Title: GvHD Prophylaxis With ATG-Fresenius S in Allogeneic Stem Cell Transplantation From Matched Unrelated Donors:
A Randomized Phase III Multicenter Trial Comparing a Standard GvHD Prophylaxis With Cyclosporine A and
Methotrexate With Additional Pretransplant ATG-Fresenius S
Citation: Finke J., Bethge W.A., Schmoor A, et al. Standard graft-versus-host disease prophylaxis with or without anti-Tcell globulin in hematopoietic cell transplantation from matched unrelated donors: a randomized, open-label, multicenter
phase 3 trial. Lancet Oncol 2009; 10: 855–64.
Reviewed by: Beverly Mojica
Purpose:
Background
Primary
Endpoint
Secondary
Endpoints
Study
Design
Study
Population
To determine whether the addition of anti-T-cell globulin (ATG-F) with methotrexate and
cyclosporine will decrease the incidence of acute graft-versus-host disease in patients
undergoing matched unrelated donor hematopoietic stem cell transplantation
 Graft-versus-host disease:
 The donor’s cells (graft) attacks the host’s cells (skin, liver, gastrointestinal tract,
lungs, bone marrow, thymus, connective tissue, exocrine glands)
 Primarily due to mismatching of human leukocyte antigens (HLA) or minor
histocompatibility antigens
 A major cause of morbidity and mortality after allogeneic hematopoietic stem
cell transplantation
 T-cells:
 Pros: faster engraftment, graft-versus-tumor effect, less incidence of infections
 Cons: higher incidence of acute and chronic graft-versus-host disease
 T-cell depletion:
 Theory: proposed to decrease the incidence and severity of aGVHD and
cGVHD by inhibiting T-cell mediated cytotoxicity from the donor
 Implications: Past studies have demonstrated that T-cell depletion resulted in
reduced incidence of GVHD, but increased incidence of relapse, rejection, and
lethal infections
 Rabbit anti-human T-lymphocyte Globulin (ATG-Fresenius® (ATG-F®),
Thymoglobulin®)
 Immunosuppressant agent; immune globulin
 MOA: Polyclonal antibody which acts on T-cell surface antigens and depletes
CD4 lymphocytes causing immunosuppression
 Duration: Lymphopenia may persist ≥1 year
 Half-life elimination, plasma: 2-3 days
 Very expensive
 Early treatment failure defined as:
 Occurrence of severe aGVHD (grade III-IV) within 100 days of transplantation
 Death within 100 days of transplantation
 Incidence of aGVHD (grade III-IV, grade II-IV, grade I-IV) over time
 Time to engraftment
 Incidence of cGVHD (limited or extensive, extensive only)
 Incidence of relapse
 Incidence of non-relapse mortality
 Disease-free survival
 Overall survival
 Infections
 Adverse events
 Randomized
 Open-label
 Multi-center
 Phase III
 Patients undergoing hematopoietic cell transplantation from matched unrelated donors
Inclusion
Criteria
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Exclusion
Criteria
Intervention
(Total
n = 202)
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Statistical
Analysis
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Patient
Population
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Age 18-60 years of age
Karnofsky performance score of > 60%
Acute Leukemia in first complete remission or beyond first remission, in relapse, or not
in remission (primary refractory , induction failure)
Chronic myeloid leukemia beyond first chronic phase
Myelodysplastic syndrome
Myelofibrosis
Donors and recipients required to be HLA-compatible (10/10 matches)
 Patients with a HLA-A, -B (DNA-based, 2 digits), HLA-DRB1, -DQB1 (DNAbased 4 digits) matched (8 out of 8 alleles) unrelated donor
Significant disease:
 Heart failure with ejection fraction (EF) <50%
 Pulmonary (forced expiratory volume in 1 s <50%)
 Renal (Scr > 1.5 mg/dL)
 Metabolic (bilirubin > 2 mg/dL)
 CNS disease currently uncontrolled by treatment
 Infections currently uncontrolled with antimicrobials
Carriers of hepatitis B surface antigen, hepatitis C antibody, or HIV
Additional concurrent or previous malignant disease
History of hypersensitivity to rabbit immunoglobulin antibodies
Previous transplantation, including autologous transplants
Pregnant or lactating women
Treatment arm (n=103):
 ATG-Fresenius S (20 mg/kg body weight at days -3 to -1 (total dose: 60 mg/kg)
 Cyclosporine A (target trough level > 200ng/ml (day -1 until day +100)
 Methotrexate: 15mg/m2 at day +1, 10mg/m2 at days +3, +6, and +11
Control arm (n=99):
 Cyclosporine A (target trough level > 200ng/ml (day -1 until day +100)
 Methotrexate: 15mg/m2 at day +1, 10mg/m2 at days +3, +6, and +11
Conditioning regimens differed across the study centers:
 Total body irradiation (8-12 Gy)
 Busulfan (14-16 mg/kg orally or equivalent for IV administration) plus
cyclophosphamide (2 x 60 mg/kg) or etoposide
 Regimens consisting of Thiopeta (>15 mg/kg) or Carmustine (>300 mg/m2)
80% power to detect significant difference in early treatment failure between the ATG-F
group and control group, requiring 176 and 192 participants, respectively
Intention-to-Treat Analysis
Per-Protocol Analysis
Safety Analysis
A logistic regression model was used to adjust for differences (disease status, study
center stratification, stem-cell source)
 Used to calculate the odds ratio (OR) with a 95% CI
A Cox regression and Fine and Gray models were used to adjust for disease status
(e.g. early v. advanced) and stem-cell source (e.g. bone marrow vs. peripheral blood)
 Used to calculate the hazard ratios (HR) with 95% CI
Similarities:
 Average age: 40 years
 Sex distribution equivalent
 Ethnic origin (Caucasian)
 Performance status
Differences:
-More advanced disease status in control group
-More seropositive CMV in ATG-F group
-More HLA-C mismatch in ATG-F group
Results
Primary
Endpoint
aGVHD or
death within
day
-100
Treatment
(ATG-F)
21.4% (95% CI
13.4-29.3)
Odds
Ratio
0.59 (95%
CI 0.301.17; p=
0.13)
33.7% (95%
CI 24.343.0)
Comment(s)
Reduction in early treatment
failure was found in the ATG-F
group
 NNT=8
Adjusted
Hazard Ratio
(HR)
0.61 (95% CI
0.43-0.88;
p=0.007)
Comment(s)
2-year cumulative
incidence of cGVHD
(limited or
extensive)
2-year
cumulative
incidence of nonrelapse mortality
0.34 (95% CI
0.21-0.55; p<
0.0001)
Significant reduction in cGVHD with ATG-F
 NNT= 4
0.68 (95% CI
0.38-1.22;
p=0.20)
Lower incidence of non-relapse mortality with ATG-F, but
not significant
 NNT= 11
2-year cumulative
incidence of relapse
1.18 (95% CI
0.69-2.03;
p=0.55)
0.91 (95% CI
0.62-1.36;
p=0.65)
0.86 (95% CI
0.57-1.30;
p=0.47)
Slightly higher incidence of relapse with ATG-F, but not
significant
 NNH= 17
Slightly higher disease-free survival with ATG-F, but not
significant
 NNT= 24
Higher over survival found in ATG-F group, but not
significant
 NNT= 14
Secondary
Endpoints
Cumulative
incidence of grade
I-IV aGVHD
2-year disease-free
survival
2-year overall
survival rate
Safety
Endpoints
Control
Infections
Bacterial (staph., strep.,
clostridium)
Fungal (Candida spp.)
Parasitic
 Viral (CMV, HSV)
 CMV infection
 Epstein-Barr virus
post-transplant
disorder (EBVPTLD)
Significant reduction in aGVHD with ATG-F
 NNT=6
Treatment
62.3%
Control
68.4%
33.0%
2.8%
74.5%
53.8%
37.9%
6.3%
64.2%
29.5%
4.8%
1.0%
Comment(s)
Similar
Similar
Similar
Higher rate of seropositive CMV in
treatment (62.3%) vs. control
(40.0%)
 Adjusted HR for CMV
infection: 1.53 (95% CI
0.96-2.44; p=0.08)
 NNH=4
Regular EBV monitoring should be
done
Adverse Events
Mucosal inflammation
Pyrexia
Treatment
68.9%
68.9%
Control
72.6%
56.8%
Hypertension
Diarrhea
Headache
55.7%
53.8%
41.5%
51.6%
50.5%
30.5%
Chills
31.1%
13.7%
Renal failure
Abdominal pain
21.7%
19.8%
17.9%
25.3%
Conclusion
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Strengths
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Limitation
Clinical
Relevance
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Comment(s)
Similar
More often in ATG-F
group
 NNH=8
Similar
Similar
More often in ATG-F
group
 NNH= 9
More often in ATG-F
group
 NNH=5
Similar
Similar
Study conclusion:
 The addition of ATG-F to standard GVHD prophylaxis regimen significantly
decreased the incidence of aGVHD and cGVHD, without having a negative
effect on survival or increasing the relapse or non-relapse mortality.
Randomization
Concealment
ITT analysis
Analyzed efficacy and safety data
Covariate analysis was used to adjust for differences
Considered clinically important outcomes
Good follow-up
Open-label
Multi-center trial
Unequal treatment
Differences in some baseline characteristics
Quality of life not measured
Cost of treatment was not considered
Study was funded by Fresenius Biotech GmbH
Longer-follow up needed for cGVHD
Only studied Caucasians
The advantages and disadvantages of in-vivo T-cell depletion with ATG-F should be
considered in the prophylaxis of GVHD
The following factors should be considered:
 Risk for infection
 Risk for relapse
 Degree of mismatch
 Age of patient
 Cost of treatment
 Quality of life
The addition of ATG-F to standard GVHD prophylaxis regimen should be reserved for:
 Those at higher risk for GVHD (e.g. unrelated donor, mismatched allogeneic
stem cell transplantation)
 Those at low-risk for relapse (e.g. patient responded to induction chemotherapy,
patient was in remission at the time of transplantation)
A study investigating the addition of ATG-F to Tacrolimus and Sirolimus will provide
better insight as to the clinical application of ATG-F for patients at City of Hope.