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Introduction Pediatric inspired regimens can achieve good outcomes in adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL) by delivering intense non-myelosuppressive chemotherapy and are considered standard. Experience with the implementation of these regimens outside of academic centers in high-income countries is limited. Furthermore, Mexican patients (with "hispanic ethnicity") have increased risk for relapse and treatment related complications. Objectives Primary objective: to determine 2-year overall survival (OS) and event-free survival (EFS). Secondary objectives: to determine the impacts of treatment abandonment and measurable residual disease (MRD) on outcomes, and to compare treatment costs with a widely used standard regimen in the United States. Patients and Methods Consecutive patients 16-45 years diagnosed with Ph-negative B-cell acute lymphoblastic leukemia after 2016 were included. The salient features of our modified-BFM regimen include the use mitoxantrone, E. coli L-asparaginase, without systemic cytarabine or high dose methotrexate designed to be delivered entirely in an outpatient basis for maximum affordability (Table 1), given that we treat an uninsured population that must cover their own treatment costs out of pocket. Genetic risk assessment was limited to BCR/ABL. Thereafter, relapse risk assessment was based exclusively on "next generation" flow cytometry measurable residual disease (MRD) after consolidation, with a planned allogeneic transplant for MRD-positive patients (≥0.001%). Treatment abandonment was defined as a missed ≥14-day period during intensive treatment or ≥1 month during maintenance. Statistical analysis was performed as intent-to-treat. Lastly, drugs included in our protocol were compared to those of CALGB 10403 with current local pricing in USD. Results Ninety-one AYAs have been treated, 47 women and 44 men, with a median age of 21 years (range, 15-45), mostly with a good functional capacity and no comorbidities (ECOG≤2: 92.1%; HCT-Ci 0-1: 97.8%); 43.8% of patients had ≥30x10 9/L white blood cells at diagnosis and 31.7% had grade ≥1 obesity. Notable grade ≥3 adverse events during induction were infections/neutropenic fever (35.6%),hepatotoxicity (11%) and thrombosis/bleeding (8.1%) with 44.3% eventually requiring hospitalization. Induction related mortality was 11%. Only n=3 were refractory to induction and the remainder assessed achieved complete remission (n=63; 95.5%) with a median follow-up of 15 months (range, 0.9-50.1). N=29 received induction and consolidation entirely on an outpatient basis, ulterior hospitalizations during therapy were rare. Treatment abandonment was common (n=24; 26.4%) usually during induction (n=8; 32%) or consolidation (n=12; 48%) and mostly related to unaffordability. For the same reason, transfers to social security healthcare systems were also frequent (n=19; 20.9%). Most patients assessed were MRD negative (n=38; 74.5%) Early relapse incidence was 32.9%; 44.4% in MRD-positive and 27.5% in MRD-negative patients (p=0.43). OS at 24 months was 61.5% (95% CI 47-73%) and EFS 49.8% (95% CI 37-62%) with excellent outcomes for MRD-negative patients (Figure 1, Panels A and B). Treatment abandonment and MRD positivity were the only independent predictors of mortality in a multivariate analysis (HR 7.8 [95% CI 2.8-21.9] and HR 4.5 [95% CI 1.4-14], respectively). Lastly, the total cumulative price for medications included in our regimen was calculated at $16,750 vs. $36,061 USD in CALGB 10403, representing a cost reduction of 53.5%. Conclusions The treatment of Hispanic ALL patients with our regimen has shown promising outcomes at a reduced cost for patients. Genetic risk assessment, induction mortality, treatment abandonment and lack of access to novel therapies for MRD positive patients remain the main barriers for improving outcomes further. Figure 1 Figure 1. Disclosures Gomez-De Leon: Novartis: Honoraria; ASH: Research Funding; Sanofi: Honoraria; Abbvie: Honoraria. González López: JANSSEN: Honoraria; AMGEN: Honoraria. Gomez-Almaguer: Roche: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Bristol-Myers-Squibb: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau.

Introduction Hyperphosphatemia could be a finding in renal failure, tumor lysis syndrome, hypoparathyroidism, and ingestion of exogenous phosphate. We present the case of a woman with hyperphosphatemia in which we finally diagnosed multiple myeloma, serum phosphate level achieved normal range after chemotherapy started. Although hyperphosphatemia in multiple myeloma is a very rare finding, there are some reports. The proposed mechanisms include a large amount of paraproteins that interferes with phosphorus level determination showing a false increased level. When samples have been deproteinated before analysis, serum phosphorus level can decrease obtaining a true level. This case reminds clinicians the importance of seeking additional causes for abnormal phosphorus levels before starting treatments that could lead to hypophosphatemia. Case report An hispanic woman at the 7th decade of life that only suffered from controlled hypothyroidism, who assisted with complaints of axial pain mainly in thoracic and lumbar segments. She denied neurological and B symptoms. She had a CT scan performed and was referred to the hematology service.On clinical examination we didn't find any neurological signs, no megalies and no palpable nodes. The patient brought a CT spine scan showing thoracic images suggestive of mets with collapse of 50% in T12-L1 and a mass in S2.With these findings we decided to start intrahospitalary studies for excluding malignancy.Her relevant laboratories were: creatinine 0,7, BUN 25, Hemoglobin 9 gr/dl VCM 102 WBC 3330 Granulocytes 55% Platelet 222.000, UN 10,7, albumin 2.8, Lactate dehydrogenase 425. A series of labs seeking secondary causes of malignancy was made including plasmatic cell neoplasie.The hepatic function was normal but an unusually high Phosphorus level was detected (19,6) with normal calcemia (8.98), the tumoral biomarkers were in normal range (CEA, CA 19-9, Ca 125, AFP) and an elevated B2 microglobulin (8) was found. Additional labs included bence jones protein and PTH, both in normal range. A new Thoracic CT described mosaic infiltrates and an extensive bone involvement suggestive of lytic metastatic changes. The abdomen CT showed multiple lytic lesions in lumbo-sacral spine and pelvis, The skull radiography had lytic lesions too. The nephrology service was required by the Hyperphosphatemia and they asked about external intake of phosphorus finding that she was taking "hydrolyzed collagen", so they started iv fluid and chelators (aluminium hydroxide and no calcium chelators).Because of unresponsive hyperphosphatemia, nephrology started hemodialysis.Hematology found high IgG levels (5500) concluding the need for bone marrow studies . Finally a the bone marrow study was performed and prescribed steroids on suspicion of Multiple myeloma. Until this day the Phosphorus level still remained in high levels (17,7) despite hemodialysis sessions. The bone marrow study revealed a plasmatic cell population of 28,9% with big and abundant cytoplasm, some of them with binucleations suggestive of infiltration by plasmatic cell neoplasie. The seric electrophoresis revealed a paraprotein (seric protein of 9,3 with a monoclonal peak of gamma region of 3,4 gr/dl), the seric immunofixation was positive for a monoclonal IgG lambda component. With this report we began chemotherapy treatment for Myeloma with CyBorD regimen (Cyclophosphamide, Bortezomib, dexamethasone). After treatment was initiated, phosphorus level began to lower and achieved normal range (4.28) in the first two weeks. Then she was discharged to continue outpatient management. Nowadays she is receiving her 3rd chemotherapy cycle without complications, her phosphorus level still remains within normality. Conclusions Spurious hyperphosphatemia in patients with paraproteinemias like multiple myeloma can occur. The IgG monoclonal can interfere with the phosphomolybdate principle used in the assay of serum phosphate on most automated chemistry analysers. For labs which do not have a multilayered film technology based system, a serial dilution analysis of the suspected analyte could be performed. Disclosures No relevant conflicts of interest to declare.

Introduction: Acute myeloid leukemia (AML) is heterogenous disease with a range of cytogenetic and molecular changes. Several molecular mutations identified in AML patients at diagnosis have prognostic implications and play important roles in guiding induction and consolidative treatment decisions. The prognostic impact of mutations peri allogeneic stem cell transplant are less well characterized. In this study, we examine the significance of pre and by D100 Post-transplant mutation status in AML patients underwent Fludarabine/Melphalan conditioned reduced intensity allogeneic stem cell transplant (SCT). Methods: AML patients who are in morphologic complete remission (CR1 or greater) with available molecular mutation at diagnosis, within 6 weeks prior to allogeneic SCT, and by 100 days post-transplant were included. Variables analyzed included baseline demographics, clinical variables (CIBMTR disease risk index (DRI), type of transplant, ELN risk, performance status) and 23 recurring molecular mutations. Analysis was also performed by grouping mutations into six pre-defined gene groups based on gene function (Table 2). Multivariable cox regression analysis was adjusted for age, gender, DRI and molecular mutation. Backward selection method was used to select the best combination of genes that is associated with overall survival (OS) and relapse-free survival (RFS). Results : A total of 142 AML patients with molecular genetic data available from 2014 to June, 2020 at Weill Cornell Medicine/New York Presbyterian Hospital were analyzed. Clinical characteristics of the patients are summarized in Table 1. The median age was 58 years (range 20 -78). Total of 261 mutations were detectable at diagnosis (Table 3). Prior to allo SCT and by D100, the detectable mutations were 87 and 40 respectively, which represent 56 and 26 patients. High-dose chemotherapy was less effective on clearing DNMT3A, ASXL1, TET2 (DAT) or IDH mutations, resulting in over-representation of DAT and IDH mutations prior to transplant. With a median follow-up time of 25 months, the median overall survival for the group was 40.8 months. The presence of mutations in TP53 at diagnosis was associated with worse OS by both univariate (HR 3.67, p=0.0030, CI 1.56-8.68) and multivariate analysis (HR 4.75, p=0.0014, CI 1.82-12.39) with median OS reduced from 49.3 to 19.3 months (p=0.002). High CIBMTR DRI (HR 0.17, p=0.0018, CI 0.05-0.51) predicted reduced OS and RFS, and Age >60 at diagnosis was associated with worse OS (HR 1.7 CI 1.04-3, p 0.03). Presence of any molecular mutation prior to transplant did not impact OS or RFS. For patients with any persistent mutations by D100 post-transplant, both OS ( HR 2.04, p 0.027, CI 1.08-3.8) and RFS (HR 1.99, p 0.025, CI 1.09-3.6,) were reduced in the univariate analysis, but not on multivariate analysis (HR 1.88, p 0.5, CI 0.99-3.49). Analysis based on six mutational groups (table 2) did not show any difference in their OS or RFS. However, worse RFS was independently associated with persistent IDH1 (HR 3.8, p 0.004, CI 1.07-56,), TET2 (HR 3.9, P 0.04, CI 1.04-14.1), and FLT3-ITD (HR 4.5, p 0.01, CI 1.7-52). Worse OS was independently associated with persistent TET2 (HR 3.9, p 0.013, CI 1.04-14.1), with a trend towards worse OS for IDH1, FLT3-ITD, with a trend towards worsening OS and RFS for ASXL1 (OS HR 7.4, p 0.06, CI 0.86 -63; RFS HR 4.9, p 0.06, CI 0.9-26) and DNMT3A (OS HR 2.3, p 0.12, CI 0.86-6.9; RFS 2.9, p 0.08, CI 0.98-8). Association with worse clinical outcomes remained significant after multivariate analysis for TET2 (both OS HR 3.98 p 0.041, CI1.07- 32 and RFS HR 5.8, p 0.032, CI 1.1- 29), IDH1 (RFS HR 8.02, p 0.049, CI 1.02 - 65) and FLT3-ITD (RFS HR 11.4, p0.010, CI 2.2- 80). Conclusions: Presence of TP53 mutations was associated with worse OS. Presence of pre-transplant mutation did not impact RFS or OS. Persistent presence of mutations in TET2, IDH1 and FLT3-ITD after Fludarabine/melphalan conditioning regimen allogeneic SCT were associated with shorter RFS and OS (in the case of TET2) independent of CIBMTR DRI. This analysis supports association of adverse outcomes in AML patients with selected persistent mutations by D100 post-transplant in reduced intensity transplant setting. Post-transplant strategies that can further eliminate persistent mutations should be investigated in prospective studies. Figure 1 Figure 1. Disclosures Lee: Pin Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Innate: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees. Desai: Kura Oncology: Consultancy; Bristol Myers Squibb: Consultancy; Agios: Consultancy; Takeda: Consultancy; Janssen R&D: Research Funding; Astex: Research Funding. Ritchie: Protaganist: Consultancy, Honoraria; Incyte: Consultancy, Honoraria, Speakers Bureau; Celgene/BMS: Consultancy, Other: travel support, Speakers Bureau; Bristol Myers Squibb: Consultancy, Research Funding; ARIAD Pharmaceuticals: Ended employment in the past 24 months, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria; Astellas: Consultancy, Research Funding; NS Pharma: Research Funding; Abbvie: Consultancy, Honoraria; Jazz: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Roboz: MEI Pharma - IDMC Chair: Consultancy; Daiichi Sankyo: Consultancy; Helsinn: Consultancy; Jazz: Consultancy; Bristol Myers Squibb: Consultancy; Glaxo SmithKline: Consultancy; Novartis: Consultancy; Janssen: Consultancy; Otsuka: Consultancy; Celgene: Consultancy; Mesoblast: Consultancy; Blueprint Medicines: Consultancy; Jasper Therapeutics: Consultancy; AbbVie: Consultancy; Actinium: Consultancy; Agios: Consultancy; Amgen: Consultancy; Astex: Consultancy; Astellas: Consultancy; AstraZeneca: Consultancy; Bayer: Consultancy; Janssen: Research Funding; Pfizer: Consultancy; Roche/Genentech: Consultancy.

Introduction: Pulmonary complications constitute a major cause of morbidity and mortality in the post-hematopoietic cell transplant (HCT) period. While Chest X-ray (CXR) is customarily used for screening, we have utilized chest computed tomography (CT) within one month of transplant. Here we aim to characterize the prevalence of abnormalities and their impact on the eligibility for allogenic (allo) HCT and outcomes post-transplant. Methodology: We conducted a single center retrospective study of all patients who were evaluated for allogenic HCT from January 2013 through December 2020 in New York Presbyterian Hospital - Weill Cornell Medicine (NYP-WCM). All patients who had chest CT as part of their pre-transplant evaluation were included for analysis. Results: We identified 478 patients who had Chest CT screening. In 396 CT chest was normal or confirmed previous abnormalities. Eighty-two patients (17%) had previously undetected abnormalities (Figure 1). The most frequent abnormalities were pulmonary nodules (defined as nodules of 4 mm or greater) in 27 patients (31%), ground-glass opacities (GGO) in 21 patients (25%), Pneumonia in 18 patients (21%). Miscellaneous findings not related to the primary disease were found in 12 patients (14%) including thyroid nodules, breast nodules and hemangioma of the liver. A new malignancy was found in 6 patients (7%) and incidental pulmonary embolism (PE) in 2 patients (2%) (Figure 2). There were 5 (6%) patients who were ultimately excluded from transplant due to CT chest findings (simultaneous CXR showed abnormalities in only 1 out of 5). Three of those patients were found to have invasive fungal infection, and the other two had unrecognized metastatic lung cancer. For 19 patients (23%), transplant was delayed for diagnostic procedure and/or treatment of pulmonary findings (CXR showed abnormalities in only 3 patients out of 19). The most common reason for delay was lung infection requiring treatment. Thirty-two patients (41%) out of 77 patients with abnormal CT scan who eventually underwent transplant, have died . Sixteen died after relapse, and 16 from non-relapse mortality (NRM) with pulmonary complications playing a role in 13 patients (Figure 3). Conclusion: 17% of patients who had a pre-transplant CT chest had abnormalities that warranted further evaluation. In 23% of these patients, these findings led to a delay in transplant for further optimization. Six percent were deemed ineligible for transplant due to absolute contraindications that were incidentally discovered on chest CT. Initial screening CXR failed to identify a significant number of abnormalities. Our data suggests that chest CT imaging should be part of the routine pre-transplant evaluation. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Introduction: Predictors routinely used to assess long-term survival after allogeneic hematopoietic cell transplantation (alloHCT) have not been specifically validated for pre-transplant risk assessment of patients getting cord blood transplantation supported by Haplo-CD34+ Progenitor cells as a myeloid bridge (haplo-cord). Methods: All consecutive adult patients with hematological malignancies who received an alternative donor alloHCT with a haplo-cord at Weill Cornell Medicine were included. Data was collected from an ongoing haplo-cord protocol (clinicaltrials.gov identifier 01810588). Plasma cell disorders were excluded. Age, CIBMTR Disease Risk Index (DRI), Karnofsky performance score (KPS), and HCT comorbidity index (HCT-CI) (routinely calculated since 06/2014), were assessed before alloHCT. The Kaplan-Meier method was used to estimate OS probabilities. Comparisons of OS were evaluated by the log-rank test. Significant predictors were considered in a Cox proportional hazards regression model using forward stepwise selection. A cumulative incidence function (CI) for relapse was calculated using a competing risk model for non-relapse mortality (NRM). We further validated our findings in the subgroup of patients with AML. Results: Between 06/2012 and 12/2018, 217 patients underwent haplo-cord transplantation. Indications for alloHCT included: 66% leukemia, 19% MDS/MPN, 15% Lymphoma. Median age was 58 yr (22% ≤ 40yrs, 33% between 41-59yrs, and 45% ≥ 60 yrs). 43% of patients were women. KPS score was ≥ 90 in 56%. DRI was high/very-high in 43% and low/intermediate in 56%. HCT-CI for 154 patients was 0 in 14%, 1-2 in 21%, 3-5 in 45% and ≥ 6 in 20%. Conditioning regimens included fludarabine with melphalan 45%, plus TBI 51%, other 4%. Median follow-up was 30 months. 2yr OS was 38% (95%CI 31-44%). 2yr CI of NRM was 35% and relapse 36%. Age (p=0.001), DRI (p Conclusion: DRI and age are highly predictive of OS for patients undergoing haplo-cord transplantation. Our finding that HCT-CI is not predictive of OS when applied to haplo-cord alloHCT is supported by previous findings investigating the role of HCT-CI in cohorts with cord blood donors (Adachi Y et al BBMT 2018 and Majhail N et al BBMT 2008). To this end, our findings demonstrate that a high HCT-CI score should not preclude patients from evaluation for alternative donor transplantation using cord blood supported by Haplo-CD34+ progenitor cells. Other prognostic tools to assess specific comorbidities impacting this transplant platform are needed for accurate pre-transplant risk assessment in order to improve decision making and clinical trial assignments. Disclosures Van Besien: Miltenyi Biotec: Research Funding.

Introduction: Haplo-cord transplantation - the co-infusion of a single umbilical cord graft with CD34-selected cells from a haplo-identical donor, offers an alternative stem cell source for patients lacking HLA-matched donors. The T-cell depleted haplo-graft acts as a myeloid bridge until replaced by durable cord hematopoiesis. Anti-thymocyte globulin (ATG) is routinely used in haplo-cord preparative regimens to reduce graft failure, graft vs. host disease (GVHD) and graft vs. graft reactions. ATG depletes T-lymphocytes through Fas-mediated apoptosis, but also indirectly stimulates T-cell destruction through antibody-dependent cellular phagocytosis (ADCP) and antibody-dependent cellular cytotoxicity (ADCC) (de Koning, Blood Adv. 2018). Excessive depletion of cord lymphocytes may compromise immune reconstitution and graft vs. tumor effects. G-CSF administration early post-transplant may sensitize cord lymphocytes to the cytotoxic effects of residual ATG. G-CSF drives myeloid precursor proliferation and activates phagocytosis, facilitating increased ADCP and ADCC of ATG-coated cells (de Koning, Blood Adv, 2018). Prior to the publication of this data, our institutional practice was to administer G-CSF to haplo-cord transplant recipients from day +6 until neutrophil engraftment. In April 2018, we altered our practice - withholding routine G-CSF treatment. We here compare our transplant outcomes 1 year before and after this practice shift. Methods: We examined consecutive adult patients with hematologic malignancy that underwent haplo-cord transplantation conditioned with fludarabine and melphalan with or without total body irradiation (400 cGy) at Weill Cornell Medicine, between 04/2017 and 04/2019. All patients received rabbit ATG (Thymoglobulin) 1.5 mg/kg on days -5, -3 and -1 (total dose 4.5 mg/kg). Data was collected as part of study 01810588 registered at clinicaltrials.gov. Probabilities of relapse, relapse-related mortality (RRM) and non-relapse mortality (NRM) were generated using cumulative incidence (CI) estimates to accommodate competing risks. Probabilities of overall survival (OS) and progression-free survival (PFS) were calculated using Kaplan-Meier estimates and inter-group comparison performed by log-rank testing. Variables with potential survival impact were evaluated in a Cox proportional hazards regression model. Results: The study included 59 haplo-cord recipients - 30 who received G-CSF (GCSF group) and 29 who did not (NO GCSF group). Groups were well matched for age, weight, disease, DRI, baseline lymphocyte count, CMV recipient/donor status and TBI treatment (Table). Neutrophil engraftment occurred at a median of 10 days in the GCSF group vs. 14 days in the NO GCSF group (p=0.0002), and platelet recovery at a median of 20 and 22 days (p=-0.61). Primary graft failure occurred in 1 GCSF patient and 2 NO GCSF patients (p=0.53). The incidence of acute GVHD (grade II-IV) by day 100 was 10% in both groups (p=0.97). There was no significant difference between GCSF and NO GCSF in the CIs of relapse, RRM or NRM at 1yr. No difference was found in 1yr OS or PFS on univariate analysis (Table). After adjusting for patient age, weight, lymphocyte count prior to ATG, disease subtype, CIBMTR disease risk index (DRI), Karnofsky performance status (KPS), comorbidity score and TBI exposure, in multivariate analysis, no effect on OS or PFS was observed. CMV reactivation was observed in 40% (GCSF) vs. 21% (NO GCSF) (p=0.11). The trend towards lower reactivations in the NO GCSF may in part be due to the introduction of letermovir prophylaxis for CMV positive transplant recipients in 02/2018. Acknowledging the limited follow up of NO GCSF patients, we note a trend towards improved CD4 counts at 1yr in this group - median 271 cells/μL (n=6, IQR25-75 = 240-342) vs. 155 cells/μL in the GCSF group (n=16, IQR25-75 = 111-473) (p=0.17). Conclusion: Our data shows that G-CSF can safely be eliminated from haplo-cord transplant. We see a delay in neutrophil engraftment but no adverse effect on early morbidity or mortality outcomes. We continue to withhold early G-CSF while assessing long-term outcomes. Longer follow-up is needed in our cohort to enable a systematic analysis of immune reconstitution. Early CD4+ cell recovery after ATG treatment has been shown to improve OS, PFS, NRM and RRM (Admiraal, Lancet Hem 2015 & 2017). Disclosures Van Besien: Miltenyi Biotec: Research Funding.

Introduction: Umbilical cord blood (UCB) transplant supported by third party CD34-selected cells results in rapid count recovery, UCB mediated GVL effects and low rates of chronic GvHD. For patients lacking haplo-identical relatives, other sources of CD34 progenitors are needed. Methods: We identified partially matched unrelated donors for patients lacking suitable haplo-identical donors -including second-degree relatives - and who otherwise were candidates for haplo-cord transplant. Most were treated on prospective studies (clinicaltrials.gov 00943800 and 01810588). For 5 patients, UCB were obtained through NCT01351545. Results: Between 12/2014 to 7/2018 of 126 candidates for haplo-cord transplant, 26 (21%) had no suitable related donor. Most common reasons were: no first or second degree partially matched donors, ill or unavailable relative, high titers of HLA-antibodies against all relatives, or evidence of hematological familial hereditary syndrome. Diagnoses were: 16 AML/MDS, 5 ALL, 2 MPN, 1 NHL, 1 plasma cell leukemia and 1 SAA. Median age was 57 (24-75). 50% were women. 42% non-Hispanic white (NHW), 19% non-Hispanic blacks (NHB), 19% Hispanic, 8% other minorities. CIBMTR Disease Risk Index (DRI): 46% intermediate, 38% high and 8% very high. Median HCT-CI was 3.5 (25%-75% IQR 2-6). Conditioning: 16 Flu/Mel/TBI (94% 400cGray), 8 Flu/Mel,1 Flu/Cy, 1 Etoposide/TBI. All except 1 received ATG 4.5 mg/kg and all received post-transplant Tacrolimus and MMF. UCB matching was 4/8, 5/8, 6/8 or 7/8 HLA in 12%, 27%, 23%, and 38%, respectively. HLA matching for unrelated haplos was 5-6/12, 7-8/12, >9/ 12 HLA in 15%, 54% and 19%, respectively. For UCB, median cells collected were 2.1 (range1.1-4.0) ×107 TNC/kg. CD34 cell dose of unrelated donor graft was 3-5 ×106 CD34/kg. Median time to ANC engraftment was 11 days (range 9-35) and platelet engraftment was 18 days (range11-124). Chimerism on day 56 are shown in figure 1. There were three patients with graft failures: Pt #5 with complete graft rejection, autologous reconstitution, but ongoing clinical remission that persists to date (Day+ 1223); Pt #13 with graft failure and subsequent relapse, rescued with second UCB HSCT but died of progression of disease; and pt #18 who died from infectious complications after graft failure. Acute GvHD occurred in 35% of patients (4 Grade I-II, 4 Grade III, and 1 Grade IV). cGvHD was rare: One patient with mild severity and a second with severe lung involvement. After a median follow up of 209 days, 6 months cumulative incidence of relapse (CIR) was 16% and non-relapse mortality (NRM) was 20%. Median OS was 14 months (95%CI 7-27). Conclusion: 20% of adults without matched related or unrelated donors, also lack suitable first or second degree haplo-identical donors. UCB transplant with partially matched unrelated donor accessory cells provides an alternative for transplantation. Engraftment is rapid, rates of acute GVHD are acceptable and incidence of chronic GVHD is very low. Prolonged survival is encouraging in this patient cohort with adverse characteristics and who would not be candidate for haplo-identical HSCT. Disclosures No relevant conflicts of interest to declare.

Background: Distinct diagnostic assays and algorithms are employed by contemporary pathologists when seeking to identify lymphoma. There is a paucity of data on the degree of concordance between pathologists diagnosing lymphoma and its subtypes in different institutional settings in Latin America. The objective of this study was to assess the concordance between lymphoma diagnoses made via tissue biopsy by local pathologists and after review of these specimens by more specialized hematopathologists. Methods: This prospective, noninterventional and multicenter study was conducted at seven sites in Mexico from January 2017 to October 2017. Eligible biopsy samples were from patients with a previous diagnosis of lymphoma on lymph node biopsy or a diagnosis of extranodal lymphoma, with adequate tissue preservation and adequate amount of tissue for the review analysis. Patients receiving either chemotherapy or corticosteroids before sampling of tissue biopsies were excluded. Seven sites representing local pathologists and three hematopathologists participated in the study. The same biopsy tissues reviewed by the local pathologists were also sent to the hematopathologists participating in this study. Physicians in charge of patients' treatment decided whether to make any changes to a patient's treatment decision when comparing diagnosis results from the local pathologists and hematopathologists. The concordance in diagnosis results were classified into 3 categories: diagnostic agreement (i.e. the local pathologist and hematopathologist diagnoses concurred), minor discrepancy (i.e. there was a difference in diagnosis but it didn't change the treatment decision) and major discrepancy (i.e. there was a difference in diagnosis and it changed the treatment decision based on guidelines from the National Comprehensive Cancer Network). Results: Of 111 samples received, 105 met eligibility criteria for full review by hematopathologists and were included for full analysis. The median (range) patient age was 53 (16-94) years. More specimens were obtained from women (n = 57; 54.3%). A total of 53 (50.5%) patients were recruited from private institutions and the remaining (52; 49.5%) from public institutions. Within the 105 biopsies, a total of 89 cases were diagnosed as lymphoma by hematopathologists, including non-hodgkin's lymphoma (NHL; n = 72; 68.6%) and hodgkin's lymphoma (HL; n = 17; 16.2%). The most common subtype of NHL diagnosed was diffuse large B cell lymphoma (DLBCL), with a total of 32 cases. Diagnostic agreement was observed in 23 (21.9%) biopsies, minor discrepancies in 32 (30.5%) biopsies and major discrepancies in 50 (47.6%) biopsies, indicating treatment decisions changed in 47.6% of the total cases. Subtypes of lymphoma that local pathologists and hematopathologists most commonly found in diagnostic agreements were DLBCL (8/23; 34.8%) and HL (6/23; 26.1%), potentially due to their higher prevalence in the overall studied samples. Three types of error from the local pathologists were observed in major discrepancies, including ambiguity or lack of full diagnosis (27/50; 54%), a change from malignant to benign lesion (11/50; 22%) and a change of the type of neoplasm (12/50; 24%). Hematopathologists reported more immunohistochemical disease markers per tissue specimen: a median of 8.7 and a mode of 8 compared to a median of 5 and a mode of 0 for local pathologists. The diagnostic concordance varied across the seven study sites; the rate of major discrepancies ranged from 0% to 100% and the rate of diagnostic agreement ranged from 0% to 81.8%. The local pathologist from only one site received formal training in hematopathology and reported no major discrepancies. When excluding results from this site, the diagnostic agreement was observed in 14 (14.9%) biopsies, minor discrepancies in 30 (31.9%) biopsies and major discrepancies in 50 (53.2%) biopsies. Conclusions: This study showed that physicians from the seven study sites in Mexico changed their original treatment decisions that were initially based on local pathologist's diagnosis in nearly one-half (47.6%) cases after they reviewed the hematopathologist's diagnosis. In addition, there was a wide variation in the percentage of diagnostic agreements and discrepancies among different study sites, where sites with more experienced pathologists demonstrated a lower rate of diagnosis discrepancies in the diagnosis of lymphoma. Disclosures Solano: Janssen: Honoraria, Research Funding. Arteaga:Janssen: Honoraria, Research Funding. Martinez Hernandez:Janssen: Honoraria, Research Funding. Cabrero Garcia:Janssen: Honoraria, Research Funding. Gomez-Almaguer:AbbVie: Consultancy; Novartis: Consultancy. Lopez:Janssen: Honoraria, Research Funding. Perez:Janssen: Honoraria, Research Funding. Maldonado:Janssen: Honoraria, Research Funding. Bernal:Janssen: Honoraria, Research Funding. Osorno:Janssen: Honoraria, Research Funding. Fernandez:Janssen: Employment. Barreyro:Janssen: Employment. Regalado:Janssen: Employment. Herrera-Rojas:Janssen: Employment.

Introduction Early bone marrow (BM) evaluation (during aplasia or at “day 14” (D14)) in patients with AML undergoing conventional induction therapy has been adopted from clinical practice in pediatric acute lymphoblastic leukemia (ALL). While it has been shown that early persistence of AML correlates with decreased complete remission (CR) rates and overall survival (OS), unlike in ALL, there are no data to indicate that early initiation of re-induction therapy based on these findings will positively influence outcome. In fact, early re-induction, especially in older patients, may increase morbidity and mortality from prolonged cytopenias, infectious complications, and longer hospital stays. Moreover, it can be challenging to determine the nature of scattered blasts identified in a hypocellular BM at D14, as they may represent normal recovering marrow elements or malignant blasts. Even if malignant, the chemosensitivityof these cells will only be fully determined by later assessment of the BM at the time of expected count recovery (“day 28”). For these reasons, early re-induction therapy may not be advisable. In this retrospective study, we sought to evaluate the validity of D14 BM assessments as post-therapy prognostication to guide treatment decisions in AML. Methods We conducted a retrospective institutional study (2006-2014) of AML patients undergoing routine induction chemotherapy where diagnostic, interim (around D14) and recovery (D21-42) BM evaluations were available for review. Clinical information and pathology data were retrieved from our institutional database. Responses at D14 were categorized morphologically into three categories: optimal response (OR, blasts ≤5%), indeterminate response (IR, blasts 6-19%), and residual leukemia (RL, blasts ≥20% or a relative decrease in blast count from baseline of Results Evaluable patients (n=98) had a mean age of 51 years (20-73), and 45% were male. The median BM blast percentages at diagnosis, D14 and recovery were respectively 54.5%, 0% and 2.5% (Figure 1). There was a significantly greater absolute decrease in blast percentage from diagnosis to D14 in patients who recovered in CR compared to those who did not achieve CR (median: 53.5% vs 23.0%, P = 0.001). In patients that got early re-induction therapy for SOR at D14, the relative differential in baseline and D14 BM blasts was significantly lower compared to patients with D14 SOR who did not get re-induction therapy (median: 21.8% vs 77.8%, P=0.004) Ninety patients did not receive early re-induction therapy. Of these, 86 (95.6%) achieved CR and 4 patients (4.4%) recovered counts with residual leukemia. Fourteen (14.3%) patients were classified as SOR at D14. Of these, 6 (6.7%) did not receive re-induction therapy and 4 of these 6 patients (67%) achieved a CR. Eight patients received early re-induction therapy based on SOR at D14 (IR = 2, RL = 6); of these, 4 patients (50%) achieved CR at count recovery. Achieving an OR at D14 was predictive of achieving CR at recovery (sensitivity = 95.3%, PPV = 97.6%). However, not achieving an OR at D14 had low specificity (50%) and NPV (33.3%) for achieving CR (P = 0.021). Conclusions Our results indicate that a SOR at the D14 BM evaluation does not uniformly identify patients with primary induction failure (low NPV) and should not be used to dictate the timing of re-induction therapy. We confirmed the PPV of achieving an OR at D14 as previously reported, but we argue that no additional prognostic data is provided by an OR at D14, beyond what can already be predicted by pre-treatment variables (e.g., age and chromosomal abnormalities). We suggest that the D14 BM should be omitted from the routine evaluation of AML patients during induction therapy outside the context of a clinical trial. Figure 1 Figure 1. Progression and percentage of blasts at diagnosis, day 14 and recovery assessments (n = 98). Disclosures No relevant conflicts of interest to declare.

While PcG protein, Bmi1, plays a critical role in development of leukemic stem cells (LSCs), we have recently shown a differential Bmi1 dependency for LSCs initiated by different oncogenic transcription factors associated with distinct prognostic outcomes. PML-RARA and AML1-ETO leukemias associated with good prognosis are dependent on Bmi1, whereas poor prognostic leukemia induced by MLL fusion that is capable of activating multiple Hox genes is Bmi1 independent. However the role of Bmi1 and the mechanisms of over-coming Bmi1 dependency in other acute myeloid leukemia (AML) subtypes are still largely unknown. Aberrations of the MN1 gene mostly as an over-expression or rarely as a fusion partner of TEL in patients carrying the translocation t(12;22)(p13;q11) are frequently found in AML and myelodysplastic syndrome (MDS). Forced expression of MN1 induces aggressive AML with a 100% penetrance in mouse models within a few weeks, a latency significantly shorter than myeloid malignancy induced by MN1-TEL. Consistently, MN1 over-expression correlates with reduced drug response and poor prognosis of AML patients as well as high level of Bmi1 expression. In spite of these striking experimental and clinical features, the molecular mechanisms underlying MN1 leukemia are still largely unknown, and little progress has been made in targeting this leukemia. In the current study, we sought out to investigate the role of Bmi1 for MN1 mediated leukemic transformation and the mechanisms underlying this aggressive leukemia. In contrast to MN1-TEL that is dependent on Bmi1 for transformation of murine primary hematopoietic cells, MN1 over-expression could transform Bmi1-/- hematopoietic progenitor cells (HPCs) and induced serially transplantable AML in mice with the same latency as MN1 transformed wild type (wt) HPCs. Further molecular analyses revealed a significant up-regulation of p16Ink4a and cellular senescence in MN1-TEL Bmi1-/- HPCs, which was absent in MN1 transformed cells. Senescence in MN1-TEL Bmi1-/- cells could be rescued by re-expression of Bmi1 or suppression of p16 respectively, consistently suggesting an inherent functional difference between MN1 and MN1-TEL reflected by contrasting Bmi1 dependences. To identify the functional domain critical for the Bmi1 independency, structure/function analysis revealed that the removal of DNA binding domain (DBD) in the TEL moiety conferred Bmi1 independent transformation to MN1-TEL (MN1-TELΔDBD). MN1-TELΔDBD was able to induce transplantable leukemia in both the wild type and Bmi1 deficient cells. Conversely, fusion of TEL DBD to full length MN1 abolished its Bmi1 independence, and failed to transform Bmi1 deficient cells. These results strongly suggest that MN1 regulated molecules/pathways critical for Bmi1 independent transformation are misguided by the TEL DBD in MN1-TEL leukemia, providing a unique platform to dissect the pathways for Bmi1 independent transformation in AML. By performing global gene expression analyses on MN1, MN1-TEL and MN1-TELΔDBD transformed cells, we identified 1727 genes differentially expressed in MN1 transformed cells compared with MN1-TEL transformed cells; whereas only 44 genes were differentially expressed in MN1-TEL versus MN1-TELΔDBD transformed cells. When we overlapped these two gene sets together, we generated a unique gene set containing 34 genes associated with Bmi1 independence, including metabolic enzymes, signaling molecules and transcription factors such as Hoxa gene that has previously implicated in Bmi1 independent leukemic transformation. To assess the functional significance and the potential of targeting the candidates in this gene list in overcoming Bmi1 independent transformation, we performed functional analyses using shRNA approaches with a focus on those pharmacologically tractable candidates to suppress Bmi1 independent leukemic transformation. As a result, we were able to identify and demonstrate two different classes of enzymes with rigid catalytic domains that are required for Bmi1 independent transformation by MN1. Together, we dissect the mechanisms underlying Bmi1-independent leukemic transformation, and provide promising novel targets for MN1 leukemia. Disclosures: No relevant conflicts of interest to declare.

Background: Platelet binding to leukocytes has been shown to induce leukocyte activation in vitro. It is unknown to what extent platelet binding to leukocytes regulates leukocyte activation in vivo. We examined the correlation between platelet binding to leukocytes (platelet-leukocytes conjugates) and leukocyte activation in various clinical conditions. Methods: We studied a total of 321 venous blood samples from 291 subjects with acute venous thromboembolism (n=25), atrial fibrillation (n=48), metabolic syndrome (n=37), congestive heart failure (n=44), antiphospholipid syndrome (n=70), early sepsis (n=35), late sepsis (n=30) and normal controls. Using flow cytometry, we measured leukocyte expression of activation marker CD11b. Platelet-leukocyte conjugate measurement was based on co-expression of CD41 and CD45. Results: Levels of platelet-leukocyte conjugates strongly correlated with CD11b expression. This finding was present in congestive heart failure (r=0.47; p=0.001), atrial fibrillation (r=0.32; p=0.02), metabolic syndrome (r=0.51; p=0.001), venous thromboembolism (r=0.74; p 0.05). For example, the relation between platelet-leukocyte conjugates and CD11b expression in venous thromboembolism is shown in Figure 2, and is best described by a straight line. The addition of quadratic term did not add any prediction of CD11b expression, as shown. Conclusions: Our findings strongly suggest that platelet binding to leukocytes is a key determinant of leukocyte activation in vivo. The degree of platelet binding to leukocytes strongly correlates with leukocyte activation after a threshold is reached in normal adults. This threshold is lost in pro-thrombotic and pro-inflammatory disease states, in which a linear increase in leukocyte activation is seen with increasing platelet binding to leukocytes. Figure 1. Figure 1. Figure 2. Figure 2.

Introduction: Endothelial microparticle binding to monocytes has been shown to induce monocyte activation in vitro. In this study, we examined the correlations between EMP binding to monocytes and monocyte levels of nitric oxide (NO), as a marker of monocyte activation in different clinical conditions. Methods: We studied 186 subjects with acute venous thromboembolism (n=25), atrial fibrillation (n=48), metabolic syndrome (n=37), congestive heart failure (n=44), and normal controls (n=32). Using flow cytometry, we measured monocyte levels of NO by flow cytometry after loading monocytes with the membrane permeable NO-selective fluorescent indicator DAF-DA. Two different populations of EMP-monocyte conjugates were also measured. EMP62E+-monocyte and EMP54+-monocyte conjugates were measured based on the detection of E-selectin (CD62E) or CD54, respectively, coexpressed with CD45 in monocytes. Results: Pearson correlation coefficients between monocyte NO levels and EMP-monocyte conjugates are shown in the Table. A highly significant correlation was found between EMP62E+-monocyte conjugates and monocyte NO levels in patients with congestive heart failure (r=0.43; p=0.003). In contrast, EMP54+-monocyte conjugates strongly correlated with monocyte NO in patients with venous thromboembolism (r=0.58; p=0.009) and metabolic syndrome (r=0.49; p=0.002). No correlation was found between these conjugates and monocyte NO levels in atrial fibrillation or normal controls. Conclusions: The binding of different species of EMP to monocytes correlates with monocyte NO levels in clinical states such as congestive heart failure, metabolic syndrome, and venous thromboembolism. However, this correlation was not found in atrial fibrillation or normal controls. Our findings support the concept that the binding of different species of EMP exert different biological effects and/or reflect different biologic processes in specific disease states. Further research is needed to determine whether the binding of EMP species to monocytes regulates nitric oxide production by monocytes and whether monocytes themselves regulate the binding of different species of EMP in different disease states. Correlation between Monocyte NO levels and EMP-Monocyte Conjugates in different conditions. EMP54+-Monocyte Conjugates EMP62E+-Monocyte Conjugates Pearson r p value Pearson r p value Metabolic Syndrome 0.49 0.002 0.13 0.54 Venous Thromboembolism 0.51 0.009 0.12 0.57 Congestive Heart Failure 0.22 0.14 0.43 0.003 Atrial Fibrillation 0.22 0.14 0.17 0.24 Normal Controls 0.03 0.85 0.27 0.13

Background: In vitro studies have shown that endothelial-cell derived microparticles (EMP) can bind and activate leukocytes. It is unknown whether EMP binding to leukocytes regulates leukocyte activation in vivo. In this study, we examined the correlation between EMP binding to neutrophils (EMP-neutrophil conjugates) and neutrophil activation in various clinical conditions. Methods: We studied a total of 251 venous blood samples from 221 subjects with several prothrombotic and inflammatory conditions, including acute venous thromboembolism (n=25), atrial fibrillation (n=48), metabolic syndrome (n=37), congestive heart failure (n=44), early sepsis (n=35), late sepsis (n=30), as well as normal controls (n=32). Using flow cytometry, we measured leukocyte expression of activation marker CD11b and 2 different populations of EMP-neutrophil conjugates. Bitmapping by forward- and side-scatter gating was used to identify neutrophils; EMP62E+-neutrophil conjugates and EMP54+-neutrophil conjugates were measured based on the detection of E-selectin (CD62E) or CD54, respectively, co-expressed with CD45 in neutrophils. Neutrophil nitric oxide (NO) levels were measured by flow cytometry after loading neutrophils with the membrane permeable NO-selective fluorescent indicator DAF-DA. Results: Levels of EMP62E+-neutrophil conjugates consistently and significantly correlated with CD11b expression. This finding was present in patients with acute venous thromboembolism (r=0.46; p=0.02), atrial fibrillation (r=0.42; p=0.003), metabolic syndrome (r=0.56; p0.05). EMP62E+-neutrophil conjugates correlated with NO levels in neutrophils in patients with congestive heart failure (r=0.48; p=0.001) and atrial fibrillation (r=0.33; p=0.02), but no correlation was seen in other disease states. Conclusions: EMP62E+-neutrophil conjugates strongly correlate with neutrophil activation in normal adults, as well as in multiple pro-inflammatory and pro-thrombotic disease states. EMP62E+-neutrophil conjugates may serve as a marker of prothrombotic and inflammatory states. Our results combined with prior in vitro studies suggest that EMP62E+ binding to neutrophils is an important and “universal” determining factor for neutrophil activation in vivo in humans. In contrast, binding of EMP54+ to neutrophils does not seem to regulate neutrophil activation. These findings also support the concept that different species of endothelial microparticles have different biologic functions. EMP binding to neutrophils seems to affect NO production in only some disease states.