Peripheral T Cell Lymphoma Prognostic Factors Dennis D

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Peripheral T Cell Lymphoma Prognostic Factors Dennis D. Weisenburger, M. D. for the International

Peripheral T Cell Lymphoma Prognostic Factors Dennis D. Weisenburger, M. D. for the International PTCL Study

Prognostic Factors l Histologic type – ALCL, ALK+ good l International Prognostic Index (IPI)

Prognostic Factors l Histologic type – ALCL, ALK+ good l International Prognostic Index (IPI) l Clinical features – B symptoms, β 2 microglobulin, bulky disease, etc; l Pathologic features – transformed cells, proliferation, EBV infection, etc;

International PTCL Study Purpose To assess the clinical applicability and reproducibility of the new

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

Case Selection l Previously-untreated adult patients (>19 yrs) with de novo peripheral T-cell or

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

International PTCL Study Sites Number Cases % North America Europe 6 sites 333 25.

International PTCL Study Sites Number Cases % North America Europe 6 sites 333 25. 2 7 sites 452 34. 2 Far East 8 sites 535 40. 6

International PTCL Study Contributing Sites l North America – Omaha, Vancouver, Bethesda, Boston, Los

International PTCL Study Contributing Sites l North America – Omaha, Vancouver, Bethesda, Boston, Los Angeles, Tucson l Europe – Barcelona, Madrid, London, Oslo, Lyon, Wuerzburg, Bologna l Far East – Seoul, Hong Kong, Singapore, Bangkok, Tokyo, Nagoya, Okayama, Fukuoka

Overall Survival Proportion by diagnosis group 1. 0 0. 9 0. 8 0. 7

Overall Survival Proportion by diagnosis group 1. 0 0. 9 0. 8 0. 7 0. 6 0. 5 0. 4 0. 3 0. 2 0. 1 0. 0 Test: p<0. 001 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 Time Diagnosis CENSOR FAIL TOTAL MEDIAN Adult T-cell leuk/lymph (ATLL) 23 103 126 0. 79 Anaplastic large cell lymphoma, ALK- 38 33 71 4. 49 Anaplastic large cell lymphoma, ALK+ 63 27 90 . Angioimmunoblastic T-cell lymphoma 87 154 241 2. 26 Peripheral T-cell lymphoma 112 218 330 2. 01 Generic NK-cell 49 85 134 0. 65

Overall Survival by diagnosis group 1. 0 0. 9 Test: p<0. 001 0. 8

Overall Survival by diagnosis group 1. 0 0. 9 Test: p<0. 001 0. 8 Proportion 0. 7 0. 6 0. 5 0. 4 0. 3 0. 2 0. 1 0. 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 Time Diagnosis 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

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 Proportion 0. 7 0. 6 0. 5 0. 4 0. 3 0. 2 0. 1 0. 0 0 1 2 3 4 5 6 7 8 9 10 11 12 Time Diagnosis Nasal NK/T-cell lymphoma, nasal type Unclassifiable or Aggressive NK-cell leu CENSOR FAIL TOTAL MEDIAN 42 50 92 1. 61 5 29 34 0. 36 2 6 8 0. 23

Survival in PTCL correlates with IPI Scores 5 yr. OS IPI 0 -1 IPI

Survival in PTCL correlates with IPI Scores 5 yr. OS IPI 0 -1 IPI 3 -5 Cutaneous ALCL 90% 86% 5% ALCL, ALK+ 71% 51% 29% Panniculitis-like 64% 42% 58% ALCL, ALK- 49% 41% 39% Nasal NK/T 41% 49%

Survival in PTCL Correlates with IPI Scores 5 yr. OS IPI 0 -1 IPI

Survival in PTCL Correlates with IPI Scores 5 yr. OS IPI 0 -1 IPI 3 -5 PTCL-NOS 32% 28% 37% Agioimmunoblastic 32% 14% 59% Enteropathy-type 20% 25% 45% ATLL 14% 19% 48% Extranasal NK/T 9% 26% 60% Hepatosplenic 7% 16% 84%

Consensus Diagnoses Cases % % T-cell PTCL, unspecified 340 25. 8 29. 3 Angioimmunoblastic

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

Overall Survival Disease Category: Peripheral T-cell lymphoma by IPI 1. 0 0. 9 Test:

Overall Survival Disease Category: Peripheral T-cell lymphoma by IPI 1. 0 0. 9 Test: p<0. 001 0. 8 Proportion 0. 7 0. 6 0. 5 0. 4 0. 3 0. 2 0. 1 0. 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 40 47 87 5. 11 2 38 72 110 2. 1 3 19 51 70 1. 41 4/5 9 39 48 0. 67

Overall Survival Disease Category: Peripheral T-cell lymphoma by Marrow Involvement 1. 0 0. 9

Overall Survival Disease Category: Peripheral T-cell lymphoma by Marrow Involvement 1. 0 0. 9 Test: p=0. 027 0. 8 Proportion 0. 7 0. 6 0. 5 0. 4 0. 3 0. 2 0. 1 0. 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Time Bone marrow involvement CENSOR FAIL TOTAL MEDIAN no 87 159 246 2. 11 yes 20 52 72 1. 12

Overall Survival Disease Category: Peripheral T-cell lymphoma by T-IPI 1. 0 0. 9 Test:

Overall Survival Disease Category: Peripheral T-cell lymphoma by T-IPI 1. 0 0. 9 Test: p<0. 001 0. 8 Proportion 0. 7 0. 6 0. 5 0. 4 0. 3 0. 2 0. 1 0. 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Time T-IPI CENSOR FAIL TOTAL MEDIAN 0 31 33 64 4. 68 1 42 76 118 2. 1 2 25 65 90 1. 46 3/4 8 35 43 0. 7

Clinical Features of PTCL-NOS IPI 0/1 28% 2 PIT 0 20% 35% 1 38%

Clinical Features of PTCL-NOS IPI 0/1 28% 2 PIT 0 20% 35% 1 38% 3 22% 2 29% 4/5 15% 3/4 13%

Overall Survival Disease Category: Peripheral T-cell Lymphoma-NOS by Transformed T-cell counts 1. 0 0.

Overall Survival Disease Category: Peripheral T-cell Lymphoma-NOS by Transformed T-cell counts 1. 0 0. 9 Test: p=0. 0078 0. 8 Proportion 0. 7 0. 6 0. 5 0. 4 0. 3 0. 2 0. 1 0. 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Time Median transformed T-cell count CENSOR FAIL TOTAL MEDIAN <=30% 37 49 86 3. 23 31 -70% 33 56 89 2. 03 >70% 19 60 79 1. 23

Overall Survival Disease Category: Peripheral T-cell Lymphoma-NOS by Ki 67+ cells 1. 0 0.

Overall Survival Disease Category: Peripheral T-cell Lymphoma-NOS by Ki 67+ cells 1. 0 0. 9 Test: p<0. 001 0. 8 Proportion 0. 7 0. 6 0. 5 0. 4 0. 3 0. 2 0. 1 0. 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Time Ki 67+ cells (%) CENSOR FAIL TOTAL MEDIAN <=25% 25 27 52 5. 26 26 -75% 35 68 103 1. 89 >75% 12 44 56 1. 36

Overall Survival PTCL-US vs. PTCL-LE 1. 0 0. 9 Test: p=0. 0032 0. 8

Overall Survival PTCL-US vs. PTCL-LE 1. 0 0. 9 Test: p=0. 0032 0. 8 Proportion 0. 7 0. 6 0. 5 0. 4 0. 3 0. 2 0. 1 0. 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Time Diagnosis PTCL, unspecified PTCL, lymphoepithelioid variant CENSOR FAIL TOTAL MEDIAN 88 204 292 1. 83 18 10 28 17. 2

Clinical Features of PTCL-US and PTCL-LE PTCL-US PTCL-LE 18% 23% 2 35% 38% 3

Clinical Features of PTCL-US and PTCL-LE PTCL-US PTCL-LE 18% 23% 2 35% 38% 3 -5 37% 39% 7% 0% 0. 38 Platelets <150 K 24% 29% 0. 62 Transformed cells >70% 33% 6% 0. 03 IPI 0/1 Mass >10 cm P= 0. 87

Final Multivariate Analysis of Prognostic Factors in PTCL-NOS Controlling for IPI OS Transformed cells

Final Multivariate Analysis of Prognostic Factors in PTCL-NOS Controlling for IPI OS Transformed cells >70% FFS Transformed cells >70% HR 2. 2 1. 6 P= 0. 0002 0. 014 Controlling for PIT OS Mass >10 cm Platelets <150 K Transformed cells >70% FFS Platelets <150 K Transformed cells >70% 2. 1 1. 7 1. 9 1. 7 1. 6 0. 04 0. 002 0. 02

Overall Survival Peripheral T-cell Lymphoma-NOS, and Disease sub-group: Angioimmunoblastic T-cell lymphoma 1. 0 0.

Overall Survival Peripheral T-cell Lymphoma-NOS, and Disease sub-group: Angioimmunoblastic T-cell lymphoma 1. 0 0. 9 Test: p=0. 89 0. 8 Proportion 0. 7 0. 6 0. 5 0. 4 0. 3 0. 2 0. 1 0. 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 Time Diagnosis Angioimmunoblastic T-cell lymphoma Peripheral T-cell lymphoma-NOS CENSOR FAIL TOTAL MEDIAN 87 154 241 2. 26 112 218 330 2. 01

Clinical Prognostic Factors of PTCL-NOS vs. Angioimmunoblastic (AI) PTCL-NOS AI P= IPI scores 3

Clinical Prognostic Factors of PTCL-NOS vs. Angioimmunoblastic (AI) PTCL-NOS AI P= IPI scores 3 -5 37% 59% <0. 0001 B symptoms 35% 69% <0. 0001 Hgb <11 g/dl 22% 40% <0. 0001

Overall Survival Disease Category: Angioimmunoblastic T-cell Lymphoma by IPI 1. 0 0. 9 Test:

Overall Survival Disease Category: Angioimmunoblastic T-cell Lymphoma by IPI 1. 0 0. 9 Test: p=0. 096 0. 8 Proportion 0. 7 0. 6 0. 5 0. 4 0. 3 0. 2 0. 1 0. 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Time IPI CENSOR FAIL TOTAL MEDIAN 0/1 15 15 30 5. 94 2 23 39 62 2. 93 3 22 45 67 1. 67 4/5 18 44 62 1. 37

Overall Survival Disease Category: Angioimmunoblastic T-cell Lymphoma by patient age 1. 0 0. 9

Overall Survival Disease Category: Angioimmunoblastic T-cell Lymphoma by patient age 1. 0 0. 9 Test: p=0. 036 0. 8 Proportion 0. 7 0. 6 0. 5 0. 4 0. 3 0. 2 0. 1 0. 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 Time Age CENSOR FAIL TOTAL MEDIAN <=60 40 60 100 3. 21 >60 47 94 141 1. 68

Overall Survival Disease Category: Angioimmunoblastic T-cell Lymphoma by performance status 1. 0 0. 9

Overall Survival Disease Category: Angioimmunoblastic T-cell Lymphoma by performance status 1. 0 0. 9 Test: p=0. 0022 0. 8 Proportion 0. 7 0. 6 0. 5 0. 4 0. 3 0. 2 0. 1 0. 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 Time Performance status CENSOR FAIL TOTAL MEDIAN Ambulatory 63 85 148 3. 1 Non-ambul. 22 67 89 1. 37

Overall Survival Disease Sub-group: Angioimmunoblastic T-cell lymphoma by B-symptoms 1. 0 0. 9 Test:

Overall Survival Disease Sub-group: Angioimmunoblastic T-cell lymphoma by B-symptoms 1. 0 0. 9 Test: p=0. 0046 0. 8 Proportion 0. 7 0. 6 0. 5 0. 4 0. 3 0. 2 0. 1 0. 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 Time B symptoms CENSOR FAIL TOTAL MEDIAN no 36 38 74 4. 8 yes 51 116 167 1. 62

Overall Survival Disease Sub-group: Angioimmunoblastic T-cell lymphoma by Platelet Count 1. 0 0. 9

Overall Survival Disease Sub-group: Angioimmunoblastic T-cell lymphoma by Platelet Count 1. 0 0. 9 Test: p=0. 017 0. 8 Proportion 0. 7 0. 6 0. 5 0. 4 0. 3 0. 2 0. 1 0. 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Time Platelet Count CENSOR FAIL TOTAL MEDIAN <150 K/cmm 19 41 60 1. 03 >=150 K/cmm 52 90 142 2. 4

Overall Survival Disease Category: Angioimmunoblastic by Transformed T-cell counts 1. 0 0. 9 Test:

Overall Survival Disease Category: Angioimmunoblastic by Transformed T-cell counts 1. 0 0. 9 Test: p=0. 14 0. 8 Proportion 0. 7 0. 6 0. 5 0. 4 0. 3 0. 2 0. 1 0. 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 Time Median transformed T-cell count CENSOR FAIL TOTAL MEDIAN <=30% 47 72 119 2. 4 31 -70% 25 51 76 1. 52 >70% 5 13 18 1. 76

Overall Survival Disease Category: Angioimmunoblastic T-cell Lymphoma by UNMC-IPI 2 1. 0 0. 9

Overall Survival Disease Category: Angioimmunoblastic T-cell Lymphoma by UNMC-IPI 2 1. 0 0. 9 Test: p<0. 001 Proportion 0. 8 0. 7 0. 6 0. 5 0. 4 0. 3 0. 2 0. 1 0. 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Time UNMC-PI 2: Age / Perf. Stat / Plt Ct<150 k CENSOR FAIL TOTAL MEDIAN 0 8 7 15 6. 03 1 20 32 52 4. 26 2 33 45 78 1. 68 3 9 37 46 1. 37 4 1 9 10 0. 51

Overall Survival Disease Sub-group: Anaplastic large cell lymphoma, ALK+ by IPI 1. 0 0.

Overall Survival Disease Sub-group: Anaplastic large cell lymphoma, ALK+ by IPI 1. 0 0. 9 0. 8 Test: p<0. 001 Proportion 0. 7 0. 6 0. 5 0. 4 0. 3 0. 2 0. 1 0. 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Time IPI CENSOR FAIL TOTAL MEDIAN 0/1 31 4 35 . 2 12 6 18 . 3 4 7 11 0. 6 4/5 4 6 10 1. 73

Overall Survival Disease Sub-group: Anaplastic large cell lymphoma, ALK+ by Hemoglobin 1. 0 0.

Overall Survival Disease Sub-group: Anaplastic large cell lymphoma, ALK+ by Hemoglobin 1. 0 0. 9 Test: p=0. 043 0. 8 Proportion 0. 7 0. 6 0. 5 0. 4 0. 3 0. 2 0. 1 0. 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Time Hemoglobin CENSOR FAIL TOTAL MEDIAN <11 g/dl 8 6 14 . >=11 g/dl 32 9 41 .

Overall Survival Disease Sub-group: Anaplastic large cell lymphoma, ALKby IPI 1. 0 0. 9

Overall Survival Disease Sub-group: Anaplastic large cell lymphoma, ALKby IPI 1. 0 0. 9 Test: p<0. 001 0. 8 Proportion 0. 7 0. 6 0. 5 0. 4 0. 3 0. 2 0. 1 0. 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Time IPI CENSOR FAIL TOTAL MEDIAN 0/1 22 5 27 . 2 8 4 12 . 3 5 11 16 1. 71 4/5 2 8 10 0. 66

Conclusions l Histologic type is a good predictor of survival l IPI is a

Conclusions l Histologic type is a good predictor of survival l IPI is a good predictor of survival in PTCL-NOS along with % of transformed cells l IPI is a poor predictor of survival in angioimmunoblastic type and better prognostic models are needed l IPI is a good predictor of survival in ALCL, ALK+ (along with Hgb <11 g/dl) and ALCL, ALK-

Conclusions l IPI is useful for stratification of most PTCL patients for risk-adapted therapies

Conclusions l IPI is useful for stratification of most PTCL patients for risk-adapted therapies l New clinical, pathological and molecular genetic predictors are needed to develop more biologically-relevant prognostic models for the various disease entities