Is Complement Blockade an Acceptable Therapeutic Strategy for Hematopoietic Cell Transplant-Associated Thrombotic Microangiopathy?

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REVIEW Is complement blockade an acceptable therapeutic strategy for hematopoietic cell transplant-associated thrombotic microangiopathy?

P Dhakal1 and VR Bhatt2

Diagnosis and management of hematopoietic cell transplant-associated thrombotic microangiopathy (TA-TMA) are very complex and controversial, given multiple ongoing issues and comorbidities in sick transplant recipients. Complement activation via classic and alternative pathways is emerging as a potential pathogenetic mechanism in the development of TA-TMA. Complement-centric diagnostic strategy using functional and genetic tests may possibly support diagnosis, enhance molecular understanding and direct drug development. Complement blockade using eculizumab has shown some promising rates of hematologic responses, however, survival may still be poor. Early discontinuation of calcineurin inhibitor where feasible, use of eculizumab, aggressive infection prophylaxis, close monitoring and early treatment of potential complications including GvHD and organ failure may improve outcomes. A number of complement inhibitors are in the development and may change treatment paradigm. Future studies are important to better understand TA-TMA as a disease process and may aim to conﬁrm the role of complement activation in TA-TMA, enhance diagnostic strategy, determine therapeutic approaches and strategies to reduce the risk of other complications particularly infection and GvHD.

Bone Marrow Transplantation (2017) 52, 352–356; doi:10.1038/bmt.2016.253; published online 24 October 2016

INTRODUCTION experts who have even raised skepticism regarding whether Hematopoietic cell transplant (HCT)-associated thrombotic micro- TA-TMA is a ‘distinct diagnosis’ or just a manifestation of other angiopathy (TA-TMA) offers diagnostic and therapeutic challenges, problems such as GvHD, sepsis, CMV viremia or graft failure in a and is associated with a high mortality rate and long-term sick transplant recipient. As vascular endothelium is a target of complications in survivors.1 The exact pathophysiology is unclear GvHD, TA-TMA has been regarded by some as a manifestation of 13 although endothelial injury may represent the final common acute endothelial GvHD. Future prospective studies should pathway.2–4 The use of high-dose chemotherapy, radiation consider this possibility and take into consideration other therapy, unrelated donor, HLA-mismatched donor, exposure to comorbidities to develop diagnostic tools and therapeutic calcineurin inhibitor (CNI), GvHD and infections are some of the approaches. Despite such limitations, we have attempted to important risk factors.4–8 Similarly, GvHD, CMV viremia, liver present a focused review on the potential role of complement dysfunction and significant gastric bleeding are some of the activation in the pathogenesis of TA-TMA and complement prognostic factors for TA-TMA.8 Manifestations of TA-TMA may blockade as an emerging therapeutic strategy. include thrombocytopenia, Coombs-negative microangiopathic hemolysis, schistocytes on peripheral blood smear, acute renal failure, mental status changes, pulmonary complications such as TRADITIONAL MANAGEMENT APPROACH severe pulmonary arterial hypertension, and dysfunction of other Change in immunosuppressive treatment with discontinuation of – organs causing multi-organ failure.9 11 Such manifestations may CNI, dose reduction or conversion to another drug is the initial be seen in patients with other HCT-related complications therapy for most cases of CNI-related TA-TMA (Figure 1).14,15 This including GvHD, sepsis and CMV infection. Consequently, the approach may be particularly successful if TA-TMA is not severe diagnosis is difficult despite the availability of consensus criteria and detected early on. Although patients may be closely established by the Blood and Marrow Transplant Clinical Trials monitored with assessment of clinical status, hemolytic para- Network or other groups.1 As the underlying mechanism for meters and organ function to capture disease worsening, a lack of TA-TMA is complex and not well understood, the management formal grading to assess the severity of TA-TMA at suspicion may options are unclear.4,11,12 Currently available therapeutic options make it hard for a clinician to decide on a more conservative include withdrawal of CNIs, possible small role of therapeutic versus aggressive management strategy. Worel et al.16 reported a plasma exchange, rituximab and more recently eculizumab. Given response rate of 64% with treatment strategy combining with- the rarity of TA-TMA and limited high-quality data, more questions drawal of CNI, daily plasma exchange until hematologic response and fewer answers are available. In fact, the authors have met was achieved and added the use of steroid in the presence of

1Department of Medicine, Michigan State University, East Lansing, MI, USA and 2Department of Internal Medicine, Division of Hematology-Oncology, University of Nebraska Medical Center, Omaha, NE, USA. Correspondence: Dr P Dhakal, Department of Internal Medicine, Michigan State University, 788 Service Road, B301 Clinical Center, East Lansing, MI 48824, USA. E-mail: [email protected] Received 1 June 2016; revised 7 August 2016; accepted 16 August 2016; published online 24 October 2016 Complement blockade P Dhakal and VR Bhatt 353

Diagnosis of TA-TMA*

If severe: • Discontinue/ Decrease CNI Proteinuria >30mg/dl switch to another drug • Elevated sC5b-9 level

No Clinical and Improvement Consider as hematologic initial treatment Improvement

Rituximab if Eculizumab† eculizumab No specific treatment unavailable† Monitor

Rituximab if Eculizumab if eculizumab fails‡ rituximab fails‡

• Continue therapy until resolution of clinical and hematologic manifestations of TA-TMA. • Monitor for infection, GVHD, renal, cardiac and other complications

Figure 1. Management of hematopoietic cell transplant-associated thrombotic microangiopathy. *Diagnosis may be established using available criteria put forward by the Blood and Marrow Transplant Clinical Trials Network or other groups. It is important to rule out other alternative diagnoses such as GvHD or sepsis.1 yWith regards to choosing eculizumab versus rituximab, no studies have compared the efficacy of the two drugs. Although the mechanism of action is unclear, rituximab has shown to be effective in up to two-third of patients in a few small studies.1 Rituximab is cheaper and may be more easily available in many centers. Oncologists and oncology pharmacists may be more familiar with rituximab than eculizumab. Hence, unless further studies are available, the choices of therapy are more based on drug availability and center preference. Eculizumab may be preferred if complement dysregulation is confirmed in a patient or in high-risk patients who present with proteinuria and elevated sC5b-9 at the time of TA-TMA diagnosis. zThe efficacy of these agents as a second-line therapy has to be tested in future studies.

GvHD, however, the severity of TA-TMA at diagnosis and survival Although plasma exchange has been used in the past to treat data are not mentioned. The risk of GvHD with discontinuation of TA-TMA, a large number of reports and case series suggest that it – CNI requires initiation of alternate immunosuppressant such as has transient acute effects at best.28 32 The role of plasma mycophenolate mofetil and prednisone.14,17 If the patient exchange in TA-TMA is limited unless perhaps a disintegrin and responds to manipulation of immunosuppressants, monitoring metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) level is low with activity o10% (unlikely in for worsening signs of TA-TMA and development of GvHD without 15 further interventions may suffice. TA-TMA) or Abs against complement factor H (CFH) are present. Some studies have reported successful use of cyclosporine in Rituximab, used frequently in thrombotic thrombocytopenic purpura, has been used in patients with TA-TMA as monotherapy tacrolimus-associated TA-TMA, although the reverse may not be as 10,33–35 successful.18–22 Replacing CNI with sirolimus is an unclear strategy or in combination with plasma exchange. Exact mechan- isms are unknown, but it is speculated to deplete CD20+ B-cell as sirolimus is also associated with TA-TMA. In mild forms of precursors, attenuate T-cell activation and reduce cytokine TA-TMA, where discontinuation of the CNI is not feasible, some 36 23,24 release. In a few small studies, the response rate has been patients may possibly respond to dose reduction only. demonstrated in up to two-third of patients; however, literature is However, replacing CNI with other immunosuppressive agents limited to case reports and series.33,37 may be more beneficial than dose reduction only.12,25,26 In this context, interleukin-2 receptor antagonists such as basiliximab and daclizumab have also shown benefits in patients with IS THERE A ROLE OF COMPLEMENT ACTIVATION IN TA-TMA? TA-TMA.12,27 However, these approaches are less well studied Limited studies indicate a potential role of complement dysregu- and cannot be routinely recommended. lation in the pathogenesis of TA-TMA cases; both classic as well as

© 2017 Macmillan Publishers Limited, part of Springer Nature. Bone Marrow Transplantation (2017) 352 – 356 Complement blockade P Dhakal and VR Bhatt 354 alternative complement pathway activation have been implicated. recipients’ susceptibility to TA-TMA in the future. These findings The classic pathway may be activated by triggers including GvHD, are certainly exciting, but not ready for use in clinical practice yet. high-dose chemotherapy and viral infections, leading to direct endothelial damage.37 Low C4 levels and C4d staining of affected 38–40 COMPLEMENT BLOCKADE, AN ACCEPTABLE THERAPEUTIC tissue may indicate classic pathway activation in TA-TMA. STRATEGY? Alternative pathway activation may result in the formation of CFH Abs. CFH Abs may be formed secondary to defective or absent Eculizumab, a monoclonal Ab against complement protein C5, CFHR1 protein leading to defects in CFHR3-CFHR1 genes, or owing prevents formation of membrane attack complex and comple- to immune dysregulation after HCT.41 The presence of CFH Abs ment activation.48 It may be an option if initial therapy with may explain the response of TA-TMA to rituximab and plasma discontinuation of CNI does not improve the disease process and 1 49 exchange, possibly through neutralization of CFH Ab activity. in patients with severe disease manifestation. Jodele et al. have Formation of CFH Ab causes uninhibited formation of the C3 proposed that eculizumab may be started without stopping CNIs convertase, C3bBb on the surface of endothelial cells, which in in some cases to avoid the risk of worsening of GvHD, however, turn forms additional molecules of C3b (the activated form of C3) this approach requires prospective evaluation taking into con- leading to a complex C3bBb•C3b. C3bBb•C3b cleaves C5 into C5a sideration the safety and cost-effectiveness of such an approach, and C5b, and promotes formation of lytic complex C5b-9 and the and a possibility that GvHD may masquerade the manifestations potent anaphylatoxin C5a, which causes injury to the endothelial of TA-TMA. Although significantly limited because of the quality of cell and ultimately the characteristic findings of TMA.42 reported studies, a 2015 review of reported use of eculizumab in Dysregulation in either the classic or alternative pathway finally TMA associated with HCT or solid organ transplant demonstrated that 24 (92%) out of 26 patients were alive at 1-year follow-up, and results in the formation of terminal complement complex. In one 50 study, patients with TA-TMA, with elevated markers of terminal the remaining 2 pediatric patients (8%) died. Although this complement activation (soluble terminal complement complex outcome appears impressive, experience of others is much less (sC5-9)) and proteinuria were associated with poor survival enthusiastic. In a more recent report, 12 patients with severe (o20%);43 this finding needs confirmation in the future studies. TA-TMA with neurological and/or renal involvement had an hematological response, and an overall survival of 50% and 33%, respectively at a median follow-up of 14 months.51 The major ‘COMPLEMENT-CENTRIC DIAGNOSTIC STRATEGY’ cause of deaths in the patients were bacterial or fungal infection, The ability to determine activation of the complement pathway acute GvHD, relapse of underlying malignancy and central 52 fi may possibly support diagnosis, guide therapy, and further nervous system complications. Vasu et al. reported ve disease understanding and drug development in TA-TMA. patients treated with eculizumab, of which four demonstrated However, their utility in clinical practice is limited because of the improvement in hematologic and renal parameters, but two lack of larger confirmatory studies, lack of standardization of succumbed to methicillin-resistant Staphylococcus aureus sepsis and Pseudomonas sepsis. Three different case reports describe technique and normal reference values, as well as limited three patients responding to the use of eculizumab, although two availability of such tests. A multitude of quantitative, functional – of them died after initial response.53 55 The causes of death were and genetic tests have been developed to capture complement acute respiratory distress syndrome of unknown cause53 and activation. Quantitative tests include measurement of serum diffuse alveolar hemorrhage.55 Larger prospective trials are complement levels and CFH Ab. Although not sensitive and needed to confirm the value of eculizumab in TA-TMA. specific, low levels of C3 and increased levels of C5a and C5b-9 At the present time, eculizumab-use may result in a hemato- complex may be observed, as in patients with atypical hemolytic 44 logic response in TA-TMA; however, the efficacy may be less in sick uremic syndrome (aHUS). Functional assays include determina- patients with severe manifestations and other comorbidities, tion of total complement hemolytic activity (CH50), sC5b-9 and Bb. and hematologic response does not guarantee survival. Close An in vitro functional complement assay, useful in diagnosing and ’ monitoring of other complications including GvHD and aggressive monitoring treatment in aHUS, utilizes patient s serum to induce infection prophylaxis may improve the outcomes associated with endothelial C5b-9 deposits on human microvascular endothelial the use of eculizumab in TA-TMA. It has been suggested that cells. Treatment with eculizumab has been found to normalize the 45 prompt initiation of eculizumab should be carried out in high-risk deposition. Studies utilizing such a technique in TA-TMA may patients who present with proteinuria and elevated sC5b-9 at the have important implications. Focal deposition of C3, C3d, C4d and time of TA-TMA diagnosis,42 however, many may recommend C5b-9 in tissue biopsies such as kidney and skin have also been awaiting for a confirmation of such strategy. As eculizumab reported, and if confirmed, may emerge as a quick and useful 15 therapy is associated with increased susceptibility to meningo- diagnostic aid. In fact, severe multi-organ damage, low C4 levels coccal infection and infections with other encapsulated and C4d staining of affected tissue such as renal arterioles may be 38–40 organisms, meningococcal vaccine or antibiotic prophylaxis with used as evidence of classic pathway activation. Moreover, C4d ciprofloxacin or penicillin V is advised.48,56–58 In HCT recipients staining has been observed in a few TA-TMA cases developing with TMA, the response to meningococcal vaccination, however, 40 after HCT or after solid organ transplants. If kidney biopsy is may be poor. performed, C4d staining along with clinical signs may be used to Eculizumab dosing in TA-TMA is also not established and support the diagnosis of TA-TMA, however, C4d deposition is not empirically follows the dosing schedule for aHUS.59 Induction 40,46 specific to TA-TMA. Mutation of one of the complement genes phase (900 mg weekly) for 4 weeks is followed by maintenance such as C3, CFB, CFH, CFHR1, CFHR3, CFHR5 and CFI may provide phase (1200 mg for first week, then 1200 mg every 2 weeks). evidence of genetic susceptibilities to develop TA-TMA,42 how- Additional 300 mg or 600 mg may be administered within 1 h ever, such a finding needs verification. It is also not clear if the test after plasma exchange.59 The dosage in children may depend on should be performed using recipient or donor DNA. A study by weight and ranges from 300 mg for 5–10 kg to 900 mg for 40 kg Jodele et al.,47 using recipients’ blood before transplantation, has or more. CH50 level, a hemolytic complement assay, has been revealed differences in susceptibilities to TA-TMA based on the proposed by Jodele et al.37 to titrate eculizumab doses as drug recipient genotype. Heterozygous CFHR3-CFHR1 deletions have monitoring is not readily available. The duration of treatment with been reported in HCT recipients with TMA in a study. Such genetic eculizumab for TA-TMA is still uncertain, but unlike aHUS, it may variations may be associated with CFH Abs.41 Thus, chromosomal be stopped after resolution of clinical symptoms and laboratory mutational analysis might be of research interest in testing the manifestations.50 If future studies confirm, functional assay to

Bone Marrow Transplantation (2017) 352 – 356 © 2017 Macmillan Publishers Limited, part of Springer Nature. Complement blockade P Dhakal and VR Bhatt 355 determine resolution of complement activation may be useful to CONFLICT OF INTEREST guide duration of therapy. In particular, the ability of patient’s The authors declare no conﬂict of interest. serum to induce endothelial C5b-9 deposits on human microvascular endothelial cells, or lack thereof after therapy with eculizumab, may be utilized to decide cessation of therapy.44 ACKNOWLEDGEMENTS At the present time, the use of eculizumab is still empirical, but VR Bhatt is supported by the 2016–2017 Physician-Scientist Training Program Grant reasonable, given a lack of good treatment option, however, from the College of Medicine, University of Nebraska Medical Center. We extend our monitoring and management of other complications have an gratitude to Dr James N George, MD, University of Oklahoma Health Sciences Center, equal or arguably more important role. for kindly reviewing this article and providing useful insight.

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