scholarly journals KIT D816 Mutated / CBF-Negative Acute Myeloid Leukemia (AML): A New Poor-Risk Subtype Associated with Systemic Mastocytosis (SM-AML)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1535-1535
Author(s):  
Mohamad Jawhar ◽  
Konstanze Döhner ◽  
Sebastian Kreil ◽  
Juliana Schwaab ◽  
Khalid Shoumariyeh ◽  
...  
Keyword(s):  
Research Funding ◽  
De Novo ◽  
Systemic Mastocytosis ◽  
Response To Treatment ◽  
Treatment Modalities ◽  
Molecular Characteristics ◽  
Molecular Analyses ◽  
Poor Risk ◽  
Myeloid Neoplasm ◽  
De Novo Aml

Abstract Systemic mastocytosis with an associated hematologic neoplasm (SM-AHN) is the most common subtype of advanced SM (advSM), diagnosed in up to 80% of patients. The AHN is most frequently diagnosed as a myeloid neoplasm, e.g., SM-MDS/MPNu or SM-CMML. Acquired mutations in KIT (usually KIT D816, KIT D816mut) are detectable in >90% of patients. The basis for the SM-AHN phenotype is usually the multi-lineage involvement, e.g. monocytes, eosinophils and other non-mast cell lineages, of KIT mutations. Core binding factor (CBF) positive AML (CBFpos AML) represents a distinct subtype and is identified in 5-8% of all AMLs. KIT mutations, most frequently KITD816mut, are detectable in up to 45% of CBFpos AML patients and are associated with an adverse prognosis. There is, however, only little information on KIT D816mut/CBFneg AML. We therefore evaluated a) clinical and molecular characteristics, b) response to treatment and, c) survival and prognostic factors in 40 KIT D816mut/CBFneg patients with histologically proven SM and associated AML (SM-AML), collected at 4 centers of the European Competence Network on Mastocytosis (ECNM). Molecular analyses (n=32) revealed at least one additional somatic mutation (median, n=3) apart from KIT D816, most frequently SRSF2 (n=12, 38%), RUNX1 (n=11, 34%), TET2 (n=11, 34%), ASXL1 (n=10, 31%), or NPM1 (n=7, 22%). At least one mutation in SRSF2, ASXL1 or, RUNX1 (S/A/Rpos) was identified in 21/32 (66%) patients. At diagnosis of SM-AML 21/40 (52%) patients had an aberrant karyotype. Secondary AML evolved in 29/40 (73%) patients from SM ± associated myeloid neoplasm and longitudinal molecular analyses revealed acquisition of new somatic mutations (TP53, n=2; NPM1, n=1; RUNX1, n=1, ASXL1, n=1; BCOR, n=1; IDH1/2, n=1) and/or karyotype evolution in 15/16 (94%) patients at the time of SM-AML. Thirty-one of 40 (78%) patients were treated with intensive chemotherapy (ICT) with a complete response (CR) rate of 40%. Allogeneic stem cell transplantation (SCT) was performed in 12/40 (30%) patients with durable CR in 6/12 (50%) patients. S/A/Rpos and/or the presence of a poor-risk karyotype were adverse predictive markers for response to treatment. To further investigate whether KITD816mut/CBFneg AMLdefines a distinct AML subtype associated with SM, two independent AML databases (AMLdatabases) were retrospectively screened and 69 KIT D816mut/CBFneg AML patients identified. The comparison between KIT D816mut/CBFneg SM-AML from ECNM (n=40) centers with KIT D816mut/CBFneg AMLdatabases(n=69) revealed remarkable similarities: a) a high KIT D816 variant allele frequency (VAF) (median 34% vs. 29%), b) with the exception of SRSF2 (38 vs. 18%), a highly similar mutation landscape, rather comparable to that of advSM (Jawhar et al., Blood 2017) than to that of de novo AML, c) in contrast to de novo AML, a low frequency of FLT3 mutations (3 vs. 7%), and d) a high frequency of an aberrant karyotype (52 vs. 42%). The median overall survival (OS) of 40 KIT D816mut/CBFneg SM-AML and 17 evaluable KIT D816mut/CBFneg AMLdatabases was 5.4 (95% confidence interval, CI [1.7-9.1]) and 26.4 (95% CI [0-61.0]) (P=0.015) months, respectively (Figure 1). However, if only the patients with ICT ± allogeneic SCT were compared, median OS between the two groupswas not different (16.7 vs. 26.4 months, P=0.4). In multivariate analyses, S/A/Rpos and a poor-risk karyotype remained the only independent poor-risk factors with regard to OS. These results were independent of treatment modalities. We conclude that KIT D816mut/CBFneg AML is a new poor-risk subtype associated with SM (SM-AML). The remarkable clinical, genetic and prognostic similarities between SM-AML and AMLdatabases suggest that a significant proportion of the AMLdatabases patients may in fact have SM-AML. We therefore strongly recommend to determine serum tryptase and KIT D816 mutation status in all AML patients, and to perform bone marrow histology in KIT D816mut patients. These simple diagnostic measures would allow reclassification to SM-AML and inclusion of KIT inhibitors in established treatment modalities of AML. Disclosures Meggendorfer: MLL Munich Leukemia Laboratory: Employment. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Döhner:Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AROG Pharmaceuticals: Research Funding; Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria; Celator: Consultancy, Honoraria; Bristol Myers Squibb: Research Funding; Celator: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Astex Pharmaceuticals: Consultancy, Honoraria; AROG Pharmaceuticals: Research Funding; Astellas: Consultancy, Honoraria; Agios: Consultancy, Honoraria; Astex Pharmaceuticals: Consultancy, Honoraria; Agios: Consultancy, Honoraria; Bristol Myers Squibb: Research Funding; Jazz: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Pfizer: Research Funding; Pfizer: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding. Sperr:Novartis: Honoraria; Pfizer: Honoraria; Daiichi Sankyo: Honoraria. Valent:Incyte: Honoraria; Pfizer: Honoraria; Novartis: Honoraria. Reiter:Incyte: Consultancy, Honoraria.

scholarly journals Clinical Characteristics and Outcomes of Patients with Newly Diagnosed De Novo Acute Myeloid Leukemia (AML) during the COVID-19 Pandemic

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2291-2291
Author(s):  
Hari S. Raman ◽  
Yael Flamand ◽  
Marlise R. Luskin ◽  
Daniel J. DeAngelo ◽  
Richard M. Stone ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Disease Burden ◽  
De Novo ◽  
Molecular Characteristics ◽  
Advisory Committees ◽  
Flt3 Mutations ◽  
De Novo Aml ◽  
Acute Myeloid

Abstract Introduction The COVID-19 pandemic disrupted non-urgent and preventive medical care. During the early peak of the pandemic, an estimated 41% of US adults delayed or avoided medical care (Czeisler et al, CDC, 2020). While there were documented declines in the number of emergency department visits for myocardial infarction, stroke and hyperglycemia, similar data is not available related to acute myeloid leukemia (AML) (Lange et al, CDC, 2020). A delay in the diagnosis of AML could lead to presentation when patients are less able to withstand chemotherapy or have a higher disease burden which could compromise overall survival (OS). In this retrospective analysis, we aim to elucidate if there was a difference in clinical, cytogenetic, or molecular presentations and if there was an effect on early mortality as determined by overall survival at 1 and 6 months. Methods We compared the clinical, cytogenetic, and baseline molecular genetics of consecutive adult patients diagnosed with de novo AML at Dana-Farber Cancer Institute/Brigham and Women's (DFCI/BWH) Hospital from March 23, 2020, the date of the Massachusetts COVID State of Emergency, to August 23, 2020 to a historical cohort of similar patients between presenting between March 23, 2017 and August 23, 2020. Data was obtained from the Hematological Malignancy Data Repository and via review of the medical record. Patients were excluded from this cohort if they were diagnosed with acute promyelocytic leukemia, had known antecedent myeloid malignancy, or if they did not have DFCI/BWH 96-gene next-generation sequencing panel (RHP) performed at the time of diagnosis. Baseline clinical, laboratory, cytogenetic, and molecular characteristics and outcomes were compared between the pre-pandemic and pandemic cohorts using chi-squared, Fisher's exact, and Wilcoxon rank sum analyses (where appropriate) at a significance of p<0.05. Results Thirty-eight AML patients presented during the COVID-19 pandemic (PAN) and 308 in the pre-pandemic (PREPAN) period. There was no statistically significant difference in the monthly rate of new patients presenting in PREPAN and PAN cohorts (8 vs. 6 new patients/month, p=0.73). The median age at presentation (64 PREPAN vs. 65 PAN, p=0.77), sex, and therapeutic approach (intensive, non-intensive, supportive care, other) were not statistically different between cohorts. Presenting white blood cell count, platelet count, and fibrinogen were not different between cohorts, while hematocrit was significantly lower in the PAN cohort (23.8% vs. 26.0%, p=0.001). There was a trend for a higher median blast percentage (28.5% vs. 13%, p=0.09) in the PAN cohort. There were no differences between the cohorts in the median number of cytogenetic abnormalities, nor in the incidence of complex karyotype, (25.3% vs. 23.7%) across PREPAN and PAN respectively. There were also no significant differences in the European LeukemiaNet (ELN) risk classification scores across the PREPAN and PAN time periods, with 57.8% vs. 52.6% of total patients presenting with adverse risk disease respectively. When specific mutations of TP53, NPM1, and FLT3 were evaluated, only FLT3 demonstrated a statistical difference with a higher proportion in the pandemic group (p=0.04). OS at 1-month (97.4% and 93.2%, p=0.15) and 6-months (71.1% and 75.0%, p-0.87) were not statistically different in the PREPAN and PAN cohorts, respectively. Conclusion These data represent a novel analysis of the presenting clinical, cytogenetic and molecular characteristics of de novo AML during the COVID-19 pandemic. In contrast to other diseases, we did not see fewer de novo AML presentations during the peak of the COVID pandemic. While the reasons are unknown and require validation in large cohorts, the symptoms of leukemia including symptomatic anemia (low hematocrit) and higher WBC and blast count possibly driven by FLT3 mutations may drive patients to seek emergent clinical evaluation despite COVID pandemic barriers. The lack of difference in cytogenetic or other prognostic entities may demonstrate a lack of symptom correlation causing patients to present for care. The higher incidence of FLT3 mutations and lower hematocrit could reflect more symptomatic presentation of AML during the COVID pandemic. Since these differences may be a surrogate for a higher disease burden, it will be important to compare outcomes at longer time points. Figure 1 Figure 1. Disclosures DeAngelo: Pfizer: Consultancy; Novartis: Consultancy, Research Funding; Jazz: Consultancy; Incyte: Consultancy; Forty-Seven: Consultancy; Autolus: Consultancy; Amgen: Consultancy; Agios: Consultancy; Takeda: Consultancy; Glycomimetrics: Research Funding; Blueprint: Research Funding; Abbvie: Research Funding; Servier: Consultancy. Stone: Bristol Meyers Squibb: Consultancy; Astellas: Membership on an entity's Board of Directors or advisory committees; BerGen Bio: Membership on an entity's Board of Directors or advisory committees; Boston Pharmaceuticals: Consultancy; Innate: Consultancy; Foghorn Therapeutics: Consultancy; Gemoab: Membership on an entity's Board of Directors or advisory committees; Glaxo Smith Kline: Consultancy; Celgene: Consultancy; Elevate Bio: Membership on an entity's Board of Directors or advisory committees; OncoNova: Consultancy; Syntrix/ACI: Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Agios: Consultancy, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Aprea: Consultancy; Arog: Consultancy, Research Funding; Jazz: Consultancy; Macrogenics: Consultancy; Novartis: Consultancy, Research Funding; Actinium: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy; Syros: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy. Garcia: AstraZeneca: Research Funding; Prelude: Research Funding; Pfizer: Research Funding; Genentech: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Winer: Abbvie: Consultancy; Takeda: Consultancy; Novartis: Consultancy.

scholarly journals The Prognostic Impact of the Diagnostic CD34+/CD38- Cell Burden and Expression of the Stem Cell Marker GPR56 after Stem Cell Transplantation Depends on the AML Origin

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 323-323
Author(s):  
Madlen Jentzsch ◽  
Marius Bill ◽  
Juliane Grimm ◽  
Dominic Brauer ◽  
Julia Schulz ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Solid Tumors ◽  
Cell Transplantation ◽  
Research Funding ◽  
De Novo ◽  
Prognostic Impact ◽  
Expression Levels ◽  
Rheumatologic Diseases ◽  
De Novo Aml

Introduction: Acute myeloid leukemia (AML) developing secondary after other hematologic diseases, or therapy related after cytotoxic treatment for solid tumors or rheumatologic diseases (s/tAML) is clinically, genetically & prognostically distinct from de novo diseases. Data indicate that s/tAML patients (pts) have inferior outcome compared to de novo cases after chemotherapy & therefore often require consolidation therapy using allogeneic stem cell transplantation (HSCT). Leukemic stem cells (LSC) initiate & maintain AML. They are also believed to exist within the CD34+/CD38- &/or high GPR56 expressing bone marrow (BM) population, which have been shown to impact adversely on outcome. The prognostic impact of LSC markers in de novovs s/tAML after HSCT with non-myeloablative conditioning intensity - where the therapeutic approach also relies on immunological graft-versus-leukemia effects - is unknown. Methods: We analyzed 379 AML pts who received an allogeneic peripheral blood HSCT in complete remission (CR, 82%) or CR with incomplete peripheral recovery (CRi, 18%) between 1999 & 2018 after non-myeloablative (3x30 mg/m2 Fludarabine & 2 Gy total body irradiation) conditioning. At diagnosis, cytogenetic & flow cytometric analyses were performed centrally. For pts with pre-treatment BM available the mutation status of CEBPA, NPM1 & presence of FLT3-ITD by fragment analyses as well as expression levels of GPR56 by qPCR were assessed. Using a next-generation targeted amplicon sequencing approach we analyzed a panel comprising 54 recurrently mutated (mut) genes in myeloid malignancies on the MiSeq platform (Illumina). Median follow up after HSCT was 3.7 years. Results: 229 pts (60%) had de novo & 150 pts (40%) had AML secondary to myelodysplastic syndrome (MDS, n=82), myeloproliferative neoplasm (MPN, n=22) or MDS/MPN (n=10), or therapy related after Non-Hodgkin lymphoma (n=9), solid tumors (n=25) or rheumatologic diseases (n=2). At diagnosis, s/tAML pts had lower white blood counts (P=.03), lower blasts in BM (P<.001) or blood (P=.007) & a higher BM CD34+/CD38- cell burden (P=.01) & GPR56 expression (P=.04). They also had worse European LeukemiaNet risk (P=.007), were less likely to have a normal karyotype by trend (P=.06), to have a core binding factor AML (P=.02), to be NPM1mut (P=.003), DNMT3Amut (P=.03) & to harbor a FLT3-ITD (P=.002) but more likely to be JAK2mut (P<.001). Comparing pts with s/tAML vsde novo AML, there was no significant different cumulative incidence of relapse (CIR, P=.85) or overall survival (OS, P=.29). Next, we evaluated the prognostic impact of the LSC-associated populations in pts with de novo or s/tAML separately. In pts with de novo AML, we observed a significantly higher CIR & shorter OS for pts harboring a high CD34+/CD38- cell burden (high vs low, 6% cut, P=.006 [Fig. 1A] & P=.003) & a higher CIR but not significantly different OS for pts with a low GPR56 expression (high vs low, median cut, P=.03 [Fig. 1B] & P=.95). Combining both parameters, we observed a stepwise higher CIR & shorter OS for pts with low expression of both variables vs pts with a low CD34+/CD38- cell burden but high GPR56 expression vs pts with a high CD34+/CD38-cell burden (P=.003 [Fig. 1C] & P=.05). In contrast, in pts with s/tAML, there was no prognostic significance of the CD34+/CD38- cell burden (CIR P=.38 [Fig. 1D] & OS P=.95), the GPR56 expression (CIR P=.64 [Fig. 1E] & OS P=.82) & both markers combined (CIR P=.57 [Fig. 1F] & OS P=.98). Also in multivariate analyses, the combination of both markers significantly impacted CIR (Hazard ratio 2.49, P<.001 after adjustment for donor type) & was the only significant factor for OS (Odds Ratio 0.68, P=.04) in de novo AML but not in s/tAML. Conclusion: While there was no significantly different CIR or OS in s/tAML compared to de novo AML pts undergoing non-myeloablative HSCT we observed a significant impact on outcome for the known LSC-associated prognosticators CD34+/CD38- cell burden & GPR56 expression levels at diagnosis only in de novo AML pts. Different underlying disease biology & possibly different LSC-associated populations may be relevant for disease reoccurrence in s/tAML. Figure Disclosures Jentzsch: Novartis: Honoraria; Jazz Pharmaceuticals: Honoraria. Niederwieser:Daichii: Speakers Bureau; Cellectis: Consultancy. Platzbecker:Abbvie: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Schwind:Daiichi Sankyo: Honoraria; Novartis: Honoraria, Research Funding.

Therapy-related acute myeloid leukemia with t(8;21), inv(16), and t(8;16): a report on 25 cases and review of the literature.

1993 ◽  
Vol 11 (12) ◽  
pp. 2370-2379 ◽  
Author(s):  
B Quesnel ◽  
H Kantarjian ◽  
J P Bjergaard ◽  
P Brault ◽  
E Estey ◽  
...  
Keyword(s):  
Topoisomerase Ii ◽  
De Novo ◽  
Hematologic Malignancy ◽  
Disease Free Survival ◽  
Previous Treatment ◽  
Response To Treatment ◽  
Prior Chemotherapy ◽  
De Novo Aml ◽  
Disease Free Survival Rate ◽  
Acute Myeloid

PURPOSE To analyze therapy-related acute myeloid leukemias (tAMLs) with t(8;21), inv(16), or t(8;16). PATIENTS AND METHODS Twenty-five patients with tAML and t(8;21)(q22;q22), inv(16)(p13;q22), or t(8;16)(p11;p13) from seven centers, along with 23 previously published cases, were studied. RESULTS Twenty-six, 16, and six patients, respectively, had t(8;21), inv(16), and t(8;16). Prior cancer was a solid tumor in 27 cases, and a hematologic malignancy in all other patients. Five patients had received prior radiotherapy (RT) alone, and 43 had received prior chemotherapy with or without RT. Prior chemotherapy included a drug that directly reacts with DNA (alkylating agent or cisplatin) and/or an agent that targets topoisomerase II (ATTop, an anthracycline or derivative or, less often, epipodophyllotoxin) in most patients. The interval between prior tumor and diagnosis of tAML was less than 3 years in most cases, and only seven patients had a preleukemic phase of disease. Morphology was M2 AML for t(8;21), M4eo for inv(16), and M4 or M5 for t(8;16). Sixteen of 21 (76%), 12 of 14 (86%), and zero of four patients with t(8;21), inv(16), and t(8;16), respectively, achieved complete remission (CR) with intensive chemotherapy. The actuarial disease-free survival rate at 24 months was 47% and 54% in patients with t(8;21) and inv(16), respectively. CONCLUSION Like other tAMLs with a karyotype specific of de novo AML [balanced 11q23 rearrangement or t(15;17)], tAMLs with t(8;21), inv(16), or t(8;16) are usually characterized by a short latent period, previous treatment often combining a drug that directly reacts with DNA and an ATTop, and absence of preleukemic phase. Hematologic characteristics and response to treatment are also identical to those of de novo AML with the same karyotypes.

A New Prognostic Disease Specific Model To Predict Survival after Intensive Antileukemic Treatment for Young Patients with Poor-Risk MDS and AML: Results of the CRIANT and AML-10 Studies Conducted by the EORTC/GIMEMA/SAKK/HOVON/EBMT Groups.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2020-2020
Author(s):  
M. Oosterveld ◽  
S. Suciu ◽  
P. Muus ◽  
M. Delforge ◽  
A. Belhabri ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
High Risk ◽  
Prognostic Value ◽  
De Novo ◽  
Survival Rates ◽  
White Blood Count ◽  
Poor Risk ◽  
Prognostic Importance ◽  
De Novo Aml ◽  
Disease Specific

Abstract The use of intensive antileukemic treatment is less widely accepted in high-risk MDS pts compared to de novo AML, due to the reported inferior results. It is questionable whether the poorer outcome reflects an intrinsic property of the involved stem cell or a higher frequency of poor prognostic factors. The purpose of this analysis is to identify disease-specific prognostic factors for outcome of young (aged <56 years) MDS and AML pts. This analysis combines the data of 591 pts in the AML-10 study and 203 pts with high-risk MDS or secondary AML (sAML) in the CRIANT study. Both groups received identical remission-induction therapy (idarubicin, cytarabine and etoposide), followed by one consolidation course with intermediate dose of cytarabine and idarubicin (IDIA). In both studies post-consolidation therapy consisted of alloSCT if an HLA-identical sibling donor was available. The remaining pts received autoSCT (ASCT) in AML-10 or were randomized between ASCT and a 2nd consolidation course in CRIANT. The CR rate was 68% (AML-10) vs. 59% (CRIANT) (p=0.02). The 4-year survival rates were 35% vs. 33% (p=0.80). DFS at 4 years was 43% (AML-10) vs. 35% (CRIANT) (p=0.18). For overall survival (OS) in both studies, study was not of importance (HR=1.09, p=0.45), but the following variables showed independent prognostic value: cytogenetic risk group (the HR for poor vs intermediate risk was 1.68, 95% CI 1.24–2.27, p=0.0008), white blood count (WBC) ≥ 100 x 109/l (HR=2.02, 95% CI 1.53–2.68, p<0.0001), age 46–55 yrs (HR=1.39, 95% CI 1.16–1.67, p=0.0004) and performance status (PS) (HR=1.32, 95% CI 1.17–1.49, p <0.0001). For DFS, the following factors were of an independent prognostic importance: cytogenetics (p<0.0001), age 46–55 (HR=1.23, p=0.05), WBC >100 (HR=1.67, p=0.02) and donor availability (HR=0.77, p=0.04). Some variables were of prognostic value for OS in only one of the studies: in the CRIANT study number of cytopenias (3 vs 0–2) and AHD >6 months appeared of prognostic importance for OS, wherease FAB subtype M2/M4 and cytogenetics inv(16)/t(8;21) were prognostic in AML-10. Therefore a specific prognostic score for OS was established for each study, AML-10 (based on cytogenetics, PS, FAB, WBC and age) and CRIANT (based on cytogenetics, nr of cytopenias, age, AHD and WBC). The AML-10 study distinguished 5 groups with an estimated 4-year survival rate of 69%, 40%, 45%, 26% and 17%, resp. The prognostic value of this score has been validated on patients treated in the AML-10 study with mitoxantrone instead of idarubicin: the 4-year survival were 76%, 46%, 41%, 33% and 18%, resp. The CRIANT study distinguished 5 groups with a 4-year survival rates of 72%, 44%, 39%, 12% and 0%, resp. In conclusion: the prognostic scores identify a group of 26% AML and 42% MDS pts, with a 4-year survival less than 20%. Apparently current treatment modalities are unsatisfactory for these poor-risk pts and novel treatment strategies should be offered to these pts in the context of clinical trials. Our finding that different variables are of prognostic importance in MDS/sAML and de novo AML pts supports the hypothesis that these are intrinsically different disorders. The CRIANT-derived score is a valuable alternative for the IPSS in intensively treated high-risk MDS pts.

Reduced Intensity Conditioned Allogeneic Stem Cell Transplantation Is as Effective in Poor Risk as Standard Risk Acute Myeloid Leukaemia (AML).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2901-2901
Author(s):  
Wendy Ingram ◽  
Ziyi Lim ◽  
Antonio Pagliuca ◽  
Stephen Devereux ◽  
Aloysius Ho ◽  
...  
Keyword(s):  
Stem Cell ◽  
De Novo ◽  
Chronic Gvhd ◽  
Mixed Chimerism ◽  
Poor Risk ◽  
Grade Ii ◽  
De Novo Aml ◽  
Standard Risk ◽  
Good Risk ◽  
Reduced Intensity

Abstract Poor risk cytogenetics and multi-lineage dysplasia are commonly found in older patients with acute myeloid leukaemia (AML) and despite intensive chemotherapy prognosis remains grim. We compared the outcome of standard risk to poor risk AML (both according to cytogenetic risk group and presence of underlying dysplasia) following reduced intensity conditioned (RIC) allogeneic haematopoietic stem cell transplantation (allo-HSCT) in 65 patients (32 males, 33 females) with a median age of 53years (range 22–65years). Conditioning regimen incorporated fludarabine(150mg), Alemtuzumab(100mg) and busulphan(8mg–16mg). 35/65 had a background of multi-lineage dysplasia (MLD-AML), 30/65 de-novo AML. According to cytogenetics, 48 were standard risk, 15 poor risk and 2 good risk (both good risk cases were in second remission). Median number of chemotherapy regimens administered prior to RIC HSCT was 3 (range 1–8), with 33/65 receiving FLAG chemotherapy and 2/65 a previous autologous HSCT. 57/65 were in complete remission (CR) at time of HSCT, 6/65 partial remission (PR) and 2/65 refractory disease. 51/65 were in first remission, 14/65 second remission. Sibling donor was used in 25/65, volunteer unrelated donor (VUD) in 40/65 (1 antigen mismatch 13/40, 2 antigen mismatch 3/40). Bone marrow (BM) was administered to 17/65 and peripheral blood stem cell (PBSC) to 48/65. Median follow-up was 389days (range 36–1731) for all patients and for those alive 633days (range 71–1731). Failure to engraft occurred in 1 patient and late graft rejection in 3 patients. The day+100 transplant related mortality for all patients was 11%. The overall survival (OS) at 1year for siblings versus VUD was 77% v 58% (p=0.46) and the disease free survival (DFS) 50% versus 53% (p=0.98). The OS for de-novo AML versus TLD-AML at 1year 73% versus 59% (p=0.34) and DFS 59% versus 46% (p=0.06). Comparison of the OS at 1year for the standard versus poor risk cytogenetic groups was 63% versus 72% (p=0.33), and DFS 50% versus 57% (p=0.68) respectively. 15/65 developed acute GvHD grade II–III. The cumulative incidence of chronic GvHD was 19% in those surviving after day+100. 46% of patients achieved full donor engraftment on lineage specific chimerism at day+100. Incremental donor leukocyte infusions (DLI) were administered to 25 patients. 16/25 received DLI for mixed chimerism, 9/16 reverted to 100% donor, 4/16 continued with stable mixed chimerism and 3/16 developed relapsed disease. 9/25 received DLI for disease relapse resulting in complete remission in 3/9 cases. 10/23 patients administered DLI developed GvHD grade II–III. In summary, RIC allo-HSCT incorporating Alemtuzumab was equally well tolerated in both sibling and VUD allografts, with a low incidence of acute and chronic GvHD. The results show favourable outcome in a poor risk cohort of patients with AML, with comparable OS compared to standard risk/de-novo AML. DFS was not affected by cytogenetic risk however comparison of de-novo AML to MLD-AML did show a trend (p=0.06) in favour of de-novo AML.

Bortezomib+Chemotherapy Based Salvage Combinations in Refractory AML, Preliminary Results

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4000-4000
Author(s):  
Miklos Udvardy ◽  
Attila Kiss ◽  
Bela Telek ◽  
Robert Szasz ◽  
Peter Batar ◽  
...  
Keyword(s):  
Cell Lines ◽  
De Novo ◽  
Case Reports ◽  
Fatal Outcome ◽  
Normal Karyotype ◽  
Secondary Aml ◽  
Poor Risk ◽  
Group 2 ◽  
De Novo Aml ◽  
Group 1

Abstract Bortezomib (Velcade) proved to be the standard element of refractory myeloma 2nd and 3rd line treatment, while many studies are suggesting excellent results in 1st line. Proteasome inhibition, the block of angiogenesis, modification of the NF-kappa-B system seems to be a challenging target in other malignant diseases, including refractory acute myeloid leukemia (AML), as well. In vitro data clearly support, that bortezomib exerts antiproliferative and pro-apoptotic effects in different AML cell-lines, along with human AML cell cultures, and moreover bortezomib was able to restore, or at least improve anthracyclin and possibly ARA-C sensitivity in different cell-lines (including AML). More recently, a Phase I trial showed bortezomib monotherapy efficient (only in few percents) in childhood refractory acute leukemia. Some case reports were shown at ASH 2007. We have tried bortezomib containing first or second line combinations in 27 (14 female, 13 male, mean age 57.6 years) patients with refractory or poor risk AML, in a small retrospective survey. The combinations were as follows: HAM or Flag-Ida, combined with bortezomib 1,3 mg pro sqm, day O and seven). The following groups were considered as refractory or poor risk AML: De novo AML, 2nd line: No response/remission to first line standard treatment (“3+7”), n=2 (Velcade- Flag-Ida treatment) De novo AML 1st line: bilineal or biphenotypic (flow-cytometry) n=2 (Velcade-Flag- Ida treatment) De novo AML with complex (numerical or more than 3 abnormalities) karyotype or normal karyotype with flt-3 TKD mutation, n=9, 1st line (Velcade-Flag-Ida n=6, Velcade- HAM protocol, n=3) Secondary AML or AML with evidence of previous more than 6 mo duration high grade MDS, n=14, 1st line: (Velcade-Flag-Ida n=9, Velcade-HAM n=5) RESULTS: Complete remission (CR) 12/27, partial remission (PR) 9/27, no remission 5/27, progression during treatment: 1/27.Best responses were seen in de novo cases. CR had been achieved in all patients of group 1 (two standard risk patients not responding to 3+7 protocol), and group 2 (biphenotypic, bilineal). The CR rate was quite appreciable in group 3, i.e. 6/9 (complex karyotype or normal karyotype with FLt-3 mutation – the response rate was excellent with flt-3 mutated cases). In group 4. (MDS, secondary AML) the results were less impressive. There were no major differences according to protocol (Flag-Ida or HAM) Allogeneous stem cell transplantation could have been performed in 1st CR in two patients (one from group 1. and another from group 2.). One of them died due to relapse, the other one is in CR since then. The combinations seem to be relatively safe. Induction related death rate was low (1 elderly patient acute thrombocytopenic bleeding with refractory MDS-AML). 5 other patients had severe neutropenic sepsis (2 with fatal outcome). Pulmonary syndrome, which may follow Velcade+ARA-C had not been documented. Other adverse events did not differ from the pattern observed with standard induction therapies.

Is Longer MDS Duration Prior to Non-Intensive AML Treatment a Favorable Prognostic Factor? Results of the 00331 Multicenter Phase II Decitabine Trial

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2185-2185
Author(s):  
Michael Lubbert ◽  
Claudia Schmoor ◽  
Björn Rüter ◽  
Mathias Schmid ◽  
Ulrich Germing ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Research Funding ◽  
Disease Duration ◽  
Cox Regression ◽  
De Novo ◽  
Performance Status ◽  
Treatment Modalities ◽  
White Blood Count ◽  
Large Trial ◽  
Comorbidity Index

Abstract Abstract 2185 Background: Secondary (s)AML from MDS is more frequent in older AML patients, and associated with an overall worse outcome with standard chemotherapy than de novo AML, particularly after MDS of longer duration (1). The azanucleoside hypomethylating agents 5-azacytidine (Vidaza) and 5-aza-2′-deoxycytidine (Decitabine, DAC) are active in MDS and, as recently shown, also AML. Compared to other predictors of response to these drugs, MDS duration prior to treatment thus far has received only limited attention, with two recent publications reporting conflicting results (2, 3). To independently validate our finding that shorter duration of MDS prior to DAC treatment may be a novel predictor of poor outcome (2, 4), we now applied this parameter to a large trial of low-dose DAC in AML pts (aged >60 years and judged ineligible for standard induction chemotherapy), about half of them with sAML from MDS with variable disease duration. Patients and Methods: Comparisons of response rate (RR, i.e. CR or PR) and overall survival (OS) from start of treatment according to MDS duration (pre-specified categorization according to quartiles) were performed post-hoc in 109 patients (pts) with previously untreated sAML (median age 72 years) treated with DAC (given over 72 hours, every 6 weeks, for up to 4 courses, followed by “maintenance” with 3 daily 1-hour infusions of DAC 20 mg/m2 every 4–6-weeks). Median WBC prior to treatment was 5.200/μl, median serum LDH 279U/l, 31.2% of pts had adverse cytogenetics, 82.6% had a performance status > 1, and 80.7% had a comorbidity index (HCT-CI) >=1. Comparisons by logistic regression and Cox regression (univariate and multivariate, adjusted for other prognostic factors showing an effect in this population of sAML pts) were performed. Results: Of the 227 AML patients treated within the 00331 trial, 109 (48%) had prior MDS with known MDS duration, with a median duration of 8 (25% quartile 3, 75% quartile 25, range 1–101) mths. The overall RR in these pts was 26/109 (24%), the overall 1 yr OS rate was 31% (94 deaths). A comparison of RR according to MDS duration revealed a trend to an increase in RR with longer duration of MDS [<3: 4/25 (16%), 3–8: 5/29 (17%), 8–25: 7/27 (26%), >=25 mths: 10/28 (36%), test for heterogeneity p=0.29, test for trend p=0.06]. Similarly, when OS from start of DAC was analyzed according to this parameter, for pts with previous MDS of longer duration there was a trend to better outcome [<3: 1 yr OS rate 23%, 3–8: 28%, 8–25: 26%, >=25 mths: 46%, test for heterogeneity p=0.17, test for trend p=0.16]. When these analyses were adjusted for other prognostic factors showing an effect in this population of sAML pts (comorbidity index, sLDH with respect to RR, and performance status, comorbidity index, and white blood count with respect to OS), the results were similar (effect of MDS duration with respect to RR: test for heterogeneity p=0.35, test for trend p=0.06, and effect of MDS duration with respect to OS: test for heterogeneity p=0.04, test for trend p=0.11). Conclusion: In this large cohort of uniformly treated pts with sAML, MDS of longer duration appeared to be associated with a better outcome, even after adjusting for important other prognostic factors. These results are supported by a similar analysis of MDS pts randomized in the 06011 EORTC intergroup trial (which compares DAC to Best Supportive Care), where MDS patients with longer (>=3 mths) disease duration prior to treatment also had better outcome (4). They warrant application of this discriminator in the evaluation also of other non-intensive AML treatment modalities. References 1. Estey et al., Blood 90:2969-77, 1997 2. Wijermans et al., Ann. Hematol. 84 Suppl 1:9-14, 2005 3. Kantarjian et al., Cancer 109:265-73, 2007 4. Lübbert, Suciu et al., Abstract submitted, ASH 2010 Disclosures: Off Label Use: decitabine is FDA-approved for treatment of MDS and AML with up to 30% blasts. In the present study, patients with AML and higher blast percentage were treated. Platzbecker: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Döhner: Pfizer: Research Funding.

Serum 2-Hydroxyglutarate Levels Predict Isocitrate Dehydrogenase Mutations and Clinical Outcome in Acute Myeloid Leukemia.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2481-2481
Author(s):  
Courtney D. DiNardo ◽  
Ross L. Levine ◽  
Kathleen J Propert ◽  
Alison W. Loren ◽  
Elisabeth Paietta ◽  
...  
Keyword(s):  
Research Funding ◽  
De Novo ◽  
Mutational Analysis ◽  
Eastern Cooperative Oncology Group ◽  
Elevated Serum ◽  
Wild Type ◽  
Serum Samples ◽  
Prognostic Information ◽  
Idh Mutations ◽  
De Novo Aml

Abstract Abstract 2481 Purpose: Cancer-associated IDH mutations produce the metabolite 2-hydroxyglutarate (2HG), but the clinical utility of serum 2HG measurements has not been previously established. We studied whether 2HG measurements in AML patients correlate with the presence of IDH mutations and whether diagnostic or remission 2HG measurements predict survival. Patients and Methods: Serum samples from 223 previously untreated adults (≤ 60 years of age) with de novo AML from the Eastern Cooperative Oncology Group E1900 clinical trial (62 IDH mutated, 161 IDH wild-type) were analyzed for 2HG concentration by reverse-phase liquid chromatography coupled to mass spectrometry (GC-MS). Results: Pretreatment 2HG levels ranged from 10 to 30000 ng/ml and were significantly elevated in IDH-mutant samples (median 3004.1 ng/ml), as compared to the wild-type cohort (median 61.2 ng/ml) (p &lt; 0.0005). 2HG levels did not differ among the specific IDH1 or IDH2 allelic variants. In ROC analysis, a discriminatory level of 700 ng/ml segregated patients with and without IDH mutations with 86.9% sensitivity and 90.7% specificity. On repeat mutational analysis of 13 IDH wild-type samples with 2HG levels &gt;700 ng/ml, IDH mutations were identified in nine samples, most often at low allele burden. IDH mutant patients with 2HG levels ≤ 200 ng/ml at complete remission experienced improved overall survival compared to those with higher 2HG levels (HR 3.5, p = 0.02) (Figure 1). Conclusion: We establish a firm association between IDH mutations and elevated serum 2HG concentration in AML. These data confirm that peripheral blood measurement of an oncometabolite provides useful diagnostic and prognostic information for cancer therapy, and furthermore can inform patient selection of IDH mutant targeted therapies. Disclosures: Levine: Agios Pharmaceuticals: Research Funding. Straley:Agios Pharmaceuticals: Employment. Yen:Agios Pharmaceuticals: Employment. Agresta:Agios Pharmaceuticals: Employment. Carroll:Agios Pharmaceuticals: Research Funding.

Efficacy of Single-Agent Decitabine in Relapsed and Primary Refractory (rel/ref) Acute Myeloid Leukemia (AML)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2518-2518
Author(s):  
Andrew Hantel ◽  
Niloufer Khan ◽  
Richard A. Larson ◽  
Lucy A. Godley ◽  
Michael J. Thirman ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Genetic Risk ◽  
Research Funding ◽  
De Novo ◽  
Median Number ◽  
Advisory Committees ◽  
Secondary Aml ◽  
Induction Regimen ◽  
De Novo Aml ◽  
Wbc Count

Abstract Introduction Improving therapy for rel/ref AML remains a challenge. Decitabine, a DNA methyl-transferase inhibitor, initially showed promise in AML as a 5-day, first-line induction regimen and more recently as a 10-day regimen in older and unfit patients (1). However, little is known about the activity of decitabine in the rel/ref patient population despite increased use. Therefore, we sought to analyze the outcomes of these pts treated at our institution. Methods To obtain data regarding decitabine efficacy in rel/ref AML, we performed a retrospective analysis of outcomes following decitabine treatment in 34 adult pts treated at The University of Chicago from January 2009 to June 2014. Permission to access patient charts was granted by the medical centerÕs Institutional Review Board. AML was defined by WHO criteria, genetic risk grouping and complete remission (CR) was according to ELN classification; PR was defined as >50% decrease in bone marrow blasts and normalization of blood counts. Rel/ref AML was defined as either having had a prior CR with recurrence of disease or having received a prior induction regimen (1-2 cycles) without CR. Results Median pt age was 62 yrs (range, 18-81) and 60% were male. Median Charlson comorbidity index (CCI) was 5 (range, 0-8); 29% had ECOG performance status 0-1 and 71% had >2. 21 pts (62%) had de novo AML (7 with myelodysplasia-related changes), 3 (9%) had therapy-related myeloid neoplasm (t-MN), and 10 (29%) had secondary AML after myelodysplastic syndrome. 6% were in the ELN favorable genetic group, 3% intermediate-I, 18% intermediate-II, and 67% adverse; 2 cases were unevaluable. The median number of prior treatment regimens was three. 9% had received prior azacitidine, 85% had received prior HiDAC, and 38% had a prior allogeneic stem cell transplant (SCT). 34 pts received a total of 71 cycles of decitabine, 20 mg/m2 daily, in 5 or 10-day cycles every 28 days. All patients received 10-day courses, 91% had an initial 10-day course, and 74% had only 10-day courses. The median number of cycles per pt was 2; 59% received >1 cycle. 7 (21%) achieved CR and 4 (12%) had a partial response (PR), for an overall response rate (OR) of 33%. Responses occurred in 24% of pts with de novo AML, 66% with t-MN, and 50% with secondary AML. Intermediate and adverse group pts had OR of 14% and 39%, respectively. All pts achieving CR did so after 1 cycle; PR required a median of 3 cycles. Pts who achieved CR or PR had a significantly lower pretreatment WBC count (median, 9.5 vs 49.5 x 103/µL in non-responders; p=0.015) and blast percentage (44 vs 59.4; p=0.035) than those who did not. Pts with secondary AML or t-MN had a higher probability of OR compared to those with de novo AML (54 vs 23%; p=0.042). Median overall survival (OS) of all pts was 256 days; prior SCT was associated with reduced OS (p=0.017). When comparing de novo to secondary AML & t-MN, 1-year OS was not significantly different (Figure 1). Responders had a significantly longer OS (median, 622 days vs 278 days for non-responders; p=0.012). Age, race, CCI, ECOG PS, genetic risk group, prior HiDAC, dysplasia, azacitidine, and number of prior treatments did not impact OR or OS. 16 (47%) pts proceeded to SCT. During treatment, 70% had a grade 3-4 non-hematologic toxicity (based on NCI CTACE v4.0); the most common was fatigue. The median number of hospitalizations for complications per patient was 2 (range, 0-7). Causes of hospitalization were febrile neutropenia (40%), infection (22%), cytopenias (18%), rash (6%), acute kidney injury (6%), and 8% were for other causes. Conclusion Decitabine treatment of 34 adults with rel/ref AML resulted in an OR of 33% (21% CR) and allowed nearly one-half of these pts to proceed to SCT. All pts achieving CR did so after 1 cycle. Responding pts had improved OS over those without response (p=0.012). Interestingly, secondary AML or t-MN were 7.8 times more likely to achieve a response compared to de novo AML (p=0.046); lower WBC count and marrow blast percentage also correlated with higher OR. Further delineation of molecular subsets associated with response to decitabine should be evaluated in a larger prospective trial in this high-risk AML population. Citation 1. Blum KA, et al. Phase I trial of low dose decitabine targeting DNA hypermethylation in patients with chronic lymphocytic leukaemia and non-Hodgkin lymphoma: dose-limiting myelosuppression without evidence of DNA hypomethylation. Br J of Haem. Jul 2010;150(2):189-195. Figure 1. Figure 1. Disclosures Off Label Use: Decitabine is indicated for treatment of MDS but is often used to treat newly diagnosed or relapsed/refractory AML. In this study we analyzed results of patients with AML who were treated with decitabine in the relapsed/refractory setting.. Thirman:AbbVie: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Gilead: Research Funding; Merck: Research Funding; AbbVie: Research Funding; Gilead: Research Funding; Merck: Research Funding. Odenike:Sunesis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Liu:Astra Zeneca/Medimmune: Consultancy; Pfizer: Consultancy; Astra Zeneca/Medimmune: Consultancy; Pfizer: Consultancy. Stock:Gilead: Membership on an entity's Board of Directors or advisory committees.

Sequential Intensified Conditioning Regimen Allogeneic Hematopoietic Stem Cell Transplantation in Adult Patients with High-Risk AML in Complete Remission: A Survey from the ALWP of the EBMT

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3105-3105
Author(s):  
Florent Malard ◽  
Myriam Labopin ◽  
Gernot Stuhler ◽  
Johanna Tischer ◽  
Joerg Thomas Bittenbring ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
High Risk ◽  
Research Funding ◽  
Antithymocyte Globulin ◽  
De Novo ◽  
Conditioning Regimen ◽  
Secondary Aml ◽  
Off Label ◽  
Advisory Boards ◽  
De Novo Aml

Abstract Introduction. Allogeneic hematopoietic cell transplant (HCT) is an established treatment modality that is potentially curative for many patients with acute myeloid leukemia (AML). The development of reduced intensity conditioning (RIC) allows performing HCT in elderly and/or in heavily pretreated patients and in those with comorbidities precluding the use of standard myeloablative conditioning. Post-transplant relapse remains a challenge after RIC, particularly in patients with adverse prognosis factors.The so-called "sequential" transplant approach (e.g. FLAMSA regimen combining both intensive chemotherapy and RIC HCT within the same procedure) initially developed in patients with refractory AML, could be a promising strategy to improve disease control and decrease the risk of relapse in high-risk AML patients in complete remission (CR). Patients and methods. In the current study we analyzed transplantation outcomes in a cohort of 411 adults AML patients in CR at time of transplant, treated between 2002 and 2013. Patients received a "sequential" conditioning regimen based on Fludarabine 30 mg/m2/d, high-dose aracytine 1-2 g/m2/d, amsacrine 100 mg/m2/d for 5 days and after a 3 days rest, total body irradiation (TBI) 4Gy, cyclophosphamide 50-120 mg/kg, and antithymocyte globulin (ATG) for 2 to 3 days (TBI group, n=269 [65%]). In 142 (35%) patients, TBI was substituted by IV Busulfan 3.2 mg/kg/d for 2 days, or orally equivalent dose (Bu group). 323 patients (79%) had de-novo AML and 88 (21%) had a secondary AML (with prior myelodysplastic syndrome). At time of transplant, 300 (73%) patients were in CR1 and 111 (27%) in CR2. Cytogenetic study in de novo AML was favorable in 19 patients (6%), intermediate in 102 (32%) and poor in 41 (13%). Cytogenetic data were missing in 161 (50%). 104 (25%) patients received matched related donors (MRD) and 307 (75%) unrelated donor (URD) HCT. Majority of patients (94%) received mobilized peripheral blood stem cells graft. Results. Median follow-up of surviving patients was 28 months and median age at transplant was 54 years (18-76). ANC>500/μL was achieved at a median of 17 (range, 9-74) days after HCT. Sixteen patients (4%) failed to engraft. Two year cumulative incidence of relapse (RI) and non-relapse mortality (NRM) were 22% (95%CI, 18-26%) and 22% (95%CI, 18-27%), respectively. The Kaplan-Meier estimate of overall (OS) and leukemia-free survival (LFS) at 2 years were 59% (95%CI, 54-65%) and 56% (95%CI, 50-61%), respectively. Acute GVHD (grade II-IV) occurred in 109 (28%) patients. The 2-year cumulative incidence of chronic GVHD was 31% (95%CI, 26-36), extensive in 17% (95%CI, 12-21). Two years RI, NRM, LFS and OS in TBI vs. Bu patients were 21.8% vs 21.7% (p=0.69), 29.4% vs 18.3% (p=0.008), 48.8% vs 59.6% (p=0.045) and 51.2% vs 64.0% (p=0.013), respectively. In multivariate analysis adjusted for variable with different distribution between Bu and TBI groups, the type of conditioning (TBI vs Bu) has no impact on RI, NRM, LFS and OS. Age over 55 at transplant was an independent adverse prognostic factor in multivariate analysis for NRM (hazard ratio (HR: 1.61, 95% CI: 1.00-2.61, p=0.05)), LFS (HR: 1.39, 95% CI: 1.00-1.92, p=0.05) and OS (HR: 1.55, 95% CI: 1.11-2.18, p=0.01). Being treated in an experienced center (defined as having including 10 or more transplants in the study) was associated with a significant lower RI (HR: 0.84, 95% CI: 0.75-0.93, p=0.001) and better LFS (HR: 0.91, 95% CI: 0.84-0.98, p=0.01) and OS (HR: 0.91, 95% CI: 0.84-0.98, p=0.02). Finally, transplantation from an URD was associated with a significant increase in NRM (HR: 2.11, 95% CI: 1.14-3.91, p=0.02). Of note, CR1 vs. CR2 and de novo vs. secondary AML had no impact on patients' outcome. Conclusions. These results in a rather large cohort of patients with AML suggest that a FLAMSA "sequential" regimen provided an efficient disease control in high-risk AML patients including in CR2 and secondary AML. Furthermore Busulfan and TBI based FLAMSA "sequential" regimens provide a similar outcome. These results should be confirmed in a multicenter well design randomized study. Disclosures Off Label Use: off-label drug use: antithymocyte globulin (ATG) for allo-SCT conditioning. Tischer:Sanofi-Aventis: Other: advisory board. Schmid:Neovii: Consultancy; Janssen Cilag: Other: Travel grand. Mayer:Janssen: Research Funding. Hallek:Pharmacyclics: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Janssen: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Boehringher Ingelheim: Honoraria, Other: Speakers Bureau and/or Advisory Boards; Mundipharma: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Celgene: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Gilead: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Roche: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; AbbVie: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding.

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