Conventional Treatment of PTCL: The Asian Perspective It’s time to take care of T-Cell lymphomas October 22-24, 2006, Bologna, Italy Conventional Treatment of PTCL: The Asian Perspective Kensei Tobinai, MD, PhD National Cancer Center Hospital, Tokyo, Japan

Topics of Today Epidemiology of PTCL in Japan JCOG Studies and Allogeneic SCT for ATL CCR4 Expression in ATL & PTCL-U and a Monoclonal Antibody Treatment Concurrent Chemoradiotherapy of Nasal NK/T-NHL

Lymphomas in Japan by WHO Classification 3,194 cases were reviewed, and consisted of 69% of B-NHL, 25% of T- or NK-NHL, and 4% of Hodgkin lymphoma. Major subtypes of T- or NK-NHL in Japan 1) 7.5% of adult T-cell leukemia-lymphoma (ATL) 19.2% in Kyushu, a south-western island 2) 6.7% of PTCL, unspecified 3) 2.6% of NK/T-NHL 4) 2.4% of angioimmunoblastic T-cell lymphoma (AILT) 5) 1.7% of T-LBL/T-ALL 6) 1.5% of ALCL Lymphoma Study Group of Japanese Pathologists：Pathol Int 2000;50:692-702

an HTLV-I-endemic island Malignant Lymphomas in the World Japan Western countries Kyusyu, an HTLV-I-endemic island Others 15% 14% 12% 21% 21% B 54% T/NK 46 % 10% B 78% T/NK 22 % 33% B 87% T/NK 13 % 32% 48% PTCLU 10% ATL 11% 12% T-LBL PTCLU NK/T AILT MF ATL Lymphoma Study Group of Japanese Pathologists: Pathol Int 2000;50:696-702 ALCL others Non-Hodgkin's Lymphoma Classification Project: Blood 1997;89:3909-18

Diagnosis of ATL Acute-type ATL (prototype) has characteristic findings, including flower cells in PB, hypercalcemia and frequent organ involvement (skin, GI-tract, lung, etc.) Peripheral T-cell phenotype (CD4+, CD8-, CD25+) Presence of antibodies to HTLV-I in serum Four clinical subtypes; acute-, lymphoma-, chronic- and smoldering types

Summary of JCOG Trials for ATL Study %CR MST (Mo) %OS JCOG 8101 (CHOP-like) 28% (15/54) 7.5 8% (4-yr) JCOG 8701 (2nd generation) 42% (18/43) 8.0 12% (4-yr) JCOG 9109 (DCF-containing) 28% (17/60) 7.4 16% (2-yr) JCOG 9303 (G-CSF-supported) 35% (33/93) 13 31% (2-yr) JCOG 9801 (9303 vs. Bi-CHOP) 32% (38/118) 11 24% (2-yr)

VEPA-B B) M-FEPA C) VEPP-B JCOG 8701 for Aggressive NHL 2nd Generation Regimen VEPA-B B) M-FEPA C) VEPP-B MST: 8.3 months

Overall Survival of 60 Eligible Patients in JCOG 9109; DCF-containing Regimen MST; 7.4 months 2-year OS; 16% 5-year OS; 10% identical to the results of JCOG8701 Tsukasaki K, Tobinai K, et al.: Int J Hematol 2003;77:164-70

JCOG 9303; a G-CSF-supported, multiagent Day 1 8 15 - 17 VCR 1 mg/m2 CPA 350 mg/m2 DXR 40 mg/m2 PSL 40 mg/m2 MCNU 60 mg/m2 VDS 2.4 mg/m2 ETP 100 mg/m2 CBDCA 250 mg/m2 30 IT-MTX+PSL on cycle 1, 3, 5 every 4 weeks for 7 cycles

Overall Survival for the 93 Eligible Patients in JCOG 9303; a G-CSF-Supported, Multiagent Regimen MST; 13 months 2-year OS; 31% Proportion surviving Months after registration Yamada Y, Tobinai K, et al.: Br J Haematol 2001;114:375-82 2

Survival according to Clinical Subtypes in JCOG 9303 Hazard ratio; 1.65 Lymphoma type MST; 19.7 months Acute type MST; 10.9 months Months after Registration Yamada Y, Tobinai K, et al.: Br J Haematol 2001;114:375-82

JCOG 9801; a Phase III Study Primary endpoint; Overall survival Eligibility Check Primary endpoint; Overall survival Informed Consent Randomization (A) JCOG 9303 a)VCAP (G-CSF) 1 w b) AMP c) VECP plus IT-MTX/Ara-C (total 24 w) (B) Bi-weekly CHOP (G-CSF) 2 w plus IT-MTX/Ara-C (total 16 w) X 8 X 6 Tsukasaki K, Tobinai K, et al.: Blood 2005;106:812a

Overall Survival of ATL Pts in JCOG 9801 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1 2 3 4 5 6 7 Hazard ratio = 0.751 (95% CI, 0.50–1.13) One sided p = 0.085 　　　　　 p = 0.029 by adjustment by Cox regression VCAP-AMP-VECP (n=57) Biweekly CHOP (n=61) Proportion OS MST, 13M 3 yr-OS, 24% MST, 11M 3 yr-OS, 13% Figure 1. Kaplan-Meier estimate of the overall survival (OS) for all randomized patients. Years after randomization Tsukasaki K, Tobinai K, et al.: Blood 2005;106:812a

Overall Survival of ATL Pts in JCOG 9801: Subgroup Analysis 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 2 3 4 5 6 7 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 2 3 4 5 6 7 Age < 56 yr Age >= 56 yr Proportion OS Proportion OS VCAP-AMP-VECP (n=28) Biweekly CHOP (n=24) VCAP-AMP-VECP (n=29) Biweekly CHOP (n=37) Years after randomization Years after randomization Figure 4. Kaplan-Meier estimate of the overall survival (OS) for all randomized patients according to age at diagnosis. Younger patients were more likely to respond to VCAP-AMP-VECP. Tsukasaki K, Tobinai K, et al.: Blood 2005;106:812a

Conclusions of JCOG9801 VCAP-AMP-VECP, a G-CSF-supported, dose-intensified multiagent regimen should be a new standard chemotherapy for newly diagnosed aggressive ATL. However, the MST of 13 months is still not satisfactory. Based on the promising results in retrospective analysis of myeloablative allo-SCT, we are planning a phase II study of the all-SCT after induction therapy with VCAP-AMP-VECP for young pts with aggressive ATL. This is our conclusion slide. Our results suggest that concurrent chemoradiotherapy using MDR-non-related agents and ETP is a promising treatment strategy for localized nasal NK/T lymphoma. Feasibility and efficacy of Level 1 will be evaluated further in the phase II portion. Tsukasaki K, Tobinai K, et al.: Blood 2005;106:812a

Allogeneic SCT with conventional conditioning provides sustained survival for pts with ATL .2 .4 .6 .8 1 Overall survival 500 1000 1500 2000 3-year OS: 45.3% (n = 40) At 7 centers in Japan Median age; 44 (28-53) Time (days) Fukushima T, et al.: Leukemia 2005;19:829-34

Feasibility Study of Reduced-intensity SCT for 15 Pts with ATL (median age, 57; 51-67) OS & EFS OS according to acute GVHD 1 1 . .8 . 8 YES (n=10) . .6 1y-OS; 39% . 6 61 % .4 . . 4 NO (n=5) .2 . 1y-EFS; 25% . 2 p=0.05 ⑥スライド 　結果を示します。 本登録の1例では、病状の急速な進行により、前処置中に他薬剤が追加投与されたため、プロトコール違反となり、15例が評価可能でした。 移植片は、全例で速やかに生着し、90日以内に14例で完全キメラが達成されましたが、1例では達成前に原病が再発しました。　3度の急性GVHD発症後敗血症を合併した1例が早期死亡されました。 4度の血液毒性は高率に見られましたが、いずれも短期間で回復し、非血液毒性の3度が2例に見られました。移植後中央値12ヶ月の現在、6例が死亡、9例が生存中です。 100 2 3 4 5 6 7 1 2 3 4 5 6 7 Days after transplant Graft versus ATL effect? RIST is a feasible treatment for ATL. Okamura J, Tanosaki R, et al.: Blood 2005;105:4143-5

CCR4 expression is an unfavorable factor in ATL. 100 CCR4-ATL CCR4, a chemokine receptor, is a kind of selective markers of Th2 phenotype. Most ATL cases (88%) are CCR4-positive by immunostaining. (n=12) 80 60 CCR4+ATL Overall survival (%) (n=90) 40 p = 0.032 20 Ishida T, et al.: Clin Cancer Res 2003;9:3625 20 40 60 80 100 months Prognostic factors affecting overall survival of ATL patients Unfavorable factors Univariate Multivariate Viables Hazard ratio (CI) p value Hazard ratio (CI) p value 全症例で生存曲線を比較したところ、CCR4陽性ATLL例は、陰性例に比較し、有意に生存期間が短いことが明らかとなった(50%生存; 9.5 vs 20.6ヶ月、左上図)。病型を急性型のみに限局し生存曲線を比較してもCCR4陽性急性型ATLL例は、陰性例に比較し、有意に生存期間が短かかった(50%生存; 8.9 vs 22.2ヶ月、図5C)。次に、皮膚病変の有無で生存曲線を比較したが、右上図、に示すように、皮膚病変の有無は生存期間になんら寄与しなかった。 (ATLLにおける予後因子解析　下表)　 単変量解析において、i) PS(Performance Status)不良、ii) B症状有り、iii) 2個以上の節外病変の存在、iv) LDH高値、v) Ca高値、vi) CCR4陽性、の6つの因子が有意な予後不良因子として抽出された。多変量解析において、B症状有り、2個以上の節外病変の存在、と共にCCR4陽性は独立した有意な(hazard ratio=2.197; 95% confidence interval, 1.080-4.469; P=.0298)予後不良因子であることが示された。 CCR4の発現は病型、病理組織学的悪性度とは無関係である。また、LDH値との相関も認めないことから、腫瘍量を反映している訳でもないと考えられる。その他のPS、B症状、Ca値等、予後不良因子との相関関係を認めない。唯一相関関係のあった皮膚浸潤に関しても、皮膚病変の有無は予後にまったく寄与しない。CCR4の発現自体が何らかの生物学的な特性を持ち予後不良因子となっていると考えられるが、その機序は現時点では不明である。 Comparison with risk factors PS B symptom Extranodal involvement LDH Ca (mg/dl) CCR4 > 2 Present > 2 sites >normal > 11.0 positive 2.11 (1.36 - 3.26) 2.47 (1.57 - 3.87) 2.54 (1.49 - 4.34) 2.12 (1.02 - 4.40) 2.49 (1.43 - 4.32) 2.10 (1.05 - 4.21) 0.001 < 0.0001 0.044 0.037 2.43 (1.52 - 3.88) 2.11 (1.21 - 3.66) 2.20 (1.08 - 4.47) - 0.0002 0.008 0.030 - -

Ishida T, et al.: Clin Cancer Res 2004;10:5494-500 Immunohistochemical Expression of CXCR3/CCR4 in T- and NK-cell Lymphomas HE CXCR3 CCR4 CCR4+ Ishida T, et al.: Clin Cancer Res 2004;10:5494-500 AILT 35% (8/23) 67% (8/12) ALK- ALCL MF in transformation 41% (7/17) PTCL, unspecified 38% (19/50)

Ishida T, et al.: Clin Cancer Res 2004;10:5494-500 CCR4 expression was an unfavorable factor of PTCL-U. A B 100 100 CXCR3+ PTCL (n = 18) All PTCL, unspecified cases 80 80 (n = 50) CXCR3- PTCL (n = 32) 60 60 Overall survival (%) Median survival: 7.7 months. Overall survival (%) 40 40 20 20 5 10 5 10 p = 0.02 years C 100 CCR4+ PTCL (n = 19) 80 60 CCR4- PTCL (n = 31) Ishida T, et al.: Clin Cancer Res 2004;10:5494-500 Overall survival (%) PTCL, unspecifiedにおけるケモカインレセプター発現様式と、臨床病態との相関を詳細に検討した。解析全50症例の予後曲線を示す(左上)。50% 生存は7.7ヶ月と、これまでの報告同様極めて不良である。この生存曲線は以前に我々が解析したATLL102症例の生存曲線とほぼ同一であることはT細胞性腫瘍を考える上で示唆的である。尚、これらのPTCL, unspecified 症例はCHOP及びCHOPに準じた治療を受けた、ほぼ均一なコホートである。 次にCCR4の発現様式と生存の解析を行った(右上)。その結果CCR4陽性症例は有意に予後不良であることが明らかになった。 CXCR3陽性群が、PTCLUのなかで予後良好群を形成することは、 T細胞腫瘍の中で比較的緩徐な経過をたどるAILTがCXCR3陽性パ ターンを示すことと併せて考えると、理解が容易である。 40 20 5 10 p = 0.02

Ishida T, et al.: Clin Cancer Res 2004;10:5494-500 Chemokine Receptors & PTCL 1) Chemokine receptors may be useful not only for further characterization of T- and NK-cell lymphomas, but also in predicting clinical outcomes. 2) Most ATL cases (88%) are CCR4-positive by immunostaining. CCR4 expression is an unfavorable prognostic factor in ATL and PTCL-U. ここまでをまとめる。 １、ケモカインレセプターの発現様式によりT細胞性腫瘍を考えると、そのnormal counterpart を反映したで合理的な分類が可能であり、また臨床経過の予測も可能である。 ２、PTCL、unspecified におけるCCR4の発現はATLL同様、独立した有意な予後不良因子であった。 ３、CCR4陽性のATLL、PTCL,unspecified はともにFoxP3の発現を認めた。このことはこれらの腫瘍がTreg由来であることを示唆するのみならず、これらの腫瘍の著しい免疫不全状態を説明しうる事実である。 Ishida T, et al.: Clin Cancer Res 2004;10:5494-500

Phase I Study of an ADCC-Enhanced, Humanized Anti-CCR4 Antibody (KW-0761) in Patients with CCR4-Positive Peripheral T-Cell Malignancies Pre-clinical studies of KW-0761 showed promising results for its clinical application to T-cell malignancies, especially to ATL. Patient enrolment will be initiated very soon in Japan.

Phase I/II Study of Concurrent Chemoradiotherapy for Untreated Localized Nasal NK/T-NHL (JCOG0211-DI) ~ 36 patients / 3 years Study design: phase I/II study Endpoints Phase I primary endpoint; toxicity Phase II primary endpoint; 2y-OS 　　　　　 secondary endpoints; %CR, PFS, etc. Based on these rationale, this clinical trial was designed. Up to 36 patients will be enrolled for 3 years. The study design is a phase I/II study. Primary endpoint in phase I is the evaluation of toxicity. In the phase II portion, primary endpoint is a 2-year overall survival, and secondary endpoints are CR rate, progression-free survival, and toxicity. Most pts with nasal NK/T-cell lymphoma have localized disease; however, a standard therapy for localized DLBCL such as CHOP followed by RT is unsuccessful in a large fraction of pts.

Hematology Division, National Cancer Center Treatment Schemes of JCOG0211-DI Initiate high-dose IF-RT and DeVIC simultaneously REGISTRATION *50 - 50.4 Gy (1.8 - 2.0 Gy / fx.) CT based 2 or 3 dimensional RT planning Clinical target volume: entire nasal cavities, nasopharynx, and the volume + 2 cm to gross tumor 7 days w 1　　　2　　　3　　　4　　　5　　　6　　　7　　　8　　　9 10 RT* DeVIC ↓　　　　　　　　　　↓ 　　　　 ↓ CBDCA d1 IV ETP d1-3 IV IFM d1-3 IV DEX d1-3 IV The doses of IF-RT and DEX (40 mg/day) were fixed. This slide shows the treatment in this clinical trial. We initiated involved field radiotherapy and DeVIC chemotherapy simultaneously within 7 days after registration. The protocol requested the CT based 2 or 3 dimensional radiation planning. Clinical target volume was entire nasal cavities, nasopharynx, and the volume with appropriate margin to gross tumor. In the phase I portion, we used a standard 3+3 design to evaluate dose-limiting toxicities. The doses of radiotherapy and dexamethasone were fixed. Two dose levels of carboplatin/etoposide/ifosfamide were evaluated: two-third-dose of DeVIC and full dose of DeVIC. Level 1 (2/3 DeVIC) CBDCA 200 mg/m2, ETP 67 mg/m2, IFM 1.0 g/m2 Level 2 (100% DeVIC) CBDCA 300 mg/m2, ETP 100 mg/m2, IFM 1.5 g/m2 Hematology Division, National Cancer Center Yamaguchi M, Tobinai K, et al.: Blood 2005;106:2685a.

Accruals and Treatments in the Phase I Portion Level ID Age /Sex Stage RT (Gy) DeVIC (course) Planned treatment 1 #01 44/M IEA 50 3 completed #02 58/M IEB #03* 45/M IIEB 50.4 2 terminated (PD) #04 61/F IIEA #05 39/M #06 42/M terminated #07 33/F #08 54/F #09 57/F #10 30/F Of all 10 enrolled patients, the planned treatment was completed in eight patients. Off treatment due to disease progression was observed in one patient of Level 1. In this patient, axillary lymph node involvement was detected in the CT scan for radiotherapy treatment planning. At Level 2, the planned treatment was terminated in one patient because of infection and suspicion of PD. *, Axillary lymph node involvement was detected in the CT scan for RT planning. Yamaguchi M, Tobinai K, et al.: Blood 2005;106:2685a.

Assessment of DLTs in JCOG0211-DI ★ Criteria for DLT (NCI-CTC ver 2.0) A Grade 4 leukopenia or neutropenia lasting for 5 days or more B Grade 4 thrombocytopenia C Non-hematologic toxicity of grade 3 or more, except for N/V or mucositis related to radiation DLT Level 1 0 / 3* Level 2 4 / 6　 #06 (stage IB) : Criteria A, B, C (Infection) #07 (stage IIA): Criteria A, C (Infection, Weight loss) #09 (stage IIA): Criteria B, C (Infection) #10 (stage IA) : Criteria C (Keratitis) RD for the phase II This slide shows the assessment of dose limiting toxicities in the phase I portion. Here are the criteria for dose limiting toxicity. At Level 1, one stage II patient who developed PD before evaluation of dose limiting toxicity was excluded. Remaining 3 patients did not develop dose limiting toxicity. At Level 2, four of six patients developed dose limiting toxicity. Thus, we decided to select the Level 1 as the recommended dose for the phase II portion. Yamaguchi M, Tobinai K, et al.: Blood 2005;106:2685a.

Responses in JCOG0211-DI Overall response In-field response CR PD NE Level 1 (n=4) 3 1 4 Level 2 (n=6) 6 We evaluated the efficacy using the International Workshop criteria for NHL. Of all 10 enrolled pts, 7 achieved CR, 2 PD, and 1 not evaluable. Of particular interest is that all 10 pts achieved local control. NE, not evaluable Yamaguchi M, Tobinai K, et al.: Blood 2005;106:2685a.

Hematology Division, National Cancer Center Preliminary Conclusions of JCOG0211-DI Concurrent chemoradiotherapy using MDR-non-related agents and etoposide appears to be a promising treatment strategy for localized nasal NK/T-cell lymphoma. Feasibility and efficacy of Level 1 (2/3 DeVIC) will be further evaluated in the phase II portion. Patient enrolment into the phase II portion will be completed within a few months. This is our conclusion slide. Our results suggest that concurrent chemoradiotherapy using MDR-non-related agents and ETP is a promising treatment strategy for localized nasal NK/T lymphoma. Feasibility and efficacy of Level 1 will be evaluated further in the phase II portion. Hematology Division, National Cancer Center Yamaguchi M, Tobinai K, et al.: Blood 2005;106:2685a.

Acknowledgements JCOG studies for ATL Tsukasaki K, Yamada Y, Fukuda H, Shimoyama M, et al. Allogeneic SCT for ATL Fukushima T, Okamura J, et al. CCR4 expression in ATL & PTCL-U Ishida T, Ueda R, et al. Phase I/II study for nasal NK/T-NHL Yamaguchi M, Oguchi M, et al.