Risk Stratification for High Risk AML
-
Upload
spa718 -
Category
Health & Medicine
-
view
174 -
download
5
description
Transcript of Risk Stratification for High Risk AML
risk stratification, prevention and management of leukemia relapse
after HSCT
Yu WangPeking University People’s Hospital &
Institute of Hematology
Contents
1• Modified DLI
2• t(8;21)
3• Ph+ leukemia
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, 2006,20:365-368Huang XJ, et al. Hematologica 2007,92:414-417Huang XJ,et al, Bone Marrow Transplant. 2009;44(5):309-16Yan CH, et al. clinical transplant. 2012; 26: 868-876
Therapeutic mDLI
Multivariate analysis for relapse:
Chronic GVHD (P=0.000, OR=5.932)
Chemo+ DLI (P=0.037, OR=1.877)
Relapse
chemo+DLI
chemo
P=0.000
Characteristics Chemo (n=32)
Chemo + DLI (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=0.000DFS
Huang XJ, et al. Leukemia 2006, 20: 365 European Journal of Haematology 91 (304–314)
Interventional mDLI
Huang XJ, et al. Blood,2012,119(14):3256-62
Risk directed 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
Prophylactic mDLI
Huang XJ ,et al. J Clin Immunol. 2008;28Huang XJ, et al. J Clin Immunol. 2008;28:276-83;
DLI46%
Control66%
P=0.02
P=0.001
DLI 36%
Control 11%
DLI 30.5%
Control 11.1%
P=0.001
DLI 36%
Control 55%P=0.017
Wang Y , et al. Bone Marrow Transplant2012 ;47:1099Wang Y, et al. Clin Transplant. 2012 ;26:835
Rela
pse
OS
ISD HID
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
Contents
1• Modified DLI
2• t(8;21)
3• Ph+ leukemia
Trial Design
Low-risk
High-risk High-risk
Risk-directed
Non risk-directed
Huang XJ, et al. Blood 2013; 121 4056
Patients Enrollment
Risk stratification treatment improves outcome
0 20 40 60 80 1000
20
40
60
80
100risk-stratification(n=69)
82.7%
Time(months)
Ov
era
ll S
urv
iva
l(%
)
Multivariate analysis
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
Results
Huang XJ, et al. Blood 2013; 121 4056
• 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 benefit KIT-mutated patients
RUNX1/RUNX1T1-based MRD-monitoring early after allogeneic transplantation
rather than c-KIT mutations in adult t(8;21) AMLallows 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
Impact of MRD at 1 month after SCT on outcomes
Results
42.8%
16.8%
85.7%
44.7%
CIR p=.02
>3 log reduction n=53
<3 log reduction n=7
LFS p>.05
>3 log reduction n=53
<3 log reduction n=7
60.8%
41.7%
OS p>.05
>3 log reduction n=53
<3 log reduction n=7 85.7%
44.7%
MRD positive post SCT p<.001
>3 log reduction n=53
<3 log reduction n=742.8%
16.8%
CIR p=.02
Multivariate analysis Results
OutcomeHazard ratio (95%Confidence interval) P
Relapse Achieving MMR at all the first 3 months yes vs
no0.07(0.02-0.26.)
0.001
Courses to achieve CR 1 vs >1 0.17(0.04-0.64) 0.009Interventional DLI yes vs no 0.09(0.02-0.43) 0.002
Leukemia free survivalAchieving MMR at all the first 3 months yes vs
no0.13(0.05-0.34)
0.001
Courses to achieve CR 1 vs >1 0.36(0.14-0.90) 0.03Interventional 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
MMR
Allo-HSCT
non-MMR
Baseline
Lose MMR Diagnosis
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
• 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 and might direct further treatment
Contents
1• Modified DLI
2• t(8;21)
3• Ph+ leukemia
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
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)
Huang XJ, et al. Biol Blood Marrow Transplant 2011 17: 649-656
Individualized intervention guided by BCR-ABL transcript levels after HLA-identical sibling donor HSCT improves HSCT outcomes for patients with CML
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
Intervention reversed the rising trends of BCR/ABL within 2m
43210-1
1.00
0.90
0.80
0.70
0.60
0.50
0.40
0.30
0.20
0.10
0.00
BC
R/A
BL(%
)
Times from oneset of intervention(months)
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(1040-1794Non- 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%
post-HCT individualized-intervention based on serial monitoring of BCR-ABL transcripts improve outcome
Acknowledgements
Stem cell collection centerHai-Yin ZhengHong XuQing ZhaoSu Wang
Department of bone marrow transplant Xiao-Jun HuangKai-Yan Liu Lan-Ping XuXiao-Hui ZhangHuan Chen Wei HanYu-Hong Chen Feng-Rong Wang Jing-Zhi Wang Yu WangChen-Hua Yan Yuan-Yuan ZhangYu Ji Yu-Qian Sun
Laboratory of PUIHDan LiYa-Zhen QinYan-Rong LiuYue-Yun Lai
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
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
meaningful international collaborations
• Academic technique collaboration
• Bench to bed practice: promote the connection between basic research and clinical practice
• Training and visit