2015…2018. T-Cell Lymphomas; We are close to the finaliza?on Bologna Royal Hotel Carlton May 7-9, 2018 How I treat ATL in Standard Treatment in front-line and prognostic index Kunihiro Tsukasaki, M.D., Ph.D. Department of Hematology International Medical Center, Saitama Medical University
Disclosures of Kunihiro Tsukasaki
Adult T-cell leukemia-lymphoma （ATL） ・ Mature T-cell malignancy of Th2/Treg origin associated with HTLV-1 ・ Several tens millions of HTLV-1 carriers in the world, endemic in south-west coast of Japan, mid-and south-America and Africa ・ About 5% of HTLV-1 carriers develop ATL during their life time ・ Clinical feature is diverse and treatment strategy is based on subtype classification
Epidemiology of ATL in Japan and USA � Rapid aging of patients with ATL; Consecutive nation-wide surveys in Japan No. of deaths from ATL 2001–2010 in Japan from vital statistics in the Portal Site of Official Statistics of Japan (e-Stat; accessed April 8, 2012). � APC; annual percent change Increase in incidence of ATL in non-endemic area of Japan and USA � Cancer Sci. 2017 Cancer Sci. 2012 Nosaka K, Tsukasaki K, et al � Chihara D, et al �
International peripheral T-cell and NK/T-cell lymphoma study: pathology findings and clinical outcomes on 1314 cases. International T-Cell Lymphoma Project: J Clin Oncol 、 2008
31 Consecutive studies by JCOG-LSG 1978 1980 1985 1990 1995 2000 2005 2010 C-MOPP/ABVd(II) ABVd(II) ABV/RT(II) Int-PET(II) HL JCOG8905 JCOG9305 JCOG9705 JCOG1305 LSG5(II) SCT(II) SCT(II) ALL/LBL JCOG8702 JCOG9004 JCOG9402 LSG1; VEPA(II) LSG9 vs mLSG4(III) DI-CHOP(rII) DLBCL R-CHOP(II/III) JCOG9002 JCOG0601 JCOG7801 JCOG9505 Agg-NHL VEPA vs VEPAM(III) LSG4(II) Up front AHSCT(II) CHOP vs Bi-CHOP(III) DLBCL ASCT(rII) JCOG8101 JCOG9506 JCOG9809 JCOG0908 JCOG8701 Aged(II) CHOP(II) MCL ASCT(II) JCOG9203 JCOG9508 JCOG0406 Ind-B-NHL R-CHOP v R-Bi-CHOP(III) JCOG0203 LSG-11(II) LSG15(II) LSG15 vs Bi-CHOP(III) Allo SCT(II) JCOG0907 JCOG9109 JCOG9303 JCOG9801 ATL IFN/AZD vs WW(III) JCOG1111 RT/DeVIC(I/II) NK/T-NHL JCOG0211 COP-MP(II) LSG13 vs mLSG8(III) Maint-IFN vs PSL(III) BD vs TD(rII) X JCOG8906 JCOG9301 JCOG0112 JCOG0904 Myeloma MPB(rII) JCOG1105
Comparison of CR rates by disease and chemotherapy in i initial LSG trials for aggressive NHL B-lymphoma PNTL ATL Total 7801(VEPA) 65/101 17/30 7/42 95/182 (64%) (57%) (17%) (52%) 8101(VEPAM) 33/40 5/9 11/30 51/82 (83%) (56%) (37%) (62%) 8701(LSG4) 123/151 28/42 18/43 193/267 (82%) (67%) (42%) (72%) ATL; adult T-cell leukemia-lymphoma PNTL; peripheral non-ATL T-lymphoma Shimoyama et al. JCO 5: 128 and JCO 6:1088,1988
Nationwide survey for ATL by JCOG-LSG: 1984-1987 (n=854) • Multi-variate analysis revealed 5 independent prognostic factors (LSG, Leuk Res, 1991) ; – PS, Age>60, LDH, Ca and No. of Total Involved Lesions • Establishment of ATL subtypes based on natural history, clinical features and prognostic factors Shimoyama M, et al. B J Haematol, 1991
Consecutive Trials for ATL by JCOG-LSG
t P- Ⅲ study of VCAP-AMP-VECP vs. CHOP-14 in aggressive ATL:JCOG9801 Aggressive ATL, age<70 acute-, lymphoma- or unfavorable chronic Randomization Stratification; Institution, PS (0,1/2-4) CHOP-14 VCAP → AMP → VECP x 8 cycles x 6 cycles with G-CSF and IT x with G-CSF and IT x 3 of Ara-C, MTX and 3 of Ara-C, MTX and PSL PSL VCAP-AMP-VECP is a more effective regimen at the expense of higher toxicities, providing the basis for future investigations in the treatment of ATL Tsukasaki K, et al. J Clin Oncol, 2007
Fukushima et al. 52nd ASH Annual Meeting, 2011. JCOG0902A : Characterization of Long- stepwise Cox regression Term Survivors and a Predictive Model Prognostic factor HR P value for Aggressive ATL (95%CI) Objective Ca ≧ 5.5mEq/L 1.688 0.007 1. Characterize long-term survivors (vs <5.5mEq/L) (1.156-2.466) 2. Develop a prognostic model (JCOG-PI) PS: 2, 3, 4 1.493 0.018 stepwise Cox regression analysis (vs 0, 1) (1.073-2.078) and external validation 1. 0 Patients Ca<5.5mEq/L and PS 0, 1 C a<5. 5m Eq/l and PS 0, 1 ( n=112) 0. 9 Overall survival Ca ≧ 5.5mEq/L and/or PS 2,3,4 all surivors test C a>=5. 5m Eq/l and/or PS, 2 t o 4 ( n=81) 0. 8 0. 7 OS according to risk groups over 5-y over 2-y sample val 0. 6 vi Sur by prognostic model JCOG9109 62 8 5 40 0. 5 l al 0. 4 MST=14.3 months JCOG9303 96 30 17 57 O ver 0. 3 HR=1.926 [95% CI, 1.423-2.606] JCOG9801 118 29 15 96 0. 2 MST=7.9 months Total 276 37 67 193 0. 1 0. 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Validation sample: 127 Year s 1. 0 gr oup1=1 ( n=58) 0. 9 Cumulative mortality rate gr oup1=2 ( n=69) Overall survival 0. 8 0. 7 External validation 0. 6 割 acute 合 0. 5 HR=2.138 [95% CI, 1.414-3.233] chronic 0. 4 lymphoma MST=17.8 months 0. 3 0. 2 MST=6.3 months 0. 1 0. 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Years after registration Years after registration 全生存期間（ 起算日： 初回治療日）
ATL-PI for acute-/lymphoma-type ATL from Japan 90% 51% Katsuya H, Tsukasaki K, et al, JCO 2012
Overall Schema for Treatment of ATL: Guideline 2013 by Japanese Society of Hematology ATL Smoldering Acute Lymphoma Chronic Unfavorable Favorable Watchful Waiting Intensive Chemotherapy PD SD, PD CR, PR • Chemo or molecular target drug 50 ~ 70 ≤ 55 • Allo-HSCT • Palliative Radiotherapy • Best supportive care Myeloablative allo-HSCT non-myeloablative allo-HSCT
Long term follow-up of indolent ATL Prognosis of ATL in relation with watchful waiting policy to clinical subtypes and treatment modalities Takasaki, Tsukasaki, et.al. Blood 2010 ・Poor prognosis of indolent ATL after long follow-up ・Improved prognosis of aggressive ATL after both chemotherapy and allo-HSCT yr Fukushima, et al．2006 Fukushima, et al．2006 Takasaki, et.al. 2007 Allo-HSCT for aggressive ATL Registry data of 386 pts Consecutive trials of chemotherapy for aggressive ATL yr Shimoyama, et al. 2006, Hishizawa M et.al. Blood 2010
Interferon/Zidobudine for ATL － Retrospective survey － Chronic and smoldering Lymphoma Acute JCOG9801 Bazarbachi, A, et al, J Clin Oncol 2010 15
Interferon/Zidobudine for ATL － Retrospective survey － Chronic and smoldering Lymphoma Acute indolent ATL with watchful waiting Bazarbachi, A, et al, J Clin Oncol 2010
Recommended strategy for the treatment of ATL Smoldering- or favorable chronic-type ATL • Symptomatic patients (skin lesions, opportunistic infections, etc): Consider AZT/IFN or Watch and Wait • Asymptomatic patients: Consider Watch and Wait Unfavorable chronic- or acute-type ATL • If outside clinical trials, check prognostic factors (including clinical and molecular factors if possible ） : – Good prognostic factors: consider chemotherapy (VCAP-AMP- VECP evaluated by a phase III trial against CHOP-14) or AZT/ IFN (evaluated by a meta-analysis on retrospective studies) – Poor prognostic factors: consider chemotherapy followed by conventional or reduced intensity allo-HSCT (evaluated by retrospective and prospective Japanese studies, respectively). – Poor response to initial therapy: Consider conventional or reduced intensity allo-HSCT International ATL Consensus Report; Tsukasaki, Ermine, Bazarbacchi, et al; J Clin Oncol, 2009
Ongoing ATL trials by JCOG-LSG allo-HSCT for aggressive ATL IFN α /AZT vs Watchful waiting (confirmatory P-II study) for indolent ATL (P-III study) Untreated aggressive ATL Untreated indolent ATL less than 65 years old less than 75 years old Induction chemotherapy randomization with VCAP/AMP/VECP Sibling donor + Sibling donor - IFN α 6 mu Watchful waiting AZT 600mg Continuous Chemo Search for Bank donor Allo-PBSCT / BMT RIST Bank donor + Donor - Continue until progressive disease Chemotherapy Allo-BMT RIST
New agents are approved and under clinical development in ATL Compound MOA Target Phase Mogamulizmab Anti-CCR4 Ab CCR4+ R ATL Approved Lenalidomide Immune modulatory R/R ATL Approved DS3201 EZH 1and 2 inhibitor R/R ATL I Nivolumab Anti-PD 1 R/R ATL II Nucleoside Reverse Transcriptase Abacavir R/R ATL II Inhibitor NY-ESO-1 T-cell receptor gene ATL with NY-ESO Ia/Ib Vaccine therapy positive Histone deacetylase Chydamide R/R ATL II inhibitor (HDACI) Tax-DC Modulation of Tax ATL Ia/Ib vaccine specific CTLs
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