1. T-cell NHL: US Perspective
Julie M. Vose, M.D.
University of Nebraska Medical Center

2. International PTCL Study
Purpose
To assess the clinical applicability and reproducibility of the new WHO classification of peripheral T-cell and
NK/T-cell lymphomas

3. Case Selection
Previously-untreated adult patients (>19 yrs) with de novo peripheral T-cell or NK/T-cell lymphoma, excluding mycosis fungoides and Sézary syndrome
Initial presentation between January 1, 1990, and December 31, 2002
Consecutive cases representative of the geographic region
Tissue biopsies adequate for diagnosis and classification
Clinical features, treatment and follow-up information

4. Regional Pathology Review
All cases reviewed and phenotyped by an expert hematopathologist at one of five regional sites
Standard phenotype panel performed on all cases with available tissue blocks, including molecular studies if indicated
All local and regional phenotypic, cytogenetic and molecular results tabulated on data sheets for review
Regional expert renders a diagnosis and quantitates various pathologic parameters

5. Expert Panel Pathology Review
Panels of four expert hematopathologists reviewed the cases individually
Diagnosis #1 – review of diagnostic slides and immunostains, along with all available flow cytometry, cytogenetic, and molecular data, but minimal clinical data (age, sex, biopsy site, and site of largest mass)
Diagnosis #2 – review again after consideration of all pretreatment and follow-up clinical data
Consensus diagnosis = 3/4 or 4/4 experts agree on diagnosis #2, with daily consensus conferences to settle disagreements

6. International PTCL Study
Study Sites Number Cases %
North America
6 sites
333
25.2
Europe
7 sites
452
34.2
Far East
8 sites
535
40.6

7. International T-cell NHL Study: Sites (N = 1320)
North America
Vancouver, Bethesda (NCI), Nebraska, Massachusetts (MGH), California (USC), Arizona
Europe
Barcelona, Norway, Wuerzburg, London, Lyon, Leeds, Madrid, Bologna/Modena
Asia
Bangkok, Hong Kong, Singapore, Tokyo, Nagoya, Okayama, Fukuoka, Seoul

8. Consensus Diagnoses Cases % % T-cell PTCL, unspecified 340 25.8 29.3
Angioimmunoblastic
243
18.4
21.0
NK/T-cell
136
10.3
11.7
ATLL
126
9.5
10.9
ALCL, ALK+ 92
7.0
8.0
ALCL, ALK- 72
5.5
6.2

9. Consensus Diagnoses Cases % % T-cell Enteropathy-type 62 4.7 5.4
Primary cutaneous ALCL 23
1.7
2.0
Hepatosplenic 19
1.4
1.6
Subcutaneous panniculitis 12
0.9
1.0
Peripheral / T-cell 1
0.1
Unclassifiable PTCL 33
2.5
2.8

10. Consensus Diagnoses Cases % % T-cell Other T/NK-cell 24 1.8 -
Blastic “NK-cell” 2
0.2
Hodgkin lymphoma 40
3.0
B-cell lymphoma 18
1.4
Unclassifiable lymphoma 9
0.7
Not lymphoma 30
2.3
Unclassifiable 38
2.8

11. Expert Agreement with Consensus Diagnosis
ALCL, ALK+
98%
PTCL, unspecified
75%
ATLL
93%
Panniculitis-like
NK/T-cell
92%
ALCL, ALK-
74%
Angioimmunoblastic
81%
Hepatosplenic
72%
Enteropathy-type
79%
Cutaneous ALCL
66%

12. Diagnosis Change to Consensus with Clinical Data
Total changed diagnoses %
PTCL, unspecified ATLL %
NK/T-cell, nasal type Nasal NK/T-cell %
PTCL, unspecified Enteropathy-type %
PTCL, unspecified Angioimmunoblastic %
Cutaneous ALCL ALCL, ALK %

13. International PTCL Study Major NHL Types by Region
Percent NA EU FE
PTCL, unspecified
34.2
21.4
22.3
Angioimmunoblastic
15.9
31.4
17.8
Anaplastic, ALK+
16.3
9.2
3.6
Anaplastic, ALK-
7.8
11.8
2.6
NK/T-cell
5.1
5.5
ATLL
2.0
1.5
24.8

14. International PTCL Study Major NHL Types by Region
Percent NA EU FE
Enteropathy-type
5.7
11.6
1.9
Hepatosplenic
3.0
2.9
0.2
Subcut panniculitis
1.3
0.7
Cutaneous anaplastic
5.4
1.1
0.9
Unclassifiable T-cell
2.5
2.3
Misc T/NK-cell

15. Overall Survival by diagnosis group Test: p<0.001 Proportion 1.0
0.9
0.8
0.7
0.6
Proportion
0.5
0.4
0.3
0.2
0.1
0.0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
Time
CENSOR
FAIL
TOTAL
MEDIAN
Adult T-cell leuk/lymph (ATLL) 23
103
126
0.79
Anaplastic large cell lymphoma, ALK- 36 33 69
4.49
Anaplastic large cell lymphoma, ALK+ 61 24 85 .
Angioimmunoblastic T-cell lymphoma 87
151
238
2.28
Peripheral T-cell lymphoma
110
218
328 2
Generic NK-cell 49 85
134
0.65

16. Overall Survival by diagnosis group Test: p<0.001 Proportion 1.0
0.9
0.8
0.7
0.6
Proportion
0.5
0.4
0.3
0.2
0.1
0.0 1 2 3 4 5 6 7 8 9 10 11 12 13
Time
CENSOR
FAIL
TOTAL
MEDIAN
Enteropathy-type T-cell lymphoma 9 52 61
0.88
Hepatosplenic T-cell lymphoma 3 16 19
0.67
Subcutaneous panniculitis-like T-cell ly 7 5 12
6.19
Primary cutaneous ALCL 20 3 23 .

17. Overall Survival
Nasak NK/T and Nasal-type NK/T and Aggressive/Unclass. NK/T
1.0
0.9
Test: p<0.001
0.8
0.7
0.6
Proportion
0.5
0.4
0.3
0.2
0.1
0.0 1 2 3 4 5 6 7 8 9 10 11 12
Time
CENSOR
FAIL
TOTAL
MEDIAN
Nasal NK/T-cell lymphoma 42 50 92
1.61
NK/T-cell lymphoma, nasal type 5 29 34
0.36
Unclassifiable or Aggressive NK-cell leu 2 6 8
0.23

18. Overall Survival PTCL-NOS Cases by IPI Test: p<0.001 Proportion
1.0
Test: p<0.001
0.9
0.8
0.7
0.6
Proportion
0.5
0.4
0.3
0.2
0.1
0.0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
Time
IPI
CENSOR
FAIL
TOTAL
MEDIAN
0/1 36 47 83
5.03 2 36 67
103
2.1 3 20 53 73
1.41
4/5 9 38 47
0.68

19. PTCL - IPI Factors in the MVA Age > 60 (p < 0.0001)
Performance status (p < 0.001)
LDH > normal (p < )
Bone marrow involvement (p = 0.026)
Gallamini, et al: Blood 103: , 2004

20. Overall Survival PTCL-NOS Cases by PIT Test: p<0.001 Proportion
1.0
Test: p<0.001
0.9
0.8
0.7
0.6
Proportion
0.5
0.4
0.3
0.2
0.1
0.0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
Time
PIT value
CENSOR
FAIL
TOTAL
MEDIAN 31 31 62
5.11 1 41 80
121
2.11 2 26 66 92
1.46
3/4 8 35 43
0.7

21. Multivariate Analysis for PTCL-NOS
Factor - FFS HR 95% CI P-Value
Non-ambulatory (1.3, 2.4)
Stage III/IV (1.1, 2.0)
Factor – OS HR 95% CI P-Value
Age > (1.3, 2.3) < 0.001
LDH > Normal (1.1, 2.0)
Non-ambulatory (1.0, 2.1) 0.04
> 1 extranodal site (1.1, 2.0)

22. PTCL-NOS Cases by Anthracycline Initial Tx
Overall Survival
PTCL-NOS Cases by Anthracycline Initial Tx
1.0
0.9
Test: p=0.14
0.8
0.7
0.6
0.5
Proportion
0.4
0.3
0.2
0.1
0.0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
Time
Anthracycline as part of initial tx
CENSOR
FAIL
TOTAL
MEDIAN
yes 98
173
271
2.1 no 14 34 48
1.57

23. PTCL-NOS Cases by Carbo/Cisplatin Initial Tx
Overall Survival
PTCL-NOS Cases by Carbo/Cisplatin Initial Tx
1.0
0.9
Test: p=0.46
0.8
0.7
0.6
0.5
Proportion
0.4
0.3
0.2
0.1
0.0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
Time
Carbo/Cisplatin as part of initial tx
CENSOR
FAIL
TOTAL
MEDIAN
yes 2 6 8
2.01 no
110
200
310
2.1

24. PTCL-NOS Cases by Stem Cell Transplant
Overall Survival
PTCL-NOS Cases by Stem Cell Transplant
1.0
0.9
Test: p=0.0076
0.8
0.7
0.6
0.5
Proportion
0.4
0.3
0.2
0.1
0.0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
Time
Hi-dose therapy (transplant)
CENSOR
FAIL
TOTAL
MEDIAN
yes 21 27 48
3.5 no 63
148
211
1.95

25. PTCL-NOS Cases by Transplant Reason
Failure-free Survival
PTCL-NOS Cases by Transplant Reason
1.0
0.9
Test: p<0.001
0.8
0.7
0.6
0.5
Proportion
0.4
0.3
0.2
0.1
0.0 1 2 3 4 5 6 7 8 9 10 11
Time
Transplant reason
CENSOR
FAIL
TOTAL
MEDIAN
inital tx 8 15 23
1.46
subseq. to recur. 24 24
0.71

26. PTCL: US Perspective
PTCL – outcomes with standard anthracycline regimens alone is not adequate
? If early stem cell transplantation improves outcomes
Definite need for novel agents and combinations with different mechanisms of action