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Background: Hematopoietic stem cell transplantation (HCT) is a primary treatment option for various inherited metabolic diseases (IMDs). Successful engraftment is crucial for favorable survival and functional outcomes and correlates with optimal conditioning in these patients with an intact immune system. Traditional regimens have used myeloablative Busulfan and Cyclophosphamide (BuCy) which is associated with significant potential morbidity. Alternate reduced toxicity regimens, like Busulfan and Fludarabine (BuFlu), are often utilized to reduce treatment related toxicities. Objective: To compare outcomes and complications with BuCy and BuFlu based conditioning regimens in patients with IMDs. Methods: This is the largest single institution retrospective analysis of University of Minnesota's transplant database for patients with IMDs who underwent HCT using BuCy + campath or BuFlu + ATG based preparative regimen from March 2008 to September 2017. Incidence of neutrophil and platelet recovery were determined using standard definitions. Complications such as graft failure, sinusoidal obstruction syndrome, hemorrhagic cystitis and respiratory failure were compared. Graft failure includes primary aplastic graft failure, primary graft failure with autologous recovery, secondary aplastic failure and secondary graft failure with autologous recovery. Incidence of viral infections post-transplant comparing two regimens were also determined. Results: Total of 99 patients were studied who underwent HCT for IMDs during the study period. Sixty-four received BuCy conditioning and 35 received BuFlu. Hurler syndrome (46%) and adrenoleukodystrophy (43%) were most common IMDs transplanted and umbilical cord blood was the most common donor source (74%). One-year overall survival was similar in both groups (81.2% in BuCy vs. 85.5% in BuFlu; p=0.8) with a similar incidence of grade 3-4 acute GVHD (9% in BuCy vs. 6% in BuFlu; p=0.5) and chronic GVHD (9% in BuCy vs. 7% in BuFlu; p=0.67) in the two groups. Neutrophil and platelet recovery were similar in both groups with significantly shorter duration of hospital stay noted in BuFlu group (median 21 d vs. 34 d, p = 0.002). The cumulative incidence of graft failure was higher with BuFlu conditioning (29% vs 14%, p= 0.08, Figure 1a). Significantly higher rates of second HCT was noted following BuFlu conditioning (27% vs. 3%, p= 0.001; Figure 1b). The incidence of adenoviral infection (14% vs. 0%, p=0.02) and hemorrhagic cystitis (23% vs. 3%, p=0.01) were notably higher in the BuCy group. Though donor myeloid engraftment was similar in both groups, donor T-cell engraftment occurred sooner with BuCy conditioning until 1-year post transplant (Figure 2). Conclusions: Reduced toxicity conditioning leads to lower rates of infections and other transplant related complications, but is associated with a high rate of graft failure in patients with IMD. Alternate immune suppressive agents should be considered to reduce graft failure and minimize toxicities. Alternate donor options, including expanded UCB, should also be considered to improve engraftment in patients with IMDs. Disclosures Shanley: Magenta Therapeutics: Research Funding. Miller:Sangamo Therapeutics: Employment. Orchard:Magenta Therapeutics: Research Funding.

Previously we demonstrated that following dUCBT, increased absolute lymphocyte (ALC) counts early are associated with improved disease free survival (DFS) (Burke, BBMT, 2011). Considering that a significant proportion of the lymphocytes at this time point are NK cells, we hypothesized that higher NK cell counts would be associated with improved transplant outcomes. We further hypothesized that patients with higher NK numbers would have more mature NK cells with increased NK function (cytotoxicity and cytokine production). To test this hypothesis we used a cohort of dUCBTpatients (n=111, separate from Burke, BBMT, 2011) and examined the number of NK cells (CD3-CD56+) in the peripheral blood after dUCBT. Patients were stratified into low (120 NK cells/mm3) groups based on absolute NK counts at D+28. The 3 patient groups did not vary based on age, gender, conditioning intensity, degree of HLA mismatch, UCB cell dose or CMVserostatus/reactivation. As shown in Figure 1, in multiple variate regression analysis, patients with low NK cell numbers experienced significantly lower DFS (HR=1.96, 95% CI: 1.02-3.77, p=0.04) (Fig 1A). There was a trend toward higher non-relapse mortality (NRM) in the low group (41% vs. 26% vs. 18% for low, medium, and high NK groups; p=0.08, Fig 1B), but no difference in relapse or aGVHD (Fig 1C and D). We used a multicolor FACS panel that includes a lineage cocktail (CD14, 19 and 3), CD56, CD117, NKG2A, KIR cocktail and CD57, which allowed us to classify the circulating D+28 NK cells into stage III, IV, V and stage VI NK cells. Interestingly, between the three groups, the proportions of NK cells in the various developmental stages did not differ significantly. We next tested the D+28 NK functionality upon a 4 hr.coculture with K562 cells, by staining NK cells for intracellular cytokines (IFN-g, TNF-a) and degranulation (CD107a). Although we tested a considerable number of patients (n=69), there was no difference in any of the three measures of NK functionality between the three patient groups, but all 3 measures were significantly lower than healthy controls. Considering that IL-15 is a key cytokine that drives NK cell maturation proliferation, and survival we tested the 3dUCBT groups for differences in serum IL-15 concentrations, but found no differences (Fig 2A). Given that the groups differed in cell numbers, we used Ki67 staining to assess whether the D+28 NK cells were differentially in cell cycle and undergoing proliferation. While the percentage of Ki67+ NK cells was significantly higher than controls, the 3 patient groups did not significantly differ from one another. We next tested the cells for the response to IL-15 stimulation. To do this, D+28cryoperserved PBMCs were thawed and rested overnight in media without cytokines. The next morning, PBMCs were stimulated with 0.2 ng of IL-15 for 15 min and the NK cells were assessed for the phosphorylation of STAT5 by FACS. Patients with low numbers of NK cells at D+28 had a defect in IL-15 signaling as demonstrated by a lower percentage of NK cells with p-STAT5, compared to patients with high NK cells (Fig 2A, 26% vs 37%, p=0.04). Many signals, including IL-15 drive the expression of key transcription factors includingTbet andEomes, which control NK cell development and functionality. To investigate the expression of these we used multicolor FACS. For T-bet, there was no difference in the mean fluorescent intensity (MFI) or percent expression between patients with either low or high NK cells at D+28 or healthy controls (Fig 2C). In contrast, patients with high numbers of NK cells at D+28 showed significantly moreEomes (by MFI) than patients with low NK numbers (Figure 2D, 675 vs 552, p=0.025). Therewas also a significantly higher proportion of NK cells expressingEomes in patients with high NK numbers compared to patients with low NK numbers or healthy controls (Figure 2E, 72.5% vs 61.3% vs 42.8%, p < 0.01). Thus, patients with low NK numbers at D+28 afterdUCBT have impaired NKEomes expression. Considering that STAT5 regulates T-bet andEomes, these studies uncover an association between IL-15 andEomes that leads to a reduction in NK cell numbers afterdUCBT which is associated with reduced DFS, likely due to increased NRM. Exogenous, supra-physiological IL-15 early afterdUCBT may overcome this defect and improve transplant outcomes. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Miller: Oxis Biotech Scientific Advisory Board: Membership on an entity's Board of Directors or advisory committees.

Background: Existing literature shows mixed conclusions regarding the impact of ABO incompatibility on outcomes following hematopoietic cell transplantation (HCT). As the future for umbilical cord blood (UCB) expansion technologies is bright, we assessed whether this typically-overlooked graft characteristic impacted various outcomes following UCB transplantation (UCBT) for non-malignant disorders (NMD). Patients and Methods: A prospectively maintained institutional BMT program database was queried for all patients undergoing first UCBT for NMD and their demographic, disease and transplant-related characteristics. For each transplant, UCB and recipient ABO compatibility was considered (1) matched, (2) major mismatched (recipient isoagglutinins against UCB antigen), (3) minor mismatched (UCB isoagglutinins against recipient antigen), or (4) bi-directional mismatched. In double UCBT, only the compatibility status of the dominant unit was considered. The impact of ABO incompatibility was assessed on the following outcomes using Kaplan-Meier and cumulative incidence functions: graft failure, aGvHD (grade II - IV and III - IV), cGvHD, platelet recovery, and overall survival. Cumulative red blood cell transfusion exposure per patient between HCT days 0 and +100 (c-RBC) was obtained from laboratory records. Donor hematopoietic chimerism values on the myeloid fraction of peripheral blood were reviewed at day +100 and most recent time assessed. HLA typing was at the antigen level for HLA-A and -B and allele level at -DRB1; in double UCBT, the matching status of the dominant unit was considered. Results: Through December 2014, 270 patients have undergone first UCBT for various NMD (inherited metabolic disorder = 165; marrow failure = 71; other = 34). The mean age at UCBT was 7.9 years (± 9.6). Most patients had a maximal performance score before UCBT (Lansky/Karnofsky of 100, n = 162; 60%) and were male (n = 164; 61%). Most patients received a single UCB unit (n = 225; 83%) and the majority of grafts were unrelated (n = 253; 94%). The average total nucleated cell dose was 8.0 x 107/kg (± 6). With respect to HLA-matching, 79 (29%) received matched, 133 (49%) single-mismatched and 57 (21%) two-mismatched grafts. Most patients received myeloablative conditioning (n = 209; 77%) and GvHD prophylaxis with cyclosporine and mycophenolate mofetil (n = 150; 56%). Negative CMV serostatus in both the graft and recipient was most common (n = 172; 64%). ABO compatibility for the cohort was as follows: matched, n = 93 (34%); major mismatch, n = 72 (27%); minor mismatch, n = 80 (30%); bi-directional mismatch, n = 23 (9%). ABO compatibility status was indeterminate in 2 transplants. Among all 4 ABO compatibility groups, no significant difference was seen in age, gender, NMD diagnosis category, conditioning intensity, HLA-matching, cell dose, number of UCB units, transplant era, performance score, GvHD prophylaxis, or CMV serostatus. Related UCB unit transplants were more likely to be ABO matched. Table 1 shows outcomes by ABO compatibility group with a median follow-up time of 4.5 years (range, 0.5 - 20). ABO compatibility status did not appear to impact any outcomes assessed, though a trend toward increased grade III - IV aGvHD was seen in recipients of major mismatched units. Table 1. Outcomes after UCBT for NMD by ABO Compatibility Status Outcome ABO Match (n=93) Minor Mismatch (n=80) Major Mismatch (n=72) Bidirectional Mismatch (n=23) P-value Overall survival, 5 y estimate (95% CI) 65% (53-74) 72% (59-81) 68% (54-78) 76% (51-89) 0.62 aGVHD (II - IV) (95% CI) 20% (12-29) 25% (15-35) 27% (16-38) 28% (8-49) 0.75 aGVHD (III - IV) (95% CI) 8% (2-15) 8% (2-14) 20% (10-29) 5% (1-14) 0.09 cGVHD at 5 y (95% CI) 8% (2-15) 7% (1-13) 8% (1-15) 5% (1-15) 0.96 Graft failure (95% CI) 19% (11-28) 20% (11-29) 25% (15-35) 17% (2-34) 0.83 Platelet recovery at 1 y (95% CI) 74% (65-83) 75% (65-85) 67% (55-78) 70% (48-91) 0.77 Day 100 chimerism, ≥ 80% (95% CI) 69% (58-79) 70% (60-81) 66% (54-78) 75% (56-94) 0.89 Most recent chimerism, ≥ 80% (95% CI) 79% (71-87) 75% (65-84) 66% (55-77) 74% (56-92) 0.33 c-RBC (Day 0 to +100) median (inter-quartile range) 11 (6-16) 10 (6-20) 10 (6-19) 14 (8-21) 0.75 y = year; CI = confidence interval Conclusion: ABO compatibility status did not seem to impact outcomes following UCBT for our large NMD cohort. Further analysis of the cohort to exclude interference on some outcomes assessed will be needed for a more definitive conclusion. Disclosures No relevant conflicts of interest to declare.

Introduction Transfusion of blood products is an essential component of the hematopoietic cell transplantation (HCT) process. Blood transfusions mainly platelets and plasma, carry several risks including, but not limited to, acute and delayed lung injury, especially in critically ill patients. The effect of transfusions on lung complications post HCT has not been previously investigated. We studied 215 adult allogeneic HCT recipients at the University of Minnesota and examined the association between transfusion of blood components and development of lung complications post HCT. Methods 215 consecutive adult allogeneic HCT recipients were retrospectively analyzed for blood product utilization. Patients without lung complications were used as a control group and those with any lung complication prior to day 180 post HCT were the study cohort. Blood utilization was quantitated as the total number of transfusion episodes and the number of transfusion episodes per week divided into three time intervals: day 0-30, day 31-60, and day 61-180 after HCT. Transfusions were analyzed as density (episodes or units per week). Lung complication data was collected from the transplant database and merged with the transfusion data. The effects of transfusion density and other factors on the odds of ever having a lung complication were modeled using multivariable logistic regression. Results 195 patients were included in the analysis and 20 were excluded, mostly due to incomplete data. 113 (58%) of the patients developed lung events prior to day 180 post HCT. Of the 113 patients with lung events, 81 (72%) were related to infectious causes. The study group with pulmonary complications and controls had similar baseline demographic characteristics (age, gender, CMV serostatus, disease and disease risk and donor source). Six months survival was significantly lower in the lung complications group (52%) versus the controls (78%) p=0.01. Patients who developed lung events received more transfusions including: episodes per week during the first month following HCT (median 4.3 (range x-y) vs. 2.7 (x-y) for controls); platelet units per week (3.5 (range x-y) vs. 2.0 (x-y)); and RBC units per week (1.8 (x-y) vs. 1.4 (x-y)); p Conclusion These data suggest that transfusion of more blood products is associated with lung complications and their use increases after the lung events. Limiting use of blood components in the post HCT period is recommended, potentially to reduce the risks of lung events. Table 1: Risk factors for Transfusion episodes/week from day 1-180 post HCT All Transfusion Episodes RBC Units Platelet Units Risk factor Relative transfusion density P-value Relative density P-value Relative density P-value Control group 1.0 1.0 1.0 ARDS/IPS 4.1 Abbreviations ARDS/IPS: Adult respiratory distress syndrome/Idiopathic pneumonia syndrome; DAH: Diffuse alveolar hemorrhage; NOS: not otherwise specified; TBI: total body irradiation; CMV: cytomegalovirus. Disclosures No relevant conflicts of interest to declare.

Allogeneic hematopoietic cell transplant (allo-HCT) results in profound immunodeficiency where patients remain susceptible to life-threatening infections for months to years. Although vaccination provides protection against viruses such as influenza, there is limited mechanistic evidence regarding the immune cell subsets directly involved. To better understand vaccination responses in allo-HCT recipients, a more specific analysis of the generation of influenza specific T cells is needed. Recently, it has been shown that a particular subset of CD4 T cells, T follicular helper (TFH) cells, play an important role in humoral responses to vaccination in humans. TFH cells express the receptor CXCR5, allowing them to traffic to secondary lymphoid tissues and provide help to B cells. We recently showed that TFH cells are also important in murine chronic graft-vs-host disease (cGVHD, Flynn and Blazar, Blood 2014), a process characterized by pathogenic B cell activity and chronic antibody deposition. Importantly, TFH cells and germinal centers were required for cGVHD and bronchiolitis obliterans in mice. Depletion of TFH effector cytokines (IL-21) or co-stimulatory ligands (ICOS and CD154) blocked germinal center formation and cGVHD. To date, no study has examined the recovery of TFH cells after allo-HCT and their association with vaccine specific responses or cGVHD. Here we investigated the reconstitution of peripheral T follicular helper cells (pTFH, CD3+CD4+CXCR5+ cells) in patients undergoing UCB (n=14) or matched sibling PBSC transplantation (n=12). Notably, UCB recipients had lower percentages of pTFH cells at day 60 following transplant compared to PBSC MRDs (2.0% ± 0.2 vs 8.6% ± 1.0, p1 year following transplant (13.84% ± 1.4 vs 9.7% ± 1.0 SEM, p=0.019). Comparing the trajectory of pTFH recovery, MRD recipients remain stable over time whereas UCB donors show a progressive rise (Figure 1). Also, in both UCB and MRD transplants, pTFH cells are mainly composed of central memory cells (CD27+/CD45RO+; 82.17% ± 2.588 vs 87.44% ± 1.664, p=0.1664), demonstrating that circulating pTFH cells are antigen experienced. Strikingly, when patients with any cGVHD (n=8) from both groups were combined and analyzed at 1 year, there were significantly lower percentages of pTFH cells compared to those without cGVHD (n=18) (6.9% ± 1.2 vs. 13.8% ± 1.3, p=0.004) (Figure 2). Lastly, we have previously demonstrated that donor source (MRD PBSC vs UCB) and time from transplant (1 yr post-allo-HCT) were associated with influenza vaccine responses. To study the role of pTFH cells in response to influenza vaccination, we analyzed samples of patients on a randomized controlled trial receiving 1 versus 2 doses of influenza vaccine following transplant from matched related or UCB donors. Blood samples were drawn pre-vaccination, then at 4 weeks patients were randomized to receive another dose of vaccine or not. Samples from each group were also collected at 8 weeks. We then evaluated polyfunctional, influenza-specific pTFH cells (expressing CD3, CD4, CXCR5, CD154) producing one, two, three or four cytokines (eg IFNy, TNFa, IL-17 and IL-2) in response to influenza peptide. Notably, these antigen-specific pTFH cells expanded with varying responses to 1 or 2 doses of influenza vaccine in vivo. These data provide biologic evidence of an increasing frequency of antigen-specific CD4 T cells following a second dose of vaccine. In combination with our data showing a correlation between absolute B cell numbers and vaccine responders (4x Ab response p=0.03, ELIspot IFNy response p These studies are the first to evaluate the recovery of pTFH cells following allo-HCT. Our data demonstrate significant differences in the proportion of pTFH cells following allo-HCT based on stem cell source and the presence of cGVHD. They also show that antigen specific pTFH cells can be detected after influenza vaccination and provide additional evidence for some of the differences in vaccine responses. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Miller: Coronado: Speakers Bureau; BioSciences: Membership on an entity's Board of Directors or advisory committees; SAB: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

High dose chemotherapy followed by autologous hematopoietic cell transplantation (AHCT) is the standard of care for patients with relapsed aggressive Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL) and after initial treatment of multiple myeloma (MM). With advances in supportive care, AHCT is increasingly being performed for patients older than 60 years of age. However, prior studies evaluating outcomes of transplant in older AHCT recipients are inconsistent, with conflicting data on risk of complications and major outcomes of non-relapse mortality (NRM), overall survival (OS) and progression free survival (PFS). Data from registry studies report lower NRM in young and old patients, in recent years, likely due to improvement in supportive care. We analyzed patients receiving an AHCT for MM or lymphoma in a contemporary cohort (2010-2012) receiving consistent treatment and supportive care. We hypothesized that with improved supportive care, there would be little or no difference in outcomes of younger (40-59 years) versus older (> 60 years) AHCT recipients, examining engraftment, OS, PFS, NRM and non-hematologic grade 3-5 toxicities within one year post AHCT. Study cohort and Methods: All patients > 40 years (n=144) who underwent an AHCT for lymphoma (NHL, n = 56; HL, n = 11) or MM (n = 77) from 2010 -2012 at University of Minnesota were included. Engraftment, OS, PFS, NRM and non-hematologic grade 3-5 toxicities within the first year post AHCT were compared between the two cohorts (age 40-59 years, > 60 years). Results. The median age at transplant was 54 years (range 40-59 years) in the younger cohort (n= 77) and 65 years (range 60-76 years) in the older cohort (n=67). Older recipients more often had MM and were less often in complete remission. Over 95% of patients in both groups had a Karnofsky performance status (KPS) of > 80% (p=0.46) while 27% in the older group versus 22% in the younger group had a HCT-CI comorbidity score of > 3 (p= 0.72). We examined 17 categories of non-hematologic grade 3-5 toxicities. The frequency of infections during neutropenia was significantly higher in the older group (64% vs. 44%; 0=0.02). The proportion of patients with any grade 3-5 toxicity was also higher in the older group (84% vs. 67%, p= 0.03). In multivariate analysis, after adjustment for gender and disease, older age (> 60) was significantly associated with higher odds ratio (OR: 2.57, 95% CI: [1.09-6.05]) of grade 3-5 toxicity (Table 1). Based on the high-risk variables shown in Table 1, the predicted probability of grade 3-5 toxicities within one year (adjusted for age, gender and disease) was highest (94%) in females > 60 years with NHL and lowest in males age 40-59 years with HL (47%). There was no difference in time to neutrophil and platelet engraftment (Table 2). Two older recipients (cumulative incidence of NRM: 3%) and no younger recipients had NRM within one year. After a median follow up of two years, the probability of OS at two years was lower in the older group (76% vs. 90%, P=0.04) but no difference was noted in disease relapse or PFS. Conclusion: AHCT can be performed safely in older recipients. However, the higher toxicity and slightly higher NRM in this population needs attention. Studies focusing on risk-stratification in older patients (including geriatric assessments) would further help predict toxicity. Further studies addressing enhanced supportive care needs for older patients who are most likely to benefit are indicated. Table 1: Risk factors for grade 3-5 toxicities Factor OR 95% CI P Age 40-59 1.00 Age 60-76 2.57 1.09 – 6.05 .03 Male 1.00 Female 2.24 0.96 – 5.24 .06 Multiple myeloma 1.00 Hodgkin lymphoma 0.82 0.21 – 3.18 .77 Non-Hodgkin lymphoma 2.67 1.07 – 6.68 .04 Table 2: Outcomes by age Age 40-59 Age 60+ P Days to ANC recovery median (IQR) 10 (10-11) 11 (10-11) 0.15 Days to Platelet > 20K median (IQR) 19 (17-21) 18 (17-21) 0.86 1 year NRM (95% CI) 0 3 (1-7) 0.05 2 year relapse (95% CI) 47 (34-60) 39 (27-51) 0.44 2 year OS (95% CI) 90 (82-98) 76 (65-87) 0.04 2 year PFS (95% CI) 53 (41-65) 55 (43-67) 0.80 Disclosures Bachanova: Seattle Genetics, Inc.: Consultancy, Research Funding.

Compared to traditional chemotherapy, allogeneic hematopoietic cell transplantation (allo-HCT) has the potential of triggering graft vs. leukemia (GVL) reactions that make this procedure uniquely curative. Despite this, relapse remains the most common cause of treatment failure. Early after allo-HCT the donor immune system reconstitutes within the host and natural killer (NK) cells are the earliest lymphocyte population to recover. Previous studies by us and other investigators have linked rapid lymphocyte recovery and/or high NK cell numbers early after transplant with less relapse. Mechanistically, the reasons for this are unknown. We hypothesized that NK cell proliferation would be associated with allo-HCT outcomes. In a large data set with short-term follow-up we compared stem cell source to NK cell proliferation at Day 28 after transplantation (using Ki67+ staining). In patients undergoing autologous (n=117), sibling (n=57), single umbilical cord blood (sUCB) (n=62) or double umbilical cord blood (dUCB) (n=50) transplantation there were significant differences in the median NK cell proliferation (2.1%, 3.3%, 3.8%, and 19.2%, respectively, p20%) and low ( Disclosures: Wagner: Novartis: Research Funding. Miller:Coronado Biosciences: Scientific Advisory Board Other.

Metachromatic Leukodystrophy (MLD) is a rare demyelinating disease caused by deficient lysosomal arylsulfatase-A (ARSA) activity and resulting pathologic sulfatide excess. Signs and symptoms vary with the age of disease onset. In early phenotypes (“late infantile” and “early juvenile”; onset < 6 years; E-MLD) rapid neurologic regression and death are observed. In late disease (“late juvenile” and “adult”; onset ≥ 6 years; L-MLD) a neuropsychiatric prodrome often precedes frank neurologic decline. For over 30 years, allogeneic hematopoietic stem cell transplantation (HSCT) has been used to halt or curb MLD progression. Yet published outcome data are scant and mixed. We report characteristics of and outcomes for 42 MLD patients following HSCT at the University of Minnesota, the largest such report to our knowledge. From 1984 to 2008, 17 E-MLD and 25 L-MLD patients were transplanted. The median age at HSCT in the E-MLD group was 5 years (range, 0 – 8 years); the median age at transplant in the L-MLD group was 20 years (range, 6 – 44 years). Twelve (29%) patients were male. Preparative regimens varied. Twenty-seven (64%) patients received myeloablative busulfan/cyclophosphamide conditioning; 11 (26%) received a cyclophosphamide/TBI regimen; 4 (10%) underwent reduced-intensity conditioning. Allograft sources also varied. 10 (24%) patients received an HLA-matched sibling marrow graft; 16 (38%) had an unrelated marrow donor (HLA-mismatched = 6); 16 (38%) received UCB grafts (HLA-mismatched = 14). Thirty-three (79%) patients were symptomatic at HSCT. The median time from symptom onset to diagnosis was 17 months in E-MLD and 50 months in L-MLD patients. Pre-HSCT brain MRI data was available for 37 patients; 36 (97%) demonstrated white-matter abnormalities. Of 40 patients with evaluable pre-HSCT nerve conduction velocity (NCV) studies, 37 (93%) had measurable peripheral neuropathy. Non-neuropsychological clinical involvement was scored per a neurologic function scale (NFS, 0 = no neurologic findings, 25 = maximal neurologic findings) spanning the domains of auditory processing, vision, motor, swallowing, incontinence, and seizures. Of 40 patients evaluable for pre-HSCT NFS, 25 (63%) had a non-zero score (range, 1 - 4) and 15 (37%) a zero score. Five-year survival was 58%. Greatest survival (70%) was seen in recipients of HLA-matched, sibling marrow. Among alternative graft recipients (n = 32), favorable survival followed UCB transplantation compared to unrelated marrow (62% versus 47%). Ten patients (24%) died of transplant-related causes by day 180 (3 from hepatic veno-occulsive disease; 2 each from graft-versus-host disease (GvHD) and sepsis; 1 each from graft failure, thrombotic thrombocytopenic purpura, and multiple organ failure syndrome). Four additional patients died within 1 year of transplant, all from infection. Four patients (all E-MLD) died from disease progression (range, 1.5 – 7.1 years post-HSCT). Fourteen patients (33%) developed grade II-IV acute GvHD; 6 (14%) developed chronic GvHD. The median survivor follow-up was 10 years; 74% demonstrated ≥ 80% donor engraftment at most recent observation. Of 30 evaluable patients, only 9 (31%) demonstrated progression of white-matter disease at median MRI follow-up of 1.26 years. For 22 patients with post-HSCT NCV studies, 17 (77%) evidenced worsening peripheral neuropathy at median follow-up 2.9 years. Twenty-four patients had evaluable post-transplant NFS scores. In E-MLD, the median increase in NFS score was 9 (range, 1 - 10) at median follow-up of 3.4 years. In L-MLD, the median increase was 3 (range, 0 - 22) at median follow-up of 3 years. Symptom status (present versus absent) at the time of HSCT neither impacted survival nor post-transplant NFS. Of 15 L-MLD patients surviving past one year, 7 had an evaluable verbal IQ (VIQ, average range 80 - 120) on both pre- and post-HSCT neuropsychological evaluations. In this subgroup, the mean pre- and post-HSCT VIQ were 83 and 75, respectively; mean follow up was 4.1 years post-HSCT. In summary, we report outcomes following HSCT for a large MLD cohort. Preliminary analysis suggests favorable clinical neurologic and neuropsychological performance following transplant for L-MLD. Ongoing analysis of the entire cohort, including comparisons against untreated siblings, aims to further define the neurological and neuropsychological benefit of HSCT for MLD. Disclosures: No relevant conflicts of interest to declare.

Systemic mastocytosis (SM) is a rare hematologic neoplasm characterized by abnormal growth and accumulation of tissue mast cells (MC) in various organ systems, including bone marrow (BM). Indolent and advanced forms of SM have been described. Whereas patients with ISM have a normal or near normal life-expectancy, patients with advanced SM, including those suffering from mast cell leukemia (MCL) have a poor prognosis. In these patients, neoplastic MC are usually resistant against conventional drugs and various targeted drugs. In rapidly progressive aggressive SM (ASM) and MCL, polychemotherapy followed by allogeneic hematopoietic stem cell transplantation (alloHCT) has been proposed. However, outcome of alloHCT in advanced SM is unknown, and it also remains uncertain whether clinically relevant graft-versus-SM (GVSM) effects may occur in these patients, as only sporadic case reports have been published. We performed a retrospective multi-center analysis to evaluate the outcome of alloHCT in patients with advanced SM. Fifty-four advanced SM patients receiving SCT in 32 transplantation centers in Europe and America were identified between 1990 and 2013. The median patient age was 45 years. Donors were: HLA identical siblings (31), unrelated donors (URD) (15), umbilical cord blood donors (UCB) (2), and haploidentical donors (1). In 5 patients, stem cell source was not defined (5). Thirty-four patients received myeloablative conditioning (MAC) and 18 received reduced intensity conditioning regimens (RIC). In 2 patients, conditioning regimen was not specified. Indications for alloHCT were SM with an associated clonal hematologic non-mast cell lineage disease (SM-AHNMD) (n=32), MCL (n=13, including one with MCL-AHNMD), 8 with ASM and 1 with myelomastocytic leukemia (MML). The most prevalent AHNMD was acute myeloid leukemia (AML, n=16). With follow-up of 35-6180 (median 365) days, SM responses (defined as ≥50% decrease in BM mast cells ± decrease in serum tryptase ± regression of other organ manifestations) were observed in 39 patients (72%), including complete responses (CR) documented in 12 patients (22%). Eleven patients had stable disease, whereas 4 patients (7%) progressed immediately after alloHCT (primary resistance). In addition, 10 patients progressed (5 of them within 100 days) after an initial response. Progression was most frequently seen in MCL patients (n=6, 50%). In the AHNMD group, only 8 patients relapsed/progressed (25%). The overall survival (OS) and SM progression-free survival (PFS) at 1 year were 63% and 50% for all patients, 77% and 68% for SM-AHNMD, 63% and 50% for ASM, and 25% and 17% for MCL, respectively. The strongest predictive variable associated with inferior survival was a diagnosis of MCL. Other factors associated with poor outcome were: Karnofsky performance status ≤70%, ≥2 SM regimens given before alloHCT (e.g., steroids, cladribine, chemotherapy, tyrosine kinase inhibitor), donor source (alternative donors-UCB and haploidentical compared to sibling or URD), SM progression within the first 100 days, normal cytogenetics (compared to t(8;21) (q22;q22), and RIC (compared to MAC). The following variables were not associated with poor outcome: patient and donor age, recipient-donor sex match status, graft source (BM vs. peripheral stem cells), BM mast cell percentage at time of alloHCT, and CR status of AML or SM response at time of alloHCT. This largest multi-center analysis of results in advanced SM provides evidence for clinical efficacy of alloHCT, presumably because of a GVSM effect of alloHCT (achieving CR, and response to donor-lymphocyte infusions and RIC alloHCT). However, responses varied among different SM categories: while patients with SM-AHNMD enjoyed excellent outcomes, the OS for MCL patients in general, was poor. Nevertheless it is remarkable that 3 of 13 patients with MCL – an otherwise fatal disease with a median survival of Disclosures: Vercellotti: Sangart Inc.: Research Funding; Seattle Genetics: Research Funding. Akin:Novartis: Consultancy. Valent:Novartis: Consultancy, Honoraria, Research Funding.

Abstract 1967 Introduction: The cardiac QT interval (QT) has gained deserved scrutiny among electrophysiologists. Reflecting the duration of the ventricular myocardial depolarization/repolarization cycle, the QT depends upon ion exchange across cardiomyocyte membranes. Ion flux perturbations (due to abnormalities of membrane-bound ion channel number, structure or function) can predispose to QT prolongation that, in turn, is associated with linearly increasing risks of ventricular tachy-arrhythmias and sudden death. As both polypharmacy and dys-electrolytemia have been reported to affect QT, we studied the interval's behavior in the potentially at-risk population of children and adults undergoing hematopoietic cell transplantation (HCT). Methods: We retrospectively reviewed over 2600 cardiologist-evaluated electrocardiograms (ECG) and transplant-related data for 995 consecutive children and adults undergoing HCT between 2006 and 2010, inclusive. Patients underwent routine pre-HCT ECG screening; repeat studies were obtained for various clinical indications. Corrected QT intervals (QTc) were noted; any study demonstrating non-sinus rhythm was disregarded. Multivariate regression models tested the association between QTc and other patient or transplant-related covariates (including age, gender, primary diagnosis, intensity of conditioning, and donor relatedness/graft-versus host disease prophylaxis for allograft recipients); reference groups representing fixed covariate characteristics were defined among the cohort for comparison. Student's t-test was used to determine the significance of aggregate intra-patient change in QTc from pre- to post-HCT. Results: Pre-HCT: 952 patients had an evaluable pre-HCT maximum QTc observed at a median Day −22. Median QTc was 428 ms (range, 330 to 569; interquartile range [IQR], 409 to 447). Statistically significant QTc variability with age was observed and reflected widely accepted age-dependent phenomena in the population-at-large. Factors predicting shorter QTc included male gender (-11 ms compared to reference group [CRG], p < 0.01) and inherited metabolic disorder (IMD) as HCT indication (-10 ms CRG, p = 0.03). Factors predicting longer QTc were myeloproliferative disorder (+22 ms CRG, p = 0.01) and acute myeloid leukemia (+7 ms CRG, p = 0.02) as HCT indications. Post-HCT: 578 patients had an evaluable post-HCT maximum QTc observed at a median Day +69. Median QTc was 454 ms (range, 367 to 619; IQR, 433 to 476). Age was not significantly predictive of maximum QTc post-HCT. Factors predicting shorter QTc were male gender (-7 ms CRG, p = 0.05) and no exposure to mycophenolate mofetil (MMF) for graft-versus-host disease (GvHD) prophylaxis (-11 ms CRG; p = 0.05). Patients diagnosed with acute lymphoblastic leukemia (ALL) demonstrated longer QTc (+17 ms CRG, p = 0.03). δQTc: 559 patients had at least one evaluable pre- and one evaluable post-HCT ECG. The median δQTc (defined per patient as [mean post-HCT QTc] - [mean pre-HCT QTc]) was 15.7 ms (range, −72 to 142; IQR, −2 to 32). A highly significant difference between post-HCT and pre-HCT QTc per patient was observed in this cohort (p < 0.01). Very Long QTc: 92 (15%) males demonstrated QTc ≥ 480 ms and 39 (10%) females demonstrated QTc ≥ 500 ms on any ECG. Of patients with ≥ 2 evaluable ECGs, 306 (50%) demonstrated prolongation ≥ 40 ms. Factors significantly predicting extreme prolongation included age < 1 year (+39 ms CRG, p < 0.01) and diagnosis of ALL (+15 ms CRG, p = 0.04); a trend toward more extreme prolongation was seen in patients with myelodysplastic syndrome (+14 ms CRG, p = 0.05). The factor protecting from extreme QTc prolongation was treatment with a related allograft (-9 ms CRG, p = 0.03); trends toward less extreme prolongation were also seen in autologous HCT and those not receiving MMF for GvHD prophylaxis. Conclusion: Prolonged QTc is associated with life-threatening ventricular tachy-arrhythmias. This retrospective analysis of a large, diverse HCT cohort shows statistically significant prolongation during transplantation. Too, we identify sub-populations demonstrating very-long QTc and/or experiencing marked QT prolongation during HCT. Further analysis regarding pharmacologic, electrolytic and HCT-related predictors as well as outcomes for the cohort is underway. Disclosures: No relevant conflicts of interest to declare.