Risk Stratification for High Risk AML

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Risk Stratification for High Risk AML
Yu Wang, MD
Peking University

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Risk Stratification for High Risk AML

  1. 1. risk stratification, prevention and management of leukemia relapse after HSCT Yu Wang Peking University People’s Hospital & Institute of Hematology
  2. 2. Contents 1 • Modified DLI 2 • t(8;21) 3 • Ph+ leukemia
  3. 3. Establishment of Modified DLI G-CSF primed peripheral blood progenitor cells instead of steady donor lymphocyte harvests Short-term CsA/MTX for prevention of DLI-associated GVHD mDLI Huang XJ,et al, Leukemia, 2006,20:365-368 Huang XJ, et al. Hematologica 2007,92:414-417 Huang XJ,et al, Bone Marrow Transplant. 2009;44(5):309-16 Yan CH, et al. clinical transplant. 2012; 26: 868-876
  4. 4. Therapeutic mDLI Multivariate analysis for relapse: Chronic GVHD (P=0.000, OR=5.932) Chemo+ DLI (P=0.037, OR=1.877) Characteristics Chemo (n=32) Chemo + DLI chemo+DLI Relapse chemo P=0.000 (n=50) P Acute GVHD post-intervention (%) 40.6 66.0 0.048 Grade 2 - 4 29.9 62.7 0.032 Grade 3 - 4 16.5 40.3 0.112 Chronic GVHD post-intervention (%) 3.1 44.3 0.000 Extensive 3.1 41.8 0.000 TRM at 1 year post-intervention (%) 0.0 14.0 0.118 P=0.000 DFS Huang XJ, et al. Leukemia 2006, 20: 365 European Journal of Haematology 91 (304–314)
  5. 5. Risk directed mDLI Interventional mDLI Multivariate analysis P OR MRD-negative posttransplant 0.000 0.255 Receiving DLI 0.000 0.269 Multivariate analysis P OR MRD-negative posttransplant 0.001 0.511 Receiving DLI 0.006 0.436 Huang XJ, et al. Blood,2012,119(14):3256-62
  6. 6. Prophylactic mDLI Control66% DLI46% P=0.02 P=0.001 DLI 36% Control 11% Huang XJ ,et al. J Clin Immunol. 2008;28 Huang XJ, et al. J Clin Immunol. 2008;28:276-83; P=0.001 DLI 30.5% Control 11.1% P=0.017 Control 55% DLI 36% Wang Y , et al. Bone Marrow Transplant2012 ;47:1099 Wang Y, et al. Clin Transplant. 2012 ;26:835 OS Relapse ISD HID
  7. 7. Multi-Center Clinical Trials Xinqiao Hospital affiliated to Third Military Medical University Peking University People`s Hospital The First affiliated Hospital of Soochow University The First affiliated Hospital of Zhejiang University Nanfang Hospital Southern Medical University Strategy to improve the clinical results  Significantly decrease GVHD  Did not compromise GVL effect  Improvement on safety of DLI
  8. 8. Contents 1 • Modified DLI 2 • t(8;21) 3 • Ph+ leukemia
  9. 9. Trial Design Low-risk High-risk High-risk Non risk-directed Risk-directed Huang XJ, et al. Blood 2013; 121 4056
  10. 10. Patients Enrollment
  11. 11. Risk stratification treatment improves outcome 0 20 40 60 80 100 100 80 60 40 20 0 risk-stratification(n=69) 82.7% Time(months) Overall Survival(%)
  12. 12. Multivariate analysis Results CIR DFS OS p p p MRD status high- vs. low-risk 0.003 0.002 0.02 Treatment choice risk- vs. non risk-directed 0.026 0.036 0.037 KIT status mutation vs. wild-type 0.049 ns ns • MRD-directed risk-stratification treatment could improve outcome of t(8;21) AML in CR1. • Allo-HSCT benefited high-risk patients and had potential to Huang XJ, et al. Blood 2013; 121 4056 benefit KIT-mutated patients
  13. 13. RUNX1/RUNX1T1-based MRD-monitoring early after allogeneic transplantation rather than c-KIT mutations in adult t(8;21) AML allows further risk stratification Blood. 2014 Jul 31. pii: blood-2014-03-563403 • MRD might be used to further distinguish between t(8;21)patients with low and high risks of relapse after allo-HSCT • the level of MRD in t (8; 21) AML guide post- HSCT therapy in the future
  14. 14. Results Impact of MRD at 1 month after SCT on outcomes CIR p=.02 42.8% <3 log reduction n=7 16.8% MRD positive post SCT p<.001 <3 log reduction n=7 85.7% 44.7% >3 log reduction n=53 LFS p>.05 <3 log reduction n=7 >3 log reduction n=53 <3 log reduction n=7 60.8% 41.7% OS p>.05 >3 log reduction n=53 85.7% 44.7% >3 log reduction n=53 42.8% 16.8% CIR p=.02
  15. 15. Multivariate analysis Results Outcome Hazard ratio (95%Confidence interval) P Relapse Achieving MMR at all the first 3 months yes vs no 0.07(0.02-0.26.) 0.001 Courses to achieve CR 1 vs >1 0.17(0.04-0.64) 0.009 Interventional DLI yes vs no 0.09(0.02-0.43) 0.002 Leukemia free survival Achieving MMR at all the first 3 months yes vs 0.13(0.05-0.34) 0.001 no Courses to achieve CR 1 vs >1 0.36(0.14-0.90) 0.03 Interventional DLI yes vs no 0.20(0.06-0.60) 0.004 • A > 3 log reduction at the first 3 months after HSCT in RUNX1/RUNX1T1 transcripts is highly predicative • Rather than c-KIT, regular MRD monitoring early after HSCT in t (8;21) AML allows further risk identification • MRD monitoring could now be incorporated in clinical trials to evaluate the role of risk directed prophylactic/preemptive therapy after HSCT
  16. 16. • t(8;21)AML is a heterogeneous disease • Allo-HSCT can improve outcome of high-risk t(8;21)AML • Rather than c-KIT, MRD post-HSCT allows further risk stratification MMR Allo-HSCT non-MMR Baseline Diagnosis Lose MMR Ind 1-2 Cons 1 Cons 2 Con 3 Cons 4 Cons 5 Cons 6 Cons 7 Cons 8 KIT-KIT+ Recommendation MRD MRD DLI/CT and might direct further treatment
  17. 17. Contents 1 • Modified DLI 2 • t(8;21) 3 • Ph+ leukemia
  18. 18. Eligibility • (1) ANC >1000/uL w/o G-CSF & PLT>50000 /uL, regardless of BCR-ABL; or • (2) BCR-ABL in BM detectable and increased for 2 consecutive tests, or ≥10-2 after the initial engraftment, although ANC/PLT below the values • (3) tolerate oral imatinib without gut GVHD or life-threatening infection Imatinib was scheduled for 3–12m after HCT, until • BCR-ABL negative ≥ 3 consecutive tests or CMR sustained ≥ 3m Withdrawn, if • grade 3 or 4 toxicity sustained >2w, despite interrupting imatinib
  19. 19. Imatinib improve outcomes Relapse: 10%vs 33% DFS: 81% vs 33% OS: 86% vs 34% FU: 31(2.5-76) vs 25 (4-72)m post-HCT Grade 3–4 AEs: 17.7% Ten (16.1%) terminated IM (<3m)
  20. 20. Individualized intervention guided by BCR-ABL transcript levels after HLA-identical sibling donor HSCT improves HSCT outcomes for patients with CML Huang XJ, et al. Biol Blood Marrow Transplant 2011 17: 649-656 Low-risk: 1 of following  > 2log red from base at +1m & cont to decline  MMoR & stable within +3m & cont to decline  II-IV aG or ext. cG & stable in MMoR within 1y  CMoR within +1 year Intervention priority order in high risk patients 1: IS-W if not so early /no GVHD/CSA pro 2: IM if early and good engraftment 3: mDLI if not so good response to IS-W/IM Pre-HSCT +1m +2m +3m +6m +9m +12m +18m +24m
  21. 21. post-HCT individualized-intervention based on serial monitoring of BCR-ABL transcripts improve outcome Intervention reversed the rising trends of BCR/ABL within 2m -1 0 1 2 3 4 1 .0 0 0 .9 0 0 .8 0 0 .7 0 0 .6 0 0 .5 0 0 .4 0 0 .3 0 0 .2 0 0 .1 0 0 .0 0 BCR/ABL(%) Time s from o n e s e t o f in te rve n t io n (mo n th s ) Intervention: high-risk n=28 • 1/28 stable molecular disease graft failure and 2nd HSCT ,DFS 3y • 25/28 (89%) CMR: median 49d ( 18-232) remained in CMR 1427d(1040-1794 Non- intervention: low-risk n=56 • BCR-ABL to 0: median +4m • 55/56 CMR , FU 1522(1055-1791)d RI 3.9% TRM 3.6% vs 8.9% LFS 89.3% vs 89.1%
  22. 22. Acknowledgements Stem cell collection center Hai-Yin Zheng Hong Xu Qing Zhao Su Wang Department of bone marrow transplant Xiao-Jun Huang Kai-Yan Liu Lan-Ping Xu Xiao-Hui Zhang Huan Chen Wei Han Yu-Hong Chen Feng-Rong Wang Jing-Zhi Wang Yu Wang Chen-Hua Yan Yuan-Yuan Zhang Yu Ji Yu-Qian Sun Laboratory of PUIH Dan Li Ya-Zhen Qin Yan-Rong Liu Yue-Yun Lai
  23. 23. challenges Chinese HSCT face • identifying the underlying mechanisms of well-developed clinical models, such as haplo-HSCT • translational researches of clinical significance (molecular aspects of target therapy for various complications after HSCT), such as: immune tolerance in HLA-mismatched HSCT the distinction between GVHD and GVL the association between infection and chronic immunologic imbalance
  24. 24. need for a FACT-like accreditation program • Standardization of “best practice”: dissemination of techniques from major centers to smaller units • under well-developed registries: role in multi-center clinical trials and data management • Training: talented personnel/inspectors
  25. 25. meaningful international collaborations • Academic technique collaboration • Bench to bed practice: promote the connection between basic research and clinical practice • Training and visit

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