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Epstein-Barr virus (EBV) viremia is a common complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The purpose of this study was to evaluate the impacts of early-onset EBV viremia in acute leukemia (AL) patients who underwent allo-HSCT with anti-thymocyte globulin (ATG)-containing myeloablative conditioning (MAC) regimen. Two hundred and ninety-six patients were included between January 2013 and December 2015. In 126 patients (42.6%) who developed early-onset EBV viremia, with a median time of 48 (range 18~99) days after allo-HSCT. The cumulative incidence of EBV viremia at 30 and 90 days after allo-HSCT were 4.1 and 39.9%, respectively. Prognostic analysis showed that the adjusted overall survival in early-EBVpos group was significantly lower than early-EBVneg group within the first 26.7 months after allo-HSCT [hazard ratio (HR), 1.63, P = 0.012], but significantly higher than those afterward (after 26.7 months: HR 0.11, P = 0.035); for the adjusted event-free survival, early-EBVpos group was significantly inferior in early-EBVpos group within the first 10.8 months after transplantation (HR: 1.55, P = 0.042), and this adverse effect was not detected any more after 10.8 months (HR: 0.58, P = 0.107). Compared with early-EBVneg group after adjusting by aGVHD and CMV viremia, HR for death from transplant-related mortality was 2.78-fold higher in patients with early-EBV viremia in piecewise constant Cox analysis (P = 0.006), and this adverse effect was not detected any more after the cut-point time (HR: 0.67, P = 0.361). No differences in terms of relapse and relapse mortality were observed between early-EBVpos and early-EBVneg group (P > 0.05). In conclusion, the impacts on transplant outcomes of early-EBV viremia were time-dependent, which may help to optimize management strategies for early-EBV viremia after allo-HSCT, especially in AL patients with ATG-containing MAC regimen.

The conditioning regimens used for the allo-HSCT include either myeloablative conditioning (MAC) or reduced intensity conditioning (RIC) regimens based on the age, performance status and co-morbidities. Studies comparing the survival outcomes of RIC and MAC allo-HSCT in AML and MDS patients have reported contradictory results. We therefore retrospectively analyzed our data of AML and MDS patients who received MAC and RIC allo-HSCT at our center and compared the long term outcome of the two conditioning regimens. One hundred twenty six consecutive patients were evaluated, 32 (25.4%) underwent MAC allo-HSCT and 94 (74.6%) underwent RIC allo-HSCT. The most common MAC regimen used was busulfan plus cyclophosphamide and the most common RIC regimen used was fludarabine plus melphalan. The median age was higher in RIC group (44 years, range 4–75 years) compared to MAC group (31 yrs, range 6–51 yrs, p = 0.001). There was no significant difference in terms of overall survival (p = 0.498), relapse-free survival (p = 0.791) and non-relapse mortality (p = 0.366) between the two groups. In multivariate analysis, only chronic graft-versus-host disease resulted in decreased risk of relapse and improved overall survival irrespective of the conditioning regimens used.

In this study, we compared the outcomes of patients with acute myelogenous leukemia (AML) in complete remission treated with myeloablative conditioning (MAC) and those treated with reduced-intensity conditioning (RIC) before allogeneic hematopoietic stem cell transplantation (allo-HCT). In addition, we explored the efficacy of dual T cell depletion using anti-thymocyte globulin (ATG) and post-transplantation cyclophosphamide (PTCy) for the prevention of graft-versus-host disease (GVHD) in patients undergoing RIC allo-HCT. Our study cohort comprised 356 adults with AML in complete remission who underwent allo-HCT between 2013 and 2018. One hundred eleven patients (31.2%) received a MAC regimen, and 245 (68.8%) received an RIC regimen. One hundred seventy-one of the patients who received an RIC regimen (68.4%) received ATG, PTCy, and cyclosporine (ATG-PTCY-CsA) for GVHD prophylaxis in accordance with our institutional protocol. Data were collected retrospectively and updated in July 2019. With a median follow-up of 14.5 months (range, 0 to 76 months), 161 patients (45.2%) died, and 66 (18.5%) relapsed. Two-year overall survival (OS), relapse-free survival (RFS), and GVHD-free/RFS (GRFS) were 55%, 52.6%, and 35%, respectively. The intensity of the conditioning regimen, with or without ATG-PTCY-CsA, did not have a significant impact on OS and RFS. However, RIC in combination with ATG-PTCY-CsA was associated with a significantly lower cumulative incidence of acute GVHD and chronic GVHD. The use of RIC with ATG-PTCy-CsA was a significant predictor for higher GRFS secondary to the reduction of clinically relevant GVHD (P= .0001). In patients with AML, RIC allografts and dual T cell modulation with ATG and PTCy led to superior GRFS. The use of this GVHD prophylaxis strategy, along with mitigation of conditioning toxicity using RIC, may result in better long-term quality of life for allo-HCT recipients.

Procedural sedation and analgesia for patients with adult congenital heart disease (ACHD) and highly elevated subpulmonic ventricular pressure require proper anesthesia care to prevent a pulmonary hypertensive crisis. We describe the monitored anesthesia care (MAC) of two patients with ACHD (a complete atrioventricular septal defect and congenitally corrected transposition of the great arteries) and highly elevated subpulmonic ventricular pressure. In both patients, preprocedural transthoracic echocardiography was useful for detecting severely elevated subpulmonic ventricular pressure. The MAC involved the infusion of propofol, dexmedetomidine, and fentanyl. Norepinephrine was continuously administered from the preanesthetic period. No hemodynamic instability or respiratory depression was observed during the MAC. Continuous administration of norepinephrine from the preinduction period was helpful for preventing hypotension. We added dexmedetomidine to our MAC regimen of propofol and fentanyl because it exerts both sedative and analgesic effects. Dexmedetomidine does not cause respiratory depression; thus, our MAC regimen is believed to be theoretically safe for patients with ACHD and elevated subpulmonic ventricular pressure. Our findings suggest that safe MAC for patients with ACHD and highly elevated subpulmonic ventricular pressure may require careful consideration of the anesthetic regimen and close observation by adequately trained personnel, which is best provided at regional ACHD centers.

Introduction Busulfan is often used in a myeloablative conditioning regimen at an IV dose of 12.8 mg/kg (BU4). A reduced intensity regimen using 6.4 mg/kg (BU2) is commonly used in older patients or those with comorbid diseases. Data on use of BU3 (9.6 mg/kg) based regimen are limited. At KFSHRC, the busulfan-based MAC regimen’s IV-BU dose is 12.8 mg/kg (BU4), but for those who do not tolerate the full MAC, BU can be reduced to 9.6 mg/kg (BU3). Objective To study the outcomes of hematological malignancy patients who received allo-HCT using BU3-based conditioning from matched related or unrelated donors. Methods A retrospective analysis of the KFSHRC-BMT Database for patients who received allo-HCT between October 2005 and December 2019. Results A total of 65 patients were identified: 47 AML (72.3%), 8 MDS (12.3%), 8 myelofibrosis (12.3%), and 2 CML (3.1%) patients. Median age was 52 years (16–66), and 35 (54%) were males. Pre-transplant status showed 57% were in CR1, 17% in CR2, and 3% not in CR. Fifty-seven (88%) patients received PBSC, 6 (9%) received BM source, and 2 (3%) received both PBSC and BM from HLA-matched related [N= 61 (93%)] or unrelated [N=4 (7%)] donors. Forty (61.5%) patients received Bu/Flu as a conditioning regimen, 14 (21.5%) received Bu/Cy, 7 (10.8%) received Bu/Flu/ATG, and 4 (6.2%) received Bu/Cy/ATG. GVHD prophylaxis consisted of cyclosporine and methotrexate for all patients. Fifty-two (80%) patients had comorbidities with comorbidity index between 1–2 in 29 (44.6%) patients and more than 2 in 23 (35.4%). Sixty-two (95%) patients engrafted; median ANC and platelet engraftment were 18 days. Acute GvHD grade II–IV and III–IV occurred in 29% and 14%, respectively. Chronic GvHD occurred in 55% and was extensive in 24% of patients. With median follow-up of 60.5 months, the 2 year- and 5 year-OS were 58.5% and 44.1% respectively. The 2 year- and 5 year-DFS were 52.9% and 44.5%, respectively. Cumulative incidence of relapse and NRM at 2 years were 29.5% and 17.4%, respectively. Day +100 TRM was 10.7%. Conclusions Allogeneic SCT using BU3-based regimen appears feasible to use in patients who are not suitable for a fully myeloablative (BU4) regimen. TRM, DFS, and OS rate were comparable to reports from studies using a BU4-based regimen, warranting prospective studies in these patients.

We have previously demonstrated a 11% incidence of post-transplant de novo thyroid disease, even with a radiation-free RIC regimen. Following the enactment of a universal late effects screening program at our institution, we compared the outcomes of 108 pediatric hematopoietic stem cell transplant recipients after a RIC regimen (n = 33) to those after a MAC regimen (n = 75) during the same time period. Overall, 10% of subjects developed thyroid dysfunction after HSCT, with a median follow-up of 669 days. Seven subjects had primary hypothyroidism prior to HSCT. Of the thirty-one subjects who received RIC, one (3.2%) developed a new thyroid disorder, compared to the nine of sixty-nine (13.0%) subjects who received MAC (p = .167). No significant associations were seen with donor type, graft-vs.-host disease, or total body irradiation. Nine of the 10 subjects who developed thyroid disease after transplant were asymptomatic. Continued follow-up of this contemporary cohort will further delineate risk factors for post-transplant-associated thyroid dysfunction and better inform discussions of transplant-associated sequelae.

We report here the results of a retrospective study designed to evaluate outcome of patients with AML with KPS score ≤80% following allo-SCT. The analysis included adult AML patients undergoing allo-SCT in CR1 between 2000 and 2018, with a KPS score at the time of transplant between 50% and 80%. A total of 2,963 patients were identified. Median age at transplant was 55 years (18-77 years). The KPS score was 80% in 85% of the patients and On multivariate analysis, transplant from a MSD was associated with a reduced risk of aGvHD (10/10 UD HR 1.8, 9/10 UD HR 2.4, haplo HR 1.9, CB HR 3.4, p In order to compare outcome following MAC and RIC conditioning regimens the analysis was restricted to patients receiving transplant from MSD or UD. Patients with a KPS score of 80% or In conclusion, allo-SCT is feasible in patients with acute myeloid leukemia in first remission and KPS score ≤80%, with acceptable NRM and survival rates. In patients with a KPS score of 80% a MAC regimen was associated with lower relapse rate, similar NRM and better GRFS as compared to RIC, while in patients with a KPS score

Compared to reduced-intensity conditioning regimen, myeloablative conditioning (MAC) for hematopoietic stem cell transplantation (HCT) reduces relapse but is avoided in older patients because of higher non-relapse mortality (NRM). To meet the need for a myeloablative regimen for older patients, we developed a novel fludarabine and busulfan MAC regimen. We fractionated the dose of busulfan and gave it for 6 days over a 2-week period and demonstrated the feasibility and safety of this approach. However, the disease-specific efficacy of this regimen is not known. The purpose of this study was to estimate the efficacy of fractionated busulfan regimen by estimating diseases specific survival outcomes. The conditioning regimen consisted of busulfan and fludarabine. On days −13 and −12 before HCT, patients received 80 mg/m2 busulfan intravenously (IV) daily in an outpatient clinic. Additional chemotherapy was administered during inpatient treatment from day −6 through day −3, including fludarabine 40 mg/m2 and busulfan IV once daily. The dosing of busulfan was determined from pharmacokinetic analyses to achieve for the course a target area under the curve of 20,000 ± 12% μmol/min, which is close to the average exposure of myeloablative dose of busulfan. One hundred fifty patients with high-risk hematological malignancies up to 75 years were enrolled in this prospective phase II study. The objective was to evaluate NRM, relapse, survival, the rates of graft-versus-host disease (GVHD), and long-term complications. The median age of the patient population was 61 years (interquartile range, 55-67). The most common diagnoses were acute myeloid leukemia (AML; N = 59 [39.3%]), myelodysplastic syndrome (MDS; n = 29 [19.3%]), and myelofibrosis (MF; N = 22 [14.7%]). Most had an unrelated donor (n = 93 [62%]) and received peripheral blood graft (n = 110 [73.3%]). Over half had an HCT-specific comorbidity index of ≥3 (n = 79 [52.7%]). The median follow-up among survivors was 43.4 months (interquartile range, 38.9-50.4). In patients with AML in complete remission, MDS, and myelofibrosis, 3-year overall survival was 66.7% (95% confidence interval [CI], 50.2-88.5%), 43.6% (95% CI, 28.6-66.4%), and 59.1% (95% CI, 41.7-83.7%) respectively. The cumulative incidence of NRM was 22% (15.3%-28.7%), extensive chronic GVHD was 27% (95% CI, 20-34%), bronchiolitis obliterans was 4.7% (95% CI, 1.3-8.1%), and secondary malignancy was 8.7% (95% CI, 4.1-13.2%) at 3 years. Lengthening the duration of busulfan (fractionation) permits safe delivery of myeloablative conditioning in older patients, leading to prolonged survival. © 2021 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Background HLA-matched sibling and unrelated donors are not always available for patients that are in need of an allogeneic haematopoietic stem cell transplant. Partially HLA-mismatched related (haploidentical) donors can be identified for the vast majority of patients but these transplants were historically complicated by excessive graft versus host disease (GVHD), nonrelapse mortality (NRM), and poor overall survival (OS). Haploidentical haematopoietic stem cell transplantation (Haplo HSCT) has become increasingly common over the last ten years, predominately due to the successful use of post-transplant cyclophosphamide (PTCy) in mitigating graft versus host disease (GVHD). Most studies using PTCy have been retrospective with various conditioning regimens and stem cell sources making interpretation of results difficult. ANZHIT-1 is a prospective Australian multi-centre phase II study of Haplo HSCT with defined conditioning and GVHD prophylaxis regimens. Methods: This is an ethics approved Phase II study (ACTRN: 12617000151336) conducted between 2015-2020 at six Australian allogeneic HSCT centres. All patients received peripheral blood Haplo HSCT from haploidentical family members. The reduced intensity regimen (RIC) was fludarabine, cyclophosphamide and 200cGy TBI and the myeloablative regimen (MAC) was fludarabine with IV busulfan 3.2mg/kg x 4. PTCy 50mg/kg D+3, D+4 was used with MMF (to D35) and a calcineurin inhibitor (CNI) as GVHD prophylaxis. CNIs were weaned and ceased by D+120 in patients who did not have evidence of GVHD. Choice of conditioning regimen was based on age and hematopoietic cell transplantation comorbidity index (HCT-CI) scores. Patients who had an HCTCI >3 or age >50yrs received RIC. Data collection was through the Australian Bone Marrow Transplant Recipient Registry. Survival was analysed using the Kaplan-Meier method. Results: Seventy eight patients were included in the study with a median follow up of 402.5 days (28-1259). There was a male predominance (66%). The median age was 53 years (range 18-69) and the median HCT-CI score was 1 (range 0-5). Thirty nine patients had acute myeloid leukaemia, 12 acute lymphoblastic Leukaemia, 14 Non Hodgkin lymphoma or Hodgkin lymphoma, 4 myelodysplastic syndrome and 9 other diagnoses. The majority received RIC (59%). Median neutrophil and platelet engraftment times were 18 days (range: 12-92) and 28 days (range: 13-262) respectively. Acute GVHD grade III-IV occurred in 14.1% of patients whilst chronic GVHD occurred in 20.5%. Moderate to severe cGVHD according to NIH consensus criteria occurred in 10.3% of patients. Overall survival probability at one year was 74.1% (95% CI: 52.9-86.8) for MAC recipients and 77.8% (95% CI: 61.6-87.8) for RIC recipients (Figure 1). Non relapse mortality (NRM) at D100 and 1 year were 2.2% and 8.7% respectively in the RIC group compared to 6.3% and 18.8% respectively in the MAC group. Causes of NRM included infection (n=5), GVHD (n=3) and VOD, respiratory failure and multi-organ failure in one patient each. Haemorrhagic cystitis and poor graft function were relatively common post-transplant morbidities but rarely contributed to NRM. Despite the use of peripheral blood stem cells and early weaning of CNIs, only 3/11 NRM deaths were due to GVHD. Relapse was the most common cause of death in the RIC group with 17.4% of patients relapsing at a median of 114 days (range 36-564) compared to only 6.3% at a median of 90.5 days (range 64-154) in the MAC group. Conclusion: This prospective Haplo HSCT trial utilising PTCY demonstrates encouraging overall survival rates. The RIC regimen had a promising toxicity profile but early relapse remains a concern despite early weaning of CNIs. In contrast, the MAC regimen is associated with a low relapse rate but NRM at one year remains significant. Further refinement of the conditioning and GVHD prophylaxis regimens will be incorporated in the follow-on study, ANZHIT-2, which will begin accrual in late 2020. Disclosures Bajel: Pfizer: Honoraria; Amgen: Honoraria, Speakers Bureau; Novartis: Honoraria; Astellas: Honoraria; Abbvie: Honoraria. Greenwood:Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hamad:Novartis: Honoraria; Abbvie: Honoraria.

Introduction: Adult T-cell leukemia lymphoma (ATLL) is a rare hematologic malignancy caused by human T-cell lymphotropic virus (HTLV-1) with dismal cure rates and poor response to conventional chemotherapy. Allogeneic Hematopoietic Stem Cell Transplantation (AlloSCT) is the only therapeutic option which may offer the chance of long-term remission and cures in a subset of patients. We sought to investigate the outcomes of transplantation in one of the largest cohorts in North America. Methods: A retrospective chart review study was conducted using the North-American ATLL and the Hematopoietic Precursor Cell transplantation databases at Montefiore Medical Center from 2011 to 2020. Variables collected include age, sex, ethnicity, ATLL subtype, molecular profile, previous treatments, conditioning regimens, type of transplant, immunosuppressive regimen, progression free survival (PFS) post-transplant and overall survival (OS) post-transplant. Results: Fourteen patients with ATLL who received an AlloSCT from 2011-2020 were identified. Fifty-seven percent (8/14) of patients were male. Seventy-one percent (10/14) of patients were African American and twenty-nine percent (4/14) were Hispanic. Median age was 51 years. Sixty-four percent (9/14) of patients had Stage IV disease at the time of diagnosis. Forty-three percent (6/14) patients had acute and fifty-seven percent (8/14) had lymphomatous ATLL. Almost all patients (92%) were treated initially with EPOCH combination chemotherapy. Twenty-eight percent (4/14) of patients received interferon/zidovudine as bridge-to-transplant. Fifty-seven percent (8/14) of patients achieved complete remission (CR) prior to AlloSCT, 7% (1/14) were in partial remission, and 28% (4/14) were relapsed or refractory. Forty-three percent (6/14) of patients received SCT from a matched-related donor (MRD), 36% (5/14) from a haplo-identical donor and 21% (3/14) from a matched-unrelated donor (MUD). Ninety-three percent (13/14) of patients received a reduced-intensity conditioning (RIC) regimen pre-transplantation. Seven percent (1/14) received a myeloablative conditioning (MAC) regimen. RIC regimens consisted of fludarabine with melphalan +/- anti-thymocyte globulin (ATG) or fludarabine with cyclophosphamide with total-body irradiation in doses less than 500 cGy. Patients receiving haplo-identical SCT also received post-transplant cyclophosphamide (PTCy) for prevention of graft vs host disease (GVHD). The MAC regimen used included busulfan with cyclophosphamide at myeloablative doses. Twenty-eight percent (4/14) of patients relapsed post-alloSCT with a median relapse-free survival of 6 months (range 4-18 months). The median OS of the whole cohort was 27 months (8-82 months). Graft-versus-host disease (GVHD) developed in 28% (4/14) percent of patients. The most common manifestation was skin GVHD. Fifty-percent (7/14) of the patients are surviving to-date. Transplant-related mortality (TRM) at day 100 was 21% (3/14) of patients. Causes of death were complex and included several diagnoses in certain patients. The most frequent diagnoses associated with death were infection (28%), graft failure (14%), GVHD (14%), veno-occlusive disease of the liver (VOD) (7%), disease progression (14%) and unknown due to patient lost to follow-up (14%). The main infectious events included fungal (2), bacterial (1), and COVID-19 (1) infection. Forty-three percent (6/14) of patients remain in complete remission to date. Conclusions: Allogeneic Stem Cell Transplantation offers long-term survival with a TRM of 21% in a disease with an inherently dismal prognosis. AlloSCT using several graft sources, is thus, a safe and well tolerated treatment modality and offers long term remissions. Disclosures Steidl: Pieris Pharmaceuticals: Consultancy; Aileron Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer Healthcare: Research Funding; Stelexis Therapeutics: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees. Verma:BMS: Consultancy, Research Funding; acceleron: Consultancy, Honoraria; Janssen: Research Funding; Medpacto: Research Funding; stelexis: Current equity holder in private company. Janakiram:ADC Therapeutics, FATE therapeutics, TAKEDA pharmaceuticals: Research Funding.

Background Allogeneic hematopoietic stem cell transplantation is the most effective treatment that can cure acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). However, myeloablative conditioning (MAC) regimens cause high non-relapse mortality (NRM). Reduced intensity conditioning (RIC) regimens can reduce NRM but increase relapse incidence (RI) and as a result of it, has the similar overall survival (OS) to the MAC regimen according to the results of published clinical trials. Nevertheless, most of these clinical trials aren't high quality studies and the results of different studies are not consistent. To clarify whether RIC is as effective as MAC but safer than it for AML in CR and MDS we write the systematic review (SR). Methods Two reviewers independently comprehensively searched the related databases and websites and hand searched the reference lists. They also independently screened and evaluated the retrieved studies and then extracted data of included studies with the Cochrane Collaboration recommended tools. Only randomized controlled trials (RCTs) were included. Hazard ratio (HR) was used to compare the OS, RI, leakemia free survival (LFS), non-relapse mortality (NRM), the incidence of acute graft versus host disease (aGVHD) and chronic graft versus host disease (cGVHD) with the generic inverse variance method. The III-IV aGVHD and graft failure (GF) were compared with the Mantel-Haenszel method pooled risk ratio (RR). A two-sided P value of less than 0·05 was considered as significant difference. Heterogeneity was significant when the P value of the Chi-square test was less than 0·1 and/or the I2 value was more than 50%. Additionally we used the GRADE principles to evaluate the quality of evidence. The SR was registered on PROSPERO with ID of CRD42020185436. Results 7770 records were retrieved. We included 6 RCTs with 1413 participants comparing RIC with MAC. Our results showed there wasn't significant difference in OS (HR=0·95 95% confidence interval (CI, 0·64, 1·4), P=0·80) and RI (HR=1·18, CI (0·88, 1·59), P=0·28). Six RCTs and 1413 pariticipants were included of the two outcomes. The result of LFS was (HR=1·09, CI (0·69, 1·74), P=0·71) between RIC and MAC, three studies and 596 participants were included. The heterogeneity was significant in the OS, RI and LFS outcomes so we combined the three outcomes with the random effects model. RIC significantly reduced NRM than TBI/Bu based MAC (HR=0·53, CI (0·36, 0·80), P=0·002), four RCTs and 633 participants were included. On the other hand, RIC didn't reduce NRM than treosulfan based MAC with the results of (HR=1·67, CI (1·02, 2·02), P=0·04) compared with treosulfan 10 g/m2*3 days regimen and (HR=0·76, CI (0·45, 1·3), P=0·32) compared with treosulfan 14 g/m2*3 days regimen, both included only 1 RCT and 460 and 320 participants were included respectively. RIC had a trend to reduce the incidence of aGVHD compared to TBI/Bu based MAC (HR=0·79, CI (0·60, 1·03), P=0·08) and III-IV aGVHD (HR=0·61, CI (0·36, 1·04), P=0·07). RIC didn't show significant difference to treosulfan based MAC regimen on the two outcomes. The heterogeneity of the NRM, aGVHD, III-IV aGVHD was non-significant and we combined the three outcomes with the fixed effect model. The cGVHD was similar between RIC and MAC (HR=1·01, CI (0·79, 1·28), P=0·96), results of included results had significant heterogeneity and random effects model was used. GF was rare in both RIC (2·6%) and MAC (1·1%) arms. The quality of evidence on OS, RI and LFS was moderate and on NRM, aGVHD, cGVHD was high. Conclusions For AML in CR and MDS paitents, RIC don't increase OS and RI compared with MAC. RIC regimens reduce NRM than the TBI/Bu based MAC regimens. RIC regimens are also good choice of preparative regimens before HSCT for AML in CR and MDS. The treosulfan based MAC has a promising result in one RCT and even causes less NRM than RIC. Nevertheless, studies are scarce and more studies are needed to confirm the result. Disclosures No relevant conflicts of interest to declare.

Background Sickle cell disease (SCD) is a hemoglobinopathy and vasculopathy resulting in vaso-occlusive crises, chronic end-organ damage, and shortened life span. The only curative therapy is allogeneic stem cell transplant (AlloSCT) (Talano/Cairo, EJH, 2015). Unfortunately, only approximately 16% of the sickle cell population has an HLA matched unaffected sibling (Bhatia/Cairo, BMT, 2014). We have demonstrated the safety and efficacy of familial haploidentical transplants (FHI) in this population with 100% engraftment (Cairo et al, JAMA Peds, 2019). However, the incidence of sinusoidal obstructive syndrome (SOS) in SCD AlloSCT recipients is approximately 32% (McPherson, BMT, 2011). Defibrotide primarily targets endothelium and can reduce endothelial cell injury (Falanga et al, Leukemia, 2003 and Scallia et al, Clin Pharm, 1996). Corbaciolgu et al (Lancet 2012) demonstrated the safety and efficacy of prophylactic defibrotide in high-risk pediatric AlloSCT recipients to significantly reduce the incidence of SOS. Objective To determine the safety and efficacy of defibrotide prophylaxis for SOS in children, adolescents and young adults (CAYA) with high-risk SCD following MAC and FHI AlloSCT, utilizing CD34+ selection with CD3 addback. Design/Methods Patients with SCD aged 2 to 35 years with high-risk SCD (stroke, ≥2 acute chest syndrome in past 2 years, ≥3 pain crises in last 2 years, abnormal TCD study, ≥1 silent infarct lesion on MRI) were enrolled after being consented (NCT02675959). Patients were in two cohorts (2 to 17.99 years and 18 to 34.99 years of age) for age-based analysis and treatment (Table 1 and 2). All patients received a MAC regimen prior to receipt of an FHI with CD34+ selection and CD3 addback peripheral blood stem cell transplantation (PBSCT), as we have already demonstrated (Cairo et al, ASH, 2018). Defibrotide was given day -10 during conditioning through day +21 following transplant. Baseline studies of organ function and biomarkers were obtained prior to transplantation. Results We have enrolled eight patients, five in cohort 1 (median age 9.9 years) and three in cohort 2 (median age of 24 years) with a gender ratio (M/F) of 4/4. Patients had hemoglobin SS (n=7) or hemoglobin SC (n=1). Patients had either a maternal (n=7) or sibling (n=1) donor. Patients had early neutrophil engraftment (median day +11 (day +7 to day +14)). All tolerated 109 ± 11doses of defibrotide. There were no severe adverse or bleeding events probably or directly related to defibrotide. No patient developed SOS. Conclusion The preliminary data suggests defibrotide is safe and well tolerated in CAYA patients with high-risk SCD following MAC and FHI AlloSCT, utilizing CD34+ selection with CD3 addback. A larger cohort and/or follow-up will be required to confirm these preliminary findings. Supported by FDA R01FD004090 and Jazz Pharmaceuticals.

Background The use of MTX for GVHD prophylaxis is associated with increased rates of oral mucositis (OM), delayed engraftment, hepatotoxicity and nephrotoxicity. Based on limited data, the EBMT and ELN working group recommend the use of FA-rescue to reduce MTX toxicity after alloHCT. We aimed to determine whether FA-rescue reduces the rate of MTX-induced toxicity in patients who receive post-transplant MTX for GVHD prophylaxis. Methods This is a double blind RCT conducted in 3 centers. We enrolled patients undergoing alloHCT from MSD or MUDs with a MAC regimen and PBSC grafts, and GVHD prophylaxis consisting CSA/MTX, plus ATG for MUDs. Patients were randomized to oral FA or placebo, stratified by center and conditioning intensity (standard vs. reduced toxicity MAC). FA administration started 24h after each MTX dose: 15 mg TID after MTX administration on day +1 and QID after MTX administration on days +3 and +6. The primary endpoint was the rate of grade 3-4 OM according to the WHO scale. A sample size of 58 subjects in each group was estimated to detect a difference in grade 3-4 OM of 50% vs. 25%. Results From 2/2016 through 7/2019, 52 patients with acute leukemia in CR (n = 45), MDS (n=6) or NHL in CR (n=1) were randomized to FA (n=28) or placebo (n=24). Patient characteristics were similar between groups (table). After enrolment of 52 patients, interim analysis revealed that the rate (46.6% vs. 45.8%, P=0.97) and duration (4 vs. 4 days) of grade 3-4 OM and the rate of OM of any severity (83.3% vs. 77.8%, P=0.65) were similar in both groups. Also, time to neutrophil and platelet engraftment, rates of febrile neutropenia and blood stream infections, VOD, need for opiates or TPN and time from HCT to discharge were not significantly different between groups. With a median follow-up of 9 months we did not observe any difference in rates of acute or chronic GVHD, DFS and OS. Conclusions The interim results, showing similar rates of grade 3-4 OM and secondary outcomes, do not support continuation of the study. FA-rescue following MTX GVHD prophylaxis does not seem to decrease regimen related toxicity and affect transplant outcomes.

Introduction Myeloablative conditioning (MAC) regimens decrease the risk of relapse in pediatric patients undergoing hematopoietic stem cell transplant (HCT) but cause significant toxicities: transplant-related mortality (TRM) and late effects. Therefore, a MAC regimen that decreases toxicity has the potential to improve overall survival (OS). Busulfan (Bu), fludarabine (Flu), anti-thymocyte globulin (ATG) and 400 cGy of total body irradiation (TBI), a reduced toxicity, MAC regimen was used in pediatric patients. Objectives To evaluate the safety and toxicity of this regimen. Secondary objectives included determining OS at 2 and 5 years, and incidence of relapse and GVHD. Methods We prospectively evaluated 40 patients ≤21 years of age undergoing HCT for high-risk leukemias who received dose-adjusted Bu, Flu, ATG and TBI. Bu pharmacokinetics were measured after a test dose and regimen dose 1 to target AUC of 4000-5000 uMol*min/day. Results Patients were treated between October 2008 and June 2018 (Table 1). OS was 67% and 51% at 2 and 5 years post-HCT, respectively. OS at 2 and 5 years was 70% and 55% for patients with myeloid disease versus 56% and 37% for patients with lymphoid disease, respectively (p=0.18) (Figure 1). Relapse occurred in 11 (28%) at a median of 7 months. TRM was 8% and 13% at 100 days and 1 year post-HCT, respectively. All patients engrafted. >Grade II acute GVHD was seen in 9 (23%); chronic GVHD was seen in 16 (40%). There was no significant impact of age, disease type, donor source or type on HCT outcomes. Long-term toxicities noted were ovarian insufficiency in 8, and short stature, hypothyroidism and learning disabilities in 2 each. Evaluation of Bu AUCs and multivariate analyses are still ongoing. Conclusions Reduced toxicity, MAC regimen was well tolerated with a low incidence of TRM. This regimen shows a trend toward better efficacy in patients with myeloid disease, however larger studies are needed.

The choice of alternative donors for HCT for patients without an HLA-matched related donor depends on several factors. We compared major HCT outcomes in 212 consecutive children transplanted at 11 centers in Brazil for acute leukemia or MDS from an HLA-matched unrelated donor (MUD, n = 95), mismatched unrelated donor (MMUD, n = 47) or unrelated umbilical cord blood (UCB, n = 70). Most had ALL (61%), bone marrow (57%) as the graft source and 95% received a MAC regimen. The 3-year OS probability were 57, 55, and 37% after HCT from MUD, MMUD, and UCB, respectively (HR 1.68, 95%CI 1.07-2.63; P = .02). In comparison with MUD, OS was similar after transplantation of a ≥ 6/8 HLA-matched or a high cell dose (>5 × 107 TNC/kg) CB unit (HR 1.41, 95%CI 0.88-2.27; P = .15). NRM was higher for UCB (HR 3.90, 95%CI 1.43-10.7; P = .01) but not for MMUD (HR 1.03, 95%CI 0.53-2.00; P > .20). Advanced disease (HR 2.05, 95%CI 1.26-3.33; P < .001) and UCB with high probability of being < 6/8 HLA-matched (HR 5.34, 95%CI 2.0-13.9; P < .001) were associated with higher mortality. Relapse and acute GVHD were similar among groups, while PGF was higher among UCB transplants (P = .002) and chronic GVHD among MMUD group (HR 2.88, 95% CI 1.05-7.88; P = .04). Our results suggest that in Brazil HCT outcomes performed with MMUD and MUD donors were comparable, while with UCB units < 6/8 HLA-matched were associated with higher NRM for children with acute leukemia or MDS.

In this prospective randomized study, we compared the outcomes of single-unit umbilical cord blood transplantation (UCBT) and unmanipulated haploidentical stem cell transplantation (haplo-SCT) with post-transplantation cyclophosphamide (PTCy) in adults with hematologic malignancies. All patients received a myeloablative conditioning (MAC) regimen consisting of thiotepa, busulfan, and fludarabine, with antithymocyte globulin (ATG) added for UCBT recipients. Nineteen patients were randomized to UCBT and the other 26 to haplo-HSCT. Four patients (15%) allocated to the haplo-HSCT arm lacked a suitable donor and were crossed over to the UCBT arm. Finally, 23 underwent UCBT and 22 underwent haplo-HSCT. The cumulative incidence of neutrophil recovery was 87% at a median of 19 days (range, 13 to 24 days) in the UCBT arm versus 100% at a median of 17 days (range, 13 to 25 days) in the haplo-SCT arm (P=.04). Platelet recovery was 70% at a median of 40 days (range, 18 to 129 days) in the UCBT arm versus 86% at a median of 24 days (range, 12 to 127 days) in the haplo-HCT arm (P=.02). Rates of acute graft-versus-host disease (GVHD) grade II-IV or grade overall chronic GVHD, and extensive chronic GVHD in the UCBT and Haplo-SCT arms were 43% versus 36% (P=.8), 9% versus 9% (P=1), 66% versus 43% (P=.04), and 41% versus 23% (P=.2), respectively. Two-year nonrelapse mortality and relapse in the 2 arms were 52% versus 23% (P=.06) and 17% versus 23% (P=.5), respectively. Two-year disease-free survival, overall survival, and GVHD/relapse-free survival in the 2 arms were 30% versus 54% (P=.2), 35% versus 59% (P=.1), and 17% versus 40% (P=.04), respectively. Our data show that in the context of an MAC regimen, haplo-SCT with PTCy provides improved outcomes compared with ATG-containing single-unit UCBT., This study was supported by an unrestricted grant from Adienne.

The use of myeloablative conditioning (MAC) in umbilical cord blood transplantation (UCBT) has been associated with high nonrelapse mortality (NRM) in patients aged >40 years, especially those having a high HLA disparity, thus limiting wider applications. We hypothesized that the NRM advantage of reduced-intensity conditioning (MC) and higher graft-versus-leukemia effect associated with greater HLA disparities would expand its use for patients (aged 40 to 60 years) without compromising efficacy and compared outcomes between RIC and MAC regimens. In total, 288 patients aged 40 to 60 years, with de novo acute myeloid leukemia, receiving UCBT with at least 2 HLA mismatches with MC (n = 166) or MAC (n = 122) regimens were included. As compared to MC, the MAC cohort included relatively younger patients, having received more single UCBT, with lower total nucleated cell counts and more in vivo T cell depletion. Median time to neutrophil engraftment, infections (bacterial, viral, and fungal), and grade II to IV acute and chronic graft-versus-host disease were similar in both groups. In the multivariate analysis, overall survival (hazard ratio [HR], 0.98; P = .9), NRM (HR, 0.68; P = .2), and relapse (HR, 1.24; P = .5) were not different between MC and MAC. Refractory disease was associated with worse survival. Outcomes of UBCT for patients aged 40 to 60 years having >2 HLA mismatches are comparable after the MC or MAC regimen. (C) 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

Posttransplant high-dose cyclophosphamide (PTCy) effectively prevents GvHD after haploidentical SCT. However, its use in HLA-matched SCT has been less explored. Fifty-six consecutive patients who underwent allo-SCT for hematological malignancies have been included in this prospective single-center protocol. Donors have been HLA-identical siblings, fully-matched unrelated or 1-allele-mismatched unrelated donors in 30%, 32%, and 37% of cases, respectively. Nine patients have received a TBI-containing MAC regimen, while the remaining (84%) received RIC platforms based on Fludarabine plus Busulfan/Melphalan. Due to the high graft failure (GF) rate (21%) in a preliminary analysis in the allo-RIC cohort (n = 29), protocol amendments have been implemented, with no further cases of GF after the introduction of mini-thiotepa (0/18). The overall incidence of grade II–IV acute GvHD is 24% (95% CI: 17–31%) with four steroid-refractory cases. Severe chronic GvHD has occurred in only 1 of 43 evaluable cases. The 1-year NRM and relapse are 18% (95% CI: 12–26%) and 30% (18–42%) and the OS and DFS are 78% and 64%, respectively. These outcomes support the feasibility of using PTCy as a SOC outside the haplo-setting, albeit mini-thiotepa (3 mg/kg) was incorporated in the standard allo-RIC platforms to prevent GF. Despite the limitations of a single-center experience and the short follow-up, these protocols show promising results with particular benefit in reducing the occurrence of moderate-to-severe GvHD.

Background Children and adolescents with HL have excellent long-term survival exceeding 95% after combined modality treatment. However, about 20% will either relapse or have PRF. Salvage HDCT followed by AHSCT is considered to be the preferential treatment. Objective To describe the outcome (OS and EFS) and prognostic factors in pediatric patients with relapsed or refractory HL (r/rHL) who underwent AHSCT. Methods We retrospectively included 43 pediatric patients with r/rHL who underwent AHSCT from July 1, 2007, till December 31, 2016, at the Children's Cancer Hospital of Egypt. MAC regimen given was CMV. Results Of the whole cohort, 88.4% of patients achieved CR, while 11.6% had a positive PET scan prior to transplantation. The 3-year OS and EFS were 85% and 70.6%, respectively. The 3-year OS for patients > 10 years was 94% versus 65.5% for patients 10 years of age or younger (P = 0.046). There is strong tendency toward better 3-year OS for patients with negative PET scan as compared to those with positive PET scan before AHSCT, 89.4% vs 60%, respectively (P = 0.059). This tendency is also applicable when looking at the 3-year EFS for the two groups, 78.3% vs 40%, respectively (P = 0.069). Conclusion Poor predictors of OS were younger age and positive PET scan before AHSCT. The latter, along with single modality treatment before AHSCT, were poor predictors of EFS.

Myeloablative conditioning (MAC) regimens are commonly used in transplantation for chronic granulomatous disease (CGD) but are associated with toxicity. Reduced-intensity conditioning (RIC) regimens have lower toxicity but may fail to achieve stable donor chimerism. We report a comparison between 4 patients who received a RIC regimen consisting of alemtuzumab (1 mg/kg), fludarabine (150 mg/m2), and melphalan (140 mg/m2) and 14 patients who received a MAC regimen consisting of busulfan (area under the curve, 1800 to 2000 µMol/min twice daily × 4 days), cyclophosphamide (50 mg/kg/day × 4), and antithymocyte globulin (15 mg/kg twice daily on days −2 and −1, then daily on days +1 and +2). Seventy-five percent (n = 3) of RIC patients developed mixed chimerism and needed either withdrawal of immune suppression (n = 1) or additional stem cell products (n = 2) to achieve stable donor chimerism. Ninety-two percent (n = 13) of patients in the MAC group maintained >95% donor chimerism. Complications included acute graft-versus-host disease (MAC 64%, RIC 0%), chronic graft-versus-host disease (MAC 28%, RIC 0%), sinusoidal obstructive syndrome (MAC 7%, RIC 0%), bacteremia (MAC 42%, RIC 0%), fungemia (MAC 14%, RIC 0%), viral disease (MAC 7%, RIC 25%), and death (MAC 21%, RIC 0%). A RIC regimen has lower toxicity but frequently requires interventions to maintain donor chimerism compared with a MAC regimen in CGD.

Introduction High-dose cytarabine (HD-AraC) is an important component of intensive post-remission therapy for acute myeloid leukemia (AML). Its efficacy in core-binding factor (CBF) AML has been well established but it remains controversial whether HD-AraC is effective before allogeneic hematopoietic stem cell transplantation (Allo-HSCT). Herein, we report our experience at Allegheny Health Network (AHN) regarding the number of cycles of HD-AraC used before Allo-HSCT and its effect on survival. Methods We retrospectively analyzed 49 patients with AML who received HD-AraC after achieving complete remission and underwent Allo-HSCT at our institution between January 2010 and June 2018. Patients with acute promyelocytic leukemia (APL), CBF-AML, and primary induction failure were excluded. The HD-AraC dosing regimen used at our institution is 3,000 mg/m2 IV every 12 hours on days 1, 3, 5 for a total of 6 doses per 28-day cycle. Fifteen patients received 1 cycle, twenty patients received 2 cycles, and fourteen patients received >2 cycles of HD-AraC. The majority of the patients (n=32, 65%) received a myeloablative conditioning (MAC) regimen. The unadjusted probabilities of overall survival (OS) were estimated using Kaplan-Meier method and a multivariate analysis was performed using multiple logistic regression model for odds ratio, 95% confidence interval, and p-value. Number of HD-AraC cycles, age, conditioning regimen, and AML risk stratification per European Leukemia Net (ELN) were used as covariates. Results Median age was 56 years (IQR: 45.1-63.3) and median days to Allo-HSCT was 155 (IQR: 127-202). Our patients received a median of 2 cycles (IQR: 1-3) of HD-AraC before Allo-HSCT. With median follow up of 10 months, the median overall survival for patients who received 1, 2, and >2 cycles of HD-AraC was 9.9, not reached, and 33 months, respectively. Patients who received 2 cycles of HD-AraC showed a trend toward lower mortality with odds ratio of 0.22 (95% CI: 0.03-1.79, p-value 0.158). Conclusion Our data shows that patients who received two cycles of HD-AraC had a lower mortality rate with a trend towards significance. However, the majority of these patients also received a MAC regimen (n=18, 90%) which is significantly (p-value 0.005) more than patients who received 1 cycle (MAC n=6, 40%) and >2 cycles (MAC n=8, 57.1%) of HD-AraC. In addition to this bias that is related to the retrospective nature of the study, the small sample size as well as this being a single center experience limits definitive conclusions. Larger studies are needed to determine the optimal number of HD-AraC as a bridge to Allo-HSCT.

Refractory cytopenia of childhood (RCC) is the most common subtype of myelodysplastic syndrome in children, and the clinical course of RCC is heterogeneous. A certain proportion of RCC patients need allogeneic hematopoietic stem cell transplantation (HSCT); however, data on HSCT outcomes are not abundant, and the optimal intensity of a preparative conditioning regimen remains uncertain. In this study, we evaluated the outcomes of HSCT in 24 patients with RCC. Eleven patients received myeloablative conditioning (MAC) consisting of high-dose cytarabine, cyclophosphamide, and either total body irradiation (TBI) or busulfan. Nine patients (38%) received a reduced-intensity conditioning (RIC) regimen; of these, 7 received low-dose TBI and cyclophosphamide (200 mg/kg) with or without antithymocyte globulin or fludarabine, and 2 patients received low-dose TBI, fludarabine, and melphalan (140 mg/m2). The remaining 4 patients had disease progression before HSCT and received the MAC regimen. With a median follow-up of 91 months (range, 6 to 263), the probability of overall survival at 5 years was 81.1% (95% CI, 57.0 to 92.5). The 5-year overall survival for the 15 patients who received MAC was 73.3% (95% CI, 43.6 to 89.1), and all 9 patients with RIC are alive without any events. Further study is needed to evaluate the efficacy of RIC for children with RCC with an expectation for reduction of late effects such as growth retardation and infertility.

Objective Late-onset non-infectious pulmonary complications (LONIPCs) contribute to higher morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Therefore, we investigated the risk factors of LONIPCs in pediatric patients. Method Between 2001 and 2011, 74 pediatric patients (range, 7 months to 22.7 years old; median 6.5 years old), including 29 with a primary immunodeficiency underwent 80 allo-HSCTs at our institution. Sixty-seven patients who survived more than 3 months after allo-HSCT were analyzed retrospectively.The median follow-up period was 1 973 days (range, 126–5 145 days). Results Nine patients (13.4%) developed LONIPCs between 90 and 3 578 days after allo-HSCT. A myeloablative conditioning (MAC) regimen and chronic GvHD were determined as significant risk factors of LONIPCs. None of 18 patients who received the reduced-intensity conditioning (RIC) regimen developed LONIPCs, although there was no difference in overall survival between the MAC and RIC regimen. Notably, two immunodeficient patients who received busulfan-based MAC regimen under two years old developed LONIPC with no history of chronic GvHD after 5 years and 10 years from SCT respectively, suggesting the direct toxicity of busulfan. Conclusion Our study's findings indicate that the RIC regimen reduces the risk of LONIPCs in pediatric patients. This article is protected by copyright. All rights reserved.

Reduced-intensity conditioning (RIC) has been shown to have similar overall survival (OS) but higher relapse rates compared with myeloablative (MAC) regimens in patients with myeloid malignancies undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). Using propensity score matching (PSM) analysis, well-balanced pairs of different variables can be compared effectively. We retrospectively compared allo-HSCT recipients with acute myeloid leukemia or myelodysplasia receiving a RIC regimen (FBT200; fludarabine 30 mg/m2/day for 4 days, busulfan 3.2 mg/kg/day for 2 days, and total body irradiation [TBI] 200 cGy) or MAC regimen (FBT400; fludarabine 50 mg/m2/day for 4 days, busulfan 3.2 mg/kg/day for 4 days, and TBI 400 cGy). A total of 248 patients (121 in the RIC group and 127 in the MAC group) were included in the analysis. No statistically significant difference was observed in 2-year OS (RIC group, 45.2 ± 5.0%; MAC group, 51.7 ± 5.2%; P = .541), nonrelapse mortality (NRM; RIC group, 28.7 ± 2.8% MAC group, 34.7 ± 4.6%; P = .368), and acute graft-versus-host disease (GVHD) (P = .171) or chronic GVHD (P = .605) at 1 year. The cumulative incidence of relapse (CIR) at 2 years was statistically significantly different between the 2 groups, however (RIC, 26.1 ± 2.6%; MAC, 14.2 ± 3.5%; P = .033). When PSM was applied to the study population, 42 case-control pairs were evenly matched. PSM analysis confirmed no statistically significant difference in 2-year OS (RIC, 49.0 ± 9.1%; MAC, 54.9 ± 7.7%; P = .718), NRM (RIC, 22.2 ± 2.3%; MAC, 33.3 ± 2.8%; P = .238), or CIR (RIC, 25.7 ± 2.6%; MAC, 9.5 ± 1.1%; P = .315) in the PSM pairs. Our findings demonstrate that after applying PSM, FBT 200 RIC conditioning has comparable OS, NRM, and CIR to FBT 400 MAC conditioning before allo-HSCT.

Children with high-risk acute myelogenous leukemia (AML) (induction failure [IF], refractory relapse [RR], third complete remission [CR3]) have dismal outcomes. Over 80% of AML patients express CD33, a target of gemtuzumab ozogamicin (GO). GO is an active drug in childhood AML but has not been studied in a myeloablative conditioning regimen. We sought to determine the safety of GO in combination with busulfan/cyclophosphamide (Bu/Cy) conditioning before allogeneic hematopoietic stem cell transplantation (alloSCT). GO was administered on day -14 at doses of 3.0, 4.5, 6.0, and 7.5 mg/m(2), busulfan on days -7, -6, -5, -4 (12.8-16.0 mg/kg), and cyclophosphamide on days -3 and -2 (60 mg/kg/day). GVHD prophylaxis consisted of tacrolimus and mycophenolate mofetil. We enrolled 12 patients: 8 IF, 3 RR, 1 CR3; median age: 3 years (1-17); median follow-up: 1379 days (939-2305). Nine received umbilical cord blood (UCB), 2 matched unrelated donors (MUDs) and 1 HLA-matched sibling donor: 3 patients each at GO doses of 3.0, 4.5, 6.0, or 7.5 mg/m(2). No dose-limiting toxicities secondary to GO were observed. Day 100 treatment-related mortality (TRM) was 0%. Myeloid and platelet engraftment was observed in 92% and 75% of patients at median day 22 (12-40) and 42 (21-164), respectively. Median day +30 donor chimerism was 99% (85%-100%). The probability of grade II-IV acute graft-versus-host disease (aGVHD) was 42% and chronic GVHD (cGVHD) was 28%. One-year overall survival (OS) and event-free survival (EFS) was 50% (95% confidence interval [CI], 20.8-73.6). GO combined with Bu/Cy regimen followed by alloSCT is well tolerated in children with poor-risk AML. GO at 7.5 mg/m(2) in combination with Bu/Cy is currently being tested in a phase II study.

Acute megakaryoblastic leukemia (AMKL) accounts for 10% of childhood acute myeloid leukemia. Although AMKL patients with Down syndrome (DS-AMKL) have an excellent survival rate, patients with non-DS-AMKL experience poor outcomes. Despite therapeutic advances, including use of intensified treatment protocols, there is no consensus on the optimal treatment strategy for non-DS-AMKL. Some study groups recommend hematopoietic cell transplantation (HCT) for patients with non-DS-AMKL in the first complete remission (CR1); however, it is unclear whether HCT in CR1 improves outcomes of these patients. To assess outcomes and risk factors of HCT for patients with non-DS-AMKL, we retrospectively analyzed 203 patients with non-DS-AMKL (male, 95; female, 108) who underwent first HCT between 1986 and 2015 using data from the Japan Society for Hematopoietic Cell Transplantation. The median age at the time of HCT was 2 years (range, 0-16). Out of 203 patients, 12 had translocation t(1;22)(p13;q13), 18 had monosomy 7, 21 had complex karyotype, and 109 had other chromosomal abnormalities. Bone marrow transplantation (BMT) was performed for 114, cord blood transplantation (CBT) for 74, and peripheral blood stem cell transplantation (PBSCT) for 15 patients. Seventy-eight patients underwent HCT from related (HLA-matched, 43; HLA-mismatched, 35), 108 from unrelated (HLA-matched, 56; HLA-mismatched, 52), and 17 from autologous donors. Ninety-two patients underwent HCT in CR1, 21 in the second CR (CR2), and 90 in non-CR. Myeloablative conditioning (MAC) regimen was defined as the use of total body irradiation (TBI) ≥8 Gy, administration of busulfan >8 mg/kg or melphalan >140 mg/m2. All other regimens were included in reduced intensity conditioning (RIC) regimen. MAC regimen was used for 192 and RIC regimen for 11 patients. Median duration of follow-up after HCT was 713 days (range, 3-10008). Out of 203 patients, 183 (90%) exhibited engraftment. Sixteen out of 20 patients who did not exhibit engraftment underwent HCT in non-CR. In the entire cohort, 5-year overall survival (OS) and event free survival (EFS) rates were 43% and 38%, respectively. Seventy-two patients died of disease relapse and 42 died of transplantation-related complications. Five-year OS/EFS rates were not significantly different between BMT (48%/43%), CBT (35%/31%), and PBSCT (31%/27%) (p = 0.221/p = 0.087). In allogeneic HCT, 5-year OS/EFS rates were significantly lower in patients who underwent HCT from HLA-mismatched donors (27%/22%) than those from HLA-matched donors (52%/47%) (p < 0.001/p < 0.001). Five-year cumulative incidence (CI) of relapse after HLA-mismatched HCT (64%) was significantly higher than that after HLA-matched HCT (45%) (p = 0.006). Five-year OS/EFS rates were not significantly different between patients with translocation t(1;22)(p13;q13) (50%/42%), those with monosomy 7 (65%/59%), and those with complex karyotype (61%/52%) (p = 0.094/p = 0.111). Five-year OS/EFS rates of patients who underwent HCT in CR1 (72%/64%) were significantly higher than those of patients who underwent in CR2 (23%/13%) and non-CR (16%/16%) (p < 0.001/p < 0.001). Five-year CI of relapse was significantly lower in CR1 (28%) than in CR2 (73%) and non-CR (73%) (p < 0.001). Five-year non-relapse mortality was significantly higher in non-CR (27%) than in CR1 (15%) and CR2 (14%) (p = 0.022). Among the 92 patients who underwent HCT in CR1, 3-year CI of relapse in patients who received RIC (67%) was significantly higher than that in patients who received MAC regimen (25%) (p = 0.021). Five-year OS/EFS rates associated with HCT from HLA-mismatched (70%/63%) and HLA-matched donors (77%/59%) were not significantly different (p = 0.609/p = 0.761). In the multivariate analysis for 5-year OS, HCT in CR2 and non-CR was found to be a significant risk factor (hazard ratio, 5.16; 95% CI, 3.36-7.92; p < 0.001). In conclusion, multivariate analysis confirmed that HCT in CR1 was a good prognostic factor for 5-year OS. Risk stratification in patients with non-DS-AMKL should be established to determine the indication for HCT in CR1. Disclosures No relevant conflicts of interest to declare.

Outcomes for adolescents and young adults (AYA) might be considerably different from children and older adults with acute leukemia (AL). Patients in this transitory period tend to be considered at higher risk for poorer outcomes. However, AYA is still underrepresented in most hematopoietic stem cell transplant (HSCT) studies. Recent evidence shows superior outcomes for AYA with acute lymphoblastic leukemia (ALL) using pediatric rather than adult first line chemotherapy regimens. The aim of this study is to analyze outcomes of umbilical cord blood transplant (UCBT) in AYA patients with ALL or acute myeloid leukemia (AML) after myeloablative conditioning regimen (MAC). Eligibility criteria included patients with AL aged 15-25 (median 19) years, transplanted between 2004 and 2016 in EBMT centers, with single or double UCBT as first allogenic transplantation after MAC regimen and reported to Eurocord. A total of 504 patients were included. Primary endpoint was overall survival (OS). Median follow-up for survivors was 38 months (1 month-11 years). Median time from diagnosis to UCBT was 11 months (1 month-17 years) (interquartile range 5-29 months). Diagnosis was ALL in 59% (n=297) and AML in 41% (n=207); 64% of patients were male. Disease status at UCBT were 42% in 1st complete remission (CR) (n=203), 2nd CR in 38% (n=183), and advanced disease in 20% (n=96). Fifty eight percent of patients (n=293) received single and 42% (n=211) double UCBT. Cyclophosphamide + TBI ± fludarabine (45%) was the most frequently used conditioning regimen. Anti-thymoglobulin (ATG) was used in 54% and GVHD prophylaxis was cyclosporine A + mycophenolate mofetil in 44% of patients. Median nucleated cell dose at collection was 3.63 (range 0.9-9.0) X107/Kg for single and 5.25 (range 2.3-10.6) X107/Kg for double UCBT. The 3-year OS was 45±2%; 3-year leukemia free survival (LFS) was 41±2% and refined GVHD free/relapse free survival (rGRFS) was 32±2%. OS was similar in ALL and AML (45±3% vs 45±4%, p-value=0.69). According to disease status at UCBT, 3-year OS was 54±4% for patients in CR1, 48±4% for CR2 and 20±4% for advanced disease (p-value Cumulative incidence function (CIF) for neutrophil engraftment at day-60 was 88% [95% confidential interval (CI) 85-90] in a median time of 24 days. CIF of acute GVHD grade II-IV at day-100 was 28% (95%CI 24-32) and out of the 233 patients with aGVHD, 73 (21%) had grade III-IV. The 1-year CIF of chronic GVHD was also 28% (95%CI 24-33) and out of the 124 patients with cGVHD, 52 (42%) had the extensive form. The 3-year CIF of transplant related mortality (TRM) was 31% (95%CI 24-33). The 3-year CIF of relapse was 28% (95%CI 24-32), and according to disease status at UCBT, relapse was 28% (95%CI 21-34) for patients in CR1, 24% (95%CI 18-31) for those in CR2 and 37% (95%CI 27-47) for advanced disease. Main causes of death were relapse (41%) and TRM (57%, mainly infections and GVHD). In multivariate analysis, disease remission at UCBT (HR 0.46, 95%CI 0.32-0.66, p-value This large series of AYA patients with AL provides detailed information on UCBT for this particular cohort with results comparable with other sources of HSCT. Due to the lack of information on pre-transplant chemotherapy (pediatric versus adult protocols), we were unable to evaluate its effect on outcomes. Nevertheless, this study contributes to a better understanding of HSCT for an age group that is not thoroughly described in most publications. Demonstrating the feasibility of UCBT in AYA patients is important to facilitate the decision of stem cell source selection when a more standard donor is not available. Disclosures Hough: University College London Hospital's NHS Foundation Trust: Employment. Angelucci:Vertex Pharmaceuticals Incorporated (MA) and CRISPR CAS9 Therapeutics AG (CH): Other: Chair DMC; Celgene: Honoraria, Other: Chair DMC; Jazz Pharmaceuticals Italy: Other: Local ( national) advisory board; Novartis: Honoraria, Other: Chair Steering Comiittee TELESTO Protocol; Roche Italy: Other: Local (national) advisory board. Bader:Medac: Patents & Royalties, Research Funding; Neovii: Research Funding; Riemser: Research Funding; Cellgene: Consultancy; Novartis: Consultancy, Speakers Bureau.

The significance of conditioning regimen intensity on the outcomes of T-cell replete HLA-haploidentical transplants is not known. This study compared outcomes of commonly used myeloablative (MAC) to reduced intensity (RIC) conditioning regimens in 1325 such transplants (AML; n=818; ALL; n=286 and MDS; n=221) in the US between 2008 and 2016. The median age of the study population was 54 years (18 - 70). Most patients (80%) with AML and ALL were in first or subsequent remission; 83% of those with MDS had refractory anemia with excess blasts at transplantation. Fifty-one percent of patients with AML and ALL had intermediate disease risk index (DRI). In contrast, 50% of patients with MDS had high or very high DRI. Patients received MAC (n=526; 40%) or RIC (n=799; 60%) transplant conditioning regimens and a uniform graft-versus-host disease (GVHD) prophylaxis: post-transplant cyclophosphamide, calcineurin inhibitor and mycophenolate. Approximately 50% of patients reported a HCT-CI score of 0-2 in MAC and RIC groups. Sixty-six percent of MAC and 42% of RIC recipients received peripheral blood grafts. Total body irradiation (TBI) + fludarabine (TBI/Flu; 33%) and busulfan with cyclophosphamide with/without Flu (Bu/Cy ± Flu; 36%) were the predominant MAC regimens. Other MAC regimens included TBI/Cy or other agents (10%), Flu/Bu4 (13%), melphalan (140 mg/m2) + Flu ± thiotepa (Flu/Mel ± TT; 9%). TBI (200cGy)/Cy/Flu (84%) was the predominant RIC regimen. Other RIC regimens included TBI 200cGy + Bu or Mel + Flu (7%), Flu/Bu2 (1%) and Flu/Mel (100mg/m2) ± TT (5mg/kg) (8%). The primary endpoint was disease-free survival (relapse or death). Cox regression models were built to study the effect of conditioning regimens on transplant outcomes after adjusting for other factors significantly associated with outcomes. Differences in transplant-outcomes were observed between ages 18-54 years and 55-70 years. The effect of age was further tested within the 18-54 and 55-70 age groups and there were no differences in outcome. In patients aged 18-54 years (n=689), 55% received MAC and 54% received RIC regimens. In patients aged 55-70 years (n=636), 22% received MAC and 78% received RIC regimens. Table 1 shows the effect (hazard ratio; HR) of conditioning regimen intensity in the two age groups adjusted for HCT-CI, recipient CMV serostatus, disease, DRI and graft type and the 2-year probabilities for the outcomes of interest. In patients aged 18-54 years who were equally likely to receive MAC or RIC regimens, relapse risks were higher after RIC regimens that resulted in lower disease-free survival. There were no differences in non-relapse mortality (NRM) or overall survival by conditioning regimen intensity. In patients aged 55-70 years who were more likely to receive RIC regimen, NRM was lower after RIC but without an advantage for relapse, disease-free or overall survival. Figure 1A and 1B show the 2-year probability of disease-free survival by conditioning regimen intensity in patients aged 18-54 and 55-70 years, respectively. Consistent with the main analysis, a subset analysis limited to AML also confirmed higher relapse (HR 1.43, p=0.03) and lower disease-free survival (HR 1.38, p=0.02) after RIC regimens in patients aged 18-54 years but not in patients aged 55-70 years. Acute GVHD (HR 1.01, p=0.94) and chronic GVHD (HR 0.82, p=0.14) did not differ by conditioning regimen intensity. Table 2 compares the effect of TBI- and non-TBI containing MAC and RIC regimens adjusted for age, HCT-CI, recipient CMV serostatus, disease, DRI and graft type. NRM risks were higher after RIC non-TBI compared to RIC TBI regimens. The predominant RIC non-TBI regimen was Flu/Mel (100mg/m2) ± TT (5mg/kg). In conclusion, a MAC regimen offers higher disease-free survival for those aged 18-54 years and can tolerate MAC regimens. For patients who are unable to tolerate MAC regimens, regardless of their age, TBI200 cGy/Cy/Flu is preferred to Flu/Mel ± TT to minimize NRM risks. Disclosures Shah: Juno Pharmaceuticals: Honoraria; Lentigen Technology: Research Funding; Exelexis: Equity Ownership; Geron: Equity Ownership; Miltenyi: Other: Travel funding, Research Funding; Oncosec: Equity Ownership. Brunstein:Gamidacell: Research Funding. Champlin:Otsuka: Research Funding; Sanofi: Research Funding. Hamadani:Celgene Corporation: Consultancy; Merck: Research Funding; Janssen: Consultancy; ADC Therapeutics: Research Funding; Sanofi Genzyme: Research Funding, Speakers Bureau; Cellerant: Consultancy; Takeda: Research Funding; Ostuka: Research Funding; MedImmune: Consultancy, Research Funding. McGuirk:Gamida Cell: Research Funding; Kite Pharma: Honoraria, Other: travel accommodations, expenses, speaker ; Fresenius Biotech: Research Funding; Pluristem Ltd: Research Funding; Bellicum Pharmaceuticals: Research Funding; Astellas Pharma: Research Funding; Novartis Pharmaceuticals Corporation: Honoraria, Other: speaker, Research Funding. Vasu:Boehringer Ingelheim Inc: Membership on an entity's Board of Directors or advisory committees. Waller:Pharmacyclics: Other: Travel Expenses, EHA, Research Funding; Cambium Medical Technologies: Consultancy, Equity Ownership; Celldex: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kalytera: Consultancy.

Background: Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) remains the only curative treatment for myelofibrosis (MF). Due to high incidence of non-relapse mortality (NRM) in patients with MF who underwent allo-HCT with myeloablative conditioning (MAC), transplants in these patients are mostly done by utilizing a reduced intensity conditioning regimen with calcineurin inhibitors for graft versus host disease (GVHD) prophylaxis. We previously published very good outcomes in patients with acute leukemia (AML and ALL) and myelodysplastic syndrome (MDS) who underwent Ex- vivo CD34+-selected T-cell depleted (TCD) allo-HSCT following MAC regimens (Barba P et al. BBMT 2017; Tamari R et al. BBMT 2018). Aim: To study retrospectively the outcomes of patients with primary or secondary myelofibrosis (PMF or SMF) who underwent a CD34+ cell-selected Allo-HSCT. Methods: Twenty-one MF patients who underwent a CD34+-selected Allo-HSCT at a single center between October 2010 and November 2017 were included in this retrospective analysis. All patients received MAC regimen including busulfan, melphalan and fludarabine and antithymocyte globulin to prevent graft rejection. None of the patients received post-transplant GVHD prophylaxis. G-CSF mobilized peripheral blood stem cell grafts were depleted of T-cells using immunomagnetic CD34+ selection by CliniMACS device. Overall survival (OS), relapse free survival (RFS), relapse, NRM and the composite endpoint of GVHD-free/relapse-free survival (GFRS: defined as grade 3-4 acute GVHD, chronic GVHD requiring systemic treatment, relapse, or death) were estimated using the Kaplan-Meier and cumulative incidence method, with death considered a competing risk for relapse. Log-rank and Gray's tests were used to assess differences in patient and treatment characteristics. Results: Patient's and donor's characteristics are summarized in table 1. Neutrophils engraftment occurred in all patients at a median of 11 days (range: 8 - 14) and 90% (N = 19) achieved platelet engraftment at a median of 24 days (range, 14 - 77). Another patient achieved platelet engraftment only after splenectomy which was performed on post-transplant day 54. With a median follow-up of 54.06 months, the estimated 3-year OS and RFS were 84.4 % (95% CI, 69.6% to >99.9%) and 74.7% (95% CI, 57.6 to 96.9%), respectively (figure 1). The cumulative incidence of grade II-IV acute GVHD at day 100 was 33.3% (95% CI 11.2-54.1%); majority (N=5) had grade II and 2 patients had grade III (N=1) and grade IV (N=1) acute GVHD. Chronic GVHD developed in 2 patients including only 1 case requiring systemic treatment. The 3-year cumulative incidence rate of relapse was 9.5% (95% CI, Conclusions: In this analysis we demonstrate that CD34+ selected Allo-HSCT following a chemotherapy only based MAC regimen is well-tolerated and an effective treatment for patients with myelofibrosis. We noted higher incidence of acute GVHD when compared to our reported outcomes in patients with acute leukemia and MDS undergoing a CD34+ selected allo-HSCT and all cases of mortality in this analysis were secondary to GVHD. This may suggest differences in the biology of the diseases and a more inflammatory milieu in pts with MF. Relapse incidence was notably low and all patients who relapsed were salvaged with further cellular therapy suggesting a strong graft-versus-leukemia effect in this disease. Disclosures Sauter: Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy; Precision Biosciences: Consultancy; Kite: Consultancy. Perales:Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees and Clinical trial support; Novartis: Other: Personal fees; Merck: Other: Personal fees; Takeda: Other: Personal fees; Abbvie: Other: Personal fees.

Shi-Xia X, Hai-Qin X, Xian-Hua T, Bo F, Xiang-Feng T. Comparison of reduced intensity and myeloablative conditioning regimens for stem cell transplantation in patients with malignancies: a meta-analysis. Clin Transplant 2011: 25: E187–E198. © 2010 John Wiley & Sons A/S. Abstract: Objective: The reduced intensity conditioning (RIC) stem cell transplantation is widely employed for the treatment of many hematologic malignancies, but the survival effectiveness is still unclear. This study conducted an updated meta-analysis to determine whether any significant difference could be found by using RIC vs. myeloablative conditioning (MAC) regimen for transplantation in patients with malignancies. Methods: We electronically searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and relevant articles (1987.01–2009.12). Comparative studies were carried out on clinical therapeutic effect of RIC and MAC on the survival outcomes and the transplantation-related complications. Results: We obtained 1776 records, and 29 studies totaling 6235 patients have been assessed. Compared with MAC regimen, the RIC regimen had a higher overall survival (OS) at one-yr and no difference at two-yr later after transplantation. RIC regimen had significantly lower rates of disease-free survival (DFS) after two-yr follow-up, lower incidences of ≥ II degree acute graft-versus-host disease (aGVHD), and lower TRM [OR, 0.61, 95% CI (0.53, 0.69)], but with a higher relapse rate [OR, 1.88(1.41, 2.51)]. No significant difference was found in rates of cytomegalovirus (CMV) infection and chronic GVHD between the regimens. Conclusions: This meta-analysis confirmed that compared with MAC condition regimen, the RIC regimen had a consistently equivalent or even better rate in OS, but with lower DFS at longer follow-up.

Salvage regimens containing mitoxantrone have been successfully used for the treatment of primary induction failure or relapsed acute myeloid leukemia. However, the combination of cyclophosphamide with mitoxantrone and cytarabine (MAC) has never been assessed in these patients. A total of 91 patients, including patients with primary induction failure (n=44) and relapsed (n=47), were treated with a salvage MAC regimen, which consisted of mitoxantrone, cytarabine and cyclophosphamide. The overall complete remission rate was 74.7 (68/91) and 72.7% (32/44) for primary induction failure, and 76.6% (36/47) for relapsed patients. The overall survival rate and disease-free survival rate were 72.1 and 59.7% at 1 year, 42.9 and 47.1% at 3 years, and 36.7 and 43.0% at 5 years, respectively. Only one patient succumbed to mortality during induction therapy. The toxicity level was acceptable. Therefore, the present study demonstrated that MAC is a highly effective and well-tolerated regimen for salvage in patients experiencing primary induction failure or relapse. This treatment significantly improved the prognosis.

We studied the impact of transcutaneous continuous carbon dioxide tension (PtcCO2) monitoring on ventilation and oxygenation during monitored anaesthesia care (MAC) in patients scheduled for shoulder surgery with continuous interscalene block. 50 patients were randomised either to the intervention (I-group) or the control (C-group) group. In both groups MAC was performed using target controlled infusion of propofol and remifentanil. MAC regimen was adapted to PtcCO2 values in the I-group, whereas the C-group was blinded for these values. Primary outcome was the incidence, degree and duration of hypoventilation stages. In the I-group and the C-group the mean ± SD [range] of PtcCO2 and PaCO2 was 5.79 ± 0.84 [4.37] and 5.44 ± 0.59 [2.78] kPa, as well as 6.41 ± 1.17 [6.29] and 6.01 ± 0.96 [7.15] kPa. Periods of PtcCO2/PaCO2 > 6.5 kPa were 21.0 ± 35.7/1.2 ± 4.2 min in the I-group and 45.6 ± 40.0/18.6 ± 26.8 min in the C-group. Severe hypercapnia (PtcCO2 and/or PaCO2 > 7.5 kPa) was dected in 3/0 patients of the I-group and in 10/3 patients of the C-group. PtcCO2 and PaCO2 showed a strong correlation (r = 0.78), but only moderate agreement with a mean bias (LOA) of −0.37 (−1.69; +0.95) kPa showing an overestimation of the PaCO2. Sensitivity and specificity of PtcCO2 to detect changes of PaCO2 was 0.94 and 0.56, respectively. In no patient SpO2 or SaO2 values lower than 90 % were measured. Despite a moderate agreement between PaCO2 and PtcCO2 the PtcCO2 monitoring significantly reduced incidence, degree and duration of hypercapnia in shoulder surgery patients with MAC.

The aim of the current study is to evaluate the different treatment modalities used in the management of high-risk metastatic gestational trophoblastic tumors (GTT) between June 1992 and December 2004 at the Gynecologic Oncology Unit, Ain Shams University. Out of 261 patients diagnosed and treated for GTT, 70 (26.8%) were high risk metastatic patients based on the National Institutes of Health clinical classification. The mean age was 29.39 +/- 9.38 years (16-55 years), with six patients (8.6%) being older than 39 years, and the mean duration of follow-up was 79.74 +/- 40.44 months (6-157 months). Forty patients (57.14%) were diagnosed after molar pregnancy, 22 (31.43%) after abortion, and 8 (11.43%) after term pregnancy. Forty-two patients (60%) were diagnosed within 4 months of the occurrence of the disease, and 28 (40%) were diagnosed after more than 4 months. Sixty-seven patients were treated using different regimens according to the protocol of treatment at that time. The MAC regimen was used initially but has been subsequently abandoned in favor of EMA-CO (etoposide, methotrexate, dactinomycin, cyclophosphamide, and vincristine [Oncovin]) regimen, which was later modified by omitting the CO arm to decrease its toxicity. If resistance developed, platinum-based therapy was given in the form of EMA-EP. Recently, our unit incorporated paclitaxel in the third-line treatment. Surgical intervention was used selectively. Fifty-seven (81.4%) patients could be cured; 43 by initial chemotherapy, with a mean of 7 +/- 0.46 courses (6-15), and 14 were salvaged by second- or third-line chemotherapy. Fourteen patients (20%) died during the study period; one was unrelated to GTT, while three died of acute respiratory distress syndrome before instituting proper therapy and two died of treatment complications. Using univariate and multivariate Cox regression analyses, the presence of brain and/or liver metastases was found to be the worst prognostic variable affecting the survival, followed by resistance to combination chemotherapy and then the type of antecedent pregnancy. The projected 5-year survival as estimated by Kaplan-Meier method was 78%.

BACKGROUND: RBCT (RBCT) requirements of stem cell transplant (SCT) recipients are often substantial and may be related to transplant type. STUDY DESIGN AND METHODS: An analysis was done of RBCT requirements and Hb recovery kinetic in the first 60 days after HLA-identical sibling allogeneic SCT in a series of 110 consecutive patients treated for various malignant diagnoses. Patients were prepared with either an antithymocyte globulin (ATG) and reduced intensity chemotherapy-based conditioning (RIC) (n = 64) or a myeloablative conditioning regimens (MAC; n = 46). Patients received marrow (n = 64) or PBPCs (n = 46). RESULTS: Overall, intensity of conditioning regimen (RIC vs. MAC; p = 0.0005) and graft source (PBPC vs. marrow; p < 0.0001) independently predicted RBCT requirements. Hb recovery was accelerated after RIC when compared to MAC allo-SCT (p = 0.02). In RIC patients, RBCTs were inversely correlated to Hb level before conditioning (p < 0.0001) and the dose of ATG (p = 0.009). Moreover, Hb level before allo-SCT significantly influenced Hb recovery kinetic after RIC but had no impact on RBCT requirements and Hb recovery after MAC. CONCLUSION: Thus, RIC conditioning creates a different pattern of erythropoiesis recovery as compared to a MAC regimen and suggest a need for studies aimed at further reducing RBCT and accelerating Hb recovery.

Background: PRF-AML is associated with a dismal prognosis. Approximately one third of patients younger than 60 years, and 50 % of older patients, with newly diagnosed AML, fail to achieve complete remission (CR) with standard induction chemotherapy. Allo-SCT in the setting of active disease is an alternative strategy. The increased availability of unrelated donors (UD) together with the use of reduced-intensity conditioning (RIC) regimens have opened the possibility for transplantation to a larger number of patients in comparison to standard myeloablative regimens (MAC). Because of the high risk of allo-SCT in this setting, there are still questions on the patient outcome depending on the donor type. Aims: The current study aimed to compare the outcomes of allo-SCT from matched sibling donors (MSD) (n=660) vs UDs (n=381), for patients with PRF AML. Methods: The major endpoints were to assess overall survival (OS), leukemia-free survival (LFS), relapse incidence (RI), and non relapse mortality (NRM). Results: 660 patients received a MSD, 296 patients a matched UD (10/10) and 85 a mismatched UD (9/10), respectively. Median age was higher in the UD group (50.5 yrs (18-74) vs 47.7 yrs (18-74), p=0.006). The median time from diagnosis to allo-SCT was similar (110 days [60-180] in the MSD group vs 111days [60-178] in the UD group; p=0.33). In the MSD allo-SCT, 57 % received a MAC regimen, 29% a RIC regimen, and 14% a sequential conditioning regimen; while, in the UD transplants, 44.4 % received a MAC regimen, 24.4% a RIC regimen, and 31.2% a sequential conditioning regimen (p50 yrs, cytogenetics, time from diagnosis to transplant and CMV positive status whereas Karnofsky status at transplant ≥90% (KS) was associated with better OS. 71% patients with a MSD and 68.6% patents with an UD reached CR after allo-SCT (p=0.73). In univariate analysis, RI at 2 years was 53.7% in MSD group and 56.4% in UD group, respectively (p=0.038). In multivariate analysis for RI, cytogenetics and time from diagnosis to transplant were the only risk factors associated with increased relapse [(HR=1.74, 95%CI,1.30-2.33, p=0.0002) (HR=1.29, 95%CI,1.06-1.58, p=0.01), respectively] whereas KS was a protective factor (HR=0.77, 95%CI,0.62-0.95, p=0.01). The incidence of aGVHD≥2 was higher in UD group (35.5% vs 27.9%, p=0.012). At 2 years, the cumulative incidence of chronic GVHD (cGVHD) was not statistically different between MSD and UD (28.9% and 25.8%, respectively, p=0.56) (univariate analysis). As for, NRM at 2 years, there was not statistical difference between MSD and UD groups (21% vs 25.1%, p=0.112). In multivariate analysis, patient age (>50 yrs) and CMV positive status were factors associated with higher NRM (HR=1.77, 95%CI, 1.27-2.47, p=0.001; HR=1.68, 95%CI, 1.14-2.47, p=0.008), while RIC regimen compared to MAC regimen was the only factor associated with lower NRM (HR=0.59, 95%CI, 0.41-0.85, p=0.005). Conclusion Allo-SCT may rescue one third of patients with primary refractory AML. Importantly, the donor type did not have any impact on PRF patients' outcomes. In contrast, time to transplant was a major prognostic factor for LFS and OS. For patients with PRF AML, that do not have a matched sibling donor, allo-HST from UD is a suitable option and thus initiation of an early search and allocating of a suitable donor is therefore indicated. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Finke: Riemser: Research Funding, Speakers Bureau; Neovii, Novartis: Consultancy, Research Funding, Speakers Bureau; Medac: Research Funding. Esteve:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Mohty:Janssen: Honoraria; Celgene: Honoraria.

Objective To validate the non-radiometric, broth-based ESP system for determining Mycobacterium avium complex (MAC) susceptibilities. Methods MAC isolates from sterile body sites of 20 adult HIV-infected patients who were failing their present MAC regimen were identified. Susceptibilities were determined and comparisons made between the agar proportion method and the ESP system for clarithromycin, ethambutol, sparfloxacin and cycloserine. Results Ninety-nine percent of the MICs generated by the ESP system were identical to or lower than the MICs determined by the agar proportion method. In vitro resistance was documented by the ESP system for 86% of the drugs that patients were taking at the time of breakthrough, and no resistance was seen to cycloserine, a drug that no patient was taking. Conclusions The ESP system, a fast and reliable method for determining MAC susceptibilities, could be used to optimize MAC regimens in a timely fashion, avoid the use of ineffective drugs, minimize emerging resistance and ultimately improve outcome.

The treatment for hematological malignancies has excelled over the past decade. A vast number of hematological malignancies are now amenable to cure with hematopoietic stem cell transplants (HSCTs) [1]. Older patients with comorbidities are poor candidates for standard myeloablative conditioning (MAC). While myeloablative therapy remains the standard curative conditioning regimen in the treatment of malignant disorders such as acute myeloid leukemia, its use is limited to patients in the younger age group, and to those in good physical health. Therefore, the older population is generally unsuited to this form of treatment, even though most hematological malignancies are often diagnosed at the age of 70-80 years. The advent of reduced-intensity conditioning (RIC) has provided these patients with a viable treatment option. Prior to undergoing HSCT, patients are treated with a conditioning regimen. This not only decreases the tumor burden, but also maximizes the capability of the donor cells to engraft successfully by suppressing the patient's immune system. Conditioning regimens vary in the amount of agent used. These compounds are often used at highly toxic dosage levels that are required to induce an immunocompromised state through a cytoreductive effect [2]. Over the past decade, conditioning regimens have considerably evolved with the development of RIC. These regimens are composed of reduced doses of cytotoxic agents in addition to a T-cell depleting agent [3]. The most commonly used regimens include fludarabine in combination with low-dose total body irradiation, or an alkylating agent such as busulfan, cyclophosphamide, or melphalan [3]. This treatment modality relies on a graft-versus-leukemia effect and has minimal associated toxicity. It is difficult to define RIC as it falls into an intermediate category between the MAC and the non-myeloablative regimens, since it does result in prolonged pancytopenia. Sources of donor cells include peripheral blood stem cells, bone marrow, and umbilical cord blood. Peripheral blood stem cells are more commonly used owing to the decreased engraftment time associated with their use [4]. Umbilical cord blood stem cells are a promising alternative source of stem cells with an associated 1-year survival rate of up to 40%, and a 9% incidence of grade III-IV acute graftversus-host disease (GVHD). However, studies have also reported a transplant-related mortality (TRM) rate of 39-48% associated with use of umbilical cord blood stem cells [5,6]. Studies assessing the influence of age on the outcomes of RIC treatment have not shown any significant association between the two. Patients in the age group >65 years have a reported non-relapse mortality (NRM) rate of 30% and 34% at 1 and 2 years respectively; whereas in the younger age group (40-54 years), the reported corresponding rates are 21% and 50% respectively [7]. A meta-analysis of results from 13 studies conducted by Zeng et al. [8] found no significant difference between MAC and RIC in terms of overall survival rate, event-free survival, and NRM. Furthermore, the incidence of GVHD was significantly lower with RIC. GVHD is an important cause of mortality associated with the MAC regimen due to the highly toxic doses of agents that are often necessary to eradicate diseased host cells from the bone marrow. The leading causes of death in patients treated with a MAC regimen are GVHD and toxicity. Thus, these findings call for extensive research on RIC regimens. The reported risk of TRM associated with MAC is 20%-60%, whereas RIC is known to be associated with higher overall survival and lower TRM at the same time [9]. A retrospective study on patients with MDS and AML treated with different conditioning regimens revealed a lower NRM in patients treated with RIC; however, there was also an increased risk of relapse in the first 12 months in these patients [10]. Although disease relapse continues to be a complication associated with both treatment regimens, RIC has a relatively higher incidence of relapse. This may be attributable to the additional host factors including, but not limited to, cytogenetics and disease status at the time of allogeneic HSCT. The use of RIC has opened up new channels to treat malignant hematological disorders in the elderly and patients with multiple comorbidities. With reduction in GVHD, in conjunction with decreased TRM, RIC provides a treatment option for patients who were previously unsuited for standard conditioning regimens. However, the RIC regimens may vary from one center to another and therefore it is conceivable that the differences in outcomes may be related to different procedures and/or different criteria used for decision making by individual physicians. This indicates the need for further studies, particularly in developing countries, so that an international consensus on protocols and guidelines for RIC may be reached.

Graft rejection (GR) following an allo-SCT occurs in 10-20% of patients with β thalassemia major (TM). The reported clinical outcome following second transplants have been associated with a high incidence of graft rejection, treatment related mortality, and graft versus host disease [Haematologica 2009; 94(9)]. There is limited data on the clinical profile and long term outcome of patients who have had a graft rejection. We undertook a retrospective analysis of patients who had a graft failure post allogeneic SCT for TM at our center. From October, 1991 to June 2016, 506 HLA matched related transplants for TM were done at our center. Of these 55 (11%) patients had a graft failure. An additional 7 patients with graft failure following an allo-SCT done at other centers were referred to us for a second transplant. Of the 62 patients with graft failure 32 (52.4%) were primary graft failures (PGF; 15 with aplasia and 17 with autologous recovery) while 30 (47.6%) were secondary graft failures (SGF; 5 with aplasia and 25 with autologous recovery). The median age of the patients who had graft failure was 8 years (range:1-19) and there were 38 (60.3%) males. On conventional risk stratification 40 (63.5%) were Class III. Eighteen (54.5%) cases with PGF and 16 (53.3%) with SGF did not receive a second transplant. From Oct 2009, at our center, a reduced toxicity myeloablative (MAC) treosulfan based conditioning regimen with a PBSC graft was offered to all high risk patients and for second transplants at the treating physician's discretion. Twenty nine (46%) of the patients with GR underwent a second allo-SCT. With the exception of one patient (first allo-SCT with an unrelated cord blood product) the donor for the second transplant was the same as the first transplant. Conditioning regimen for second SCT was busulfan based MAC in 7 (24%), treosulfan based MAC in 12 (41.3%) and the remaining received non-myeloablative conditioning regimens (fludarabine based, low dose TBI, OKT3, Cy-OKT3) often in view of pancytopenia and perceived inability to tolerate a MAC. All patients receiving a treosulfan based regimen had a PBSC graft. A BM graft was used in 7 (41%) of the remaining cases. None of the patients conditioned with a treosulfan based regimen had a graft rejection though one patient died of Grade IV acute GVHD. Of the remaining 17 patients 10 died following a second GR, 3 died of regimen related toxicity. Four are alive of which one has recurrent TM and the rest are well and transfusion independent at 55, 80 and 204 months from second transplant (all busulfan based MAC). The baseline characteristics and clinical outcomes of patients who received a treosulfan based MAC regimen versus the rest is summarized in table 1 and figure 1. On a univariate analysis a non-treosulfan based conditioning regimen and time from GR to second transplant of In conclusion there has been a significant improvement in clinical outcomes in our experience with the use of a treosulfan based reduced toxicity MAC regimen for second allo-SCT for TM. It would be reasonable, where feasible, to defer the second transplant by a year following the first graft rejection. Disclosures No relevant conflicts of interest to declare.

Background: The use of tyrosine kinase inhibitor (TKI)-based chemotherapy has demonstrated improved complete remission (CR) rates and increased applicability to allogeneic hematopoietic cell transplantation (HCT), thus allowing better survival in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL). However, the sensitivity of Ph-positive ALL to reduced-intensity conditioning (RIC) versus myeloablative conditioning (MAC) by minimal residual disease (MRD) kinetics is not well established. Previously, we have confirmed that monitoring MRD kinetics is very important to predict long-term outcomes. Here, we examined a cohort of patients with Ph-positive ALL in CR1 and tried to compare the long-term outcomes of RIC-HCT vs MAC-HCT according to pre-HCT MRD kinetics. Methods: During the period between 2000 and 2014, 173 adults (median age, 39 years [range, 16-65 years]) with Ph-positive ALL were included in this analysis. All patients received allogeneic HCT (68 RIC [fludarabine 150mg/m2 + melphalan 140mg/m2] and 105 MAC [total body irradiation 13.2Gy + cyclophosphamide 120mg/kg]) in CR1 following two courses of first-line TKI (138 imatinib and 35 dasatinib)-based chemotherapy and had data on prospectively determined quantitative MRD kinetics. A total of 52 patients were excluded because of >CR1 pre-HCT status (n=26), transplants receiving umbilical cord blood grafts (n=14), and no TKI use before HCT (n=12). All but one RIC transplants received peripheral blood stem cells as a graft source (40 matched sibling donor, 11 matched unrelated donor, 17 mismatched unrelated donor), while MAC transplants used either bone marrow (n=73; 57 matched sibling donor, 8 matched unrelated donor, 6 mismatched unrelated donor) or peripheral blood stem cells (n=32; 2 matched sibling donor, 20 matched unrelated donor, 10 mismatched unrelated donor). The median time to transplant was 154 days (range, 119-291 days) in RIC transplants and 141 days (range, 112-280 days) in MAC transplants, respectively. Calcineurin inhibitors (cyclosporine for sibling donor transplants, tacrolimus for unrelated donor transplants) and methotrexate was used for graft-versus-host disease (GVHD) prophylaxis and antithymocyte globulin was administered to the patients who received mismatched unrelated donor grafts. If residual leukemia was detected in the absence of GVHD at 3 months after transplantation, calcineurin inhibitors were rapidly discontinued. MRD monitoring was centrally evaluated by real-time quantitative PCR (4.5 log sensitivity) through handling of bone marrow samples. Results: After a median follow-up of 70.4 months (range, 16.0-176.8 mo), RIC regimen showed comparable 5-year cumulative incidence of relapse (CIR; 30.2% vs 27.9%, P=0.750), non-relapse mortality (NRM; 20.3% vs 15.5%, P=0.318), disease-free survival (DFS; 49.7% vs 56.6%, P=0.296), and overall survival (OS; 59.3% vs 62.1%, P=0.540) compared to MAC regimen. We further analyzed the impact of conditioning intensity on CIR and DFS according to MRD kinetics. Based on the MRD kinetics during the pre-HCT TKI-based chemotherapy courses, we classified patients into 3 subgroups: early-stable molecular responders (EMR, n=59), late molecular responders (LMR, n=57), and poor molecular responders (PMR, n=53). In all MRD-based subgroups of patients, no significant difference in CIR (EMR: 16.3% vs 6.2%, P=0.280; LMR: 10.5% vs 21.4%, P=0.334; PMR: 63.6% vs 59.4%, P=0.372) or DFS (EMR: 68.1% vs 78.1%, P=0.381; LMR: 49.6% vs 59.5%, P=0.369; PMR: 27.3% vs 34.2%, P=0.250) was observed between RIC and MAC. In multivariate analysis, LMR (HR, 2.36; 95% CI, 0.81-6.86; P=0.114) or PMR (HR, 9.05; 95% CI, 3.40-24.1; P Conclusion:RIC-HCT showed comparable long-term outcomes to MAC-HCT in all MRD-based subgroups of patients with Ph-positive ALL in CR1. Our data suggest that RIC-HCT is worthy of further investigation in prospective trials of adult Ph-positive ALL. Disclosures Kim: ILYANG: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Introduction: Allogeneic transplantation is the only curative option for patients with high risk leukemias or MDS. Only one third of them have an HLA identical sibling donor and around 60-70% will find an unrelated donor, that´s why haploidentical stem cell transplantation (HAPLO-HSCT) offers a therapeutic option to most of these patients. Myeloablative conditioning (MAC) produce better disease control than reduced intensity conditioning regimens (RIC), but with higher toxicity, rendering long term similar results. Patients and methods: We retrospectively evaluated the results of our MAC-HAPLO regimens in patients diagnosed with high risk leukemias or MDS (Fludarabine 30 mg/m2 x5 days, Cyclophosphamide14,5 mg/kg x2 days, IV Busulfan 3,2 mg/kg x 3 days (BUX3), or Fludarabine 40 mg/m2 x4 days and IV Busulfan 3,2 mg/kg x 4 days (BUX4)) with GVHD prophylaxis based on PT-CY (50 mg/kg on days +3 and +4) and a calcineurin inhibitor plus mycophenolate from day +5, performed in GETH centers (Spanish Group for Hematopoietic Transplantation). Results: From Feb-2012, 65 MAC-HAPLO HSCT have been reported by 14 centers. Median age was 41 years (15-67), 66% were males and all were in advanced disease phase or presented high risk features (AML 47/ALL 8/MDS 5/ Others 5). Previous HSCT had been employed in 12% (autologous in 5, allogeneic in 3), and in 88% the HAPLO-HSCT was their first transplant. Disease status at HAPLO-HSCT was morphologic CR in 80%, but disease persisted in 52% (MRD+ by flow or molecular markers 32%, morphologic disease 20%). Their disease risk index (DRI) was high or very high in 65%, and the comorbidity index (HCT-CI) was higher than 2 in 18%. PBSC was the graft source in 56 (86%), non T-cell depleted in all cases. The haploidentical donor was the patient´s mother (21.5%), father (12%), siblings (43%) or offspring (23%). MAC regimen was BUX3 in 25 (38.5%) and BUX4 in 40 patients (61.5%). Median infused CD34+ cells were 5.31 x10e6/kg (2.75-11.42). There were no graft failures. Median neutrophils engraftment was reached at day +17 (12-29) and platelets >20K at day +26 (11-150). Complete chimerism was obtained at a median of 28 days (13-135) in 60 evaluated patients. Cumulative incidence (CI) of non-relapse mortality (NRM) was 12.5% at day +100 and 19% at 1 year. CI of grade II-IV acute GVHD was 28.5% at day +100, and grade III-IV was 6.5%. CI of chronic GVHD at 2 years was 28%, being extensive in 8% . No differences in acute or chronic GvHD CI were seen when comparing BUX3 against BUX4. After a median follow-up of 17 months (5-50), estimated 24-months event-free survival (EFS) and overall survival (OS) were 58,5% and 60% respectively. CI of relapse or progression was 21%. No significant differences in NRM, EFS, OS and relapse incidence were detected between BUX3 and BUX4. The impact of CR prior to MAC-HAPLO, the DRI or chronic GvHD in the disease control have not been apropiately demostrated probably due to the limited number of events in our series. Conclusions: IV Busulfan based MAC-HAPLO with PT-CY in the treatment of high risk leukemias and MDS offers good disease control with manageable toxicity, with either BUX3 or BUX4. These efective MAC regimens combined with peripheral blood HAPLO donors could control high risk hematologic diseases in the long term. Severe acute or chronic GvHD are low frecuency events, but relapses persist as the main problem in this patients population. Disclosures No relevant conflicts of interest to declare.

Introduction:The development of RIC regimens enabled HSCT also for elderly patients who had contraindications for intensive conditioning regimens. The aim of this study is to evaluate the effects of conditioning regimens on outcomes of alllo-HSCT for adult patients with acute leukemia. Method:In this study, we retrospectively analysed 490 acute leukemia patients who underwent allo-HSCT between June 1988 to June 2015 at Ankara University School of Medicine Department of Hematology. We compared the outcomes of MAC vs RIC conditioning by Fisher's test and chi-square test. Kaplan-meier curves were used for survival. The factors that effect on survival were evaluated by univariate analysis-log-rank test and multivariate analysis-cox regression. Results: In our study, the median age of participants was 32 with M/F ratio of 285 (57.9%) / 207 (42.1%). The patients were diagnosed as acute myeloid leukemia (AML) in 344 patients (69.9%), acute lymphoblastic leukemia (ALL) in 140 patients (28.5%) and others in 8 patients (1.6%). Pre-transplant active disease detected in 105 (22.7%) patients. Patients received grafts from related donors in 397 (80.7%) transplants. The most common stem cell source was peripheral blood in 378 patients (76.8%) followed by bone marrow in 99 patients (20.1%). MAC was used in 224 (90.4%) recipients whereas RIC was used in 47 (9.6%). The age, unrelated transplants, number of AML patients and intermediate-high risk patients were significantly higher in RIC group (44 vs 31, p Conclusion: Lower OS and RFS were observed in the RIC conditioned patients compared to MAC in our study. In the treatment of young patients who do not have comorbidities for intense conditioning regimens, show good performance status and are high risk; the initial use of standard myeloablative conditioning regimens is feasible. However, the lower number of RIC transplants and the variations between groups in terms of patient and donor characteristics might effect the results of this study. Therefore, conducting further prospective studies with larger cohorts would be beneficial to enhance our knowledge. Disclosures No relevant conflicts of interest to declare.

Background: Value is defined as health outcomes achieved per dollar spent. While risk-stratified AL HCT survival estimates are made possible by the Stem Cell Therapeutic Outcomes Database (SCTOD), an assessment of healthcare value is not possible as they do not include cost adjustments based upon clinical risk. We report a risk-based cost analysis, modeled on AL pts undergoing HCT at our institution that can potentially serve as a simple, statistically significant risk-based comparison tool. Methods: All AL pts who underwent HCT at City of Hope between 1/1/2010 and 12/31/2014 were included. Detailed data were captured from multiple electronic record sources in our database. Total direct costs were assessed for each pt from 14 days prior to 100 days post HCT. Categorical data were tested for associations by Chi-square; continuous data that were normally distributed were tested by T-test, while non-normal data were tested by Wilcoxon rank sum test. Univariate and multivariable logistic regression models were used to identify predictors associated with HCT costs ≥ median and ≥ 80th percentile. Univariate and multivariable Cox proportional hazards regression were used to identify predictors of overall survival (OS). All p-values were 2-sided with alpha level of 0.05. Results: This analysis included 389 pts (AML 352; ALL 37); median age was 52.5 years (yr) [range 1-74; 107 (27.5%) age ≥ 60]; 48% were female. At the time of HCT 204 (52%) were in 1st complete remission [CR], 87 (22%) in 1st relapse (rel)/2nd CR, and 98 (25%) >2nd CR/Induction Failure [IF]; ECOG performance status was ≥1 in 29.5% and Sorrer comorbidity score ≥1 in 56%. 214 (55%) and 175 (45%) received myeloablative (MAC) or reduced intensity (RIC) conditioning regimen, respectively; 231 (59%) had matched unrelated donor [MUD] or mismatched related donor (MRD) HCT. Graft-versus-host prophylactic (GVHD) regimen consisted of tacrolimus/sirolimus for 80% pts. 207 pts were enrolled on a therapeutic intervention trials and 121 had Medicare and/or Medicaid (Medi-Cal) as payer. Median follow-up was 12.9 months. The estimated 1- yr unadjusted OS for the entire group post-HCT was 71% (95% CI 66%-75%), 80% (74%-85%) for pts in 1st CR, 68% (57%-77%) for pts in 1st rel/2nd CR, and 56% (45%-65%) for pts >2nd CR/ IF. OS was similar for sibling matched and MUD/MRD transplants (1-yr OS 73% vs. 70%). In a multivariable analyses, disease status, MUD/MRD donor, MAC regimen, GVHD prophylaxis other than tacrolimus/sirolimus, ECOG ≥1, and Medicare and/or Medicaid as payer significantly predicted for cost ≥ median (Figure1A). Using Akaike Information Criterion (AIC) scores, donor type and disease status at HCT were found to be more informative variables with regard to higher cost of HCT. Disease status, MUD/MRD, MAC regimen, Medicare and/or Medicaid as payer and ECOG ≥1 also significantly predicted cost ≥ 80th percentile (Figure1B). In a multivariable analysis for OS (Figure 1C) , only >2nd CR/IF and HCT cost exceeding median had significantly higher hazard of death. Of note, despite reaching statistical significance in univariate analysis age, cytogenetics, treatment on protocol, and Sorrer score lost significance in adjusted higher costs and OS multivariable models. Conclusions: Our data suggest that: 1. Higher levels of care complexity drive higher costs, 2. Patients with more advanced disease status and inferior performance status have higher costs, 3. Statistically significant drivers of higher care costs are predictable prior to HCT. These risk factors are easily abstractable from medical records and provide prospective, equitably comparisons of risk-based costs between transplant centers. These data compliment the outcomes data available from the SCTOD and may enable providers and payers to make meaningful value comparisons between transplant centers. They may also help establish alternative models for payer contracting that include consideration of clinical risk-stratification. Of note, given the favorable survival outcomes of pts with higher cost-risk features (i.e., advanced disease status at HCT and MUD/MRD), the higher care costs associated with effective care of higher complexity pts are justified. While validation of this model is necessary using large payer or multi-institutional databases, we propose that similar clinical-economic models can be created for pts with other blood cancers requiring high complexity care. Figure 1 Figure 1. Figure 2 Figure 2. Figure 3 Figure 3. Disclosures Forman: Mustang Therpapeutics: Other: Construct licensed by City of Hope.

BACKGROUND Gestational trophoblastic disease (GTD) includes gestational trophoblastic tumour and hydatidiform mole. Many women of reproductive age are affected by this disease although its incidence differs by geographical location. A number of chemotherapy regimens are used for treating the disease, such as methotrexate, actinomycin D and cyclophosphamide (MAC), methotrexate, actinomycin D, cyclophosphamide, doxorubicin, melphalan, hydroxyurea and vincristine (CHAMOC), etoposide, methotrexate and actinomycin (EMA) plus cyclophosphamide and vincristine (CO) (EMA-CO), etoposide, methotrexate and actinomycin (EMA) plus etoposide and cisplatin(EP) (EMA-EP). The efficacy of these drugs has not been systematically reviewed. OBJECTIVES To determine the efficacy and safety of combination chemotherapy in treating high-risk GTT. SEARCH STRATEGY Electronic searches of Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 2, 2008), MEDLINE, EMB and CBM, May 2008. Four journals were handsearched and other searching methods were used for identifying more studies. SELECTION CRITERIA The review included randomised controlled trials (RCTs) or quasi-RCTs of combination chemotherapy for treating high-risk GTT. Patients with placental-site trophoblastic tumour (PSTT), who had received chemotherapy in the previous two weeks, or patients with chemotherapy intolerance were excluded. DATA COLLECTION AND ANALYSIS Two investigators independently collected data using a data extraction form. Meta-analysis was not performed and the review was conducted as a narrative review. MAIN RESULTS One study with 42 participants was included in this review. It indicated that a MAC regimen was better than a CHAMOCA regimen for high-risk GTT because of lower toxicity. The quality of the study was unclear. AUTHORS' CONCLUSIONS The methodological limitations of the included study prevent any firm conclusions about the best combination chemotherapy regimen for high-risk GTT. High quality studies are required.

We assessed the safety and efficacy of melphalan, arsenic trioxide (ATO) and ascorbic acid (AA) (MAC) combination therapy for patients with multiple myeloma (MM) who failed more than two different prior regimens. Patients received melphalan (0.1 mg/kg p.o.), ATO (0.25 mg/kg i.v.) and AA (1 g i.v) on days 1-4 of week 1, ATO and AA twice weekly during weeks 2-5 and no treatment during week 6 of cycle 1; during cycles 2-6, the schedule remained the same except ATO and AA were given twice weekly in week 1. Objective responses occurred in 31 of 65 (48%) patients, including two complete, 15 partial and 14 minor responses. Median progression-free survival and overall survival were 7 and 19 months respectively. Twenty-two patients had elevated serum creatinine levels (SCr) at baseline, and 18 of 22 (82%) showed decreased SCr levels during treatment. Specific grade 3/4 haematological (3%) or cardiac adverse events occurred infrequently. Frequent grade 3/4 non-haematological adverse events included fever/chills (15%), pain (8%) and fatigue (6%). This steroid-free regimen was effective and well tolerated in this heavily pretreated group. These results indicate that the MAC regimen is a new therapeutic option for patients with relapsed or refractory MM.

Background: A recent prospective study (Socie & al Blood 2011) demonstrated that the addition of antithymocyte globulins (ATG) to prophylaxis for graft versus host disease (GVHD) in the setting of standard myeloablative conditioning (MAC) regimen matched unrelated donor (UD) allogeneic stem cell transplantation (HSCT) resulted in a decrease in incidence of chronic GVHD without an increase of relapse or non-relapse mortality. However, stem cell source was mostly peripheral blood stem cells (PBSC) and patients (pts) were compatible at HLA-A, HLA-B, HLA-DRB1 and HLA-DQB1 (eight out of eight alleles). A retrospective study using the same setting (Mohty & al Leukemia 2012) found very similar results with donor/recipient pairs matched at 10 loci (ten out of ten alleles). However, one third of the pts received PBSC as stem cells source and 20% of the pts were transplanted with a mismatch donor (9 out of 10 alleles). We thus conducted this study to assess the impact of ATG in pts with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) transplanted with MAC using bone marrow only (BM) from matched 10/10 UD. Patients and methods: We includedall consecutive pts older than 18 years who received a first HSCT in France for AML or MDS with BM from a matched 10/10 UD after a standard conditioning regimen (fractionated total body irradiation (TBI)-Cyclophosphamide(Cy), n=106 or Endoxan-Cy, n=91) between June 2000 and June 2012. Clinical data were prospectively collected using ProMISe (Project Manager Internet Server), an internet-based data registry system shared by all centers of the French Society of Bone Marrow Transplantation and Cell Therapies (SFGM-TC). This study was approved by the scientific committee of the SFGM-TC. Results: A total of 197 adult pts met the criteria and were analyzed (165 AML (84%) and 35 MDS). 54 (27%) pts received ATG in the conditioning regimen whereas 143 (73%) did not. Median follow up was of 20.3 months [0.4-156]. Both groups (with or without ATG) were well balanced except for the number of CD34+ cells infused (higher in the ATG group: 3.07x106/kg [0.7-13] vs 2.71x106/kg [0.6-89] for none ATG group (p=0.03)) and GvHD prophylaxis (more likely cyclosporine plus methotrexate with ATG (94%) vs 84% without, p=0.05). The probability of acute GvHD grade II-IV was similar between both groups: 41.3% with ATG vs 49.6% without, p=0.2. Incidence rate of severe acute GVHD grade III-IV at day 100 tended to be lower in the ATG group as compared with the none ATG group (20.3% vs 9.5%, respectively, p=0.052). The cumulative incidence (CI) of chronic GVHD at 2 years was 42% in the ATG group vs 28% in the none ATG group and 37% vs 44% at 4 years, respectively (p=0.18). The probability of extensive chronic GVHD at 2 years was identical between both groups (12% with ATG vs 16% without, p=0.95). CI of non-relapse related mortality (NRM), relapse as well as disease free survival (DFS) and overall survival (OS) were similar between the 2 groups (Table 1). In multivariate analysis, advanced disease status was the only parameter associated with decreased DFS (HR 0.37, 95% CI [0.19-0.70], p=0 .02) and OS (HR 0,41, 95% CI [0,24;0,71], p

Background: Allogeneic stem cell transplantation (SCT) is the most intensive therapeutic modality for children with acute lymphoblastic leukemia (ALL) who are resistant to the conventional chemotherapy. The preparative regimen given to those patients is mostly myeloablative conditioning (MAC) and it is the major cause of short or long term post-transplant complications in spite of the potent anti-leukemic effect. Reduced intensity conditioning (RIC) regimen is commonly applied to elderly patients who are ineligible to MAC regimen but only a small number of children received RIC regimen to date and the precise transplant outcome of SCT with RIC regimen for children with ALL is not well understood. To interpret the clinical implication of RIC regimens in children, we have conducted nationwide retrospective analysis by comparing the transplant outcomes with RIC and MAC regimens in children with ALL. Patients and Methods: From 2000 to 2010, 1334 children with ALL undergone their first allogeneic SCT either by RIC (n=133) or MAC (n=1201) regimen in Japan. Clinical outcomes of SCT was accumulated in the database of The Japan Society for Hematopoietic Cell Transplantation (JSHCT) and the definition of RIC or MAC was based on the internationally recognized criteria in which MAC was defined as > 8Gy of fractionated TBI, >5Gy of single TBI, >8mg/kg or >280mg/m2 of busulfan, otherwise categorized as RIC. Disease status at transplant for RIC/MAC was first complete remission (CR, 60/508), 2nd CR (27/347), and more advanced stages (42/329), respectively, (P=0.125). Stem cell source for RIC/MAC was related bone marrow (BM, 33/380), unrelated BM (36/410), related peripheral blood (11/78), and unrelated cord blood (53/333), respectively, (P=0.017). Serological HLA compatibility of RIC/MAC was matched (66/750), or mismatched (62/426), respectively, (P=0.007) Results: In univariate analysis, five year overall survival (OS) of RIC and MAC in each disease status were not significant different, i.e. 75.2% and 73.4% at first CR (P=0.991), 50.5% and 56.7% at 2nd CR (P=0.748), and 26.7% and 30.3% at more advanced stages (P=0.683), respectively. Five year relapse free survival (RFS) of RIC and MAC in each disease status were also not different, i.e. 62.3% and 68.2% at first CR (P=0.249), 46.6% and 54.0% at 2nd CR (P=0.519), and 14.9% and 27.0% at more advanced stages (P=0.295), respectively. Neutrophil engraftment was obtained 91.7% in RIC and 96.2% in MAC by day 100 (P=0.491). Five year relapse rate was significantly higher in RIC than MAC, i.e. 43.1% vs 33.6%, P=0.020, but five year treatment related mortality (TRM) of RIC and MAC was not significantly different, i.e. 15.7% vs 15.3%, respectively (P=0.952). In multivariate analysis adjusted by other covariates, conditioning regimen of RIC compared to MAC did not significantly affect OS (HR=1.10, P=0.488), RFS (HR=1.25, P=0.093), relapse (HR=1.11, P=0.530), TRM (HR=0.89, P=0.621) or engraftment (HR=0.99, P=0.983). In 133 RIC patients, poor prognostic factors of OS identified in multivariate analysis were advanced stages at SCT (HR=3.91, P Conclusion: Our data showed that SCT with RIC for children with ALL showed similar transplant outcome compared to those who received MAC. These data suggest that RIC regimen could be considered as one of the therapeutic modality of SCT for children with ALL who needs allogeneic SCT. RIC may have a role also for children, since it may reduce late effects of MAC regimen or high-dose TBI for long-term survivors. To confirm these results, prospective randomized study with multi-institutional basis is mandatory. Disclosures No relevant conflicts of interest to declare.

Introduction Myelofibrosis (MF) is a heterogenous myeloproliferative disorder arising at the level of pluripotent hematopoietic stem cells. It is characterized by reactive marrow fibrosis resulting in extramedullary hematopoeisis, cytopenias, hepatosplenomegaly and constitutional symptoms. The only curative treatment for MF patients is allogeneic hematopoietic cell transplantation (HCT). However, advanced age, comorbidities and disease-related complications are challenging factors for allogeneic HCT. Reduced intensity conditioning (RIC) regimens have lead to an increased frequency of allogeneic HCT for MF patients in recent years. We here report our own experience with allogeneic HCT in MF. Methods By searching our database of allogeneic HCT we identified a total of 55 patients with primary or secondary myelofibrosis that underwent allogeneic HCT from 1997 to 2012. Retrospective analysis of data and review of patient charts was performed. Results Among the 55 MF patients were 32 males and 23 females with a median age of 54 years (range 28-75). The median interval from diagnosis to HCT was 123 months (range 2-269). Conditioning regimens were either myeloablative (MAC, 18/55 patients (33%)) or RIC (37/55 patients (67%)). Median age was 58 years (range 45-75) for RIC und 47 years (range 28-60) for MAC. As graft source either peripheral blood stem cells (n= 46) or bone marrow (n= 9) was used from either matched related (MRD, n=17, 31%), matched unrelated (MUD, n=21, 38%) or mismatched unrelated donors (MMUD, n=17, 31%). The MAC regimen consisted of 12 Gy total body irradiation in combination with high-dose cyclophosphamide (TBI/Cy, 78%) or high-dose busulfan and cyclophosphamide (Bu/Cy, 22%). Fludarabine and busulfan were the most frequently applied drugs for RIC (Flu/Bu, n=31, 84%), in a few cases fludarabine in combination with TBI (n=1, 3%) or treosulfan-containing regimens (n=3, 8%) were used. Two patients with accelerated disease were treated with the FLAMSA-protocol, followed by busulfan and cyclophosphamide containing RIC. As graft versus host disease (GVHD) prophylaxis, a combination of calcineurine inhibitors and methotrexate or mycophenolate mofetil was used, in 80% (n=44) antithymocyte globuline was additionally applied. Kaplan Meier estimated overall survival at 4 years was 62% for all patients and 62% after RIC compared to 58% with MAC (p= 0.42) with a median follow-up of patients alive of 49 months (range 9-151). Cumulative incidence of non relapse mortalitiy (NRM) overall and for MAC and RIC was 31%. The overall survival of patients with MRD, MUD and MMUD was 60%, 61% and 61%, respectively. NRM of patients with matched and unmatched donors was not significantly different (MRD 31% versus MUD 35% versus MMUD 33%). Engraftment of neutrophils (ANC>500/µL) was achieved at a median of 16 (range 9-31) days and 23 (range 13-60) days for patients in the MAC and the RIC-group, respectively (p= 0.0051). Platelet recovery (PLT>20.000/µL) occurred at a median of 24 (range 11-51) days after MAC and 21 (range 8-41) days after RIC (p= 0.2866). Despite the significantly delayed engraftment, the risk for severe or lethal infection was lower in the RIC- than in the MAC-group (n=3 versus n=1). Graft rejection occurred only in 3 patients after RIC. Acute GVHD occurred in 31% (n=17) of the patients. As expected, patients with MAC, compared to RIC, had a higher risk of acute GVHD (71% (n=12) versus 29% (n=5), p< 0.0001). Chronic GVHD occured in 59% of the patients, with 44% extensive and 56% limited cases. Chronic GvHD was more frequent after RIC compared to MAC (59% versus 41%, p= 0.1462). Patients with an extensive GVHD only survived in 18%, whereas patients with a mild or limited GvHD survived in 39% (p= 0.2059). Overall the occurence of GVHD was associated with a poorer outcome. Conclusion Our retrospective single center study confirms existing data that allogeneic HCT following RIC may have a similar outcome compared to MAC although used in an older and more comorbid patient population. Allogeneic HCT even with MMUD thus is a potentially curative treatment option in up to 60% of patients with primary or secondary MF. Disclosures: No relevant conflicts of interest to declare.

Abstract 3103 Introduction: Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) provides the best chance of long-term survival for patients with intermediate or high-risk acute myeloid leukemia (AML). The major limitation of this procedure is the risk of treatment related mortality (TRM). Use of reduced intensity conditioning (RIC) regimen has become standard practice among older candidates with comorbidities. Although RIC regimen have been used for over a decade in older patients, the benefit of this approach in younger patients with AML compared with the risk of toxicity of standard regimen (MAC) is still discussed. We compared the outcomes for patients with AML over 35 years using RIC or MAC HSCT. Patients, methods, and transplantation characteristics: From January 2000 to December 2010, 132 consecutive patients older than 35 years with AML (18 secondary AML) received HSCT in our center, either from siblings (n=87) or HLA 10/10 allele-matched donors (n=45). MAC (n=72) and RIC (n=60) regimens were defined as previously described (Bacigalupo, 2009). Seventy-three patients were in first complete remission (CR1); 30% of patients had poor risk cytogenetics (MRC classification). Karnofsky performance status was scored at time of HSCT. Engraftment, acute and chronic graft-versus-host disease (GvHD), transplantation-related mortality (TRM), relapse rate as well as overall survival (OS) at 4 years were compared according to the intensity of the conditioning regimen. First a classical multivariable Cox analysis was conducted. In a second step, baseline confounding factors were adjusted for using inverse probability-of-treatment weighting (IPTW). Results of the comparison: Patient characteristics according to the intensity of the conditioning regimen were similar for AML type (de novo versus secondary), gender, karnofsky performance status, CR#, donor type and number of CD34+ infused. Particularly, cytogenetic risks were comparable in both groups. Patients were younger in the MAC group (median age 44 years [range 35 to 56 years] vs 54[37 to 66] for RIC, p Conclusion: In patients with AML over 35 years, MAC regimen lead to a non significant higher rate of treatment related mortality with no benefit in terms of relapse when compared with RIC regimen. Until prospective trials are completed, this study supports the use of a RIC regimen for patients with AML older than 35 years who are transplanted either from siblings or matched unrelated donors. Disclosures: Fenaux: Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; GSK: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.