Solid Organ Transplantation: 2012 Update on Current and...

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Solid Organ Transplantation: 2012 Update on Current and Emerging Approaches to Treatment CME/CE

View this activity online at:www.medscape.org/anthology/kidneytran


Dorry L. Segev, MD, PhD

Flavio Vincenti, MD

Ron Shapiro, MD

Supported by an independent educational grant from

Supported by an independent educational grant from

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This article is a CME/CE-certified activity.To earn credit for this activity visit:

medscape.org/anthology/kidneytran

Released: 12/19/2012; Valid for credit through 12/19/2013

Target AudienceThis activity is intended for transplant surgeons, general surgeons, nephrologists, hepatologists, cardiologists, pulmonologists, cardiothoracic surgeons, nurses, transplant coordinators, pharmacists, and other healthcare providers who care for solid organ transplantation (SOT) recipients.

GoalThe goal of this activity is to enable clinicians in evaluating the need for applying new approaches in clinical practice, with the goals of minimizing toxicities and maximizing patient and graft survival rates.

Learning ObjectivesUpon completion of this activity, participants will be able to:

1. Evaluate recent approaches to calcineurin inhibitor-sparing in SOT recipients

2. Interpret data on emerging therapies for prevention of antibody-mediated and cell-mediated rejection in SOT recipients

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AuthorsDorry L. Segev, MD, PhDAssociateProfessorofSurgeryandEpidemiology;DirectorofClinicalResearch,TransplantSurgery,JohnsHopkinsUniversitySchool of Medicine, Baltimore, Maryland

“ParticipationbyDrSegevinthedevelopmentofthisproductdoesnotconstituteorimplyendorsementbytheJohnsHopkinsUniversityortheJohnsHopkinsHospitalandHealthSystem.”

Disclosure: Dorry L. Segev, MD, PhD, has disclosed the following relevant financial relationships:Served as an advisor or consultant for: sanofi-aventis, Pfizer, Inc.

Dr Segev does intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States.

Dr Segev does intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States.

Flavio Vincenti, MDProfessor of Clinical Medicine/Kidney Transplant, University of California, San Francisco, San Francisco, California

Disclosure: Flavio Vincenti, MD, has disclosed the following relevant financial relationships:Received grants for clinical research from: Genentech, Inc.; Novartis Pharmaceuticals Corporation; Bristol-Myers Squibb CompanyOwns stock, stock options, or bonds from: Sanofi; Astellas Pharma, Inc.

Dr Vincenti does not intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States.

Dr Vincenti does not intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States.

Ron Shapiro, MDProfessor of Surgery, Associate Clinical Director, Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center Montefiore, Pittsburgh, Pennsylvania

Disclosure: Ron Shapiro, MD, has disclosed the following relevant financial relationships:Served as an advisor or consultant for: Alexion Pharmaceuticals, Inc.; Bristol-Myers Squibb Company; Genentech, Inc.; Novartis Pharmaceuticals Corporation; StemCells, Inc.

Dr Shapiro does intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States.

Dr Shapiro does intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States.


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EditorsSusan L. Smith, MN, PhDGroup Scientific Director, Medscape, LLC

Disclosure: Susan L. Smith, MN, PhD, has disclosed no relevant financial relationships.

Laura FeikerClinical Editor, Medscape, LLC

Disclosure: Laura Feiker has disclosed no relevant financial relationships.

Kristen L. DascoliClinical Editor, Medscape, LLC

Disclosure: Kristen L. Dascoli has disclosed no relevant financial relationships.

CME ReviewerNafeez Zawahir, MDCME Clinical Director, Medscape, LLC

Disclosure: Nafeez Zawahir, MD, has disclosed no relevant financial relationships.

Nurse PlannerLaurie E. Scudder, DNP, NPNurse Planner, Continuing Professional Education Department, Medscape, LLC; Clinical Assistant Professor, School of Nursing and AlliedHealth,GeorgeWashingtonUniversity,Washington,DC

Disclosure: Laurie E. Scudder, DNP, NP, has disclosed no relevant financial relationships.

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Evaluating Advances in the Prevention and Treatment of Antibody-Mediated Rejection CME/CEDorry L. Segev, MD, PhD

Posted: 12/19/2012

Thesensitizedkidneytransplantcandidate--sensitizedtohumanleukocyteantigens(HLA)becauseofpreviouspregnancies,blood transfusions, or transplants -- represents one of the most significant challenges in modern kidney transplantation. In 2010, of the 80,571 candidates on the Organ Procurement and Transplantation Network kidney transplant wait list, 12,051 had a panel reactive antibody (PRA) of ≥80%.[1] It is expected that patients with a PRA value of ≥80% will have a positive cross-match with more than 80% of the general population, including potential live and deceased donors; as such they will be required to either forego many transplant offers or undergo desensitization. An additional 15,822 transplant candidates had a PRA of 10% to 79%, with similar challenges.[1]

As expected, sensitization has a profound impact on wait times for a kidney transplant. Among candidates on the kidney transplant wait list in 2001, median waiting time for candidates with a PRA of 0% to 9% was 3 years; median wait time for candidates with a PRA of 10% to 79% was 6 years; median wait time for candidates with a PRA of ≥ 80% was more than 9 years. In other words, by October 1, 2010, fewer than half of these patients had received a kidney transplant.[1]

Desensitization protocols potentially have brought transplantation within reach for the tens of thousands of patients with donor-specific antibody (DSA), especially those with a healthy, willing, but otherwise incompatible live donor. Successful engraftment using these protocols is promising, protecting the patient from what would otherwise inevitably be immediate, hyperacuterejection.However,theriskforantibodymediatedrejection(AMR)followingtransplantremainsrelativelyhighinpatients with DSA,[2] even in the setting of successful desensitization, thus emphasizing the need to develop novel pharmacologic agents and other modalities for treating AMR. This article highlights several recent advances in desensitization protocols to prevent AMR as well as new paradigms for treatment of AMR.

For the purposes of this article, advances in desensitization are considered in the context of live-donor kidney transplantation (LDKT) in which the recipient has DSA against a healthy, willing, live donor. A recent study illustrates that this is a relatively widely adopted paradigm in the United States.[3] In a national survey, 70% of kidney transplant centers reported LDKT across DSA of the strength indicated by a positive single-bead assay but negative-flow cytometric assay, 51% reported crossing positive-flow cytometric assay but negative cytotoxic crossmatch DSA, and 18% reported crossing positive cytotoxic cross-match DSA barriers.[3] The most commonly used protocol was plasmapheresis with low-dose intravenous immunoglobulin (IVIG). In this well-established protocol, a predetermined number of plasmapheresis treatments are performed and low-dose IVIG (100 mg/kg) is administered based on the initial DSA strength. The DSA strength is monitored throughout the pretransplant treatments, and the number and/or frequency of treatments are increased as necessary. A similar regimen is administered posttransplantation, with the number of treatments based on the DSA strength. Some centers’ protocols involve the administration of rituximab, an anti-CD20 antibody, particularly when the DSA strength is high. [Note: The US Food and Drug Administration has not approved rituximab for this use.] Most centers perform protocol biopsies throughout the first posttransplant year for the purposes of detecting and treating subclinical rejection. In addition, the DSA strength is monitored -- more frequently in the early posttransplant course and less frequently thereafter -- depending on DSA patterns, histologic findings, and the occurrence of any proinflammatory events; these events, including infections, surgeries, myocardial infarctions, and traumatic injuries were recently described to be associated with a5.3-foldincreaseinHLA-specificantibodyamongsensitizedwait-listedpatientsanda2.5-foldincreaseinHLA-specificantibodyin recipients of positive cross-match recipients.[4]

A recent desensitization protocol involves eculizumab, a humanized IgG monoclonal antibody with a high affinity for C5, which blocks terminal complement activation through this pathway. [Note: The US Food and Drug Administration has not approved rituximab for this use.] Stegall et al[5] described the first series of 26 sensitized kidney transplant candidates who underwent desensitization using eculizumab followed by LDKT; they were compared in a nonrandomized fashion with 51 historical controls who underwent plasmapheresis-based desensitization without eculizumab. In this study of patients with baseline flow-cytometric assaychannelshiftsof<450(thosewithhigherstrengthDSAwereexcluded)plasmapheresiswasusedtoreduceflow-cytometricassays to channel shifts of <300 on the day of transplant surgery; plasmapheresis was initially used in the eculizumab group but


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subsequently discontinued as it was “deemed unnecessary for the prevention of AMR.”[5]AMRwasreportedin41.2%ofthecontrolgroup compared with 7.7% of the eculizumab-treated group. Additionally, of the patients who underwent a 1-year protocol biopsy--42of51controlsand15of26eculizumab-treatedpatients--transplantglomerulopathywasreportedin35.7%ofthecontrol group compared with 6.7% of eculizumab-treated group. Although the study sample was small and the design was nonrandomized, the study results are encouraging and consistent with the use of complement inhibition in the treatment of AMR.[5]

Thevalueofdesensitizationprotocolswasquantifiedinastudyof211highlyHLA-sensitizedpatients(meanPRA,82%;≥32%ofthe cohort with PRA of ≥98% and ≥50% with previous kidney transplants) who underwent desensitization and LDKT.[6] Patient survival rates were compared with 2 carefully matched control cohorts on the kidney transplant wait list: those who continued to receive dialysis throughout the study period (dialysis-only cohort) or those who were followed in an “intention-to-treat” manner andunderwenteitherdialysisorHLA-compatibletransplantation(dialysis-or-transplantationcohort).

The211patientswhoreceiveddesensitizationandLDKT--74withpositivecytotoxiccross-match,88withpositive-flowcyto-metric assay but negative cytotoxic cross-match, and 38 with positive multiplex bead assay but negative-flow cytometric assay -- experienced a dramatic survival benefit compared with the matched cohorts (P<0.001), with survival of 90.6% at 1 year (vs 91.1% and 93.1% at 1 year in the dialysis-only and dialysis-or-transplantation cohorts, respectively), 85.7% at 3 years (vs 67.2% and 77.0%, respectively),80.6%at5years(vs51.5%and65.6%,respectively),and80.6%at8years(vs30.5%and49.1%,respectively).Thesurvival benefit began after 1 year and extended through the entire 8-year period of the study.[6]

Furthermore, a significant survival benefit was seen regardless of DSA strength. For patients with a positive cytotoxic cross-match, survivalfollowingdesensitizationandLDKTwas78.0%at8yearsvs27.1%inthedialysis-onlyand44.6%inthedialysis-or-transplantation matched controls. For patients with a positive flow-cytometric assay but negative cytotoxic cross-match, survival was79.7%at8yearsforthoseundergoingdesensitizationvs33.4%and49.3%inthematchedcohorts.Forpatientswithapositivemultiplexbeadassaybutnegative-flowcytometricassay,survivalwas90.8%at4yearsinthoseundergoingdesensitization(thefollow-upwasshorterforthiscohort)vs57.4%and67.3%inthematchedcohorts.[6]

Althoughdesensitizationprotocolsachievepromisingengraftmentratesandsignificantsurvivalbenefit,upwardsof40%ofpatients in some series experience an episode of AMR.[6]Inaddition,evenpatientswhoreceiveHLA-compatibletransplantsthatdo not require desensitization, particularly those with a relatively high PRA, can experience AMR. Better therapies for AMR are needed.

A 2012 systematic review of articles addressing the efficacy of acute AMR treatment regimens identified 5 randomized and 8 nonrandomized studies of relatively small sample size and marked heterogeneity (including the definition of AMR itself ).[7] Protocols evaluated in the study included plasmapheresis, immunoadsorption, high-dose IVIG, eculizumab, rituximab, splenectomy, and bortezomib (a proteasome inhibitor).[Note: Immunoadsorption is not approved for use in the United States.] Of the randomized trials, only 1 trial -- a stratified, randomized trial in 2007 of immunoadsorption in 10 patients that was terminated early with an adjusted relative risk of 0.8 (95% CI, 0.2-0.9) -- was conducted since 1990. Of the nonrandomized studies reviewed, 2wereconductedbefore1990.Theremaining6studieswerepublishedin2009orlater(4inabstractformonly);ofthese,1studyevaluated plasmapheresis, 2 evaluated rituximab, 2 evaluated bortezomib, and 1 compared rituximab with bortezomib. The authors concluded that evidence demonstrating any efficacy of rituximab or bortezomib was “very low” according to the GRADE system.[7]

Not considered in this systematic review were a number of recent case reports and small case series describing single-center experiences with AMR treatment using these agents; these small reports included anecdotes on the use of eculizumab.[8] Given the evidence of the success of eculizumab in desensitization, it is not surprising to find evidence of its success in treating AMR, particularly severe AMR in which the antibody burden is so high that plasmapheresis cannot clear circulating antibody quickly enough. In this scenario, successful treatment with emergent splenectomy was recently described in a patient who was not a candidate for splenectomy; a case report demonstrated successful salvage therapy using eculizumab, with a marked decrease in C5b-C9 complex deposition shown in the kidney.[9]However,aswithmanyoftheagentsdiscussedpreviouslyinthisarticle,theefficacy of this treatment has not yet been reported in a randomized trial.

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Donor-specificantibodies,includingHLAsensitization,transplantationacrossDSA,andtreatmentofAMR,remainmajorchallenges in the modern era of kidney transplantation. The significance of this challenge grows each year as a higher proportion of new candidates are sensitized -- a failed allograft is rapidly becoming one of the major indications for kidney transplantation. Although preliminary results for potential treatments are encouraging, we are far from being able to prevent or treat AMR. The need for continued research, development of novel agents, and accelerated pathways to test and approve these agents is more critical than ever.

This article is part of a CME/CE certified activity. The complete activity is available at:http://www.medscape.org/viewprogram/32708

AbbreviationsAMR = antibody mediated rejection

ASCERTAIN = Assessment of Everolimus in Addition to Calcineu-

rin Inhibitor Reduction in the Maintenance of Renal Transplant

Recipients

BPAR = biopsy-proven acute rejection

CENTRAL = CErtican Nordic Trial in RenAL Transplantation

cGFR = Calculated Glomerular Filtration Rate

CNI = calcineurin inhibitor

CrCl = creatinine clearance

CsA = cyclosporine A

DSA = donor-specific antibodies

eCrCl = estimated creatinine clearance

ELITE = Efficacy Limiting Toxicity Elimination

EVL = everolimus

GFR = Glomerular Filtration Rate

HLA=humanleukocyteantigens

ITT = intention-to-treat

IVIG = intravenous immunoglobulin

LDKT = live donor kidney transplantation

mGFR = measured Glomerular Filtration Rate

MPA = mycophenolic acid

mTOR = mammalian target of rapamycin

PRA = panel reactive antibody

RCT = randomized, controlled trial

SMART = Supra Maximal Atacand Renal Trial

SRL = sirolimus

ST = steroid

UPr/Cr = urinary protein creatinine ratio

References 1. The US Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients. OPTN / SRTR annual report: Transplant data 2000-2009. http://www.srtr.org/annual_reports/2010/ iKI_Candidates_wait_time.htm?o=2&g=1&c=14. Accessed October 30, 2012.2. Blume OR, Yost SE, Kaplan B. Antibody-mediated rejection: pathogenesis, prevention, treatment, and outcomes. Journal of Transplantation.2012;2012.doi:10.1155/2012/201754. http://www.hindawi.com/journals/jtran/2012/201754/. Accessed November 11, 2012.3. Garonzik-WangJM,MontgomeryRA,KucirkaLM,BergerJC,WarrenDS, Segev DL. Incompatible live donor kidney transplantation in the United States: results of a national survey. Clin J Am Soc Nephrol. 2011;6:2041-2046.4. LockeJE,MargoCM,SingerAL,etal.Useofantibodytocomplement protein C5 for salvage treatment of severe antibody mediated rejection. Am J Transplant. 2009;9:231-235.

5. Stegall MD, Diwan T, Raghavaiah S, et al. Terminal complement inhibition decreases antibody-mediated rejection in sensitized renal transplant recipients. Am J Transplant. 2011;11:2405-2413.6. MontgomeryRA,LonzeBE,KingKE,etal.DesensitizationinHLA- incompatible kidney recipients and survival. N Engl J Med. 2011;365:23-31.7. RobertsDM,JiangSH,ChadbanSJ.Thetreatmentofacuteantibody- mediated rejection in kidney transplant recipients-a systematic review. Transplantation.2012;94:776-783.8. SadakaB,AllowayRR,ShieldsAR,SchmidtNM,WoodleES.Protea some inhibition for antibody-mediated allograft rejection. Semin Hematol. 2012;49:263-269.9. LockeJE,ZacharyAA,WarrenDS,etal.Proinflammatoryeventsare associated with significant increases in breadth and strength of HLA-specificantibody.Am J Transplant. 2009;9:2136-2139.


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CNI Sparing With mTOR Inhibitors in Kidney Transplantation CME/CEFlavio Vincenti, MD

Posted: 12/19/2012

Beginning in the late 1970s and early 1980s, investigators broke convention with the use of the cyclosporine -- the first approved calcineurin inhibitor (CNI) -- and defined a new era in solid organ transplantation (SOT) by improving allograft survival and making widespread clinical application of extrarenal transplantation possible. Several decades later we cannot exactly say that we are at the corner of healthy and happy. Despite the introduction of numerous agents in several classes that followed the introduction of cyclosporine and tacrolimus -- the other CNI -- and drastic improvements in short-term outcomes, the balance between long-term effectiveness and safety remains elusive. Consequently, few issues in immunosuppression are as controversial as the use of the CNIs. Efforts to minimize the toxicities attributed to CNIs, in particular nephrotoxicity, include various strategies aimed at minimizing, eliminating, and avoiding these agents. Three CNI-sparing strategies -- CNI withdrawal or elimination, CNI minimization, and CNI avoidance -- have been studied, most under the umbrella of SRL-based immunosuppression.

Medscape: Three renal-sparing strategies aimed at decreasing exposure of kidney transplant allografts to the nephrotoxic effects of CNIs have been studied. Will you give us a brief history lesson on this?

Flavio Vincenti, MD: Prior to the introduction of the mammalian target of rapamycin (mTOR) inhibitors, the first attempts at CNI sparing used the strategy of complete CNI avoidance. My colleagues and I conducted one of those studies. In a multicenter study we investigated the avoidance of CNIs with the use of induction with daclizumab followed by a maintenance regimen of myco-phenolic acid (MPA) and steroids. Although recipient and allograft survival rates were excellent (97% and 96%, respectively), the acuterejectionratewas48%intheCNIavoidancegroup[1]; this strategy was abandoned.

Whensirolimus--thefirstmTORinhibitor--wasintroducedanotherCNI-avoidancestrategyusingsirolimuswithorwithoutMPAwas investigated in several randomized, controlled trials (RCTs).[2-4]However,thisstrategywasabandonedbecauseacuterejectionrates were unacceptably high; because a CNI was not used, high mTOR inhibitor doses (especially for sirolimus) were used, which resulted in high rates of complications and withdrawal from studies. The use of sirolimus-based immunosuppression for CNI avoidance in de novo kidney-transplant recipients is associated with worse outcomes compared with outcomes in patients treated with CNI-based maintenance immunosuppression regimens.

CNI minimization strategies using reduced-dose CNI with the addition of or increased doses of MPA or sirolimus were also investigated,[4-6] but were abandoned because statistically significant benefits of CNI minimization were either not demonstrated or were transient. Recently, ASSET, an everolimus-facilitated, tacrolimus-minimization study in de novo kidney-transplant recipients, was conducted to demonstrate superior renal function at 1 year in the minimization arm (tacrolimus target trough level of1.5-3ng/mLvs4-7ng/mL).[7] The rates of biopsy-proven acute rejection (BPAR) and graft loss were low, and the strategy showed anacceptablesafetyprofile.However,statisticallysuperiorrenalfunctionwasnotachievedinthetacrolimusminimization arm.[7]

Finally, there is CNI elimination -- ie, CNI is withdrawn at some point after transplantation and replaced by an mTOR inhibitor in combination with MPA and corticosteroid. For this strategy, the patient is initiated on a CNI and MPA for the first few months after transplant when the risk for rejection is greatest; then the CNI is converted to an mTOR inhibitor. MPA and corticosteroid round out the maintenance regimen. This strategy has been evaluated in several RCTs of conversion to sirolimus (Table 1)[9-13] and conversion to everolimus, the second-generation mTOR inhibitor (Table 2).[14-16]These studies of conversion strategies demonstrate optimal utilization of the mTOR inhibitors for CNI-sparing immunosuppression in kidney transplantation.

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Table 1. Trials of CNI Elimination Using Sirolimus in Kidney Transplantation

Trial

SMART[8]

Design: observational follow-up of patients fol-lowed within the SMART[9] study framework for 36 mo (N=132)

Aim: to compare the effect of an early CNI-free immunosuppression regimen with a standard immunosuppression with on renal function 36 mo after transplantation

Rapamune Maintenance Regimen[10]

Design: prospective, open-label, randomized, multicenter(N=525)

Aim:

Spare-the Nephron[11]

Design: prospective, open-label, randomized, multicenter(N=305)

Aim: to test the hypothesis that renal transplant recipients who are withdrawn from CNI-based therapy early after transplantation and maintained on MMF in combination with SRL will have improved mGFR

CONCEPT[12]

Design: prospective, open-label, multicenter(N=237)

Aim: to evaluate conversion from a CsA-based regimen to a SRL-based regimen 3 months after transplantation

CONVERT[13]

Design:(N=830)

Aim: to evaluate the efficacy and safety of converting maintenance renal transplant recipients from CNIs to SRL

Strategy

Earlyconversion(10-24d): CNI to SRL

Endpoint: eGFR

Early conversion (3 mo): CsA to SRL

Endpoint: cGFR

Early (30-180 d) with-drawal

Endpoint: mGFR

Early conversion (3 mo): CsA to SRL

Endpoint: eCrCl (accord-ing to Cockcroft and Gault) at wk 52

Late (6-120 mo) conver-sion: CNI to SRL

Endpoint: GFR (Nankiv-ell), cumulative rates of BPAR, allograft loss, or death at 12 mo

Findings

• At36mo,renalfunctioncontinuedtobesuperiorin SRL-treated patients (ITT-eGFR at 36 mo: 60.88 vs 53.72 [CsA] mL/min/1.73 m2, P=.031).• Significantlymorepatientsdiscontinuedtherapyin theSRLgroup59.4%vs42.3%(CsA).• Patient(99%[SRL]vs97%[CsA]andgraft;96%(SRL) vs94%[CsA])survivalat36mowasexcellentinboth arms.

• SRL-STtherapyresultedinsignificantlybettergraft survival, either when including death with a functioninggraftasanevent(84.2%vs91.5% [CsA], P=.024)orwhencensoringit(90.6%vs96.1% [CsA],P=026).• CalculatedGFR(43.8vs58.3mL/min,P<.001) and meanarterialbloodpressure(101.3vs97.1mmHg, P=.047)werealsoimprovedwithSRL-ST.• DifferencesintheincidencesofBPARafter randomization (6.5% vs 10.2%, SRL-CsA-ST vs SRL-ST, respectively)andmortality(7.9%vs4.7%)werenot significant.

Patients who were maintained on MMF/CNI for ≤6 mo and then converted to maintenance immunosuppres-sion with MMF/SRL had greater improvement in mGFR vs patients remaining on MMF/CNI.

• CrClatwk52wassignificantlybetterintheSRL group(68.9vs64.4mL/min,P=.017).• Patientandgraftsurvivalwerenotstatistically different.• Theincidenceofacuterejectionepisodes,mainly occurring after withdrawal of steroids was not statistically higher in the SRL group (17% vs 8%, P=.071).

• At2years,SRLconversionamongpatientswith baselineGFR>40mL/min/1.73m2 was associated with excellent patient and graft survival, no difference in BPAR, increased urinary protein excretion, and a lower incidence of malignancy compared with CNI continuation.• Superiorrenalfunctionwasobservedamong patientswhoremainedonSRLthrough12-24mo, particularly in the subgroup of patients with baseline GFR>40mL/min/1.73m2 and UPr/Cr ≤0.11.


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Table 2. Trials of CNI Elimination Using Everolimus in Kidney Transplantation

Trial

ZEUS [14]

Design: 36-mo, open-label, multicenter RCT(N=300)

Aim: to determine the long-term effect of con-version CNI therapy to an mTOR inhibitor

ASCERTAIN [15]

Design:24-mo,open-label,multicenterRCT(N=394ITT;127CNIeliminationvs144CNIminimization)

Aim: to determine whether introduction of EVL with elimination or minimization of CNI would improve graft function in maintenance renal transplant patients with renal impairment at the time of conversion

CENTRAL[16]

Design: 12-mo, open-label, multicenter RCT(N=202)

Strategy

Early(4.5mo)conver-sion: CsA to EVL

Endpoint: change in eGFR

Late (>6 mo, mean 5.6 yr) conversion: CNI to EVL

Endpoint: change in mGFR

Early (7 wk) conversion: CsA to EVL

Endpoint: change in mGFR

Findings

eGFR was significantly higher with EVL vs CsA at month 24(7.6mL/min/1.73m2 vs 11.0 mL/min/1.73 m2, P <.001) and month 36 (7.5 mL/min/1.73m2vs11.4mL/min/1.73m2, P<.001).

The incidence of BPAR from randomization to month 36 was13.0%intheeverolimusarmvs4.8%intheCsAarm(P = .015), but this was not associated with deleterious effects.

No overall renal benefit of EVL was shown, adverse events and discontinuations were more frequent in the EVL group

Post hoc analyses showed that patients with baseline CrCl >50 mL/min had a significantly greater increase in measured GFR after CNI elimination vs controls (dif-ference11.4mL/min/1.73m2 vs 20.8 mL/min/1.73m2, P=.017).

Conversion from CsA to EVL at wk 7 after kidney transplantation was associated with a greater improvement in mGFR at 12 mo vs CsA-treated controls, but discontinuations and BPAR were more frequent.

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Medscape: What is it about the mTOR inhibitors that is appealing for CNI-sparing?

Dr Vincenti: The mTOR inhibitors are attractive as CNI-sparing agents for several reasons. First, when administered with mycophenolate mofetil (MMF) mTOR inhibitors may provide better efficacy for prevention of rejection. Although there may be a slightly higher risk for rejection following conversion from a CNI, the rejection episodes tend to be mild and reversible; the small risk for rejection associated with these regimens is acceptable. Second, the mTOR inhibitors are not nephrotoxic, so this strategy allows for improvement in renal function. Third, the mTOR inhibitors are antiproliferative agents; they are the only immunosuppressive drugs with antineoplastic effects. They inhibit the phosphatidylinositol 3-kinase pathway, a family of lipid kinases involved in cell growth, survival, and proliferation.[17] Studies show that the use of sirolimus is associated with a lower risk for malignancies, especially nonmelanoma skin cancers.[18-20] Another potential benefit of the mTOR inhibitors is a positive impact on cardiovascular risk factors. A study by Paoletti showed improvement in left ventricular hypertrophy in kidney transplant recipients with diabetes who were converted from a CNI to an mTOR inhibitor,[21] and experimental studies have also shown a beneficial effect on vasculopathy in heart transplant allografts.[22,23] Finally, the mTOR inhibitors are associated with lower rates of viral infections, especially cytomegalovirus infection and possibly BK virus infection.[24]

Medscape: Could you tell us more about the antineoplastic properties of the mTOR inhibitors?

Dr Vincenti: This is one of the most appealing aspects of the mTOR inhibitors. In fact, mTOR inhibitors have antiproliferative activity against several types of malignancies,[25,26] and are being investigated for use in a number of others.[27] This is important because malignancy is a major cause of morbidity and death after solid organ transplantation, especially among patients who maintain their allograft beyond 5 or 10 years.[28,29] Therefore, any immunosuppressive agent that helps protect transplant recipients from cancer and metastases is potentially very beneficial in the long-term. Several studies have shown a reduction in the incidence of malignancies in kidney transplant recipients.

Patients in the CONVERT study who were converted to sirolimus had a reduction in the rate of malignancies.[13] Sirolimus was shown to dramatically inhibit the progression of Kaposi’s sarcoma while providing effective immunosuppression among kidney transplant patients.[30]

Two studies have been recently published in The New England Journal of Medicine. One of the best studies in my opinion, TUMORAPA, by Euvard and colleagues[19] evaluated the effect of switching from a CNI to sirolimus in patients who had had at least 1 squamous cell carcinoma. The primary study endpoint was survival-free of squamous cell carcinoma at 2 years after randomization. New squamous cell carcinoma developed in 22% of patients who were converted to sirolimus compared with an incidence of 39% in patients who were maintained on a CNI. Time to tumor recurrence was longer in patients converted to sirolimus (15 months) vs patients maintained on a CNI (7 months). There were more serious adverse events in patients converted to sirolimus, but these occurred mostly in patients who were converted within 7 days compared with the patients who underwent a gradual conversion. The other study by Campbell and colleagues[18] evaluated conversion from a CNI to sirolimus in kidney transplant recipients with a history ofnonmelanomaskincancer(NMSC).TheannualrateofNMSCwassignificantlylowerwithsirolimus(1.31vs2.48lesions/patient-year; P=.022)andalowerproportionofsirolimus-treatedpatientsdevelopedneworrecurrentNMSC(56.4%vs80.9%;P=.015) or new squamouscellcarcinoma(41.0%vs70.2%;P=0.006). Though the rate of squamous cell carcinoma was lower rate in the sirolimus-treated vs the CNI-treated group (P =.038); the rate of basal cell carcinoma rate was similar in both groups.

Medscape: How is CNI withdrawal and conversion to an mTOR inhibitor done?

Dr Vincenti: There are 2 important factors to consider with CNI conversion to an mTOR inhibitor: when to convert to the mTOR inhibitor and how quickly to discontinue the CNI. Early conversion is associated with greater improvement in renal function, and late conversion is associated with more proteinuria. The optimum time for conversion is about 3 months posttransplant. Progressive -- over a few weeks -- discontinuation of the CNI is safer (less rejection) and more effective than abrupt -- within 1 week -- discontinuation.[31]


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Medscape: What are the pitfalls to CNI withdrawal and conversion to mTOR inhibitors?

Dr Vincenti:WelearnedfromtheCONVERTstudyofconversionfromaCNItosirolimusthatpatientswithareasonableGFR(>40mL/min/1.73 m2)atthetimeofconversionaremostlikelytobenefit;thosewithalowGFR(<40mL/min/1.73m2) are least likely to benefit.[13]Thelow-GFRtreatmentarm(lessthan40mL/min/1.73m2) was halted due to a high incidence of treatment failure, including graft loss. These patients likely had significant underlying kidney disease that was unlikely to improve with the use of an mTOR inhibitor.

TheZEUStrialevaluatedthelong-termeffectofconversionfromaCNItoeverolimusat4.5monthsaftertransplantation.[14] At 3 years, the CNI had to be reintroduced in about 25% of converted patients due to inability to tolerate everolimus or acute rejection following conversion.Theincidenceofacuterejectionintheconversiongroupwas13%vs4.8%intheCNIarm(P=.015).[14] Renal function was better in the conversion group and remained stable at 3 years, but the incidence of proteinuria in was higher this group. Urine protein levelsvaluesweresignificantlyhigherintheeverolimusgroupat24and36months,andtheproportionofpatientsintheeverolimusgroupwithsevereproteinuria(urineprotein,≥0.5g/d)at24monthswassignificantlyhighervsthoserandomlyassignedtoCsA.Theproportionofpatientswithmoderateproteinuria(urineprotein,>1.0g/d)was5.8%intheeverolimusgroupvs4.2%intheCsAgroup. Patients with mild proteinuria were easily treated with conventional therapy, either an angiotensin converting enzyme inhibitor and or an angiotensin II receptor blocker.

Another important contributor to graft loss, the development of donor-specific antibodies (DSA), was recently evaluated. An analysis from patients from 1 center who participated in 2 trials comparing the effect on renal function of early conversion to an everolimus-based regimen vs a cyclosporine-based regimen showed that conversion to an everolimus-based regimen is associated with an increased risk for the development of DSA and antibody-mediated rejection.[32] DSA developed in 10.8% of patients in the cyclosporine arm at a median of 991 days compared with 23% in the everolimus-conversion arm at a median of 551 days.[32] The investigators used a multivariate regression model to identify patients at greater risk for developing DSA. This model could be incorporated as part of a strategy to decide who could most benefit from conversion to an mTOR inhibitor.

Medscape: Will you summarize the differences between sirolimus and everolimus?

Dr Vincenti: Though there has been no head-to-head comparison of sirolimus with everolimus, there is no evidence for a difference in efficacy or beneficial effects, such as decreased malignancy and cardiovascular risk. Everolimus, a derivative of sirolimus, has a 2-hydroxyethylchainsubstitutionatposition40onthesirolimusmolecule,whichmakesitmorehydrophilicandbioavailablethan sirolimus. The pharmacokinetic profiles of everolimus and sirolimus are different. The half-life of everolimus is shorter, and consequently twice-daily dosing is necessary, which can facilitate keeping recipients within narrow drug exposure targets. Beyond that, the efficacy of everolimus seems to be similar that of sirolimus, and their toxicity profiles are similar. The main issue with using mTOR inhibitors in combination with CNIs is their synergistic nephrotoxicity.

Medscape: Why CNI elimination and conversion?

Dr Vincenti:The1-yearallograftandpatientsurvivalratesafterkidneytransplantationareexcellent.However,beyond1year,therateof graft loss at year 1 to 3, 3 to 5, and 5 to 10 years has not significantly improved, despite a reduction in acute rejection rates.[33] The only way to improve long-term outcomes is to maintain and improve renal function, decrease cardiovascular events and malignancies because these are the major causes of either primary graft loss or graft loss due to premature patient death. Conversion strategies using mTOR inhibitors have the potential to do this.


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Recipients






CsA = cyclosporine A




EVL = everolimus












SRL = sirolimus

ST = steroid


References 1. Vincenti F, Ramos E, Brattstrom C, et al. Multicenter trial exploring calcineurin inhibitors avoidance in renal transplantation. Transplantation. 2001;71:1282-1287. 2. Flechner SM, Kurian SM, Solez K, et al. De novo kidney transplantation without use of calcineurin inhibitors preserves renal structure and function at two years. Am J Transplant.2004;4:1776-1785.3. Larson TS, Dean PG, Stegall MD, et al. Complete avoidance of calcineurin inhibitors in renal transplantation: a randomized trial comparing sirolimus and tacrolimus. Am J Transplant.2006;6:514-522.4. EkbergH,Tedesco-SilvaH,DemirbasA,etal.Reducedexposureto alcineurin inhibitors in renal transplantation. N Engl J Med. 2007;357:2562-2575. 5. EkbergH,GrinyoJ,NashanB,etal.Cyclosporinesparingwith mycophenolate mofetil, daclizumab and corticosteroids in renal allograft recipients: the CAESAR Study. Am J Transplant. 2007;7:560-570. 6. EkbergH,BernasconiC,Tedesco-SilvaH,etal.Calcineurininhibitor minimization in the Symphony study: observational results 3 years after transplantation. Am J Transplant. 2009;9:1876-1885. 7. LangerRM,HenéR,VitkoS,etal.Everolimusplusearlytacrolimus minimization: a phase III, randomized, open-label, multicentre trial in renal transplantation. Transplant Int. 2012;25:592-602.8. GubaM,PratschkeJ,HugoC,etal.Earlyconversiontoasirolimus-based, calcineurin-inhibitor-free immunosuppression in the SMART trial: observationalresultsat24and36monthsaftertransplantation. Transplant Int. 2012;25:416-423.9. GubaM,PratschkeJ,HugoC,etal.Renalfunction,efficacy,andsafetyof sirolimus and mycophenolate mofetil after short- term calcineurin inhibitor-based quadruple therapy in de novo renal transplant patients: one-year analysis of a randomized multicenter trial. Transplantation. 2010;90:175-183. 10. Oberbauer R, Segoloni G, Campistol JM, et al. Early cyclosporine withdrawal from a sirolimus-based regimen results in better renal allograft survivalandrenalfunctionat48monthsaftertransplantation.Transpl Int. 2005;18:22-28.

11. Pearson TC, Mulgaonkar S, Patel A, et al. Efficacy and safety of mycophenolate mofetil (MMF)/sirolimus (SRL) maintenance therapy after calcineurin inhibitor (CNI) withdrawal in renal transplant recipients: final results of the Spare-the-Nephron (STN) trial. Am J Transplant. 2008;8:213.12. Lebranchu Y, Thierry A, Toupance O, et al. Efficacy on renal function of early conversion from cyclosporine to sirolimus 3 months after renal transplantation: Concept study. Am J Transplant. 2009;9:1115-1123. 13. Schena FP, Pascoe MD, Alberu J, et al. Conversion from calcineurin inhibitors to sirolimus maintenance therapy in renal allograft recipients: 24-monthefficacyandsafetyresultsfromtheCONVERTtrial. Transplantation.2009;87:233-242.14.BuddeK,BeckerT,ArnsA,etal.Everolimus-basedregimen calcineurin-inhibitor-free regimen in recipients of de-novo kidney transplants: An open-label, randomised, controlled trial. Lancet. 2011;377:837-847.15.HoldaasH,RostaingL,SéronD,etal.Conversionoflong-termkidney transplant recipients from calcineurin inhibitor therapy to everolimus: a randomized,multicenter,24-monthstudy.Transplantation. 2012;92:410-418.16. Mjörnstedt L, Sørensen SS, von zur Mühlen B, et al. Improved renal function after early conversion from a calcineurin inhibitor to everolimus: a randomized trial in kidney transplantation. Am J Transplant. 20012;12:2744-2753.17. Borders EB, Bivona C, Medina P. Mammalian target of rapamycin: Biological function and target for novel anticancer agents. Am J Health Syst Pharm. 2010;67:2095-2106. 18.CampbellSB,WalkerR,TaiSS,JiangQ,RussGR.Randomizedcontrolled Trial of sirolimus for renal transplant recipients at high risk for nonmelanoma skin cancer. Am J Transplant.2012;12:1146-1156.19. Euvard S, Morelon E, Rostaing L, et al. Sirolimus and secondary skin-cancer prevention in kidney transplantation. N Engl J Med. 2012;367:329-339. 20.FeldmeyerL,HofbauerGFL,BöniT,FrenchLE,HafnerJ.Mammaliantarget of rapamycin (mTOR) inhibitors slow skin carcinogenesis, but impair wound healing. Br J Dermatology.2012;166:422-424.


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20.FeldmeyerL,HofbauerGFL,BöniT,FrenchLE,HafnerJ.Mammaliantarget of rapamycin (mTOR) inhibitors slow skin carcinogenesis, but impair wound healing. Br J Dermatology.2012;166:422-424.21. Paoletti E, Marsano L, Bellino D, Cassottana P, Cannella G. Effect of everolimus on left ventricular hypertrophy of de novo kidney transplant recipients: A 1 year, randomized, controlled trial. Transplantation. 2012;93:503-508. 22.RaichlinE,BaeJH,KhalpeyZ,etal.Conversiontosirolimusasprimary immunosuppression attenuates the progression of allograft vasculopathy after cardiac transplantation. Circulation. 2007;116:2726-2733. 23. Zuckermann A, Keogh A, Crespo-Liero MG, et al. Randomized controlled trial of sirolimus conversion in cardiac transplant recipients with renal insufficiency. Am J Transplant.2012;12:2487-2497.24.NashanB,GastonR,EmeryV,etal.Reviewofcytomegalovirusinfection findings with mammalian target of rapamycin inhibitor-based immuno suppressive therapy in de novo renal transplant recipients. Transplantation. 2012;11:1075-1085.25. McCormack FX, Inou Y, et al. Efficacy and safety of sirolimus in lymphangioleiomyomatosis. N Engl J Med.2011;364:1595-1606.

26.WagnerM,RohV,StrehlenM,etal.Effectivetreatmentofadvanced colorectal cancer by rapamycin and 5-FU/oxaliplatin monitored by TIMP-1. J Gastrointest Surg. 2009;13:1781-1790. 27. Platanias LC. mTOR inhibitors in cancer treatment. Future medicine. 2011. http://www.futuremedicine.com/doi/abs/10.2217/ebo.11.303. Accessed December 10, 2012.28. Vajdic CM, van Leeuwen MT. Cancer incidence and risk factors after solid organ transplantation. Int J Cancer. 2009;125:1747-1754.29. Engels EA, Pfeiffer RM, Fraumeni JF Jr, et al. Spectrum of cancer risk among US solid organ transplant recipients. JAMA. 2011;306:1891-1901. 30. Stallone G, Schena A, Infante B, et al. Sirolimus for Kaposi’s sarcoma in renal-transplant recipients. N Engl J Med. 2005;352:1317-1323. 31. Rostaing L, Kamar N. mTOR inhibitor/proliferation signal inhibitors: entering or leaving the field? J Nephrol. 2012;23:133-142.32.LiefeldtL,BrakemeierS,GlanderP,etal.Donor-specificHLAantibodiesina cohort comparing everolimus with cyclosporine after kidney transplantation. Am J Transplant. 2012;12:1192-1198. 33. Naesens M, Kuypers DRJ, Sarwal M. Calcineurin inhibitor nephrotoxicity. Clin J Am Soc Nephrol. 2009;2:481-508.

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The Year in Review: Most Notable Studies in Kidney Transplantation CME/CERon Shapiro, MD

Posted: 12/19/2012

Despite notable advances in the field of kidney transplantation over the past 30 years, the expected long-term outcomes have not been achieved.[1] Researchers have been challenged to pursue 2 main strategies as potential solutions for moving the needle to the right on the long-term health and survival scale, the investigation of: new agents with new mechanisms of action; and ways to use available agents more effectively and safely. Thus, kidney transplant clinicians find themselves at a crossroads of continued reliance on traditional agents and regimens as the cornerstone of maintenance immunosuppressive regimens and emerging therapies. Medscape spoke with Ron Shapiro, MD, professor of surgery and associate clinical director at Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center Montefiore in Pennsylvania about his choices for the important publications in the field of kidney transplantation in 2012 that shed important light on this situation.

Medscape: The publication at the top of your list is on a phase 2b study by Leventhal and colleagues published in the journal Science Translational Medicine. Why was this your top pick?.

Ron Shapiro, MD: This study was published in Science Translational Medicine and then presented as the first plenary talk at the 2012 American Transplant Congress (ATC) in Boston, Massachusetts.[2] This very important paper describes a therapy that appears to induce true immune tolerance in patients undergoing kidney transplantation. The techniques used in this approach -- kidney transplantation and stem cell transplantation with nonmyeloablative conditioning -- are readily available and not particularly toxic.Thoughnotparticularlywellmatchedforhumanleukocyteantigens(HLA)--nonidenticalHLAlivingdonorswereused--patients did not develop graft-versus-host disease or engraftment syndrome.

Chimerism was achieved in a high percentage of patients, and these patients were weaned off immunosuppression at approximately 1 year after transplantation. The approach was not completely successful; 1 patient developed viral sepsis and lost thetransplantedkidney.However,theresultswerefairlydramatic;itappearstobearelativelysafeandstraightforwardwayofachieving tolerance. The approach is a potential “game changer” for kidney transplantation.

Limitations of this approach are that it used in only living donors and it is resource intensive; currently only 3 patients per month are being treated. The current barrier to widespread implementation is determining how to industrialize the process and create a business model whereby it could become a viable approach. The approach is dependent on preparing donor stem cells in a way that enriches the facilitating cells, but the technique is proprietary so we don’t much about it.

Medscape: What did you mean by true tolerance?

Dr Shapiro: True tolerance is stable graft function without rejection after all immunosuppression is completely withdrawn. Interestingly, using the approach described macrochimerism was achieved without graft-versus-host disease or engraftment syndrome, which has occurred with other models of tolerance induction.

Medscape: Is the need to establish a business model for the viability of this approach a unique challenge in ransplantation?

Dr Shapiro: Yes. Most therapies for solid organ transplantation involve new immunosuppressive agents that go through a process of discovery followed by phase 1, 2, and 3 clinical trials. The resulting product is then approved by the US Food and Drug Administration (FDA) as a drug. The therapeutic approach used by Leventhal and colleagues is different. Their model involves the administration of multiple agents and the use of patient-specific stem cell preparations. Eventually immunosuppression is withdrawn. The challenge is how to do this in a large-scale manner. Currently, the stem cells are prepared at the University of Louisville and the transplants take place at Northwestern University. This approach is still a cottage industry and only 3 patients per month are treated, which would not come close to fulfilling the needs of a single kidney transplant center with more than 100 living donors per year, much less the thousands of living-donor transplants performed annually in the United States.[2] Again, the


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challenge from both technical and business model perspectives is how to make this innovative approach to transplantation applicable to thousands of kidney transplant candidates. From the perspective of corporate sponsorship this is a very different business model.

Medscape: You chose 2 publications comparing induction therapy using alemtuzumab with conventional induction agents. What is important about these studies?

Dr Shapiro: It is difficult to conduct registration trials of induction agents because of economic limitations. The most commonly used lymphocyte-depleting induction agent is thymoglobulin. Thymoglobulin is used off label for induction at the time of trans-plantation. Alemtuzumab is approved as a third-line agent for treating leukemia but has been used off label as an induction agent for kidney transplantation by some centers, beginning in 1998 when it was first used by Sir Roy Calne in conjunction with low-dose cyclosporine maintenance monotherapy.

ThestudybyHanawayandcolleaguespublishedintheNewEnglandJournalofMedicineistheclosestwewillcometoaregistra-tion trial of alemtuzumab.[2] This multicenter trial compared outcomes of induction therapy using alemtuzumab with outcomes of conventional induction therapy using either basiliximab in low-risk recipients or rabbit antithymocyte globulin (rATG) in high-risk recipients. In terms of biopsy-proven acute rejection, alemtuzumab was superior to basiliximab in low-risk recipients and compa-rable to rATG in high-risk recipients. There was a trend toward decreased patient survival at 3 years in the basiliximab group and the incidence of late rejection was higher in the alemtuzumab group. The study demonstrated that alemtuzumab is an effective induction agent for kidney transplantation.[3] Because the economics of the drug will not allow it to be submitted for true registra-tion trials with the FDA, these results are as close as we are going to get a registration trial. Despite the limitations of the study, the research demonstrated a very important clinical application.

The corporate structure supporting alemtuzumab has changed. The company that originally manufactured the drug was sold. The current plan is for alemtuzumab to be rebranded, used for treatment of multiple sclerosis, and sold at a very different price structure. The company is offering the drug to transplantation and cancer programs free of charge. It will be interesting to see what happens with this agent. It has always had an orphan status and is now going to be even more of an orphan drug.

The single-center trial conducted by Farney and colleagues was a 5-year extension of a randomized trial that included anyone receiving a kidney transplant or kidney-pancreas transplant; it involved both perfect and not-so-perfect kidneys.[4] The results showed comparable 5-year patient graft survival rates between the alemtuzumab and rATG treatment groups, though significantly less early acute rejection and slightly fewer chronic kidney changes (chronic allograft nephropathy) were seen in the alemtuzumab-treated group.[4]Together,datafromthetrialsbyHanawayandcolleagues[3] and Farney and colleagues[4] suggest that alemtuzumab is an effective and reasonable agent for kidney transplant recipients.

Medscape: What did you mean when you said this is the closest we will come to a registration trial of alemtuzumab?

Dr Shapiro: As I understand it, the economics of induction are that it is $150 million-per-year market. The cost of developing and getting alemtuzumab through FDA approval as an induction agent for transplantation would be so high that it is cost prohibitive; this would be particularly true now that the drug will be offered free of charge. The reality is that alemtuzumab is an interesting agent but it is not economically feasible for it to meet the requirements of the registration trial process to be approved for use in transplantation.

Medscape: You chose 2 abstracts on the use of the T-cell costimulation blocker belatacept. The first by Larsen and colleagues reported on the 4-year results of the long-term extension of BENEFIT.[5-7] How do these data add to our knowledge of the use of belatacept?

Dr Shapiro: Belatacept is the first new primary maintenance immunosuppressive agent to be approved in recent years. [5,6] The abstractbyLarsenandcolleaguesreportdatafromthe4-yearextensionoftheBENEFITtrial.Theprimaryobjectivewastoassesslong-term safety and tolerability of belatacept. Data confirmed that the nonnephrotoxic nature of belatacept translates into a substantially better glomerular filtration rate (GFR) in patients who receive good-quality kidneys. [7] The mean calculated GFR (mL/min/1.73 m2)at48monthswas73.8±19.6forthemore-intensivebelataceptregimen,75.1±17.0fortheless-intensivebelataceptregimen,and50.0±18.7forthecyclosporineregimen.

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Though the incidence of acute rejection was substantially higher in the belatacept arms compared with the cyclosporine arm in the phase 3 trials, patient survival and graft survival were not adversely impacted. [5,6] The majority of rejection in belatacept-treated patients occurred early (before 3 months posttransplantation) in the BENEFIT trial. Late acute rejection (between36and48months)wasveryrareinthe4-yearextensiondata.[7] Belatacept has been associated with an excessively high incidence of posttransplant lymphoproliferative disorder in Epstein-Barr virus-seronegative patients so it cannot be used in those patients, and this problem compromises the ability to develop use of this drug in pediatric patients.

Despite its limitations, belatacept has been associated with better renal function over an extended period of time and the half-life of kidneys transplanted under belatacept-based immunosuppression may increase. Although belatacept is expensive, if kidney allografts last longer this may have important long-term implications for a field with too few organs and limited organ half-life. The 10-year graft survival rate has not changed very much during the past 20 or so years, and belatacept may have the potential for improving this rate.

Medscape: The second abstract is by Kirk and colleagues on the use of belatacept with alemtuzumab induction and sirolimus maintenance therapy.[8] What are the lessons from these data?

Dr Shapiro: This study examined the use of induction therapy using alemtuzumab and belatacept maintenance immunosuppression in a corticosteroid-avoidance protocol.

This research, which inexplicably was accepted as a poster presentation (vs oral abstract presentation) at the 2012 ATC, included patients who were beyond 1 year posttransplantation and weaned from sirolimus to belatacept monotherapy. [7] They were treated with a monthly IV infusion of belatacept and did not receive prednisone or mycophenolate mofetil. This is not tolerance but the immunosuppression is minimal. In a personal conversation [that I had] with Alan Kirk [June 2012 at the ATC in Boston, Massachusetts], he said 10 patients in his study had been weaned off sirolimus; this is a very exciting development. The regimen is well tolerated, associated with a very low incidence of acute rejection, and affords the possibility of weaning patients off sirolimus and maintaining them on a once-monthly dose of belatacept. Additional follow-up and a larger trial are needed, but these early data are fascinating.

Medscape: The pipeline for transplant immunosuppression has been relatively static over the past decade with the excep-tion of a few early-phase blips. Your final choice is a late-breaking abstract presented by Yang and colleagues on a phase 1b study of ASKP1240 at the 24th International Congress of the Transplantation Society in July 2012 in Berlin, Germany.[9] Why did you include a phase 1b study in your top picks?

Dr Shapiro: The success of kidney transplantation -- 90% 1-year graft survival rate for deceased-donor recipients and 95% graft survival rate for living-donor recipients -- has made it difficult to develop competitive new immunosuppressive agents,[9] and there are few new drugs in the pipeline.

Thephase1bstudybyYangandcolleaguesevaluatedananti-CD40monoclonalantibody.[9] Data from this early safety trial of differentdosessuggesttheCD40ligandappearstobeawell-tolerated,safe,andefficaciousagent.Phase2andphase3clinicaltrials are needed, but this agent appears to be an interesting and potentially exciting development in monoclonal antibody therapy. Even though this is very preliminary work, the findings are worth noting.



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Recipients






CsA =cyclosporine A




EVL = everolimus












SRL = sirolimus

ST = steroid


References 1. Naesens M, Kuypers DRJ, Sarwal M. Calcineurin inhibitor nephrotoxicity. Clin J Am Soc Nephrol.2009;2:481-508.2. Leventhal J, Abecassis M, Miller J, et al. Chimerism and tolerance without GVHDorengraftmentsyndromeinHLA-mismatchedcombinedkidney and hematopoietic stem cell transplantation. Sci Transl Med. 2012;4:124ra28.3. HanawayM,WoodleES,MulgaonkarS,etal.;INTACStudyGroup. Alemtuzumab in kidney transplantation: A prospective, randomized, multicenter trial, 3 year results. N Engl J Med. 2011;364:1909-1919.4. FarneyA,RogersJ,HartL,etal.Longtermresultsofaprospective randomized study of alemtuzumab vs rabbit anti-thymocyte globulin induction in kidney and kidney pancreas transplantation. Proceedings of the American Transplant Congress; June 2-6, 2012; Boston, MA. Abstract 101.5. Vincenti F, Charpentier B, Vanrenterghem Y, et al. A Phase III Study of Belatacept-based immunosuppression regimens versus cyclosporine in renal transplant recipients (BENEFIT Study). Am J Transplant. 2010;10:536-546.

6. Durrbach A, Pestana JM, Pearson T, et al. A phase III study of belatacept versus cyclosporine in kidney transplants from extended criteria donors (BENEFIT-EXT study). Am J Transplant. 2010;10:547-557.7. LarsenC,AlberuJ,MassariP,etal.4-yearresultsfromthelong-term extension of the belatacept BENEFIT study. Proceedings of the American Transplant Congress; June 2-6, 2012; Boston, MA. Abstract 186.8. Kirk AD, Mehta AK, Guasch A, et al, Kidney transplantation using alemtuzumab induction and belatacept/sirolimus maintenance therapy. Proceedings of the American Transplant Congress; June 2-6, 2012; Boston, MA. Abstract 560.9. YangH,VincentiF,KlintmalmG,etal.Aphase1B,randomized, double-blind, parallel group, placebo-controlled, single dose, pharmacokinetic, pharmacodynamic safety and tolerability study of ASKP1240indenovokidneytransplantation.Proceedingsofthe24th International Congress of the Transplantation Society; July 15-19, 2012; Berlin, Germany. Abstract MON.C020.02.

DisclaimerThe material presented here does not necessarily reflect the views of Medscape, LLC, or companies that support educational programming on medscape.org. These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or employing any therapies described in this educational activity.

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