A Novel Approach of Hematopoietic Stem Cell

Abstracts / Biol Blood Marrow Transplant 22 (2016) S19eS481

ALTERNATIVE DONORS

549 Predictable Fast CD4+ Reconstitution and Prevention of Graft Failure in High-Risk Patients following Cord Blood Transplantation by Individualized Dosing and Therapeutic Drug Monitoring of Anti-Thymocyte Globulin Rick Admiraal 1, 2, Charlotte van Kesteren 1, 2, Lysette Ebskamp-van Raaij 3, Amelia M. Lacna 3, Birgitta Versluys 1, Marc Bierings 1, Caroline A. Lindemans 1, Stefan Nierkens 2, 3, Jaap-Jan Boelens 1, 2. 1 Pediatric Blood and Marrow Transplantation Program, University Medical Center Utrecht, Utrecht, Netherlands; 2 U-DANCE, Tumorimmunology, Lab Translational immunology, University Medical Center Utrecht, Utrecht, Netherlands; 3 Applied Tumor Immunology Section, Lab Translational Immunology, University Medical Center Utrecht, Utrecht, Netherlands Introduction: Survival chances after unrelated cord blood transplantation (CBT) largely depends on presence of immune reconstitution (IR). IR may be significantly hampered by high exposure of anti-thymocyte globulin (ATG) after CBT resulting in significant in vivo T-cell depletion. ATG exposure prior to CBT however is suggested to reduce the probability of graft-versus-host-disease (GvHD) and graft failure (GF). By individualizing ATG dosing and thereby ATG exposure (Preand Post-CBT), the outcomes may improve. Here, we describe the preliminary results of a study using individualized dosing and therapeutic drug monitoring (TDM) of ATG (Thymoglobulin) in patients receiving CBT with high-risk features for GF. Methods: From 2014, patients (children and young adults) receiving CBT, after standard myeloablative busulfan (Bu; 90mg*l/h) and fludarabine (Flu) in the UMC Utrecht at high-risk for GF and/or for whom fast IR was essential because of ongoing infections, were included. High-risk for GF was defined as increased inflammation with an intact or activated T-cell function; e.g. hemoglobulinopathies, Chronic Granulomatous Disease (CGD), Hemophagocytic Lympho-Histiocytosis (HLH) and Immune Deficiencies with auto-immune phenomena. Early 2015, we amended the study protocol by adding TDM. Dosage and timing of

Figure 1.

S365

ATG was calculated with a validated population pharmacokinetic (PK)-model (Admiraal et al, Clin. PK 2014). We targeted to very low ( 40 AU*day/mL (80 AU*day/mL for TDM-patients). In TDM-patients, doses were adjusted according to individual PK if necessary. Main endpoints were CD4+ IR (twice >50/uL within 100days) and GF. Other endpoints: acute-GvHD, viral reactivations (CMV, EBV, Adv, HHV6) and overall survival (OS). CD4+ IR was compared to recent cohort (Admiraal et al: Lancet Hematology 2015). Results: Fourteen patients are included (3 CGD, 2 CID, 2 SAA, 1 b-thalassemia, 1 HLH, 5 other) of whom 5 received TDM. Median follow up is 199 days. Mean cumulative dose of ATG was 11.8 (3 e 30) mg/kg, starting at a median of 12 (7-17) days before HCT. In all TDM-patients, both actual pre-CBT AUC (mean 104, range 73-140) and post-CBT AUC (3.4, 0.1-6) were within the target. CD4+ IR was significantly improved when compared to historical controls (all had CD4+ IR before day 40) and comparable to patients not receiving ATG (Fig 1a). No GF (all full donor) occurred, 1 patient had aGvHD II. Two patients experienced a transient (< 2 wk) viral reactivation of CMV/Adenovirus. OS at 6 months is 89%+-10% with 1 TRM due to pulmonary failure associated with pre-existent lung disease (Fig 1b). Conclusions: Individualized dosing of ATG (on FluBu-platform), with added TDM is feasible, showed fast CD4+ IR and encouraging other outcomes. It may improve the outcomes of CBT in patients with high-risk features for GF and a need for fast CD4+ reconstitution.

550 A Novel Approach of Hematopoietic Stem Cell Transplantation for Severe Thalassemia from Haploidentical Donors with Favorable Outcomes Usanarat Anurathapan 1, Suradej Hongeng 1, Samart Pakakasama 1, Nongnuch Sirachainan 1, Duantida Songdej 1, Ampaiwan Chuansumrit 1, Borje S. Andersson 2. 1 Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand; 2 Department

Abstracts / Biol Blood Marrow Transplant 22 (2016) S19eS481

of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX Thalassemia, a hemoglobinopathy which is common in Asian descendants, in its severe forms, has a poor prognosis. Allogeneic stem cell transplantation (allo-SCT) in severe thalassemia patients is an only way to cure the disease, however available HLA-matched donors for the patients were hardly identified. We recently reported an alternative strategy, pre-transplant immunosuppression (PTIS), combination of fludarabine (Flu) and dexamethasone (Dxm), would immunosuppress the patients to facilitate engraftment when followed by a reduced-toxicity conditioning (RTC) regimen, antithymocyte globulin (ATG), Flu and IV busulfan (Bu), to prepare high risk thalassemia patients for allo-SCT. We explored the use of an alternative, mismatched related (“haplo-”), donor in thalassemia patients. We enrolled severe thalassemia patients including a high risk group, so called class 3 Lucarelli classification, aged more than 7 years old and had a liver size more than 5 cms below the costal margin. All patients received two courses of PTIS, 40 mg/m2/day of IV Flu and 25 mg/m2/day of IV Dxm on day -68 to -64 and day -40 to -36, followed by RTC regimen, 1.5 mg/kg/ day of ATG on day -12 to -10, 35 mg/m2/day of Flu on day -8 to -3 and 130 mg/m2/day of Bu on day -8 to -5, was administered followed by unmanipulated peripheral blood stem cell (PBSC) from haploidentical donors. Graft-versus-host disease (GVHD) prophylaxis consisted of 50 mg/kg/day of cyclophosphamide (PTCy) on day +3 and +4 and tacrolimus or sirolimus was started together with a short course of mycophenolate mofetil. Twenty five patients received haplo-SCT at the median age of 10 (2-20) years. Twenty one patients had beta-thalassemia/hemoglobin E while the rest of patients had homozygous beta-thalassemia. Twelve patients had class 3 disease, their median age at the time of haplo-SCT was 14 (10-20) years. One of the patients had haplo-SCT as a second transplant after a matched-related allo-HSCT complicated with primary graft failure with autologous reconstitution. Sixteen patients received PBSC from the mother while the rest received from the father, the median CD34+ cell dose at 11.6 (4.0-19.0) x 106 cells/kg of body weight of recipients. The median time of neutrophil engraftment and platelet engraftment were 14 (11-18) and 30 (20-45) days, respectively. Two patients who suffered from primary graft failure had anti-HLA antibodies. Nine patients developed grade II acute GVHD, while four patients developed mild reversible veno-occlusive disease. Only three patients developed limited chronic GVHD. One patient died of GVHD complications. The 2-year overall and thalassemia-free survival rates are 93% and 88%, respectively, at the median follow up time was 11 (6-30) months. We concluded our new program, PTIS followed by RTC regimen and PTCy-based GVHD prophylaxis, had rapid and durable engraftment, yet a low risk of serious GVHD in the severe thalassemia patients.

551 Outcome of Unmanipulated HLA-Mismatched/ Haplo-Matched Hematopoietic Cell Transplantation from Related Donors in Patients with Fanconi Anemia Using Low Dose Post HCT Cyclophosphamide for Gvhd Prophylaxis Mouhab Ayas, Khawar Siddiqui, Hassan El-solh, Abdullah Al-Jefri, Ali Al-Ahmari, Ibrahim Al-Ghemlas, Mahasen Saleh,

Abdulrahman Al-Musa, Ashraf Khairi, Samer Markiz, Hasan Shahin, Amal Al-Seraihy. Department of Pediatric Hematology/Oncology, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia Background: Allogeneic Hematopoietic Cell Transplantation (HCT) is currently the only treatment modality to restore normal hematopoiesis in Fanconi anemia (FA) patients (pts); excellent results have been obtained with matched related donor HCT but outcomes of alternative donor HCT are less favorable. In non-FA pts, several reports documented high rates of stable engraftment/low risk of graft-versus-host disease (GVHD) using unmanipulated HLA-mismatched stem cells from related donors and post HCT high-dose cyclophosphamide (PT-CY) for GVHD prophylaxis. High dose alkylating agents like cyclophosphamide in FA pts are associated with increased toxicity and mortality but lower doses of PT-CY may lead to increased GVHD. We performed HCT from HLA-mismatched related donors in 9 FA pts using a non-myeloablative regimen and low dose PT-CY, and report here our preliminary results. Patients and Methods: Nine FA pts (age  14 years) underwent mismatched unmanipulated related HCT from January 2012 to August 2015, 7 were female (77.8%), median age at HCT was 8.4 years (Mean: 8.1, SD: 2.9, 2.8-12.1). Eight underwent HCT because of pancytopenia, pre-HCT bone marrows had no evidence of myelodysplasia but 1 had (t3:11). One patient had acute lymphoid leukemia with complex karyotype and was in remission at HCT. Conditioning was with fludarabine 30mg/m2/day x 5, antiThymocyte globulins 5mg/kg/day x 4, total body irradiation (200 cGy) x 1. GVHD prophylaxis was cyclosporine and mycophenolate and PT-CY 25 mg/kg on days +3, and +5. Donor was father in 7 pts, mother 1 and brother 1. All were partially HLA-mismatched with the recipients: 3 haplomismatched, 5 mismatched in one class I locus and in DR-B1, one mismatched in DR-B1 only. Stem cells source was bone marrow in 8 pts, peripheral blood in 1; median CD-34 dose was 5.91 x 10 6/kg of recipient’s weight (2.58-10.0, Mean: 6.3, SD: 2.3). Results: Absolute neutrophil count (ANC) recovery occurred in all patients, median of 14 days (12-15), while Platelettransfusion independence occurred in 8, median of 19 days (16-112). Severe mucositis developed in 2 pts and hemorrhagic cystitis in 2. Grade I-II GVHD of skin occurred in 2 pts and grade III-IV GVHD of skin/gut in 2 (1 patient improved, and 1 expired). Eight patients are now alive with normal hematopoiesis; all eight have 100% donor chimerism both myeloid and lymphoid. The 1 death occurred secondary to severe GVHD. At a median follow-up of 10.3 months (95%CI: 0.0-21.8), the probability of survival is 0.8330.152. Conclusion: In FA pts lacking matched related donors, use of mismatched related HCT with low dose PT-CY is a viable option; it is well tolerated with a high rate of engraftment and an acceptable incidence of GVHD. Survival with normal hematopoiesis is excellent. Larger patients’ cohorts and longer follow ups are, however, needed to further validate this approach and to ascertain long term stability of the mismatched graft. ˇ

S366

552 Viral Reactivation after T-Cell Replete Haploidentical Transplantation Using Myeloablative Conditioning and Post-Transplant Cyclophosphamide Evandro Bezerra1, Roberto Luiz da Silva1, 2, Jayr Schmidt Filho1, Marina Santos2, Marina Nascimento1, Aline Simoes2,