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.
19
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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
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]
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)
References: 1) Gabardi S, Martin S, Olyaei A, et al. Chapter 55: Solid organ transplantation. In: Chisholm-Burns M, Wells
B, Schwinghammer T, et al. Pharmacotherapy principles and practice 4th edition. New York, NY: McGraw-Hill;http://ppp.mhmedical.com.ezproxy.lib.utexas.edu/content.aspx?bookid=1793§ionid=120647223. Accessed August 01, 2017.
2) Halloran, P. Immunosuppression drugs for kidney transplantation. N Engl J Med. 2004;351:2715-29. 3) Organ Procurements and Transplantation Network (OPTN) and Scientific Registry of Transplant
Recipients (SRTR). OPTN/SRTR 2015 Annual Data Report. U.S. Department of Health and Human Services, Health Resources and Services Administration; Rockville, MD: 2017.
4) Thiyagarajan U, Ponnuswamy A, Bagul A, et al. Thymoglobulin and its use in renal transplantation: a review. Am J Nephrol.2013;37:586-601.
5) Mourad G, Morelon E, Noel C, et al. The role of thymoglbulin induction in kidney transplantation: an update. Clin Transplant. 2012;26:e450-64.
6) Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guidelines for the care of kidney transplant recipients: a summary. Kidney Int. 2010;77:299-311.
7) Anti-thymocyte globulin [rabbit] for intravenous use (Thymoglobulin®) package insert. Cambridge, MA. Genzyme Corp. April 2017.
8) Wong W, Agrawal N, Pascual M, et al. Comparison of two dosages of thymoglobulin used as a short-course for induction in kidney transplantation. Transplant International. 2006;19:629-35.
9) Kho M, Bouvy A, Cadogan M, et al. The effect of low and ultra-low dosages thymoglobulin on peripheral T, B, and NK cells in kidney transplant recipients. Transpl Immunol. 2012;26:186-90.
10) Lexi-Drugs Online™. Lexi-Comp Online™ [database online]. Hudson, OH: Lexi-Comp, Inc.; 2016. Available at: http://online.lexi.com.ezproxy.lib.utexas.edu. Accessed July 10, 2017.
11) Gurk-Turner C, Airee R, Philosophe B, et al. Thymoglobulin dose optimization for induction therapy in high risk kidney transplant recipients. Transplantation. 2008;85(10):1425-30.
12) Stratta RJ, Sundberg AK, Farney AC, et al. Experience with alternateday thymoglobulin induction in pancreas transplantation with portal-entericdrainage. Transplant Proc. 2005;37:3546‐48.
13) Peddi VR, Bryant M, Roy-Chaudhury P, et al. Safety, efficacy, and cost analysis of thymoglobulin induction therapy with intermittent dosing based on CD3 lymphocyte counts in kidney and kidney-pancreas transplant recipients. Transplantation. 2002;73:1514–8.
14) Djamali A, Turc-Baron C, Portales P, et al. Low dose antithymocyte globulins in renal transplantation: daily versus intermittent administration based on T-cell monitoring. Transplantation. 2000;69:799–805.
15) Brennan D, Daller J, Lake K, et al. Rabbit antithymocyte globulin versus basiliximab in renal transplantation. N Engl J Med. 2006;355:1967-77.
16) Noel C, Abramowicz D, Durand D, et al. Daclizumab versus antithymocyte globulin in high-immunological-risk renal transplant recipients. J Am Soc Nephrol. 2009;20:1385-92.
17) Goggins W, Pascual M, Powelson J, et al. A prospective, randomized, clinical trial of intraoperative versus postoperative thymoglobulin in adult cadaveric renal transplant recipients. Transplantation. 2003;76(5):798-802.
18) Brennan D, Flavin K, Lowell J, et al. A randomized, double-blinded comparison of thymoglobulin versus Atgam for induction immunosuppressive therapy in adult renal transplant recipients. Transplantation. 1997;67:1011-18.
19) Mohty M, Bacigalupo A, Saliba F, et al. New directions for rabbit antithymocyte globulin (Thymoglobulin®) in solid organ transplants, stem cell transplants and autoimmunity. Drugs. 2014;74:1605-34.
20) Kelm P, Cooper J, Weiss A, et al. Reduced dose rabbit anti-thymocyte globulin induction for prevention of acute rejection in high-risk kidney transplant recipients. Transplantation. 2009;88(7):891-96.
21) Nafar M, Dalili N, Poor-Reza-Gholi F, et al. The appropriate dose of thymoglobulin induction therapy in kidney transplantation. Clin Transplant. 2017;31(e12977):1-8. https://doi.org/10.1111/ctr.12977.
KINCAIDE
20
22) Agha I, Rueda J, Alvarez A, et al. Short course induction immunosuppression with thymoglobulin for renal transplant recipients. Transplantation. 2002;73(3):473-75.
23) Peddi V, Bryant M, Roy-Chaudhury P, et al. Safety, efficacy, and cost analysis of thymoglobulin induction therapy with intermittent dosing based on CD3+ lymphocyte counts in kidney and kidney-pancreas transplant recipients. Transplantation. 2002;73(9):1514-18.
24) Tsapepas D, Mohan S, Tanriover B, et al. Impact of small variations in the delivered dose of rabbit antithymocyte induction therapy in kidney transplantation with early corticosteroid withdrawal. Transplantation. 2012;94(4):325-30.
25) Tenney J, Mokaddem S, Shah V, et al. Antithymocyte globulin dosing effects on biopsy-proven acute rejection and infection risk. Ann Transplant. 2015;20:285-89.
26) Pennington C, Tischer S, Lee E, et al. Evaluation of a weight-based rabbit anti-thymocyte globulin induction dosing regimen for kidney transplant recipients. Pharmacotherapy. 2015; doi: 10.1002/phar.1624.
27) Stevens R, Wrenshall L, Miles C, et al. A double-blind, double-dummy, flexible-design, randomized multicenter trial: early safety of single-versus divided-dose rabbit anti-thymocyte globulin induction in renal transplantation. Am J Transplant. 2016; doi:10.1111/ajt.13659.
28) Hardinger K, Schnitzler M, Miller M, et al. Five-year follow-up of thymoglobulin versus Atgam induction in adult renal transplantation. Transplantation. 2004;78:136-41.
29) Martin S, Roberts K, Malek S, et al. Induction treatment with rabbit antithymocyte globulin versus basiliximab in renal transplant recipients with planned early steroid withdrawal. Pharmacotherapy. 2011;31:566-73.