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Down the Rabbit Hole: Optimized Dosing for Rabbit Anti-Thymocyte Globulin Induction in High Risk Renal Transplant Recipients Elisabeth Kincaide, PharmD PGY2 Solid Organ Transplant Pharmacy Resident University Health System Division of Pharmacotherapy, The University of Texas at Austin College of Pharmacy Pharmacotherapy Education and Research Center University of Texas Health San Antonio August 14 and 18, 2017 Learning Objectives: 1. Define acute rejection in renal transplant recipients 2. Describe induction therapy in renal transplantation 3. Summarize the current literature for rabbit anti-thymocyte globulin induction dosing strategies in high risk renal transplant recipients 4. Identify optimal rabbit anti-thymocyte globulin induction dosing in high risk renal transplant recipients

Transcript of Down the Rabbit Holesites.utexas.edu/pharmacotherapy-rounds/files/2017/08/...Down the Rabbit Hole:...

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Down the Rabbit Hole: Optimized Dosing for Rabbit Anti-Thymocyte Globulin

Induction in High Risk Renal Transplant Recipients

Elisabeth Kincaide, PharmD PGY2 Solid Organ Transplant Pharmacy Resident

University Health System Division of Pharmacotherapy, The University of Texas at Austin College of Pharmacy

Pharmacotherapy Education and Research Center University of Texas Health San Antonio

August 14 and 18, 2017

Learning Objectives: 1. Define acute rejection in renal transplant recipients2. Describe induction therapy in renal transplantation3. Summarize the current literature for rabbit anti-thymocyte globulin induction dosing strategies

in high risk renal transplant recipients4. Identify optimal rabbit anti-thymocyte globulin induction dosing in high risk renal transplant

recipients

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Down the Rabbit Hole: Optimized Dosing for Rabbit Anti-Thymocyte Globulin Induction in High Risk

Renal Transplant Recipients

Elisabeth Kincaide, PharmD PGY2 Solid Organ Transplant Pharmacy Resident

August 14 and 18, 2017 University Health System and McDermott Building

Learning Objectives: At the completion of this activity, the participant will be able to:

1. Define acute rejection in renal transplant recipients

2. Describe induction therapy in renal transplantation

3. Summarize the current literature for rabbit anti-thymocyte globulin induction dosing strategies in high risk renal transplant recipients

4. Identify optimal rabbit anti-thymocyte globulin induction dosing in high risk renal transplant recipients

Assessment Questions:

1. All of the following are risk factors for acute rejection in renal transplantation, except: a. Advanced recipient age b. Elevated panel reactive antibody c. Extended criteria donor d. Repeat renal transplant

2. Which agent is most efficacious for induction therapy in high-risk renal transplant recipients?

a. Basiliximab b. Daclizumab c. Methylprednisolone d. Rabbit anti-thymocyte globulin

3. Optimal induction dosing for rabbit anti-thymocyte globulin in high risk KTR may include:

a. 1.5 mg/kg x 1 day b. 1.5 mg/kg x 3 days c. 15 mg/kg x 5 days d. 1.5 mg/kg x 14 days

***To obtain CE credit for attending this program please sign in. Attendees will be emailed a link to an electronic CE Evaluation Form. CE credit will be awarded upon completion of the electronic form. If you do not receive an email within 72 hours, please contact the CE Administrator at [email protected] ***Faculty (Speaker) Disclosure: Elisabeth Kinciade has indicated she has no relevant financial relationships to disclose relative to the content of her presentation

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I. Acute rejection in renal transplantation1,2

a. Cell mediated through alloreactive T-cells b. Typically occurs within 5 to 90 days after transplant, but can occur anytime

II. Allorecognition1,2 a. Prime event which initiates immune response b. Recognition of antigens displayed by the transplanted organ

III. T-cell activation1,2 a. APC activate T-cells through two signals

i. Interaction between T-cell receptor and foreign antigens ii. Interaction between co-stimulatory receptors on the APC ligands and T-cells

IV. Clonal expansion1,2 a. Under the influence of cytokines, activation leads to clonal expansion b. Antibodies will flag graft cells for destruction c. Endothelial damage and graft ischemia occurs

V. Scientific Registry of Transplant recipients/Organ Procurement and Transplantation (SRTR/OPTN) acute rejection rates in adult kidney transplant recipients 12 mo. post transplantation3

Acute Rejection

Figure 1: Steps in acute rejection

Figure 2: SRTR/OPTN Acute Rejection Rates

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VI. Numerous risk factors for rejection have been identified3-5 a. Risk factors are not equivalent b. Criteria to meet “high risk” is extremely center-specific

Table 1: Factors increasing risk for rejection

Young recipient age

Increased donor age

African American recipients

Repeat transplant

Elevated PRA

Multiple HLA mismatches

DSA

Positive cross match

Blood group incompatibility

Risk for DGF, i.e. prolonged ischemic time, DCD, ECD, obesity, high donor creatinine

Refer to Appendix A for abbreviations

I. Maintenance therapy

a. Purpose: prevent acute and chronic rejection b. Combination therapy is used to target different steps of the immune cascade while

minimizing drug-related toxicity II. Most common triple immunosuppression at the time of transplant includes the following3

a. Tacrolimus: 95% b. Mycophenolate: 93% c. Corticosteroid: 70%

I. Induction therapy1,4,5

a. Purpose: provide a high level of immunosuppression when the risk of rejection is the highest

b. Essential in patients at high risk for rejection II. KDIGO guidelines recommendations6

a. Interleukin-2 receptor antagonist as first line i. Basiliximab

b. Suggest a lymphocyte-depleting agent for high risk KTR i. rATG

Maintenance Immunosuppression

Induction Therapy in Renal Transplantation

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III. Induction agents

Figure 3: Immunosuppression therapy in KT

IV. Immunosuppression a. Daclizumab and basiliximab are IL-2 receptor blockers

i. Daclizumab was removed from the market in 2009 b. Campath® is no longer commercially available and can only be obtained through the U.S.

Campath Distribution Program c. Anti-thymocyte globulin

i. Atgam® equine formulation ii. Thymoglobulin® rabbit formulation

V. OPTN/SRTR annual data report induction agent use in adult KTRs3

Figure 4: OPTN/SRTR induction agent use

Basiliximab (Simulect®)

Daclizumab

Lymphocyte depleting

Non-lymphocyte

depleting

Alemtuzumab (Campath®)

Anti-thymocyte globulin (equine

and rabbit)

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I. Description7

a. Purified, pasteurized IgG obtained from immunizing rabbits with human thymocytes b. Serum is harvested and immunoglobulins are isolated c. Human red blood cells are used to deplete cross-reactive antibodies to non-T-cell antigens d. Exogenous viruses are removed

II. Mechanism of action7 a. Polyclonal antibody b. Lymphocyte depletion by complement-dependent cell lysis c. Cytotoxic antibodies directed against antigens expressed on human T-lymphocytes d. Targets: CD2, CD3, CD4, CD8, CD25, CD45 e. Ultimate effect: lymphocytopenia in blood and T-cell depletion in spleen and lymph nodes f. Rapid and dose dependent T-cell depletion g. T-cell recovery: one year8,9

III. Adverse events and warnings10 a. Anaphylaxis b. Central nervous system: chills, headache, fever, malaise, insomnia c. Cardiovascular: hypertension, peripheral edema, tachycardia, hypotension d. Respiratory: dyspnea, pulmonary disease e. Hematologic: leukopenia, thrombocytopenia, leukocytosis, anemia f. Immunosuppression: increased infection and malignancy risk

i. Administer antibacterial, antifungal, and antiviral prophylaxis as clinically indicated g. Cytokine release syndrome

i. Pre-medicate with corticosteroids, acetaminophen and/or antihistamine one hour prior to infusion

IV. Monitoring7,10 a. CBC with deferential and platelet count b. Vital signs during administration c. Lymphocyte count monitoring is recommended

i. Total lymphocyte and/or T-cell subsets, e.g. CD3 monitoring11-14

V. rATG induction data in high risk KTR15,16

Table 2: Trial summaries of rATG background literature

Study Design N Intervention(s) MTN Result Safety

Brennan (2006)15

Prospective, Randomized

1:1, open label, multi-

center

278

rATG 1.5 mg/kg

POD0-4 (7.5 mg/kg

cumulative) vs. Bas 20 mg

POD0 and 4

CsA + MMF + steroids

Treatment failure of rATG 25% vs. Bas

38%, estimated group difference of -13% (95% CI: -24% to -2%); p=0.0202

↓BPAR in rATG

cohort Bas (26%) vs. rATG

(16%); p=0.02

↑ Infection in rATG group 86% vs. 75%; p=0.03

↑ leukopenia in rATG group 33% vs. 15%; p<0.001

3 subjects with lymphomas in rATG arm vs. 0

Rabbit Anti-Thymocyte Globulin (Thymoglobulin®)

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Table 2: Trial summaries of rATG background literature

Study Design N Intervention(s) MTN Result Safety

Noel (2009)16

Prospective, randomized

230

rATG 1.25 mg/kg POD0-7

(10 mg/kg cumulative) vs. Dac 1 mg/kg x

5 doses

TAC + MMF+

steroids

Treatment failure of rATG 25% vs.

Dac 34%, estimated group difference -8% (95% CI: -20%

to 4%)

↓BPAR in rATG cohort

Dac (28%) vs. rATG (15%); p=0.016

↑ infections/pt in rATG group 2.5 vs. 1.8; p=0.014

↑CMV 19% rATG vs. 11% Dac (p=0.093)

↓ PLT, WBC and lymphocyte count in rATG arm at 1 wk; p<0.001

1 subject in rATG arm developed metastatic melanoma

VI. See Appendix B for rATG efficacy data in KTR in both high and low risk populations

VII. FDA indications and dosing in renal transplantation7

Table 3: FDA-labeled indications of rabbit anti-thymocyte globulin

Indication Approval Date Dose

Treatment of acute rejection December 1998 1.5 mg/kg of body weight daily for

7 to 14 days

Prophylaxis of acute rejection April 2017 1.5 mg/kg of body weight daily for

4 to 7 days Administer the first dosage over a minimum of 6 h and subsequent doses over a minimum of 4 h

a. First dose given intraoperatively (Appendix C)17

i. Blocking adhesion molecules that play a role in ischemia-reperfusion injury b. Dose modifications

i. Reduce dose by one-half 1. WBC 2,000 to 3,000 cells/mm3 2. Platelet count 50,000 to 75,000 cells/mm3

ii. Consider stopping treatment 1. WBC count falls <2,000 cells/mm3 2. Platelet count falls <50,000 cells/mm3

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VIII. rATG induction dosing debate a. Initial dosing of rATG was cumulative doses approximately 10.5 mg/kg18 b. rATG dosing has been reported in numerous studies (Appendix C for trial summaries of rATG

dosing in renal transplantation induction therapy) c. Transplant centers across the U.S. have not reached a consensus d. Cumulative dosing trends are declining19

I. rATG induction in high immunological risk KTR11,20,21

Table 4: Trial summaries of literature review

Study Design N Intervention

Gurk-Turner (2008)11 Retrospective 96

<7.5 mg/kg vs. >7.5 mg/kg in high risk KTR

Klem (2009)20 Retrospective 93

4.5 mg/kg over three days vs. 6 mg/kg over four days in high risk KTR

Nafar (2017)21 Prospective, open-label 90

4.5 mg/kg over three days vs. 4.5 mg/kg over one day vs.

6 mg/kg over three days

Clinical Question

What is the optimal dose of rabbit anti-thymocyte for induction therapy

in high risk KTR?

Figure 5: Total cumulative dosing of rATG reported by year with standard MTN regimen, adapted from Mohty et al.

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I. Gurk-Turner (2008)11

Table 5: Thymoglobulin dose optimization for induction therapy in high risk KTR11

Objective Evaluate the total rATG dosing on graft outcomes in high immunological risk KTR

Methods

Design Retrospective cohort study

Patient Population

Inclusion

Prior renal allograft transplantation OR

PRA >40%

Intervention Group I: rATG dose <7.5 mg/kg

Group II: rATG dose >7.5 mg/kg

1.5 mg/kg was initiated intraoperatively and continued daily, target 7 – 10 doses

Absolute CD3 lymphocytes were monitored daily, target <50 cells/mm3

rATG doses increased if target CD3 were not achieved

rATG doses reduced if WBC <2500 cells/mm3 or platelets <75,000 cells/mm3 Maintenance and Infection Prophylaxis

Tacrolimus when SCr <4 mg/dL or by POD4, trough goal 8 to 9 ng/mL

Mycophenolate mofetil 1000 mg PO twice daily

Methylprednisolone IV POD0 – 2, tapered to oral prednisone (goal for African Americans 0.3 mg/kg and 0.15 mg/kg for all others)

GCV 3000 PO mg/d or VGCV 900 PO mg/d, starting POD1 x 3 months

TMP/SMX SS daily and clotrimazole 100 mg TID x 6 months

Outcomes Graft and patient survival, incidence of AR, and 12-month SCr

Graft loss defined as return to dialysis, retransplantation, or death with functioning graft

Statistics Data presented as mean +/- SD or counts and percentages

Students t-test, chi-square or Fisher’s exact test

Linear regression models to examine independent association between drug dosing and 1-year SCr

Survival analysis methods to examine the independent association of rATG dosing and graft survival

Schoenfeld test and log-minus-log survival plots were utilized for proportionality assumptions

Stat/SE 9.2 software package (StataCorp, College Station, TX)

Results

Baseline Characteristics

N=96 (group I: N=33 and group II: N=63)

Retransplantation (85%), PRA>40% (19%)

Approximately 45 years old, comparable donor source and HLA mismatch

rATG dose (mg): 5.7 +/- 1.6 in Group I vs. 10.3 +/- 2.1 in Group II; P<0.001

Group II had more African Americans (44.4% vs. 21.2%, P=0.03)

84.8% in Group I and 85.7% in Group 2 had daily CD3 counts <50 cells/mm3 (P=0.44)

Numerically higher females, % PRA, and delayed graft function in Group II

Mean HLA class I mismatch 2.3 and DR mismatch 1.1 of total population (NS)

Literature Review

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Endpoints Outcome

Group I N=33

Group II N=63

P-Value

Graft survival (%) [study period]

82.5% 79.4% 0.54

Patient mortality (%) [study period]

3 (9) 4 (6.3) 0.65

Incidence of AR (%) [12 mo.]

9.5% 8.8% 0.9

SCr (mg/dL) (± SD) [12 mo.]

1.6 ± 0.7 1.8 ± 1 0.3

Biopsy-proven BKN (cases)

6 2 0.02

CMV antigenemia (cases)

2 3 0.5

Average WBC (x 103 cell/mm3)

7.5 ± 3.8 7.8 ± 2.9 0.65

Leukopenia (<2500 cells/mm3)

38% 22% 0.09

Thrombocytopenia (%)

26.5% 21.1% 0.5

Average PLT count (cells/mm3)

132K 162K 0.001

-Hematological AE reported [administration of rATG therapy]

No independent association between rATG dose and graft survival found o rATG dose: hazard ratio 0.96, P=0.74, 95% CI: 0.78 – 1.2 o Group II vs. Group I: hazard ratio: 0.85, P=0.79, 95% CI: 0.26 – 2.7

Author’s Conclusion

Induction therapy in KTR, with previous renal transplant or elevated PRA percentage (>40%), with rATG doses equal to 7.5 mg/kg or less are as safe and effective compared to greater than 7.5 mg/kg doses in rates of AR and graft outcomes

Investigators recommend no more than 5 doses of 1.5 mg/kg for rATG induction therapy in high risk KTR (7.5 mg/kg total cumulative dose)

Reviewer’s Critique

Strengths Triple maintenance immunosuppression with TAC, MMF, and steroid

25.4 month mean follow up

Limitations Retrospective review, selection bias, exclusion criteria not reported

Results measured at different points in time

Not reported why investigators chose a cutoff for CD3 <50 cells/mm3

Dose adjustments based on protocol were not reported

Whether or not cumulative rATG dose included treatment of acute rejection was not specified

DSA not reported with baseline characteristics

Data not well displayed or reported (BKN, retransplantation analysis, TMP/SMX and MMF discontinued)

Small sample size, unpowered to detect relative hazard with statistical significance

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Take Home Points

rATG dosing based upon daily CD3 levels, potentially showing that different doses may be optimal for different individuals, majority of the group required higher dosing >7.5 mg/kg

Large selection bias, rATG >7.5 mg/kg were likely at a higher risk of rejection, therefore doses <7.5 mg/kg may have led to different efficacy outcomes

Significantly higher BKN and thrombocytopenia in doses <7.5mg/kg may indicate that group had lower immune system with a quicker response to rATG

II. Klem (2009)20

Table 6: Reduced dose rabbit anti-thymocyte globulin induction for prevention of acute rejection in high risk KTR20

Objective Compare rATG duration of three day vs. four day in high risk renal transplant recipients

Methods

Design Retrospective analysis

Patient Population

Inclusion:

Single organ renal transplant and one of the following:

o Retransplantation o African American race o PRA >20%

Major exclusion:

Multi-organ transplant

DGF requiring dialysis within the first 48 hours of transplant

Intervention Induction therapy with rATG o 1.5 mg/kg/day x three days o 1.5 mg/kg/day x four days

First rATG dose was intraoperative

Dosing based off postoperative course and suitability for discharge

Maintenance and Infection Prophylaxis

TAC, trough goal 7 to 10 ng/mL until 3 mo. or CsA, trough goal 200 to 300 ng/dL

Mycophenolate agent or SRL 2 mg daily, trough goal >5ng/dL

Methylprednisolone IV POD0 – 2, tapered to oral prednisone POD3, tapered to a goal of 5 mg daily by 6 mo. post-transplant

VGCV 450 mg/d, x 3 mo to 6 mo (CMV D+/R-)

TMP/SMX SS daily or pentamidine 300 mg monthly x 6 months

Outcomes Biopsy-proven or treated acute rejection episodes

Patient survival

Graft survival

Median hospitalization LOS for transplantation surgery

eGFR based on Modification of Diet in Renal Disease equation

Infectious complications

Statistics Chi-squared tests, Fisher’s exact test, two-group t-tests, and Wilcoxon rank sum

Results

Baseline Characteristics

N=83 (three day rATG N=39; four day rATG N=44)

Approximately 48 years old, 61% Caucasian, 70% deceased donor, 18% African American

Retransplantation (54%) overall; higher in four dose cohort 64% vs. 44%; p=0.07

76% population with PRA >20%; 45% with PRA >80%

Cold ischemia time >24 h greater in four dose cohort 12% vs. 0

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Mean SCr POD2 greater in the four-dose regimen 3.2% vs. 1.9%; P=0.005

Mean HLA mismatch 3.5 of the total population (NS)

Regimen Three dose

N=39 Four dose

N=44 P-value

TAC/MPA/Pred 74% 45% 0.01

TAC/SRL/Pred 26% 53%

CsA/SRL/Pred 0 2%

Endpoints Clinical Endpoints

Total N=83

Three dose N=39

Four dose N=44

P-value

Acute rejection, n (%)

6 mo. 8 (10) 4 (10) 4 (10) 1.00

12 mo. 9 (11) 4 (10) 5 (11) 1.00

Steroid responsive

5 2 3

Humoral 1 1 1

Graft and patient survival, (%)

6 mo. 100 100 100 1.00

12 mo. 100 100 100 1.00

Mean eGFR, (SD; mL/min)

6 mo. 60.2 (16.3) 64.2 (16.2) 56.7 (15.7) 0.03

12 mo. 58.7 (18.1) 63.4 (20.3) 54.6 (14.9) 0.03

Median eGFR, (range; mL/min)

6 mo. 57.9

(31 – 101.6) 62

(35.2 – 100.6) 56.7

(31 – 101.6) 0.03

12 mo. 57.4

(27.5 – 119.6) 60.1

(28.1 – 119.6) 54.5

(27.5 – 92) 0.02

BKV viremia, n (%)

Total (%) 10 (12.1) 2 (5.1) 8 (18.2) 0.094

6 mo. 7 2 5

12 mo. 3 0 3

Other infections, n (%)

CMV 2 (2) 2 (2) 0 0.22

Total bacterial

17 (20) 9 (23) 8 (18) 0.58

Neutropenia <1000 PMN/mL within 12 mo., n(%)

6 (7) 2 (5) 4 (9) 0.68

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Transplant hospitalization length of stay (median days)

4 d (3 – 12) 3 (3 – 8) 4 (3 – 12) 0.004

Author’s Conclusion

Supports the use of tailored rATG induction therapy in high risk KTR with immediate graft function

Reviewer’s Critique

Strengths

High risk factors better matched between groups for a retrospective study

BKV surveillance protocol

Attempt to control for confounders by excluding patients who received hemodialysis with 48 h post transplantation

Limitations Retrospective, selection bias

Donor information lacking

Not all AR confirmed with biopsy

Standard maintenance immunosuppression therapy was not used, greater SRL and CsA use in the four dose cohort

Center was comparing efficacy of SRL vs. MPA during study period

Neutropenia assessed over 12 mo. Take Home Points

Improvement of graft function on POD2 and suitability for discharge drove providers to stop rATG therapy in the three dose group

Confounders within this study, including differences in maintenance regimens

Due to retrospective nature and unmatched baseline characteristics, outcomes may have differed had the four dose group received three doses

III. Nafar (2017)21

Table 7: The appropriate dose of thymoglobulin induction therapy in kidney transplantation21

Objective Identify the most efficient and less toxic rATG dose in adult KTR

Methods

Design Randomized, prospective, open-label, single-center clinical trial

Patient Population

Inclusion:

Positive PRA (>0%)

History of previous transplant

18 – 65 years old

ECD

Exclusion:

Multiple organ transplants

Serological evidence of HIV

Hepatitis B or C recipients or donors

Participation in another investigational study

Cold ischemia time >6 h Intervention Arm A: 4.5 mg/kg IV over 3 days

Arm B: 4.5 mg/kg IV x 1 day

Arm C: 6 mg/kg IV over 3 days

First rATG dose over 6 h beginning intra-operatively, subsequent over 4 h

rATG doses halfed if WBC 2000 to 3000 cells/mm3 or platelets 50 to 75,000 cells/mm3

rATG doses held if WBC <2000 cells/mm3 or platelets <50,000 cells/mm3

Maintenance and Infection Prophylaxis

TAC (trough goal 7 to 10 ng/mL x 1 mo. and 5 to 7 ng/mL thereafter

MMF 2 g pre-transplant, then 500 mg twice daily restarted on POD5

TMP/SMX for PCP ppx; universal CMV ppx VGCV x at least 3 mo.

Surgical prophylaxis and fluconazole for oropharyngeal candidiasis

Outcomes Primary: rate and severity of acute rejection (biopsy-proven) 12 mo. post-transplant year

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Secondary: CMV infection, length of hospital stay, rate of readmission, incidence in hematological abnormalities, and renal function

Statistics Sample size was determined on an alpha of 0.05 and a power of 0.80 with at least 30 patients per group

Paired t-test for observations within each group, unpaired t-test for continuous variables, and Fisher’s exact test for categorical variables

All were two-tailed, a P-value of <0.05 was considered significant

Intention-to-treat Results

Baseline Characteristics

100 screened, 10 excluded: kidney-pancreas transplant (N=2), positive HCV serology (N=1), participation in another study (N=4), cold ischemia time >6 h (N=3)

N=90 adult KTR (N=30 patients per arm)

Mean recipient age was 51 years old; mean donor age 34 years; 51% deceased donor; 30% previous transplant; mean PRA 12%; ECD 5%; mean cold ischemia time 41 minutes (NS)

Protocol biopsies 12 mo. post-transplant achieved in 57% Endpoints

Efficacy Outcomes Arm A N=30

Arm B N=30

Arm C N=30

P-value

SCr (mg/dL) (± SD)

Baseline 7.5 ± 0.6 9.5 ± 1.2 8 ± 1.1 0.125

1 mo. 1.5 ± 0.2 2 ± 0.5 1.9 ± 0.5 0.001

6 mo. 1.3 ± 0.3 1.5 ± 0.7 1.6 ± 0.3 0.343

12 mo. 1.5 ± 0.3 1.5 ± 0.8 1.6 ± 0.5 0.331

GFR (mg/mL) (± SD)

Baseline 9.3 ± 1.6 10.5 ± 2 9.8 ± 1.8 0.346

1 mo. 59.5 ± 6 55.3 ± 8 56 ± 7 0.002

6 mo. 68.5 ± 6 66 ± 10 65 ± 7 0.432

12 mo. 64.5 ± 7 63.5 ± 7 64 ± 8 0.631

Rejection types (n)

Cellular 1 1 1 1

Humoral 1 1 1

Histologic evidence, n(%)

Glomerulitis 2 (7%) 1 (4%) 1 (4%) 0.03

Peritubular capillaritis 2 (7%) 0 1 (4%)

Safety Outcomes Arm A N=30

Arm B N=30

Arm C N=30

P-value

Infection (%) 7 (23%) 10 (33%) 9 (30%) 0.01

Viral 1 2 2

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Fungal 0 1 2

Bacterial 6 7 5

BKN, n(%) 2 (7) 2 (7) 7 (23) 0.001

CMV infection (%) 5 (16%) 8 (26%) 10 (33%) 0.003

Length of stay (days) 7.4+/-1.8 10+/-2.2 10.1+/-2.5 0.002

Readmission 11 (33%) 13 (42%) 12 (40%) 0.034

WBC (cells/mL), 5th d 4,800+/-500 5,100+/-300 4,000+/-400 0.031

PLT (cell/mL), 5th d 132,000+/-

21000 108,000+/-

10000 128,000+/-

11000 0.001

Author’s Conclusion

Efficacy was similar amongst all three arms, but rATG 4.5 mg/kg over three days (1.5 mg/kg/day) regimen had significantly fewer complications

Reviewer’s Critique

Strengths Randomized, prospective, no differences in baseline characteristics

Recent (2014 to 2015)

Triple immunosuppression

Hematologic monitoring reporting around the time during rATG administration

Acute rejection confirmed on biopsy

Biopsy surveillance protocol

First study looking at 4.5 mg/kg single dose in high risk KTR Limitations Only risk factor for is rejection retransplantation (~30% of the population)

Patient population differs from U.S.

Small sample size, effect size not reported

ITT: 10% of Arm C received fewer than 3 doses; 16% in Arm B did not receive predetermined dose; groups inadequate to measure endpoints

Statistics only reported between the groups

Only 57% of enrolled patients had protocol biopsies at the end of the first year

Take Home Points

Not truly a high risk population, i.e. mean PRA 12%, ECD 5%, mean cold ischemia time 40 minutes, 30% retransplantation

Overall, safety results favored the 4.5 mg/kg over 3 days cohort; BKN was significantly higher in the 6 mg/kg cohort

Approximately half of the subjects did not receive their biopsies

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I. Summary11,20,21

Table 8: Literature review outcomes

Gurk-Turner (2008) Klem (2009) Nafar (2017)

Dosing strategy 1.5 mg/kg/d

based on CD3 1.5 mg/kg

x 3 d 1.5 mg/kg

x 4 d 1.5mg/kg

x 3 d 4.5mg/kg

x 1 d 2 mg/kg

x 3 d

Cumulative dose

<7.5 mg/kg >7.5 mg/kg 4.5 mg/kg 6 mg/kg 4.5 mg/kg 4.5 mg/kg 6 mg/kg

ACR/AMR 10% 9% 10% 11% 7% 7% 7%

Graft survival 83% 79% 100% 100%

- - -

Patient survival 91% 94% - - -

eGFR (mL/min) - - 63 46 65 64 64

BKN 6 2 5.1% 18.2% 7% 7% 23%

CMV 2 3 2% 0 16% 26% 33%

Infections - - 23% 18% 23% 33% 30% Note: Bolded items were found statically significant;

Gurk-Turner ACR/AMR and patient/graft survival measured over duration >12 mo.; all other outcomes reported at 12 mo.

II. Recommendation11,20,21 a. High immunological risk

i. African American, retransplantation, elevated PRA 10% to >80%, prolonged ischemia time, ECD

b. rATG daily dose: 1.5 mg/kg i. 1.5 mg/kg day

1. Improved safety profile compared to alternative dosing strategies 2. Decreased LOS and readmission

c. Duration of therapy: three vs. four day i. Recommend three day duration for patients with improved graft function,

e.g. SCr <3 mg/dL d. Dosing range

i. 4.5 mg/kg to 6 mg/kg given as 1.5 mg/kg daily dose III. Future rATG research in high risk KTR

a. Prospective, randomized studies i. Adequately powered

ii. Including adherence measurement for maintenance immunosuppression b. Intermittent dosing vs. two to three days in high immunological risk patients c. Three vs. four day duration d. Greater risk factors for inclusion criteria

i. Development of standardized risk stratification calculator for dosing rATG e. Monitoring linked to efficacy outcomes

i. Establish appropriate CD3 and/or absolute lymphocyte count (ALC) targets ii. Economic analysis of alternative dosing regimens

1. Measure outcomes on LOS, readmission, and laboratory costs

Conclusion and Recommendation

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Appendix A: Abbreviations

AEs: adverse events

APC: antigen presenting cells

AR: acute rejection

ATGAM®: anti-thymocyte globulin equine

Bas: basiliximab

BCAR: biopsy-confirmed acute rejection

BKN: BK nephropathy

BKV: BK-virus

BPAR: biopsy-proven acute rejection

CMV: cytomegalovirus

CNI: calcineurin inhibitor

Dac: daclizumab

DB: double-blind

DCD: donation after cardiac death

DD: double-dummy

DD-rATG: divided-dose rabbit anti-thymocyte globulin

DGF: delayed graft function

DSA: donor specific antibody

ECD: expanded criteria donor

eGFR: estimated glomerular filtration rate

GCV: ganciclovir

IL-2: interleukin-2

KDIGO: kidney disease improving global outcomes

KT: kidney transplant

KTR: kidney transplant recipients

LOS: length of stay

MC: multi-center

MMF: mycophenolate mofetil

Mo: months

N: number

NI: non-inferior

PLT: platelet

POD: post-operative day

PRA: panel of reactive antibodies

RCT: randomized control trial

SC: single-center

SCr: serum creatinine (mg/dL)

SD-rATG: single-dose rabbit anti-thymocyte globulin

SRL: sirolimus

TAC: tacrolimus

TMP/SMX: trimethoprim/sulfamethoxazole

VGCV: valganciclovir

Appendix B: Trial summaries of rATG induction efficacy data

Study Design Intervention(s) Result

Brennan (1999)18

Prospective, DB, randomized

rATG vs. ATGAM® ↓ BPAR in rATG [Atgam (25%) vs. rATG (4%); p=0.009]

“Event-free survival” was superior in rATG (94% vs. 63% p=0.0005)

Hardinger (2004)28

Randomized, DB (5-year) rATG vs. ATGAM® ↑ Graft survival in rATG (92%) vs. Atgam (66%); p=0.007

Brennan (2006)15 Prospective, randomized rATG vs. Bas ↓ BPAR in rATG cohort [Bas (26%) vs. rATG (16%); p=0.02]

Noel (2009)16

Prospective, randomized rATG vs. Dac ↓ BPAR in rATG cohort [Dac (28%) vs. rATG (15%); p=0.016]

Martin (2011)29 Retrospective, SC rATG vs. Bas ↓ BPAR less severe in rATG cohort [Bas (26%) vs. rATG (7%); p=0.02]

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Appendix C. Additional review of rATG dosing in renal transplant recipients

Study Design N Intervention(s) Result(s)

Agha (2002)22 Prospective, non- randomized

88

3 mg/kg followed by 1.5 mg/kg/d

for a total of three days vs. 1.5 mg/kg/d for 7 days

- AR (5 vs. 4%; p=1.0), graft survival (p=0.464) and patient survival (p=0.464) were similar

- Lymphocyte depletion was more sustained and hospitalization significantly shorter in the three-day group

Peddi (2002)23 Prospective 41

High risk kidney and kidney-pancreas recipients dosed

1.5 mg/kg rATG when CD3+ counts rose >20 cells/mm3

- Mean total cumulative rATG dose was 4.5 mg/kg (average 3 doses per patients)

- 4.9% patients died - 12.2% acute rejection episodes

Goggins (2003)17

Prospective, randomized

58 Intraoperative vs. postoperative doses of rATG induction therapy

at 1 mg/kg/dose x 3 to 6 days

- rATG intraoperative group was associated with significantly less DGF (14.% vs. 35.5%) and lower mean SCr on POD 10 and 14 (P<0.05)

- AR rates were numerically lower 3.6% vs. 16%) in the intraoperative group

Wong (2006)18

Prospective, non-randomized

16 3-day induction at

1 mg/kg/d vs. 1.5 mg/kg/d

- T-cell subsets (CD3+ and CD4+) were significantly lower at day 30, 90 and 180 and CD8+ lower at day 30 the 1.5 mg/kg group (p<0.05)

- No episodes of acute rejection in either group

Tsapepas (2012)24 Retrospective 242

Cumulative dose of 5 to 6 mg/kg vs.

>6 mg/kg followed by steroid-sparring

maintenance

- Significantly less BPAR in the >6 mg/kg cohort 11% vs. 21% (p<0.042)

- Renal function and safety were similar

Tenney (2015)25 SC, retrospective 142 3 vs. 5 doses of rATG - NS difference in BPAR, CMV or BK viremia

Pennington (2015)26 SC, retrospective 261

<5mg/kg vs. >5 mg/kg

cumulative dose based on ABW

- No statistical difference in BCAR (p=0.944), CMV (p=0.385), BKV (p=0.55), or BKN (p=0.579)

Stevens (2016)27 Prospective, RCT,

MC, DB, DD 95

SD-rATG 6 mg/kg vs. DD-rATG 1.5 mg/kg/dose

- SD-rATG was NI compared to DD-rATG (p=0.58) in the composite endpoint: fever, hypoxia, hypotension, cardiac complications, and DGF at 7 days

- No difference in secondary end-points at 12-months: patient survival, graft survival, and rejection (p=0.78, p=0.47, p=0.35, respectively)

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