October 2013 Volume 11, Issue 10, Supplement 15

Atypical Hemolytic Uremic Syndrome (aHUS): Treating the Patient

Plus: A Review of Case Studies

Jeffrey Laurence, MD

Professor of Medicine Division of Hematology and Medical Oncology New York Presbyterian Hospital and Weill Cornell Medical College New York, New York

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Atypical Hemolytic Uremic Syndrome (aHUS): Treating the Patient Jeffrey Laurence, MD 4

Management of Atypical Hemolytic Uremic Syndrome (aHUS): A Review of Case Studies Jeffrey Laurence, MD 16

Clinical Advances in Hematology & Oncology Volume 11, Issue 10, Supplement 15 October 2013 3 REVIEW ARTICLE

Atypical Hemolytic Uremic Syndrome (aHUS): Treating the Patient

Jeffrey Laurence, MD Professor of Medicine Division of Hematology and Medical Oncology New York Presbyterian Hospital and Weill Cornell Medical College New York, New York

Abstract: The 3 major thrombotic microangiopathies (TMAs) are thrombotic thrombocytopenic purpura (TTP), atypical hemolytic uremic syndrome (aHUS), and Shiga toxin–producing Escherichia coli (STEC)-HUS. These conditions are often clinically identical, but they require different treatment. The TMAs can be distinguished based on factors such as presenting platelet count and serum creatinine level, assessment of ADAMTS13 activity and inhibitor assays, and evaluation for STEC if diarrhea is present. aHUS is a chronic, genetic disorder that is based, in most cases, on an inability to regulate the alterna- tive complement pathway. In the absence of appropriate therapy, up to 50% of aHUS patients progress to end-stage renal disease within a year, and 25% die during the acute phase. Patients who present with clinical and laboratory evidence of a TMA should begin immediate treatment with plasma therapy, but there is no role for plasma infusion or plasma exchange in the long-term management of aHUS. Eculizumab is a potent inhibitor of the terminal complement pathway. It was recently approved by the US Food and Drug Administration for the treatment of patients with aHUS to inhibit complement- mediated thrombotic microangiopathy, including adverse effects on renal function. Eculizumab should be initiated as early as possible after making the diagnosis of aHUS, in order to attempt optimal recovery of renal function and prevent an ongoing TMA with extrarenal manifestations.

Introduction is approximately 2 to 4 per million, and This review, the second of a 2-part STEC-HUS is recognized primarily in series on aHUS, briefly summarizes One year ago, I wrote a primer for distin- outbreaks of variable expression. Yet the how the different TMAs are diagnosed, guishing among the 3 major thrombotic high morbidity and mortality associated and then describes advances in the microangiopathies (TMAs): thrombotic with untreated TTP and inappropriately treatment of aHUS. thrombocytopenic purpura (TTP), treated aHUS, and the divergent treat- atypical hemolytic uremic syndrome ments they require, mandate 3 steps: Distinguishing Among the (aHUS), and Shiga toxin–producing • First, recognition of the existence of TMAs: Review of Current Escherichia coli (STEC)-HUS.1 These a TMA. Diagnostic Criteria conditions are often clinically identical. • Second, the ability to distinguish A further impediment to reaching an between aHUS and TTP. Initiation of appropriate treatment for accurate diagnosis is that they are ultra- • Third, rapid institution of appropri- aHUS requires an accurate diagnosis. rare. The incidence of TTP and aHUS ate therapy. Up to 50% of aHUS patients progress

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4 Clinical Advances in Hematology & Oncology Volume 11, Issue 10, Supplement 15 October 2013 ATYPICAL HEMOLYTIC UREMIC SYNDROME (AHUS): TREATING THE PATIENT

to end-stage renal disease (ESRD) odds ratio for aHUS vs TTP is 23.4 in diarrhea, particularly bloody diarrhea, within a year, and 25% die during the the setting of a platelet count exceeding is a classic sign of STEC-HUS. How- acute phase in the absence of appro- 30,000/mm3.4 Near normal platelet ever, up to one-third of aHUS cases priate therapy.2 In this context, it is counts occur in up to 20% of aHUS involve diarrhea, which can be bloody, particularly important to distinguish cases at presentation.9 and it is also not uncommon in TTP.15 aHUS—a chronic, genetic disorder This again highlights the importance that is based, in most cases, on an Document Clinical Involvement of rapidly assessing both Shiga toxin inability to regulate the alternative The above laboratory abnormalities and ADAMTS13 activity in a TMA complement pathway—from a clini- must be accompanied by disruption of accompanied by diarrhea. cally related but pathologically distinct at least 1 organ system. The most com- condition, TTP. The latter is, in virtu- monly involved systems in any TMA are Order an ADAMTS13 Activity and ally all instances, an acute, acquired renal, neurologic, and gastrointestinal. Inhibitor Assay Before Initiating disease, characterized by severe However, neurologic symptoms occur Plasma Therapy deficiency (<5% of normal activity in 48% of aHUS cases,1 and 4 recent The vast majority of TTP cases can levels) of the von Willebrand cleaving studies have shown that a serum creati- be distinguished from aHUS on the protease ADAMTS13, secondary to nine level higher than 1.7 to 2.3 mg/dL basis of an ADAMTS13 activity an immunoglobulin G (IgG) autoan- (150-200 μmol/L) is unusual in TTP.4,5,7,8 lower than 5% in the presence of an tibody against this enzyme.3-5 The adjusted odds ratio for aHUS vs anti-ADAMTS13 inhibitor, usu- There are 5 critical steps to reaching TTP is 9.1 with serum creatinine levels ally an IgG autoantibody. Both tests a specific TMA diagnosis: documenta- that exceed this range.4 Conversely, in should be ordered. The incidence of tion of the TMA, documentation of approximately 20% of initial aHUS autoantibodies to ADAMTS13 in clinical involvement, investigation of any presentations, serum creatinine levels are the healthy population is only 4%, diarrhea, ordering of an ADAMTS13 normal,10 whereas classic TTP involves and they are usually of a low titer.3 In activity and inhibitor assay before initiat- the kidneys in more than 50% of cases addition, a myriad of conditions apart ing plasma therapy, and understanding (although with lower serum creatinine from the TMAs, including malig- the components of response to plasma levels than in aHUS). nancy, hepatic and renal disease, and therapy in the TMAs. The one possible exception to systemic infection, may be associated the rule that any organ or tissue can with ADAMTS13 activity levels below Document a TMA be involved in any TMA is the lung. the range for healthy controls (which TMAs present with 2 main features: Although severe cardiovascular or is 67% to 100%). However, in the thrombocytopenia and a microangio- renal involvement can lead to pul- absence of evidence for a TMA, none pathic hemolytic anemia, characterized monary symptoms in all TMAs, the of those patients should have activity by fragmented red blood cells (schisto- vascular endothelium of the lungs levels less than 10%, regardless of the cytes) on peripheral blood smear, low is not involved in TTP, whereas occurrence of thrombocytopenia, in haptoglobin levels, a decline in baseline pulmonary pathology is frequent in clear distinction to acute TTP.3 hemoglobin, an elevated lactate dehy- untreated aHUS.11 For example, in It takes from 2 to 7 days to obtain drogenase (LDH), and a negative direct one large autopsy series, the lung was these test results, which are performed Coombs assay. However: not involved in TTP,12 whereas 3 of 3 only by specialty laboratories. Given • Although schistocytes are the sine qua cases of aHUS had pulmonary micro- that constraint, the value of reaching non of a TMA, they may be infrequent thrombi.13 Premortem, pulmonary a preliminary diagnosis of aHUS vs on initial presentation, particularly in involvement was seen in 2.2% of a TTP in a TMA patient based on the aHUS, occurring at less than 1 per series of 46 children,14 and in 5% of presenting platelet count and serum high-power microscopic field. children and adults10 with aHUS. creatinine level must be emphasized. • An elevated LDH is typical of any hemolytic anemia, but isoenzyme Investigate Any Diarrhea Understand the Components of analysis documents that a substantial In the presence of diarrhea, STEC- Response to Plasma Therapy in the portion of the increase in LDH in HUS must be excluded. It is diagnosed TMAs the TMAs reflects its release from by polymerase chain reaction or cul- In TTP, the platelet count; hemoglo- ischemic tissues.6 ture-based assays for Shiga toxin–pro- bin; haptoglobin; and total LDH, • In terms of the thrombocytopenia, a ducing E. coli, using stool or a rectal including its isoenzyme subsets, are platelet count higher than 30,000/mm3 swab. Gastrointestinal signs and symp- normalized, and creatinine is nor- at presentation almost eliminates a toms cannot be relied upon to distin- malized or reduced by at least 25% diagnosis of TTP.4,5,7,8 The adjusted guish among the TMAs. Prodromic from pretreatment baseline, in more

Clinical Advances in Hematology & Oncology Volume 11, Issue 10, Supplement 15 October 2013 5 REVIEW ARTICLE

than 80% of cases following plasma tion, as assessed with flow cytometry at markedly elevated levels when so exchange (PEx). These responses for P-selectin on platelet membranes,21 induced, will affect the integrity of cell should occur, on average, after a mean and by continued decline in estimated membranes of normal cells as well as of of 5 to 9 daily plasma exchanges.1 glomerular filtration rates (eGFR).22 pathogens unless checked by comple- They should persist for at least 1 Approximately 30% to 80% of these ment regulatory factors. Measurement month following cessation of PEx to patients advance to ESRD or death of circulating C3, C5a, and MAC define a complete response to plasma despite hematologic responses to plasma. might therefore appear to be a logical in that disorder.16 There is sufficient This outcome is described in detail in the part of a diagnostic workup for aHUS. ADAMTS13 enzyme in fresh frozen section on aHUS treatment. However, a pathognomonic finding plasma to effect a complete hemato- of C3 consumption with maintenance logic and tissue remission in TTP. In Distinguishing Among of proximal complement proteins, as addition, pheresis, often used along the TMAs: Additional reflected by a low C3 level accompanied with immunosuppressive agents (eg, Considerations by a normal or elevated C4, is seen in corticosteroids, rituximab), serves to less than 20% of aHUS cases. In several deplete or block the anti-ADAMTS13 Evaluating Components of the reviews, serum C3 was normal in up autoantibody inhibitor. Alternative Complement System to 80% of aHUS patients.9,15,23 In one In contrast, the vast major- Overt signs and symptoms of aHUS can report of 19 cases occurring in the pres- ity of aHUS cases involve familial, occur at any age, despite the fact that the ence of identifiable CFH mutations, 11 germline mutations in complement genetic predisposition is present at birth. patients did have very low to moderately or complement regulatory proteins. Events that superactivate the alterna- low circulating C3 levels. But 8 (42%) Functional alterations in these factors tive complement pathway and/or cause of the clinically identical patients with permit chronic amplification of the microvascular endothelial cell injury may mutations had normal C3 levels.23 alternative complement pathway. This be required to unmask the inability to Complement pathways, including sup- potentiates platelet activation, platelet control the alternative complement sys- pressed C3 and elevated C5b-9, can also aggregation, and terminal comple- tem. These events can include infection, be activated in classic TTP.24 ment complex–mediated endothelial pregnancy, surgery, autoimmune disease, cell injury throughout the microvas- malignancy, and the use of certain drugs, Assessment of complement regula- culature.1,9,17-19 The platelet count, such as cocaine, cancer chemotherapeu- tory protein activity, mutations, or haptoglobin, and hemoglobin may tics, and calcineurin inhibitors. With autoantibodies is not useful to the transiently normalize and LDH levels this background, one might anticipate diagnosis of aHUS in the majority of may dramatically decline in 30% to that measuring terminal complement cases. To prevent the panoply of activi- 80% of aHUS patients treated with components in the circulation, or ties related to unchecked activation of PEx alone. This wide variability in ini- screening for mutations in complement the alternative pathway, most mam- tial response rates is dependent upon and its regulators, would aid in distin- malian cells have membrane-bound the nature of the complement-related guishing aHUS from TTP. As previously regulators that block complement mutation involved in a particular described in depth,1 this is not the case, activation. Their highest concentration patient.17 There is sufficient comple- for the following reasons: is on microvascular endothelial cells. ment factor H (CFH), complement They function in concert with the factor I (CFI), and thrombomodulin Altered levels of circulating comple- soluble complement regulators.9,17,25,26 (which can inactivate C3a and C5a) ment components are not useful in Soluble CFH and CFI, and the mem- in fresh frozen plasma to effect those diagnosing aHUS. Both the classic and brane-bound proteins MCP (CD46) changes, including transient restora- alternative complement systems activate and CD55, regulate conversion of tion of functional CFH activity in C3, converting it to C5, which is then C3 to C5. Membrane-bound CD59 CFH-deficient patients.20 In contrast broken down into the terminal comple- regulates C5b-9. However, identifiable to the use of PEx in TTP, however, the ment components C5a (anaphylatoxin) mutations in 1 or more of these pro- LDH and creatinine rarely normalize, and C5b-9 (membrane attack com- teins, along with the related molecules and the risk of ESRD and death is not plex [MAC]). The importance of the complement factor H-related proteins 1 significantly affected. Maintenance alternative pathway, and its relevance and 3 (CFHR1, CFHR3), C3, comple- of even those initial LDH responses to aHUS, is that as part of the innate ment factor B, and thrombomodulin, requires continued PEx.17 immune system, it is always activated, account for disease susceptibility in This failure to effect a meaningful at low levels, and ready to be amplified only half of cases.23,27 Thus, they are an clinical response with PEx in aHUS is by a myriad of stressors, such as those unreliable means of excluding an aHUS reflected in persistent platelet activa- listed above. C5a and MAC, produced diagnosis. In addition, such testing takes

6 Clinical Advances in Hematology & Oncology Volume 11, Issue 10, Supplement 15 October 2013 ATYPICAL HEMOLYTIC UREMIC SYNDROME (AHUS): TREATING THE PATIENT

months, and is not generally available. CFHR1/CFHR3 or abnormalities in Table 1. Disorders Associated It is hypothesized that more exten- other complement regulatory genes.31-33 With Secondary Thrombotic sive, genome-wide sequencing will This issue is considered in depth in the Microangiopathies That May Obscure eventually reveal complement-related section on treatment. the Diagnosis, and Thus Delay Effective Treatment, of aHUS abnormalities in most aHUS patients. Such analyses will be complicated by Intercurrent Disorders May Autoimmune disorders, including the fact that nonsynonymous mutations Obfuscate the Diagnosis of aHUS systemic lupus erythematosus, involving amino acid substitutions in An additional confounding factor in systemic sclerosis, and catastrophic CFH, the most frequently involved pro- reaching a diagnosis of a TMA, and antiphospholipid syndrome tein in aHUS, are present in 0.5% to 5% specifically aHUS, is the failure to con- of healthy controls who have no family sider that myriad disorders, particularly Bone marrow, peripheral blood history of aHUS.28 Genetic testing can autoimmune diseases—such as systemic stem cell, and organ transplanta- be useful, however, in the counseling of lupus erythematosus (SLE) and systemic tion, including transplant compli- family members of an affected proband. sclerosis—can present with signs and cations such as graft-vs-host disease Carriers might be closely monitored symptoms similar to any TMA. In turn, Pregnancy, including preeclampsia when experiencing events that trigger aHUS can occur in the setting of SLE and postpartum HELLP marked complement activation. Clearly, and related conditions, as these disorders Cancer chemotherapy (particularly there is room to improve gene-based are potent activators of the alternative gemcitabine and mitomycin C) diagnostics in this disorder. and classic complement pathways. As In terms of measuring activity of noted above, such complement activa- Calcineurin inhibitors circulating CFH, the soluble protein tion also occurs in STEC-HUS34 as well Cocaine and certain opiates responsible for more than 30% of adult as during pregnancy, organ and tissue Malignant hypertension aHUS cases, other problems arise. More transplantation, cancer and its chemo- aHUS, atypical hemolytic uremic syndrome; HELLP, than 90% of CFH-related aHUS cases therapy, and following the use of certain hemolysis with elevated liver enzymes and low platelets. involve heterozygous, monoallelic muta- drugs.1,35 A list of the most common Adapted from Coppo P, Veyradier A. Cardiovasc tions. Reduction in expression of even coexisting conditions that can mask a Hematol Disord Drug Targets. 2009;9:36-50.35 50% of normal activity levels is sufficient diagnosis of aHUS in a patient with a to affect vulnerability to aHUS during defect in regulation of the alternative body-mediated rejection is suspected. events such as infection, pregnancy, and complement pathway is presented in The thrombi of TTP are typically surgery.10,29 Measurements of circulat- Table 1. Unless a TMA distinct from “white clots,” composed of platelets, ing CFH protein are available but not the intercurrent disorder is considered, with only small amounts of fibrin pres- useful in most cases, given the wide and the appropriate diagnostic proce- ent. Immunohistochemical staining range considered normal—265 µg/mL dures described above are undertaken, will show entrapped von Willebrand to 684 µg/mL20—and the fact that accurate treatment decisions cannot be factor (vWF).38 This finding reflects functional activity, not antigen con- made. This issue is revisited in the sec- its pathophysiology, in particular the centration, is usually involved. A small tion on treatment. inability to cleave ultra-large molecular pilot study suggested that assessment of weight multimers of vWF, which form CFH by a functional assay can be used Utility of a Tissue Biopsy massive platelet tethers in the face of to monitor aHUS and, by implication, Historically, biopsies were rarely a deficiency in ADAMTS13 activity. diagnose cases of CFH-related aHUS.30 performed to distinguish TTP from Vascular and perivascular inflam- However, normal ranges have not been aHUS. They were of little clinical matory cell infiltrations are minimal established for clinically relevant func- relevance, as the US Food and Drug or absent,38 consistent with the fact tional activity, and there is no standard Administration (FDA) had not that endothelial cell damage in TTP assay for its assessment. approved a therapy specific for aHUS is apoptotic in nature, and such pro- Autoantibodies to CFH have also until September 2011. However, biop- grammed cell death, as opposed to been described in 6% to 10% of aHUS sies may now be important in difficult necrosis, typically lacks an inflamma- patients, leading to decreased factor H diagnostic situations.36 Gingival tissue, tory component.11 function, at least as assessed in vitro.25,31 skin, or bone marrow are suggested In contrast, biopsy of similar sites The clinical relevance of these auto- sites to sample, regardless of whether in aHUS typically reveals “red clots,” antibodies, and the need to suppress there is an apparent lesion.37 Because or microthrombi in which fibrin domi- them, is controversial. Virtually all the TMAs, both primary and second- nates, and an inflammatory infiltrate patients with aHUS and the anti-CFH ary, are systemic disorders, a kidney may be seen.12,38 Deposits of terminal autoantibody also have a deficiency of biopsy is rarely required unless anti- complement components C5a and

Clinical Advances in Hematology & Oncology Volume 11, Issue 10, Supplement 15 October 2013 7 REVIEW ARTICLE

MAC are classically present in involved to ESRD.19,40,41 Delay in confirming Use of Hepatorenal Transplantation vessels, and are detectable by immuno- an aHUS diagnosis and instituting in aHUS histochemistry or immunofluorescence appropriate therapy often results in Supported by the knowledge that the on fresh or fixed tissues.36,39 ESRD or death within a year, regard- major source of CFH is the liver, Remuzzi It must be emphasized that the less of whether PEx had induced a and colleagues performed the first suc- sensitivity and specificity of such biopsy transient hematologic remission. The cessful combined orthotopic split liver results in distinguishing TTP from incidence of ESRD or death within a and kidney transplant for an infant with aHUS, or from TMAs arising in the year varies somewhat according to the aHUS and CFH mutation.43 However, setting of conditions that can unmask mutation responsible for disease sus- these procedures were highly problematic, an underlying inability to control ceptibility, but it is always high. Rates given that surgery itself is a key activator complement activation, have not been are 60% to 80% with CFH, CFI, of the alternative complement pathway. authenticated in clinical trials. Tissue- complement factor B, and TM defi- Complement activation occurs in the based testing should not be done rou- ciencies; 30% to 40% with CFHR1/ graft organ during this procedure, and tinely, but rather on a case-by-case basis. CFHR3 changes; and less than 20% vascular injury, thrombosis, or death Prospective studies are needed to define with MCP mutations.17 occurred in 90% of cases.44,45 and standardize such an approach. If a putative TTP or other A modified procedure involves pro- TMA patient is not responding to viding large quantities of plasma before Treating aHUS PEx according to generally accepted and during the transplants in conjunc- measures of hematologic, clinical, and tion with heparin, aspirin prophylaxis, There Is No Role for Plasma Infusion organ system changes, or if he or she and ongoing immunosuppressive agents. or Plasma Exchange in the Long- requires prolonged PEx to effect and/ This approach dramatically reduced mor- Term Management of aHUS or maintain a remission, it is then bidity and mortality and preserved organ A new patient presenting with clinical important to reevaluate the diagnosis function.44 It led to a Consensus Study and laboratory evidence of a TMA and consider aHUS. Response to PEx Group statement, published in 2009, that should immediately begin treatment in TTP may be defined in terms of the “patients who have ESRD and a CFH or with plasma therapy while awaiting amount of plasma usually required to CFI mutation should be considered for the results of the tests described above induce a complete response. The first combined liver-kidney transplantation to distinguish among TTP, aHUS, and randomized study of PEx vs plasma because of the high risk for graft loss to STEC-HUS. Testing should include infusion in TTP that was defined disease recurrence.”45 However, the group evaluation of the presenting platelet clinically and without the benefit of added a critical warning: “The gravity of count and serum creatinine level, ADAMTS13 testing demonstrated the risk associated with the procedure has not assessment of ADAMTS13 activity superiority of PEx over plasma infu- been eliminated.”45 and inhibitor assays, and evaluation sion.16 Forty-seven percent of patients In fact, of the first 15 aHUS for STEC if diarrhea is present. PEx receiving PEx had a complete response patients treated with this protocol, 12 rather than plasma infusion is the after the first treatment cycle, which achieved long-term remissions and were initial standard of care for such an involved an average of 21.5 L ± 7.8 L considered cured. But 3 died from sur- undifferentiated TMA. If an apheresis of fresh frozen plasma exchanged gical complications (Julien Zuber, MD, station is not immediately available, over 9 days. In an additional 31% of PhD, personal communication, August and renal function permits, then fresh patients, 1 or 2 further cycles of PEx 2013). Of practical importance, the frozen plasma infusions (40-60 mL/kg were required to effect a complete liver is rarely involved significantly in body weight daily) may instead be response.16 These findings are similar aHUS; the likelihood that most aHUS initiated while awaiting PEx. to those in many later trials of PEx, patients will have a Model for End-Stage Mortality from TTP declined in which complete remissions were Liver Disease (MELD) score sufficiently from more than 90% to less than obtained with a mean cumulative high to position themselves on a liver 10% with institution of PEx,16 but infused plasma volume of 43 L ± 77 L.42 transplant list is low. With the approval the outcome is highly unfavorable Each exchange involves 40 to 60 of anticomplement therapy, this mode in aHUS patients treated with PEx mL/kg of plasma, or 1 to 1.5 plasma of treatment is rarely indicated. alone. As noted above, most patients volumes, which can be infused within will experience ongoing tissue injury, 5 to 9 days. If the patient has not Use of Anticomplement Therapy With as evidenced by platelet activation and responded as defined by all of the Eculizumab in the Control of aHUS failure to normalize the LDH, and parameters listed above, then the clini- Eculizumab (Soliris) is a recombinant, discontinuing PEx is associated with cian should reevaluate the diagnosis fully humanized monoclonal antibody high relapse rates and progression and therapy. that binds with high affinity to human

8 Clinical Advances in Hematology & Oncology Volume 11, Issue 10, Supplement 15 October 2013 ATYPICAL HEMOLYTIC UREMIC SYNDROME (AHUS): TREATING THE PATIENT

C5.46 It is thought to prevent entry of C5 Age 2 months Adults into the C5 convertase, thereby inhibit- Duration From ing its cleavage and subsequent release of <1 month 286 months C5a (anaphylatoxin) and recruitment of aHUS Diagnosis to Study Identied Genetic None identied Multiple per patient C5b, blocking formation of the terminal Complement Mutations membrane attack complex, MAC (C5b- 9).46 It preserves the proximal parts of the TMA in Patients With Normal platelet count Reduced platelet count complement cascade, which are crucial Degree of Organ Damage CKD Stage 1 CKD Stage 5 for opsonization of most microorganisms and the clearance of immune complexes. Dialysis None 3 times a week However, in blocking C5 activation, it impedes immune responses to certain PEx/PI No intervention* 230 interventions encapsulated bacteria. In adults, these are mainly the Neisseria species, menin- Renal Transplant None 3 prior kidney grafts lost gococcus, and gonococcus. Vaccination and prophylactic antibiotic strategies to mitigate this potential problem are Figure 1. Characteristics of aHUS patients enrolled in prospective and observational described later in this section. studies of eculizumab. *Based on study definition. aHUS, atypical hemolytic uremic syndrome; CKD, chronic kidney disease; PEx/PI,85 plasma exchange/infusion; TMA, Eculizumab is a hybrid of 2 IgG 90% subtypes 2 and 4 and was designed to thrombotic microangiopathy.80 (62–97) (56–94) minimize development of autoantibod- 80% ies and Fc receptor–mediated func- Prospective data have been derived ues occurred in 88% of these patients tions.40,46 It is administered as an intra- from70% 2 phase 2 trials, one involving by week 64.41 Normalization of LDH venous infusion over 30 minutes, and patients with recently diagnosed, pro- occurred in 82% of patients at week 26 has an estimated half-life of 11 to 12 gressing60% aHUS (trial 1, also known and 88% by week 64.41 These changes days. In an adult weighing more than as C08-002; N=17), and another were reflected in clinical response: 88% 50% 40 kg, therapy is initiated with 4 weekly recruiting patients with long-term remained freeTMA event‐free status: of TMA events at weeks doses of 900 mg, followed by a biweekly disease receiving prolonged PEx or 26 and 64, serumFor 12 consecutive creatinine weeks, declined no by 40% decrease in platelet count >25% maintenance phase of 1200 mg. This plasma infusions (trial 2, also known at least 25%from in 76% baseline, by ANDweek no 64,PEx/PI, and 4 schedule usually maintains drug trough as30% C08-003; N=20). A third study was of 5 patientsAND on dialysisno new dialysis discontinued the levels of 50 to 100 µg/mL, which is a retrospective, observational survey of procedure, all without plasma therapy. sufficient to achieve complete terminal aHUS20% patients younger than 18 years Trial 2 results, with patients on complement blockade, as assessed by (Medical Practice Setting C09-001; long-standing plasma therapy, were 40 10% hemolytic complement CH50 activity. N=30). As shown in Figure 1, these 3 also impressive. As shown in Figure 2, Patients Achieving TMA Event–Free Status Minimal drug is detectable in cord trials included a broad16/20 range of patients, 17/20initiation of eculizumab led to a TMA blood samples from pregnant women from0% age 2 months to adults, with dis- event-free status in 80% of patients receiving eculizumab. At least 23 live ease duration from26 Weeksless than 1 month1 Yearat 26 weeks and 85% at 1 year of births have been recorded in the 11 to more than 2 decades, and across treatment. Furthermore, there was years during which eculizumab has broad stages of chronic kidney disease. a continuous26-week decline in mean eGFRExtension been used in the treatment of paroxys- The studiesPretreatment were notPeriod controlled for 2 for theTreatment entire Periodpre-eculizumabTreatment obser -Period mal nocturnal hemoglobinuria (PNH),25 reasons: because there was no clearly vation period of 420 days, despite with no evidence of fetal deformities.47 established effective reference treatment the treating physician’s best applica- 19,41 22 Until recently, the majority20 for aHUS and because of the rarity of tion of plasma therapy (Figure 3). of published data with eculizumab the disease. (Controlled trials with ecu- Institution of eculizumab resulted in in aHUS came from case reports and lizumab were undertaken, however, for significant (P<.01) increases in mean industry-sponsored prospective15 trials an equally rare condition, PNH.) eGFR, beginning within 2 to 4 weeks that had been released only in abstract In trial 1, which involved cases of therapy and extending throughout form.15,18,29,48-52 Those results, which of recent onset, progressive disease, the 504-day observation period.22 10 led to the approval of eculizumab platelet counts were normalized in 82% These data support the conclusions for the treatment of aHUS by the of patients, and all hematologic values of one recent review that “eculizumab FDA and by the European Medicines5 were normalized in 76% by week 26 appears to be becoming the treatment Agency (EMEA), are now available in of treatment.41 Normalization of both of choice for aHUS without initial complete articles.41 platelet counts and all hematologic val- plasma therapy.”31 0

ClinicalMean Change From Baseline (mL/min/1.73m  ) –5 Advances in Hematology & Oncology Volume 11, Issue 10, Supplement 15 October 2013 9

–10 -70 -68 -66 -64 -62 -60 -58 -56 -54 -52 -50 -48 -46 -44 -42 -40 -38 -36 -34 -32 -30 -28 -26 -24 -22 -20 -18 -16 -14 -12 -10 -8 -6 -4 -2 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56 58 60 62 64

No. of patients 3 6 10 9 11 13 12 16 15 12 14 14 15 16 16 17 20 20 20 19 20 20 19 20 20 19 18 17 18 18 14 11 13 9 Age 2 months Adults

Duration From <1 month 286 months aHUS Diagnosis to Study Identied Genetic None identied Multiple per patient Complement Mutations

TMA in Patients With Normal platelet count Reduced platelet count

Degree of Organ Damage CKD Stage 1 CKD Stage 5

Dialysis None 3 times a week

PEx/PI No intervention* 230 interventions

Renal Transplant None 3 prior kidney grafts lost REVIEW ARTICLE

85 90% enabled discontinuation of hemodialy- 80 (62–97) (56–94) sis was 4 months should not be seen 80% as a limit to the potential for complete

70% renal recovery. In terms of other laboratory param- 60% eters consistent with a TMA, platelet counts should normalize, or at least 50% TMA event‐free status: increase significantly, by weeks 1 to 2 For 12 consecutive weeks, no of treatment (after 1 or 2 doses of ecu- 40% decrease in platelet count >25% from baseline, AND no PEx/PI, lizumab), in concert with cessation of all 30% AND no new dialysis plasma therapy and no need to initiate new dialysis. By week 4, there should be 20% continued increases in platelet counts;

10% normalization of the haptoglobin; and

Patients Achieving TMA Event–Free Status a normalization, or at least a marked 16/20 17/20 0% decrease, in LDH. 26 Weeks 1 Year Monitoring plasma levels of the drug does not appear to be helpful, at

Figure 2. TMA event-free status was achieved in 80% of patients26-week at 26 weeks, and Extension least in adults. One measure of drug 85% of patientsPretreatment at 1 year, withPeriod eculizumab therapy. PEx/PI,Treatment plasma Period exchange/infusion;Treatment Period activity may be obtained through a 25 TMA, thrombotic microangiopathy. Data from Licht C et al. ASH Abstract 985. Blood. simple CH assessment; it should be 22 50 2012;120(21). completely suppressed within a day of 20 There were no complement-related For example, in one series, 13 initiating eculizumab. But it is clear, genetic mutations or CFH autoanti- renal transplant recipients were given from my own experience and that of

15 body detectable in 24% of patients in eculizumab for posttransplant aHUS several colleagues, that certain patients trial 1 and 30% of patients in trial 2, recurrence.53 A complete reversal of may not maintain a clinical or labora- but the presence or absence of these ongoing TMA activity was obtained in tory response via the standard biweekly 10 abnormalities had no impact on clini- all of these patients, and the interval dosing schedule. They may require cal response to drug.41 This finding is between onset of the aHUS episode adjustment to every 10 to 12 days to 5 consistent with earlier case series19,33 and drug initiation inversely correlated maintain a stable course. as well as several studies showing that with the degree of recovery in renal There is generally no role for PEx 53 0 mortality or progression to ESRD are function. In a more recent review after initiation of eculizumab. How- identical whether or not patients have a of 11 pediatric and 13 adult patients ever, if PEx is continued during the complement-related mutation.2,9 with aHUS treated with eculizumab, 4-week treatment induction period, a

Mean Change From Baseline (mL/min/1.73m  ) –5 hematologic recovery occurred in supplemental dose of 600 mg of ecu- The Extent and Kinetics of Clinical 100%.19 Creatinine declined by at least lizumab must be administered within –10 and Laboratory Responses to -70 -68 -66 -64 -62 -60 -58 -56 -54 -52 -50 -48 -46 -44 -42 -40 -38 -36 -34 -32 -30 -28 -26 -24 -22 -20 -18 -16 -14 -12 -10 -825%-6 -4 -2 0in2 90%4 6 8 10 of12 14 the16 18 20pediatric22 24 26 28 30 32 34cases36 38 40 but42 44 46 48 50 526054 56 58minutes60 62 64 after each PEx. Dosage Eculizumab in only 69.2% of adult cases. Again, adjustment for hemodialysis has not

No. of patients 3 Following6 10 9 11 a13 recognized12 16 15 12 14episode14 15 16of16 17 the20 shorter20 20 19 the20 20interval19 20 20between19 18 17onset18 18 14 been11 13 determined,9 but in my experi- aHUS, 90% of adults relapse within of clinical symptoms and eculizumab ence, supplemental doses have not 1 year absent appropriate treatment.40 therapy, the better the response.19 been given. Beyond the first year, the risk of It is presently unclear whether relapse is approximately 25%.40 These there is an outer limit, related to time Adverse Events rates are almost certainly underes- on hemodialysis or extent of sclerosis In the previously described trials, the timates; prior to the availability of on kidney biopsy performed prior to most frequently reported adverse events eculizumab, most patients with severe initiating eculizumab, when dialysis (≥15% per patient incidence) were aHUS progressed to ESRD with their cannot be successfully discontinued hypertension, upper respiratory tract first episode. Clearly, eculizumab with the drug. In the 2 prospective and urinary tract infections, diarrhea, should be initiated as early as pos- studies described above, some recovery headache, anemia, emesis, nausea, and sible after the diagnosis of aHUS is of renal function was seen across all leukopenia.41 None of these events made. This is of most importance CKD stages. But the numbers were were severe enough to require cessation when attempting to realize maximal relatively small; the fact that the lon- of therapy or dose modification. No recovery of renal function. gest duration for which eculizumab patients experienced infusion reactions

10 Clinical Advances in Hematology & Oncology Volume 11, Issue 10, Supplement 15 October 2013 Age 2 months Adults

Duration From <1 month 286 months aHUS Diagnosis to Study Identied Genetic None identied Multiple per patient Complement Mutations

TMA in Patients With Normal platelet count Reduced platelet count

Degree of Organ Damage CKD Stage 1 CKD Stage 5

Dialysis None 3 times a week

PEx/PI No intervention* 230 interventions

Renal Transplant None 3 prior kidney grafts lost

85 90% 80 (62–97) (56–94) 80%

70%

60%

50% TMA event‐free status: For 12 consecutive weeks, no 40% decrease in platelet count >25% from baseline, AND no PEx/PI, 30% AND no new dialysis

20%

10% Patients Achieving TMA Event–Free Status ATYPICAL16/20 HEMOLYTIC 17/20UREMIC SYNDROME (AHUS): TREATING THE PATIENT 0% 26 Weeks 1 Year

26-week Extension Pretreatment Period Treatment Period Treatment Period 25

20

15

10

5

0

Mean Change From Baseline (mL/min/1.73m  ) –5

–10 -70 -68 -66 -64 -62 -60 -58 -56 -54 -52 -50 -48 -46 -44 -42 -40 -38 -36 -34 -32 -30 -28 -26 -24 -22 -20 -18 -16 -14 -12 -10 -8 -6 -4 -2 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56 58 60 62 64

No. of patients 3 6 10 9 11 13 12 16 15 12 14 14 15 16 16 17 20 20 20 19 20 20 19 20 20 19 18 17 18 18 14 11 13 9

Figure 3. Estimated glomerular filtration rates continue to improve following initiation of eculizumab in patients with chronic atypical hemolytic uremic syndrome. The pretreatment period includes use of plasma and plasma exchange. Adapted from Licht C et al. ASH abstract 985. Blood. 2012;120(21).22 that required discontinuation. How- ciprofloxacin at 500 mg twice daily, One should use caution when ever, severe infusion reactions are a risk rifampin at 600 mg orally twice daily, administering eculizumab to patients attendant upon administration of any or penicillin VK at 250 mg 4 times with any systemic infection. However, foreign protein, and if they occur, the daily. It is also good practice to check if a patient develops a meningococcal drug should be stopped and appropri- antimeningococcal antibody titers if or other infection while taking this ate medical therapy provided. the patient has an underlying immune drug, it should not be discontinued. Severe and fatal meningococcal deficiency. Finally, recall that current Recall that infection is one of the major infections have occurred in patients trivalent and tetravalent vaccines do activators of the alternative comple- treated with eculizumab, primarily in not protect against meningococcal ment pathway, and the consequences the setting of PNH. As described ear- serotype B. That serotype is of very low of an infection would appear to out- lier, this reaction relates to the drug’s prevalence in the United States but weigh any immune benefit achieved by potent inhibition of terminal comple- common in Europe. Therefore, outside stopping the drug in that setting. ment components. Patients must be of the United States and Canada, pro- immunized with a meningococcal phylactic antibiotics, usually penicillin, Defining Treatment Duration With vaccine, preferably the tetravalent are often continued for the duration of Eculizumab preparation, at least 2 weeks prior to eculizumab treatment. The duration of treatment with ecu- administration of the first dose of The importance of this informa- lizumab is an unresolved issue. One eculizumab. In acute aHUS, the risk tion is reinforced by the fact that might hypothesize that if the original of delaying anticomplement therapy eculizumab is available only through a condition(s) that unmasked the disease often outweighs the risk of acute Risk Evaluation and Mitigation Strat- was removed, then extended therapy meningitis. It is thus standard prac- egy (REMS) program that prescribers with the drug would be unnecessary tice to vaccinate and simultaneously must enroll in. It is a simple procedure, until and unless the unmasking factor start a 2-week course of prophylactic with details available by telephone recurred. For example, in a study of 30 antibiotics. I have used 3 oral agents: (888-765-4747). index cases with aHUS and identified

Clinical Advances in Hematology & Oncology Volume 11, Issue 10, Supplement 15 October 2013 11 REVIEW ARTICLE

mutations in CFH, CFI, and/or MCP, closely for clinical signs of a TMA as to therapy based upon the presence of there was a 67% clinical penetrance as well as any changes in hemoglobin, anti-CFH autoantibodies.41 In the vast assessed by renal disease by age 40 years, LDH, and creatinine for at least 12 majority of instances, such patients and 100% by age 65 years.54 Yet in 30 weeks. However, based upon my own have germline mutations in comple- relatives of those index cases, who bore experience, clinical case reports, and ment regulatory proteins, so it is unclear identical mutations, there was only an the opinions of other experts,40 I would what role, if any, the autoantibody has 11% penetrance in terms of onset of recommend that such close follow-up in their disease. However, some investi- renal disease by age 40 years; one such evaluation take place twice a month for gators have raised the issue of whether relative did not develop overt renal dis- the first 2 months and then monthly for immunosuppression alone, using ease until age 88 years.54 a year. Data gathered through prospec- steroids and pulses of high-dose cyclo- That being said, it is clear that in tive studies are clearly needed. In one phosphamide, might be effective. Such most instances, eculizumab cannot attempt at obtaining such information, a protocol induced sustained remissions be stopped after the 4-week induc- our group is following the terminal in 4 pediatric aHUS patients, only 1 tion. For example, among the 67 complement component (C5a and of whom required maintenance pred- patients treated in the 2 prospective MAC) staining patterns of patients who nisone, after follow-up periods of 4 (N=37) studies and one observational have had serial biopsies (skin, ileum) months (1 patient), 4 years (2 patients), (N=30) study reviewed above, clinical performed as part of their clinical assess- and 6 years (1 patient).31 This scenario, deterioration and laboratory signs ment over the course of 1 to 2 years. It which represents 6% to 10% of aHUS of TMA were observed in 27% of appears that 1 to 1.5 years of therapy cases in children (but, in my experi- patients who discontinued therapy are necessary to resolve MAC deposi- ence, far fewer in adults), suggests the or dose-interrupted within the first tion in tissue microvasculature, despite need for further study of the treatment year. Five of the patients who did the fact that the patients are in clinical options in CFH autoantibody–associ- not receive the recommended dose and laboratory remission while on the ated disease. or duration of eculizumab developed drug (unpublished data). This finding reactions such as changes in mental is consistent with the turnover rate of Treating aHUS Arising in the status, seizures, angina, thrombosis or microvascular endothelium, which is Context of Other Conditions dyspnea, thrombocytopenia, elevated in the range of 100 to 1000 days, vary- As summarized in Table 1, many condi- LDH, and elevated serum creatinine ing by tissue lineage. However, it does tions linked to activation of the alterna- following the first missed dose. Of the not imply that alternative complement tive complement pathway can them- 4 patients who were then immediately pathway activation itself would be ter- selves present with signs and symptoms restarted on the drug, 3 were able to minated in the absence of drug mainte- of a TMA. Unless the occurrence of regain normal renal function. The nance, nor are there any controlled trials aHUS as a secondary disorder in such fourth patient progressed to ESRD to relate such preliminary biopsy obser- settings is recognized, appropriate despite intensive eculizumab therapy. vations to the clinical course while off therapy will not be initiated. Noris and Relapse has been reported in of eculizumab. colleagues found that 25% (47 of 191) several case studies of patients who After eculizumab has been discon- of patients with aHUS have coexisting discontinued eculizumab within a tinued, it is important to consider the disorders, regardless of whether a known year of initiating therapy.19,29,39,48,50,55 likelihood of aHUS relapse if the event mutation in a complement regulatory For example, clinical relapse occurred that unmasked the disease is expected pathway could be identified.19 These dis- after eculizumab was discontinued in to recur. Prophylactic administration orders included malignant hypertension 2 patients with classic CFH mutations: of eculizumab may then be indicated. (30%); posttransplant TMA, including a 20-year-old woman with postpartum Likely scenarios could include a second use of calcineurin inhibitors (23%); and aHUS relapsed within 6 months of pregnancy in a patient with a prior preg- pregnancy-related conditions (21%).17 stopping the drug, which had main- nancy-related aHUS, and renal trans- As mentioned, eculizumab is indicated tained her in complete remission for plantation, particularly in patients with a only for the treatment of patients 9 months,55 and one of our own early high risk of another TMA manifestation. with aHUS to inhibit complement- patients, a 28-year-old man with But again, this is highly speculative. mediated thrombotic microangiopathy. postinfection aHUS, relapsed within Appropriate use of eculizumab in these 30 days of stopping the drug that had Treating aHUS Associated With settings may demand more than just maintained a complete remission for CFH Autoantibody documenting a TMA with altered 2 months.39 According to the package The 2 prospective, industry-sponsored platelet count, hemolysis, schistocytes, insert for eculizumab, after stopping trials of eculizumab in aHUS described serum complement abnormalities, and treatment, patients should be followed above found no difference in response organ involvement in conjunction with

12 Clinical Advances in Hematology & Oncology Volume 11, Issue 10, Supplement 15 October 2013 ATYPICAL HEMOLYTIC UREMIC SYNDROME (AHUS): TREATING THE PATIENT

normal ADAMTS13 activity. Adjust- pletely distinct from aHUS and usually pregnancy-related HELLP (hemolysis, ments may be necessary for patients responds to PEx or second-line immu- elevated liver enzymes, low platelet with such conditions as: nosuppressive therapies. However, the count) and preeclampsia, history of stem massive platelet thrombi generated as cell and organ transplantation, graft-vs- Autoimmune disease. SLE may mani- a consequence of severe ADAMTS13 host disease, and gemcitabine-associated fest as a lupus nephritis with altered cre- deficiency in TTP does activate the TMA. As one might anticipate, patients atinine; schistocytes as a consequence of alternative complement pathway,58 as who have TMAs associated with those renal injury; elevated LDH; hemolysis, does free heme, which is released as a conditions and diagnosable as aHUS per which may be Coombs negative; and consequence of any hemolytic anemia, the criteria outlined at the beginning of a low C3 level. ADAMTS13 activity including that associated with TTP.59 this review are generally unresponsive to should be greater than 5% to 10%. With a coexistent complement regula- PEx but have been successfully treated However, aHUS arising from alterna- tory defect, aHUS might then develop. with eculizumab.61-65 tive complement activation as a con- This scenario appeared to be the case in As noted above, transient responses sequence of SLE could look the same. a young man we treated who presented to PEx in aHUS vary from 30% to Kidney biopsy may be necessary to dis- with a TMA characterized by a plate- 80%, depending upon the mutations tinguish the vasculitis typical of lupus, let count less than 20,000/mm3 and implicated. Different complement- which may occur along with deposi- ADAMTS13 activity less than 5% with linked mutations may also be critical in tion of immunoglobulin and proximal a classic IgG ADAMTS13 inhibitor. determining susceptibility to a comple- complement components C4 and C1q, He remained comatose, with recurrent ment-linked TMA in certain settings, from the TMA, pauci-inflammatory grand mal seizures, for 22 days despite such as stem cell transplants. Mutations response, and deposition of terminal receiving plasma exchange of more than common in aHUS outside the stem cell complement components (C5a and 220 L, as well as rituximab, vincristine, transplant setting are much rarer than in MAC) that are consistent with aHUS. and steroids. He woke from the coma TMAs following such transplants, so it is Catastrophic antiphospholipid syn- when eculizumab was initiated.36 important to establish careful monitoring drome (CAPS) is a prothrombotic disor- Workup revealed MAC deposition in of how these patients respond to C5-tar- der involving multiple small vascular beds the microvasculature on skin biopsy.36 geted intervention with eculizumab.66 and activation of terminal complement An initial attempt to identify a comple- components. It can also present with ment regulatory mutation through When treatment with eculizumab is signs and symptoms of a TMA that are available commercial channels was unclear. There are minor subsets of indistinguishable from those in aHUS.56 negative36—recall that such platforms aHUS patients, diagnosed as described If CAPS does not respond to appropriate will not recognize at least 30% of above, in whom the disease is therapy, one should rule out the exis- known aHUS-linked mutations—but a genetically based but does not involve tence of underlying aHUS, which could subsequent, extensive genetic analysis in complement. Therefore, these patients respond to eculizumab as illustrated in a the laboratory did reveal a CFH muta- would not necessarily be expected to recent case report.57 tion consistent with aHUS.39 respond to eculizumab. One recently Similarly, thienopyridines (ticlopi- identified such syndrome involves STEC-HUS. Eculizumab is not dine and clopidogrel) can cause a TMA mutations in DGKE, a gene encoding approved or indicated for the treatment characterized by an ADAMTS13 of diacylglycerol kinase-ε. Mutations are of STEC-HUS. However, Shiga toxin less than 5% with an ADAMTS13 cosegregated with clinical aHUS in 9 is a potent diarrhea-associated infec- inhibitor, which would be appropri- unrelated kindreds.67 The mechanism tion, and related disorders can trigger ately classified by these criteria as TTP. of how pathologic thrombosis and endothelial complement deposition.58 This disorder, however, is usually resis- aHUS develop in this setting, and how If a patient had an underlying inability tant to PEx. We reported CFH muta- it might be treated, is unclear.67 to regulate complement, then classic tions in 4 of 4 cases of thienopyridine- aHUS, and not just STEC-HUS, could linked TTP resistant to PEx.60 The role The Cost of Treating aHUS develop. Indeed, eculizumab has been of eculizumab in these thienopyridine- On a per weight basis, eculizumab is used in this setting when supportive induced TMAs is unknown. the ninth most expensive drug in our care and PEx were ineffective.34 pharmacy. The cost may be a factor TTP. As emphasized above, TTP is Pregnancy, malignancy, chemother- prompting clinicians to prematurely generally an acquired, not familial, dis- apy, medications, and transplantation. discontinue the drug, or to prefer order related to an inability to regulate Mutations linked to complement con- initiating treatment with PEx. In a platelet thrombus formation rather trol and thought to be etiologic in aHUS pediatric population, where drug dos- than to regulate complement. It is com- have also been identified in patients with ing is weight-based, cost should not be

Clinical Advances in Hematology & Oncology Volume 11, Issue 10, Supplement 15 October 2013 13 REVIEW ARTICLE

an issue. As one group emphasized, in • Eculizumab should be initiated Microangiopathies. Prognostic value of anti-ADAMTS 13 antibody features (Ig isotype, titer, and inhibitory these cases “the cost is significantly less as early as possible after making effect) in a cohort of 35 adult French patients under- than that of dialysis and regular PEx.”68 the diagnosis of aHUS, in order to going a first episode of thrombotic microangiopathy It is a concern with hospitalized adult attempt optimal recovery of renal with undetectable ADAMTS 13 activity. Blood. 2007;109(7):2815-2822. patients, however, among whom drug function and prevent an ongoing 6. Cohen JA, Brecher ME, Bandarenko N. Cellular cost affects DRG-based reimburse- TMA with extrarenal manifestations. source of serum lactate dehydrogenase elevation in ments. (Most insurance plans cover its • Many conditions linked to activation patients with thrombotic thrombocytopenic purpura. J Clin Apher. 1998;13(1):16-19. use in the outpatient setting.) Zuber and of the alternative complement path- 7. Cataland SR, Yang S, Wu HM. The use of ADAMTS13 colleagues have analyzed the expense way can themselves present with signs activity, platelet count, and serum creatinine to differen- of aHUS inpatient treatment. They and symptoms of a TMA. Unless the tiate acquired thrombotic thrombocytopenic purpura from other thrombotic microangiopathies. Br J Haema- took into account the cost of plasma— possibility of aHUS occurring in tol. 2012;157(4):501-503. approximately $4200 for a single PEx— patients with other potential inciting 8. Kremer Hovinga JA, Vesely SK, Terrell DR, Läm- as well as charges related to factors such disorders is considered, appropriate mle B, George JN. Survival and relapse in patients with thrombotic thrombocytopenic purpura. Blood. as personnel, equipment amortization, therapy cannot be initiated. 2010;115(8):1500-1511, quiz 1662. arteriovenous catheterization, dialysis, • The vast majority of cases of aHUS 9. Noris M, Caprioli J, Bresin E, et al. Relative role extrarenal complications, and vascular appear related to germline mutation(s) of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype. catheter infections. Overall, the cost of 3 in 1 or more complement regulatory Clin J Am Soc Nephrol. 2010;5(10):1844-1859. months of treatment with eculizumab in proteins. Given the current nature 10. Loirat C, Frémeaux-Bacchi V. Atypical hemolytic adults is on the same order of magnitude of generally available technology to uremic syndrome. Orphanet J Rare Dis. 2011;6(1):60-90. 11. Mitra D, Jaffe EA, Weksler B, Hajjar KA, Soderland as the money saved by rescuing a renal detect these mutations, they cannot C, Laurence J. Thrombotic thrombocytopenic purpura allograft from early failure.53 be identified in at least 30% of cases. and sporadic hemolytic-uremic syndrome plasmas induce However, disease severity, mortality, apoptosis in restricted lineages of human microvascular endothelial cells. Blood. 1997;89(4):1224-1234. Summary and response to eculizumab are equiv- 12. Hosler GA, Cusumano AM, Hutchins GM. alent whether or not such mutations Thrombotic thrombocytopenic purpura and hemo- • Eculizumab (Soliris) is a potent can be identified in a given patient. lytic uremic syndrome are distinct pathologic entities. A review of 56 autopsy cases. Arch Pathol Lab Med. inhibitor of the terminal complement 2003;127(7):834-839. pathway. It is indicated for the treat- Acknowledgment 13. Upadhyaya K, Barwick K, Fishaut M, Kashgarian ment of patients with aHUS to inhibit This article was supported by funding from M, Siegel NJ. The importance of nonrenal involve- ment in hemolytic-uremic syndrome. Pediatrics. complement-mediated thrombotic Alexion Pharmaceuticals, Inc. This article 1980;65(1):115-120. microangiopathy, including adverse reflects the opinions and views of the author 14. Sellier-Leclerc A-L, Frémeaux-Bacchi V, Dragon- effects on renal function. and was developed independently of Alex- Durey M-A, et al; French Society of Pediatric Nephrol- ogy. Differential impact of complement mutations on • A new patient presenting with labo- ion Pharmaceuticals, Inc. Dr Laurence is a clinical characteristics in atypical hemolytic uremic ratory and clinical signs of a TMA member of the Speakers’ Bureau of Alexion syndrome. J Am Soc Nephrol. 2007;18(8):2392-2400. should immediately begin plasma Pharmaceuticals, Inc. and has received a 15. Ohanian M, Cable C, Halka K. Eculizumab safely reverses neurologic impairment and eliminates need for therapy while awaiting the results research grant from them. dialysis in severe atypical hemolytic uremic syndrome. of tests to distinguish among TTP, Clin Pharmacol. 2011;3:5-12. aHUS, and STEC-HUS. Evaluation References 16. Rock GA, Shumak KH, Buskard NA, et al; Cana- dian Apheresis Study Group. Comparison of plasma should include ADAMTS13 activ- exchange with plasma infusion in the treatment of ity and inhibitor assays, testing for 1. Laurence J. Atypical hemolytic uremic syndrome thrombotic thrombocytopenic purpura. N Engl J Med. (aHUS): making the diagnosis. Clin Adv Hematol Shiga toxin, and consideration of 1991;325(6):393-397. Oncol. 2012;10(suppl 17):1-12. 17. Noris M, Remuzzi G. Atypical hemolytic-uremic the likelihood of an aHUS vs TTP 2. Caprioli J, Noris M, Brioschi S, et al; International syndrome. N Engl J Med. 2009;361(17):1676-1687. diagnosis based on presenting platelet Registry of Recurrent and Familial HUS/TTP. Genetics 18. Waters AM, Licht C. aHUS caused by complement of HUS: the impact of MCP, CFH, and IF mutations count and serum creatinine level. The dysregulation: new therapies on the horizon. Pediatr on clinical presentation, response to treatment, and Nephrol. 2011;26(1):41-57. relative risk of an aHUS vs a TTP outcome. Blood. 2006;108(4):1267-1279. 19. Zuber J, Fakhouri F, Roumenina LT, Loirat C, diagnosis in a patient with a TMA is 3. Franchini M, Montagnana M, Targher G, Lippi G. Frémeaux-Bacchi V; French Study Group for aHUS/ Reduced von Willebrand factor-cleaving protease levels C3G. Use of eculizumab for atypical haemolytic much greater if the presenting platelet in secondary thrombotic microangiopathies and other 3 uraemic syndrome and C3 glomerulopathies. Nat Rev count is more than 30,000/mm and diseases. Semin Thromb Hemost. 2007;33(8):787-797. Nephrol. 2012;8(11):643-657. the serum creatinine is more than 1.7. 4. Coppo P, Schwarzinger M, Buffet M, et al; French 20. Licht C, Weyersberg A, Heinen S, et al. Successful Reference Center for Thrombotic Microangiopathies. • The clinician should recognize the plasma therapy for atypical hemolytic uremic syndrome Predictive features of severe acquired ADAMTS13 defi- caused by factor H deficiency owing to a novel muta- amount of plasma usually required ciency in idiopathic thrombotic microangiopathies: the tion in the complement cofactor protein domain 15. to effect a complete response in TTP, French TMA reference center experience. PLoS ONE. Am J Kidney Dis. 2005;45(2):415-421. 2010;5(4):e10208. which typically involves 5 episodes of 21. Licht C, Pluthero FG, Li L, et al. Platelet-associated 5. Ferrari S, Scheiflinger F, Rieger M, et al; French complement factor H in healthy persons and patients PEx. There is no role for PEx in aHUS. Clinical and Biological Network on Adult Thrombotic with atypical HUS. Blood. 2009;114(20):4538-4545.

14 Clinical Advances in Hematology & Oncology Volume 11, Issue 10, Supplement 15 October 2013 ATYPICAL HEMOLYTIC UREMIC SYNDROME (AHUS): TREATING THE PATIENT

22. Licht C, Muus P, Legendre CM, et al. Eculizumab 37. Bell WR, Braine HG, Ness PM, Kickler TS. Improved 52. Greenbaum L, Legendre CM, Babu S, et al. Eculi- (ECU) safety and efficacy in atypical hemolytic uremic survival in thrombotic thrombocytopenic purpura- zumab (ECU) in atypical hemolytic uremic syndrome syndrome (aHUS) patients with long disease duration hemolytic uremic syndrome. Clinical experience in 108 (aHUS) patients with progressing thrombotic micro- and chronic kidney disease (CKD): 2-year results [ASH patients. N Engl J Med. 1991;325(6):398-403. angiopathy (TMA): 2-year data [ASH abstract 2084]. abstract 985]. Blood. 2012;120(21). 38. Tsai H-M. Pathophysiology of thrombotic throm- Blood. 2012;120(21). 23. Frémeaux-Bacchi V, Fakhouri F, Garnier A, et al. bocytopenic purpura. Int J Hematol. 2010;91(1):1-19. 53. Zuber J, Le Quintrec M, Krid S, et al; French Study Genetics and outcome of atypical hemolytic uremic syn- 39. Tsai E, Chapin J, Laurence JC, Tsai HM. Use of Group for Atypical HUS. Eculizumab for atypical drome: a nationwide French series comparing children eculizumab in the treatment of a case of refractory, hemolytic uremic syndrome recurrence in renal trans- and adults. Clin J Am Soc Nephrol. 2013;8(4):554-562. ADAMTS13-deficient thrombotic thrombocytopenic plantation. Am J Transplant. 2012;12(12):3337-3354. 24. Réti M, Farkas P, Csuka D, et al. Complement purpura: additional data and clinical follow-up. Br J 54. Sullivan M, Rybicki LA, Winter A, et al. Age-related activation in thrombotic thrombocytopenic purpura. J Haematol. 2013;162(4):558-559. penetrance of hereditary atypical hemolytic uremic syn- Thromb Haemost. 2012;10(5):791-798. 40. Fakhouri F, Frémeaux-Bacchi V, Loirat C. Atypi- drome. Ann Hum Genet. 2011;75(6):639-647. 25. Skerka C, Józsi M, Zipfel PF, Dragon-Durey cal hemolytic uremic syndrome: From the rediscovery 55. Carr R, Cataland SR. Relapse of aHUS after discontinu- M-A, Fremeaux-Bacchi V. Autoantibodies in haemo- of complement to targeted therapy. Eur J Intern Med. ation of therapy with eculizumab in a patient with aHUS lytic uraemic syndrome (HUS). Thromb Haemost. 2013;24(6):492-495. and factor H mutation. Ann Hematol. 2013;92(6):845-846. 2009;101(2):227-232. 41. Legendre CM, Licht C, Muus P, et al. Terminal com- 56. Giannakopoulos B, Krilis SA. The pathogen- 26. Roumenina LT, Jablonski M, Hue C, et al. plement inhibitor eculizumab in atypical hemolytic-ure- esis of the antiphospholipid syndrome. N Engl J Med. Hyperfunctional C3 convertase leads to comple- mic syndrome. N Engl J Med. 2013;368(23):2169-2181. 2013;368(11):1033-1044. ment deposition on endothelial cells and contrib- 42. Lara PN Jr, Coe TL, Zhou H, Fernando L, Hol- 57. Shapira I, Andrade D, Allen SL, Salmon JE. Brief utes to atypical hemolytic uremic syndrome. Blood. land PV, Wun T. Improved survival with plasma report: induction of sustained remission in recurrent 2009;114(13):2837-2845. exchange in patients with thrombotic thrombocytope- catastrophic antiphospholipid syndrome via inhibition 27. Noris M, Remuzzi G. Genetics and genetic testing nic purpura-hemolytic uremic syndrome. Am J Med. of terminal complement with eculizumab. Arthritis in hemolytic uremic syndrome/thrombotic thrombocy- 1999;107(6):573-579. Rheum. 2012;64(8):2719-2723. topenic purpura. Semin Nephrol. 2010;30(4):395-408. 43. Remuzzi G, Ruggenenti P, Codazzi D, et al. Combined 58. Noris M, Mescia F, Remuzzi G. STEC-HUS, atypi- 28. Neumann HPH, Salzmann M, Bohnert-Iwan B, et kidney and liver transplantation for familial haemolytic cal HUS and TTP are all diseases of complement activa- al. Haemolytic uraemic syndrome and mutations of the uraemic syndrome. Lancet. 2002;359(9318):1671-1672. tion. Nat Rev Nephrol. 2012;8(11):622-633. factor H gene: a registry-based study of German speak- 44. Saland JM, Shneider BL, Bromberg JS, et al. 59. Frimat M, Tabarin F, Dimitrov JD, et al. Complement ing countries. J Med Genet. 2003;40(9):676-681. Successful split liver-kidney transplant for factor H activation by heme as a secondary hit for atypical hemo- 29. Mache CJ, Acham-Roschitz B, Frémeaux-Bacchi associated hemolytic uremic syndrome. Clin J Am Soc lytic uremic syndrome. Blood. 2013;122(2):282-292. V, et al. Complement inhibitor eculizumab in atypical Nephrol. 2009;4(1):201-206. 60. Chapin J, Eyler S, Smith R, Tsai HM, Laurence hemolytic uremic syndrome. Clin J Am Soc Nephrol. 45. Saland JM, Ruggenenti P, Remuzzi G; Consensus J. Complement factor H mutations are present in 2009;4(8):1312-1316. Study Group. Liver-kidney transplantation to cure ADAMTS13-deficient, ticlopidine-associated thrombotic 30. Massart A, Golmarvi S, Hachimi-Idrissi S, et al. atypical hemolytic uremic syndrome. J Am Soc Nephrol. microangiopathies. Blood. 2013;121(19):4012-4013. Complement factor H functional assay may help to 2009;20(5):940-949. 61. Fakhouri F, Jablonski M, Lepercq J, et al. Factor H, monitor atypical haemolytic uraemic syndrome: a pilot 46. Rother RP, Rollins SA, Mojcik CF, Brodsky RA, membrane cofactor protein, and factor I mutations in study. Acta Clin Belg. 2013;68(1):9-14. Bell L. Discovery and development of the comple- patients with hemolysis, elevated liver enzymes, and low 31. Sana G, Dragon-Durey M-A, Charbit M, et al. ment inhibitor eculizumab for the treatment of par- platelet count syndrome. Blood. 2008;112(12):4542-4545. Long-term remission of atypical HUS with anti-factor oxysmal nocturnal hemoglobinuria. Nat Biotechnol. 62. Salmon JE, Heuser C, Triebwasser M, et al. Muta- H antibodies after cyclophosphamide pulses. Pediatr 2007;25(11):1256-1264. tions in complement regulatory proteins predispose Nephrol. 2013 Jul 19. [Epub ahead of print] 47. Kelly R, Arnold L, Richards S, et al. The manage- to preeclampsia: a genetic analysis of the PROMISSE 32. Józsi M, Licht C, Strobel S, et al. Factor H auto- ment of pregnancy in paroxysmal nocturnal haemo- cohort. PLoS Med. 2011;8(3):e1001013. antibodies in atypical hemolytic uremic syndrome globinuria on long term eculizumab. Br J Haematol. 63. Jodele S, Licht C, Goebel J, et al. Abnormalities in correlate with CFHR1/CFHR3 deficiency.Blood . 2010;149(3):446-450. the alternative pathway of complement in children with 2008;111(3):1512-1514. 48. Nürnberger J, Philipp T, Witzke O, et al. Eculi- hematopoietic stem cell transplant-associated thrombotic 33. Goodship T, Smith RJ, Legendre CM, et al. Eculi- zumab for atypical hemolytic-uremic syndrome. N Engl microangiopathy. Blood. 2013;122(12):2003-2007. zumab (ECU) is effective in patients (pts) with atypi- J Med. 2009;360(5):542-544. 64. Peffault de Latour R, Xhaard A, Frémeaux-Bacchi cal hemolytic uremic syndrome (aHUS) regardless of 49. Zimmerhackl LB, Hofer J, Cortina G, et al. Pro- V, et al. Successful use of eculizumab in a patient with underlying genetic mutations or complement factor H phylactic eculizumab after renal transplantation in post-transplant thrombotic microangiopathy. Br J Hae- (CFH) auto-antibodies [ASN abstract TH-PO442]. atypical hemolytic-uremic syndrome. N Engl J Med. matol. 2013;161(2):279-280. Proc Amer Soc Nephrol. 2012. 2010;362(18):1746-1748. 65. Ustwani OAI, Lohr J, Dy G, et al. Eculizumab 34. Lapeyraque A-L, Malina M, Frémeaux-Bacchi V, et 50. Larrea CF, Cofan F, Oppenheimer F, Campistol therapy for gemcitabine induced hemolytic uremic al. Eculizumab in severe Shiga-toxin-associated HUS. JM, Escolar G, Lozano M. Efficacy of eculizumab in syndrome: case series and concise review. J Gastrointest N Engl J Med. 2011;364(26):2561-2563. the treatment of recurrent atypical hemolytic-uremic Oncol. In press. 35. Coppo P, Veyradier A. Thrombotic microan- syndrome after renal transplantation. Transplantation. 66. Ricklin D, Cines DB. TMA: beware of comple- giopathies: towards a pathophysiology-based clas- 2010;89(7):903-904. ments. Blood. 2013;122(12):1997-1999. sification. Cardiovasc Hematol Disord Drug Targets. 51. Licht C, Muus P, Legendre C, et al. Eculizumab is 67. Lemaire M, Frémeaux-Bacchi V, Schaefer F, et al. 2009;9(1):36-50. an effective long-term treatment in patients with atypi- Recessive mutations in DGKE cause atypical hemolytic- 36. Chapin J, Weksler B, Magro C, Laurence J. cal hemolytic uremic syndrome (aHUS) previously uremic syndrome. Nat Genet. 2013;45(5):531-536. Eculizumab in the treatment of refractory idiopathic receiving chronic plasma exchange/infusion (PE/PI): 68. Kim JJ, Waller SC, Reid CJ. Eculizumab in atypical thrombotic thrombocytopenic purpura. Br J Haematol. extension study results clinically relevant [ASH abstract hemolytic-uremic syndrome allows cessation of plasma 2012;157(6):772-774. 3303]. Blood. 2011;118(21). exchange and dialysis. Clin Kidney J. 2012;5:34-36.

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Management of Atypical Hemolytic Uremic Syndrome (aHUS): A Review of Case Studies

Jeffrey Laurence, MD Professor of Medicine Division of Hematology and Medical Oncology New York Presbyterian Hospital and Weill Cornell Medical College New York, New York

anagement of atypical giopathic hemolytic anemia, thrombo- In addition, the patient had hemolytic uremic syndrome cytopenia, and acute renal failure. The prominent central nervous disease and (aHUS) poses several clinical patient’s ADAMTS13 activity level was remained in a coma for more than 7 Mchallenges. The following published case 68%. She underwent plasma exchange, weeks. This point is important because studies highlight important points con- and on day 3, she developed generalized many clinicians erroneously equate cerning events that precipitate aHUS; tonic-clonic seizures and was unrespon- severe CNS disease in the presence of interpretation of ADAMTS13 activity sive. On day 4, eculizumab therapy was TMA with TTP. In fact, almost half of in the differential diagnosis of aHUS; initiated, in a regimen of 900 mg intra- patients with aHUS have prominent the overlap in clinical manifestations venously each week for 4 weeks followed neurologic disease. of the thrombotic microangiopathies, by maintenance therapy at 1200 mg Another interesting aspect of this including severe central nervous system biweekly. After her third weekly infu- case is the way the patient presented. disease; use of the anti-complement sion of eculizumab, the patient no She ate a salad and developed bloody drug eculizumab in the treatment of longer needed hemodialysis, although diarrhea. Typically, when patients have aHUS; consideration of therapeutic she was still unresponsive. On week 7, bloody diarrhea in association with costs; and treatment duration. she abruptly awoke from her coma. She TMA, the initial thought is Shiga gradually improved neurologically and toxin–related HUS or STEC-HUS. aHUS in an Adult With TMA was close to her pre-illness state at the The authors appropriately tested for Presenting With Bloody time of the report. the presence of Shiga toxin, and it was Diarrhea and Mental Status negative. In the vast majority of cases, Changes Key Points aHUS results from the genetic inability There are several important messages to control complement activation, and Salem and colleagues1 reported a case raised by this case study. This patient’s the infections that cause diarrhea— of a 66-year-old woman with throm- diagnosis of TMA was made in the tra- particularly bloody diarrhea—are the botic microangiopathy (TMA). She ditional manner, based on laboratory most potent activators of the alternate presented to an intensive care unit findings and a clinical problem. The complement pathway. Therefore, it is with nausea, abdominal cramps, and patient was not thrombocytopenic on not uncommon for an aHUS patient intermittent bloody diarrhea. Nine days presentation, a reminder that patients to present with diarrhea, and it may be earlier, she had eaten a salad at a restau- with aHUS can have normal or near- bloody, regardless of Shiga toxin status. rant. She tested negative for Shiga toxin. normal platelet counts on presenta- ADAMTS13 activity was also The patient was not thrombocytopenic tion. The median platelet count in an measured. It was 68%, which is in the on presentation, but during the 36 aHUS patient is 30,000/µL to 40,000/ normal range, but more specifically, hours in which she was hospitalized, her µL, and can be near-normal on initial it was higher than 5%. aHUS is most platelet count decreased to 100,000/µL. presentation, in distinct contrast to the commonly distinguished from TTP She had 3+ schistocytes per high-power other major TMA, thrombotic throm- by an ADAMTS13 activity above 5% field. She developed anuria and mental bocytopenic purpura (TTP), which to 10%, in the absence of an autoan- status changes. is associated with a median platelet tibody inhibitor. The patient’s plasma She was transferred to the institu- count of 20,000/µL or lower.2 Indeed, exchange was stopped when the results tion of Salem and colleagues, where she this patient’s platelet count was normal of the ADAMTS13 test returned and was intubated for airway protection. upon initial hospitalization, declining proved normal, and treatment with Laboratory studies showed microan- some 36 hours after admission. eculizumab was initiated. Eculizumab

16 Clinical Advances in Hematology & Oncology Volume 11, Issue 10, Supplement 15 October 2013 ATYPICAL HEMOLYTIC UREMIC SYNDROME (AHUS): TREATING THE PATIENT

is the only therapy approved by the Although it is not necessary to cessful due to hematologic relapses. US Food and Drug Administration test patients for complement regula- She received 9 packed red blood cell (FDA) for this disease. There is no role tory factor mutations characteristic transfusions in 4 months and blood for plasma in the therapy of aHUS. All of aHUS, the authors in this case did priming for the plasma exchange ses- patients with an undifferentiated TMA so. They found an unusual mutation. sions. She developed 3 exacerbations of are usually given plasma until a defini- Approximately 30% of aHUS patients her TMA, all following infections. tive diagnosis is made. Indeed, there is have a mutation in complement factor Given that the responses to plasma enough complement regulatory protein H (CFH).4 This patient’s mutation were only partial, eculizumab was initi- in normal, fresh, frozen plasma to tide was in a relatively unusual part of the ated 2 weeks after administration of a the patient over in terms of hematologic system, complement 3. This mutation tetravalent meningococcus vaccine. After responses, but plasma will do little to does not cause loss of function; it the first dose, the patient’s hematologic impede ongoing tissue damage. causes a gain of function mutation in abnormalities resolved, and plasma Not only did the patient have the complement system that serves to exchange was stopped. One month later, prominent central nervous system dis- superactivate the pathway, or heighten dialysis was no longer needed. At the age ease, but she also had renal disease and the response of complement. of 18 months, her estimated glomerular was on hemodialysis. Eculizumab is filtration rate was 42 mL/min/1.73m2, usually administered in a weekly dose aHUS in an Infant and her neurodevelopmental progress for 4 weeks and then in a maintenance was excellent. dose every other week. At the time of the Kim and coworkers5 report a case of patient’s third weekly dose, her kidney a previously healthy 7-month-old Key Points function improved enough to discon- girl who presented with symptoms of This patient first presented with easy tinue dialysis. In another 3 weeks, her paleness and easy bruising that were bruising and low counts of platelets central nervous system disease improved. preceded by croup. She was anemic and hemoglobin. Her renal function This case highlights a question I and thrombocytopenic, but her kidney was normal, so she was thought to have am not infrequently asked by physi- function was normal. Six weeks later, an infectious process, possibly viral, cians: Can a patient who has been in a she developed dark urine, oliguria, which can cause hemolytic anemia or coma for a few months, and who has fluid overload, and hypertension. She thrombocytopenia. Six weeks later, been diagnosed with aHUS, still benefit did not have diarrhea or vomiting. however, when she became oliguric from treatment? This patient was in a Her hemoglobin was 4.5 g/dL, and with persistent thrombocytopenia and coma for 7 weeks, and she still was able her platelets were 72,000/µL. She had elevated creatinine, she was diagnosed to abruptly awake. The level of response microangiopathic hemolytic anemia with a TMA. to eculizumab can be quite dramatic. and elevated urea and creatinine. Her ADAMTS13 level was 25%, The authors noted that the patient The clinical diagnosis of aHUS was which can be misleading in terms of had to be intubated, but they did not made, and hemodialysis was initiated. distinguishing TTP from aHUS. The provide the reason for the intubation. It On the second day of hospitalization, authors noted that the normal range for may have been due to lung disease, which she underwent plasma infusion. On the ADAMTS13 activity in their hospital is a prominent issue in aHUS, whereas in fourth day, plasma exchange was initi- is 55% to 166%. The key point here TTP, TMA of the lung is very rare. ated. She underwent 9 plasma exchange is that the normal ranges reported by The authors did not report on the sessions in the first 2 weeks. She then hospitals are for people with healthy patient’s immune status in terms of developed hypertensive encephalopa- kidneys and livers, and no evidence of meningococcus, nor did they indicate thy, which required ventilation, contin- endothelial cell damage. In the pres- whether they gave her prophylactic uous venovenous hemofiltration, and ence of liver and kidney damage, there antibiotics. It should be noted that pressors. The encephalopathy resolved is an enzyme production problem. eculizumab blocks the terminal comple- after 5 days, and plasma exchange was Injury to endothelial cells can release ment components, which increases the continued 3 times weekly. von Willebrand factor, which can bind risk for gonorrhea and meningococ- The patient’s ADAMTS13 activity ADAMTS13, altering levels so they do cemia. It is necessary to vaccinate the was outside the range of normal for a not fall into the normal range. Thus, patient3; we recommend the tetravalent healthy infant or adult at 25%, but was they must be less than 5% to 10%, not vaccine against meningococcus. On clearly greater than 5% to 10%. The just lower than the reference range, to the day that the patient is vaccinated, methylmalonic acid level was normal. make a TTP diagnosis. The authors prophylactic therapy with antibiotics Dialysis was initiated to manage noted that the results of the standard should be administered for 2 weeks to her renal failure. Attempts to discon- complement tests they ordered, C3 and allow the vaccine to take effect. tinue plasma exchange were unsuc- C4, were normal. It might be expected

Clinical Advances in Hematology & Oncology Volume 11, Issue 10, Supplement 15 October 2013 17 REVIEW ARTICLE

that aHUS would lead to a low serum care unit. When eculizumab is given rheas, are the most potent activators of C3 with a normal or high C4, because on a weight-based basis for patients the alternate complement pathway. This it is a disease of uncontrolled activation who weigh less than 40 kg, it results in case highlights the second most potent of the terminal complement pathway. cost savings for the institution. activator, pregnancy. A TMA that However, such a classic pattern is seen occurs in pregnancy, or one that seems in only approximately 15% of cases, An aHUS Patient Who to be associated with the syndrome and C3 levels are low in less than half of Discontinues Therapy known as HELLP (hemolysis, elevated classic aHUS cases. liver enzymes, low platelet count), The authors measured meth- Carr and Cataland6 describe the case of eclampsia, or preeclampsia, may instead ylmalonic acid levels, a particularly a 20-year-old woman who developed a be an unmasking of the inability to con- important consideration in infants and TMA a week after delivery of a child. trol complement leading to aHUS. This children. Vitamin B12 deficiency, and The patient presented with bilateral is particularly important to consider in particularly pernicious anemia, can lower extremity edema, malaise, and the postpartum setting, as in this case, rarely mimic the laboratory and clini- bruising. Her hemoglobin was 6.0 g/dL, because the vast majority of classic cal signs of aHUS. her platelet count was 28,000/µL, a HELLP, eclampsia, and preeclampsia This patient received plasma serum creatinine was 5.27 mg/dL, and syndromes should resolve postpartum. exchanges for 2 weeks and still became her lactate dehydrogenase (LDH) was The authors made the diagnosis encephalopathic. She developed severe 2,114 U/L. She had 2+ schistocytes on relatively quickly, based on a normal central nervous system disease and peripheral smear. ADAMTS13 activity ADAMTS13. Because the patient had required ventilation. The tetravalent was 100%. A kidney biopsy suggested renal failure, they performed a kidney meningococcus vaccine was given to pre- TMA and acute tubular necrosis. Treat- biopsy. I would argue that based on pare for initiation of eculizumab therapy ment began with plasma exchange and her other diagnostic indicators—the 2 weeks later. In severe cases such as this prednisone. After 7 days, she achieved platelet count of 28,000/µL, elevated one, I favor rapid intervention rather a partial hematologic response, but LDH, serum creatinine of 5.3 mg/dL, than withholding the drug pending an her kidney function worsened and schistocytes in peripheral smear, and immune response to the vaccine. Ecu- she required hemodialysis. Based on ADAMTS13 of 100%—the kidney lizumab can be given at the same time her lack of improvement with plasma biopsy was unnecessary. However, the as the vaccine, as long as prophylactic exchange, her normal ADAMTS13 kidney biopsy was consistent with the antibiotics are also administered. activity, and findings consistent with a TMA. Treatment with eculizumab The first dose of eculizumab was TMA, the diagnosis of aHUS was then was initiated. followed by recovery of hematologic made, and treatment with eculizumab After 9 months, the patient decided parameters and improvement in renal was initiated. After 2 weeks, her platelet to discontinue therapy. She felt perfectly function. Dialysis was stopped a month count and LDH reached normal levels. fine, and her kidneys and laboratory after the first dose, and the patient had After 6 weeks, dialysis was no longer findings were normal. Six months later, full neurologic improvement. Plasma needed. Serum creatinine returned to she returned with complaints of fatigue had been given because the patient was normal levels after 12 weeks of treatment and easy bruising. Similar to the first thought to have TTP. The plasma had with eculizumab. Testing showed that case, these symptoms followed a respi- some effect on the patient’s hemato- the patient had a mutant allele for CFH. ratory tract infection that most likely logic parameters, but did not prevent After 9 months of treatment with superactivated the alternative comple- ongoing damage to her brain or her eculizumab, the patient elected to ment pathway. The patient was again kidneys. When appropriate therapy discontinue it. Six months later, she diagnosed with a classic TMA. She rap- was started, the recovery was dramatic. presented with fatigue, facial edema, idly began hemodialysis and treatment This case raises another point, and easy bruising that occurred after an with eculizumab. After 3 weeks, dialysis concerning costs of aHUS therapy. upper respiratory infection. Her platelet was no longer needed. Eculizumab is the only FDA-approved count was 54,000/µL, her serum creati- In the vast majority of cases, aHUS therapy for aHUS, but it is an expensive nine was 5.06 mg/dL, and she had 1+ is a chronic condition. Patients are born drug. The authors make the point that schistocytes. Hemodialysis and eculi- with a predisposition to it, that is, a in children—or anyone weighing less zumab were initiated. Three weeks later, complement or complement regulatory than 40 kg—dosing is weight-based. hemodialysis was no longer required. mutation. However, clinical penetrance For this infant, the cost of eculizumab varies greatly, and there have been was significantly less than dialysis and Key Points reports in the literature of first clinical regular plasma exchange. In addition, The first case highlighted the fact that presentation at the age of 88 years.7 this patient had to stay in the intensive infections, particularly infectious diar- Presentation of aHUS may relate to the

18 Clinical Advances in Hematology & Oncology Volume 11, Issue 10, Supplement 15 October 2013 ATYPICAL HEMOLYTIC UREMIC SYNDROME (AHUS): TREATING THE PATIENT

particular complement-linked muta- the patient off the drug by lengthening Acknowledgment tion inherited as well as exposure to the interval between the recommended This article was supported by funding from potent complement-activating events, biweekly maintenance doses after 12 or Alexion Pharmaceuticals, Inc. This article mainly pregnancy, infection, autoim- 18 months. There is some biologic basis reflects the opinions and views of the author mune disease, and surgery. for this suggestion. However, much and was developed independently of Alex- This case also emphasizes that the more information is needed before any ion Pharmaceuticals, Inc. Dr Laurence is a point at which eculizumab therapy such recommendation can be made. member of the Speakers’ Bureau of Alexion might be discontinued is unknown. The article by Carr and Cataland appro- Pharmaceuticals, Inc. and has received a This patient stopped therapy after 9 priately concludes that “. . . caution research grant from them. months. The drug package insert rec- should be exercised when considering ommends close follow-up for at least the discontinuation of eculizumab. References 12 weeks thereafter,3 and I would argue More detailed studies involving a larger for such follow-up to last at least a year number of subjects, both with and with- 1. Salem G, Flynn JM, Cataland SR. Profound neu- rological injury in a patient with atypical hemolytic and include examination of levels of out mutations, will be required before uremic syndrome. Ann Hematol. 2013;92(4):557-558. creatinine, platelets, and LDH. definitive recommendations can be 2. Zuber J, Fakhouri F, Roumenina LT, Loirat C, This case highlights the ability to made regarding the discontinuation of Frémeaux-Bacchi V; French Study Group for aHUS/ C3G. Use of eculizumab for atypical haemolytic rescue a patient following serious clini- therapy with eculizumab after achieving uraemic syndrome and C3 glomerulopathies. Nat Rev cal relapse after stopping eculizumab. remission.”6 I absolutely agree with that Nephrol. 2012;8(11):643-657. The patient relapsed 6 months after she statement. It may take a while to obtain 3. Soliris [package insert]. Cheshire, CT: Alexion Phar- maceuticals; 2011. had received 9 months of therapy. Ecu- that information. There are now regis- 4. Noris M, Remuzzi G. Genetics and genetic testing lizumab was immediately restarted, and tries of patients with aHUS; a patient in hemolytic uremic syndrome/thrombotic thrombocy- she did fine. However, among patients need not be receiving drug therapy to topenic purpura. Semin Nephrol. 2010;30(4):395-408. 5. Kim JJ, Waller SC, Reid CJ. Eculizumab in atypi- in the 2 prospective clinical trials lead- enroll. Information from the registry cal haemolytic-uraemic syndrome allows cessation ing to FDA approval of eculizumab for will help determine the best approach. of plasma exchange and dialysis. Clin Kidney J. aHUS,8 there were 5 patients who had 2012;5(1):34-36. 6. Carr R, Cataland SR. Relapse of aHUS after dis- elected to discontinue therapy. All expe- Conclusion continuation of therapy with eculizumab in a patient rienced recrudescence of their disease. with aHUS and factor H mutation. Ann Hematol. Eculizumab was restarted in 4, but only These case studies describe the recent 2013;92(6):845-846. 7. Sullivan M, Rybicki LA, Winter A, et al. Age-related 3 could be rescued clinically. The fourth and dramatic evolution in the treat- penetrance of hereditary atypical hemolytic uremic syn- patient developed end-stage renal disease. ment of patients with aHUS. Research drome. Ann Hum Genet. 2011;75(6):639-647. Published studies, case reports, and my is under way to clarify the questions 8. Legendre CM, Licht C, Muus P, et al. Termi- nal complement inhibitor eculizumab in atypi- own experience appear to suggest that it raised by these cases in order to opti- cal hemolytic-uremic syndrome. N Engl J Med. might be possible to consider tapering mize management. 2013;368(23):2169-2181.

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