費城染色體陽性急性淋巴性血癌之治療進展 (如果太過次專，請當成聽故事) 費城染色體陽性急性淋巴性血癌之治療進展 (如果太過次專，請當成聽故事) 鄭兆能 成大小兒血液腫瘤科

Survival of Childhood ALL by Treatment Era at St. Jude 94% ± 1% XV, XVI (n=754) 2000-current 84% ± 2% XIIIA,XIIIB,XIV (n=465) 1991-1999 81% ± 2% XI, XII (n=546) 1984-1991 74% ± 2% X (n=428) 1979-1983 48% ± 2% V-IX (n=825) 1967-1979 21% ± 4% I-IV (n=90) 1962-1966

2013 Lancet

EFS According to Genotype and Phenotype Pui et al. Lancet 2008;371:1030-43.

Ph(+)ALL 2005 前 悲慘的過去

Age, Initial WBC, Early response

Treatment outcome 1986-1996 326 pts, < 20 y/o Multi-centers, different protocols 7yr EFS:25%, OS:36% Good risk factors: EFS~40% Lower initial WBC Younger age Good early response Matched Sibling Donor HSCT  better than C/T Arico M, NEJM 2000

Treatment outcome 1995-2005 (Without TKI) 610 pts, < 18 y/o Multi-centers, different protocols CR rate: 89% 7yr EFS:32%, OS:45% (improved vs NEJM 2000 EFS: 25%, OS: 36%) Good risk factors: the same Matched Sibling Donor HSCT = MUD HSCT (EFS: 43.5%, OS:54.0%) > C/T Arico M, JCO 2010

Gleevec (Tyrosine Kinase Inhibitor) BULLETS for Ph(+)

Imatinib + C/T for Ped Ph+ALL – COG AALL0031(USA) Between 2002 and 2006 (COG AALL0031) Ph+ ALL (N=93) Conventional induction (without TKI) If remission  entering AALL0031 (柿子先挑好的吃) Not randomized: 由主治醫師決定是否 HSCT 剛開始還不知道如何搭配化療 -- 5th cohort (N=50) – continuous IM after induction --- the largest IM exposure

Chemotherapy Backbone Example: TPOG-ALL-2013 MRD detection Time point Induction Day 15 Post Induction (Day 35) Continuation Week 7 (1st intensification) Continuation Week 17 (2nd intensification) Induction Consolidation Continuation

Outcome of COG AALL0031 Cohort 5 (the best outcome) The largest IM exposure Continuation: 340mg/m2/day since consolidation phase to maintenance 4th cycle 2-week on/2-week off schedule since 5th maintenance cycle to end of therapy (total 12 cycles x 8 weeks/cycle) Schultz KR, JCO 2009

2009 看見曙光 似乎可以不用移植 化療 + 標靶治療 (我不喜歡移植)

Long-Term Outcome of AALL0031 trial

Long-Term Outcome MRD 還是重要，但是TKI把結果拉近

先只做化療+TKI的病人復發後 20/30 (67%) attained to CR2 85% duration for > 3 months Same as historical control IM exposure - no impact on failure to CR2 11/17 BMT rescue 化療+TKI第一線也不怕 ~ TKI no negative impact on outcome of BMT in CML ~ ~ TKI no negative impact on achievement of CR2 ~

Conclusion of COG AALL0031 Tolerable with C/T+IM No advantage of 1st CR HSCT Treatment paradigm shift TKI minimize the value of MRD Additional cytogenetic changes  poor Schultz KR, JCO 2009 Schultz KR, Leukemia 2014

Imatinib for Ped Ph+ALL – EsPhALL (歐洲) 2 Imatinib for Ped Ph+ALL – EsPhALL (歐洲) 2004 and 2009 (被前一篇提早結束) Conventional induction (without TKI) 108 good risk and 70 poor risk according to early response Randomized to receive Imatinib or not in good risk group (early termination) All receive Imatinib in poor risk group 移植與否看VS。當時醫療環境CR1移植

Germany BFM Chemotherapy Backbone (比 COG 弱) Imatinib 使用時段

> 75% of patients received HSCT EsPhALL – 大部分病人還是HSCT > 75% of patients received HSCT

Outcome of Good Risk Group 雖然大部分病人都移植，移植前有使用 TKI，成果還是比較好 (MRD的概念)

EsPhALL – 只化療+TKI還是不好 Only IM + C/T  relapse rate still high 4/9 relapse in good-risk 7/11 relapse in poor-risk EsPhALL vs AALL0031 IM exposure day less than AALL0031 (126 days vs. 616 days) Less intensive C/T than AALL0031

至此，我的想法 Ph(+) ALL 不要移植的條件 天時：Good initial presentation factors (low WBC, no additional cytogenetic change, young age) 地利：Continuous TKI exposure + Intensive chemotherapy backbone 人和：Bcr-Abl qPCR negative (CMR)

HyperCVAD + Imatinib Adult Adult Ph(+) ALL still poor HSCT DFS OS censored for HSCT OS Adult Ph(+) ALL still poor HSCT

3 2ndG TKI - Dasatinib

2012 SIOP Preliminary report

COG AALL0031 vs AALL0622 COG AALL0622: 最終結果尚未發表

Imatinib vs Dasatinib 本人的看法： No comparative study till now Dasatinib: less tolerable but CNS penetration Wait for AALL0622 final report 本人的看法： If prepare for HSCT in CR1,  Imatinib enough But, if not suitable for HSCT or prefer CT only  Dasatinib

HyperCVAD + Dasatinib Adult N=72, HSCT: 12 HyperCVAD+Dasatinib > HSCT (> 40 y/o)

4 New trial: COG AALL1122 Dasatinib since induction Day 15 Less intensive chemotherapy backbone than AALL0031 (EsPhALL) HSCT only in selection patients ~~ Ongoing ~~

5 3rdG TKI - Ponatinib Adult No Ped Data Adult patients – HyperCVAD + Ponatinib MD Anderson Cancer Center

Adult HyperCVAD + Ponatinib N=37, HSCT=9

Ponatinib vs Dasatinib Adult Ponatinib vs Dasatinib Propensity score matching (傾向分數配對) 研究法(N:41, HSCT: 8)比較第二代與第三代 + HyperCVAD 化療

HyperCVAD+TKI (1st -3rdG) without HSCT Adult HyperCVAD+TKI (1st -3rdG) without HSCT Achievement of CMR at 3 months ~ excellent long-term outcome without HSCT

目前的治療策略考慮 Optimal Induction Therapy Best TKI ? Less intensive induction with maximal TKI Best TKI ? HSCT or not ? 只要化療，最好第三代 Surrogate marker: MRD, which time point ? Protocol oriented (HyperCVAD  CMR at 3M) 何時能確定只化療不夠 -->Transplant Post-transplant TKI, which TKI ?

成大小兒科提供給 Ph(+)ALL 一個不用移植的機會 N=12 Persistent MRD (+)  HSCT, MRD(-): 1 Finish C/T, OFF TKI, MRD(-): 3 Finish C/T, on TKI, MRD(-): 3 Finish C/T, on TKI, MRD(+): 1 Continuation C/T, MRD(-), on TKI: 1 Continuation C/T, persistent MRD (+): 1 Newly diagnosed Ph(+) ALL in 2017.3: 1 Relapse in 2017.4: 1

Ped. ALL re-classfication Past: Low risk group ALL Standard risk group High risk group Including Ph(+) Future: LR SR Ph(-) ALL HR ALL SR C/T + TKI Ph(+) ALL (inc. Ph-like) Factors ?? HR HSCT

謝謝聆聽 敬請指教