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. 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. 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
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. 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
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. • 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
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. 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. 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. 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. 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. 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. 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. meaningful international collaborations
• Academic technique collaboration
• Bench to bed practice: promote the connection
between basic research and clinical practice
• Training and visit