allo-HSCT For Acute Myeloid Leukemia Research Articles

Post-transplant cyclophosphamide and early mixed donor Chimerism in myeloid malignancies; a single-center experience

BackgroundAllogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only curative option for high-risk myeloid malignancies. Post-transplant cyclophosphamide (PT-Cy) has proven to be effective for graft versus host disease (GVHD) prophylaxis. Given that graft-versus-tumor (GVT) effect plays a major role in reducing the risk of disease relapse, the application of PT-Cy must balance the risk of relapse. Mixed chimerism (MC) refers to a state of concurrent presence of recipient and donor cells post allo-HSCT which may precede relapse disease. ObjectiveWe investigated the impact of PT-Cy on early MC (EMC) and disease relapse in patients with a myeloid malignancy post allo-HSCT. Study designThis retrospective single-center study included patients that underwent allo-HSCT between 2015 and 2021. Patient and disease characteristics were collected from the electronic health records. EMC was defined as <95% donor cells at day 90–120 post allo-HSCT. ResultsA total of 144 patient that received an allo-HSCT were included in the study. One hundred and eight (75%) patients received PT-Cy as part of the GVHD prophylaxis regimen. The majority underwent allo-HSCT for acute myeloid leukemia (62%) or myelodysplastic syndrome (31%). Sixty-five percent received allo-HSCT from a matched unrelated donor transplant and 65% received a myeloablative conditioning regimen. A lower rate of chronic GVHD (p = 0.03) and a higher rate of EMC (p = 0.04) were observed in patients that received PT-Cy. PT-Cy was not associated with overall survival (OS) and relapse-free survival (RFS). Multivariable analysis identified measurable residual disease status (p = 0.003), hematopoietic cell transplantation-specific comorbidity index (p = 0.012) and chronic GVHD (p = 0.006) as independent prognostic variables for OS. AML-adverse risk (p = 0.004) and EMC (p = 0.018) were independently prognostic for RFS. While EMC overall was not significantly associated with higher risk of relapse, EMC was associated with shorter RFS within adverse-risk AML patients. ConclusionOur study shows that PT-Cy was associated with an increased risk of EMC. The predictive value of EMC for relapse remains unclear and may depend on the underlying disease, which should be validated in a larger cohort.

Impact of prior solid tumor on outcomes of allogeneic hematopoietic stem cell transplantation for AML or MDS.

7048 Background: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) offers a definitive treatment of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Prior solid tumor (PST) is felt to portend a worse post-transplant prognosis. The aim of this study was to evaluate the impact of PST history on allo-HSCT outcome. Methods: We retrospectively identified patients with AML or MDS who underwent first allo-HSCT at the Fred Hutchinson Cancer Research Center between 2010 and 2018. Cox regression analysis was used to identify factors associated with mortality among patients with PST, and to compare outcomes of patients with and without PST. Multivariable models were fit, adjusting for cytogenetic risk level, time from PST diagnosis to transplant, receipt of reduced-intensity conditioning (RIC), and age at transplant. Survival estimates were obtained using the Kaplan-Meier method. Results: 1198 patients were included for analysis, of which 101 had a history of PST. After a median follow up of 1301 days among survivors, there was a total of 558 deaths and 322 relapses among all patients. Patients with history of PST were older (62.5 vs 54.9 yrs) and a higher proportion received RIC (52.5% vs 27.3%). The most common PSTs included breast (38/101, 38%), prostate (13/101, 13%), colon (9/101, 9%), thyroid (8/101, 8%), and uterine (7/101, 7%). Among those with known staging (n = 66), stage 1 (28/66, 42%) was the most common, followed by stage 2 (17/66, 26%) then stage 3 (15/66, 23%). The most common therapies provided were surgery (95/101, 95%), cytotoxic chemotherapy (41/101, 41%), radiation (45/101, 45%), and endocrine therapy (25/101, 25%). The unadjusted hazard ratio (HR) of mortality in the PST group relative to the non-PST group was 1.10 (95% confidence interval [CI] 0.83-1.47, p = 0.52). After adjustment for patient age, disease, patient/donor CMV status, KPS, cytogenetic risk, source of stem cells, and donor type, the adjusted HR was 0.91 (95% CI 0.68-1.22, p = 0.59). The unadjusted HR for relapse was 1.15 (95% CI 0.79-1.67, p = 0.48), and adjusted HR was 1.11 (0.76-1.11, p = 0.61). Among patients with PSTs, high-risk cytogenetics were associated with increased mortality (adjusted HR = 2.21; 95% CI 1.16-4.2, p = 0.016) and relapse (adjusted HR = 1.91; 95% CI 1.01-3.60, p = 0.047). Longer time from PST diagnosis to transplant led to a numerically increased mortality in the unadjusted (HR = 1.05; 95% CI 1.00-1.11, p = 0.057) and adjusted (HR = 1.05; 95% CI 1.00-1.11, p = 0.69) models treating time as a continuous linear variable. Conclusions: In our study, a history of PST did not impact overall survival or relapse rate among patients who underwent first allo-HSCT for AML or MDS. As in the overall population, post-transplant outcomes were primarily driven by cytogenetic risk level. However, it is likely that selection of patients with PST for transplantation was biased based on overall risk assessment.

Donor Lymphocyte Infusion Is a Feasible Way to Improve Survival in Patients with Acute Myeloid Leukemia and Myelodysplastic Syndromes Who Relapse after Allogeneic Stem Cell Transplantation

Introduction: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) yet the major cause of death remains relapse after transplantation which occurs in 30-70% of patients for whom the prognosis is dismal. Since the 1990's donor lymphocyte infusion (DLI) has been proven able to induce remission after allo-HSCT and the use of therapeutic DLI at relapse has widely increased. The immunological mechanism in DLI is primarily T-cell-mediated graft-versus-leukemia (GVL) effect driven by genetic differences between donor and recipient in minor and major histocompatibility antigens. DLI treatment at relapse can additionally reverse T-cell exhaustion and increase T-cell receptor diversity, both of which are GVL-enhancing mechanisms. Risks and complications with DLI-treatment are primarily graft-versus-host disease (GVHD). Though dose escalation schedules have been suggested to increase the GVL-effect while minimizing the risk of GVHD, uniform therapeutic algorithms are still lacking, treatment is often individually scheduled, and outcome results are often disappointing with reported 2-year overall survival rates at 14-29% in AML relapse patients (Greiner J, Götz M, Bunjes D, Hofmann S, Wais V. Immunological and Clinical Impact of Manipulated and Unmanipulated DLI after Allogeneic Stem Cell Transplantation of AML Patients. J Clin Med. 2019;9(1):39). During the last decade, treatment with the hypomethylating agent azacitidin (Aza) has become another potential treatment in patients with myeloid malignancies. Immunological mechanisms of GVL in Aza-treatment for relapse include epigenetically reactivation of pro-apoptotic pathways and demasking of tumor-antigens while increased expression of regulatory T-cells protects from GVHD. In recent years DLI and Aza have been used for synergistical effect post-HSCT relapse both in patients who are un-fit to receive high-dose cytoreductive therapy as well as consolidation after reinduction. The aim of this analysis is to report results of retrospective single center-study of patients treated with DLI +/- Aza over a period of twenty years.Methods: Between 2001 and 2020 50 adult patients with relapse after allo-HSCT for AML(n=38) or MDS (n=12) were treated with DLI at the Department of Hematology, Transplant Unit, at Rigshospitalet, Copenhagen University Hospital, table 1. Only patients free from active GVHD were selected as DLI-candidates. Median follow-up time was 57 (1-170) months. Reinduction with high-dose chemotherapy was administered in 35 (70%) of patients prior to DLI and 34 (68%) patients were in complete morphological remission (CR) before DLI. DLI-products were unmanipulated and obtained from leukapheresis of unstimulated peripheral blood in matched related or unrelated donors of the original stem cell graft. Patients received a median of 3 (1-5) doses of DLI with median total doses of 6,1x10 7 (5x10 6- 4,65x10 8) CD3 postive T-cells per kg. Aza was used together with DLI from 2012 and administrered in 28 (56%) patients with a median of 6 (2-20) cycles. Reported outcomes are overall survial (OS) and relapse-free survival (RFS) in patients in CR prior to DLI.Results: At end of follow-up 20 patients were alive, 11 of these in CR and 2 in partial remission. In 7 patients, DLI was discontinued due to the development of GVHD after 1-2 doses, 6/7 of these patients had unrelated donors. Overall, 2 (4%) patients died from GVHD after DLI. Seven patients received a second HSCT after DLI treatment and were censored at this date in survival analyses. Figure 1a+b shows OS in all patients (n=50) and RFS in patients in CR prior to DLI (n=34). 2-year OS was approximately 59% and 5-year OS was 20%. 2-year RFS was approximately 32% and 5-year RFS was 8%. None of the analyzed baseline factors showed significant associations to the probability of OS, table 2, or RFS (data not shown). Reinduktion before first DLI and increasing doses of transplanted CD3 T cell per kg showed trends towards superior survival probability but failed to reach significant levels, possibly due to the limited patient number.Conclusion: Treatment vith DLI +/- Aza is effective and safe as relapse-treatment after allo-HSCT in myeloid diseases. In selected patients, a short-term (2-year) overall survival of 59% is achieved, and 20% of the patients remain long term survivors. [Display omitted] DisclosuresFischer-Nielsen: A.F.N. is employee and shareholder of StemMedical A/S, a biotech company working with cell-enriched fat grafting.: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company.

Allo-HSCT for acute myeloid leukemia with myelodysplastic-related changes: a clinical analysis

目的评价异基因造血干细胞移植（allo-HSCT）治疗急性髓系白血病伴骨髓增生异常相关改变（AML-MRC）的疗效及预后因素，分析AML-MRC患者基因突变谱系并探讨影响移植预后的分子生物学特征。方法对2006年至2020年于中国医学科学院血液病医院接受allo-HSCT的75例AML-MRC患者进行回顾性分析。将75例患者分为：H组［既往有骨髓增生异常综合征（MDS）或MDS/骨髓增殖性肿瘤（MPN）病史］、C组（新诊断的AML-MRC伴MDS相关细胞遗传学异常）和M组（新诊断的AML-MRC伴多系发育异常），分析三组患者临床特征差异以及对移植预后的影响。对43例患者行骨髓靶向二代测序（137个基因）。结果①75例AML-MRC患者，男41例，女34例，中位年龄41（18～56）岁，中位随访时间为35（95％ CI 30～49）个月，中位总生存（OS）时间为78个月（95％CI 23个月～未达到）。移植后3年OS率为57.1％（95％CI 45.6％～71.4％），无事件生存（EFS）率为52.0％（95％CI 40.8％～66.1％），累积复发率（CIR）为26.8％（95％CI 16.6％～30.0％），移植相关死亡率（TRM）为22.7％（95％ CI 13.2％～33.8％）。多因素分析显示，移植前处于非第1次完全缓解（CR1）状态是移植后OS和EFS的独立危险因素。影响OS的独立危险因素还包括−5/5q−染色体核型异常、移植后未发生慢性移植物抗宿主病（慢性GVHD）。②75例患者中H组59例（78.7％），其中20例转化为白血病（转白）前曾接受去甲基化药物治疗；C组9例（12.0％），M组7例（9.3％）。M、H、C组移植后3年OS率分别为71.4％（95％CI 44.7％～100.0％）、55.0％（95％CI 41.8％～72.5％）、55.6％（95％ CI 31.0％～99.7％）（P＝0.700），EFS率分别为71.4％（95％CI 44.7％～100.0％）、46.5％（95％CI 34.0％～63.8％）、55.6％（95％CI 31.0％～99.7％）（P＝0.600）；原发性AML-MRC与继发性AML-MRC相比，移植后3年OS、EFS率差异无统计学意义［61.9％（95％CI 41.9％～91.4％）对55.0％（95％ CI 41.8％～72.5％），P＝0.600；61.9％（95％CI 41.9％～91.4％）对46.5％（95％CI 34.0％～63.8％），P＝0.400］。转白前接受去甲基化治疗（20例）与未接受去甲基化治疗（39例）患者比较，转白时间差异无统计学意义［195（16～937）d对162（9～3167）d，P＝0.804］，且两组患者OS和EFS差异无统计学意义（P＝0.400，P＝0.700）。③对43例（57.3％）患者骨髓样本行二代基因测序，共发现73个突变类型，检出率最高的是U2AF1（11例，25.6％），其他检出率>10％的突变包括RUNX1（10例，23.3％）、NRAS（10例，23.3％）、ASXL1（6例，14.0％）、PTPN11（5例，11.6％）、TET2（5例，11.6％）。单因素分析显示U2AF1［P＝0.875，HR＝1.110（95％ CI 0.295～4.195）］、RUNX1［P＝0.685，HR＝0.728（95％ CI 0.157～3.375）］、NRAS［P＝0.919，HR＝0.923（95％CI 0.196～4.334）］突变对移植后OS没有影响。结论−5/5q−染色体异常、未发生慢性GVHD、移植前非CR1状态是影响AML-MRC患者移植后OS的独立危险因素；MHC亚组分类不是影响移植预后的因素；去甲基化药物治疗可能无助于延缓MDS患者转白以及延长移植后OS期。

Dissecting the AML Patients with FLT3-ITD into High-Risk and Low-Risk Relapsed Ones Based on Pre-Transplantation Minimal Residual Disease Determined By Multiparameter Flow Cytometry

Acute myeloid leukemia (AML) with fms-related tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD) often have a poor clinical prognosis. Though several previous studies had demonstrated that allogeneic hematopoietic stem cell transplantation (allo-HSCT) could improve its outcomes, there were a number of studies indicated that FLT3 mutational status was still an independent risk factor for adverse outcomes after allo-HSCT in AML. The minimal residual disease prior to transplantation (pre-MRD) has been proved to be able to predict leukemia relapse after allo-HSCT. However, due to limitation of detecting techniques, FLT3-ITD is not a very suitable marker of MRD. Thus, in this study we attempted to investigate that impact of pre-MRD determined by multiparameter flow cytometry (MFC) on the transplant outcomes of AML patients with FLT3-ITD mutation. Total 20 patients who received human leukocyte-antigen (HLA)-matched sibling donor transplantation (MSDT) and 63 patients who received unmanipulated haploidentical HSCT (haplo-HSCT) were enrolled in this study. Pre-MRD was determined using MFC. The results showed that all patients acquired stable neutrophil engraftment. Patients who received haplo-HSCT with positive pre-MRD had a longer period of time to neutrophil engraftment compared to those with negative pre-MRD (median: 15 days vs. 13 days, P=0.033). Patients undergoing MSDT or haplo-HSCT were classified into four groups based on the status of pre-MRD: group 1, with positive pre-MRD before MSDT; group 2, with negative pre-MRD before MSDT; group 3, with positive pre-MRD before haplo-HSCT; group 4, with negative pre-MRD before haplo-HSCT. The cumulative incidence of grade II-IV° acute graft-versus-host disease (aGVHD) and chronic GVHD were comparable between group 1 and 2 as well as group 3 and group 4 (P>0.05). Through Kaplan-Meier analysis, it showed that patients of group1 had the worst clinical outcomes. They had the highest cumulative incidence of relapse (2-year CIR, 75.0%), the lowest leukemia-free survival (2-year LFS, 25.0%) and the overall survival (2-year OS, 25.0%) among all four groups. The other three groups of patients had the comparable CIR (2-year CIR: group 2 vs. group 3 vs. group 4, 12.5% vs.30.3% vs. 20.9%, P>0.05) and LFS (2-year LFS: group 2 vs. group 3 vs. group 4, 87.5% vs. 62.5% vs. 66.5%, P>0.05). Multivariate analysis indicated that disease status (>CR1) and pre-MRD were associated with a higher CIR and a lower LFS when patients were classified into above four groups determined by MFC and transplant type. These results indicated that the AML patients with FLT3-ITD were able to be dissected into high-risk and low-risk relapsed groups based on pre-transplantation MRD determined by MFC. In addition, haplo-HSCT might overcome the negative impact of pre-MRD on patient outcomes compared to MSDT. DisclosuresNo relevant conflicts of interest to declare.

Mesenchymal stem cells enhance the impact of KIR receptor-ligand mismatching on acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation in patients with acute myeloid leukemia but not in those with acute lymphocytic leukemia.

Killer cell immunoglobulin-like receptor (KIR) receptor-ligand mismatch has been shown to be protective for acute and chronic graft-versus-host disease (aGVHD, cGVHD) following allogeneic hematopoietic stem cell transplantation (allo-HSCT) for acute leukemia. Mesenchymal stem cells (MSC) have been considered as one of the most promising prophylaxis for severe GVHD. However, there are no prospective or retrospective studies determining whether they can work synergistically on GVHD. To investigate the potential influence of KIR matching and MSCs, and their synergism on aGVHD and cGVHD after allo-HSCT in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) patients. Data from 104 patients with AML and 50 patients with ALL treated with allo-HSCT in the transplantation unit were retrospectively analyzed. KIR genotyping was performed by the PCR-SSO method. The amplicons were quantified on the Luminex 200 flow analyzer and analyzed using the Quick-Type for Lifecodes software to generate KIR data. Cox proportional hazards models were used in multivariate analyses. KIR receptor-ligand matching was associated with an increased risk of grade II-IV aGVHD compared to KIR receptor-ligand mismatching (p<0.001) in AML patients, but KIR ligand-mismatching had no significant effect on aGVHD or cGVHD in ALL patients. In contrast, MSCs reduced the incidence of grade II-IV aGVHD in both AML and ALL patients (AML: p=0.006; ALL: p=0.008) regardless of KIR mismatching. The combination of KIR receptor-ligand mismatch and MSC transplantation significantly suppressed grade II-IV aGVHD occurrence in AML patients (p=0.039). In the KIR mismatch group, the incidence of aGVHD was 2.8% in patients receiving MSC compared to 14.6% in those who did not (p=0.047). KIR receptor-ligand mismatch, MSC transplantation and their combined use significantly reduced the risk of aGVHD after allo-HSCT. These data provide a clinically applicable strategy to reduce aGVHD, thus improving allo-HSCT outcome.

Donor lymphocyte infusions after first allogeneic hematopoietic stem-cell transplantation in adults with acute myeloid leukemia: a single-center landmark analysis

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is potentially curative for acute myeloid leukemia (AML). The inherent graft-versus-leukemia activity (GvL) may be optimized by donor lymphocyte infusions (DLI). Here we present our single-center experience of DLI use patterns and effectiveness, based on 342 consecutive adult patients receiving a first allo-HSCT for AML between 2009 and 2017. The median age at transplantation was 57 years (range 19–79), and the pre-transplant status was active disease in 58% and complete remission (CR) in 42% of cases. In a combined landmark analysis, patients in CR on day +30 and alive on day +100 were included. In this cohort (n=292), 93 patients received cryopreserved aliquots of peripheral blood-derived grafts for DLI (32%) and median survival was 55.7 months (2-year/5-year probability: 62%/49%). Median survival for patients receiving a first dose of DLI “preemptively,” in the absence of relapse and guided by risk marker monitoring (preDLI; n=42), or only after hematological relapse (relDLI; n=51) was 40.9 months (2-year/5-year: 64%/43%) vs 10.4 months (2-year/5-year: 26%/10%), respectively. Survival was inferior when preDLI was initiated at a time of genetic risk marker detection vs mixed chimerism or clinical risk only. Time to first-dose preDLI vs time to first-dose relDLI was similar, suggesting that early warning and intrinsically lower dynamics of AML recurrence may contribute to effectiveness of preDLI-modified GvL activity. Future refinements of the preemptive DLI concept will benefit from collaborative efforts to diagnose measurable residual disease more reliably across the heterogeneous genomic spectrum of AML.

Myeloablative intravenous busulfan-containing regimens for allo-HSCT in AML or MDS patients over 54years old: combined results of three phase II studies.

An optimal pretransplant conditioning regimen for allogeneic hematopoietic stem cell transplantation (allo-HSCT) in older adults has not been established. Three prospective multicenter phase II studies were conducted, in which 142 patients older than 54years (median age, 61years; range 55-70years) with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) received a myeloablative dose of intravenous busulfan (ivBu, 12.8mg/kg) along with fludarabine (180mg/m2) ± low dose total body irradiation for allo-HSCT between September 2009 and February 2013. A total of 103 AML and 39 MDS patients including 21 related bone marrow (BM) or peripheral blood (PB), 50 unrelated BM, and 71 unrelated cord blood (UCB) transplantation were enrolled. Grade 3 or greater toxicities were observed in 105 patients. Neutrophil engraftment was achieved in 70 out of the 71 related PB/BM or unrelated BM recipients, and 61 out of the 71 UCB recipients. The cumulative incidence rates of relapse and non-relapse mortality after 2years were 24.0 and 24.1%, respectively. The overall and event-free survival rates at 2years were 53.3 and 47.4%, respectively. The myeloablative dose of ivBu was well tolerated without increased toxicity-related mortality in older adults who underwent allo-HSCT with any donor source.

Clinicopathological features of myeloid sarcoma and DLBCL in the breast: a comparative study

Objective: To study the clinicopathological features, diagnosis and differential diagnosis of myeloid sarcoma of the breast. Methods: Ten cases of myeloid sarcoma (MS) and 19 cases of diffuse large B cell lymphoma (DLBCL) of the breast were selected from Peking University People's Hospital from February 2005 to September 2019. The cases were evaluated by microscopy and immunohistochemistry basing on WHO classification (2008 and 2017). Results: For the 10 cases of MS, the mean and median age was 33.8 and 31 years (range 23 to 47 years) respectively. All patients presented with breast masses; six presented with B symptoms (6/10); and LDH level was elevated in four patients. The largest tumor dimension was 1.0 to 5.3 cm (mean 2.7 cm). All 10 patients had history of acute myeloid leukemia (AML), and in one patient, the AML occurred after chemotherapy for hydatidiform mole. One case was classified as M0, four were M2, two were M4 and three were M5. For the AML, all patients received chemotherapy and nine were treated by allogeneic hematopoietic stem cell transplant (allo-HSCT) and the breast masses occurred4 months to 2 years post-transplant. Using Ann Arbor staging, five cases were stage Ⅰ, three were stage Ⅱ, and 2 were stage Ⅳ. The MS was found in the left breast (two cases); right breast (three cases) and both breasts (five cases). Lymphocyte in peripheral blood, B symptom and site of lesion had statistical significance between myeloid sarcoma and DLBCL(P<0.05). The tumor cells were primitive, expressing MPO, CD43, CD117, etc. All ten patients had follow-up information, and the median survival period was 14.4 months (range 1 to 50 months). Seven patients died. The prognosis of patients with MS was worse than DLBCL(P=0.002). Conclusions: The clinical history, pathologic morphology, immunophenotyping and molecular studies are very important for diagnosing MS tumors in the breast, and MS may occur after allo-HSCT for AML. Tumor resection, chemotherapy, radiotherapy and donor lymphocyte infusion are recommended for treatment. The prognosis is poor.

An Anti-CD300f Antibody Drug Conjugate Depletes Hematopoietic Stem Cells and Primary Acute Myeloid Leukemia (AML): Facilitating a Targeted Conditioning Regimen for Allogeneic Stem Cell Transplantation in AML

Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT) significantly reduces the rate of relapse in Acute Myeloid Leukemia (AML) but comes at the cost of significant Treatment Related Mortality (TRM). Despite the reduction in relapse overall, it remains common, especially in high risk groups. There is increasing evidence that many cases of relapse are driven by residual AML that can be detected with minimal residual disease techniques. A large proportion of the morbidity that prevents most patients accessing allo-HSCT is due to nonspecific toxic conditioning agents which are required to remove recipient Hematopoietic Stem and Progenitor Cells (HSPC) allowing for successful engraftment. We propose that a targeted conditioning agent against AML and HSPC can facilitate a reduction in relapse and TRM in allo-HSCT. CD300f is expressed evenly across HSPC subtypes. CD300f has equivalent transcription and protein expression as CD33 on AML. We have developed an anti-CD300f antibody which efficiently internalises into target cells. Harnessing this ability to internalise, we have generated a highly potent anti-CD300f Antibody Drug Conjugate (ADC) with a pyrrolobenzodiazepine (PBD) warhead which selectively depletes AML cell lines in vitro. Colony Forming Units were inhibited when cultured in the presence of the ADC. The anti-CD300f ADC has a rapid onset of action with >99% cytotoxicity of the AML cell line HL-60 occurring within 24 hours. The ADC synergises with fludarabine, making it a natural combination to use in a minimal toxicity conditioning regimen. The growth of subcutaneous tumours in mice engrafted with the AML cell line U937 was significantly reduced by a single dose of our ADC (at 150 μg/kg or 300 μg/kg). In a bone marrow engraftment model with HL-60, our ADC prolongs the survival at a single dose of 300 μg/kg (Fig 1A). In a humanised mouse model, 85% of all CD34+ cells and 90% of the primitive CD34+ CD38- CD90+ population were depleted with a single injection of our ADC at 300 μg/kg (Fig1 B). There was significant reduction in primary AML cells with a single injection of our ADC at 300 μg/kg (Fig 1C). This proof of principle work establishes an anti-CD300f ADC as an attractive potential therapeutic to develop which will reduce the toxicity of allo-HSCT and the relapse rate afterwards. We have demonstrated that CD300f is expressed across HSPC and AML. Our antibody to CD300f is efficiently internalised and capable of delivering a PBD warhead. Our ADC synergised with fludarabine and has a rapid onset of action. We have demonstrated that our ADC prolongs survival in mouse cell line models as well as depletes both HSPC and primary AML in vivo. A targeted conditioning agent has the potential to reduce relapse risk and toxicity of allo-HSCT in AML.

PCN291 ACUTE GRAFT VERSUS HOST DISEASE (GVHD), CHRONIC GVHD AND NON-RELAPSE MORTALITY (NRM) ASSOCIATED WITH MISMATCHED ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION (ALLO-HSCT): A SYSTEMATIC REVIEW

When HLA-matched stem cell grafts are unavailable, mismatched sources may be used, which are often associated with increased risk of serious complications. We reviewed published evidence to assess complications associated with mismatched allo-HSCT in acute myeloid leukemia (AML) patients by graft source. Embase®, MEDLINE®, Cochrane databases and conference abstracts (ASCO, ASH) were systematically reviewed in November 2018. Main inclusion criteria: studies from 2008-2018, AML patients, allo-HSCT, mismatched, interventional prospective studies which reported complications. Main exclusion criteria: non-interventional, retrospective studies. Two analysts reviewed each abstract and publication using PICOS (Patient, Intervention, Comparators, Outcomes, Study Design) criteria and all results were recorded using preferred reporting items for systematic reviews and meta-analyses (PRISMA) diagram. Rates of acute GVHD, chronic GVHD, and NRM were extracted and compared. A total of 1,335 records were reviewed and 8 studies satisfied inclusion criteria. The incidence of grade III-IV acute GVHD events was 10.0% among patients receiving UM171-expanded umbilical cord blood (UCB) grafts, 12.2% with NiCord®-expanded-UCB, 19.4% with StemEx®-expanded-UCB and ranged from 3.2-21.2% with other mismatched allo-HSCT (majority mixed bone marrow/peripheral blood). Incidence of moderate-severe chronic GVHD was found to be 0.0% with UM171-expanded-UCB at 24 months, 11.5% with NiCord®-expanded-UCB at 12 months, 19.0% in unmanipulated-UCB grafts at 12 months and ranged from 6.5-10.6% in mismatched allo-HSCT assessed at time points between 12-24 months. GVHD prophylaxis regimens varied across studies. NRM at 24 months was 4.7% with UM171-expanded-UCB, 20.3% with NiCord®-expanded-UCB, 19.0% with unmanipulated-UCB and 23.0-30.0% with alternate graft sources. Patients treated with UM171-expanded-UCB grafts experienced the lowest rates of NRM and moderate-severe chronic GHVD at 24 months relative to UCB and other mismatched graft sources identified in the SLR. Additionally, rates of grade III-IV acute GVHD were lower in UM171-expanded-UCB grafts compared to most, but not all, other sources identified.

Improved survival outcomes and restoration of graft-vs-leukemia effect by deferasirox after allogeneic stem cell transplantation in acute myeloid leukemia.

Deferasirox is an oral iron‐chelating agent having possible antileukemia and immune modulatory effects. Few reports have evaluated deferasirox in the setting of allogeneic hematopoietic stem cell transplantation (allo‐HSCT). We investigated the impact of deferasirox after allo‐HSCT in acute myeloid leukemia (AML). Of 326 consecutive patients undergoing allo‐HSCT in remission, analysis of 198 patients not receiving deferasirox revealed the negative prognostic effect of hyperferritinemia (≥1000 ng/mL) before and after allo‐HSCT on survival mainly due to increase in relapse. Of 276 patients with hyperferritinemia at 1 month after allo‐HSCT, 128 patients (46%) received deferasirox. Deferasirox induced a faster decline in serum ferritin level with a manageable safety profile, which significantly reduced relapse rather than nonrelapse mortality, resulting in better survival compared to patients not receiving deferasirox. Of note, the deferasirox group had a significantly higher incidence of chronic graft‐vs‐host disease, indicating improved graft‐vs‐leukemia (GVL) effects evidenced by the presence of suppressed regulatory T cells and sustained higher proportion of NK cells in peripheral blood. This study firstly demonstrates the improved survival and restoration of GVL effects of patients with AML by deferasirox, which also clarifies the detrimental effect of hyperferritinemia through after allo‐HSCT.

Post-Transplant Cyclophosphamide Versus Antithymocyte Globulin in Patients with Acute Myeloid Leukemia Undergoing Allogeneic Stem Cell Transplantation from One Antigen HLA-Mismatched Donors: A Retrospective Analysis from the Acute Leukemia Working Party of the EBMT

Introduction. Several alternative donor sources are currently available for patients who lack an HLA-matched related or unrelated donor, including haploidentical, cord blood and one antigen HLA-mismatched donors (9/10 mMUD). Use of post-transplant (allo-HSCT) cyclophosphamide (PTCY) as graft-versus-host disease (GVHD) prophylaxis allowed outcome improvements in the haploidentical setting. Its use has also been reported as a safe and feasible option in 9/10 mMUD transplants. However, to date, the main strategy used as GVHD prophylaxis in 9/10 mMUD allo-HSCT is in vivo T-cell depletion with antithymocite globulin (ATG). Data comparing these two different anti GVHD prophylaxis strategies in 9/10 mMUD allo-HSCT are limited.Methods. We compared PTCY versus ATG as GVHD prophylaxis in patients undergoing 9/10 mMUD allo-HSCT for which high-resolution HLA-allele typing was available in the ALWP/EBMT data registry. Included were adult patients (age>18 years) undergoing their first allo-HSCT for acute myeloid leukemia (AML) during the period 2007-2017. All disease status were allowed. Propensity score matching was performed to reduce and eliminate confounding effects. Each patient receiving PTCY was matched with two patients receiving ATG using the nearest neighbor or exact matching. Variables included in the propensity score model were: disease status at time of allo-HSCT, conditioning regimen, age, secondary AML, female donor to male recipient, source of stem cells, patient and donor CMV serology status.Results. Globally, 93 patients receiving PTCY were identified and matched with 179 patients receiving ATG. Secondary AML was reported in 20% and 18% of patients in ATG and PTCY groups, respectively. Most patients were in first complete remission at time of allo-HSCT (55% and 56% in PTCY and ATG group, respectively), while nearly 29% of patients in both groups underwent allo-HSCT with active disease. Ciclosporine (csA) and mycophenolate mofetil (MMF) were the systemic immunosuppressive agents more frequently associated to either PTCY (42%) or ATG (49%). Other well represented associated immunosuppressive agents were tacrolimus and MMF in ATG group (20%), followed by 14% of patients receiving csA alone with ATG. In PTCY group, 39% of patients received csA and methotrexate as associated immunosuppressive agents. Conditioning regimen was myeloablative in 50% of patients in both groups. Peripheral blood was the preferred stem cell source (91% in both groups). Among the variables not included in the propensity score model, some differences were observed between the two groups. Median follow-up was longer in the ATG group (27.4 versus 14.2 months, p<0.01). Gender was more frequently male in PTCY group (60% versus 45%, p<0.02). Median year of allo-HSCT was 2014 and 2015 in ATG and PTCY groups, respectively (p<0.01). Similar engraftment rates were observed for both groups (95% and 96% in PTCY and ATG groups, respectively). At 2 years, leukemia-free survival (LFS) was higher in patients receiving PTCY (55% vs 35%, p<0.05), severe (grade III-IV) acute GVHD was lower (9% vs 19%, p<0.04) and GRFS higher (37% vs 21%, p<0.02) as compared to patients receiving ATG, while no differences were observed in relapse incidence (RI)( 29% vs 37%, p=0.31), overall survival (OS, 56% vs 38%, p=0.06) and in non-relapse mortality (NRM) (16% vs 29%, p=0.06). Main causes of death were similarly distributed in both groups, with infectious complications being more frequently represented (25% and 22% in the PTCY and ATG groups, respectively). Grade II-IV acute GVHD (30% vs 32%, p=0.39) and chronic GVHD (39% vs 36%, p=0.35) were also similar in the two groups.Conclusions. In patients undergoing 9/10 mMUD allo-HSCT, use of PTCY as GVHD prophylaxis is a safe and feasible option, representing a possible valid and superior alternative to ATG. Use of PTCY, indeed, may ensure a lower incidence of severe acute GVHD and higher LFS and GRFS as compared to ATG. These registry based results may serve the basis for a prospective randomized trial comparing PTCY to ATG as anti GVHD prophylaxis in 9/10 mMUD allo-HSCT. DisclosuresHilgendorf:Novartis: Other: Travel support, Research Funding; Medac: Other: Travel support, Research Funding. Ganser:Novartis: Membership on an entity's Board of Directors or advisory committees. Finke:Novartis: Consultancy, Honoraria, Other: travel grants, Research Funding; Riemser: Consultancy, Honoraria, Research Funding; Medac: Consultancy, Honoraria, Other: travel grants, Research Funding; Neovii: Consultancy, Honoraria, Other: travel grants, Research Funding. Mohty:MaaT Pharma: Consultancy, Honoraria.

Effects of post-remission chemotherapy before allo-HSCT for acute myeloid leukemia during first complete remission: a meta-analysis.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is most frequently used to treat acute myeloid leukemia (AML). Whether patients should routinely receive consolidation chemotherapy before proceeding to transplant after achieving first complete remission (CR1) has been a subject of debate. We performed a systematic review and meta-analysis of studies examining the impact of post-remission chemotherapy before allo-HSCT in patients with AML in CR1. Six studies including 1659 patients were included in the meta-analysis. The pooled hazard ratio (HR) for overall survival was 0.9 (95% confidence interval [CI] 0.77-1.05, P = 0.182), and the pooled HR for leukemia-free survival was 0.87 (95% CI 0.75-1.0, P = 0.07). No survival advantage was observed for post-remission chemotherapy before reduced-intensity conditioning or myeloablative conditioning (MAC) allo-HSCT for AML in CR1. The pooled relative risk for relapse incidence (RI) was 1.02 (95% CI 0.82-1.28, P = 0.834). Post-remission chemotherapy before allo-HSCT did not significantly affect the RI in patients with AML in CR1. The analyses revealed no significant benefit of post-remission consolidation chemotherapy in patients who received allo-HSCT. We recommend proceeding to allo-HSCT as soon as CR1 is attained.

Integrated meta-omic analyses of the gastrointestinal tract microbiome in patients undergoing allogeneic hematopoietic stem cell transplantation

In patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT), treatment-induced changes to the gastrointestinal tract (GIT) microbiome have been linked to adverse outcomes, most notably graft-versus-host disease (GvHD). However, it is presently unknown whether this relationship is causal or consequential. Here, we performed an integrated meta-omic analysis to probe deeper into the GIT microbiome changes during allo-HSCT and its accompanying treatments. We used 16S and 18S rRNA gene amplicon sequencing to resolve archaea, bacteria, and eukaryotes within the GIT microbiomes of 16 patients undergoing allo-HSCT for the treatment of hematologic malignancies. These results revealed a major shift in the GIT microbiome after allo-HSCT including a marked reduction in bacterial diversity, accompanied by only limited changes in eukaryotes and archaea. An integrated analysis of metagenomic and metatranscriptomic data was performed on samples collected from a patient before and after allo-HSCT for acute myeloid leukemia. This patient developed severe GvHD, leading to death 9 months after allo-HSCT. In addition to drastically decreased bacterial diversity, the post-treatment microbiome showed a higher overall number and higher expression levels of antibiotic resistance genes (ARGs). One specific Escherichia coli strain causing a paravertebral abscess was linked to GIT dysbiosis, suggesting loss of intestinal barrier integrity. The apparent selection for bacteria expressing ARGs suggests that prophylactic antibiotic administration may adversely affect the overall treatment outcome. We therefore assert that such analyses including information about the selection of pathogenic bacteria expressing ARGs may assist clinicians in "personalizing" regimens for individual patients to improve overall outcomes.

High Disease-Free and Overall Survival Rate Following Allogeneic Hematopoietic Stem Cell Transplantation for FLT3-Mutated Acute Myeloid Leukemia Even in Non-Remission Status

[Background] FMS like tyrosine kinase 3 (FLT3) mutations occur in about 30% of patients with acute myeloid leukemia (AML). Patients with FLT3-mutated AML have a poor prognosis and are referred for early allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first complete remission (CR1). So far, there is still limited data available on allo-HSCT for FLT3-mutated AML in non-remission status.[Objective and method] To assess the clinical features and outcome of allo-HSCT for FLT3-mutated AML, we retrospectively analyzed patients underwent first allo-HSCT for FLT3-mutated AML excluding acute promyelocytic leukemia (FAB M3) from January 2011 to March 2016.[Result] During the study period, 332 patients received first allo-HSCT for AML in our institute. One hundred and thirty-eight were tested for the presence of FLT3-mutation and 35 showed positive results and were subjected to the analysis. The median follow-up day of survivors was 602 (101-1867). The median age of the patients was 55 years (range, 21-72). Twenty-one patients had de novo AML, 12 had AML with myelodysplasia related changes, and 2 had therapy related AML. Eighteen had normal karyotype, 4 had complex, and 13 had others. Seven were in remission (5 in CR1, and 2 in CR2), and 28 were in non-remission (8 in primary induction failure, 13 in relapse 1, and 7 in chemo naïve status). Twenty-nine patients used unrelated cord blood, 2 did unrelated bone marrow, and 4 did related peripheral blood stem cell as grafts. All but 1 received myeloablative pretransplant conditionings. At 2 years after transplantation, overall survival (OS), disease free survival (DFS), relapse rate (RR), and non-relapse mortality (NRM) of whole studied population were 65.9%, 50.2%, 28.4%, and 21.4%, respectively. Among those in non-remission before transplantation, OS, DFS, RR, and NRM at 2 years post-transplant were 62.2% (Figure 1A), 49.9%(Figure 1B), 24.3%, and 25.8%, respectively. Only younger age (<55 years) was the factor associated with better OS with statistical significance in multivariate analysis.[Conclusion] Our data indicated that allo-HSCT could overcome the poor prognosis of FLT3-mutated AML even for those in non-remission status, despite the profound chemo-resistant character of FLT3-mutated AML. [Display omitted] [Display omitted] DisclosuresIzutsu:Abbvie: Research Funding; Gilead: Research Funding; Celgene: Research Funding; Janssen Pharmaceutical K.K.: Honoraria; Eisai: Honoraria; Kyowa Hakko Kirin: Honoraria; Chugai Pharmaceutical: Honoraria, Research Funding; Takeda Pharmaceutical: Honoraria; Mundipharma KK: Research Funding.

Impact of NCCN Risk Stratification and Minimal Residual Disease on Allogeneic Hematopoietic Stem Cell Transplantation in Acute Myeloid Leukemia

Introduction: Cytogenetic abnormality is considered to be an independent prognostic factor in newly diagnosed acute myeloid leukemia (AML). However, recent studies have demonstrated that acquired gene mutations also play an important role in the pathogenesis and prognosis of AML. It has been well known that minimal residual disease (MRD) pre-conditioning has remarkable impact on disease-free survival (DFS) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in acute lymphoblastic leukemia, but the effect of MRD pre-transplant on allo-HSCT in AML is still unclear. Objective: In present study, the effect of NCCN risk stratification which has integrated gene mutations into cytogenetics as well as MRD pre-transplant on DFS after allo-HSCT in AML was studied in order to learn whether risk-directed conditioning and prevention of relapse are needed. Methods: Between April 2012 and March 2015, consecutive 258 patients with AML in complete remission (CR) (186 cases in CR1 and 72 cases in CR2) who underwent allo-HSCT in our hospital were analyzed retrospectively. The median age was 25 (1.8-64) years. Male (M) to female (F) was 147:111. The median disease course was 6 (1-51) months. According to 2015-NCCN risk stratification, 63 (24.4%) cases were in low risk, 112 (43.4%) cases in intermediated risk, and 83 (32.2%) cases in high risk. MRD in bone marrow pre-conditioning was detected by eight-color flow cytometry. Results: With the median follow up 18 (5-41) months, overall 2-year DFS was78.0%. No significant difference in DFS was found among low-risk (78.6%), intermediated-risk (76.0%) and high-risk (80.3%) patients (P=0.886). 205 (79.5%) cases were MRD- and 53 (20.5%) cases were MRD+ before conditioning. DFS after transplant in MRD+ patients was significant lower than that in MRD- patients(65.0% vs. 81.4%, P=0.003). Univariate analysis showed that DFS was not associated with patient age (≤14years vs.>14years, P=0.292), disease course before HSCT (≤6 months vs.>6months, P=0.532), WBC counts at diagnosis (≤50×109/L vs.>50×109/L, P=0.120), CBC recovery pre-HSCT (yes vs. no, P=0.664), disease status (CR1 vs. CR2, P=0.201), extramedullary leukemia before transplant (yes vs. no, P=0.532), conditioning regimen (BUCy/Flu-based vs. TBICy/Flu-based, P=0.753), donor type (identical sibling vs. unrelated vs. haploidentical, P=0.743), donor-recipient gender (M-M vs. M-F vs. F-M vs. F-F, P=0.245), donor-recipient blood type (compatibility vs. major incompatibility vs. minor incompatibility vs. major and minor incompatibility, P=0.402), mononuclear cells infused (≤8×108/kg vs.>8×108/kg, P=0.583), CD34+ cells infused (≤4×106/kg vs.>4×106/kg, P=0.946), and CD3+ cells infused (≤1.6×108/kg vs.>1.6×108/kg, P=0.143). DFS was significant lower in the patients with secondary AML (79.4% in primary AML vs. 53.5% in secondary AML, P=0.006) and MRD+ cases before transplant (81.4% in MRD- vs. 65.0% in MRD+, P=0.003). Accumulative non-relapse mortality (NRM) was significant higher in secondary AML (11.7% in primary AML vs. 33.3% in secondary AML, P=0.004) and MRD+ patients (10.5% in MRD- vs. 21.9% in MRD+, P=0.010). Accumulative relapse rate was significant higher in CR2 cases (8.0% in CR1 vs. 17.5% in CR2, P=0.046). Multivariate analysis showed that MRD pre-HSCT was the only impact factor on DFS and NRM with higher DFS (P=0.020) and lower NRM (P=0.045) in MRD- cases. Conclusions: Allo-HSCT has attenuated the influence of cytogenetics and gene mutations on DFS in AML. Secondary AML has lower DFS and higher NRM. Although disease status (CR1 vs. CR2) has no significant influence on DFS, relapse rate in CR2 is higher than that in CR1. MRD pre-conditioning was a key impact factor on DFS after allo-HSCT in AML but not conditioning regimen and donor type. DisclosuresNo relevant conflicts of interest to declare.

Therapeutic Management of Acute Myeloid Leukemia Patients after Stratification on Age, Prognosis and Allogeneic Hematopoietic Stem Cell Transplantation Eligibility

We evaluated in this study the therapeutic management of all newly diagnosed acute myeloid leukemia (AML) patients followed in our center between July 2007 and September 2013, after stratification on age, prognostic factors, whether they were candidate to allogeneic hematopoietic stem cell transplantation (allo-HSCT), transplanted or not with the evaluation of each therapeutic strategy and its impact on overall survival. A total of 572 consecutive newly diagnosed AML patients were included; there were 311 (54%) males and 261 females with a median age of 63 years (range: 20-92), 406 (71%) were de novo AML and 166 (29%) secondary AML. Complete cytogenetic and molecular biology data were collected for all patients and prognosis was differentiated according to the European LeukemiaNet classification (Dohner et al. Blood 2010). Accordingly, 335 (59%) patients were unfavorable, 83 (15%) favorable, 48 (8%) intermediate I and 106 (18%) were in intermediate II category. Following the Acute Leukemia French Association (ALFA) guidelines for allo-HSCT in AML, patients with intermediate II and unfavorable prognosis ≤ 65 years should receive intensive chemotherapy followed by allo-HSCT in the presence of related or unrelated HSCT donors. We divided the population into two sub-populations, the first was considered as “young” with age ≤ 65 years (N=318, 56%) and the second considered as “old” with age > 65 years (N=254, 44%). In the young population, there was 4 groups, group 1: patients with good prognosis (favorable/intermediate1) who received intensive chemotherapy within or according to ALFA protocols (N=105, median age= 47 years); group 2: patients with poor prognosis (intermediate2 /unfavorable) who received intensive chemotherapy within or according to ALFA protocols followed by allo-HSCT (N=126, median age= 50 years), group 3: patients with poor prognosis who received only intensive chemotherapy without allo-HSCT (N=69, median age= 57 years), and group 4: patients with poor prognosis who could not be treated due to early death (N=18). In the old population we distinguished, group 1: patients with good prognosis who received moderate intensity chemotherapy within or according to ALFA protocols (N=25, median age=73 years); group 2: patients with poor prognosis who received azacitidine (N=25, median age=76 years), group 3: patients with poor prognosis who received moderate intensity chemotherapy (N=89, median age=76 years), group 4: patients with poor prognosis who received low dose Ara-C (N=28, median age=76 years), group 5: patients with poor prognosis who received other treatment (N=38, median age=77 years) and finally group 6: patients with poor prognosis considered as palliative or who did not receive any treatment (N=49, median age=77 years). After a median follow-up of 34 months (range: 4-77) for surviving patients, the 2-years probability of overall survival (OS) in the “young” population for groups 1,2,3 and 4 was 84%, 56%, 31% and 0% respectively; and in the “old” group it was 71%, 37%, 31%, 5%, 21% and 0% for groups 1,2,3,4,5 and 6 respectively (figure).We showed that newly diagnosed AML patients with good prognosis all ages included could achieve very good survival rates after intensive chemotherapy; allo-HSCT after induction chemotherapy remains the best therapeutic option for fit patients with poor prognosis while the same fit patients with no donor have significantly lower survival (p<0.001) and for whom allo-HSCT could be proposed by using haploidentical donors in case of cord blood or unrelated donors absence. Interestingly, in the “old” population, we showed that poor prognosis patients receiving azacytidine had a significantly better survival compared to those receiving low dose Ara-C (p=0.015), with a comparable outcome to those receiving induction chemotherapy. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Acquired Haemophilia a after Allogeneic Stem Cell Transplant for Acute Myeloid Leukemia: Occurred during Cyclosporin a Used for Chronic Graft Versus Host Disease and Tolerance Induction with Rituximab

Background: Acquired haemophilia A (AHA) is a potentially life-threatening bleeding disorder occurring in patients without a previous personal or family history of bleeding. Development of immune-mediated autoantibodies against coagulation factor VIII is associated with a wide range of clinical disorders including pregnancy, autoimmune disorders, malignancy, or with no apparent disease. AHAs occurring after autologous hematopoietic stem cell transplantation (auto-HSCT) HSCT for an autoimmune disease have been reported by the EBMT Autoimmune Disease Working Party, but AHA secondary to allogeneic (allo-) HSCT was rarely reported, except for a literature by Lozier JN, et al reported a AHA occurred after allo-HSCT for sickle cell disease. Here we reported a AHA secondary to allo-HSCT for acute myeloid leukemia (AML).Case report: A 54 years old female patient was diagnosed as having AML on March 7th 2011 in Nanfang Hospital, Guangzhou, China. She acquired complete remission after induction therapy with IA protocol, and then she received consolation therapy with IA and high dose cytarabine. As having HLA 10/10 loci matched sibling donor, she underwent allo-HSCT on July 4th 2011. The conditioning regimen consisted of fludarabine and busulfan, and standard short term methotrexate and cyclosporin A (CsA) was used to prevent acute graft versus host disease. She acquired hematopoietic reconstitution on day 11 after transplantation. She had no acute GVHD, but she acquired limited chronic GVHD 11 months after transplantation. CsA, prednisone and azathioprine was given to treat chronic GVHD. After chronic GVHD was gradually controlled, azathioprine and prednisone were stopped, CsA was tapered step by step. On October 5th 2013, she experienced onset of severe soft tissue haemorrhage (left upper arm, right gluteal and lower right leg) associated with a long aPTT and low FVIII activity (1.3%). Other pertinent coagulation studies were normal. The Bethesda assay showed a factor VIII inhibitor at 2.8 Bethesda units (BU)/ml, confirming a diagnosis of acquired AHA. Autoimmune and viral screens were negative. Considering of AHA happened during CsA used for chronic GVHD treatment, CsA was stopped, cyclophosphamide (CTX) and prednisone were given to treat AHA. The patients underwent 3 episodes of severe soft tissue haemorrhage during treatment, and factor VIII inhibitor increased to 1587.2 Bu/ml. Rituximab were started concomitant with prednisone treatment. After one dose of 375 mg/m2 and 4 doses of low dose Rituximab 100mg per week treatment, the inhibitor titre to human FVIII declined, and the patient had no signs of haemorrhage, Concomitantly, the patient’s FVIII activity rose to >100%, and remained normal after completion of 2 doses of rituximab and a complete taper of prednisone over the next 3 months.Conclusions: This is rarely AHA case emerged after allo-HSCT for AML. Prednisone and CTX were ineffective for this patient. Low dose Rituximab combined with prednisone may be a useful choice for the treatment of AHA occurring after allo-HSCT. DisclosuresLiu:National Natural Science Foundation of China (81270647, 81300445, 81200388): Research Funding; National High Technology Research and Development Program of China (863 Program) (2011AA020105): Research Funding; National Public Health Grand Research Foundation (201202017): Research Funding; Natural Science Foundation of Guangdong Province (S2012010009299): Research Funding; the project of health collaborative innovation of Guangzhou city (201400000003-4, 201400000003-1): Research Funding; the Technology Plan of Guangdong Province of China (2012B031800403): Research Funding; the project of the Zhujiang Science & Technology Star of Guangzhou city (2013027): Research Funding.

Late Relapses Following Reduced Intensity Conditioning Allogeneic Haematopoietic Stem Cell Transplantation for Myeloid Malignancies Can Be Effectively Salvaged with Intensive Chemotherapy Followed by Cellular Therapy.

Abstract 2265Poster Board II-242While reduced intensity conditioning (RIC) haematopoietic stem cell transplantation (HSCT) regimens have expanded the scope of transplantation, use of these regimens are associated with a higher relapse rate. Disease relapse following following allo-HSCT in acute myeloid leukemia(AML) and high-risk myelodysplastic syndromes(MDS) is associated with a particularly poor prognosis. We performed a retrospective analysis on 157 consecutive patients with high risk (AML/MDS) who received a uniform fludarabine-busulphan based RIC HSCT at our centre between Jul 2002 and Oct 2006 and identified 45(28%) patients who had subsequent cytogenetic or morphological relapse. We proceeded to analyse the patient/disease characteristics of the 45 patients to predict response to salvage therapy. The patient diagnoses were: 19 MDS RAEB I/II, 17 AML, 6 CMML, 3 CML-blast crisis. All patients had received intensive chemotherapy prior to transplantation (median 2 courses, range 1-6). 7 patients were receiving a second allo-HSCT. At time of transplantation, 34 patients had <5% bone marrow blasts, with 11(24.4%) having >5% blasts. 81% of patients had intermediate/poor risk cytogenetics. The median patient age at time of relapse was 52yrs (range:24-72). The median time to relapse was 246 days(range:34-1034). The median survival following relapse was 203 days, with a 2-year OS from time of relapse of 24%+/-6%. On univariate analysis, the time to relapse post-HSCT was the most significant predictive factor of OS post-relapse. All patients who had relapsed <180 days post-HSCT (n=22) died of disease progression within 6 months of relapse. 2-yr OS post-relapse for patients who had relapsed >180 post-HSCT was 43%+/-10% (p<0.01). There was no significant difference in disease type, stage at transplant, cytogenetics between early and late relapsing patients. In addition, patients with >5% blasts at time of allograft had an inferior post-relapse 2-yrs OS when compared with those in remission (9% vs 29%, p=0.1). Patients were further analysed based on the salvage treatment received; no therapy: 5, donor lymphocyte infusions(DLI) only:6, chemotherapy only:12, intensive chemotherapy (defined as a regimen containing high dose arabinose cytarabine) followed by DLI:17, second allograft:5. There was a significant difference in therapy given dependant on the time-post relapse, with 18/22 patients who had early relapse receiving either no therapy, or DLI/chemotherapy alone, while 18/23 late relapsing patients received intensive chemotherapy+DLI or a 2nd allograft. At one year post-relapse, only 1 patient who received DLI only (out of those who received no therapy/DLI only/chemotherapy only) was alive. In contrast, 10/22 patients who received either intensive chemotherapy+DLI or a 2nd allograft were alive and in durable remission with a median survival post-relapse of 1767 days (range:1123-2581), with no significant difference in outcomes between either form of therapy (2 year post-relapse OS: chemo/DLI 47% vs 2nd allograft 40%).In conclusion, the disease kinetics and time to relapse following RIC HSCT play a significant role in determining subsequent outcomes. The prognosis of patients who relapse within 6 months remains extremely poor. In contrast, we demonstrate that of patients who relapse after 6 months, treatment with chemotherapy followed by cellular therapy (either in the form of intensive chemotherapy followed by DLI, or a 2nd RIC followed by HSCT), can effectively salvage a significant proportion of patients with attainment of durable long-term remissions. Disclosures:Off Label Use: fludarabine, alemtuzumab- used off-label for transplant conditioning. Marsh:Genzyme: Consultancy, Honoraria.