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In recent years considerable variations in conditioning protocols for allogeneic hematopoietic cell transplantation (allo-HCT) protocols have been introduced for higher efficacy, lower toxicity, and better outcomes. To overcome the limitations of the classical definition of reduced intensity and myeloablative conditioning, a transplantation conditioning intensity (TCI) score had been developed. In this study, we compared outcome after two frequently used single alkylator-based conditioning protocols from the intermediate TCI score category, fludarabine/melphalan 140 mg/m2 (FluMel) and fludarabine/treosulfan 42 g/m2 (FluTreo) for patients with acute myeloid leukemia (AML) in complete remission (CR). This retrospective analysis from the registry of the Acute Leukemia Working Party (ALWP) of the European Society of Bone Marrow Transplantation (EBMT) database included 1427 adult patients (median age 58.2 years) receiving either Flu/Mel (n = 1005) or Flu/Treo (n = 422). Both groups showed similar 3-year overall survival (OS) (54% vs 51.2%, p value 0.49) for patients conditioned with FluMel and FluTreo, respectively. However, patients treated with FluMel showed a reduced 3-year relapse incidence (32.4% vs. 40.4%, p value p value = 0.06) compared to patients treated with FluTreo. Our data may serve as a basis for further studies examining the role of additional agents/ intensifications in conditioning prior to allo-HCT.

Allogeneic stem-cell transplantation allows the delivery of curative graft-versus-leukemia (GVL) in patients with acute myeloid leukemia/myelodysplasia (AML/MDS). Surveillance of T-cell chimerism, measurable residual disease (MRD) and blast HLA-DR expression may inform whether GVL effectiveness is reduced. We report the prognostic impact of these biomarkers in patients allografted for AML/MDS. 187 patients from FIGARO, a randomized trial of reduced-intensity conditioning regimens in AML/MDS, were alive and relapse-free, at the first MRD timepoint and provided bone marrow for flow cytometric MRD monitoring and blood samples for T-cell chimerism analysis, requested to month+12. 29 (15.5%) patients had at least one MRD-positive result post-transplant. MRD-positivity was associated with reduced overall survival (OS) (HR:2.18, p=0.0028) as a time-varying Cox variable and remained significant irrespective of pre-transplant MRD status in multivariate analyses (p

Terminal complement blockade by humanised monoclonal antibody eculizumab has been used to treat transplantation-associated thrombotic microangiopathy (TA-TMA) in recent years. This retrospective international study conducted by the Paediatric Diseases (PDWP) and Inborn Error Working Party (IEWP) of the European Society for Blood and Marrow Transplantation (EBMT) describes outcome and response of 82 paediatric patients from 29 centres who developed TA-TMA and were treated with eculizumab between January 2014 and May 2019. The median time from hematopoietic stem cell transplantation (HSCT) to TA-TMA manifestation was 92 days (range: 7-606) and from TA-TMA diagnosis to the start of eculizumab treatment 6 days (range: 0-135). Most patients received eculizumab weekly (72%, n = 55) with a standard weight (kg)-based dose (78%, n = 64). Six months from beginning of eculizumab therapy, the cumulative incidence of TA-TMA resolution was 36.6% (95% CI: 26.2-47) and the overall survival (OS) was 47.1% (95% CI: 35.9-57.5). All 43 patients with unresolved TA-TMA died. The cause of death was HSCT-related in 41 patients. This study also documents poor outcome of patients without aGvHD and their frequent concomitant viral infections. Considering recent publications, intensified eculizumab dosing and complement monitoring could potentially improve upon outcomes observed in this study.

Chronic graft-versus-host disease (cGvHD) is a major cause of non-relapse morbidity and mortality following allogeneic stem cell transplant. Over half of patients with moderate or severe cGvHD fail to respond adequately to first-line treatment with systemic steroids, and although a range of second-line options have been employed, a lack of prospective evidence means there is no standard of care. The AZTEC trial is a prospective, single-arm, phase II study investigating the safety and activity of azacitidine for the treatment of cGvHD in patients who are resistant to, or intolerant of, systemic steroid therapy. The co-primary outcomes were treatment tolerability, and activity measured as objective response according to modified National Institutes of Health criteria. Fourteen patients were recruited to the first stage of the trial, of whom seven completed the planned six cycles of azacitidine 36 mg/m2 days 1–5 per 28-day cycle. Azacitidine was tolerated by 13/14 patients, and 7/14 showed an objective response. Clinical responses were mirrored by improvements in patient-reported cGvHD symptoms and quality of life. AZTEC demonstrates that azacitidine is a safe and promising option for the treatment of cGvHD, and continued evaluation in the second stage of this phase II efficacy study is supported.

PURPOSE Reduced-intensity conditioning (RIC) regimens have extended the curative potential of allogeneic stem-cell transplantation to older adults with high-risk acute myeloid leukemia (AML) and myelodysplasia (MDS) but are associated with a high risk of disease relapse. Strategies to reduce recurrence are urgently required. Registry data have demonstrated improved outcomes using a sequential transplant regimen, fludarabine/amsacrine/cytarabine-busulphan (FLAMSA-Bu), but the impact of this intensified conditioning regimen has not been studied in randomized trials. PATIENTS AND METHODS Two hundred forty-four patients (median age, 59 years) with high-risk AML (n = 164) or MDS (n = 80) were randomly assigned 1:1 to a fludarabine-based RIC regimen or FLAMSA-Bu. Pretransplant measurable residual disease (MRD) was monitored by flow cytometry (MFC-MRD) and correlated with outcome. RESULTS There was no difference in 2-year overall survival (hazard ratio 1.05 [85% CI, 0.80 to 1.38] P = .81) or cumulative incidence of relapse (CIR) (hazard ratio 0.94 [95%CI, 0.60 to 1.46] P = .81) between the control and FLAMSA-Bu arms. Detectable pretransplant MFC-MRD was associated with an increased CIR (2-year CIR 41.0% v 20.0%, P = .01) in the overall trial cohort with a comparable prognostic impact when measured by an unsupervised analysis approach. There was no evidence of interaction between MRD status and conditioning regimen intensity for relapse or survival. Acquisition of full donor T-cell chimerism at 3 months abrogated the adverse impact of pretransplant MRD on CIR and overall survival. CONCLUSION The intensified RIC conditioning regimen, FLAMSA-Bu, did not improve outcomes in adults transplanted for high-risk AML or MDS regardless of pretransplant MRD status. Our data instead support the exploration of interventions with the ability to accelerate acquisition of full donor T-cell chimerism as a tractable strategy to improve outcomes in patients allografted for AML.

Background: The success of unrelated haemopoietic cell transplantation (HCT) is limited by graft-versus-host disease (GVHD), which is the main post-transplantation challenge when HLA-matched donors are unavailable. A sequence dimorphism in exon 1 of HLA-B gives rise to leader peptides containing methionine (Met; M) or threonine (Thr; T), which differentially influence natural killer and T-cell alloresponses. The main aim of the study was to evaluate the role of the leader dimorphism in GVHD after HLA-B-mismatched unrelated HCT. Methods: We did a retrospective cohort study of 33 982 patients who received an unrelated HCT done in Australia, Europe, Japan, North America, and the UK between Jan 1, 1988, and Dec 31, 2016. Data were contributed by participants of the International Histocompatibility Working Group in Hematopoietic Cell Transplantation. All cases were included and there were no exclusion criteria. Multivariate regression models were used to assess risks associated with HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 mismatching. Among the 33 982 transplantations, the risks of GVHD associated with HLA-B M and T leaders were established in 17 100 (50·3%) HLA-matched and 1457 (4·3%) single HLA-B-mismatched transplantations using multivariate regression models. Leader frequencies were defined in 2 004 742 BeTheMatch US registry donors. Findings: Between Jan 20, 2017, and March 11, 2019, we assessed 33 982 HCTs using multivariate regression models for the role of HLA mismatching on outcome. Median follow-up was 1841 days (IQR 909–2963). Mortality and GVHD increased with increasing numbers of HLA mismatches. A single HLA-B mismatch increased grade 3–4 acute GVHD (odds ratio [OR] 1·89, 95% CI 1·53–2·33; p

Chronic graft-versus-host disease (cGvHD) is a major cause of non-relapse morbidity and mortality following allogeneic stem cell transplant. Over half of patients with moderate or severe cGvHD fail to respond adequately to first-line treatment with systemic steroids, and although a range of second-line options have been employed, a lack of prospective evidence means there is no standard of care. The AZTEC trial is a prospective, single-arm, phase II study investigating the safety and activity of azacitidine for the treatment of cGvHD in patients who are resistant to, or intolerant of, systemic steroid therapy. The co-primary outcomes were treatment tolerability, and activity measured as objective response according to modified National Institutes of Health criteria. Fourteen patients were recruited to the first stage of the trial, of whom seven completed the planned six cycles of azacitidine 36 mg/m

The inclusion of familial myeloid malignancies as a separate disease entity in the revised WHO classification has renewed efforts to improve the recognition and management of this group of at risk individuals. Here we report a cohort of 86 acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) families with 49 harboring germline variants in 16 previously defined loci (57%). Whole exome sequencing in a further 37 uncharacterized families (43%) allowed us to rationalize 65 new candidate loci, including genes mutated in rare hematological syndromes (ADA, GP6, IL17RA, PRF1 and SEC23B), reported in prior MDS/AML or inherited bone marrow failure series (DNAH9, NAPRT1 and SH2B3) or variants at novel loci (DHX34) that appear specific to inherited forms of myeloid malignancies. Altogether, our series of MDS/AML families offer novel insights into the etiology of myeloid malignancies and provide a framework to prioritize variants for inclusion into routine diagnostics and patient management., Familial myeloid malignancies have recently been classified as separate disease entities. Here, using whole-exome sequencing of affected pedigrees - the authors highlight genetic variants associated with these conditions.

Dr Andrew W Creamer (AWC), Respiratory Registrar : A 70-year-old retired teacher was referred to the respiratory clinic with a 12-month history of progressive exertional dyspnoea and dry cough. He denied haemoptysis, constitutional symptoms or diurnal variation. He took omeprazole, amlodipine and ezetimibe for a long-standing history of dyspepsia, hypertension and hypercholesterolaemia. He was an ex-smoker with a 30 pack-year history. He reported monophasic colour change in his fingers in the cold, but denied any other connective tissue disease (CTD) symptoms. He denied any significant environmental exposures such as organic dusts or moulds. His vital signs were normal. There was evidence of mechanic’s hands (a hyperkeratotic eruption with fissuring and cracking on the palmar and radial aspects of the fingers, strongly associated with idiopathic inflammatory myopathies) but no other features of CTD or clubbing. Bibasal fine inspiratory crepitations were audible on chest auscultation. Cardiovascular examination was normal. Initial investigations revealed pancytopenia (figure 1) with unremarkable liver and renal function, prompting referral to local haematology services for further assessment. Figure 1 Baseline blood tests at presentation. Abnormal values are highlighted in bold. Pancytopenia was evident, in the context of normal B12, folate and ferritin. Lung function testing revealed a restrictive pattern with significantly reduced gas transfer (figure 2), while 6 min walk test demonstrated baseline saturations of 95% on air dropping to 77% on exertion, achieving 260 m (48% of theoretical distance). Figure 2 Lung function tests at baseline and 4-month follow-up. Spirometry demonstrated a restrictive pattern with reduction in gas transfer factor. KCO, carbon monoxide transfer coefficient; TLCO, transfer factor for carbon monoxide. Chest X-ray showed prominent interstitial lung markings in the mid and lower zones (figure 3). High-resolution CT thorax (HRCT) demonstrated centrilobular emphysema throughout the lungs and a basally predominant interstitial process with features suggestive of non-specific interstitial pneumonia (NSIP) (figure …

Allogeneic stem-cell transplantation is an important curative strategy in acute myeloid leukaemia (AML) consequent upon the development of a graft-versus-leukaemia (GVL) effect. Disease relapse is the major cause of transplant failure and novel therapeutic strategies are required in patients with measurable residual disease (MRD) post-transplant. Recognizing that full donor T cell chimerism serves as a biomarker of GVL and that mixed donor T cell chimerism reflects the presence of bi-directional tolerance, we report the first prospective correlation of the impact of post-transplant T cell chimerism and MRD in patients allografted for AML/MDS. Methods: 186 patients from FIGARO, a prospective randomized trial of reduced intensity conditioning regimens in AML/MDS, were alive and relapse free, at the first MRD timepoint and provided post-transplant bone marrow samples for flow cytometric MRD monitoring (day+42, month+3/+6/+9/+12) and peripheral blood samples for T cell chimerism analysis (3-monthly during the first year). Results were not available to clinicians. Flow cytometric MRD incorporating an unsupervised immunophenotypic analysis approach was used on 778 sequential samples. The prognostic significance of post-transplant MRD from each sampling timepoint was assessed by landmark analysis. Results: 29 (15.6%) patients were MRD+ at one or more timepoints in the first year after transplant. The presence of post-transplant MRD was associated with reduced OS (HR:2.19, p=0.0026) and RFS (HR:5.36, p Next, we examined the impact of T-cell chimerism, and post-transplant MRD on outcomes. In patients with mixed-donor T-cell chimerism (MDTC) at month+3 or +6, the presence of post-transplant MRD (preceding or at time of first MDTC) was associated with decreased OS (p=0.001) and RFS. Specifically, 2yr RFS in MRD+ patients was 23.1% (95%CI:5.6-47.5), compared to 63.6% (95%CI:44.9-77.5) in patients who were MRD negative (p=0.004) (Figure). In contrast, in 48 patients with full donor T-cell chimerism (FDTC) at months 3 and 6, only 5 patients were MRD+ post-transplant and their outcomes were equivalent to patients who were MRD negative (FDTC/MRD negative 2yr RFS: 80.9% (95% CI:65.3-90.0)). Downregulation of HLA class II molecules on AML blasts after transplant may result in immune evasion from GVL: we examined whether this had an additional impact on outcome in post-transplant MRD+ patients. Both RFS and OS were significantly lower in MRD+ patients when MRD+ blasts had down-regulated HLA-DR expression. In MRD+ patients, 2yr OS was 20.0% (95%CI:3.1-47.5) in those with HLA-DR down-regulation, versus 57.9% (95%CI 33.2-76.3) in those without (p=0.001). Conclusion We demonstrate that dynamic assessment of post-transplant MRD is an important predictor of outcome in patients allografted for AML/MDS, with additional prognostic value to pre-transplant MRD assessment. Post-transplant MRD and T-cell chimerism results are most informative when combined, underlining the importance of a GVL effect in AML/MDS. This suggests post-transplant strategies which result in FDTC may improve outcomes in patients allografted for AML/MDS. Our data also supports the clinical relevance of monitoring for leukemic immune escape as HLA-DR down-regulation identifies a post-transplant MRD positive subgroup at risk of almost inevitable relapse. Figure 1 Figure 1. Disclosures Loke: Novartis: Other: Travel; Janssen: Honoraria; Amgen: Honoraria; Pfizer: Honoraria; Daichi Sankyo: Other: Travel. Protheroe: Jazz Pharmaceuticals: Honoraria; Astellas: Honoraria; Kite Gilead: Honoraria. Dillon: Amgen: Other: Research support (paid to institution); Astellas: Consultancy, Other: Educational Events , Speakers Bureau; Jazz: Other: Education events; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: educational events; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Session chair (paid to institution), Speakers Bureau; Menarini: Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research Support, Educational Events. Craddock: Novartis Pharmaceuticals: Other: Advisory Board ; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Introduction The clinical manifestations of COVID-19 infection in recipients of allogeneic hematopoietic stem cell transplantation (HSCT) have been reported in multiple retrospective cohorts of patients, but there have been no prospective studies to date. Previous studies report that HSCT recipients are at higher risk, with cumulative incidence of death between 17-35%. Although an excessive pro-inflammatory viral response has been documented in the general population, its role in the immune incompetent HSCT setting has not been documented. We present a combined prospective and retrospective national study run through the UK IMPACT trial network to characterize the clinical and immunological features of COVID-19 infection in 96 adult and pediatric recipients of HSCT in the United Kingdom. Methods HSCT recipients of any age and transplanted for any indication, with an RT-PCR-proven COVID-19 infection, were eligible for this study. Patients within 72 hours of COVID-19 diagnosis, who had not received cytokine-targeted treatment, were recruited to a prospective cohort. All other patients were eligible for a retrospective cohort. Prospective patients provided blood samples within 72 hours of COVID-19 diagnosis, and again within 72 hours of clinical deterioration (defined as requirement for oxygen administration) if applicable. Follow-up data were collected on patients 30 and 100 days after COVID-19 diagnosis. Results 100 patients were recruited from 16 sites across the UK between May 2020-June 2021, comprising 12 in a prospective cohort and 88 recruited retrospectively. 96 patients were evaluable, as 4 proved ineligible post-registration. Patients were diagnosed with COVID-19 at a median of 11 months after HSCT. Patient/HSCT characteristics are shown Table 1. The most common symptoms associated with the onset of COVID-19 were fever in 8 prospective (73%) and 35 (41%) retrospective patients, followed by cough in 5 (45%) prospective and 35 (41%) retrospective patients and dyspnea in 4 (36%) prospective and 16 (19%) retrospective patients. 8 (73%) prospective and 40 (47%) retrospective patients were actively immunosuppressed at the time of COVID-19 infection. 16% of the patients had moderate/severe disease at baseline. At day 30 (±2 days) after COVID-19 diagnosis, 2 prospective and 8 retrospective patients continued to demonstrate SARS-CoV-2 positivity on respiratory PCR testing. The median time to viral clearance was 40 (IQR 17-78) days for the prospective and 34 (IQR 15-70) days for the retrospective cohort. Prolonged (more than 14 days) neutropenia was reported in 4 (5%) patients in the retrospective cohort, prolonged thrombocytopenia in 2 (18%) prospective and 11 (13%) retrospective patients. 1 retrospective patient developed secondary hemophagocytic lymphohistiocytosis, and graft rejection was reported in 1 (1%) retrospective patient, within 30 days of COVID-19 diagnosis. In the prospective cohort, 3 (27%) patients died, all by day 30, and all due to COVID-19. In the retrospective cohort, 13 (17%) patients died by day 30, rising to 18 (21%) by day 100, 61% of deaths were attributed to COVID-19. Lower baseline platelets (p=0.013, Mann-Whitney U test), lymphocytes (p=0.012), albumin (p=0.028), and higher baseline CRP (p=0.007), were seen in patients who died following COVID-19 diagnosis. Additionally, exploratory univariate logistic regression of the retrospective cohort found mortality at day 100 to be associated with increased age at diagnosis (OR 1.04, 95% CI 1.01-1.08, p=0.04), and no requirement compared with requirement for invasive ventilation (OR 0.02, 95% CI 0.00-0.16, p=0.001). The 11 prospective patients showed normal levels of interleukin (IL)-2, -4, -10, interferon gamma and tumor necrosis factor alpha at COVID-19 presentation. IL-6 was minimally raised (up to 127 pg/ml, nv Conclusion Our study confirms a significant mortality rate in patients affected by COVID-19 post HSCT and confirms age as well as requirement for invasive ventilation to be independent risk factors associated with death at day 100. Baseline laboratory data at disease presentation can identify patients at higher risk of COVID-19 related death. In the prospective cohort of our study, pathophysiology of the viral disease did not seem related to cytokine storm-mediated inflammation. Figure 1 Figure 1. Disclosures Protheroe: Jazz Pharmaceuticals: Honoraria; Astellas: Honoraria; Kite Gilead: Honoraria. Peggs: Autolus: Consultancy, Current equity holder in publicly-traded company. Craddock: Novartis Pharmaceuticals: Other: Advisory Board ; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding. Nicholson: BMS/Celgene: Consultancy; Kite, a Gilead Company: Other: Conference fees, Speakers Bureau; Novartis: Consultancy, Other: Conference fees; Pfizer: Consultancy. Amrolia: ADC Therapeutics: Other: Named inventor on a patent which is being transferred to ADCT.; Autolus: Patents & Royalties.

Cytarabine remains the backbone of therapy in acute myeloid leukemia (AML). The ability to assess intracellular cytarabine triphosphate (ara-CTP) levels in patients receiving cytarabine represents a major goal in the prediction of treatment response. This study, conducted within a clinical setting, aimed to assess ara-CTP levels in circulating peripheral blasts from non-M3 AML patients receiving cytarabine at one of three dosing levels, using a novel biosensor assay. Results from the initial 72 hours post-commencement were correlated with day 28 remission status, with feasibility parameters concurrently assessed. Intracellular ara-CTP was detectable in ex vivo blasts post-treatment for standard-dose (SD) and high-dose (HD) patients (p0.05), and quantification revealed a 27-fold increase in intracellular steady-state concentration between the two dosing levels. For low-dose cytarabine, high rates of patient discharge and low intracellular concentrations limited analysis; however, assessment of intracellular ara-CTP concentration was achievable in a dwindling population of blasts for SD and HD treatment cohorts, with 4 hours post-treatment commencement potentially being most predictive of clinical response (r = -0.912, p = 0.0113). Concurrent assessment of peripheral leukemia-associated immunophenotype (LAIP)-positive cells revealed a decline in burden (0-72 hours), which correlated with remission status (p0.05). Unexpectedly high rates of night sampling led to challenges associated with sampling rates, but did not have an impact on patient compliance. Additional training of night staff improved feasibility substantially. Multiple peripheral sampling during the initial 72 hours of treatment is feasible in newly diagnosed patients, and ara-CTP is detectable over the initial 24 hours, facilitating prediction of chemosensitivity of leukemic blasts to cytarabine.

INTRODUCTION: Allogeneic stem cell transplantation (allo-SCT) is an important curative strategy in adults with high risk acute myeloid leukemia (AML) and myelodysplasia (MDS). Disease relapse represents the major cause of treatment failure and whilst retrospective analyses have identified that pre-transplant measurable residual disease (MRD) is an important predictor of transplant outcome this has never been examined prospectively. The advent of reduced intensity conditioning (RIC) regimens has substantially increased the number of older adults eligible for allo-SCT but the optimal RIC regimen in high risk AML remains unknown. Registry data have demonstrated improved outcomes using a sequential transplant regimen utilizing cytosine arabinoside (araC)/amsacrine (AMSA) cytoreduction followed by a fludarabine (Flu)/busulfan (Bu) based RIC regimen (FLAMSA-Bu). However, although the FLAMSA-Bu regimen is now widely used in adults with high risk AML and MDS its benefit has not been evaluated in a randomized trial. We report the results of a randomized trial evaluating the FLAMSA-Bu regimen compared with standard RIC regimens which also represents the first prospective evaluation of the impact of pre-transplant MRD levels on transplant outcome. PATIENTS AND METHODS: 244 patients (median age 59 yrs) with high risk AML (n=164) or high risk myelodysplasia (n=80) were randomized 1:1 to a control arm determined by investigator's choice of either Flu/B2/ATG (Flu, Bu 3.2 mg/kg x 2 days, ATG 2.5 mg/kg x 2 days); Flu/Mel/Alemtuzumab (A) (Flu, Mel 140 mg/m2, A 50 mg) or Flu/Bu2/A (Flu, Bu 3.2 mg/kg x 2 days, A 50 mg) versus an experimental arm of FLAMSA-Bu (Flu, araC 2g/m2 x 4 days, AMSA 100mg/m2 x 4 days, Bu -total dose 11.2 mg/kg). Patients over the age of 60 received an adjusted FLAMSA-Bu regimen utilising a reduced dose of araC (1mg/m2 x 4 days) and a total Bu dose of 6.4 mg/kg. Patients were transplanted using either an HLA identical sibling (n=49) or matched (10/10 or 9/10) unrelated donor (n=195). All patients received cyclosporine GVHD prophylaxis. 155 patients with AML were in CR1 or CR2 at the time of transplant and 9 had primary refractory disease. MRD was monitored by flow cytometry (applying different-from-normal analysis when no diagnostic/relapse leukemic aberrant immunophenotype was available). Pre-transplant MRD levels were measured up to four weeks prior to transplantation in 201 patients (MRD positive = 80 (40%), MRD negative = 94 (47%), inadequate sample = 27 (13%)). MRD results were not reported to clinicians. The primary outcome was overall survival. RESULTS: Baseline characteristics including CR1/CR2 status, adverse cytogenetics and MRD levels were similar between regimens. Median follow up was 35 months. Transplant outcomes were comparable between patients allografted in the control and FLAMSA-Bu arms. 2 yr overall survival (OS) and cumulative incidence of relapse (CIR) were 61% and 30% respectively in the control arm vs 62% and 26% for the FLAMSA-Bu arm. Transplant related mortality at 100 days was 3.0% in patients allografted using the control regimen vs 14% in patients allografted using the FLAMSA-Bu regimen and 17% vs 21% at 1 year. In the study cohort pre-transplant MRD positivity was associated with both an increased CIR compared to patients testing MRD negative (2 yr CIR 42% vs 19%, p=0.009) and decreased OS (2 yr OS 52% vs 71%, p=0.048). The FLAMSA-Bu regimen failed to improve OS or reduce CIR in either MRD positive or MRD negative patients. CONCLUSIONS: This trial, the largest randomized trial of RIC regimens in AML to date, did not detect any benefit of intensification of the conditioning regimen in adults with high risk AML or MDS. Specifically, the FLAMSA-Bu regimen was not associated with improved transplant outcome in patients who were MRD positive pre-transplant. These data include the first demonstration in a prospective analysis that the presence of pre-transplant MRD measured in real time is associated with reduced OS consequent upon an increased risk of disease relapse. Further randomized studies of novel conditioning regimens in adult AML, crucially with integrated MRD studies, are now required but these results support exploration of alternative strategies, such as pre or post-transplant pharmacological intervention, as the most promising strategy to reduce the risk of disease relapse post allograft. Disclosures Russell: Jazz: Consultancy, Honoraria, Speakers Bureau; DSI: Consultancy, Honoraria, Speakers Bureau; Pfizer Inc: Consultancy, Honoraria, Speakers Bureau; Astellas: Consultancy, Honoraria, Speakers Bureau. Freeman:Jazz Pharmaceuticals: Speakers Bureau. OffLabel Disclosure: We report data using the combination of fludarabine, busulphan, amsacrine and cytosine arabinsoide as a conditioning regimen in patients allografted for high risk acute myeloid leukemia

Non-myeloablative allogeneic hematopoietic cell transplantation (HCT) offers a potentially curative therapy for older patients with hematologic malignancies. However, the treatment modality is underutilized and, to date, there are only limited data on outcomes in people older than 60 years. This study describes the toxicities and outcomes of non-myeloablative allogeneic HCT, conditioned with low-dose total body irradiation with or without fludarabine, in patients aged 60-75 years enrolled in prospective multicenter clinical trials. Increasing age was not associated with adverse outcome. Relapse risk and comorbidity burden predicted survival; fit patients with low risk of disease relapse did well after transplant regardless of age. Despite demonstrating the feasibility of non-myeloablative allogeneic HCT in patients aged 60-75 years, the study raises important questions regarding how best to manage older patients with high-risk hematologic malignancies and how to optimize our approach to allogeneic HCT in this age group.

The clinical course of 2009 H1N1 influenza in Allo-SCT patients is unknown. Data were collected in the UK from October 2009 to April 2010 on laboratory-confirmed cases of H1N1 influenza in Allo-SCT recipients. H1N1 infection was diagnosed in 60 patients, median age 42 years, at a median of 10 months post-SCT. Twenty-one patients (35%) developed pneumonia and nine (15%) required admission to intensive care units. Actuarial mortality was 7% at 28 days and 19% 4 months post-diagnosis of 2009 H1N1 influenza. Increasing age and pre-existing lung disease were risk factors for pneumonia (P=0.006 and 0.037, respectively); older age was a risk factor for death (P=0.012). Morbidity and mortality from 2009 H1N1 influenza in SCT patients exceeds that of immunocompetent patients, but parallels that in other critically ill hospitalised cohorts; the elderly and those with chronic pulmonary disease are at greatest risk.