The presentation was made at the annual Asia Pacific Blood and marrow transplant meeting (APBMT) in 2014 held at Hanzhou, China.

1. 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, Jayant
Gawande, 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

2. BACKGROUND
• Auto-immune like disorder
• 60 – 80 % incidence
• Major cause of long term morbidity and
mortality

4. 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

5. However….
• Paucity of Indian data
• Acute leukemia pts
• Impact on Overall Survival
• Infectious complications and impact on
mortality in Indian subcontinent

6. PATIENTS AND METHODS
• Single centre retrospective analysis
• All patients undergoing allo HSCT for acute
leukemia
• January 2008 – March 2013

7. • 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)

8. • Rabbit ATG
– Unrelated transplants
– Related transplants with 8/10 or 9/10 match
• Chronic GVHD
– Extensive stage
– Limited stage

9. 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

10. 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

11. 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

12. OUTCOME MEASURES
• Overall Survival
• Relapse Free Survival
• Incidence of relapse
• Slippage of chimerism
• Transplant related mortality
• Infective complications

13. 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

14. RESULTS – PATIENT CHARACTERISTICS
No of transplants 77
Median age 30 (5-61) years
Males, n (%) 52 (68%)
Diagnosis
AML
ALL
Biphenotypic leukemia
52 (67.5%)
23 (29.9%)
2 (2.6%)
Stem cell source
PBSC
Cord blood
Marrow
70 (91%)
2 (2.5%)
5 (6.5%)
Fully matched transplants 61 (79%)

15. RESULTS – INCIDENCE AND PATTERN
Incidence of cGVHD, n(%) 40 (52%)
Extensive stage
Limited 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

16. 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
M
68%
F
32%
Gender
ALL
30%
AML
67%
Biphenoty
pic
Leukemia
3%
Diagnosis
Biphenotypic Leukemia (3%)
CR1
55%CR2
26%
19%
Disease status at transplant
Relapse/Refractory
Baseline Characteristics (n = 77)
Percent
GR
IR
PR
0
20
40
60
80
100
ALL AML
4 10
74
40
22
8
42 NK
HR
SR

17. Baseline Characteristics (n = 77)
0
20
40
60
80
100
BoneMarrow
Umbilicalcord
Peripheralbloodstemcells
MatchedRelatedtransplant
MatchedUnrelatedtransplant
Haplo-indenticaltransplant
FullIntensity
ReducedIntensity
Yes
No
Cyclosporine+Methotrexate
Cyclosporine+Mycophenolate
mofetil
Cyclosporine+Mycophenolate+
Cyclophosphamide
Stem cell source Transplant type Conditioning
regimen
TBI used GVHD Prophylaxis
Percent

18. 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

19. 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

20. 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

21. 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

22. 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

23. OVERALL SURVIVAL
MEDIAN OS
cGVHD Not Reached
No cGVHD 10.2 months
P <0.0001
PROJECTED 5-YR OS
cGVHD 62%
No cGVHD 29%
P = 0.0037

24. RELAPSE FREE SURVIVAL
MEDIAN RFS
cGVHD 37.7 months
No cGVHD 9.3 months
P <0.001
PROJECTED 3 YR RFS
cGVHD 55%
No cGVHD 29%
P = 0.021

25. 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

26. 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

27. 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

28. CONCLUSIONS
• Female donor to male recipient transplants
• Diagnosis of ALL

29. CONCLUSIONS
• Less relapses
• Lower incidence of slippage of chimerism
• Improved RFS
• Improved OS

30. 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.