Rapid and Robust CD4+ and CD8+ T-, NK-, BTitel and Monocyte Cell Reconstitution after Nicotinamide-Expanded Cord Blood (NiCord) Subtitel Transplantation Boelens/Nierkens lab Jaap Jan Boelens, Central Immune Monitoring Lab (UMC Utrecht) Laboratory of Translational Immunology
Take home messages CD4+ reconstitution after NiCord treatment at 1 days is at least as fast as unmanipulated CBT and BMT in young adolescents NK-, B- and monocyte cell reconstitution seems faster than unmanipulated CBT/BMT In-depth immune monitoring may lead to better predictors for outcome Optimal comparison of IR in randomized controlled Phase III trial is underway
Cord blood as stem cell source Advantages Readily available stem cell source Some mismatch is allowed (donor available for many patients) Less chronic GvHD vs. Matched Unrelated donor Eapen M et al Lancet 21 Potent anti-tumor activity Milano F et al NEJM 216 Number at risk Cord blood HLA-matched P=.7 for comparison of HLA-matched vs cord blood P=.2 for comparison of HLA-mismatched vs cord blood 45 23 11 2 1 14 31 23 11 4 Unrelated Donor HLA-Matched Adjusted Unadjusted HLA-Mismatched Adjusted Unadjusted Cord Blood Adjusted Unadjusted Milano F et al. NEJM 216 HLA-mismatched 35 7 6 3 1
Cord blood as stem cell source Low Cell Dose Disadvantages Low stem cell dose leads to delayed hematopoietic recovery Increased resource utilization Higher Resource Utilization Slow Engraftment & Graft Failure Delayed Immune Recovery Potential Solution Ex-Vivo Expansion Cord Blood Stem Cells Higher Morbidity and Non-relapse Mortality Higher Rate of Infections
Expanded cord blood units: NiCord Ex-vivo expanded cell product derived from an entire unit of umbilical cord blood CD133+ cultured fraction CD133- non-cultured, T-cell containing fraction is cryopreserved until transplantation Culture system: Nicotinamide Cytokine supplemented culture media TPO, IL-6, FLT-3 ligand and SCF Culture length: 21 +/- 2 days Phase I/II median CD34+ cells infused: 6.4 x 1 6 /kg Phase I/II median CD3+ cells infused: 2.3 x 1 6 /kg Nicotinamide With courtesy of M. Horwitz
Expanded cord blood units: NiCord Ex vivo expanded cell product derived from an entire mode unit of How umbilical fast do lymphocytes cord blood repopulate in NiCord transplanted patients? CD133+ cultured fraction CD133- non-cultured, T-cell containing fraction is cryopreserved until transplantation Culture system Nicotinamide, a vitamin B6 derivative Cytokine supplemented culture media TPO, IL-6, FLT-3 ligand and SCF Nicotinamide How fast do lymphocytes repopulate Culture length; 21 +/- 2 days Phase I/II median CD34+ cells infused: 6.4 x 1^6/kg Phase I/II median CD3+ cells infused: 2.3 x 1^6/kg Waiting on feedback for MOA See animation in presentation in NiCord transplanted patients? With courtesy of M. Horwitz
Demographic and baseline characteristics: Phase I/II NiCord N (%) Number of evaluable patients 36 (1) Age (years) 13-18 19-39 4 + Median (range) HLA Match Score 4/6 5/6 6/6 4 (11) 11 (31) 21 (58) 44 (13-63) 26 (72) 8 (22) 2 (6) Conditioning Regimen Weight (Kg) With courtesy of M. Horwitz Regimen A (TBI, Fludarabine +/- Cyclophosphamide or Thiotepa) Regimen B (Thiotepa, Busulfan, Fludarabine) Regimen C (Clofarabine, Fludarabine, Busulfan) Median (range) 15 (42) 19 (54) 2 (6) 75 (41-125)
Engraftment of neutrophils and platelets Neutrophils Platelets 94.4% patients engrafted 89.7% 8.6% patients engrafted Cumulative Incidence of Neutrophil Engraftment 11.5d 21d NiCord N=36 CIBMTR Control N=146 34d 46d 67.1% P<.1 P<.1 CIBMTR controls matched for age, conditioning, disease status, cell count, HLA, performance: 8% ducb and 2% sucb With courtesy of M. Horwitz; The information presented here includes data obtained from the Center for International Blood and Marrow Transplant Research.
Lymphocyte immune reconstitution is associated with complication risk Conditioning Allo-HCT Immune Reconstitution Adequate IR: less complications ATG+ Delayed IR: higher risk for complications weeks months years De Koning et al. BBMT 216
Effect of CD4 T cell immune reconstitution on NRM / relapse 1 Unsuccessful immune reconstitution Successful immune reconstitution 1 NRM (%) 8 6 4 P=.32 Relapse (%) 8 6 4 P=.33 2 2 5 1 15 2 25 3 Number at risk Unsuccessful IR 97 48 3 15 1 5 5 1 15 2 25 3 Number at risk Unsuccessful IR 22 7 6 4 4 2 Successful IR 154 12 73 45 24 5 Successful IR 41 28 18 12 7 2 Successful IR = >5x1e 6 /L within 1 days Admiraal et al. Lancet Hematol 215
Good CD4+ reconstitution protects for virus complications Has changed local clinical practice: If viral reactivation WITH CD4+ IR, do not start pre-emptive antiviral Tx Adenovirus reactivation and CD4+ immune reconstitution B No AdV vs. AdV with IR No AdV vs. AdV without IR AdV with IR vs. AdV without IR P=.67 P<.1 P=.3 66% 12% 32% 1% 68% 3% No adenovirus reactivation (n=228) Adenovirus reactivation with CD4 reconstitution (n=23) Adenovirus reactivation without CD4 reconstitution (n=22) Admiraal et al, JACI 217 Number at risk 228 11 64 35 23 13 1 4 22 7 6 1 z
Immune reconstitution substudy at central laboratory Primary endpoint for this study: Comparison of probability of CD4 immune reconstitution Secondary endpoint: Reconstitution over time of CD4+, CD8+, monocytes, natural killer (NK)- and B-cells Controls: UMCU CBT (n=27); median age = 15 (12-18); 1% CloFluBu, malignancy. UMCU BMT (n=2); median age = 14 (12-2); 1% CloFluBu, malignancy.
CD4 immune reconstitution probability is similar to adolescent UCB/BM controls CD4+ IR 1...2.4.6.8 1..8.6.4.2. NiCord (n=22) CB (n=27) BM (n=2) CD4+ IR probability P=.99 p=.76 >9% IR IR = >5x1e 6 /L within 1 days 2 4 6 8 1 Time (days) Admiraal et al, Lancet Hematol 215; JACI 217 Days after HCT
NiCord: CD4 and CD8 T cell immune reconstitution (n=22) CD4 CD8 1 1 ns ns 75 75 NiCord 5 CB 5 Group Cells (x1e 6 /L) BM 25 25 5 1 15 Time after HCT (days) 5 1 15 5 1 15 Time after HCT Time after HCT
B- and NK-cell immune reconstitution B cells NK cells 1 p=.26 2 p<.1 75 15 5 Cells (x1e 6 /L) 1 25 5 5 1 15 Time after HCT 5 1 15 Time after HCT
Monocyte immune reconstitution 5 5 Monocyte reconstitution (x1e 6 /L) 4 Monocyte reconstitution (x1^6/l) 4 3 3 2 2 1 1 Group Gamida CB BM 5 1 15 Time after HCT (days) 5 1 15 Time after HCT
Phase III Study of NiCord for Allogeneic Transplantation in Patients with Hematologic Malignancies Patients with High- Risk Hematologic Malignancies AML, MDS, ALL, CML, lymphoma Age 12-65 Eligible for Allogeneic Bone Marrow Transplantation RANDOMIZE N=12 NiCord Standard Cord Blood Primary Endpoint Time to neutrophil engraftment No Suitable Donor 11 sites initiated in the U.S., Europe and Asia Additional sites are being opened
Take home messages CD4+ reconstitution after NiCord treatment at 1 days is at least as fast as unmanipulated CBT and BMT in young adolescents NK-, B- and monocyte cell reconstitution seems faster than unmanipulated CBT/BMT In-depth immune monitoring may lead to better predictors for outcome Optimal comparison of IR in randomized controlled Phase III trial is underway
Lab Boelens/Nierkens Coco de Koning Maud Plantinga Niek van Til Charlotte van Kesteren Colin de Haar Lotte Spel Rick Admiraal Celina Szanto Vania Lo Presti Jurgen Langenhorst Ester Dünnebach Denise van den Beemt Brigitte van den Broek Adult Program Jurgen Kuball Moniek de Witte Eefke Petersen Laboratory of Translational Immunology Duke Cancer Institute Mitchel Horwitz Pediatric BMT program Utrecht Marc Bierings Birgitta Versluys Caroline Lindemans Corinne Gerhardt Arianne de Wildt Pharmacy UMC Utrecht Erik van Maarseveen Alwin Huitema Karin van Veghel Amelia Lacna Lysette Ebskamp-van Raaij Eveline Delemarre Marielle Tempelman Participating transplant centers M Horwitz- Duke University G. Sanz, P. Montesinos- Valencia Pau Montesinos- Valencia P. Stiff- Chicago D. Valcarcel- Barcelona M. Jagasia- Nashville D. Cilloni- Turin J. Boelens, J. Kuball- Utrecht R. Hanna- Cleveland L. Piu, W. Hwang- Singapore J. Wagner, C. Brunstein- Minnesota
NiCord Phase I/II Outcome Relapse Year 2 Estimate: 33.2% (95% CI 15.9, 51.6) NRM: Year 2 Estimate: 23.8%; (95% CI 1.9, 39.5) Estimated Disease-Free Survival 1yr: 49.1% (95% CI 32.2%, 64.8%) 2yr: 43.% (95% CI 24.2%, 6.5%) Estimated Overall Survival 1yr: 51.2% (95% CI 32.9%, 66.8%) 2yr: 51.2% (95% CI 32.9%, 66.8%) agvhd grade II-IV: 44.% (95% CI: 27.7%, 59.9%) agvhd grade III-IV: 11.1% (95% CI: 3.4%, 23.8%) cgvhd (mild/moderate/severe): Month 12 Estimate 4.5% (95% CI: 23.7%, 56.7%) cgvhd (moderate/severe) Month 24 Estimate 9.8% (95% CI: 2.4%, 23.7%) With courtesy of M. Horwitz
Demographic and Other Baseline Characteristics NiCord N (%) Acute Lymphoblastic Leukemia 9 (25) High risk first complete morphologic remission (CR1) 5 Second Remission 4 Primary Diagnosis Acute Myelogenous Leukemia 17 (47) First complete morphologic remission (CR1) 13 Second Remission 4 Myelodysplastic Syndrome 7 (19) Chronic Myelogenous Leukemia 2 (6) Hodgkin s Disease 1 (3) Low 8 (22) Disease Risk Intermediate 15 (42) High 13 (36)
Characteristics UMCU CBT and BMT patients CB (n=27) BM (n=2) Age 13-18 19-39 4+ Median (range) 27 15 (12-18) 19 1 14 (12-2) HLA Match score 4/6 5/6 6/6 8/8 8/1 9/1 1/1 8 9 8 1 1 2 3 15 Conditioning regimen (Clo)BuFlu 27 2 Weight (kg) Median (range) 21-74 32-88