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ong>Solidong> ong>Organong> ong>Transplantationong>: ong>2012ong> ong>Updateong> on Current and Emerging Approaches to Treatment CME/CE

ong>Solidong> ong>Organong> ong>Transplantationong>: ong>2012ong> ong>Updateong> on

Current and Emerging Approaches to Treatment CME/CE

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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View this activity online at:

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ong>Solidong> ong>Organong> ong>Transplantationong>: ong>2012ong> ong>Updateong> on Current and Emerging Approaches to Treatment CME/CE

This article is a CME/CE-certified activity.

To earn credit for this activity visit:

medscape.org/anthology/kidneytran

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

Target Audience

This 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.

Goal

The 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 Objectives

Upon 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

Credits Available

Physicians - maximum of 1.25 AMA PRA Category 1 Credit(s)

Nurses - 1.25 ANCC Contact Hour(s) (1.25 contact hours are in the area of pharmacology)

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ong>Solidong> ong>Organong> ong>Transplantationong>: ong>2012ong> ong>Updateong> on Current and Emerging Approaches to Treatment CME/CE

Authors

Dorry L. Segev, MD, PhD

Associate Professor of Surgery and Epidemiology; Director of Clinical Research, Transplant Surgery, Johns Hopkins University

School of Medicine, Baltimore, Maryland

“Participation by Dr Segev in the development of this product does not constitute or imply endorsement by the Johns Hopkins

University or the Johns Hopkins Hospital and Health System.”

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, MD

Professor 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 Company

Owns 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, MD

Professor of Surgery, Associate Clinical Director, Thomas E. Starzl ong>Transplantationong> 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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Editors

Susan L. Smith, MN, PhD

Group Scientific Director, Medscape, LLC

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

Laura Feiker

Clinical Editor, Medscape, LLC

Disclosure: Laura Feiker has disclosed no relevant financial relationships.

Kristen L. Dascoli

Clinical Editor, Medscape, LLC

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

CME Reviewer

Nafeez Zawahir, MD

CME Clinical Director, Medscape, LLC

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

Nurse Planner

Laurie E. Scudder, DNP, NP

Nurse Planner, Continuing Professional Education Department, Medscape, LLC; Clinical Assistant Professor, School of Nursing and

Allied Health, George Washington University, Washington, DC

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

Pg.5


ong>Solidong> ong>Organong> ong>Transplantationong>: ong>2012ong> ong>Updateong> on Current and Emerging Approaches to Treatment CME/CE

Evaluating Advances in the Prevention and Treatment of

Antibody-Mediated Rejection CME/CE

Dorry L. Segev, MD, PhD

Posted: 12/19/ong>2012ong>

The sensitized kidney transplant candidate -- sensitized to human leukocyte antigens (HLA) because of previous pregnancies,

blood transfusions, or transplants -- represents one of the most significant challenges in modern kidney transplantation. In 2010,

of the 80,571 candidates on the ong>Organong> Procurement and ong>Transplantationong> 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,

hyperacute rejection. However, the risk for antibody mediated rejection (AMR) following transplant remains relatively high in

patients 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

a 5.3-fold increase in HLA-specific antibody among sensitized wait-listed patients and a 2.5-fold increase in HLA-specific antibody

in 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

assay channel shifts of


www.medscape.org/anthology/kidneytran

subsequently discontinued as it was “deemed unnecessary for the prevention of AMR.” [5] AMR was reported in 41.2% of the control

group compared with 7.7% of the eculizumab-treated group. Additionally, of the patients who underwent a 1-year protocol

biopsy -- 42 of 51 controls and 15 of 26 eculizumab-treated patients -- transplant glomerulopathy was reported in 35.7% of the

control 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]

The value of desensitization protocols was quantified in a study of 211 highly HLA-sensitized patients (mean PRA, 82%; ≥32% of

the 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

and underwent either dialysis or HLA-compatible transplantation (dialysis-or-transplantation cohort).

The 211 patients who received desensitization and LDKT -- 74 with positive cytotoxic cross-match, 88 with positive-flow cytometric

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


ong>Solidong> ong>Organong> ong>Transplantationong>: ong>2012ong> ong>Updateong> on Current and Emerging Approaches to Treatment CME/CE

Donor-specific antibodies, including HLA sensitization, transplantation across DSA, and treatment of AMR, remain major

challenges 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

Abbreviations

AMR = antibody mediated rejection

ASCERTAIN = Assessment of Everolimus in Addition to Calcineurin

Inhibitor Reduction in the Maintenance of Renal Transplant

Recipients

BPAR = biopsy-proven acute rejection

CENTRAL = CErtican Nordic Trial in RenAL ong>Transplantationong>

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 = human leukocyte antigens

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 ong>Organong> Procurement and ong>Transplantationong> 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, ong>2012ong>.

2. Blume OR, Yost SE, Kaplan B. Antibody-mediated rejection:

pathogenesis, prevention, treatment, and outcomes. Journal of

ong>Transplantationong>. ong>2012ong>;ong>2012ong>. doi:10.1155/ong>2012ong>/201754.

http://www.hindawi.com/journals/jtran/ong>2012ong>/201754/.

Accessed November 11, ong>2012ong>.

3. Garonzik-Wang JM, Montgomery RA, Kucirka LM, Berger JC, Warren DS,

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. Locke JE, Margo CM, Singer AL, et al. Use of antibody to complement

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. Montgomery RA, Lonze BE, King KE, et al. Desensitization in HLAincompatible

kidney recipients and survival. N Engl J Med.

2011;365:23-31.

7. Roberts DM, Jiang SH, Chadban SJ. The treatment of acute antibodymediated

rejection in kidney transplant recipients-a systematic review.

ong>Transplantationong>. ong>2012ong>;94:776-783.

8. Sadaka B, Alloway RR, Shields AR, Schmidt NM, Woodle ES. Protea

some inhibition for antibody-mediated allograft rejection. Semin

Hematol. ong>2012ong>;49:263-269.

9. Locke JE, Zachary AA, Warren DS, et al. Proinflammatory events are

associated with significant increases in breadth and strength of

HLA-specific antibody. Am J Transplant. 2009;9:2136-2139.

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CNI Sparing With mTOR Inhibitors in Kidney ong>Transplantationong> CME/CE

Flavio Vincenti, MD

Posted: 12/19/ong>2012ong>

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 longterm

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 mycophenolic

acid (MPA) and steroids. Although recipient and allograft survival rates were excellent (97% and 96%, respectively), the

acute rejection rate was 48% in the CNI avoidance group [1] ; this strategy was abandoned.

When sirolimus -- the first mTOR inhibitor -- was introduced another CNI-avoidance strategy using sirolimus with or without MPA

was investigated in several randomized, controlled trials (RCTs). [2-4] However, this strategy was abandoned because acute rejection

rates 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

of 1.5-3 ng/mL vs 4-7 ng/mL). [7] The rates of biopsy-proven acute rejection (BPAR) and graft loss were low, and the strategy showed

an acceptable safety profile. However, statistically superior renal function was not achieved in the tacrolimus

minimization 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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ong>Solidong> ong>Organong> ong>Transplantationong>: ong>2012ong> ong>Updateong> on Current and Emerging Approaches to Treatment CME/CE

Table 1. Trials of CNI Elimination Using Sirolimus in Kidney ong>Transplantationong>

Trial

SMART [8]

Design: observational follow-up of patients followed

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

Early conversion (10-24

d): CNI to SRL

Endpoint: eGFR

Early conversion (3 mo):

CsA to SRL

Endpoint: cGFR

Early (30-180 d) withdrawal

Endpoint: mGFR

Early conversion (3 mo):

CsA to SRL

Endpoint: eCrCl (according

to Cockcroft and

Gault) at wk 52

Late (6-120 mo) conversion:

CNI to SRL

Endpoint: GFR (Nankivell),

cumulative rates of

BPAR, allograft loss, or

death at 12 mo

Findings

• At 36 mo, renal function continued to be superior in

SRL-treated patients (ITT-eGFR at 36 mo: 60.88 vs

53.72 [CsA] mL/min/1.73 m 2 , P=.031).

• Significantly more patients discontinued therapy in

the SRL group 59.4% vs 42.3% (CsA).

• Patient (99% [SRL] vs 97% [CsA] and graft; 96% (SRL)

vs 94% [CsA]) survival at 36 mo was excellent in both

arms.

• SRL-ST therapy resulted in significantly better graft

survival, either when including death with a

functioning graft as an event (84.2% vs 91.5%

[CsA], P=.024) or when censoring it (90.6% vs 96.1%

[CsA],P=026).

• Calculated GFR (43.8 vs 58.3 mL/min, P40 mL/min/1.73 m 2 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.

• Superior renal function was observed among

patients who remained on SRL through 12-24 mo,

particularly in the subgroup of patients with baseline

GFR >40 mL/min/1.73 m 2 and UPr/Cr ≤0.11.

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Table 2. Trials of CNI Elimination Using Everolimus in Kidney ong>Transplantationong>

Trial

ZEUS [14]

Design: 36-mo, open-label, multicenter RCT

(N=300)

Aim: to determine the long-term effect of conversion

CNI therapy to an mTOR inhibitor

Strategy

Early (4.5 mo) conversion:

CsA to EVL

Endpoint: change in

eGFR

Findings

eGFR was significantly higher with EVL vs CsA at month

24 (7.6 mL/min/1.73 m 2 vs 11.0 mL/min/1.73 m 2 , P 50 mL/min had a significantly greater increase in

measured GFR after CNI elimination vs controls (difference

11.4 mL/min/1.73 m 2 vs 20.8 mL/min/1.73m 2 ,

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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ong>Solidong> ong>Organong> ong>Transplantationong>: ong>2012ong> ong>Updateong> on Current and Emerging Approaches to Treatment CME/CE

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

of nonmelanoma skin cancer (NMSC). The annual rate of NMSC was significantly lower with sirolimus (1.31 vs 2.48 lesions/patientyear;

P=.022) and a lower proportion of sirolimus-treated patients developed new or recurrent NMSC (56.4% vs 80.9%; P=.015) or new

squamous cell carcinoma (41.0% vs 70.2%; P=0.006). Though the rate of squamous cell carcinoma was lower rate in the sirolimustreated

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: We learned from the CONVERT study of conversion from a CNI to sirolimus that patients with a reasonable GFR (>40 mL/

min/1.73 m 2 ) at the time of conversion are most likely to benefit; those with a low GFR (1.0 g/d) was 5.8% in the everolimus group vs 4.2% in the CsA

group. 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-hydroxyethyl chain substitution at position 40 on the sirolimus molecule, which makes it more hydrophilic and bioavailable

than 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: The 1-year allograft and patient survival rates after kidney transplantation are excellent. However, beyond 1 year, the rate

of 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.

This article is part of a CME/CE certified activity. The complete activity is available at:

http://www.medscape.org/viewprogram/32708

Pg.13


ong>Solidong> ong>Organong> ong>Transplantationong>: ong>2012ong> ong>Updateong> on Current and Emerging Approaches to Treatment CME/CE

Abbreviations

AMR = antibody mediated rejection

ASCERTAIN = Assessment of Everolimus in Addition to Calcineurin

Inhibitor Reduction in the Maintenance of Renal Transplant

Recipients

BPAR = biopsy-proven acute rejection

CENTRAL = CErtican Nordic Trial in RenAL ong>Transplantationong>

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 = human leukocyte antigens

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. Vincenti F, Ramos E, Brattstrom C, et al. Multicenter trial exploring

calcineurin inhibitors avoidance in renal transplantation. ong>Transplantationong>.

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. Ekberg H, Tedesco-Silva H, Demirbas A, et al. Reduced exposure to

alcineurin inhibitors in renal transplantation. N Engl J Med.

2007;357:2562-2575.

5. Ekberg H, Grinyo J, Nashan B, et al. Cyclosporine sparing with

mycophenolate mofetil, daclizumab and corticosteroids in renal allograft

recipients: the CAESAR Study. Am J Transplant. 2007;7:560-570.

6. Ekberg H, Bernasconi C, Tedesco-Silva H, et al. Calcineurin inhibitor

minimization in the Symphony study: observational results 3 years after

transplantation. Am J Transplant. 2009;9:1876-1885.

7. Langer RM, Hené R, Vitko S, et al. Everolimus plus early tacrolimus

minimization: a phase III, randomized, open-label, multicentre trial in renal

transplantation. Transplant Int. ong>2012ong>;25:592-602.

8. Guba M, Pratschke J, Hugo C, et al. Early conversion to a sirolimus-based,

calcineurin-inhibitor-free immunosuppression in the SMART trial:

observational results at 24 and 36 months after transplantation.

Transplant Int. ong>2012ong>;25:416-423.

9. Guba M, Pratschke J, Hugo C, et al. Renal function, efficacy, and safety of

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.

ong>Transplantationong>. 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

survival and renal function at 48 months after transplantation. 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-month efficacy and safety results from the CONVERT trial.

ong>Transplantationong>. 2009; 87:233-242.

14. Budde K, Becker T, Arns A, et al. Everolimus-based regimen

calcineurin-inhibitor-free regimen in recipients of de-novo kidney

transplants: An open-label, randomised, controlled trial. Lancet.

2011;377:837-847.

15. Holdaas H, Rostaing L, Séron D, et al. Conversion of long-term kidney

transplant recipients from calcineurin inhibitor therapy to everolimus: a

randomized, multicenter, 24-month study. ong>Transplantationong>.

ong>2012ong>;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. Campbell SB, Walker R, Tai SS, Jiang Q, Russ GR. Randomized controlled

Trial of sirolimus for renal transplant recipients at high risk for

nonmelanoma skin cancer. Am J Transplant. ong>2012ong>;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. ong>2012ong>;367:329-339.

20. Feldmeyer L, Hofbauer GFL, Böni T, French LE, Hafner J. Mammalian target

of rapamycin (mTOR) inhibitors slow skin carcinogenesis, but impair

wound healing. Br J Dermatology. ong>2012ong>;166:422-424.

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www.medscape.org/anthology/kidneytran

20. Feldmeyer L, Hofbauer GFL, Böni T, French LE, Hafner J. Mammalian target

of rapamycin (mTOR) inhibitors slow skin carcinogenesis, but impair

wound healing. Br J Dermatology. ong>2012ong>;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.

ong>Transplantationong>. ong>2012ong>;93:503-508.

22. Raichlin E, Bae JH, Khalpey Z, et al. Conversion to sirolimus as primary

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. ong>2012ong>;12:2487-2497.

24. Nashan B, Gaston R, Emery V, et al. Review of cytomegalovirus infection

findings with mammalian target of rapamycin inhibitor-based immuno

suppressive therapy in de novo renal transplant recipients.

ong>Transplantationong>. ong>2012ong>;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. Wagner M, Roh V, Strehlen M, et al. Effective treatment of advanced

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, ong>2012ong>.

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. ong>2012ong>;23:133- 142.

32. Liefeldt L, Brakemeier S, Glander P, et al. Donor-specific HLA antibodies in a

cohort comparing everolimus with cyclosporine after kidney

transplantation. Am J Transplant. ong>2012ong>;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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ong>Solidong> ong>Organong> ong>Transplantationong>: ong>2012ong> ong>Updateong> on Current and Emerging Approaches to Treatment CME/CE

The Year in Review: Most Notable Studies in Kidney

ong>Transplantationong> CME/CE

Ron Shapiro, MD

Posted: 12/19/ong>2012ong>

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

ong>Transplantationong> Institute, University of Pittsburgh Medical Center Montefiore in Pennsylvania about his choices for the important

publications in the field of kidney transplantation in ong>2012ong> 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

ong>2012ong> 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. Though not particularly well matched for human leukocyte antigens (HLA) -- nonidentical HLA living donors were used --

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

the transplanted kidney. However, the results were fairly dramatic; it appears to be a relatively safe and straightforward way of

achieving 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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www.medscape.org/anthology/kidneytran

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 transplantation.

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 lowdose

cyclosporine maintenance monotherapy.

The study by Hanaway and colleagues published in the New England Journal of Medicine is the closest we will come to a registration

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 comparable

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 registration

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, data from the trials by Hanaway and colleagues [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

abstract by Larsen and colleagues report data from the 4-year extension of the BENEFIT trial. The primary objective was to assess

long-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 m 2 ) at 48 months was 73.8 ± 19.6 for the more-intensive belatacept regimen, 75.1± 17.0 for the less-intensive belatacept

regimen, and 50.0 ± 18.7 for the cyclosporine regimen.

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ong>Solidong> ong>Organong> ong>Transplantationong>: ong>2012ong> ong>Updateong> on Current and Emerging Approaches to Treatment CME/CE

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

(between 36 and 48 months) was very rare in the 4-year extension data. [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 ong>2012ong> 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 ong>2012ong> 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 exception

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 ong>Transplantationong> Society in July ong>2012ong> 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.

The phase 1b study by Yang and colleagues evaluated an anti-CD40 monoclonal antibody. [9] Data from this early safety trial of

different doses suggest the CD40 ligand appears to be a well-tolerated, safe, and efficacious agent. Phase 2 and phase 3 clinical

trials 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.

This article is part of a CME/CE certified activity. The complete activity is available at:

http://www.medscape.org/viewprogram/32708

Pg.18


www.medscape.org/anthology/kidneytran

Abbreviations

AMR = antibody mediated rejection

ASCERTAIN = Assessment of Everolimus in Addition to Calcineurin

Inhibitor Reduction in the Maintenance of Renal Transplant

Recipients

BPAR = biopsy-proven acute rejection

CENTRAL = CErtican Nordic Trial in RenAL ong>Transplantationong>

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 = human leukocyte antigens

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. 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

GVHD or engraftment syndrome in HLA-mismatched combined kidney

and hematopoietic stem cell transplantation. Sci Transl Med.

ong>2012ong>;4:124ra28.

3. Hanaway M, Woodle ES, Mulgaonkar S, et al.; INTAC Study Group.

Alemtuzumab in kidney transplantation: A prospective, randomized,

multicenter trial, 3 year results. N Engl J Med. 2011;364:1909-1919.

4. Farney A, Rogers J, Hart L, et al. Long term results of a prospective

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, ong>2012ong>; 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. Larsen C, Alberu J, Massari P, et al. 4-year results from the long-term

extension of the belatacept BENEFIT study. Proceedings of the American

Transplant Congress; June 2-6, ong>2012ong>; 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, ong>2012ong>; Boston,

MA. Abstract 560.

9. Yang H, Vincenti F, Klintmalm G, et al. A phase 1B, randomized,

double-blind, parallel group, placebo-controlled, single dose,

pharmacokinetic, pharmacodynamic safety and tolerability study of

ASKP1240 in de novo kidney transplantation. Proceedings of the 24th

International Congress of the ong>Transplantationong> Society; July 15-19, ong>2012ong>;

Berlin, Germany. Abstract MON.C020.02.

Disclaimer

The 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.

Medscape Education © ong>2012ong> Medscape, LLC

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