ALBERT

Description: Key Points Ex vivo fucosylation of cord blood cells improves their homing capacities, leading to faster neutrophil and platelet engraftments. This method is quick, safe, and does not require a GMP laboratory; therefore, it can be used widely.

Description: Abstract 3398 Poster Board III-286 Background: The curative potential of hematopoietic stem cell transplantation (HSCT) in chronic granulomatous disease (CGD) is dependant upon achievement and maintenance of long-term donor chimerism and availability of suitable donor for every patient. Methods: Ten children with clinically severe CGD (x-linked recessive, n=6; autosomal recessive, n=4) received HSCT following myeloablative conditioning at Duke University Medical Center between August 1997 and July 2009. Diagnoses were made by respiratory burst assays +/− mutation analyses. Prior to transplant, patients had a median of 3 (range, 2-9) serious bacterial or fungal infections. One patient had an active invasive aspergillous infection of the chest wall and lung at the time of transplant. The patients were transplanted at a median age of 64.5 months (range, 8-140), weighed a median of 19.6 kg (range, 9.6-60), and had a performance status of 80 to 100 (Lansky). One patient was referred to Duke for second transplant after he developed primary graft failure following a reduced intensity transplant at another center. Graft sources were matched sibling bone marrow (SibBM) in 5, unrelated donor cord blood (UCB) in 4, and sibling cord blood (SibCB) in 1 patient. SibBM and SibCB donors were 6 of 6 HLA matched. UCB units matched at 4/6 (n=1) or 5/6 (n=3) and contained a median precyropreservation total nucleated cell dose of 3.8×10—7 per kg. SibBM patients were cytoreduced with Busulfan (Bu) and Cyclophosphamide (Cy) with or without ATG. Use of Bu/Cy/ATG in the first UCB recipient resulted in primary graft failure. All subsequent CB recipients were cytoreduced with Fludarabine(Flu)/Bu/Cy/ATG. Five patients were given irradiated granulocyte transfusions from family donors during the neutropenic period. Engraftment, chimerism, graft versus host disease (GvHD), and survival were evaluated using descriptive statistics. Results: All patients are alive and disease free with a median follow-up of 55 (range, 1-144) months. Neutrophil engraftment occurred in a median of 16 days (range, 11-20) in BM and 29 (range, 16-43) in CB recipients. Platelet engraftment occurred in a median of 41 days (range, 33-45) in BM and 123 days (range, 29-169) in CB recipients. Two UCB recipients who had primary graft failure were successfully retransplanted using Flu/Cy with either TBI (200cGy) or Campath. At the most recent follow up (range, 1-84 months post transplant) chimerism was all donor in 8 patients and 94% in one patient. All patients have normal respiratory burst assays, are free of new infections, and are doing well with a Lansky score of 80-100 at their last follow up. Acute grades III/IV GvHD developed in 2 patients and extensive chronic GvHD occurred in only 1 patient. Conclusions: Myeloablative hematopoietic stem cell transplant leads to correction of neutrophil dysfunction, durable high-level chimerism, excellent survival, and low incidence of GvHD. Patients transplanted with UBC had equivalent outcomes to those transplanted with HLA-matched sibling donors. Disclosures: No relevant conflicts of interest to declare.

Description: INTRODUCTION: More active high-dose regimens are needed for refractory or poor-risk relapsed Hodgkin's lymphomas (HL), where BEAM offers poor results. Post-BEAM maintenance treatment with brentuximab vedotin (BV) x 48 weeks has recently been shown in the AETHERA trial to prolong progression-free survival (PFS) compared to placebo (2-year PFS 63% vs. 51%). We previously developed a regimen of infusional gemcitabine combined with busulfan and melphalan (Gem/Bu/Mel) pursuing inhibition by Gem of DNA damage repair. The encouraging results we saw in HL patients led us to conduct a phase 2 trial of Gem/Bu/Mel in HL patients at high risk of post-ASCT relapse. METHODS: HL patients ages 12-65 with ≥1 of the following criteria were eligible: Persistent active disease after 1st-line chemotherapy, CR1 〈 1 year, or extranodal disease at relapse/PD. Gem was administered as a loading dose of 75 mg/m2 followed by infusion at a fixed dose rate of 10 mg/m2/min over 4.5 hours on days -8 and -3 (total daily dose of 2,775 mg/m2). Each Gem infusion was immediately followed by the corresponding dose of Bu or Mel. Bu was administered intravenously from days-8 to -5 targeting a daily AUC of 4,000. Mel was infused at 60 mg/m2/day on days -3 and -2. ASCT was on day 0. Post-HDC involved field radiotherapy (IFRT) was considered to lesions 〉5 cm at the time of HDC or persistently PET+ at the 1-month post-HDC evaluation. The trial had 80% power to detect a 2-year PFS increase from 50% to 65%.The concurrent BEAM cohort included all patients eligible for this trial who received BEAM off study due to no financial coverage for ASCT in a trial or patient/physician preference. RESULTS: Eighty patients were enrolled on study between 6/11-04/15 (Table 1). There was no transplant-related mortality (TRM). The toxicity profile was manageable, including mucositis (49% G2, 40% G3), skin (22% G2, 11% G3), self-limited transaminase elevation (30% G2, 19% G3), and hyperbilirubinemia (24% G2, 19% G3) with no cases of VOD. There was 1 case of G2 pneumonitis and none of cardiac, renal or CNS toxicity. Neutrophils and platelets engrafted at median days +10 (8-12) and +12 (9-21), respectively. Eight patients received post-HDC IFRT to mediastinum ± neck ± sternum at 30.6-39.6 Gy, starting on median day +42 (41-53) post-HDC, which was well tolerated. No patients received maintenance BV. Table 1. Patient characteristics Variable Study file (N=80) Concurrent BEAM cohort (N=31) P Median age (range) 31 (13-65) 39 (23-65) 0.02 Primary refractory / poor-risk relapse 41% / 59% 37% / 63% 0.6 # prior relapses 1 80% 70% 0.3 〉1 20% 30% Median # prior chemotherapy lines (range) 2 (2-6) 2 (2-7) 0.3 Prior disease-free interval (months) 12 20% 23% Prior xRT 21% 27% 0.6 Relapse within prior xRT field 10% 3% 0.4 Extranodal relapse/PD 36% 53% 0.08 B symptoms at relapse/PD 11% 10% 0.8 Bulky relapse (any lesion 〉5 cm) 39% 17% 0.02 # risk factors (primary refract/CR11 relapse 50% 73% 0.08 B symptoms 55.6% 70.4% 0.2 Bulky relapse 67% 72% 0.2 Extranodal 67% 72% 0.4 The BEAM cohort included 31 patients treated between 06/11-04/15 (Table 1) with no BV maintenance. There were fewer cases of PET+ tumors at HDC (P=0.003) and of bulky relapses (P=0.02) than the Gem/Bu/Mel file, but was matched for the other risk factors. It had no TRM. Despite a higher number of PET+ tumors at HDC, the Gem/Bu/Mel file had significantly superior 2-year PFS (65% vs. 51%, P=0.03) and 2-year OS (95.5% vs. 70%, P=0.001) than the BEAM cohort. CONCLUSIONS: Gem/Bu/Mel without maintenance BV was safe and effective in patients with refractory or poor-risk relapsed HL, with comparable results to those from the AETHERA trial using BEAM and maintenance BV. A randomized trial is necessary to compare Gem/Bu/Mel and BEAM. Figure 1. Figure 1. Disclosures Off Label Use: Gemcitabine, busulfan and melphalan are not FDA approved at high doses for Hodgkin's lymphoma. Alousi:Therakos, Inc: Research Funding. Andersson:Otsuka Research and Development, Inc.: Consultancy. Fanale:Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Research Funding; Infinity: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Research Funding; Genentech: Research Funding; Medimmune: Research Funding; Novartis: Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Molecular Templates: Research Funding; ADC Therapeutics: Research Funding; Onyx: Research Funding; Gilead: Research Funding.

Description: Introduction Chronic graft-versus-host disease (cGVHD) remains a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Perturbations in immune reconstitution following allo-HSCT are believed to be integral to the pathophysiology of cGVHD. We hypothesized that skewing in T cell repertoire around day 80 would be predictive of cGVHD, while maintenance of a broad repertoire would be protective. One method used to assess skewing is the Gini Index, a conventional measure of income inequality. In this prospective study, we utilized a rapid FACS based method of TCR Vβ repertoire analysis within CD4+ and CD8+ in patients at day 80-110 post allo-HSCT to determine whether preferential TCR skewing predicts the development of cGVHD. Methods Peripheral blood samples were obtained from 79 consented patients at day 80-110 following allo-HSCT at The University of Texas MD Anderson Cancer Center from October 2012 to November 2015. All patients were in remission of their disease at the time of blood sampling. Fresh PBMC were analyzed by FACS after staining for CD3, CD4, CD8 and IOTest Beta Mark 24 TCR Vβ kit. The TCR Gini Index scores (GS) were calculated for the T cell subsets, and ranged from 0 to 100. Low GS indicate more equal distribution of TCR-Vβ families (i.e. broad repertoire), whereas high GS reflect unequal distribution of TCR-Vβ families (i.e. repertoire skewing). Predictive thresholds of GS were identified in quartiles analysis and confirmed by Receiver Operating Characteristic (ROC) curve.The association between GS and the rate of cGVHD since the date of blood sampling was evaluated using competing-risks regression analysis. The diagnosis of cGVHD was based on the 2014 National Institutes of Health guidelines. Results The median age at transplant was 53 years (range 21-75) and 60% of patients were male. The most common transplant indication was AML/MDS (52%) followed by lymphoma (16%), ALL (14%), and other (18%). Graft source was peripheral blood (54%), bone marrow (43%) and umbilical cord blood (UCB) (3%) with donors being matched unrelated (65%), matched-related (24%), mismatch related (9%) and UCB (3%). Forty three (54%) patients were not in remission at the time of transplant. At the time of enrollment, 47% had history of grade II-IV acute GVHD and 44% were on systemic steroids. At a median follow up of 2 years since blood sampling, 16 patients developed cGVHD (cumulative incidence (CI) 23%; 95% Confidence Interval: 15-35). The median time from HSCT to cGVHD was 174 days (range 111-551 days). None of the clinical or demographic characteristics listed above, except history of acute GVHD, was significantly associated with the incidence of cGVHD. GS were significantly predictive of the incidence of cGVHD. The 2 year %CI of cGVHD was 47% in patients who had CD4+ TCR GS 〉55% (n=19) compared with 16% in those with CD4+ GS ≤55% (n=60) (hazard ratio (HR) =3.4, P=0.01). In contrast to CD4+, lower CD8+ GS predicted for higher incidence of cGVHD. The 2 year %CI of cGVHD was 39% in patients (n=34) with CD8+ GS ≤60% compared with 10% in patients (n=45) with CD8+ GS 〉60% (HR=4.5, P=0.009). When both CD4+ and CD8+ GS were considered in combination, the 2 year incidence of cGVHD was highest in patients (n=6) with both low CD8+ (≤60%) and high CD4+ (〉55%) GS, and lowest in patients (n=32) with high CD8+ (〉60%) and low CD4+ (≤55%) GS (%CI: 83% vs 4%, P=0.001). The combined effect of high CD4+ and low CD8+ TCR skewing was more pronounced in patients with a history of grade II-IV acute GVHD. Low CD8+ (≤60%, n=28) or high CD4+ (〉55%, n=13) GS occurring separately were associated with comparable rates of cGVHD (%CI: 31% and 27%, p=0.8), irrespective of history of grade II-IV acute GVHD (Figure). Conclusions High CD4+ and low CD8+ TCR Gini indices were independent predictors of cGVHD. Our results indicated that the higher skewing of CD8+ TCR appeared to be protective of cGVHD and the opposite for CD4+. Our study is the first to test the usefulness of FACS-based TCR measurement and Gini Index score in a clinical setting to help predict the development of cGVHD and provide greater insights into the pathogenesis of cGVHD. Using this convenient FACS-based method to identify patients who are at risk of developing cGVHD could be beneficial from development of effective preventive or therapeutic strategies. Figure Figure. Disclosures No relevant conflicts of interest to declare.

Description: Introduction: Matched related donor (MRD) hematopoietic cell transplant (HCT) is an accepted treatment for sickle cell disease (SCD) despite risk of graft-versus-host disease and graft rejection. Alemtuzumab is a potent lymphocytic medication that can reduce the risk of GVHD; however, it is associated with mixed donor chimerism (MDC) and graft loss when used with submyeloablative conditioning. We explored the use of myeloablative chemotherapy in conjunction with alemtuzumab in MRD HCT for SCD as a method to concurrently prevent GVHD and promote durable engraftment. Methods: We retrospectively reviewed engraftment, GVHD and survival for patients that underwent MRD HCT for SCD at Texas Children's Hospital between 2003-2017. All patients received busulfan dose adjusted to achieve target area under the curve of 800-1200μM per minute with doses administered intravenously every 6 hours for 4 days and cyclophosphamide 50mg/kg daily for 4 days. GVHD prophylaxis included intravenous alemtuzumab daily for 3-4 doses starting on day -5 (5-15kg=3mg, 15-30kg=5mg, 〉30kg= 10mg daily), methotrexate and a calcineurin inhibitor. Donor chimerism was evaluated via short tandem repeats (STR) or fluorescent-in-situ hybridization (FISH) of nucleated cells from the peripheral blood. If MDC was detected, follow-up chimerism studies were obtained every 1-4 weeks until stabilization on 2 or more consecutive evaluations. Persistent MDC was defined by the presence of recipient cells on 2 consecutive evaluations without return to full donor chimerism at last follow-up. Results: Thirty-eight consecutive patients underwent MRD transplant (3 non-sibling and 35 sibling) with a median age at transplant of 8.6 yrs (range: 2.9-18.4yr). Stem cell source consisted of bone marrow grafts for all patients. Two patients concurrently received cord blood from the same donor to augment cell dose. Neutrophil engraftment was achieved in all patients at a median time of 19 days (range: 13-24 days). Incidence of persistent MDC was 62.8% with a median last chimerism of 94% donor cells (range: 24-100%). Three of 22 patients (13.6%) with persistent MDC had

Description: Background: Sinusoidal obstructive syndrome (SOS) is a potentially catastrophic complication of stem cell transplantation (SCT) which disproportionately affects younger patients. The incidence of SOS may vary widely depending on the diagnostic criteria (Baltimore versus Seattle), and delays in initiation of definitive treatment remains the most important predictor of outcome. Recently proposed pediatric diagnostic and severity grading criteria by the European Society of Blood and Marrow Transplantation (EBMT) may offer increased sensitivity and allow for more prompt diagnosis, but the extent to which these have been adopted and/or validated by centers in the United States is unclear. Methods: This is a retrospective analysis of all patients undergoing SCT on the Pediatric service at MD Anderson Cancer Center from 2009-2019. Patient records were reviewed for diagnosis of SOS. Among patients identified with SOS, application of Baltimore, Seattle and pediatric EBMT (pEBMT) criteria were compared. Descriptive statistics were used for data analysis where appropriate. Results: A total of 248 patients received 268 transplants during the study period. Patient characteristics are summarized in Table 1. When Baltimore criteria was used the incidence of SOS was 4.5% (n=12) as compared to 8.2% (n=22) when the Seattle or pEBMT criteria were applied. At diagnosis, the majority of these patients had moderate to very severe disease according to pEBMT criteria. The median time to diagnosis of SOS varied according to diagnostic criteria used, with a trend to earlier diagnosis with pEBMT criteria (13 days post-SCT with pEBMT versus 15 days with Seattle/Baltimore) as shown in Table II. Prior exposure to inotuzumab and gemtuzumab were associated with high rates of SOS (75% and 86% respectively). Anicteric SOS, refractory thrombocytopenia and rising bilirubin from a baseline value on 3 consecutive days or bilirubin ≥2 mg/dL within 72 hours were present in 63.6%, 77.3% and 91% of patients with SOS, when pEBMT criteria were applied. Late-onset SOS (diagnosed after 21 days post-SCT) was present in 22.7% of patients when Seattle or pEBMT criteria were applied (n=5) and could not be diagnosed per Baltimore criteria. Severe SOS was eventually observed in 95% of patients. Severe ascites requiring paracentesis (23%), impaired coagulation (77%), respiratory distress requiring supplemental oxygen and/or invasive pulmonary ventilation ( 55%), delirium (32%), acute kidney injury/KDIGO Stage 3/requiring renal replacement therapy (50%) were observed. Defibrotide treatment was initiated in 55% of patients with a median duration of treatment of 26 (3-74) days and complete resolution of SOS was observed in 42% of these patients. For patients who were initiated on defibrotide on the day of diagnosis (n=7) versus those who were not (range 1-11 days) the median time to complete resolution of SOS was 35 and 20 days respectively (p=0.2). Conclusions: To our knowledge, this is the first reported retrospective analysis of SOS among pediatric and adolescent young adult SCT patients in the United States using pEBMT SOS diagnostic and severity criteria. Our study was limited by small sample size associated with single center analyses. Use of the pEBMT criteria showed a trend to earlier time to diagnosis by a median of two days. This is a potentially clinically significant finding, as a delay in initiation of defibrotide among children with severe SOS, has been associated with statistically significant decreased rates of complete resolution. Inherent flaws of the Baltimore and Seattle criteria are the time restriction and reliance of hyperbilirubinemia for the diagnosis in children and adolescents and young adults. Our retrospective analysis suggests that pEBMT criteria for the diagnosis of SOS among children and young adults may be appropriate, especially given the rates of anicteric and late-onset SOS seen in this population. Disclosures Petropoulos: Foundation for the Accreditation of Cellular Therapy (FACT): Membership on an entity's Board of Directors or advisory committees, Other: Foundation for the Accreditation of Cellular Therapy (FACT). Kebriaei:Amgen: Research Funding; Jazz: Consultancy; Pfizer: Honoraria; Kite: Honoraria. Wierda:Xencor: Research Funding; Janssen: Research Funding; Loxo Oncology Inc.: Research Funding; KITE pharma: Research Funding; Juno Therapeutics: Research Funding; Gilead Sciences: Research Funding; Acerta Pharma Inc: Research Funding; Pharmacyclics LLC: Research Funding; Genentech: Research Funding; GSK/Novartis: Research Funding; AbbVie: Research Funding; Cyclcel: Research Funding; Oncternal Therapeutics Inc.: Research Funding; Miragen: Research Funding; Sunesis: Research Funding. Mahadeo:Recipient of unrestricted medical education grant from Jazz: Research Funding; PI for ATARA EBV CTL Trials: Other: Other .