Improved outcome in children compared to adolescents and young adults after allogeneic hematopoietic stem cell transplant for acute myeloid leukemia: a retrospective study from the Francophone Society of Bone Marrow Transplantation and Cell Therapy (SFGM-TC)

Abstract Background There are currently few data on the outcome of acute myeloid leukemia (AML) in adolescents after allogeneic HSCT. The aim of this study is to describe the outcome and its specific risk factors for children, adolescents and young adults after a first allogeneic HSCT for AML. Methods In this retrospective study, we compared the outcome of AML patients receiving a first allogeneic HSCT between 2005 and 2017 according to their age at transplantation’s time: children (< 15 years, n = 564), adolescent and post-adolescent (APA) patients (15–25 years, n = 647) and young adults (26–40 years; n = 1434). Results With a median follow-up of 4.37 years (min–max 0.18–14.73 years), the probability of 2-year overall survival (OS) was 71.4% in children, 61.1% in APA patients and 62.9% in young adults (p = 0.0009 for intergroup difference). Both relapse and non-relapse mortality (NRM) Cumulative Incidence (CI) estimated at 2 years were different between the age groups (30.8% for children, 35.2% for APA patients and 29.4% for young adults—p = 0.0254, and 7.0% for children, 10.6% for APA patients and 14.2% for young adults, p < 0.0001; respectively). Whilst there was no difference between the three groups for grade I to IV acute GVHD CI at 3 months, the chronic GVHD CI at 2 years was higher in APA patients and young adults (31.4% and 36.4%, respectively) in comparison to the children (17.5%) (p < 0.0001). In multivariable analysis, factors associated with death were AML cytogenetics (HR1.73 [1.29–2.32] for intermediate risk 1, HR 1.50 [1.13–2.01] for intermediate risk 2, HR 2.22 [1.70–2.89] for high cytogenetics risk compared to low risk), use of TBI ≥ 8 Grays (HR 1.33 [1.09–1.61]), disease status at transplant (HR 1.40 [1.10–1.78] for second Complete Remission (CR), HR 2.26 [1.02–4.98] for third CR and HR 3.07 [2.44–3.85] for active disease, compared to first CR), graft source (HR 1.26 [1.05–1.50] for Peripheral Blood Stem Cells compared to Bone Marrow) and donor age (HR 1.01 (1–1.02] by increase of 1 year). Conclusion Age is an independent risk factor for NRM and extensive chronic GVHD. This study suggests that APA patients with AML could be beneficially treated with a chemotherapy-based MAC regimen and bone marrow as a stem cells source.

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Improved Outcome in Young Children Compared to Adolescents and Adults After Allogeneic Hematopoietic Stem Cell Transplant for Acute Myeloid Leukemia: a Retrospective Study From Francophone Society of Bone Marrow Transplantation and Cell Therapy (SFGM-TC) (SFGM-TC)

10.21203/rs.3.rs-718867/v1 ◽

2021 ◽

Author(s):

Cécile POCHON ◽

Marie Detrait ◽

Jean-Hugues Dalle ◽

Gérard Michel ◽

Nathalie Dhédin ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Acute Myeloid Leukemia ◽

Retrospective Study ◽

Myeloid Leukemia ◽

Chronic Gvhd ◽

Cell Transplant ◽

Intermediate Risk ◽

Allogeneic Hsct ◽

Acute Myeloid

Abstract Background: There are currently few data on the outcome of acute myeloid leukemia (AML) in adolescents and young adults (AYAs) after allogeneic HSCT. The aim of this study is to describe the outcome and its specific risk factors for children, AYAs and adults after a first allogeneic HSCT for AML. Methods: In this retrospective study, we compared the outcome of AML patients receiving a first allogeneic HSCT between 2005 and 2017 according to their age at transplantation’s time: children (<15 years, n=564), AYAs (15-25 years, n=647) and adults (26-40 years; n= 1434). Results: With a median follow-up of 4.37 years (min-max 0.18 – 14.73 years), the probability of 2 year-overall survival (OS) was 71.4% in children, 61.1% in AYAs and 62.9% in adults (p=0.0009 for intergroup difference). Both relapse and non-relapse mortality (NRM) Cumulative Incidence (CI) estimated at 2 years were different between the age groups (30.8% for children, 35.2% for AYAs and 29.4% for adults - p=0.0254, and 7.0% for children, 10.6% for AYAs and 14.2% for adults, p<0.0001; respectively). Whilst there was no difference between the 3 groups for grade I to IV acute GVHD CI at 3 months, the chronic GVHD CI at 2 years was higher in AYAs and adults (31.4% and 36.4%, respectively) in comparison to the children (17.5%) (p<0.0001). In multivariable analysis, factors associated with death were AML cytogenetics (HR1.73 [1.29-2.32] for intermediate risk 1, HR 1.50 [1.13-2.01] for intermediate risk 2, HR 2.22 [1.70-2.89] for high cytogenetics risk compared to low risk), use of TBI ≥ 8 Grays (HR 1.33 [1.09-1.61]), disease status at transplant (HR 1.40 [1.10-1.78] for second Complete Remission (CR), HR 2.26 [1.02-4.98] for third CR and HR 3.07 [2.44-3.85] for active disease, compared to first CR), graft source (HR 1.26 [1.05-1.50] for Peripheral Blood Stem Cells compared to Bone Marrow) and donor age (HR 1.01 (1-1.02] by increase of one year). Conclusion: Age is an independent risk factor for NRM and extensive chronic GVHD. This study suggests that AYAs AML patients should be treated with chemotherapy-based MAC regimen and bone marrow as stem cells source.

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Bone marrow niche-mediated survival of leukemia stem cells in acute myeloid leukemia: Yin and Yang

Cancer Biology and Medicine ◽

10.20892/j.issn.2095-3941.2016.0023 ◽

2016 ◽

Vol 13 (2) ◽

pp. 248-259 ◽

Cited By ~ 44

Author(s):

Hong-Sheng Zhou ◽

Bing Z. Carter ◽

Michael Andreeff ◽

Bing Z. Carter ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Leukemia Stem Cells ◽

Bone Marrow Niche ◽

Yin And Yang ◽

Acute Myeloid

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Patient Heterogeneity in Acute Myeloid Leukemia: Leukemic Cell Communication by Release of Soluble Mediators and Its Effects on Mesenchymal Stem Cells

Diseases ◽

10.3390/diseases9040074 ◽

2021 ◽

Vol 9 (4) ◽

pp. 74

Author(s):

Elise Aasebø ◽

Annette K. Brenner ◽

Maria Hernandez-Valladares ◽

Even Birkeland ◽

Olav Mjaavatten ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Extracellular Matrix ◽

Acute Myeloid Leukemia ◽

Mesenchymal Stem Cells ◽

Conditioned Medium ◽

Untreated Control ◽

Myeloid Leukemia ◽

Control Mscs ◽

Acute Myeloid

Acute myeloid leukemia (AML) is an aggressive bone marrow malignancy, and non-leukemic stromal cells (including mesenchymal stem cells, MSCs) are involved in leukemogenesis and show AML-supporting effects. We investigated how constitutive extracellular mediator release by primary human AML cells alters proteomic profiles of normal bone marrow MSCs. An average of 6814 proteins (range 6493−6918 proteins) were quantified for 41 MSC cultures supplemented with AML-cell conditioned medium, whereas an average of 6715 proteins (range 6703−6722) were quantified for untreated control MSCs. The AML effect on global MSC proteomic profiles varied between patients. Hierarchical clustering analysis identified 10 patients (5/10 secondary AML) showing more extensive AML-effects on the MSC proteome, whereas the other 31 patients clustered together with the untreated control MSCs and showed less extensive AML-induced effects. These two patient subsets differed especially with regard to MSC levels of extracellular matrix and mitochondrial/metabolic regulatory proteins. Less than 10% of MSC proteins were significantly altered by the exposure to AML-conditioned media; 301 proteins could only be quantified after exposure to conditioned medium and 201 additional proteins were significantly altered compared with the levels in control samples (153 increased, 48 decreased). The AML-modulated MSC proteins formed several interacting networks mainly reflecting intracellular organellar structure/trafficking but also extracellular matrix/cytokine signaling, and a single small network reflecting altered DNA replication. Our results suggest that targeting of intracellular trafficking and/or intercellular communication is a possible therapeutic strategy in AML.

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7-Ketocholesterol Promotes Oxiapoptophagy in Bone Marrow Mesenchymal Stem Cell from Patients with Acute Myeloid Leukemia

Cells ◽

10.3390/cells8050482 ◽

2019 ◽

Vol 8 (5) ◽

pp. 482 ◽

Cited By ~ 5

Author(s):

Jessica Liliane Paz ◽

Debora Levy ◽

Beatriz Araujo Oliveira ◽

Thatiana Correia de Melo ◽

Fabio Alessandro de Freitas ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Cholesterol Oxidation ◽

Specific Cell ◽

Hematopoietic Stem ◽

Shh Pathway ◽

Number Of Cells ◽

Acute Myeloid

7-Ketocholesterol (7-KC) is a cholesterol oxidation product with several biological functions. 7-KC has the capacity to cause cell death depending on the concentration and specific cell type. Mesenchymal stem cells (MSCs) are multipotent cells with the ability to differentiate into various types of cells, such as osteoblasts and adipocytes, among others. MSCs contribute to the development of a suitable niche for hematopoietic stem cells, and are involved in the development of diseases, such as leukemia, to a yet unknown extent. Here, we describe the effect of 7-KC on the death of bone marrow MSCs from patients with acute myeloid leukemia (LMSCs). LMSCs were less susceptible to the death-promoting effect of 7-KC than other cell types. 7-KC exposure triggered the extrinsic pathway of apoptosis with an increase in activated caspase-8 and caspase-3 activity. Mechanisms other than caspase-dependent pathways were involved. 7-KC increased ROS generation by LMSCs, which was related to decreased cell viability. 7-KC also led to disruption of the cytoskeleton of LMSCs, increased the number of cells in S phase, and decreased the number of cells in the G1/S transition. Autophagosome accumulation was also observed. 7-KC downregulated the SHh protein in LMSCs but did not change the expression of SMO. In conclusion, oxiapoptophagy (OXIdative stress + APOPTOsis + autophagy) seems to be activated by 7-KC in LMSCs. More studies are needed to better understand the role of 7-KC in the death of LMSCs and the possible effects on the SHh pathway.

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Gpr44 Mediates the Selenium-Dependent Anti-Leukemic Effect in Acute Myeloid Leukemia

Current Developments in Nutrition ◽

10.1093/cdn/nzaa067_062 ◽

2020 ◽

Vol 4 (Supplement_2) ◽

pp. 1835-1835

Author(s):

Fenghua Qian ◽

Diwakar Tukaramrao ◽

Jiayan Zhou ◽

Nicole Palmiero ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Acute Myeloid Leukemia ◽

Murine Model ◽

Myeloid Leukemia ◽

Hematopoietic Stem ◽

Cell Counts ◽

Pparγ Agonist ◽

Acute Myeloid

Abstract Objectives The relapse of acute myeloid leukemia (AML) remains a significant concern due to persistent leukemia stem cells (LSCs) that are not targeted by existing therapies. LSCs show sensitivity to endogenous cyclopentenone prostaglandin J (CyPG) metabolites that are increased by dietary trace element selenium (Se), which is significantly decreased in AML patients. We investigated the anti-leukemic effect of Se supplementation in AML via mechanisms involving the activation of the membrane-bound G-protein coupled receptor 44 (Gpr44) and the intracellular receptor, peroxisome proliferator-activated receptor gamma (PPARγ), by endogenous CyPGs. Methods A murine model of AML generated by transplantation of hematopoietic stem cells (HSCs- WT or Gpr44−/−) expressing human MLL-AF9 fusion oncoprotein, in the following experiments: To investigate the effect of Se supplementation on the outcome of AML, donor mice were maintained on either Se-adequate (Se-A; 0.08–0.1 ppm Se) or Se-supplemented (Se-S; 0.4 ppm Se) diets. Complete cell counts in peripheral blood were analyzed by hemavet. LSCs in bone marrow and spleen were analyzed by flow cytometry. To determine the role of Gpr44 activation in AML, mice were treated with Gpr44 agonists, CyPGs. LSCs in bone marrow and spleen were analyzed. Mice transplanted with Gpr44−/- AML cells were compared with mice transplanted with wild type AML cells and the progression of the disease was followed as above. To determine the role of PPARγ activation in AML, PPARγ agonist (Rosiglitazone, 6 mg/kg, i.p, 14 d) and antagonist (GW9662, 1 mg/kg, i.p. once every other day, 7 injections) were applied to Se-S mice transplanted with Gpr44−/- AML cells and disease progression was followed. Results Se supplementation at supraphysiological levels alleviated the disease via the elimination of LSCs in a murine model of AML. CyPGs induced by Se supplementation mediate the apoptosis in LSCs via the activation of Gpr44 and PPARγ. Conclusions Endogenous CyPGs produced upon supplementation with Se at supraphysiological levels improved the outcome of AML by targeting LSCs to apoptosis via the activation of two receptors, Gpr44 and PPARg. Funding Sources NIH DK 07,7152; CA 175,576; CA 162,665. Office of Dietary Supplements, USDA Hatch funds PEN04605, Accession # 1,010,021 (KSP, RFP).

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Discovery of proangiogenic CD44+mesenchymal cancer stem cells in an acute myeloid leukemia patient’s bone marrow

Journal of Hematology & Oncology ◽

10.1186/s13045-020-00899-x ◽

2020 ◽

Vol 13 (1) ◽

Author(s):

Huynh Cao ◽

Jeffrey Xiao ◽

Mark E. Reeves ◽

Kimberly Payne ◽

Chien Shing Chen ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Acute Myeloid Leukemia ◽

Cancer Stem Cells ◽

Myeloid Leukemia ◽

Acute Myeloid

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Bone Marrow Mesenchymal Stem Cells Support Acute Myeloid Leukemia Bioenergetics and Enhance Antioxidant Defense and Escape from Chemotherapy

Cell Metabolism ◽

10.1016/j.cmet.2020.09.001 ◽

2020 ◽

Vol 32 (5) ◽

pp. 829-843.e9 ◽

Cited By ~ 2

Author(s):

Dorian Forte ◽

María García-Fernández ◽

Abel Sánchez-Aguilera ◽

Vaia Stavropoulou ◽

Claire Fielding ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Acute Myeloid Leukemia ◽

Mesenchymal Stem Cells ◽

Myeloid Leukemia ◽

Antioxidant Defense ◽

Marrow Mesenchymal Stem Cells ◽

Acute Myeloid

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Patients with FLT3 Negative Acute Myeloid Leukemia and Normal Cytogenetic who Have the Combination Mutations (NPM1-/CEBPA-) Have Better Survival Than Patients Who Have the Combination Mutations (NPM1+/CEBPA+)

Blood ◽

10.1182/blood.v118.21.4874.4874 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4874-4874

Author(s):

Shamail Butt ◽

Pascal Akl ◽

Himanshu Bhardwaj ◽

Samer A Srour ◽

Terry Dunn ◽

...

Keyword(s):

Bone Marrow ◽

Overall Survival ◽

Acute Myeloid Leukemia ◽

Mutation Analysis ◽

Myeloid Leukemia ◽

Risk Group ◽

Intermediate Risk ◽

Cebpa Mutations ◽

Normal Cytogenetics ◽

Acute Myeloid

Abstract Abstract 4874 Introduction: Acute Myeloid Leukemia (AML) is the most common type of acute leukemia in adults. About 50% of patients with AML have normal karyotype, and are categorized as intermediate risk group. However, the clinical behavior and response to treatment in this group is heterogeneous. As a result, there is strong interest in characterizing molecular genetic features in the intermediate-risk AML patients that might rectify their stratification risk. In this group, FLT3-ITD (Internal Tandem Duplication) and FLT3-TKD (Tyrosine Kinase Domain) mutations are known to confer unfavorable risk whereas NPM1 and CEBPA mutations are known to be favorable risk markers. The purpose of this study is to analyze the combination of NPM1 and CEBPA mutations in presence or absence of FLT3 mutations on prognosis of AML patients referred to the State's largest tertiary care center over a period of 10 years for the treatment of leukemia. Patients and Method: We performed a retrospective chart review of all patients with AML evaluated at University of Oklahoma Health Sciences Center between January 2000 and December 2010. Patient's age, gender, race, laboratory and clinical data as well as bone marrow biopsy and aspirate findings were reported. PCR and Fragment Analysis were conducted on all available DNA preserved bone marrow materials to test the FLT3, NPM1 and CEBPA mutations. For statistical analysis, Kaplan-Meyer curve was used. Results: A total of 239 patients were evaluated. Male to female ratio was 2/1. Median age at diagnosis was 46y. 21 out of the 239 patients were less than 18 year old. DNA samples were present on 132 patients and mutation analysis for FLT3, CEBPA and NPM1 was performed. Correlation between mutations and AML prognosis was determined. 67/132 (50.8 %) patients were categorized into intermediate risk group (majority of patients had normal cytogenetics). 14/67 (20.9%) pts were FLT3+ (FLT3-ITD or FLT3-TKD mutation). 17/67 (23.9%) were NPM1+. 7/67 (10.4%) were CEBPA +. Kaplan-Meier curve was used to identify cumulative proportion surviving over time. FLT3 presence or absence itself was not identified to be statistically significant (p 0.416) in terms of overall survival. Interestingly, presence or absence of combined NPM1/CEBPA mutation in FLT3 negative patients, among intermediate risk group, was found to be statistically significant (p<0.05) in determining overall survival. In this subgroup, presence of NPM1/CEBPA combination (NPM1+/CEBPA+) was associated with poor prognosis (figure 2, lower curve), while absence of NPM1/CEBPA combination (NPM1-/CEBPA-) carries a better prognosis (figure 2, upper curve). Conclusion: Results of our study highlight the importance of performing combinations of mutation analysis in evaluation of overall prognosis in AML patients. FLT3-/NPM1+ profile in patients with normal cytogenetics is thought to confer a favorable prognosis. We demonstrated in this study that using combination mutation analysis in patients with FLT3- can change the risk stratification in patients with intermediate risk group and might affect therapeutic interventions in this patient population. Larger prospective studies are needed in the future for further validation of our findings. Disclosures: No relevant conflicts of interest to declare.

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TIM-3 Is a Promising Target to Eradicate Acute Myeloid Leukemia Stem Cells Sparing Normal Hematopoietic Stem Cells

Blood ◽

10.1182/blood.v118.21.559.559 ◽

2011 ◽

Vol 118 (21) ◽

pp. 559-559

Author(s):

Toshihiro Miyamoto ◽

Yoshikane Kikushige ◽

Takahiro Shima ◽

Koichi Akashi

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Acute Myeloid Leukemia ◽

Hematopoietic Stem Cells ◽

Myeloid Leukemia ◽

Leukemia Cell ◽

Cytotoxic Activities ◽

Antibody Treatment ◽

Hematopoietic Stem ◽

Acute Myeloid

Abstract Abstract 559 Acute myeloid leukemia (AML) originates from self-renewing leukemic stem cells (LSCs), an ultimate therapeutic target for permanent cure. To selectively kill AML LSCs sparing normal hematopoietic stem cells (HSCs), one of the most practical approaches is to target the AML LSCs-specific surface or functionally indispensable molecules. Based on differential transcriptome analysis of prospectively-purified CD34+CD38− LSCs from AML patient samples and normal HSCs, we found that T-cell immunoglobulin mucin-3 (TIM-3) was highly expressed in AML LSCs but not in normal HSCs (Kikushige et al., Cell Stem Cell, 2010). In normal hematopoiesis, TIM-3 is mainly expressed in mature monocytes and a fraction of NK cells, but not in granulocytes, T cells or B cells. In the bone marrow, TIM-3 is expressed only in a fraction of granulocyte/macrophage progenitors (GMPs) at a low level, but not in HSCs, common myeloid progenitors, or megakaryocyte/erythrocyte progenitors. In contrast, in human AML, TIM-3 was expressed on cell surface of the vast majority of CD34+CD38− LSCs and CD34+CD38+ leukemic progenitors in AML of most FAB types, except for acute promyelocytic leukemia (M3). FACS-sorted TIM-3+ but not TIM-3− AML cells reconstituted human AML in the immunodeficient mice, indicating that the TIM-3+ population contains most of functional LSCs. To selectively eradicate TIM-3-expressing AML LSCs, we established an anti-human TIM-3 mouse IgG2a antibody, ATIK2a, possessing antibody-dependent cellular cytotoxic and complement-dependent cytotoxic activities in leukemia cell lines transfected with TIM-3. We first tested the effect of ATIK2a treatment on reconstitution of normal HSCs in a xenograft model. ATIK2a was intraperitoneally injected to the mice once a week after 12 hours of transplantation of human CD34+ cells. Injection of ATIK2a did not affect reconstitution of normal human hematopoiesis except removing TIM-3-expressing mature monocytes. In contrast, injection of TIM-3 to the mice transplanted with human AML samples markedly reduced leukemic repopulation. In some mice transplanted with AML bone marrow, only normal hematopoiesis was reconstituted after anti-TIM-3 antibody treatment, suggesting that the antibody selectively killed AML cells, sparing residual normal HSCs. To further test the inhibitory effect of ATIK2a on established human AML, eight weeks after transplantation of human AML cells, engraftment of human AML cells was confirmed by blood sampling and thereafter ATIK2a was injected to these mice. In all cases tested, ATIK2a treatment significantly reduced human TIM-3+ AML fraction as well as the CD34+CD38− LSCs fraction. In addition, to verify the anti-AML LSCs effect of ATIK2a treatment, human CD45+AML cells from the primary recipients were re-transplanted into secondary recipients. All mice transplanted from primary recipients treated with control IgG developed AML, whereas none of mice transplanted with cells from ATIK2a-treated primary recipients developed AML, suggesting that functional LSCs were effectively eliminated by ATIK2a treatment in primary recipients. Thus, TIM-3 is a promising surface molecule to target AML LSCs. Our experiments strongly suggest that targeting this molecule by monoclonal antibody treatment is a practical approach to eradicate human AML. Disclosures: No relevant conflicts of interest to declare.

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Allogeneic Transplanst for ACUTE Myeloid Leukemia: Cut Off Levels of WT1 Expression in 207 Patients and Pre-Emptive Therapy of Relapse

Blood ◽

10.1182/blood.v126.23.1866.1866 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1866-1866

Author(s):

Carmen Di Grazia ◽

Simona Geroldi ◽

Raffaella Grasso ◽

Maurizio Miglino ◽

Nicoletta Colombo ◽

...

Keyword(s):

Bone Marrow ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Cell Transplant ◽

Allogeneic Hsct ◽

Group A ◽

Leukemia Relapse ◽

Group B ◽

Acute Myeloid ◽

Marrow Cells

Abstract Leukemia relapse remains a significant problem in patients with AML undergoing an allogeneic stem cell transplant(HSCT). Wilms Tumour 1 (WT1) expression has been shown to be a sensitive marker of minimal residual disease (MRD), both in patients after induction chemotherapy, as well as in patients undergoing an allogeneic HSCT. Hypotheses. The present study had 2 hypotheses: (1) WT1 expression in marrow cells of AML patients post-HSCT, will predict leukemia relapse and (2) WT1 based pre-emptive immunotherapy (IT) such as abrupt cyclosporin discontinuation and/or donor lymphocyte infusion (DLI), will prevent leukemia relapse. Patients. Bone marrow WT1 expression, was monitored in 207 patients with acute myeloid leukemia (AML) before and monthly after an allogeneic HSCT, until day +150, and then at every other outpatient access. Eligible for IT were patients without acute or chronic GvHD, with increased WT1 expression and a a marrow in hematologic remission. The trigger for IT was 180 WT1 copies in a first group of 122 patients (group A): this was based on the fact that WT1 expression in normal bone marrow is up to 180 copies . In a subsequent group of 85 patients (group B) the cut off for IT, was 100 copies, due to the fact that a first analysis of group A had shown 100 copies to be an earlier predictor of relapse (BJH 2013; 160: 503). DLI were given in escalating doses, starting at 1x105 CD3+ cells/kg in alternative donor grafts and at 1x106/kg in HLA identical grafts. DLI were escalated ½ log every month, in the absence of GvHD, to a maximum dose of 1x107/kg. Sixtyfour patients were eligible for IT, but only 35 received IT: reasons for non intervention were ongoing GHD, unavailable donor and delay in WT1 results. Results-Hypothesis N.1. Following transplantation, WT1 expression, was highly predictive of leukemia relapse: 12 relapses in 99 patients with WT1 < 100 copies /104 abl (12%); 19 relapses in 55 patients with WT1 between 101 and 180 copies (35%) and 37 relapses in 53 patients with WT1 >180 copies (70%) (p<0.0001). The median interval between WT1 positivity and relapse was 75 days in group A and 60 days in group B. Results-Hypothesis N.2. 35 patients received pre-emptive immune intervention, 17 in group A and 18 in group B. The latter had more patients beyond first remission at transplant (56% vs 23%) , more myeloablative regimens (100% vs 65%) and more family haploidentical donors (72% vs 6%); age was comparable. The risk of relapse was 13/17 (76%) for group A and 3/18 (17%) for group B (p<0.001), despite the larger proportion of patients beyond CR1 at transplant. GvHD following DLI occurred in 15% of patients. DLI-related mortality was 0%. The overall 3 year survival for patients in group A and B was 69% vs 47% (p=0.3). The relapse risk in patients of group A eligible but not receiving IT (n=21) was 74%; in group B (n=8) it was 50%. In conclusion, WT1 expression post-transplant is a strong predictor of leukemia relapse in patients with AML, and can be used to trigger pre-emptive immunotherapy, in approximately 50% of eligible patients. IT triggered at a WT1 cut-off level of 100 copies in bone marrow cells, is more effective, as compared to180 copies, in preventing leukemia relapse. Disclosures No relevant conflicts of interest to declare.

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