chronic graft versus host disease - risk factors, pattern and transplant outcomes
TRANSCRIPT
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RISK FACTORS, PATTERN AND TRANSPLANT OUTCOMES OF CHRONIC GRAFT VERSUS HOST
DISEASE IN ACUTE LEUKEMIA PATIENTS UNDERGOING ALLOGENIC HEMATOPOIETIC STEM
CELL TRANSPLANT
*Alok Gupta, MD, DM1, Sachin Punatar, MD, DM1, JayantGawande, MD, DM1, Bhausaheb Bagal, MD, DM1, Libin Mathew1
and Sadhana Kannan, MSc2, Navin Khattry, MD, DM1
1Bone Marrow Transplant Unit, ACTREC, Tata Memorial Centre, Mumbai, India; 2Biostatistics, ACTREC, Tata Memorial Centre,
Mumbai, India
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BACKGROUND
• Auto-immune like disorder
• 60 – 80 % incidence
• Major cause of long term morbidity and mortality
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Known risk factors and impact on outcomes
• Older age of patient or donor
• Female donor to male recepient
• Mismatched or unrelated donor
• PBSC versus BM
• Acute GVHD
• Malignant vs Non-malignant disorders
• Improves DFS
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However….
• Paucity of Indian data
• Acute leukemia pts
• Impact on Overall Survival
• Infectious complications and impact on mortality in Indian subcontinent
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PATIENTS AND METHODS
• Single centre retrospective analysis
• All patients undergoing allo HSCT for acute leukemia
• January 2008 – March 2013
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• Conditioning regimen
– Full intensity (TBI-Cy or Bu-Cy)
– Reduced intensity (Fludarabine based)
• Standard GVHD prophylaxis
– CsA + MTX (CsA 1.5 mg/kg BD from D-1, MTX 15 mg/m2 D+1, 10 mg/m2 D+3, D+6, D+11)
– CsA + MMF (CsA as above, MMF 600 mg/m2 BD)
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• Rabbit ATG
– Unrelated transplants
– Related transplants with 8/10 or 9/10 match
• Chronic GVHD
– Extensive stage
– Limited stage
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TREATMENT OF cGVHD
• Topical steroids – Budesonide gargles for oral GVHD
– Budesonide nebulization for lung GVHD
– Topical steroid and tacrolimus for skin GVHD
– CsA and steroid eye drops for ocular GVHD
– Oral budesonide for gut GVHD
• Additional for lung GVHD– Azithromycin – immune modulator
– Imatinib – decrease fibrosis
– Montelukast – mast cell stabilizer
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TREATMENT OF cGVHD
• Systemic steroids
– Visceral GVHD
– Not responding to topical steroids
• CsA or MMF – as steroid sparing agents in patients whose GVHD flared up as steroids were tapered or when GVHD did not respond to steroids
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RISK FACTORS ANALYSED
• Patient and donor age• Diagnosis• Gender mismatch• Disease status at transplant• Stem cell source• Use of ATG• GVHD prophylaxis• Degree of HLA match• CD3 and CD34 cells infused• Acute GVHD
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OUTCOME MEASURES
• Overall Survival
• Relapse Free Survival
• Incidence of relapse
• Slippage of chimerism
• Transplant related mortality
• Infective complications
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STATISTICAL METHODS
• Categorical data – Chi square test
• Continuous data – Mann Whitney test
• Multivariate analysis – Logistic regression
• P values – 2 sided
• Survival analysis – Kaplan-Meier method
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RESULTS – PATIENT CHARACTERISTICS
No of transplants 77
Median age 30 (5-61) years
Males, n (%) 52 (68%)
DiagnosisAMLALLBiphenotypic leukemia
52 (67.5%)23 (29.9%)2 (2.6%)
Stem cell sourcePBSCCord bloodMarrow
70 (91%)2 (2.5%)5 (6.5%)
Fully matched transplants 61 (79%)
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RESULTS – INCIDENCE AND PATTERN
Incidence of cGVHD, n(%) 40 (52%)
Extensive stageLimited stage
60%40%
Median time to onset 5 months
Thrombocytopenia at onset 6 (15%)
De novo chronic GVHD, n(%) 19 (47%)
Systemic steroids, n(%) 23 (58%)
Median duration of steroids 5 months
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ALL- HR- High Risk (TLC > 100 x 109 /L at baseline or poor risk cytogenetics or not achieving CR after induction or persistent disease at transplant or > CR-2 ), SR- Standard Risk (according to cytogenetics) AML- PR- Poor Risk (TLC > 100 x 109 /L at baseline or poor cytogenetics or not achieving CR after induction or persistent disease at transplant or > CR-2) , IR- Intermediate Risk (according to cytogenetics), GR- Good Risk (according to cytogenetics)NK- Not Known
M68%
F32%
Gender
ALL30%
AML67%
Biphenotypic
Leukemia3%
Diagnosis
Biphenotypic Leukemia (3%)
CR155%CR2
26%
19%
Disease status at transplantRelapse/Refractory
Baseline Characteristics (n = 77)P
erc
en
t
GR
IR
PR
0
20
40
60
80
100
ALL AML
4 10
74
40
22
8
42 NK
HR
SR
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Baseline Characteristics (n = 77)
0
20
40
60
80
100
Bo
ne
Ma
rro
w
Um
bilic
al c
ord
Peri
ph
era
l b
loo
d s
tem
cell
s
Ma
tch
ed
Rela
ted
tra
ns
pla
nt
Ma
tch
ed
Un
rela
ted
tra
ns
pla
nt
Hap
lo-i
nd
en
tica
l tr
an
sp
lan
t
Fu
ll In
ten
sit
y
Red
uc
ed
In
ten
sit
y
Yes
No
Cyclo
sp
ori
ne
+ M
eth
otr
exa
te
Cyclo
sp
ori
ne
+ M
yc
op
hen
ola
tem
ofe
til
Cy
clo
sp
ori
ne
+ M
yc
op
hen
ola
te +
Cyclo
ph
osp
ham
ide
Stem cell source Transplant type Conditioningregimen
TBI used GVHD Prophylaxis
Percent
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SITES OF cGVHD
62.50%
42.50%
40%
30%27.50%
20%
4%
0.00%
10.00%
20.00%
30.00%
40.00%
50.00%
60.00%
70.00%
Oral cavity Liver Skin Lung Eye Gut Others
P
e
r
c
e
n
t
a
g
e
Organ/Site Involved
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cGVHD (n=40) No cGVHD(n=37)
P VALUE
Median age, y 29 31 0.575
Males, n(%) 28 (70%) 24 (64.9%) 0.631
Diagnosis
Acute Lymphoid Leukemia (ALL), n (%)
Acute Myeloid Leukemia (AML), n (%)
Biphenotypic leukemia, n (%)
17 (42.5%)
23 (57.5%)
0 (0)
6 (16.2%)
29 (78.4%)
2 (5.4%)
0.020
Baseline Risk*, n
Good (or standard) Risk
Intermediate Risk
Poor Risk
Not known
2
7
25
6
4
14
14
5
0.138
Relapse/Refractory disease at transplant 12.5% 27.0% 0.231
Univariate analysis of risk factors –Patient related
ALL – Standard risk or Poor risk
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Univariate analysis of risk factors –donor related
cGVHD (n=40) No cGVHD(n=37)
P VALUE
Median donor age, y 31.5 33 0.860
Gender mismatch transplant 62.5% 40.5% 0.054
Female donor to male recipient 42.5% 16.2% 0.012
ABO mismatch 20 (50%) 12 (32.4) 0.118
Stem cell source
Bone Marrow
Umbilical Cord
Peripheral blood stem cells
2 (5.0)
1 (2.5)
37 (92.5)
3 (8.1)
1 (2.7)
33 (89.2)
0.855
Degree of HLA matching
Full matched (6/6 or 10/10)
1 mismatched (5/6 or 9/10)
Haplo-identical transplant
34 (85)
6 (15)
0 (0)
27 (73.0)
5 (13.5)
5 (13.5)
0.121
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Univariate analysis of risk factors –transplant related
cGVHD (n=40) No cGVHD(n=37)
P VALUE
Type of transplant, n (%)
Matched Related transplant
Matched Unrelated transplant
Haplo-indentical transplant
35 (87.5)
5 (12.5)
0 (0)
30 (81.1)
5 (13.5)
2 (5.4)
0.321
Total body irradiation used, n (%) 20 (50.0) 12 (32.4) 0.118
ATG used, n (%) 5 (12.5) 7 (18.9) 0.438
Graft versus Host disease prophylaxis, n (%)
Cyclosporine + Methotrexate
Cyclosporine + Mycophenolate mofetil
30 (75.0)
10 (25.0)
23 (62.2)
14 (37.8)
0.224
Prior acute GVHD, any grade, n (%) 21 (52.5) 13 (35.1) 0.630
Prior acute GVHD, grade II-IV, n(%) 9 (22.5%) 5 (13.5%) 0.307
CD 34 cell dose x 106/kg 5.11 5.12 0.899
CD 3 cell dose x 106/kg 147.80 177.65 0.039
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Multivariate analysis of risk factors
Risk factors HR 95% CI P value
Diagnosis of ALL 3.977 0.997 - 15.86 0.050
Female donor to male recipient transplant 4.776 1.35 – 16.86 0.015
CD 3 cell dose infused 0.995 0.989 – 1.001 0.082
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OVERALL SURVIVAL
MEDIAN OScGVHD Not ReachedNo cGVHD 10.2 monthsP <0.0001
PROJECTED 5-YR OScGVHD 62% No cGVHD 29%P = 0.0037
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RELAPSE FREE SURVIVAL
MEDIAN RFScGVHD 37.7 monthsNo cGVHD 9.3 monthsP <0.001
PROJECTED 3 YR RFScGVHD 55%No cGVHD 29%P = 0.021
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OUTCOME MEASURES
cGVHD (n=40) No cGVHD (n=37) P value
Incidence of relapse 17.5% 51.4% 0.002
Slippage of chimerism
15.0% 43.2% 0.006
Transplant related mortality
7.5% 2.72% 0.342
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INFECTIVE COMPLICATIONS
cGVHD (n=40) No cGVHD(n=37)
P value
CMV reactivation, n(%) 29 (72.5%) 20 (54%) 0.09
Median no of episodes of CMV reactivation
2 1.5 0.75
Adenoviral reactivation, n(%) 11 (27.5%) 5 (13.5%) 0.13
BKV reactivation, n(%) 7 (17.5%) 6 (16.2%) 0.88
EBV reactivation, n(%) 2 (5%) 3 (8.1%) 0.58
Fungal infections, n(%) 5 (12.5%) 6 (16.2%) 0.63
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CONCLUSIONS
• Incidence of chronic GVHD is approximately 50% of our patients with acute leukemia
• About 60% of them have extensive cGVHD
• Occurs after a median of 5 months
• Oral cavity is the commonest site involved
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CONCLUSIONS
• Female donor to male recipient transplants
• Diagnosis of ALL
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CONCLUSIONS
• Less relapses
• Lower incidence of slippage of chimerism
• Improved RFS
• Improved OS
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CONCLUSIONS
• No increase in TRM in patients with chronic GVHD
• Though CMV reactivation was somewhat higher in those with cGVHD, there was no increase in other infections.