Time Of Hematopoietic Cell Transplantation Research Articles

NaïVe T Cell Depletion of PBSC Grafts Results in Very Low Rates of Chronic Gvhd and High Survival

BackgroundGraft-versus-host disease (GVHD) frequently causes morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT) as a result of organ damage and infections. In HLA-identical HCT, GVHD results from recognition by donor T cells of minor histocompatibility (H) antigens on recipient tissues. Complete T cell depletion (TCD) of donor hematopoietic cell products is more effective than pharmacologic immunosuppression for preventing GVHD, but is complicated by delayed immune reconstitution and consequent life-threatening infections.Approaches to HCT which preferentially deplete the T cells that primarily cause GVHD and preserve pathogen-specific T cells may improve HCT outcomes.Mature CD3+ CD8+ and CD3+ CD4+ T cells can be classified into CD45RA+ CD62L+ naïve (TN) and CD45RO+ memory (TM) subsets, the latter of which includes effector memory (TEM) and central memory (TCM) cells. Murine studies in which allogeneic TCD bone marrow (BM) is transplanted with purified T cells from individual T cell subsets to irradiated minor H antigen disparate recipients have demonstrated that the most severe GVHD results from transplanting T cells of the TN subset. Purified TCM causes mild GVHD and TEM do not cause detectable GVHD and can transfer immunity to pathogens.In vitro studies have similarly demonstrated that human donor CD8+ T cells specific for recipient minor H antigens are found predominantly within the TN cell subset, suggesting selective TN cell depletion may alter the GVHD incidence and/or severity in human HCT.Methods and resultsWe developed an effective process for engineering human peripheral blood stem cell (PBSC) grafts that depletes CD45RA+ TN cells and retains CD34+ stem cells and functional CD45RO+ TM cells specific for a broad range of opportunistic pathogens (Bleakley BBMT 2014). We are conducting clinical trials to evaluate the selective depletion of TN cells from HLA-matched allogeneic PBSC grafts for the prevention of GVHD in patients with acute leukemia, the first of which has been published (Bleakley JCI 2015, N=35). Seventy patients have now been treated on three consecutive phase II trials. The median age was 34 years (1-56 years), 56% of patients had a diagnosis of ALL, 46% had previously relapsed or had detectable disease (MRD or relapse) at the time of HCT, and 23% had unrelated donor (URD) grafts. Intensive myeloablative, TBI-containing (13.2Gy) conditioning was used for 63 patients, whilst 7 patients received a medium intensity ’midi’ preparative regimen, including 4Gy of TBI. The TN-depletion procedure was successfully performed on URD PBSC products shipped overnight from donor centers throughout the US, as well as on MRD PBSC collected at our centers. Reliable engraftment with high-level donor chimerism was observed in recipients of ’midi’ as well as intensive myeloablative conditioning. The 2-year estimates of overall survival, disease-free survival, survival free of relapse and chronic GVHD (CRFS) and survival free of relapse, grade II-IV acute GVHD, and chronic GVHD (GRFS) are 79%, 73%, 69% and 63% respectively. Median follow-up among survivors is 26 months. The frequency and severity of chronic GVHD is remarkably low (5%) compared to historical rates of 40-60% chronic GVHD in HLA-matched PBSC transplantation with conventional calcineurin inhibitor-based immunosuppression. Relapse and non-relapse mortality (NRM) are acceptably low at 19% and 8%, respectively. No NRM occurred in patients <40 years. Updated results will be presented.ConclusionsThe outcomes of recipients of TN-depleted PBSC grafts compare very favorably to published results of HCT for patients with acute leukemia. For example, the 69% incidence of CRFS at 2 years in TN-depleted recipients compares with reported 2-year GRFS rates of 37% and 17% in recipients of allogeneic PBSC from HLA-matched related donors with or without ATG (Kroger et al. NEJM 2016). Our results suggest that TN-depletion of PBSC grafts may reduce the risk of chronic GVHD without negatively impacting other important HCT outcomes. DisclosuresRiddell:Juno Therapeutics: Equity Ownership, Patents & Royalties, Research Funding; Cell Medica: Consultancy, Honoraria; Adaptive Biotechnologies: Consultancy, Honoraria.

Neurocognitive Trajectory of Patients with Childhood Cerebral Adrenoleukodystrophy Who Received Allogeneic Hematopoietic Cell Transplantation at an Early Stage of Cerebral Disease

Adrenoleukodystrophy (ALD) is an X-linked disorder of very long chain fatty acid metabolism which may manifest with adrenal gland and/or central nervous system disease. Thirty-five percent of affected boys develop cerebral involvement (cALD) during childhood. Characterized by progressive cerebral demyelination and resulting in devastating neurological and cognitive decline, cALD is usually fatal within years of clinically-evident disease. The only treatment known to enhance long-term survival and stabilize cerebral disease for boys with cALD is hematopoietic cell transplantation (HCT). It is well-established that the risk for negative long-term outcomes is significantly lower when HCT occurs at an earlier stage of cerebral white matter disease (ALD MRI severity score [Loes score] < 10). Nevertheless, there is limited knowledge of broad-based neurocognitive outcomes of patients transplanted with early-disease cALD. We studied all patients who underwent HCT for cALD at the University of Minnesota between January 1, 1991 and October 20, 2014. HCT preparative regimens varied with time, although most patients underwent myeloablative conditioning. Transplant allograft sources varied. Neurocognitive data were available for 63 patients who had a pre-transplant Loes MRI severity score < 10. Within this cohort, patients with less extensive cerebral disease (Loes ≤ 4) at the time of HCT had significantly higher scores on baseline tests of intellectual functioning than those with more cerebral involvement (Loes >4). This difference was particularly apparent on measures of nonverbal (visual) reasoning and processing speed. Furthermore, patients with more MRI-evident white matter disease at HCT showed more dramatic declines in neurocognitive test performance over time. In a subset of 20 patients who were followed for at least 4 years post-transplant, 15 patients (75%) demonstrated significant neurocognitive deficits (>1.5 SD below the mean) in at least one of the following domains: overall intellectual functioning (30%), attention (39%), verbal memory (33%), visual-motor integration (40%) and fine motor skills (58%). Results of this study provide evidence that within this patient group (boys undergoing HCT for cALD with Loes score < 10), patients have better neurocognitive outcomes when minimal cerebral disease is evident on neuroimaging prior to transplant. These data represent the largest analysis of cognitive outcomes in patients with early-disease cALD who underwent HCT. Our findings provide a benchmark for comparison to alternative or additional interventions for patients with cALD. Opportunities to enhance standard methods of detecting early cerebral disease and to intervene at the earliest possible stage of cALD should be explored. The emergence of newborn screening for adrenoleukodystrophy will provide avenues for improved pre-transplant monitoring and timing of intervention to preserve cognitive functioning and quality of life among patients with cALD. DisclosuresNo relevant conflicts of interest to declare.

Adaptive NK Cell Expansion Is Associated with Reduced Relapse of Lymphoid Malignancies after Autologous Hematopoietic Cell Transplant

Introduction: Our group previously reported that latent or reactivated cytomegalovirus (CMV) after hematopoietic cell transplantation (HCT) leads to expansion of a CD56dimCD57+NKG2C+ "adaptive" natural killer (NK) cell subset that displays characteristics of immune memory. Here we report on the impact of these adaptive NK cells on outcomes after autologous (auto) HCT in patients with lymphoid malignancies.Methods: Based on our prior studies in allogeneic transplant, we hypothesized that patients with high absolute numbers of CD56dimCD57+NKG2C+ "adaptive" NK cells at day 28 post auto HCT ("high group") would have lower risk of relapse compared to those with low numbers ("low group"). Secondary outcomes included overall survival (OS) at 2 years and incidence of bacterial, fungal and viral infections 3 months post HCT. Patients with CMV reactivation were excluded because of low incidence (5%). Recursive partitioning was used to differentiate a high (≥1.529 adaptive NK cells/µL, n=88) from low (<1.529 cells/µL, n=25) group based on the largest Gray test statistic at day 28, which predicted the risk of relapse. Kaplan-Meier curves were used to estimate the probability of relapse and disease free survival (DFS) through 2-year post-HCT, and the log-rank test was used for comparisons. Fine-Gray and Cox regression was used to examine the independent effect of factors on relapse and DFS, respectively.Results: Overall, mean age at HCT was 55.8 years, 52% were males and 64% were CMV seropositive. Diagnoses included Hodgkin (13%) and non-Hodgkin lymphoma (36%) and multiple myeloma (51%) [Table 1]. Almost all patients (96%) in the low group vs. 77% in the high group had Karnofsky performance scores (KPS) of 90 or higher at the time of HCT, p=0.04.There were no other differences between the baseline characteristics of the groups. Cumulative incidence of relapse at 2-years was 34% (95% confidence interval [CI] 23-44%) in the high group compared with 70% (95% CI 49-91%) in the low group (p=0.0012). 2-year DFS rates were 63% (95% CI 51-72%) and 30% (95% CI 12-50%), respectively (p=0.0032) [Figure 1]. Overall survival (OS) at 2-years was 87% (95% CI 77-92%) in the high group vs. 84% (95% CI 63-94%) in the low group, p=0.70. Cumulative incidence of bacterial infections (25% vs. 24%, p=0.91), viral infections (2% vs. 0%, p=0.9) or fungal infections at 90 days (4% each, p=0.9) were similar in high and low groups. After adjusting for CMV serostatus, diagnosis, disease status, age, gender, KPS and comorbidity index in multivariate analysis, the high group had significantly lower risk of relapse (hazard ratio [HR] 0.22, 95% CI 0.11-0.46, p<0.0001) and improved DFS (HR 0.28, 95% CI 0.13-0.56, p<0.001) compared with the low group. The protective effect of CD56dimCD57+NKG2C+ NK cells on relapse (HR 0.12, 95% CI 0.05-0.30, p<0.0001) and DFS (HR 0.14, 95% CI 0.06-0.33, p<0.0001) was noted only in CMV seropositive patients, but not in seronegative individuals.Conclusion: We show that patients with lymphoid malignancies with high absolute counts of "adaptive" CD56dimCD57+NKG2C+ NK cells at day 28 post auto HCT had significantly superior DFS and lower risk of relapse compared with patients with low absolute "adaptive" NK cell counts. There was no difference in the risk of bacterial, fungal or viral infections or in OS between the groups. These provocative data suggest that interventions to increase numbers of these adaptive NK cells might provide a novel means of enhancing protection against relapse following auto HCT. [Display omitted] [Display omitted] DisclosuresCichocki:Fate Therapeutics, Inc: Research Funding. Miller:Oxis Biotech Scientific Advisory Board: Membership on an entity's Board of Directors or advisory committees.

Busulfan (Bu) in Combination with Double Nucleoside Analogues Fludarabine (Flu) and Clofarabine (Clo) Plus Vorinostat As a Novel Reduced Toxicity Conditioning Regimen for Allogeneic Hematopoietic Cell Transplantation (HCT) in Patients (pts) with Acute Leukemia

The combination of IV Bu and Flu is an effective and well-tolerated HCT conditioning regimen for patients with advanced acute leukemia. However, relapse remains the main reason for treatment failure. We combined two nucleoside analogues Flu and Clo, and showed cytotoxic synergy when combined with Bu, first in pre-clinical models, and subsequently in a randomized clinical study (Andersson BBMT 2011). We selected the optimized regimen from Andersson et al, and combined with escalating doses of the histone deacetylase inhibitor vorinostat in attempts to augment disease control without increasing toxicity. Herein, we describe our initial experience with this novel regimen for patients with advanced acute leukemia or MDS undergoing allogeneic HCT.Methods: Vorinostat (200mg to 1200mg) was escalated in cohorts of 3 patients, and administered 1 hour prior to the fixed regimen of Flu 10 mg/m2 followed by Clo 40 mg/m2 followed by Bu. The nucleoside analogs were infused over 1 hour once daily for 4 days, followed on each day by Bu, infused over 3 hours to a pharmacokinetically targeted daily area under the curve (AUC) of 5500 μMol-min ± 5%. Dilantin was given for seizure prophylaxis. GVHD prophylaxis was based on tacrolimus andmini-MTX, with the addition of rabbit anti-thymocyte globulin (4 mg/kg total dose) for unrelated donor transplants. The presence of minimal residual disease (MRD) was determined by multiparameter flow cytometry.Results: 21 patients (7 AML, 14 ALL) with median age 43 years (range 19-60) received an allogeneic matched sibling (n=10) or unrelated donor (n=11) HCT in CR1 (n=13), CR2 (n=1), primary induction failure (n=5), or relapse (n=2). Twelve patients had MRD or overt disease present at time of HCT. Ten patients had high-risk karyotype defined by t(9;22) (n=3), t(4;11) (n=2), complex (n=2), or del 5 or 7 (n=3). Median time from diagnosis to HCT was 5 months (range 3-48). Median time to ANC > 0.5 x 109/L and platelets > 20 x 109/L were 11 (range 10-15) and 12 days (5-30), respectively. Excluding grade 1 toxicities, the most commonly reported toxicities were nausea with maximum grade 2 (71%), followed by grade 2 or 3 mucositis (64%). Grade 2 or 3 reversible elevation of liver function tests was noted in 54% of pts, including 1 case of reversible VOD. No renal toxicities were noted. Two patients with prior systemic treatment for acute GVHD died of infections (disseminated adenovirus and E.coli sepsis). Ten patients achieved CR and clearance of MRD by day +30 after HCT; one patient had progressive disease and on patient died before disease restaging. Eighteen patients achieved 100% donor chimerism at 30 days following HCT, 2 patients remain with mixed chimerism by 100 day assessment following HCT, and 1 patient died before assessment. The incidence of grades II-IV acute GVHD is 43% and chronic extensive GVHD among 18 evaluable patients is 24%. With a median follow-up of 10 months among surviving patients (1-22), overall and progression-free survival at 6 months is 95% and 71%, respectively. Early results suggest excellent disease control in MRD negative patients (Figure).Conclusion: The Vorinostat-Flu-Clo-Bu combination is well-tolerated and did not add appreciable toxicity in these patients with high-risk leukemia. Longer follow-up is needed to better assess disease control. [Display omitted] DisclosuresCiurea:Spectrum Pharmaceuticals: Other: Advisory Board; Cyto-Sen Therapeutics: Equity Ownership. Patel:Ziopharm Oncology: Equity Ownership, Patents & Royalties; Intrexon: Equity Ownership, Patents & Royalties.

Impact of the Timing of Complete Remission and Transplantation on Estimates of Event-Free Survival in Acute Myeloid Leukemia

Background:Event free survival (EFS) is often used as an endpoint in AML clinical trials. EFS-based endpoints are controversial due to the lack of a consistent definition for the timing of complete remission (CR), and consideration of hematopoietic cell transplantation (HCT). Here, we examined the impact of the timing of achievement of CR and censoring for HCT in the estimation of the EFS, and assessed its robustness as an endpoint in AML.Methods:All prospective trials since 2003 using anthracycline and cytarabine chemotherapy for newly diagnosed patients (pts) with AML conducted through the Alliance for Clinical Trials in Oncology, and whose primary endpoint data has been reported, were included (5 trials total). Trial 1 - randomized phase III study in older AML pts (n=504, median age 69, 61% male); trial 2 - single-arm phase II study in older FLT3-mutated AML pts (n=54, median age 67, 56% male); trial 3 - randomized phase III study in younger AML pts (n=546, median age 48, 55% male); trial 4 - randomized phase III study in younger FLT3-mutated AML pts (n=717, median age 48, 45% male); and trial 5 - single arm phase II study in core-binding factor AML pts with no restriction on age (n=61, median age 51, 51% male). Induction failure was defined as one of: no CR by 60 days (Definition 1), no CR by the end of all protocol induction courses (Definition 2), or no CR by the end of all protocol treatment (Definition 3). CR was defined as <5% blasts in a cellular marrow with recovery of >1000 neutrophils/ul (>1500 neutrophils/ul for trial 1), >100,000 platelets/ul, and no red cell transfusion requirement. EFS was defined as the time from randomization / registration to the first evidence of induction failure using each of the 3 methods above, relapse, or death from any cause. Patients last known to be alive without relapse were censored at the date of last contact. Including the 3 induction failure definitions and consideration of censoring or no censoring for HCT, the Kaplan Meier estimates of EFS were computed for the six different definitions of EFS.Results:The number of deaths was respectively 464, 38, 307, 357, and 13 across the 5 trials, with a median follow-up of 99.7, 28.2, 60.1, 58.2, and 33.5 months on the alive patients, respectively. Not considering HCT, in trial 1, the median EFS ranged from 2.0 to 4.3 months (115% difference); in trial 2, the median EFS ranged from 6.9 to 8.3 months (20% difference); in trial 3, the median EFS ranged from 9.8 to11.2 months (14% difference); and in trial 4, the median EFS ranged from 5.5 to 9.7 months (76% difference). The median EFS was not achieved in trial 5; however the 1-year EFS estimates ranged from 78 to 83% (6% difference). Consistently across all trials, as expected, the EFS estimate using the 60-day induction failure yielded the shortest estimates, whereas the end-of-treatment induction failure yielded the longest estimates. Results were similar both with and without censoring at the time of HCT as the event of interest occurred prior to transplantation in most cases.Conclusions:Although relapse and death are firm endpoints, the determination of failure to achieve CR is not consistent across studies. While there is minimal impact of censoring at HCT on EFS estimates, the median EFS estimates differed considerably based on the timing of CR used to define induction failure, with the magnitude of difference being large enough in most cases (observed range: 14% to >100%) to lead to incorrect conclusions about efficacy in a single arm trial if the trial definition was not consistent with the definition used for the historical control. The timing of CR should be carefully examined in the historical control data used to guide the design of the next trial. [Display omitted] DisclosuresUy:Glycomimetics: Consultancy; Boehringer Ingelheim: Consultancy. Stone:Celator: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy; Amgen: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy; Novartis: Consultancy; Jansen: Consultancy; Pfizer: Consultancy; ONO: Consultancy; Juno Therapeutics: Consultancy; Merck: Consultancy; Roche: Consultancy; Seattle Genetics: Consultancy; Sunesis Pharmaceuticals: Consultancy; Xenetic Biosciences: Consultancy.

Significance of Peri-Transplant Dynamics of Minimal Residual Disease (MRD) in Adults with Acute Myeloid Leukemia (AML) in Morphological Remission Undergoing Myeloablative Allogeneic Hematopoietic Cell Transplantation

Background: Numerous studies from others and our institution have demonstrated that the presence of minimal residual disease (MRD), detected at the time of hematopoietic cell transplantation (HCT), is strongly and independently associated with increased relapse risk and short survival in adults with acute myeloid leukemia (AML) undergoing myeloablative allogeneic HCT in morphologic complete remission (CR). In contrast, very little information is available regarding the prognostic significance of peri-transplant MRD dynamics in these patients. Since bone marrow staging studies with multiparameter flow cytometric (MFC) assessment for MRD are routinely obtained not only before but also at approximately day +28 following transplantation at our institution, we here retrospectively studied the relationship between peri-HCT MRD dynamics and post-transplant outcomes in a large patient cohort. We asked whether persistence or disappearance of MRD might identify cohorts of patients in whom post-transplant therapy was particularly indicated or unnecessary.Patients and Methods: AML patients ³18 years of age were eligible for this retrospective analysis if they were in first or second morphologic CR or CR with incomplete blood count recovery (CRi) irrespective of the presence of MRD, underwent allogeneic HCT with myeloablative conditioning between 2006 and 2014, received peripheral blood or bone marrow as stem cell source, and had pre-HCT bone marrow staging studies available that included 10-color MFC assessments for MRD. MRD was identified as a cell population showing deviation from normal antigen expression patterns compared with normal or regenerating marrow; any level of residual disease was considered MRDpos. We considered post-HCT MRD assessments in patients in whom bone marrow re-staging with MFC MRD analysis were obtained 28±7 days after transplantation. For this analysis, the primary endpoint of interest was overall survival, which was estimated using the Kaplan-Meier method.Results: 311 patients were identified and included in this study. Consistent with our previous analyses, patients with MRD at the time of HCT (MRDpos; n=76) had significantly shorter survival than MRDneg patients (n=234; estimated 3 year post-HCT survival: 26% [95% confidence interval: 17-37%) vs. 73% [66-78%], P <0.001). 310 patients survived at least 21 days following transplantation; for 279 of these (89.7%), post-HCT MRD assessments were obtained at day +28±7 and available for analysis. 214 patients (76.7%) had no MFC evidence of MRD before and after HCT (MRDneg/MRDneg), 2 (0.7%) were MRDneg/MRDpos, 49 (17.6%) were MRDpos/MRDneg, and 14 (5.0%) were MRDpos/MRDpos. Of the 65 patients who had detectable MRD either before and/or after transplantation, 58 had decreasing levels of MRD (MRDdecr) over the peri-HCT period, whereas 7 patients had increasing MRD levels (MRDincr) around the time of transplantation. As depicted in Figure 1, MRDneg/MRDneg patients had excellent long-term outcomes (survival at 3 years after day +28 MRD assessment: 76% [69-82%]), whereas both MRDneg/MRDpos patients died within 70 days after the day +28 MRD assessment. Interestingly, for patients who were MRDpos before transplantation, outcomes were relatively poor regardless of whether or not they had persistent MRD around day +28 after transplantation (MRDpos/MRDneg patients: 23% [12-36%]; for MRDpos/MRDpos patients: 19% [4-44%]). However, long-term survival was only observed among MRDdecr patients (at 3 years after day +28 MRD assessment: 24% [14-37%]), whereas all MRDincr patients died a median of 97 (range: 15-808) days following the post-HCT MRD assessment (Figure 2).Conclusion: Patients who have no evidence of MRD before and after HCT have excellent long-term outcomes. In contrast, patients who are MRDpos before transplantation have poor survival expectations regardless of whether or not they clear MRD within the first 28 days after transplantation, but long-term survival is only found among some patients with decreasing MRD levels over the peri-transplant period. This finding suggests that patients who are MRDpos at the time of HCT should be considered for pre-emptive therapeutic strategies given their high risk of disease recurrence regardless of the day +28 MRD information. [Display omitted] [Display omitted] DisclosuresRadich:Incyte: Consultancy; Ariad: Consultancy; Gilliad: Consultancy; Novartis: Consultancy, Research Funding. Walter:Amphivena Therapeutics, Inc.: Consultancy, Research Funding; Seattle Genetics, Inc.: Research Funding; Covagen AG: Consultancy; AstraZeneca, Inc.: Consultancy; Pfizer, Inc.: Consultancy; Amgen, Inc.: Research Funding.

Outcomes after Umbilical Cord Blood Transplantation for Myelodysplastic Syndromes: A Center for International Blood and Marrow Transplant Registry (CIBMTR®) Study

Background:Although, widespread application of innovative sequencing technologies is rapidly unraveling the molecular underpinnings driving the pathogenesis of myelodysplastic syndromes (MDS), allogeneic hematopoietic cell transplantation (HCT) remains the only therapeutic modality that has demonstrated curative potential. However, a significant proportion of patients lack a human leukocyte antigen (HLA)-matched sibling or unrelated donor, and alternative donor sources are needed to extend HCT to patients that are otherwise suitable. There have been few published series solely dedicated to describing the outcomes of adult patients who have undergone umbilical cord blood transplantation (UCBT) for MDS.Methods:We identified 176 adult MDS patients who underwent UCBT, at 59 centers, between 2004 and 2013 from the CIBMTR database. The primary endpoints were the estimated incidences of graft-vs-host-disease (GVHD), relapse, transplant-related mortality (TRM), disease free survival (DFS), and overall survival (OS). Multivariate models were built to assess the ability of the revised International Prognostic Scoring System (IPSS-R) to predict post-HCT outcome.Results:Median age at the time of transplant was 56 (18-73) with 32%, 27%, 34% having a comorbidity score (HCT-CI) of 0, 1-2, or ≥ 3, respectively. The median time from diagnosis to transplant was 9 (< 1-147) months; 23% of patients did not receive pre-HCT chemotherapy; 72% has a marrow blast count ≤ 5%. IPSS-R scores are shown in Table 1. Myeloablative and reduced-intensity/non-myeloablative conditioning was used in 35% and 65%, respectively; 43% incorporating ATG/alemtuzumab. Double units were used in 80%; median total nucleated cell dose (TNC) of 4 × 107 /kg (< 1-29); considering the unit with the higher number of HLA incompatibilities with the recipient, 60% had ≥ 2 mismatches. The 100-day probability of grade 2-4 acute GVHD was 38%. The 3-year probabilities of chronic GVHD, relapse, TRM, DFS, and OS was 28%, 32%, 40%, 28%, and 31%, respectively. In multivariate analysis using marginal Cox model to adjust for center effect, increasing IPSS-R score at the time of HCT was associated with inferior post-HCT TRM, DFS, and OS (Table 2). IPSS-R was associated with neither GVHD nor relapse. HCT-CI was associated with TRM (P = .001), DFS (P = .02), and OS (P = .001), and conditioning intensity was associated with relapse (P < .001). A higher proportion of myeloablative HCTs were done for those with high-risk disease by IPSS-R, but the interaction between conditioning intensity and IPSS-R for relapse was not significant.Conclusions:Treatment decisions and clinical trial design can be informed by providing a descriptive analysis of UCBT for MDS that incorporates a large number of patients from multiple centers. In this analysis, TRM was significantly associated with HCT-CI scores. Interestingly, IPSS-R, a model that specifically quantifies disease risk, at the time of HCT did not predict for post-HCT relapse, but did for TRM.Table 1Pre-HCT risk scoresIPSS-R prior to transplantVery low18 (10)Low41 (23)Intermediate33 (19)High34 (19)Very high22 (13)Missing28 (16)Table 2Multivariate analysis*TRMIPSS-RNRR95% CI Lower Limit95% CI Upper LimitP -valueOverallP -valueVery low/Low641.006Intermediate34.68.341.35.30High/Very high541.761.122.75.01Missing282.05.934.52.08DFSIPSS-RNRR95% CI Lower Limit95% CI Upper LimitP -valueOverallP -valueVery low/Low641.02Intermediate34.83.501.37.50High/Very high541.391.021.91.04Missing281.63.952.81.08OSIPSS-RNRR95% CI Lower Limit95% CI Upper LimitP -valueOverallP -valueVery low/Low651.008Intermediate35.88.511.50.60High/Very high551.551.122.14.01Missing281.72.913.26.09* When adjusting for center effect and HCT-CI DisclosuresNo relevant conflicts of interest to declare.

Pre-Emptive Donor Lymphocyte Infusion with CD19-Directed, CAR-Modified T Cells Infused after Allogeneic Hematopoietic Cell Transplantation for Patients with Advanced CD19+ Malignancies

Background: Allogeneic hematopoietic cell transplantation (HCT) can be curative in a subset of patients with advanced lymphoid malignancies but relapse remains a major reason for treatment failure. Donor-derived, non-specific lymphocyte infusions (DLI) can confer an immune anti-malignancy effect but can be complicated by graft-versus-host-disease (GVHD). Chimeric antigen receptor (CAR)-modified T cells directed toward CD19 have demonstrated dramatic efficacy in patients with refractory ALL and NHL. However, responses are often associated with life-threatening cytokine release syndrome. Aim: We hypothesized that infusing CAR-modified, CD19-specific T-cells after HCT as a directed DLI would be associated with a low rate of GVHD, better disease control, and a less severe cytokine release syndrome since administered in a minimal disease state. Methods: We employed a non-viral gene transfer using the Sleeping Beauty (SB) transposon/transposase system to stably express a CD19-specific CAR (designated CD19RCD28 that activates via CD3z &amp; CD28) in donor-derived T cells for patients with advanced CD19+ lymphoid malignancies. T-cells were electroporated using a Nucleofector device to synchronously introduce two DNA plasmids coding for SB transposon (CD19RCD28) and hyperactive SB transposase (SB11). T-cells stably expressing the CAR were retrieved over 28 days of co-culture by recursive additions of g-irradiated activating and propagating cells (AaPC) in presence of soluble recombinant interleukin (IL)-2 and IL-21. The AaPC were derived from K562 cells and genetically modified to co-express CD19 as well as the co-stimulatory molecules CD86, CD137L, and a membrane-bound version of IL-15. Results: To date, we have successfully treated 21 patients with median age 36 years (range 21-62) with advanced CD19+ ALL (n=18) or NHL (n=3); 10 patients had active disease at time of HCT. Donor-derived CAR+ T cells (HLA-matched sibling n=10; 1 Ag mismatched sibling n=1; haplo family n=8; cord blood n=2) were infused at a median 64 days (range 42-91 days) following HCT to prevent disease progression. Transplant preparative regimens were myeloablative, busulfan-based (n=10) or reduced intensity, fludarabine-based (n=11). All patients were maintained on GVHD prophylaxis at time of CAR T-cell infusion with tacrolimus, plus mycophenolate mofeteil for cord, plus post-HCT cyclophosphamide for haplo donors. The starting CAR+ T-cell dose was 106 (n=7), escalated to 107 (n=6), 5x107 (n=5), and currently at 108 (n=3) modified T cells/m2 (based on recipient body surface area). Patients have not demonstrated any acute or late toxicity to CAR+ T cell infusions. Three patients developed acute grades 2-4 GVHD (liver n=1, upper GI n=1, skin=1) which was within the expected range after allogeneic HCT alone. Of note, the rate of CMV reactivation after CAR T cell infusion was 24% vs. 41 % previously reported for our patients without CAR T cell infusion (Wilhelm et al. J Oncol Parm Practice, 2014, 20:257). Nineteen patients have had at least 30 days follow-up post CAR T-cell infusion and are evaluable for disease progression. Forty-eight percent of patients (n=10) remain alive and in complete remission (CR) at median 5.2 months (range 0-21.3 months) following CAR T cell infusion. Importantly, among 8 patients who received haplo-HCT and CAR, 7 remain in remission at median 4.2 months. Conclusion: We demonstrate that infusing donor-derived CD19-specific CAR+ T cells, using the SB and AaPC platform, in the adjuvant HCT setting as pre-emptive DLI may provide an effective and safe approach for maintaining remission in patients at high risk for relapse. Graft-vs-host disease did not appear increased by administration of the donor derived CAR-T cells. Furthermore, the add-back of allogeneic T cells appears to have contributed to immune reconstitution and control of opportunistic viral infection. Disclosures Huls: Intrexon and Ziopharm: Employment, Equity Ownership. Singh:Intrexon and Ziopharm: Equity Ownership, Patents &amp; Royalties. Olivares:Intrexon and Ziopharm: Equity Ownership, Patents &amp; Royalties. Su:Ziopharm and Intrexon: Employment. Figliola:Intrexon and Ziopharm: Equity Ownership, Patents &amp; Royalties. Kumar:Ziopharm and Intrexon: Equity Ownership. Jena:Ziopharm Oncology: Equity Ownership, Patents &amp; Royalties: Potential roylaties (Patent submitted); Intrexon: Equity Ownership, Patents &amp; Royalties: Potential royalties (Patent submitted). Ang:Intrexon and Ziopharm: Equity Ownership. Lee:Intrexon: Equity Ownership; Cyto-Sen: Equity Ownership; Ziopharm: Equity Ownership.

Outcomes of Allogeneic Hematopoietic Cell Transplantation in Patients with Myelofibrosis with Prior Exposure to Janus Kinase 1/2 Inhibitors

The impact of Janus kinase (JAK) 1/2 inhibitor therapy before allogeneic hematopoietic cell transplantation (HCT) has not been studied in a large cohort in myelofibrosis (MF). In this retrospective multicenter study, we analyzed outcomes of patients who underwent HCT for MF with prior exposure to JAK1/2 inhibitors. One hundred consecutive patients from participating centers were analyzed, and based on clinical status and response to JAK1/2 inhibitors at the time of HCT, patients were stratified into 5 groups: (1) clinical improvement (n = 23), (2) stable disease (n = 31), (3) new cytopenia/increasing blasts/intolerance (n = 15), (4) progressive disease: splenomegaly (n = 18), and (5) progressive disease: leukemic transformation (LT) (n = 13). Overall survival (OS) at 2 years was 61% (95% confidence interval [CI], 49% to 71%). OS was 91% (95% CI, 69% to 98%) for those who experienced clinical improvement and 32% (95% CI, 8% to 59%) for those who developed LT on JAK1/2 inhibitors. In multivariable analysis, response to JAK1/2 inhibitors (P = .03), dynamic international prognostic scoring system score (P = .003), and donor type (P = .006) were independent predictors of survival. Among the 66 patients who remained on JAK1/2 inhibitors until stopped for HCT, 2 patients developed serious adverse events necessitating delay of HCT and another 8 patients had symptoms with lesser severity. Adverse events were more common in patients who started tapering or abruptly stopped their regular dose ≥6 days before conditioning therapy. We conclude that prior exposure to JAK1/2 inhibitors did not adversely affect post-transplantation outcomes. Our data suggest that JAK1/2 inhibitors should be continued near to the start of conditioning therapy. The favorable outcomes of patients who experienced clinical improvement with JAK1/2 inhibitor therapy before HCT were particularly encouraging, and need further prospective validation.

Hematopoietic Cell Transplantation in Patients with Medication-Related Osteonecrosis of the Jaws.

Patients with medication-related osteonecrosis of the jaw (MRONJ) are at risk for developing infections and often require long-term antimicrobial therapy for management. It is unclear whether patients with multiple myeloma (MM) who develop MRONJ experience increased morbidity when they undergo hematopoietic cell transplantation (HCT). The aim of this study was to characterize the course of HCT in MM patients with MRONJ. A retrospective chart review was conducted for patients with MM and MRONJ who underwent HCT between December 2005 and December 2014. Data collected included bisphosphonate use, MRONJ stage, positive blood cultures, number of febrile days, and length of hospital stay. Eleven patients (median age, 61; range, 46 to 71) fulfilled the criteria. Patients received zoledronic acid (72.7%), pamidronate (18.1%), or a combination of both (9%). At the time of HCT, 10 patients were in stage 1 MRONJ with 1 in stage 0. All patients had only mandibular involvement. No patient developed pain/infection at the MRONJ site during hospitalization. Bacteremia with positive blood cultures for Staphylococcus aureus occurred in 3 patients (27.2%), and 4 patients (36.3%) developed fever lasting between 4 to 6days (of who 1 had positive blood cultures). The median length of hospital stay was 17days (range, 7 to 22days). These data suggests that patients with MM and MRONJ who undergo HCT are not at increased risk of developing symptoms associated with the MRONJ site or HCT-related infectious complications, and their MRONJ is not worsened by HCT.

Central Nervous System Involvement in Acute Myeloid Leukemia Patients Undergoing Hematopoietic Cell Transplantation

Knowledge regarding the rate of central nervous system (CNS) involvement and risk factors for its development in acute myeloid leukemia (AML) patients undergoing allogeneic hematopoietic cell transplantation (HCT) are limited. In this study we retrospectively evaluated CNS involvement in 327 patients who underwent myeloablative HCT at our institute in which all patients have cerebrospinal fluid examined by morphology or flow cytometry before HCT. Twenty-two patients (7%) had CNS AML involvement at pre-HCT evaluation. Covariates associated with such involvement were higher WBC at diagnosis, prior CNS or other extramedullary disease, and evidence of systemic disease at pre-HCT evaluation. History of prior CNS disease and disease status at pre-HCT evaluation allowed stratification of patients into 3 risk groups: 35% (20 patients), 16% (51 patients), and 3% (256 patients) rates of pre-HCT CNS involvement. Treatment of pre-HCT CNS disease was uniformly successful regardless of whether cranial irradiation therapy was used. Perhaps as a result, presence of CNS pre-HCT had no independent influence on post-HCT outcome, which was primarily influenced by status of systemic disease at time of HCT.

Therapy-Related Acute Lymphoblastic Leukemia: Cytogenetic Features and Hematopoietic Cell Transplantation Outcome

The clinical and pathologic characteristics and treatment outcome of therapy-related acute lymphoblastic leukemia (t-ALL) remains less defined compared to therapy-related acute myeloid leukemia. Although MLL rearrangement is the most characteristic genetic abnormality associated with t-ALL, other chromosomal alterations have been described.We examined the pathologic features and treatment outcome of a cohort of t-ALL patients who were undergoing allogeneic hematopoietic cell transplantation (HCT) in order to better define the cytogenetic profile of t-ALL, and to determine the outcome of t-ALL with allogeneic HCT. We reviewed all consecutive cases of adult ALL that had undergone allogeneic HCT at our institution between 1998 and 2014. Data on previous malignancy, chemotherapy, radiation, cytogenetic abnormalities and survival were collected and analyzed.We identified 28 cases of t-ALL who had history of chemotherapy and/or radiation prior to ALL diagnosis and subsequently undergone allogeneic HCT at our institution. The median age was 48 years (range 29-61), and 57% of patients were female. The most common prior diagnosis was breast cancer (n=9), followed by multiple myeloma (n=4), sarcoma (n=4), thyroid cancer/disease (n=4), lymphoma (n=3), germ cell tumor (n=2, including a case of combined germ cell and CLL), melanoma (n=1), and colon cancer (n=1). The median interval from initial diagnosis of malignancy to diagnosis of t-ALL was 7.3 years (range; 0.9-50.7). Thirty-nine percent had prior combination of chemotherapy and radiation therapy, 32% had prior radiotherapy alone and 29% had prior chemotherapy alone. Four patients had undergone autologous-HCT prior to t-ALL onset. All cases had B-cell phenotype. Median initial WBC was 8 X 109/L (range 1.2-323). Interestingly, in our cohort the most common cytogenetic abnormality was t(9;22) [Philadelphia chromosome] (39%), and followed by MLL rearrangement (25%). The median interval from diagnosis of previous malignancy to ALL diagnosis was 9.3 years for Ph+ ALL, 2.1 years for MLL-rearranged ALL, and 7.9 years for other cytogenetic types of t-ALL. The median initial WBC on presentation was 8 X 109/L for Ph+ ALL, 17 X 109/L for MLL-rearranged ALL, and 8 X 109/L for other cytogenetic types of t-ALL. Disease status at the time of HCT was as follows: 20 patients were in CR1, 2 were in CR2, 3 were in first relapse and another 3 after induction failure. Conditioning regimen was full intensity in 16 patients and reduced intensity in 12. Four-year Leukemia-free survival (LFS) and overall survival (OS) for the whole cohort were 46% and 49%, respectively. The 4-year LFS and OS for MLL-rearranged cases, Ph+ cases and other cytogenetic types were (62% vs. 43% vs. 40%, p=0.68) and (60% vs. 56% vs. 35%, p=0.71), respectively. In this cohort, only one patient relapsed with the original disease (CLL) after allogeneic HCT. The 100 days non-relapse mortality for evaluable patients was 8%.Ph+ t-ALL is an under recognized subtype of t-ALL and appears to be at least as common as MLL rearrangement among t-ALL. The HCT outcome of t-ALL appears to be similar to de novo ALL. DisclosuresNo relevant conflicts of interest to declare.

Vascularized Composite Allograft Tolerance Across MHC Barriers in a Large Animal Model

Vascularized composite allograft (VCA) transplantation can restore form and function following severe craniofacial injuries, extremity amputations or massive tissue loss. The induction of transplant tolerance would eliminate the need for long-term immunosuppression, realigning the risk-benefit ratio for these life-enhancing procedures. Skin, a critical component of VCA, has consistently presented the most stringent challenge to transplant tolerance. Here, we demonstrate, in a clinically relevant miniature swine model, induction of immunologic tolerance of VCAs across MHC barriers by induction of stable hematopoietic mixed chimerism. Recipient conditioning consisted of T cell depletion with CD3-immunotoxin, and 100 cGy total body irradiation prior to hematopoietic cell transplantation (HCT) and a 45-day course of cyclosporine A. VCA transplantation was performed either simultaneously to induction of mixed chimerism or into established mixed chimeras 85-150 days later. Following withdrawal of immunosuppression both VCAs transplanted into stable chimeras (n=4), and those transplanted at the time of HCT (n=2) accepted all components, including skin, without evidence of rejection to the experimental end point 115-504 days posttransplant. These data demonstrate that tolerance across MHC mismatches can be induced in a clinically relevant VCA model, providing proof of concept for long-term immunosuppression-free survival.

MPS specific physical symptom score and daily living skills in MPS VI

understanding of the role of the patient's medical problems in their quality-of-life and psychological status and for use as a treatment outcome measure. We have developed a Physical Symptom Score (PSS) by quantifying the medical history, and validated the PSS with qualityof-life (QOL) and daily living skills (DLS) measures. We hypothesize that a summative history of medical problems in multiple organ systems as reflected in the PSS is associatedwith ability to carry out daily living skills and with quality-of-life outcomes. Our subjects, all participants in an MPS longitudinal study, were 43MPS I patients (Hurler syndrome= 26, attenuated= 17) aged 5.3 to 25.5 years, and treated with either hematopoietic cell transplant or enzyme replacement therapy. Medical and treatment histories were taken by the first author using the study medical history case report forms. Clinical files were reviewed to check accuracy and obtain additional medical information. A scoring system was devised to include frequency and severity of the organ system involvement in four medical domains: skeletal/orthopedic, vision, hearing, and cardio-respiratory. The scoring system also quantified the patient's number of surgical procedures using general anesthesia, and the absence or presence of hydrocephalus, with or without shunt placement. To validate the PSS, assessment tools called the Child Health Questionnaire Parent Form 50 (CHQ-PF50) and the Vineland Adaptive Behavioral Scales (VABS) Second Edition were administered as proxies for the daily living skills and quality-of-life domains. To document the inter-rater reliability of the MPS Specific Physical Symptom Score, a second examiner independently scored, and the inter-rater score agreement was 100%. The PSS of the 43 MPS I patients was negatively correlated with DLS (r= -0.67) and QOL (r = -0.52) in the MPS attenuated patient group. For the Hurler patient group the PSS was slightly negatively correlated with QOL (r = -0.33), but was uncorrelated with DLS. We have demonstrated the reliability of the PSS and the validity of the scale for MPS attenuated patients. While a small negative correlation was found with the QOL in Hurler syndrome, no relationship was found with DLS. Explanations might include: 1) the medical problems occurred mostly around the time of hematopoietic cell transplant, with more subsequent elapsed time than in the attenuated patients; 2) differing expectations of parents between the two groups; and 3) hematopoietic cell transplant yields more medical stability over time. The next step is to include a larger MPS I sample to see whether these results can be replicated, and to examine the role of parental expectations and long-term medical symptom stability. (Supported by the Lysosomal Disease Network, NIH U54NS065768).

Frequency and Impact Of Allogeneic Hematopoetic Stem Cell Transplantation and Preparative Regimen In Patients With High and Intermediate Risk Acute Myeloid Leukemia: A Single Small Center Experience

BackgroundAllogeneic hematopoietic cell transplantation (HCT) likely prolongs survival in high and intermediate risk adults with acute myeloid leukemia (AML). Prior studies, however, suggest that only about 15-20% of AML patients especially older than 50 with abnormal cytogenetics receive HCT. In this report, we evaluated the impact of transplant and preparative regimen on high- or intermediate-risk AML patients treated in our center. MethodsWe retrospectively reviewed all patients who were diagnosed with AML (non promyelocytic) in our center between 2002 and 2012. Primary objective was to study the impact of HCT and preparative regimen in high and intermediate risk AML patients. Demographics and disease-related variables were collected. OS was defined as the time from diagnosis to the time of death or last follow up. ResultsBetween 2002 and 2012, 123 patients with high or intermediate risk AML patients were treated at our center. Median age at diagnosis was 60 (range 19-89). 82 patients had high-risk features while 41 had intermediate risk features. Median OS for all patients was 368 days.Of these 124 patients, fifty-one patients (41%) received allogeneic HSCT at a median of 4.6 months from diagnosis. Median age of patients who received HCT was 53 while median age of patients who did not get HCT was 68. Of the 51 patients who received HCT, 13 patients with median age of 61 received a reduced toxicity/ Intensity conditioning regimen (RIC) while 37 patients with median age of 49 received a fully myelo-ablative regimen (MA). One got transplant elsewhere with unknown regimen. Median percentage of blasts in bone marrow at time of HCT was 3 and 3.5% for the RIC and MA regimens, respectively. Number of patients who had 10% or more blasts in the bone marrow at transplant was 9 of the 37 patients (24%) who received MA regimen and 3 of the 13 patients (23%) who received RIC regimen.Median OS for patients who received HCT was 551 days while it was 200 days for patients who did not receive HCT (p=0.0013) Fig1. The median OS for patients who got RIC was 1095 days but less at 434 days for MA patients but not statistically significant (p=0.64) Fig2. The cumulative incidence of relapse was not different between the two groups. [Display omitted] [Display omitted] ConclusionIn this small cohort of consecutive patients from a single center, the results suggest that HCT can be performed in patients with high and Intermediate-risk AML patients including older patients using RIC. RIC in older patients and MA in younger patients did not differ in term of OS. However this is limited by the small number of patients and a larger prospective evaluation is needed taking into consideration better models encompassing performance status and co-morbidities. Disclosures:No relevant conflicts of interest to declare.

Comparison Of Minimal Residual Disease As Outcome Predictor For AML Patients In First Complete Remission Undergoing Myeloablative Or Nonmyeloablative Allogeneic Hematopoietic Cell Transplantation

BackgroundMinimal residual disease (MRD) has been recognized as a strong, independent predictor of increased relapse risk and poor outcome for patients with acute myeloid leukemia (AML) in first complete remission (CR) undergoing myeloablative (MA) allogeneic hematopoietic cell transplantation (HCT). As the relationship between MRD and outcome is less studied for AML patients undergoing nonmyeloablative (NMA) HCT, we herein conducted a comparative analysis to assess this association relative to that seen in MA HCT. Patients and MethodsWe studied 272 consecutive patients receiving NMA (n=63) or MA (n=209) HCT for AML in first CR or CR with incomplete blood count recovery (CRi) between May 2006 and May 2012. Pre-HCT bone marrow aspirates were obtained in all patients and analyzed by routine karyotyping and ten-color flow cytometry. MRD was identified as a cell population showing deviation from normal antigen expression patterns as compared with normal or regenerating marrow. Any level of residual disease was considered MRDpos. Data are current as of April 1, 2013. ResultsBaseline characteristics of the study cohort are summarized in Table 1. Patients undergoing NMA HCT were significantly older than those undergoing MA HCT (p<0.001), more often were male (p=0.03), had more comorbidities (p<0.001), more often had secondary leukemias (p=0.05), and more often had incomplete blood count recovery at the time of HCT (p<0.001). Sixteen NMA patients (25.4%) and 40 MA patients (19.1%) were MRDpos, with medians of 0.31% (range: 0.02-2.8%) and 0.29% (0.007-7.8%) abnormal blasts for MRDpos NMA and MA patients, respectively. Three-year estimates of relapse among NMA patients were 31% (18-44%) and 64% (35-82%) for MRDneg and MRDpos patients, respectively, and 21% (15-29%) and 53% (37-68%), respectively, among MA patients (Figure 1A). Among NMA patients, the 3-year estimates of OS were 53% (37-66%) and 49% (21-73%) for MRDneg and MRDpos patients, respectively; among MA patients, 3-year OS was estimated to be 74% (65-80%) and 36% (20-51%), respectively (Figure 1B). This unexpectedly similar outcome in OS for MRDneg and MRDpos NMA patients was largely accounted for by the considerably higher non-relapse mortality (NRM) in MRDneg patients (29% [17-42%]) compared to MRDpos patients (0%), which was the reverse of findings in MRDneg and MRDpos MA patients (8% [5-13%] vs. 21% [10-34%], respectively; Figure 1C). Hazard ratio analysis confirmed a highly statistically significant difference between MA and NMA patients in the association of MRD status with NRM (p<0.001), but not with relapse (p=0.45). There was also evidence of a differential association of MRD status with OS (p=0.03). After adjustment for HCT type (NMA vs MA), age, cytogenetic risk, type of AML, number of cycles of induction chemotherapy, type of consolidation therapy, pre-HCT karyotype, pre-HCT blood counts, and HCT-comorbidity index, being MRDpos was associated with increased risk of relapse (HR=3.31 [1.91-5.73], p<0.001).Table 1NMA HCTMA HCTMRDneg (n=47)MRDpos (n=16)MRDneg (n=169)MRDpos (n=40)Median Age at HCT (range), years62.2 (20.0-75.0)63.7 (33.1-74.0)44.7 (0.6-69.7)47.6 (2.5-66.8)Male Gender, %61.7%87.5%51.5%57.5%Cytogenetics, %Favorable6.7%0%4.2%0%Intermediate71.1%50.0%72.1%51.3%Adverse22.2%50.0%23.6%48.7%Secondary AML, %42.6%62.5%29.0%55.0%Pre-HCT Consolidation Therapy, %No8.5%25.0%16.0%37.5%Yes91.5%75.0%84.0%62.5%Median CR Duration (range), days115 (35-318)76.5 (35-356)121 (18-465)93 (16-383)Pre-HCT Peripheral Blood Counts, %Recovered72.3%68.9%91.7%85.0%Not recovered27.7%31.3%8.3%15.0%Pre-HCT Routine Cytogenetics, %Normalized karyotype51.1%37.5%52.7%47.5%Abnormal karyotype6.4%43.8%8.9%27.5%Missing/non-informative data42.6%18.8%38.5%25.0%Median HCT Comorbidity Index (range), days3 (0-11)4 (2-10)2 (0-6)2 (0-7)Unrelated Donor, %72.3%62.5%65.1%72.5% ConclusionThe negative impact of MRD on post-transplant relapse risk among AML patients in CR1 undergoing NMA HCT is similar to the negative impact seen in patients undergoing MA HCT. Because of the high rate of NRM among MRDneg NMA patients the survival difference between MRDneg and MRDpos patients was much larger in MA than NMA patients in this analysis.▪ Disclosures:No relevant conflicts of interest to declare.

Outcome Of Hematopoietic Cell Transplantation (HCT) In Pediatric Patients With Non-Hodgkin Lymphoma (NHL): Single Institution Results From Saudi Arabia

Although HCT is an accepted component of the treatment strategy for relapsed/refractory pediatric NHL, only few studies have reported on the outcome for these patients. Most have reported on small numbers of patients, with survivals ranging from 27% to 75%.Clinical data were retrospectively retrieved for patients with NHL who had undergone HCT. Pre-HCT information, including pathologic diagnosis, response to first- and second-line therapy and pre-HCT disease status were collected, in addition to details of the transplant process and patient and disease outcome.Between 1996 and 2012, 28 pediatric patients with NHL underwent HCT. Primary diagnosis for these patients included Burkitt lymphoma (n=13), Large B-cell lymphoma (n=4), T-Lymphoblastic lymphoma (n=4), NK/T cell lymphoma/leukemia (n=3), Peripheral T-cell lymphoma (n=2), B-lymphoblastic lymphoma ((n=1) and anaplastic large cell lymphoma (n=1). The median age at HCT was 7.65 years (mean 8.2; range 1-14.3). Twenty had suffered a relapse of their disease, while five had primary progression; three patients with NK/T lymphomas underwent HCT as part of their first-line therapy. Fourteen patients had autologous (autoHCT) and 14 had allogeneic HCT (alloHCT). Among alloHCT, 11 had matched-related grafts while 3 had unrelated umbilical cord blood (UCB) grafts. At the time of HCT, 23 patients were in CR (CR1=7, CR2=15, CR3=1), and 5 had partial responses. HCT conditioning was myeloablative for all patients; in 18 patients, it was TBI-based. Fourteen patients suffered recurrence of their lymphoma post HCT at a median of 1.17 months from HCT (mean 6.2; range 0.63-42); 4 died in CR due to transplant-related toxicity, of these 3 were post alloHCT and one post autoHCT. Three patients have developed secondary malignancies (SMN; 2 post alloHCT and 1 post autoHCT). 10 patients were alive at last follow-up, all of whom were in CR. The 5-year estimated OS from SCT is 38.7%, with and EFS of 26%. There was no difference in 5-year OS or EFS among patients who received alloHCT v. autoHCT (OS 28.6% v. 49%; p=0.53, EFS 14.3% v. 37.5%; p=0.25) and among patients who did or did not receive TBI (OS 33.3% v. 48%; p=0.37, EFS 27.8% v. 18.8%; p=0.66). OS/EFS for patients with Burkitt lymphoma was 23.1%. Of the three patients with NK/T cell lymphoma two remain alive in CR 13.7 and 5.1 years after HCT.The outcome of relapsed/refractory non-Hodgkin lymphoma of childhood remains suboptimal. In addition to a high post-HCT relapse rate of 50%, HCT-related toxic mortality and SMN contribute to the poor outcome for this cohort of patients. Disclosures:No relevant conflicts of interest to declare.

Allogeneic Hematopoietic Cell Transplantation in Septuagenarians

Allogeneic Hematopoietic Cell Transplantation in Septuagenarians

Improved Survival over the Last Decade in Pediatric Patients Requiring Dialysis after Hematopoietic Cell Transplantation

It is not unusual for children to require dialysis for fluid and electrolyte management after hematopoietic cell transplantation (HCT). Previous studies have documented high mortality in children who require dialysis after HCT, but recent data are lacking. The purpose of this study was to compare the incidence of dialysis after pediatric HCT and the survival of patients who received dialysis in 2 decades, 1990-1999 and 2000-2009. A total of 1427 patients age <21 years who underwent a first HCT at the University of Minnesota between January 1990 and December 2009 were reviewed using prospectively collected data from the institutional HCT database. The incidence of dialysis during the first 100 days post-HCT and survival at 1 year post-HCT in the 2 cohorts were determined. Comparisons between patients who did and did not require dialysis were made using the χ2 and Fisher exact tests as appropriate. Kaplan-Meier estimates and 95% confidence intervals for 1-year post-HCT overall survival were reported by dialysis group and compared using the log-rank test. Predictors of overall survival among patients requiring dialysis were assessed using univariate and multivariate Cox regression analyses. The incidence of dialysis was not significantly different in the 2 cohorts (8.2% for 1990-1999 versus 8.9% for 2000-2009; P = .6326). Patients requiring dialysis were significantly more likely to survive to or past 1 year in the 2000-2009 cohort compared with the 1990-1999 cohort (23% versus 11%; P < .0001). Multivariate analyses found that older age at the time of HCT, primary disease type, pulmonary hemorrhage, and HCT in 1990-1999 were associated with increased mortality in the dialyzed population. The use of cyclosporine was associated with increased survival in the patients who received dialysis. Dialysis is an important complication of pediatric HCT with an incidence that has remained constant over the last 2 decades. Survival was improved in the 2000-2009 cohort regardless of dialysis status. Despite a recent significant reduction in mortality in patients requiring dialysis, mortality remains higher in these patients than in those who do not need dialysis.

A Phase II Trial Combining Radiolabeled Anti-CD45 Antibody with Fludarabine and Low-Dose Total Body Irradiation (TBI) Followed by Related or Unrelated Hematopoietic Cell Transplantation for Patients Under Age 50 with Advanced Acute Myeloid Leukemia (AML) or High-Risk Myelodysplastic Syndrome (MDS)

Abstract 1924Innovative therapeutic approaches are needed to reduce the morbidity and high relapse rates in patients with advanced AML or high-risk MDS following myeloablative hematopoietic cell transplantation (HCT). Success with stable donor chimerism and low toxicity following infusion of allogeneic peripheral blood stem cells (PBSC) with reduced-intensity regimens affords an opportunity to induce a graft-versus-leukemia (GVL) effect with minimal acute morbidity. GVL effects, however, appear to be most potent in patients with low tumor burden at the time of HCT. In an attempt to improve outcomes, we previously transplanted 58 patients older than age 50 with advanced AML (beyond first remission) or high-risk MDS (≥5% marrow blasts at the time of HCT) in a Phase I trial using 131I-labeled anti-CD45 antibody (BC8) in conjunction with fludarabine (FLU) and 2Gy total-body irradiation (TBI). Data from this study suggested that 131I-anti-CD45-targeted radiotherapy could be safely integrated into a reduced-intensity conditioning regimen for older, high-risk patients with AML or MDS yielding encouraging survival outcomes. These results prompted us to evaluate a similar strategy in younger patients (ages 16–50) with advanced AML or high-risk MDS who may not be able to receive a high dose HCT conditioning regimen.In this phase I dose–escalation trial 14 patients received a dose of 131I-BC8 that delivered 10–27 Gy of targeted radiation to the healthy organ receiving the highest dose combined with FLU (30 mg/m2 daily for 3 days), 2 Gy TBI, and HLA-matched related (n = 7) or unrelated (n = 7) PBSC grafts. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and mycophenolate mofetil. The 131I radiation dose was escalated until the maximum planned dose of 28 Gy was reached without any appreciable dose limiting toxicity. The median patient age was 39.5 (range, 23.8–49.7) years. Thirteen patients had AML, with 9 patients in second complete remission, 3 with primary refractory disease, and 1 in active relapse. One patient had advanced CMML with >5% blasts. Treatment with the 131I-BC8 Ab/FLU/TBI regimen produced a complete remission in 7 patients (50%), and 11 of the 12 evaluable patients had 100% donor CD3+ and CD33+cell engraftment by day 28 after HCT; an additional patient had 79% CD3 and 82% CD33 positive donor marrow cells at day 28. The absolute neutrophil count surpassed 500/μL at a median of 15 (range, 13–22) days. Self-sustained platelet levels of 20,000/μL were reached at a median of 11 (range, 11–27) days after HCT. Five patients (36%) are surviving relapse-free 46 to 99 months (median 87 months) after HCT. Seven patients (50%) have died, with five patients relapsing 0.9 to 45 months after HCT. No non-relapse mortality occured by day 100; however, two patients died 14 and 18 months after HCT of cardiomyopathy and GVHD complications, respectively.This study demonstrates that, in addition to a standard reduced intensity conditioning regimen, an average of 27 Gy of targeted 131I radiotherapy can be delivered to bone marrow, an average of 20Gy to the liver, and an average of 84 Gy to the spleen without a marked increase in day 100 mortality for younger patients. This strategy may thus provide a reasonable alternative for patients with high-risk AML/MDS who may not be able to tolerate a high dose conditioning HCT. Disclosures:No relevant conflicts of interest to declare.