Peking University People’s Hospital & Institute of Hematology
Beijing Key Laboratory of HSCT, Beijing, P.R.China
Xiao-Jun Huang M.D
Donor Lymphocyte Infusion in Patients with
Hematological Malignancies after Transplantation:
Past, Present and Future

DLI is the most effective methods for relapse
Kolb HJ, et al. Blood,1995,86:2041-50
Schmid, et al. J Clin Oncol,2007,25:4938-45
Background
Patients receiving DLI (n=228)
Patients not receiving DLI (n=171)
P＜0.0001

Limitation of traditional DLI
 High occurrence of acute GVHD (49-91%)
 Pancytopenia
 Less effective for acute leukemia
 Can not be used successfully for prophylaxis
of relapse after allo-HSCT
Kolb HJ, et al. Blood,1995,86:2041-50
Schmid, et al. J Clin Oncol,2007,25:4938-45
Deol A, et al. Cancer Treatment Reviews,2010,36:528
Background

New strategies for DLI
 Count control of infused lymphocyte
 Infusion of allo-depleted donor T cells
 Infusion of mHAg-specific CTLs
 Infusion of in vivo G-CSF primed lymphocyte
Kolb HJ, et al. Blood,2008,112:4371-4383
Cicei F, et al. Lancet Oncol,2009,10:489-500
Deol A, et al. Cancer Treatment Reviews,2010,36:528
Huang XJ. et al. Blood Rev. 2013 Jan;27(1):55-62.
Background

Effects of G-CSF on immune and
hematopoietic cells in healthy donors
Background
HuangXJ, et al. Clin Transplant 2011: 25: 13–23

Modified Donor Lymphocyte Infusion(mDLI)
Huang XJ, et al. Haematologica. 2007 Mar;92(3):414-7.
Huang XJ, et al. Bone Marrow Transplant. 2009,44(5)
Huang XJ, et al. BBMT. 2011 ;17(2):197-204
mDLI Safety
G-CSF mobilized PB
Short course of
Immunosuppressive Agents
Modified
DLI
Advantage of mDLI
⑴ Safety：Lower aGVHD rate
⑵ Feasibility: Keeping GVL Effect
mDLI Feasibility
Background

Short-term MTX/CSA prophylaxis reduces
incidence of GVHD
Huang XJ, et al, Leukemia, 2006,20:365-368
Huang XJ, et al. Haematologica 2007,92:414-417
Huang XJ, et al, Bone Marrow Transplant. 2009;44(5):309-16
Background
49.5%
31.6%
14.4%
9.3%
Matched-DLI Haplo-DLI

mDLI for the treatment of leukemia relapse after
unmanipulated Haplo-HSCT
Retrospective study (n=20)
Patient charactersitics
Male/Female: 15/5
Median age: 23 (6-50) years
Diagnosis: AML (7 cases), ALL (10 cases), and CML (3 cases)
Transplant protocol:
unmanipulated HBMT using modified Bu/Cy+ATG conditioning
regimens
Follow-up: 1118 (754-1468) days after transplant and 808 (627-
1388) days after DLI
Huang, et al. Haematologica,2007,92(3):414-417
1. Therapeutic mDLI

Huang, et al. Haematologica,2007,92(3):414-417
Results
Median counts of MNCs in PBPCs
1.55 (0.8-11.02) ×108/kg
Median counts of CD3+ cells in PBPCs
0.61 (0.23-4.56) ×108/kg
Grades III-IV acute GVHD 30%
Cumulative incidence of cGVHD 64%
Two-year probability of LFS 40%
Our results suggest that mDLI is a potentially effective
therapeutic option for patients who relapsed after
unmanipulated haploidentical HSCT.
1. Therapeutic mDLI

mDLI for the treatment of leukemia relapse after
unmanipulated HSCT—Update data
Leukemia patients
relapsed after HSCT
(n=84)
Chemotherapy alone
(n=34)
Chemotherapy plus DLI
(n=50)
No differences in patient
characteristics, except for patients in
chemotherapy plus DLI group had a higher
number of BM blast than chemotherapy
group.
Huang, et al. PUIH, unpublished data
1. Therapeutic mDLI

A B
C D
Chemotherapy + DLI
Chemotherapy alone
P=0.016 P=0.000
P=0.000
P=0.000
2-4 acute GVHD Chronic GVHD
Relapse Leukemia free survival
Huang, et al. PUIH, unpublished data
1. Therapeutic mDLI

Conclusion of Part one
1. mDLI was a potentially effective therapeutic
option for patients who relapsed after HSCT
2. Chemotherapy plus DLI is superior to
chemotherapy alone for treatment of patients
who relapsed after transplantation
Huang XJ, et al, Leukemia, 2006,20:365-368
Huang XJ, et al. Haematologica 2007,92:414-417
Huang XJ, et al, Bone Marrow Transplant. 2009;44(5):309-16
Huang XJ, et al. PUIH, unpublished data
1. Therapeutic mDLI

2.Prophylactic DLI
Relapse prevention using mDLI after HLA-identical transplant
A multi-center study
Wang Y, Huang XJ, et al. Clin Transplant, 2012 DOI: 10.1111/j.13990012.2012.01626.x
Retrospective study (n=123)
Patient characteristics
Male/Female: 88/35
Median age: 37 (range, 11-56) years
Diagnosis: AML (86 cases), ALL (37 cases
Transplant protocol:
HLA-identical sibling transplant using modified Bu/Cy
conditioning regimens
Follow-up: As of December 31, 2010

P=0.35
P=0.021
Patients who received prophylactic DLI had a higher
incidence of chronic GVHD
2.Prophylactic DLI
Wang Y, Huang XJ, et al. Clin Transplant, 2012 DOI: 10.1111/j.13990012.2012.01626.x

Prophylactic mDLI significantly decrease relapse rate and
increase the survival of patients with advanced-stage
66%
46%
P=0.02
P=0.001
36%
11%
2.Prophylactic DLI
Wang Y, Huang XJ, et al. Clin Transplant, 2012 DOI: 10.1111/j.13990012.2012.01626.x

mDLI for the prophylaxis of relapse after Haplo-HSCT in
patients with advance leukemia—Risk-factor analysis
Retrospective study (n=88)
Patient characteristics
Male/Female: 53/35
Median age: 30 (range, 8-57) years
Diagnosis: AML (54 cases), ALL (34 cases）
Transplant protocol:
unmanipulated HBMT using modified Bu/Cy+ATG conditioning
regimens
Follow-up: A median time of 248 (34-2777) days after
transplantation
Wang Y, Huang XJ, et al. BMT, 2012.213
2.Prophylactic DLI

Our results suggest that higher OS was associated with use of
prophylactic GPBSCI, AML and female sex in patients who underwent
umanipulated HBMT
Wang Y, Huang XJ, et al. BMT, 2012.213
2.Prophylactic DLI

Conclusion of Part Two
Huang, et al. J Clin Immunol,2008,28:276-283
Wang Y, Huang XJ, et al. BMT, doi:10.1038/bmt.2012.213
 Prophylactic mDLI can significantly decrease the
relapse rate and increase the survival of patients
with advanced stage acute leukemia
 It can be recommended as a routine therapy choice
after either HLA-identical sibling or Haplo-HSCT
2.Prophylactic DLI

Therapeutic
Prophylactic
High-risk
mDLI
Decrease relapse
Improve survival
Patients with Leukemia
Standard-risk
MRD(-) MRD(+
)
Prophylactic mDLI ?
Decrease
relapse ?
?
Hypothesis
?
?
3. Risk directed mDLI

The levels of WT1 could predict relapse of
acute leukemia
Zhao XS, et al. Ann Hematol. 2012;91:183-192.
Zhao XS, et al. BMT. 2012;47:499-507
3. Risk directed mDLI

Reduce relapse and improve survival?
Our objects- reduce relapse?
Monitoring of MRD
Risk-stratification based on MRD state
Intervention with DLI or IL-2
3. Risk directed mDLI

Patients Subgroups
814 patients
MRD (-): 709 patients (Group A)
MRD (+): 105 patients
IL-2: 49 patients (Group B)
DLI: 56 patients (Group C)
Huang XJ, et al. Blood,2012,119(14):3256-62
3. Risk directed mDLI

Relapse
Total: 22.0% (95% CI 18.4-25.6%)
Group A: 18.1% (95% CI 14.6-21.6%)
Group B: 64.4%(95% CI 44.8-84.0%)
Group C 27.8% (95% CI 12.1-43.5%)
Yan CH, Huang XJ, et al. Blood,2012,119(14):3256-62
3. Risk directed mDLI

Risk factors of relapse
Univariate analysis P
Disease type 0.016
Remission state 0.001
MRD-state posttransplant 0.001
Intervention for MRD 0.001
Multivariate analysis P OR
MRD-negative post-transplant 0.000 0.255
Receiving DLI 0.000 0.269
Huang XJ, et al. Blood,2012,119(14):3256-62
3. Risk directed mDLI

GVHD and TRM
Group A:
Acute GvHD of any grade posttransplant: 30.2%
2-4 acute GvHD: 15.2%
3-4 acute GvHD: 4.9%.
Chronic GvHD posttransplants: 38.8%
Extensive chronic GvHD posttransplants: 32.9%
Variable MRD- negative MRD- positive P*
MRD-positive
P#
IL-2 DLI
Acute GvHD (%) post-intervention 10.2 30.8 0.017
≥Grade-2 8.2 27.9 0.017
≥Grade-3 4.1 8.4 0.471
Chronic GvHD (%) post-intervention 37.3 42.9 0.982
Extensive chronic GvHD 30.5 34.2 0.858
Incidence of TRM at 3 years post-HSCT
(%)
19.7 12.7 0.08 11.4 14.4 0.897
Huang XJ, et al. Blood,2012,119(14):3256-62
3. Risk directed mDLI

Disease-free survival
Huang XJ, et al. Blood,2012,119(14):3256-62
3. Risk directed mDLI

Risk factors of DFS
Univariate analysis P
Disease type 0.017
Remission state 0.002
MRD-state posttransplant 0.003
Intervention for MRD 0.005
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
3. Risk directed mDLI

Overall survival
Huang XJ, et al. Blood,2012,119(14):3256-62
3. Risk directed mDLI

Risk factors of OS
Univariate analysis P
Disease type 0.025
Remission state 0.002
MRD-state posttransplant 0.003
Intervention for MRD 0.001
Multivariate analysis P OR
MRD-negative post transplant 0.007 0.644
Receiving DLI 0.002 0.553
Huang XJ, et al. Blood,2012,119(14):3256-62
3. Risk directed mDLI

Conclusion of Part Three
Risk stratification-directed modified DLI
could reduce relapse and improve survival of
patients with standard risk acute leukemia
patients after HSCT
Huang XJ, et al. Ann Hematol. 2012;91:183-192.
Huang XJ, et al. BMT. 2012;47:499-507
Huang XJ, et al. Blood,2012,119(14):3256-62
3. Risk directed mDLI

Future of DLI
 G-CSF-mobilized peripheral blood progenitor cell,
 in vitro generated donor T cells against leukemia-antigens,
 Positive selected T cells, NK cells,
 Suicide gene-transduced donor T cells
Which graft for DLI is better ?
What is the optimal dose ?
What is the optimal schedule to maintain
GVL effect?
Huang XJ. et al. Blood Rev. 2013 Jan;27(1):55-62.

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
Dai-Hong Liu Lan-Ping Xu
Huan Chen Wei Han
Xiao-Hui Zhang
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