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