thrombotic microangiopathy with targeted cancer agents

Review

Thrombotic Microangiopathy with Targeted Cancer Agents

John A. Blake-Haskins1,2, Robert J. Lechleider2, and Robert J. Kreitman3

AbstractThrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) are clinically

similar disorders characterized by microvascular thrombosis, hemolysis, thrombocytopenia, and end-

organ damage. Although they may present with overlapping symptoms, multiple etiologies have been

proposed for these thrombotic microangiopathies (TMA). Chemotherapy-induced TMA, which has been

described with the use of mitomycin, gemcitabine, and other drugs, has a poor prognosis. Recently, reports

of TMA associated with targeted cancer agents have surfaced in the literature. We discuss the clinical

presentation, outcome, and etiology of TMA reported with the use of immunotoxins, monoclonal

antibodies, and tyrosine kinase inhibitors. A search of PubMed and meeting abstracts was conducted

for cases of TMA with the use of targeted cancer agents. The defining symptoms, laboratory values, time to

onset, and patient outcomes were compiled. Consistent definitions of TMA and grading of severity in these

cases are lacking. However, presentation of TMA in these cases revealed the importance of monitoring for

renal toxicity, hemolysis, and thrombocytopenia. Patient outcomes seem to differ from those seen in cases

of chemotherapy-induced TMA and may reflect a different underlying etiology. Little is known about the

pathogenesis of TMA with targeted cancer agents. In contrast to chemotherapy-induced TMA, partial to full

reversibility may be a common outcome. However, further research is warranted into optimalmanagement

of patients diagnosed with TMA following treatment with targeted agents. Clin Cancer Res; 17(18);

5858–66. �2011 AACR.

The thrombotic microangiopathies (TMA) are a group ofdisorders characterized by occlusive microvascular throm-bosis, thrombocytopenia, and end-organ damage. Theprincipal subtypes of TMA are thrombotic thrombocyto-penic purpura (TTP) and hemolytic uremic syndrome(HUS). In turn, both TTP and HUS may each have severaldistinct subtypes caused by differing pathophysiologicmechanisms.

TTP is classically described by a pentad of clinical symp-toms, including thrombocytopenia, microangiopathichemolytic anemia (MAHA), neurologic abnormalities,renal failure, and fever. HUS may also present with manyoverlapping signs and symptoms (1). However, a diagnosisof TTP is usually reserved for cases in which neurologicabnormalities such as seizure and vision loss predominate,

whereas HUS is diagnosed in cases in which renal failure isthe most prominent sign.

The differentiation between TTP and HUS, their classi-fication, etiologies, and prognoses have been the subject ofmuch discussion. Recent research has focused on identify-ing the causes of TTP and HUS at the molecular level. Ofparticular interest is the relationship between severely lowlevels of the serum metalloprotease ADAMTS13 with TTP.Bianchi and colleagues reported that ADAMTS13 activityless than 5% of normal is specific for TTP (2). Note,however, that reduced ADAMTS13 levels have also beenobserved in patients diagnosed with HUS (3).

As extensively reviewed (4, 5), Von Willebrand factor(vWF) is initially secreted from Wiebel-Palade bodies asmultimers tethered to the endothelial cell surface, wherethey provide glycoprotein Iba receptor sites for plateletadhesion and thrombus formation. ADAMTS13 cleavesthe multimeric vWF, regulating thrombus formation.However, a significant decrease in ADAMTS13 orADAMTS13 activity allows pathogenic thrombus forma-tion as seen in TTP (Fig. 1). Familial TTP is a rare andrecurrent disorder caused by an inherited deficiency inADAMTS13 (6). Development of autoantibodies againstthis same enzyme may lead to a more common form ofacquired TTP.

The majority (�90%) of HUS cases appear in childreninfected with verocytotoxin-producing bacteria (7).Following infection of the colon, the Shiga-like toxins(Stx1 and Stx2) enter the bloodstream and bind to cells

Authors' Affiliations: 1University of Maryland School of Pharmacy, Balti-more; 2MedImmune, LLC, Gaithersburg; 3Laboratory of Molecular Biology,National Cancer Institute, NIH, Bethesda, Maryland

Note: R.J. Lechleider was formerly at MedImmune, LLC. J.A. Blake-Haskins contributed to concept design andwriting the article; R.J. Lechlei-der edited and reviewed the manuscript; R.J. Kreitman contributed toconcept design, editing, and review of the manuscript.

Corresponding Author: Robert J. Kreitman, Clinical ImmunotherapySection, Laboratory of Molecular Biology, National Cancer Institute,NIH, Building 37 Room 5124b, 9000 Rockville Pike, Bethesda, MD20892. Phone: 301-496-6947; Fax: 240-220-7677; E-mail:[email protected]

doi: 10.1158/1078-0432.CCR-11-0804

�2011 American Association for Cancer Research.

ClinicalCancer

Research

Clin Cancer Res; 17(18) September 15, 20115858

on April 9, 2019. © 2011 American Association for Cancer Research. clincancerres.aacrjournals.org Downloaded from

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displaying globotriaosylceramide receptors (Gb3 andGb4), including the glomerular endothelial and epithelialcells (1, 8). The toxins result in cell death because ofinhibition of protein formation and result in the releaseof TNF-a, interleukin (IL)–1, IL-6, and IL-8. Theseinflammatory cytokines may potentiate renal injury sec-ondary to infiltration by neutrophils and lead to upre-gulation of the Gb3 receptor. In addition, TNF-a and IL-8have been shown to cause vWF secretion, whereas IL-6inhibits cleavage of ultralarge multimers in vitro (9).Other direct effects of Stx1 include stimulation of endo-thelial cells to express tissue factor and secrete vWF, aswell as activation of platelets (1, 10).The etiology of the remaining 10% of "atypical" HUS

(aHUS) cases is heterogeneous and largely linked to muta-tions in factors of the complement system (11, 12). The endresult of these mutations is an overactive complementsystem causing endothelial cell damage, detachment,and eventual activation of the coagulation cascade. Thealternative pathway of complement may play a role intypical HUS as well. Orth and colleagues showed in vitroactivation of complement by Stx2 and proposed thatcomplement may contribute to kidney damage in typicalHUS (8).Finally, both TTP and HUS have been associated with

malignancy, hematopoietic stem cell transplantation, andspecific medications. Historically, review articles of drug-induced TMA have focused on immunosuppressants, anti-aggregating agents, and cytotoxic chemotherapy (13–16).Among cytotoxic chemotherapy agents, mitomycin andgemcitabine (Table 1) are particularly associated withTMA, and the U.S. Food and Drug Administration(FDA)–approved labeling warns of this risk (17, 18).The etiology of chemotherapy-induced TMA is thought

to be nonspecific, toxic insult to the microvasculature.Direct endothelial cell injury has been reproduced in ananimal model of mitomycin-induced HUS and mostlikely plays a central role (14). Following endothelialinjury and exposure of the subendothelium, plateletactivation and subsequent clotting within the microvas-culature may occur.

Thrombotic Microangiopathy Induced byTargeted Agents

ImmunotoxinsImmunotoxins are proteins comprised of a cell-selective

ligand chemically conjugated or genetically fused to a toxin(19, 20). The cell-selective portion of the immunotoxin iscommonly a monoclonal antibody, antibody fragment,growth factor, or cytokine that binds to specific cell-surfacereceptors. Once bound to a surface antigen, immunotoxinsenter the target cell through endocytosis and undergoprocessing to release the toxin into the cytosol (21). Severalof these agents have shown promising activity in clinicaltrials; however, TMA has been reported with their use, andthe mechanism behind this adverse effect is not completelyunderstood.

CAT-3888, formerly called BL22, is an immunotoxin thattargets CD22 and has been investigated for the treatment ofhairy cell leukemia (HCL), non-Hodgkin lymphoma, andchronic lymphocytic leukemia (22–24). During phase Iand II testing of CAT-3888, 9 cases of grade 1 to 4HUSwerereported in 8 of the 82 subjects treated (22–24). In addi-tion, HUS was reported in 1 of 2 HCL patients treated byspecial exemption prior to the opening of the phase II trial(22). Subjects in the phase I study were treated with 6 to12 days of plasmapheresis, whereas those on the phase IIstudy were given only supportive care. HUS was completelyreversible in 9 of the 10 cases, regardless of treatment, withup to 57 months of follow-up in the phase I study. Notethat the first of the 10 cases was not evaluable for revers-ibility because the patient had an aggressive lymphoma andrefused additional treatment for rapidly progressivedisease. However, this patient, who became anuric withHUS, resumed normal urination prior to dying of progres-sive lymphoma. ADAMTS13was reported to be adequate inall cases, suggesting that ultralarge multimers of vWF werenot circulating in these patients.

Moxetumomab pasudotox, formerly known as CAT-8015 or HA22, is an affinity-matured recombinant anti-CD22 immunotoxin that offers enhanced binding affinitycompared with CAT-3888 (25). A preliminary report of anongoing phase I trial in HCL suggests that HUS may occurwith lower frequency in patients treated with moxetumo-mab pasudotox compared with CAT-3888 (26). Two of 28subjects treated had experienced reversible, grade 2 HUSfollowing moxetumomab pasudotox administration. Theclinical presentation of HUS seems to be similar to thatseen in subjects treated with CAT-3888. However, in bothof these cases, the peak creatinine was <2.0 mg/dL and thenadir platelet count was >100,000/mL.

Combotox is an investigational combination of 2 degly-cosylated ricin A chain (dgA) immunotoxins directedagainst CD19 and CD22 (27). This combination has beenevaluated in a phase I study (N ¼ 22) in which 2 cases ofHUS were observed (27). Both subjects were reported tohave followed a similar clinical course of vascular leak,respiratory insufficiency, HUS, and eventual death. Thesevere morbidity and mortality in these subjects may have

Translational Relevance

Thrombotic microangiopathies (TMA) are known tooccur in malignancy and have been linked to cytotoxicchemotherapy, including mitomycin and gemcitabine.The pathogenesis of chemotherapy-induced TMA islikely due to direct endothelial cell injury. Recently,case reports of TMA related to the use of targeted canceragents have also surfaced in the literature. Little isknown about the etiology of TMA in these cases. Herein,we review the clinical presentation, outcome, and pro-posed mechanisms of TMA associated with the use ofmonoclonal antibodies, immunotoxins, and tyrosinekinase inhibitors.

TMA with Targeted Cancer Agents

www.aacrjournals.org Clin Cancer Res; 17(18) September 15, 2011 5859




been related to complicating vascular leak syndrome (VLS)rather than HUS. In fact, VLS has proved to be a prominenttoxicity for large, conjugated immunotoxins because ofeither their long plasma half-lives or residues that bindto endothelial cells (28). The authors of this study suggestthat HUS in these patients may be associated with low orabsent levels of circulating tumor cells and possibly withhigh serum concentrations of the immunotoxins.

DAB486IL-2 is a recombinant immunotoxin targetingIL-2 with the membrane translocation and ADP-ribosyla-tion domains of diphtheria toxin, and it is the precursor ofDAB389IL-2 (denileukin diftitox; ref. 29). During a phase Itrial (N ¼ 23) of DAB486IL-2, the maximum tolerated dosewas determined by HUS toxicity in 2 patients (30). Similartoxicity was noted in 1 patient in a later phase II study(N ¼ 14; ref. 31). The HUS experienced by this patient was

© 2011 American Association for Cancer Research

MAC

Platelet aggregation

Platelet

aggregation Platelet aggregation

Subendothelium

ADAMTS13

Endothelial

cell

Endothelial

cells

Endothelial cell

C5a

Endothelial cell

åProstacyclin

vWF secretion

Neutrophil

recruitment

Cell injury

and activation

Cell injury

and activation

MAC

Wiebel-Palade

body

vWF

A Reduced ADAMTS13 activity

Anti-ADAMTS13 antibodies

Inherited ADAMTS13 deficiency

B Dysregulated complement

Mutations in CFH, MCP, C3, CFB

C Drug cytotoxicity

Mitomycin gemcitabine

Figure 1. Proposed pathophysiology of TMAs. A, formation of pathogenic thrombi in TMA may arise from reduced ADAMTS13 activity. ADAMTS13bound to the surface of endothelial cells can cleave ultralarge multimers of vWF. When the activity of ADAMTS13 is reduced because of anti-ADAMTS13antibodies or an inherited deficiency, the uncleaved multimers of vWF induce platelet aggregation. B, in atypical HUS, mutations in complement proteins leadto unregulated formation of C5a and C5b-9 (membrane-attack complex). Recruitment of neutrophils, endothelial cell injury, and exposure of thesubendothelium results in a prothrombotic state. C, drug cytotoxicity can also result in direct injury to the endothelium and lead to TMA. The exactpathogenesis of TMA in these cases is unknown but may involve decreased levels of prostacyclin, secretion of vWF, or exposure of the subendotheliumleading to thrombus formation.

Blake-Haskins et al.

Clin Cancer Res; 17(18) September 15, 2011 Clinical Cancer Research5860




described as "mild"; it was reversible and did not recurupon retreatment at a reduced dose. Recurrent HUS mayhave been avoided in this case because of the presence ofantitoxin antibodies, but the authors do not report onlevels of neutralizing antibodies in this study. To ourknowledge, no published case reports associate HUS withdenileukin diftitox.The mechanism behind TMA induced by immunotoxins

is not well understood. Animal models of ricin-inducedHUS provide evidence toward a pathway for renal injury(32, 33). Administration of unconjugated ricin to mice andrats leads to the development of a syndrome closely re-semblingHUS in humans. The animals develop glomerularthrombosis, renal failure, hemolysis, and thrombocytope-nia. Accompanying these pathologic changes are rapidincreases in the proinflammatory cytokines MCP-1, TNF-a, IL-1b, and IL-6. Upregulation of these cytokines maypromote an inflammatory environment and subsequentinfiltration of the glomeruli with macrophages that stim-ulate secretion of vWF.Each of the above-mentioned immunotoxins uses dif-

ferent protein toxins and targets different cellular receptors.Messmann and colleagues speculate that both targeted andnontargeted endothelial cell binding of toxins may play anintegral role in the pathogenesis of HUS with the use ofCombotox (27). Identification of low levels of CD19,CD22, and IL-2 receptors on glomerular endothelial cellswould support the theory of targeted cell death in immu-notoxin-induced TMA. However, the presence of CD22 onglomerular endothelium seems unlikely to be a majormechanism, as one would expect moxetumomab pasudo-tox to cause HUS at lower concentrations than CAT-3888because it binds with 15-fold higher affinity to this cell-surface receptor. Other mechanisms, such as cross-reactiv-ity to a different target or nonspecific uptake into cells bypinocytosis, may possibly be related to immunotoxin-in-duced HUS (21).

ImmunotherapyApolizumab (Hu1D10) is a humanized monoclonal

antibody against an antigen on the b chain of HLA-DRcalled 1D10. HUS was observed to be a dose-limiting

toxicity in 1 subject during a phase I and II trial (N ¼ 23)of apolizumab (34). No schistocytes were observed byperipheral blood smear.

HUS has also been reported in a phase I study ofapolizumab plus rituximab (35). In this study, subjectswere administered weekly doses of 375 mg/m2 rituximabfollowed by increasing doses of apolizumab. The dose-limiting toxicity was reported to beHUS, but the number ofsubjects experiencing HUS and their clinical presentationwere not described. The authors reported that 1D10 wasfound on endothelial cells and might have played a role inthe pathogenesis of HUS in these patients.

Alemtuzumab is a monoclonal antibody that targetsCD52 on the surface of B and T lymphocytes. During anexperimental study (N ¼ 41) in rheumatoid arthritis, a 49-year-old female developed HUS after receiving her seconddose of alemtuzumab (36). Following 2 days of plasma-pheresis, renal function returned to normal and the patientmade a complete recovery. Alemtuzumab has been notedto cause elevation of serum TNF-a and IL-6. Similar to oneof the proposed mechanisms behind TMA following treat-ment with cytotoxic chemotherapy, cytokine release maybe partly responsible for HUS in this subject.

Anti-VEGF therapyAmong the targeted oncology drugs associated with

TMA, those that inhibit the VEGF pathway are the mostwidely studied. A series of 21 case reports of TMA associatedwith VEGF inhibition have been published in the past 5years (37–44). These cases have been observed with the useof multiple anti-VEGF agents, suggesting a potential class-wide effect.

Eremina and colleagues describe 6 biopsy-documentedcases of TMA resembling HUS following bevacizumabadministration (39). All of the patients described in thisseries developed proteinuria or increased serum creatininefollowing the initiation of bevacizumab, ultimately leadingto renal biopsy. However, beyond these indications of renalinjury, the clinical presentation was not uniform across allpatients. Following discontinuation of bevacizumab,improvement in renal function was noted, suggesting atleast partial reversibility.

Table 1. Characteristics of TMA associated with mitomycin and gemcitabine

Chemotherapy Incidence Clinical presentation Onset Prognosis

Mitomycin 2–15% Severe MAHA; thrombocytopenia;renal dysfunction; elevated lactatedehydrogenase; elevated bilirubin;pulmonary edema

Cumulative doses >30 mg/m2

and >1 year of treatmentMortality �75%related to renal failure

Gemcitabine 0.25–0.4% 2,000–48,000 mg/m2 and5–8 months of treatment

Mortality �60%; renal failure34–69%; reversal of anemiaand thrombocytopeniamay be common

NOTE: Data summarized in this table are from references 13–16.






Reports of TMA are not limited to bevacizumab, as theyalso appear for agents that target the VEGF pathway bydifferent mechanisms. Three cases of renal TMA have beenreported with the use of sunitinib (37, 41, 42). One case ofTMAassociatedwith afilbercept has alsobeen reported (44).

Combination therapy of bevacizumab and sunitinib in aphase I trial resulted in TMA of greater severity. Feldmanand colleagues report 5 cases of MAHA along with 3additional cases of "MAHA-like features" in a trial of 25patients (43). MAHA was graded according to CommonTerminology Criteria for Adverse Events (CTCAE) version3.0 guidelines for TMA (45). Two patients with grade 3MAHA also developed neurologic symptoms.

Those patients described as having MAHA-like featurespresented similarly, but without schistocytosis or neuro-logic symptoms. Following discontinuation of anti-VEGFtherapy, all subjects showed improvement. The high rate ofTMA in this trial (8 of 25 subjects) and the development ofextra-renal complications in 2 subjects indicate a moresevere manifestation of TMA with combined blockade ofthe VEGF pathway.

Eremina and colleagues have provided a detailed proposalfor a mechanism of VEGF-induced TMA. They propose thatinhibition of VEGF in the glomerular microvasculature pre-vents the formation andmaintenance of a healthy, fenestrat-ed endothelium (39). Without active VEGF signaling, theendothelium is compromised, along with the filtration bar-rier of the glomerulus. The authors’ proposed pathway toTMA is supportedbyelegant animalmodels inwhichonly therenal podocytes are genetically deprived of the VEGF gene. Inthismodel, the knockoutmicedeveloped features in linewiththose seen in human cases of bevacizumab-induced TMA.

ImatinibImatinib inhibits multiple tyrosine kinase inhibitors,

including bcr-abl, those for platelet-derived growth factor

stem cell factor, and c-kit, and it has been associated withTMA. Al Aly and colleagues report on a 22-year-old womanwith hypereosinophilic syndrome who developed TMAafter receiving imatinib (46). ADAMTS13activitywas belowthe normal range, whereas the ADAMTS13 inhibitor levelwasmarkedly elevated. The patient was treated with plasmaexchange and hemodialysis, leading to a hematologic re-covery but persistent renal impairment.

Discussion

Diagnosing thrombotic microangiopathyAlthough a diagnosis of TMA is centered on recognizing

microvascular thrombosis, red blood cell destruction, andplatelet consumption, no guidelines currently exist tocompletely define TMA or its severity. The difficulty inevaluating TMA is reflected in the similar CTCAE defini-tions of HUS and TTP (45, 47). Moreover, the CTCAE failsto provide more than a cursory outline of severity gradingfor TMA. Further delineation of critical signs and symptomsof HUS and TTP are warranted considering their heteroge-neous causes and prognoses. Severity defined by laboratoryvalue cut-offs would be particularly beneficial. An exampleof a more detailed scheme for grading TMA is shown inTable 2.

The clinical presentation of TMA seems to have somecommon characteristics for the cases described in thisreview (Table 3). Renal dysfunction was almost universalas manifested by elevations in creatinine and/or worsen-ing proteinuria. Similarly, evidence of hemolysis wasfrequent, and laboratory values for hemoglobin, reticu-locyte count, lactate dehydrogenase (LDH), haptoglobin,and bilirubin were outside of normal limits. Interesting-ly, identification of fragmented erythrocytes by peri-pheral smear was not documented in all TMA casesdescribed. In fact, even in cases of biopsy-proven TMA

Table 2. Proposed detailed grading of thrombotic microangiopathies

Grade Description

Grade 1: Evidence of erythrocyte destruction, withoutclinical consequences

The appearance of schistocytosis (�5/HPF) in a patient withno schistocytosis at baseline or an increase (�5/HPF) inthe frequency of schistocytes over baseline

Grade 2: Laboratory findings without clinicalconsequences

Microangiopathic anemia (schistocytosis; #Hgb by 1 g/dL)and mild renal insufficiency ("creatinine, grade 1)

Grade 3: Laboratory findings with clinicalconsequences (e.g., renal insufficiency,petechiae)

Microangiopathic anemia (schistocytosis; #Hgb by 1 g/dL),and either grade 4 thrombocytopenia or moderate renalinsufficiency ("creatinine, at least grade 2 if normal atbaseline or at least one grade worse than baseline)

Grade 4: Laboratory findings with life-threateningor disabling consequences (e.g., CNShemorrhage and/or bleeding, or thrombosisand/or embolism, or renal failure)

Microangiopathic anemia (schistocytosis; #Hgb by 1 g/dL),and either clinically significant hemorrhage requiringintervention or renal insufficiency requiring intervention(i.e., plasmapheresis, dialysis)

Grade 5: Death Death

Abbreviations: CNS, central nervous system; HPF, high-powered field; Hgb, hemoglobin; #, decreasing; ", increasing.






Tab

le3.

Com

parison

ofthrombotic

microan

giop

athy

asso

ciated

with

targeted

canc

erag

ents

Targeted

therap

yCAT-388

8Moxe

tumomab

pas

udotox

CombotoxDAB48

6IL-2

Apoliz

umab

Alemtuzu

mab

Bev

acizum

abSun

itinib

Afilberce

ptBev

acizum

aban

dsu

nitin

ib

Imatinib

Num

ber

ofca

ses

102

23

�31

93

18

1Timeto

onse

t2–

3cy

cles

3–5cy

cles

3–5day

sNR

11dos

es2dos

es4–

29dos

es2wee

ksto

7mon

ths1cy

cle

NR

5dos

es

Clinical

prese

ntation

Thromboc

ytop

enia

þþ

þþ

þþ

�þ

þþ

Dec

reas

edHgb

þþ

þþ

þ�

þþ

þHem

olysis

þþ

þþ

þþ

þEleva

ted

retic

uloc

yte

coun

t

þ

Eleva

tedbilirubin

þþ

Dec

reas

edha

ptog

lobin

þþ

þþ

Sch

istocy

tes

þ�

��

þEleva

tedLD

Hþ

þþ

þþ

þEleva

ted

crea

tinine

þþ

þþ

þþ

þþ

þ

Proteinuria

þþ

þþ

Dec

reas

edurineou

tput

þ�

Dec

reas

edalbum

inþ

þ

Pulmon

ary

þEdem

aþ

þHyp

ertens

ion

þþ

þþ

Neu

rologic

��

Biopsy

confirm

ation

þþ

þþ

Outco

me

9of

10fully

reve

rsible,

1dea

thdue

toprogres

sive

disea

se

2of

2fully

reve

rsible

2of

2de

aths

1fully

reve

rsible

(othersNR)

1dea

th(othersNR)Fu

lly reve

rsible

1fully

reve

rsible,

7partia

llyreve

rsible

with

persisten

tproteinuria,

1dea

thdue

toprogres

sive

disea

se

3of

3fully

reve

rsible

Partia

llyreve

rsible

3fully

reve

rsible,

5NR

Partia

llyreve

rsible

(hem

atolog

icreco

very;

dialys

isde

pen

dent)

Abbreviations

:NR,no

treported;Hgb

,he

mog

lobin.






following anti-VEGF therapy, schistocytes were only not-ed in 4 of 10 cases. However, doing biopsies to evaluateTMA is not appropriate for all patients. Thrombocytope-nia was noted in most cases of TMA, but with varyingseverity. In the cases reviewed, consequences of throm-bocytopenia, such as petechiae and hemorrhage, werenot discussed. Strict monitoring of renal function, plate-let count, and for signs of nonautoimmune hemolyticanemia is recommended for patients receiving thesetargeted therapies.

Treatment and outcomeMany interventions for TMA have been described

(Table 4). Optimal treatment of drug-induced TMA,and especially TMA induced by targeted agents, has yetto be proved. In the cases summarized in this review,plasma exchange and plasmapheresis were both used,but they may not be necessary if ADAMTS13 activity isunaltered in these patients. As noted for the cases ofHUS associated with CAT-3888 and moxetumomabpasudotox, supportive care alone resulted in full recoveryfor several subjects. An advantage of these moleculescompared with larger immunotoxins is their smaller size(�62 kDa), leading to relatively rapid (2–3 hours) half-life and fewer complications because of vascular leaksyndrome. Until more is known about the mechanismof TMA following the use of targeted agents, immediatediscontinuation of the offending drug may be the mostimportant step in treatment. For patients with aHUS

refractory to plasma exchange, eculizumab has resultedin clinical remission in selected cases (48–50). Likewise,rituximab has shown a high response rate without severetoxicity in a trial of refractory TTP (N ¼ 24) and shouldbe considered for these patients (51).

Reintroducing the drug at lower dose levels may be astrategy to avoid recurrent TMA, while allowing for con-tinued treatment. Retreatment following TMA has beensafely carried out with CAT-3888, DAB486IL-2, and beva-cizumab (24, 31, 39). However, it may be difficult tochoose an appropriate dose for reintroduction, and carefulconsideration of the potential risks and benefits to thepatient should take place.

TMA with several of the targeted cancer agents seems tobe reversible. HUS was fully reversible in 11 of the 12subjects administered the immunotoxins CAT-3888 andmoxetumomab pasudotox, at least 1 of the subjects givenDAB486IL-2, and in the 1 case report involving alemtuzu-mab. Partial to full reversibility was also noted for anti-VEGF–treated patients; however, persistent proteinuria wascommon. Deaths were reported for both HUS cases seenwith Combotox and in 1 of the cases of apolizumabtreatment.

Unlike TMA induced by mitomycin and gemcitabine,there may not be a correlation between dose, cumulativedose, or time to onset and the use of targeted therapy.Perhaps any relationship between dose and time on ther-apy will become clearer as additional case reports arecompiled.

Table 4. Managing thrombotic microangiopathies

TMA Intervention Proposed mechanism of action Comment

Familial TTP Infusions of fresh-frozenplasma

Source of exogenous ADAMTS13 Reverses or preventsepisodes of TTP inthese cases

Acute, acquired TTP Plasma exchange Removal of ultralarge multimers of vWF,immune complexes, and autoantibodiesto ADAMTS13

Survival improvedfrom �10% to 70–90%

Acute, acquired TTP Glucocorticoids orsplenectomy

Decreased formation of immune complexes Has been used in combinationwith plasma exchangein severe cases

Acute, acquired TTP Rituximab Depletion of B cells responsible forproduction of anti-ADAMTS13 antibodies

Has been successfullyused in TTP refractoryto plasma exchange andin relapsed TTP

aHUS Eculizumab Binds complement protein C5, preventingformation of C5a and C5b-9(the membrane-attack complex)

Has been used in aHUSrefractory to plasmaexchange and followingrenal transplant to preventrecurrent aHUS

"Typical" HUS Dialysis Renal replacement therapy Dialysis may not be necessaryin mild cases

NOTE: Data summarized in this table are from references 1, 15, and 48–51.






Conclusions

As strategies to treat cancer begin to incorporate moretargeted therapeutics, such as monoclonal antibodies,immunotoxins, and small molecule inhibitors, it will beimportant to recognize the unique toxicities that accom-pany their use. TMA is one such toxicity that has beenassociated with these targeted agents, and research into itspathogenesis is in its infancy. Detailed evaluation of biopsyresults, laboratory values, and ADAMTS13 levels of futurecases may be warranted. In addition, animal models suchas those used by Eremina and colleagues may help tofurther define the mechanisms of these disorders (39).Preliminary analysis seems to show a reversible course of

TMA in the majority of patients described in this review.

However, until preferable methods of prevention andtreatment are determined, management of TMA shouldfocus on strict monitoring for and early recognition ofthe signs and symptoms of HUS or TTP.

Disclosure of Potential Conflicts of Interest

J.A. Blake-Haskins: postdoctoral fellow sponsored by MedImmune, LLC.R. Lechleider: employee, MedImmune, LLC. However, the majority of theagents reviewed have no relation to MedImmune. R.J. Kreitman is acoinventor on the government-owned patent for anti-CD22 recombinantimmunotoxins, although these agents constitute a minority of thosereviewed.

Received March 25, 2011; revised June 10, 2011; accepted June 18, 2011;published OnlineFirst August 3, 2011.

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2011;17:5858-5866. Published OnlineFirst August 3, 2011.Clin Cancer Res John A. Blake-Haskins, Robert J. Lechleider and Robert J. Kreitman Thrombotic Microangiopathy with Targeted Cancer Agents

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