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

BACKGROUND

• Auto-immune like disorder

• 60 – 80 % incidence

• Major cause of long term morbidity and mortality

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

However….

• Paucity of Indian data

• Acute leukemia pts

• Impact on Overall Survival

• Infectious complications and impact on mortality in Indian subcontinent

PATIENTS AND METHODS

• Single centre retrospective analysis

• All patients undergoing allo HSCT for acute leukemia

• January 2008 – March 2013

• 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)

• Rabbit ATG

– Unrelated transplants

– Related transplants with 8/10 or 9/10 match

• Chronic GVHD

– Extensive stage

– Limited stage

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

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

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

OUTCOME MEASURES

• Overall Survival

• Relapse Free Survival

• Incidence of relapse

• Slippage of chimerism

• Transplant related mortality

• Infective complications

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

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%)

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

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

Baseline Characteristics (n = 77)

0

20

40

60

80

100

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Um

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Un

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Yes

No

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Stem cell source Transplant type Conditioningregimen

TBI used GVHD Prophylaxis

Percent

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

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

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

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

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

OVERALL SURVIVAL

MEDIAN OScGVHD Not ReachedNo cGVHD 10.2 monthsP <0.0001

PROJECTED 5-YR OScGVHD 62% No cGVHD 29%P = 0.0037

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

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

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

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

CONCLUSIONS

• Female donor to male recipient transplants

• Diagnosis of ALL

CONCLUSIONS

• Less relapses

• Lower incidence of slippage of chimerism

• Improved RFS

• Improved OS

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.