Eculizumab use in a tertiary care nephrology center: data from the Vienna TMA cohort

Eculizumab is a recombinant humanized monoclonal IgG2/4 antibody that binds to the human C5 complement protein and inhibits the activation of the terminal complement complex. It is approved for treatment of paroxysmal nocturnal hemoglobinuria (PNH), myasthenia gravis (MG), and atypical hemolytic uremic syndrome (aHUS)/complement gene-variant mediated thrombotic microangiopathy (cTMA) [1].

Defective complement regulation causes the kidney diseases cTMA and C3-glomerulopathy (C3G). These diseases are characterized by endothelial and mesangial cell damage due to dysregulation of the alternative complement cascade on cell surfaces in cTMA, and in C3G by the deposition of complement components in the mesangium and subendothelial space, or within the glomerular basement membrane [2]. Secondary TMAs (sTMAs) are caused by other underlying conditions, such as infections, autoimmune disease, or medical treatment. Ultimately, cessation of those triggers should lead to resolution of the TMA [3].

Thrombotic microangiopathies and C3G frequently lead to end-stage renal disease (ESRD) or death if untreated. Eculizumab use has tremendously improved kidney and patient survival in patients with cTMA. In contrast to cTMA, eculizumab is not licensed for use in patients with C3G or sTMA. However, a few case reports or case series have shown favorable outcomes in patients with C3G or sTMA [4, 5].

Because therapy with eculizumab bears a certain risk for life threatening infectious diseases, is costly for National Health Systems and cumbersome for patients, some experts recommend cessation of treatment in patients with cTMA depending on the risk of disease recurrence [6, 7]. In this context, practice patterns of Eculizumab use in patients with TMA and C3G are not well described. We therefore used the Vienna TMA cohort and the hospital pharmacy database at the Medical University of Vienna to identify patients with a history of Eculizumab use between 2012 and 2019 [8‐12]. We describe the clinical characteristics, dose and duration of eculizumab therapy, and the outcomes of patients with cTMA, sTMA, and C3G.

This analysis of patients with different diagnoses receiving eculizumab provides several insights that might help physicians with the decision to initiate eculizumab therapy in the future.

Eculizumab is a drug that is approved for the treatment of cTMA, and is used off-label for severe cases of sTMA, C3G and other indications. The high cost of the drug remains a challenge for public health systems and therefore, the indications to use eculizumab need to be well defined. Current KDIGO guidelines recommend starting eculizumab in all cases of cTMA. However, many experienced centers still start with plasma therapy when cTMA is suspected and only initiate eculizumab when plasma therapy fails [14]. In our study, 85% of patients with cTMA and 80% of patients with sTMA still received plasma therapy before eculizumab was started. This approach may reduce financial and patient burdens. Furthermore, KDIGO guidelines suggest lifelong treatment with eculizumab in patients with cTMA. In our cohort, eculizumab was continued in patients at high risk of relapse after discontinuation (e.g. CFH or C3 variants) or with CKD stages IV and V (not on dialysis), because a relapse might lead to ESRD in those patients. However, administration of the drug was halted in individuals who responded well to treatment or were still dependent on RRT after approximately 6 months of treatment. In our cohort, 50% of cTMA patients showed markedly improved renal function after 6 months. Renal replacement therapy could be stopped in three patients after 4 months of treatment and in another patient after 6 months of treatment. Notably, patients with features of chronic TMA on the kidney biopsy and high serum creatinine at initial presentation showed less improvement in kidney function. Time from the beginning of the cTMA disease flare to initiation of complement blockade was a median of 15 days (IQR 6–20), which is in line with other studies [15]. Genetic variants were found in most patients diagnosed with cTMA, but in none of the patients with sTMA or C3G. Notably, CFH and CD46 risk haplotypes were found in all patients, regardless of diagnosis. The significance of these findings has to be explored in future studies.

A total of six patients diagnosed with sTMA were treated with eculizumab. Median age at presentation was 30 years (IQR 19–46), which is younger than the average sTMA patient described in the literature [16]. All of these patients had severe TMA manifestations with lower mean hemoglobin levels and platelet counts as compared to the cTMA patients. Furthermore, all suffered from AKI and 66% of them were dependent on RRT. Five of six patients received plasma therapy before the initiation of complement blockade. Hence, young age, severity of TMA, and unresponsiveness to conventional treatment led to the decision to initiate eculizumab therapy in these patients. Mean treatment duration was shorter than in cTMA patients and none of the patients received long term complement blockade. Hematological response was seen in four of six patients. However, the two non-responsive patients had just undergone bone marrow transplantation before the treatment which could explain the lack of response. Concerning renal response, one patient was able to stop RRT after 4 weeks and another two after 6 months, however, two of these three patients received eculizumab for less than 4 months. In the setting of sTMA, only two patients showed a clear response to eculizumab treatment and were weaned off treatment after approximately 6 months of therapy. The other four patients showed no clear response and hence therapy was terminated. Larger observational reports of eculizumab administration across different types of sTMA are scarce and, in general, management of secondary TMAs is not well established due to a lack of general guidelines. Currently, most literature discusses TMA after bone marrow transplantation and reports concerning the effectiveness of eculizumab in this setting are conflicting because hematological and renal response may be promising, but overall survival is still poor [17‐20]. The two patients that presented after bone marrow transplantation had a very different disease course. One patient had TMA some years after transplantation and regained renal function 4 months after termination of therapy with eculizumab, while the other showed no response to complement blockade and died shortly after diagnosis. The other patients received eculizumab related to malignant hypertension, solid organ transplantation, carcinoma and CAPS. The patient who was diagnosed with TMA after lung transplantation did not respond at all to eculizumab and remained dependent on RRT. The patients with TMA due to malignant hypertension and CAPS both responded well to therapy and were weaned off RRT. However, significant CKD persisted in both of these patients. In case of CAPS, eculizumab seems to be a viable treatment option, since the complement system is involved in the pathogenesis of the disease and case reports demonstrate good response to complement blockade. However, this suggestion is based only on case reports and series [21].

Two patients diagnosed with C3G received eculizumab in our cohort. One patient died of pulmonary embolism 2 weeks after therapy initiation, so no statement can be made concerning therapy response. The other patient received complement blockade because of gradual deterioration of kidney function after all other standard forms of care were unsuccessful. Both serum creatinine and urinary protein to creatinine ratio remained stable at a high level after 4 weeks and 6 months of therapy. In addition, more chronic lesions and sclerosis were diagnosed on a kidney biopsy. Therefore, the medication was stopped after 8 months of therapy. The patient progressed to ESRD in the following years. In general, eculizumab remains a treatment option in C3G, however, reported response rates in the literature are below 50% [22, 23].

Overall, 26% of patients experienced adverse events during eculizumab therapy. Two patients died while under therapy, but it is unclear whether the drug contributed to their death. One patient experienced drug-induced liver injury, which led to discontinuation of the drug, however, after switching to an extended dosing interval, liver enzymes remained in the reference range. One patient decided to discontinue eculizumab therapy due to worsening of arterial hypertension; another 2 patients showed exanthema and leukopenia, which disappeared spontaneously without halting the drug or changing the dosing schedule. Usually, eculizumab is a well-tolerated drug, however, severe adverse events can occur, including fatal infections and several rare adverse events. Therefore, the prescription needs to be deliberate [24‐26].

In summary, eculizumab is the treatment of choice for cTMA patients that do not respond to conventional therapies. In patients with sTMA and C3G, the response rates to therapy are much lower and therefore, the decision to start the therapy needs to be considered carefully.

Due to the high cost of eculizumab and significant patient burden, some centers still perform plasma therapy first and only administer the drug after the failure of plasma therapy. The optimal duration of treatment and dosing schedule need to be decided on a patient to patient basis and still remain subject to future research. Patients diagnosed with sTMA or C3G may benefit from therapy. However, currently, there are no established clear-cut indications for complement blockade, and the high cost of treatment, the low response rates and the potentially serious side effects need to be considered carefully.