ® ), a monoclonal antibody against C5, binds to C5 and blocks its cleavage into C5a and C5b, ultimately preventing the formation of the MAC matrix [93][94][95] (Table 1). Eculizumab was the first drug approved by Food and Drug Administration (FDA) [96] for the treatment of paroxysmal nocturnal haemoglobinuria (PNH) [97] and atypical haemolytic uremic syndrome (aHUS) [98], and it is currently under clinical evaluation for its application in several other diseases and conditions, such as GBS [99], neuromyelitis optica [100], kidney and liver transplant rejection [101], systemic lupus erythematosus [102], chemotherapy-induced thrombotic microangiopathy (TMA) [103], and generalized myasthenia gravis [104]. Biosimilars of eculizumab, such as ABP 959 (NCT03818607), BCD-148 (NCT04060264) and SB12 (NCT04058158), are in phase 3 of evaluation for treatment of patients with PNH.…”

Section: Targeting C5mentioning

confidence: 99%

Emerging Role of C5 Complement Pathway in Peripheral Neuropathies: Current Treatments and Future Perspectives

et al. 2021

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The complement system is a key component of innate immunity since it plays a critical role in inflammation and defense against common pathogens. However, an inappropriate activation of the complement system is involved in numerous disorders, including peripheral neuropathies. Current strategies for neuropathy-related pain fail to achieve adequate pain relief, and although several therapies are used to alleviate symptoms, approved disease-modifying treatments are unavailable. This urgent medical need is driving the development of therapeutic agents for this condition, and special emphasis is given to complement-targeting approaches. Recent evidence has underscored the importance of complement component C5a and its receptor C5aR1 in inflammatory and neuropathic pain, indicating that C5a/C5aR1 axis activation triggers a cascade of events involved in pathophysiology of peripheral neuropathy and painful neuro-inflammatory states. However, the underlying pathophysiological mechanisms of this signaling in peripheral neuropathy are not fully known. Here, we provide an overview of complement pathways and major components associated with dysregulated complement activation in peripheral neuropathy, and of drugs under development targeting the C5 system. C5/C5aR1 axis modulators could represent a new strategy to treat complement-related peripheral neuropathies. Specifically, we describe novel C5aR allosteric modulators, which may potentially become new tools in the therapeutic armory against neuropathic pain.

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Section: Targeting C5mentioning

confidence: 99%

Emerging Role of C5 Complement Pathway in Peripheral Neuropathies: Current Treatments and Future Perspectives

et al. 2021

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“… 42,46-49 Some groups have identified mutations or polymorphisms in complement regulatory genes in patients who respond, suggesting a role for complement dysregulation in the underlying pathophysiology. 50 Further data are needed before any definitive recommendation about the role of complement inhibition in subgroups of drug-induced TMA can be made.…”

Section: Drug-associated Tmamentioning

confidence: 99%

How I treat microangiopathic hemolytic anemia in patients with cancer

Thomas

Scully

2021

Blood

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Microangiopathic hemolytic anemia (MAHA) in patients with cancer requires urgent diagnosis and treatment. MAHA associated with thrombocytopenia, suggests a thrombotic microangiopathy (TMA), where there is thrombus formation affecting small or larger vessels. It may be directly related to the underlying malignancy (either the initial presentation or with progressive disease); to its treatment or it may be a separate incidental diagnosis. Although less common, it is vital to differentiate incidental thrombotic thrombocytopenia purpura (TTP) or atypical haemolytic uraemic syndrome (aHUS) in cancer patients presenting with a TMA as quickly as possible, as they have different treatment strategies, and prompt initiation of treatment has a critical impact on outcome. In the oncology patient, widespread microvascular metastases or extensive bone marrow involvement can cause MAHA and thrombocytopenia. A disseminated intravascular coagulation (DIC) picture may be precipitated by sepsis or driven by the cancer itself. Cancer therapies may cause a TMA either by dose-dependent toxicity, or an idiosyncratic immune-mediated reaction after development of drug-dependent antibodies. Many of the causes of TMA seen in the oncology patient do not respond to plasma exchange and, where feasible, treatment of the underlying malignancy is important in controlling both cancer-TMA and DIC driven by the disease. The potential for drug-induced TMA should be considered and any putative causal agent stopped. We will discuss the differential diagnosis and treatment of MAHA in patients with cancer using clinical cases to highlight management principles.

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“…Although most of the current literature on eculizumab therapy for gemcitabine-induced TMA is limited to observational studies or case reports, the data support a more formal investigation into the efficacy of complement blockade for gemcitabine-induced TMAs and other DI-TMAs. Rapid hematologic responses and kidney recovery after eculizumab therapy for DI-TMAs are consistently reported in the available literature, however many patients did not receive eculizumab until several weeks into their TMA course (3,(10)(11)(12)(13)(14)(15). In the cohort of 12 patients described by Grall and colleagues, the median time between TMA diagnosis and eculizumab therapy initiation was 15 days with a range of 4-44 days (3).…”

mentioning

confidence: 96%

“…It is possible that a similar biological process occurs in DI-TMAs as well, particularly those involving chemotherapy or immune modulating drugs. In fact, complement gene mutations were found in two patients who developed DI-TMA from chemotherapy (14). Complement mutations are also more common in patients who developed TA-TMA (7).…”

mentioning

confidence: 97%

“…In this issue of the Journal of Gastrointestinal Oncology, Van den Eeckhaut et al describe their successful experience with using the C5 inhibitor, eculizumab, to treat gemcitabine-induced TMA in a patient with pancreatic adenocarcinoma (9). Gemcitabine is a well-known instigator of TMA and the report by Van den Eeckhaut and colleagues adds to growing literature describing the successful use of eculizumab in gemcitabine-induced TMA (3,(9)(10)(11)(12)(13)(14)(15). Grall et al described 12 patients with gemcitabine-induced TMA who were treated with eculizumab and reported a complete hematological remission in 83% of patients and a higher glomerular filtration rate in eculizumab-treated patients at follow up compared to historical controls (3).…”

mentioning

confidence: 99%

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