ALBERT

Description: Purpose In patients with relapsed acute myeloid leukemia (AML) 〉 60 years of age we analyzed age at relapse, interval from first complete remission (CR1) to relapse, cytogenetic risk at initial diagnosis, prior allogeneic stem cell transplantation (alloSCT) and FLT3/NPM1 mutational status as possible prognostic factors for overall survival (OS). Introduction After achieving CR1 more than 50% of elderly AML patients eventually relapse. Prognostic factors for OS are poorly defined in this patient population. For younger patients with relapsed AML a risk score has been described including age at relapse, interval from CR1 to relapse, cytogenetic risk at initial diagnosis and prior stem cell transplantation (SCT) as prognostic factors. We sought to investigate whether these are also prognostic factors in elderly patients with relapsed AML. In addition, we assessed the prognostic impact of FLT3- and NPM1 mutational status (wild-type (wt) or mutated (mut)) at diagnosis. Patients and methods In the ongoing multicenter OSHO trial #69 for AML patients 〉 60 years we evaluated data of all relapsed patients. Overall survival was calculated from the day of first relapse until the day of death using the Kaplan Meier method. Univariate analysis was performed to test for the influence of age at relapse, interval from CR1 to relapse, cytogenetic risk at initial diagnosis, prior alloSCT and FLT3/NPM1 mutational status. Subsequently, independent prognostic factors were defined in a multivariate analysis with age at relapse, time from CR1 to relapse, cytogenetic risk at initial diagnosis and prior alloSCT as covariates. Results From April 2005 until April 2013 904 patients were registered. 733 of these received intensive induction chemotherapy which resulted in CR1 in 447 (61%) pts. In this patient group 260 relapses were observed after a median interval, calculated from the day of CR1, for living patients of 2.7 years (range 0.1 to 7.5). Median age at relapse was 69 years (range 60 – 85) with 129 (49.6%) pts. being 60 to 68 years old, 102 (39.2%) pts. being 69 to 74 years old and 29 (11.1%) pts. being 75 to 85 years old. Median interval from CR1 to relapse was 0.58 years (0.07 – 6.28). 114 (43.8%) relapses occurred up to 6 months after CR1, 119 (45.8%) between 7 and 18 months after CR1 and 27 (10.4%) later than 18 months after CR1. Only five (1.9%) relapsed pts. showed good risk cytogenetics at diagnosis, whereas it was of intermediate risk in 159 (61.1%) pts., of poor risk in 68 (26.2%) pts. and unknown in 28 (10.8%) pts. Forty-one (15.8%) pts. had received prior alloSCT in CR1. Information on FLT3- and NPM1 mutational status at diagnosis was available in 194 (74.6%) pts. 110 (42.3%) pts. had FLT3/NPM1 wt/wt, 48 (18.5%) pts. had FLT3/NPM1 wt/mut, 23 (8.8%) pts. had FLT3/NPM1 mut/wt and 13 (5.0%) pts. had FLT3/NPM1 mut/mut. OS rate at 2 years of all relapsed pts. was 13 ± 2%. For patients younger than 69 years and for those 69 years of age or older OS rate at 2 years was 17 ± 4% and 9 ± 3%, respectively (p=0.03). The interval between CR1 and first relapse also affected 2 year-OS with 7 ± 3%, 15 ± 4% and 36 ± 12% for pts. with relapse up to 6 months, 7 to 18 months and later than 18 months after CR1, respectively ( 18 months: p=0.009). OS rate at 2 years was also influenced by cytogenetic risk at initial diagnosis with 17 ± 3% for pts. having good or intermediate risk cytogenetics and 3 ± 2% for those with poor risk cytogenetics (p〈 0.0005). Prior alloSCT had a negative influence on OS. Two-year OS rate was 10 ± 5 and 13 ± 3% (p= .015) for patients with prior alloSCT vs. those without prior alloSCT, respectively. FLT3/NPM1 mutational status at diagnosis had no impact on OS. In univariate analysis age at relapse (p

Description: Abstract 3921 Poster Board III-857 The t(14;18)(BCL2/IgH) translocation is the genetic hallmark of follicular lymphoma (FL). Circulating t(14;18)-positive cells can not only be detected in FL patients but also in healthy subjects without lymphoma. Several epidemiological and molecular studies suggest that these t(14;18)-positive cells might represent lymphoma precursor cells and are associated with known FL risk factors like age and geographical differences in lymphoma incidence. We used epidemiological data and blood samples of a population-based study to verify associations of FL risk factors and t(14;18)-positive cells reported so far and to test for new associations. The study of health in Pomerania (SHIP) collects epidemiological data, a basic health status and blood samples from 4310 randomly selected inhabitants of the study region in the northeastern part of Germany. We tested buffy coat-DNA samples from 4152 study participants (median age 50 years, range 20-81 years, 2100 women) by real-time PCR for the presence and frequency of t(14;18)-positive cells. t(14;18)-PCR results were evaluable from 2620 subjects, 1533 subjects were tested positive (58.1%, median number of t(14;18)-positive cells in positive subjects 3.9 per million nucleated cells, range 0.6 – 9299 per million nucleated cells). t(14;18)-prevalence was lowest in the age group 20-29 years (42.2%) and increased up to the group 50-59 years (67.0%) but did not further increase up to the age of 81 years. In accordance with previous reports there was a significant increase of the t(14;18)-frequency with age up to the age of 69 years (linear regression, p〈 0.0001) in this study. In the SHIP cohort, t(14;18)-prevalence was lower in females compared to males (53.2% versus 63.5%, p〈 0.0001), but there was no significant difference in t(14;18)-frequency between males and females. Smoking status (current, former and never smoker) had no influence on t(14;18)-prevalence or frequency. This study confirms the association of t(14;18)-prevalence with age and shows for the first time that the t(14;18)-prevalence in females is lower than in males. The later finding parallels the observation of a lower FL incidence in females. In contrast to previous studies, smoking was not associated with detection of t(14;18)-positive cells when the analysis was adjusted for age and sex. In summary, this study confirms that the prevalence of t(14;18)-positive cells in non-lymphoma subjects is associated with established FL risk factors. Thus our report adds to the accumulating evidence that circulating t(14;18)-positive cells in non-lymphoma subjects may represent a biomarker of FL risk. Disclosures: No relevant conflicts of interest to declare.

Description: Purpose: This multicenter study investigated the efficacy and safety of high-dose methotrexate (HD-MTX) induction followed by high-dose busulfan/thiotepa with autologous stem-cell transplantation (HD-BuTT) and response-adapted whole-brain radiotherapy (WBRT) in patients with newly diagnosed primary CNS lymphoma. Patients and methods: 23 patients (median age 55 years) were treated in five centres. Patients received HD-MTX (4h-infusion; 8g/m2; 〉60y: 6g/m2) on d1 and d10 followed by leucapheresis. Then patients were stratified according to their results on neuroimaging: In case of at least a partial response, HD-BuTT consisting of 16mg busulfan / 10mg thiotepa per kg body weight followed by peripheral stem cell transplantation was given. Patients without response to induction or without complete response after high-dose therapy received WBRT (45Gy) as further treatment. Results: 16 patients received the planned treatment with HD-MTX followed by HD-BuTT. CR / PR rates for these patients were 19 % / 69 % after HD-MTX, 69 % / 13 % after HD-BuTT, 81 % / 6 % after HD-BuTT plus WBRT, respectively. Included the patients with early WBRT due to toxicity (n=2) and non-responders to HD-MTX induction (n=4) the overall response rate for all 23 patients was 83 % (intention-to-treat). Outcome was significantly influenced by the response to MTX-induction. There were three treatment-related deaths. Irradiated patients (n=9) had a high incidence of severe neurotoxicity leading to death in 3 patients. At a median follow-up of 15 months the median EFS and OS for all patients were 17 and 20 months, after HD-BuTT 27 months and “not reached”, respectively. Patients older than 60 years and younger patients have achieved similar outcomes. Conclusion: This study showed that HD-methotrexate induction followed by HD-BuTT is a feasible treatment option for newly diagnosed primary CNS lymphoma. Patients achieving CR after HD-BuTT show no signs of clinical neurotoxicity with median survival not reached yet. Time on treatment is 2–3 months only, but the induction treatment needs improvement to be more effective. WBRT in this study was associated with a high incidence of severe neurotoxicity and should therefore be avoided.

Description: Abstract 2014 Introduction: Mantle cell lymphoma (MCL) has a poor prognosis under conventional therapy. Allo-SCT after conventional or reduced-intensity conditioning is here a promising approach. Methods: Two prospective trials were conducted to investigate the efficacy of chemotherapy-based conditioning followed by allo-SCT for treatment of MCL: Trial #074 was open for patients with de-novo MCL and #060 for patients requiring salvage therapy. At least a pR to (re)-induction therapy was mandatory for proceeding to allo-SCT. Conditioning consisted of treosulfan (12g/m2) and fludarabin (150mg/m2). Busulphan (16mg/kg) and cyclophosphamide (120mg/kg) was optional for younger patients. ATG was given prior to mismatched or mud SCT. Assessment of minimal residual disease was performed with real-time PCR-amplification of t(11;14) or of specific CDR3-sequences. Results: 39 patients have been recruited into both trials (#060: n=15, #074: n=24). 31 patients are male and 8 are female with a median age of 59y (33–69). In de-novo patients the median MIPI was 5 (2–9). Salvage patients were pre-treated with 8 (6–13) cycles chemotherapy. (Re)-Induction prior to TX consisted mainly of R-CHOP or R-DHAP. 33 patients proceeded to allo-TX from mrd or mud. 2 patients died from progressive disease prior to TX, 1 patient had no suitable stem cell donor, in one case the diagnosis was revised and 2 patients were withdrawn. 26 patients (79%) were conditioned with Treo/Flu and 7 (21%) with Bu/Cy. 76% (n=25) of patients received a graft from an unrelated donor. Toxicity was moderate and incidence of acute GvHD was 51%. The median follow-up after allogeneic stem cell transplantation was 18 months with a range from 0,26 to 113,7 months. The median disease-free and median overall survivals have not been reached. Three patients have relapsed after transplantation between 5,4 and 26,7 months after transplantation. One of these suffered from blastic variant of MCL. 26 patients are alive with a median KI of 100% (range 50%-100%) after SCT with a median follow-up of 18 months (0,3–114) without differences between both trials (p=0,67). 6 patients have died from infections and cerebral bleeding (n=1) and one from infection related to an acute GvHD IV° due to DLI for relapse (blastic variant) ten months after SCT in CR of MCL. Molecular analyses showed a 2–4log reduction of circulating lymphoma cells after chemotherapy alone. Blood became negative by qPCR after allo-SCT in all 5 patients analysed so far. An intermediate increase of circulating lymphoma cells in 4 patients was successfully treated by rituximab, withdrawal of Cy-A and DLI. Conclusion: Allo-SCT is a standard salvage therapy for suitable patients and an option for patients with de-novo MCL. Long-term remissions can be reached and negativity of mrd analyses by qPCR strongly supports curative potential of allo-SCT. GvL-effect has curative potential even in the case of relapsed blastic variant of MCL. Disclosures: Sayer: Medac:.

Description: In a prospective multicenter phase III trial (M 39023) advanced stage follicular lymphoma (FL) patients were randomized to receive eight cycles of MCP (mitoxantrone, chlorambucil, prednisolone) chemotherapy alone or in combination with rituximab (R-MCP). This study was carried out to determine the effects of this therapy on circulating lymphoma cells (CLC) and to assess the value of CLC quantitation as a molecular marker of disease activity and as a prognostic parameter. CLC numbers were determined by real-time quantitative PCR for the t(14;18)-MBR translocation or by allele-specific PCR for rearranged immunoglobulin heavy chain genes. Quantitative PCR of a reference gene (wild type K-ras) allowed the exact quantitation of cells tested per sample and to exclude samples with insufficient DNA content (〈 500,000 cells). We analyzed serial blood samples from 43 patients obtained before, during and after completion of therapy. Baseline clinical characteristics and response to therapy of the 43 patients of this study were not significantly different to all 201 FL patients of the clinical trial except for a higher complete response (CR) rate in the R-MCP group (18/25 (72%) in this study versus 52/105 (50%) in the clinical trial, p=.04). Similar to the results of the clinical study, response rate and CR rate in the present study were significantly higher in the R-MCP arm than after therapy with MCP alone (25/25 (100%) versus 13/18 (72%), p= .009, and 18/25 (72%) versus 5/18 (28%), p= .006, respectively). Clearance of CLC at the end of therapy was achieved in 21/25 patients (84%) treated with R-MCP compared to 0/18 (0%) after MCP alone (p〈 .0001). R-MCP patients achieved a greater reduction of CLC after completion of therapy and a greater reduction of CLC per treatment cycle than patients treated with MCP alone, even if the comparison was restricted to patients with clinical response (3.88 log and 1.18 log reduction versus 2.21 log and 0.23 log reduction, p= .001 and p〈 .0001). A ≥ 2 log reduction of CLC after completion of therapy was associated with a favourable clinical response (p= 0.0007) and prolonged event-free survival (p= 0.02) regardless of treatment arm. Among patients with a ≥2 log CLC reduction there was no significant difference in EFS between patients with PCR negative samples and patients with PCR positive blood samples at completion of therapy (p= 0.091). In conclusion, R-MCP led to a rapid and sustained eradication of CLC in the majority of patients. The results of serial determinations of CLC numbers showed a good correlation with the quality and duration of the clinical response. Therefore, quantitative molecular disease monitoring could help to develop individualized treatment strategies for patients with advanced stage FL.

Description: Abstract 893 Introduction: A European collaborative harmonization study involving 61 laboratories is being conducted under the auspices of the European Treatment and Outcome Study (EUTOS) for CML that aims to facilitate reporting of molecular BCR-ABL quantification results according to the International Scale (IS). The aim of this analysis was to investigate the effectiveness of this process and specifically the stability of conversion factors (CF) over time. Methods: The currently accepted way of adopting the IS is to establish and validate a laboratory-specific CF which is then used to convert local results to the IS. For round 1, preliminary CFs were calculated by centrally distributing standard samples containing 10–20 million WBC approximating to 10%, 1%, 0.1%, and 0.01% BCR-ABL IS. Rounds 2 and 3 were employed to refine the CF calculations using 25–30 CML patient samples from each participating laboratories covering a range of BCR-ABL levels between 0.01% and 10%. Log BCR-ABL values for the same samples were compared between reference and local laboratories applying the Bland-Altman bias plot. In order to judge the stability of each laboratory`s methodology, a CF index (ratio of round 3 CF divided by round 2 CF) was calculated and evaluated according to its capability to achieve optimum concordance of results. Results: Of the 61 laboratories participating in round 1, evaluable patient samples have been provided to date by 56 and 30 laboratories in rounds 2 and 3, respectively. Of the 30 laboratories with complete data, 12 had stable CFs (defined as a CF index within 0.75–1.33) whereas 18 laboratories were outside this range. Comparison of the CFs derived from round 2 with those derived from round 3 revealed better and more consistent concordance between laboratories with stable CFs compared to those with unstable CFs. For the 12 stable laboratories, 79% (round 3 CF) vs 79% (round 2 CF) of the samples were within a 2-fold range (0.5–2.0) and 93% vs 89% were within a 3-fold range (0.33–3.0). For the 18 unstable laboratories, 74% vs 55% of the samples were within a 2-fold range (0.5–2.0), p=0.0005 and 92% vs 77% were within a 3-fold range (0.33–3.0), p=0.0005. 2 of 12 laboratories with stable CFs and 8 of 18 laboratories with unstable CFs indicated changes in either one or more components of their procedures (cDNA synthesis, PCR platform, RQ-PCR protocol) that may have impacted on their CFs. Conclusion: These data indicate that CFs may be unstable in some laboratories even in the absence of significant changes to laboratory protocols. Further, it supports the need for continuous revalidation of CFs. In laboratories with unstable CFs we suggest revalidation within 3 to 6 months whereas those with stable CFs should be assessed on a yearly basis. We also suggest that laboratories with unstable CFs need to rigorously examine their internal processes to identify potential sources of variation. Disclosures: Müller: Novartis: Honoraria, Research Funding. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.

Description: In patients with follicular lymphoma (FL) circulating lymphoma cells (CLC) can be detected by quantitative real-time PCR with a high sensitivity and reproducibility. Sustained molecular remission is associated with a significantly longer relapse-free survival whereas evidence of PCR detectable MRD was associated with recurrent disease in several studies. Furthermore, we and other reported long-term remission in some FL patients being persistently PCR positive. However, molecular monitoring to guide therapy and to predict clinical relapses is not routinely performed or integrated in clinical studies. Between 1996 and 2006 a long-term molecular monitoring of CLC was done in all FL patients with a PCR-detectable t(14;18) translocation. CLC numbers were determined by a standardized quantitative real-time PCR for the detection of lymphoma cell specific t(14;18) rearrangement [Dölken,L. et al.; Biotechniques1998;25:1058–1064]. The K-ras wild-type gene served as reference gene to determine the number of cells in a given sample. We identified 9 patients who developed a relapse after chemotherapy alone (n=4), or in combination with rituximab (n=2), radiotherapy (n=1) and autologous stem cell transplantation (n=2) and for whom at least 4 PBMNC samples (median 5 samples; range 4–8) were collected at different time points before and after the clinical relapse. All patients had either decreasing or stable numbers of t(14;18) positive cells within a period of at least 6 months before clinical relapse. Only one patient had an early relapse 4 months after start of initial chemotherapy, all other patients had a relapse 1 – 6 years later. Being in clinical remission 8/9 patients had CLC numbers 〈 100/105 PBMNC. 4/9 patients had a molecular remission before they relapsed. A median CLC increase of 2log (range 1–4log) in association with relapse could be observed in all patients after a molecular remission or a decreasing or a stable amount of circulating t(14;18) positive lymphoma cells was achieved. The corresponding clinical relapse was diagnosed at a median of 1.5 months later after the first PBMNC sample with a ≥1log CLC increase. We defined a molecular relapse by a 2log CLC increase in 2 consecutive blood samples within 6 months. 6/9 patients fulfilled these criteria when applying this definition. In 3/9 patients the kinetics of increase of CLC was below this arbitrary chosen threshold. In conclusion, increasing numbers of CLC precede clinical relapse in all patients. Only two thirds of relapses would have been classified by our definition of molecular relapse if this study had been performed prospectively. However, sensitive, reproducible and quantitative techniques are now available to detect very low levels of circulating lymphoma cells. A lasting molecular remission is of predictive value for an improved failure-free survival. Hence, the optimal timing and frequency of molecular monitoring remains further unclear especially when aimed at the prediction of clinical relapses and has to be confirmed in large prospective studies.

Description: Introduction Detection of minimal residual disease (MRD) in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) in complete hematological remission (CR) offers a potential therapeutic window allowing early interventions in order to prevent overt hematological relapse. Due to the absence of generic markers in AML/MDS, MRD assessment seems to be a complex procedure. As prospective clinical studies are sparse, we initiated a retrospective survey within the SAL (Study Alliance Leukemia) study group and members of the German Cancer Consortium to evaluate the current clinical use of the approach and related clinical outcome of treated patients. Patients Based on questionnaires we analyzed 84 patients from five clinical centers (pts, m/f=46/38; median age 52 yrs (19-74)) with either AML (n=77) or MDS (n=7) in CR after conventional intensive chemotherapy (CTx; n=23) or allogeneic hematopoietic stem cell transplantation (allo-HSCT; n=61), undergoing preemptive therapy. Mutations, cytogenetic aberrations or donor chimerism analysis for transplanted pts were monitored as MRD markers. Thirty-three pts had a normal and 14 pts - a complex karyotype; 6 pts carried -7 and/or inv(3); other aberrations were detected in 29 pts; in 2 pts no data were available. Among molecular aberrations, NPM1 (n=23) and FLT3-ITD (n=13) were the most frequent, followed by CBFβ/MYH11 (n=8), RUNX1/RUNX1T1 (n=8) and MLL/AF6 (n=3). In 20 pts no mutations were found. For 5 pts data on molecular diagnostics were not available and MRD was assessed by chimerism. Results The median time to MRD positivity after completion of intensive therapy was 12 months (range, 1-97). Subsequent MRD-guided therapy in pts treated only with CTx included hypomethylating agents (HMA, 34%), clofarabine (17%), additional intensive CTx (9%), targeted therapy (gemtuzumab ozogamycin, 9%), low-dose cytarabine (9%), and allo-HSCT (22%). Other treatment strategies included interferon alfa and sorafenib. In transplanted patients the most preferred treatment for the molecular relapse was donor lymphocyte infusion (26 pts, 43%; median number of DLI=3, range, 1-6), alone or in combination (54% with HMA). 32 MRD-based treated pts (43%) did not experience a hematological relapse and were either alive (23 pts, median observation time 953 days, range, 30-3660), or died due to another cause (9 pts) with median survival of 359 days (range, 125-954). In 9 pts without hematological relapse more than one MRD recurrence was observed. In the remaining 57% relapsing patients, median time to hematological relapse was 252 days (range, 24-1161) after MRD positivity. Interestingly, in some pts the hematological relapse was observed in the absence of the known mutation, indicating that the disease probably progressed due to another subclone. Thus, an accurate initial diagnostic is essential, ideally a multiple gene approach and comprehensive follow-up. Conclusions The retrospective analysis demonstrates that MRD-guided therapies have already entered routine practice in patients with AML and MDS. The heterogeneous nature of both cancer entities is reflected by the variety of MRD surveillance protocols among clinical centers. Therefore, clinical trials are needed to better define molecular markers and subsets of patients who might benefit from this approach. Disclosures Mayer: Janssen: Research Funding. Thiede:AgenDix GmbH: Equity Ownership. Platzbecker:Novartis: Honoraria; GlaxoSmithKline: Honoraria, Research Funding; Celgene: Honoraria; Amgen, Inc.: Honoraria.

Description: Abstract 2293 Regulation of the balance between symmetric and asymmetric cell division is considered to be important for hematopoietic stem cell (HSC) division and homeostasis. Recently, several polarity regulators have been shown to influence HSC function using RNAi-screening approaches. Llgl1 is a known regulator of cell polarity in drosophila and epithelial cells, however, its role in HSC remains elusive. Using a previously published conditional knockout mouse model with exon 2 of Llgl1 being flanked by loxP-sites we generated Llgl1loxP/loxP Mx-Cre+ animals and induced deletion of Llgl1 (Llgl1−/−) by administration of pIpC as determined by PCR. After deletion of Llgl1 no significant abnormalities in hematopoiesis were evident for 16 weeks in the peripheral blood. However, bone marrow of Llgl1−/− animals revealed up to a 2-fold increase in HSC (CD34lo Flk2− LSK). When transplanted competitively into recipient animals Llgl1−/− cells showed a significant competitive advantage compared to Llgl1+/+ controls, and that competitive advantage increased over time in serial transplants. In tertiary recipient mice the bone marrow was dominated by Llgl1−/− cells with a chimerism of above 90%. Llgl1 deleted animals show increased numbers of cycling HSC (CD34lo LSK) when compared to their wildtype counterparts as detected by Ki-67 staining (64.94% ± 2.537 Llgl1+/+ HSC vs 50.81% ± 4.213 Llgl1−/− HSC in G0; p=0.0184*) and BrdU incorporation and this effect was restricted to the HSC compartment. The Llgl1 deleted cells proved to be better able to reconstitute hematopoiesis after being stressed in ex vivo culture, and protected the survival of recipient mice to a higher extent than wildtype cells. Gene-expression analysis on sorted Llgl1−/− versus Llgl1+/+ steady state HSC revealed known regulators of HSC self-renewal capacity (such as Hox-genes and self-renewal associated transcription factors) to be among the top regulated downstream targets. The observed phenotype suggests that Llgl1 expression might influence leukemogenesis and its close homologue Llgl2 has been described recently as an early hit in malignant transformation of chronic neutropenia. Thus, we analyzed Llgl1 gene-expression in human acute myeloid leukemia (AML). Llgl1 was the top polarity regulator to be down-regulated in leukemia initiating cells of different phenotype (L-MPP or L-GMP), when compared to their normal counterparts (MPP or GMP). Moreover, reduced Llgl1 expression was associated with inferior overall survival in two independent patient cohorts treated for AML: Low expression of Llgl1 as measured by Affymetrix gene arrays was associated with decreased survival in 83 karyotypic normal (CN-) AML patients below the age of 60 (p=0.0092**). This finding could be confirmed in an independent CN-AML cohort (n=80, p=0.0056**) by qRT-PCR. Moreover, the Llgl1−/− GEP signature obtained from murine HSC was not associated with a specific genetic subgroups of a human AML dataset, but AML cases matching this signature showed again decreased overall survival (p=0.0089**). Genetic inactivation of Llgl1 contributes to fitness and viability of hematopoietic stem cells in vivo. Given its impact on survival in patients treated for AML it is tempting to speculate on its role in development and maintenance of leukemia stem cells (LSC). Disclosures: No relevant conflicts of interest to declare.