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

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

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

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

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

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

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

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

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

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

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%

Diagnosis Change to Consensus with Clinical Data Total changed diagnoses 6.5% PTCL, unspecified ATLL 38.7% NK/T-cell, nasal type Nasal NK/T-cell 7.0% PTCL, unspecified Enteropathy-type 7.0% PTCL, unspecified Angioimmunoblastic 6.3% Cutaneous ALCL ALCL, ALK- 3.3%

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

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

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

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 .

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

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

PTCL - IPI Factors in the MVA Age > 60 (p < 0.0001) Performance status (p < 0.001) LDH > normal (p < 0.0001) Bone marrow involvement (p = 0.026) Gallamini, et al: Blood 103: 2474-2479, 2004

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

Multivariate Analysis for PTCL-NOS Factor - FFS HR 95% CI P-Value Non-ambulatory 1.7 (1.3, 2.4) 0.001 Stage III/IV 1.5 (1.1, 2.0) 0.006 Factor – OS HR 95% CI P-Value Age > 60 1.7 (1.3, 2.3) < 0.001 LDH > Normal 1.5 (1.1, 2.0) 0.006 Non-ambulatory 1.5 (1.0, 2.1) 0.04 > 1 extranodal site 1.5 (1.1, 2.0) 0.008

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

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

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

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

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