Auto-HCT versus Allo-HCT for T-Cell Lymphoma.
Conclusion: In this limited set of patients with T-Cell ma-lignancy and in a subset with T-Cell Lymphoma, overall survival after autologous and allogeneic HCT appears equivalent to pub-lished series utilizing conventional conditioning regimens. We conclude that FBT might offer certain patients an alternative conditioning regimen whose co-morbid status places them at risk for TRM from conventional regimens.
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Mesenchymal Stem Cell Infusion in Haploidentical Hematopoietic Stem Cell Transplantation in Patients with Hematological Malignancies
Onder Arslan1, Ayse Eser Elcin2, Erden Atilla1,3, Sukran Seker2, Pinar Baydin2, Mehmet Gunduz1,4, Mehmet Ozen1,5, Ulas Darda Bayraktar6, Osman Ilhan1, Meral Beksac1, Yasar Murat Elcin7, Gunhan Gurman1,2. 1Ankara University School of Medicine Department of Hematology, ANKARA, Turkey;2Ankara University Stem Cell Institute, Ankara, Turkey;3Baylor School of Medicine Center for Cell and Gene Therapy, Houston, Texas;4Ankara Ataturk Research and Training Hospital, Ankara, Turkey;5Ufuk University School of Medicine Department of Hematology, Ankara, Turkey;6Memorial Sisli Hospital, Istanbul, Turkey; 7Ankara University Faculty of Science Department of Chemistry Division of Biochemistry, Ankara, Turkey
Background: Haploidentical allogeneic stem cell transplan-tation (HASCT) is an emerging alternative treatment method
for patients without suitable donors. However, graft versus host disease (GVHD) incidence is higher in HASCT. Mesen-chymal stem cells (MSCs) have recently become quite important in areas of regenerative medicine and immuno-therapy due to their unique biological properties. The purpose of this study is to observe the effect of MSCs on reducing graft versus host disease (GVHD) and contribution to engraft-ment success in HASCT in order to widen the application of HASCT.
Material and Methods: Eighteen voluntary patients with hematological malignancies were recruited for the study at Ankara University School of Medicine Department of Hema-tology, but 6 patients were included. The isolation, replication and storage of MSCs from the bone marrow of donors was carried out in the GMP (Good Manufacturing Practice) laboratories of Ankara University Stem Cell Institute. Myeloablative or reduced intensity conditioning regimens were demonstrated in Table 1. Hematopoietic stem cell infusions were obtained from bone marrow of donors. At post transplant day 6, MSC infusions were applied. Posttransplant cyclophosphamide (Cy) 50 mg/kg/day, mycophenolate mofetil and tacrolimus were administered for GVHD prophylaxis.
Results: The median age of the 6 high-risk male patients included in the study (5 AML, 1 ALL) was 49 (range, 26-66). Patient characteristics are given inTable 1. Median CD34+ cell/kg and MSC/kg were 1.73× 106/kg (range, .94-3× 106/ kg) and 1.25× 106/kg (range, 1-2.5× 106/kg). No major or minor complications occurred in any of the patients during HASCTs or MSC infusions. Neutrophil and platelet engraft-ments were achieved in all patients except one patient (83%). Median neutrophil and platelet engraftment times were 21 (range, 16-25) and 27 (range, 19-33) days. The engraftment failure was successfully treated with addition-al stem cell transplantation. GVHD developed in 3 patients (50%), and all patients responded to treatment. The inci-dences of grade I-II and grade III-IV GVHD were 33% and 17%. Rescue treatments were administered to 2 of 3 pa-tients (50%) who developed recurrence. At the end of the study, 4 patients were died with a median survival of 6 months (range, 3-15 months) (Table 2).
Conclusion: MSC application in HASCT is a reliable method of treatment that does not cause major complications in the early posttransplant period. Similar to other HASCT studies, the frequency of engraftment was 83%. It is thought that MSC did no effect on engraftment in this study. The incidence of
Table 1
Characteristics of Patients (ALL: Acute Lymphoblastic Leukemia, AML: Acute Myeloid Leukemia, Bu: Busulphan, CR: Complete Remission, Cy: Cyclophos-phamide, F: Female, Flu: Fludarabine, M: Male, MRD: Minimal Residual Disease, TBI: Total Body Irridation)
GVHD was %50. The number of cases in early study is insuf-ficient for the application to be evaluated in terms of disease recurrence, infection rates and survival. It is necessary to in-crease the number of patients in order to demonstrate the efficacy of MSC in engraftment success in HASCT and pre-vention of GVHD.
CORD BLOOD
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Immunomodulating Properties of Notch-Expanded Cord Blood
Christian Bradley1, Sawa Ito2, Shelly Heimfeld3,4, Prachi Jain1 , Fariba Chinian1 , A. John Barrett1 , Colleen Delaney3,4 .1
Hematology Branch, National Heart, Lung, and Blood Institute, Bethesda, MD;2Stem Cell Allogeneic Transplantation Section, Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD;3Fred Hutchinson Cancer Research Center, Seattle, WA;4Nohla Therapeutics, Seattle, WA
Notch-mediated expanded cord blood stem and progenitor cell products successfully provide bridging hematopoietic support after transplant or intensive chemotherapy in pilot studies validating their multipotent stem cell properties. This product is a T cell depleted product, derived from the ex vivo expansion of CD34+ cells isolated from umbilical cord blood. Interestingly, patients receiving this product in the setting of myeloablative cord blood transplant experienced a significant reduction in severe grades 3-4 GVHD as com-pared to a control cohort.
The immunological properties of this expanded progenitor cell product are unknown but the clinical outcomes raise the possibility that Notch- expanded cord blood progenitor cells may have unanticipated immunomodulatory properties. We therefore conducted preliminary experiments to compare phenotypical and functional immune profiles of Notch-mediated expanded cord blood cells (n= 3) with unmanipulated cord blood (n= 6) or peripheral blood stem cells (n= 6). Phenotype of myeloid derived suppressor cell (MDSC) and PDL-1 expression were analyzed by flow
cytometry. The T cell suppression assay was performed using Karpas cell line as control reference suppressor cells. We also evaluated the impact of interferon gamma (IFNγ) in this system. Notch-expanded cord bloods were enriched with CD34 cells with higher PDL1 expression as well as a higher fraction early MDSC (eMDSC) in comparison to non-expanded cord blood. All three expanded cord blood products suppressed mature adult CD4 T cells in a dose-dependent manner, comparable to, or somewhat less than the Karpas control cells. Interest-ingly expanded cord blood did not suppress naïve CD4 T cells isolated from cord blood cells (Figure 1). However, assays using sorted MDSC and CD34 cells from expanded cord blood abol-ished the suppression effect. IFNγ did not potentiate the suppressive properties of expanded cord blood cells. Notch-mediated expanded cord bloods have modest immune suppressive properties which may explain the immune-evading effects in vivo. Further experiments are needed to identify the cell population responsible for the apparent re-duction in GVHD and allo-immunization.
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Long-Term Follow-Up of Adult Double Unit Cord Blood (CB) Transplantation (dCBT) Recipients Reveals High Rates of Progression-Free Survival after a Novel Cy/ Flu/ Thio/ TBI 400 Intermediate Intensity Conditioning Regimen
Ioannis Politikos1, Sean M. Devlin2, Alexandra G. Jacob1, Molly Maloy1, Christopher Mazis1, Kristine Naputo1, Aishat Afuye1, Andromachi Scaradavou3, Richard J. O’Reilly3, Scott T. Avecilla4, Hugo Castro-Malaspina1, Parastoo B. Dahi1, Sergio A. Giralt1, Boglarka Gyurkocza1, Ann A. Jakubowski1, Esperanza B. Papadopoulos1, Jonathan U. Peled1,
Miguel-Angel Perales1, Craig S. Sauter1, Brian C. Shaffer1, Gunjan L. Shah5, Roni Tamari1, Marcel R.M. van den Brink1, James W. Young1, Doris M. Ponce1, Juliet N. Barker1. 1Department of Medicine, Adult Bone Marrow Transplant Service, Memorial Sloan Kettering Cancer Center, New York, NY;2Department of Biostatistics and Epidemiology, Memorial Table 2
Patients’ posttransplant status
Figure 1. Suppressive potency of Notch-mediated expanded cord blood
prod-ucts. Three individual Notch-mediated expanded cord products (NOH001, NOH002, and NOH003) were tested for the potency of proliferation sup-pression against mature CD4 T cells. Karpas suppressor units was calculated by setting the % suppression of the products to a ratio of 100% suppression of Karpas cell line, standard reference suppressor cells.
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