Peking University Peoples Hospital & Institute of Hematology Beijing Key Laboratory of HSCT, Beijing, P.R.ChinaXiao-Jun Huang M.DDonor Lymphocyte Infusion in Patients with Hematological Malignancies after Transplantation: Past, Present and FutureDLI is the most effective methods for relapseKolb HJ, et al. Blood,1995,86:2041-50Schmid, et al. J Clin Oncol,2007,25:4938-45Background

Patients receiving DLI (n=228)Patients not receiving DLI (n=171)P0.0001

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-HSCTKolb HJ, et al. Blood,1995,86:2041-50Schmid, et al. J Clin Oncol,2007,25:4938-45Deol A, et al. Cancer Treatment Reviews,2010,36:528Background

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,2008,112:4371-4383Cicei F, et al. Lancet Oncol,2009,10:489-500Deol A, et al. Cancer Treatment Reviews,2010,36:528Huang XJ. et al. Blood Rev. 2013 Jan;27(1):55-62.Background

Effects of G-CSF on immune and hematopoietic cells in healthy donorsBackgroundHuangXJ, et al. Clin Transplant 2011: 25: 1323

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 SafetyG-CSF mobilized PBShort course of Immunosuppressive Agents ModifiedDLI Advantage of mDLI SafetyLower aGVHD rate Feasibility: Keeping GVL Effect

mDLI Feasibility

Background

Short-term MTX/CSA prophylaxis reduces incidence of GVHDHuang XJ, et al, Leukemia, 2006,20:365-368Huang XJ, et al. Haematologica 2007,92:414-417Huang XJ, et al, Bone Marrow Transplant. 2009;44(5):309-16

Background

49.5%31.6%14.4%9.3%Matched-DLIHaplo-DLImDLI for the treatment of leukemia relapse after unmanipulated Haplo-HSCTRetrospective 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 DLIHuang, et al. Haematologica,2007,92(3):414-4171. Therapeutic mDLI

Huang, et al. Haematologica,2007,92(3):414-417

ResultsMedian counts of MNCs in PBPCs 1.55 (0.8-11.02) 108/kgMedian counts of CD3+ cells in PBPCs 0.61 (0.23-4.56) 108/kgGrades 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 mDLImDLI for the treatment of leukemia relapse after unmanipulated HSCTUpdate dataLeukemia 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

ABCDChemotherapy + DLIChemotherapy aloneP=0.016P=0.000P=0.000P=0.0002-4 acute GVHDChronic GVHDRelapseLeukemia free survivalHuang, et al. PUIH, unpublished data

1. Therapeutic mDLIConclusion of Part onemDLI was a potentially effective therapeutic option for patients who relapsed after HSCT

Chemotherapy plus DLI is superior to chemotherapy alone for treatment of patients who relapsed after transplantationHuang XJ, et al, Leukemia, 2006,20:365-368Huang XJ, et al. Haematologica 2007,92:414-417Huang XJ, et al, Bone Marrow Transplant. 2009;44(5):309-16Huang XJ, et al. PUIH, unpublished data

1. Therapeutic mDLI2.Prophylactic DLIRelapse prevention using mDLI after HLA-identical transplantA multi-center studyWang Y, Huang XJ, et al. Clin Transplant, 2012 DOI: 10.1111/j.13990012.2012.01626.xRetrospective 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=0.35P=0.021Patients who received prophylactic DLI had a higher incidence of chronic GVHD2.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-stage66%46%P=0.02P=0.00136%11%2.Prophylactic DLIWang 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 leukemiaRisk-factor analysisRetrospective 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 transplantationWang Y, Huang XJ, et al. BMT, 2012.2132.Prophylactic DLI

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

2.Prophylactic DLI

Conclusion of Part TwoHuang, et al. J Clin Immunol,2008,28:276-283Wang Y, Huang XJ, et al. BMT, doi:10.1038/bmt.2012.213Prophylactic 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-HSCT2.Prophylactic DLI

TherapeuticProphylacticHigh-riskmDLIDecrease relapseImprove survivalPatients with LeukemiaStandard-riskMRD(-)MRD(+)Prophylactic mDLI ?Decrease relapse ?Improve survival ??Hypothesis??

3. Risk directed mDLIThe 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 mDLIReduce relapse and improve survival? Our objects- reduce relapse?Monitoring of MRDRisk-stratification based on MRD stateIntervention with DLI or IL-2

3. Risk directed mDLIPatients Subgroups814 patients MRD (-): 709 patients (Group A)MRD (+): 105 patientsIL-2: 49 patients (Group B)DLI: 56 patients (Group C)Huang XJ, et al. Blood,2012,119(14):3256-62

3. Risk directed mDLI

RelapseTotal: 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):3256-623. Risk directed mDLI

Risk factors of relapseUnivariate analysisPDisease type 0.016Remission state 0.001MRD-state posttransplant0.001Intervention for MRD 0.001Multivariate analysisPORMRD-negative post-transplant 0.0000.255Receiving DLI 0.0000.269Huang XJ, et al. Blood,2012,119(14):3256-62

3. Risk directed mDLIGVHD and TRMGroup 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%VariableMRD- negativeMRD- positiveP*MRD-positiveP#IL-2DLIAcute GvHD (%) post-intervention10.230.80.017 Grade-28.227.90.017 Grade-3 4.18.40.471Chronic GvHD (%) post-intervention37.342.90.982 Extensive chronic GvHD 30.534.20.858Incidence of TRM at 3 years post-HSCT (%)19.712.70.0811.414.40.897Huang XJ, et al. Blood,2012,119(14):3256-62

3. Risk directed mDLI

Disease-free survivalHuang XJ, et al. Blood,2012,119(14):3256-62

3. Risk directed mDLIRisk factors of DFSUnivariate analysisPDisease type 0.017Remission state 0.002MRD-state posttransplant0.003Intervention for MRD 0.005Multivariate analysisPORMRD-negative posttransplant 0.0010.511Receiving DLI 0.0060.436Huang XJ, et al. Blood,2012,119(14):3256-62

3. Risk directed mDLI

Overall survivalHuang XJ, et al. Blood,2012,119(14):3256-62

3. Risk directed mDLIRisk factors of OSUnivariate analysisPDisease type 0.025Remission state 0.002MRD-state posttransplant0.003Intervention for MRD 0.001Multivariate analysisPORMRD-negative post transplant 0.0070.644Receiving DLI 0.0020.553Huang XJ, et al. Blood,2012,119(14):3256-62

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

3. Risk directed mDLI

Future of DLIG-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 cellsWhich 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.AcknowledgementsStem cell collection centerHai-Yin ZhengHong XuQing ZhaoSu Wang

Department of bone marrow transplant Xiao-Jun HuangKai-Yan Liu Dai-Hong Liu Lan-Ping XuHuan Chen Wei HanXiao-Hui ZhangYu-Hong Chen Feng-Rong Wang Jing-Zhi Wang Yu WangChen-Hua Yan Yuan-Yuan ZhangYu Ji Yu-Qian SunLaboratory of PUIHDan LiYa-Zhen QinYan-Rong LiuYue-Yun Lai