scholarly journals European LeukemiaNet 2017 risk stratification for acute myeloid leukemia: validation in a risk-adapted protocol

2021 ◽  
Author(s):  
Alex Bataller ◽  
Ana Garrido ◽  
Francesca Guijarro ◽  
Guadalupe Oñate ◽  
Marina Diaz-Beya ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Risk Stratification ◽  
Myeloid Leukemia ◽  
Tp53 Mutation ◽  
Risk Group ◽  
Risk Groups ◽  
Treatment Protocols ◽  
Poor Outcome ◽  
Risk Patients ◽  
Acute Myeloid

The 2017 European LeukemiaNet (ELN 2017) guidelines for the diagnosis and management of acute myeloid leukemia (AML) have become fundamental guidelines to assess the prognosis and post-remission therapy of patients. However, they have been retrospectively validated in few studies with patients included in different treatment protocols. We analyzed 861 patients included in the CETLAM-12 risk-adapted protocol, which indicates cytarabine-based consolidation for patients allocated to the ELN 2017 favorable-risk group, while it recommends allogeneic stem cell transplantation as a post-remission strategy for the ELN 2017 intermediate- and adverse-risk groups. We retrospectively classified patients according to the ELN 2017, with 327 (48%), 109 (16%) and 245 (36%) patients allocated to the favorable, intermediate and adverse risk group, respectively. The 2 and 5 year-overall survival (OS) were 77 and 70% for favorable risk patients, 52 and 46% for intermediate risk patients, and 33 and 23% for adverse risk patients, respectively. Furthermore, we identified a subgroup of patients within the adverse group (inv(3)/t(3;3), complex karyotype and/or TP53 mutation/17p abnormality) with a particularly poor outcome, with a 2-year OS of 15%. Our study validates the ELN 2017 risk stratification in a large cohort of patients treated with an ELN-2017 risk-adapted protocol, based on alloSCT after remission for non-favorable ELN subgroups, and identifies a genetic subset with a very poor outcome which warrants investigation of novel strategies.

Integrative prognostic risk score in acute myeloid leukemia with normal karyotype

Blood ◽  
2011 ◽  
Vol 117 (17) ◽  
pp. 4561-4568 ◽  
Author(s):  
Frederik Damm ◽  
Michael Heuser ◽  
Michael Morgan ◽  
Katharina Wagner ◽  
Kerstin Görlich ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Risk Score ◽  
Myeloid Leukemia ◽  
Risk Group ◽  
Normal Karyotype ◽  
Risk Groups ◽  
Risk Of Death ◽  
Risk Patients ◽  
Acute Myeloid

Abstract To integrate available clinical and molecular information for cytogenetically normal acute myeloid leukemia (CN-AML) patients into one risk score, 275 CN-AML patients from multicenter treatment trials AML SHG Hannover 0199 and 0295 and 131 patients from HOVON/SAKK protocols as external controls were evaluated for mutations/polymorphisms in NPM1, FLT3, CEBPA, MLL, NRAS, IDH1/2, and WT1. Transcript levels were quantified for BAALC, ERG, EVI1, ID1, MN1, PRAME, and WT1. Integrative prognostic risk score (IPRS) was modeled in 181 patients based on age, white blood cell count, mutation status of NPM1, FLT3-ITD, CEBPA, single nucleotide polymorphism rs16754, and expression levels of BAALC, ERG, MN1, and WT1 to represent low, intermediate, and high risk of death. Complete remission (P = .005), relapse-free survival (RFS, P < .001), and overall survival (OS, P < .001) were significantly different for the 3 risk groups. In 2 independent validation cohorts of 94 and 131 patients, the IPRS predicted different OS (P < .001) and RFS (P < .001). High-risk patients with related donors had longer OS (P = .016) and RFS (P = .026) compared with patients without related donors. In contrast, intermediate-risk group patients with related donors had shorter OS (P = .003) and RFS (P = .05). Donor availability had no impact on outcome of patients in the low-risk group. Thus, the IPRS may improve consolidation treatment stratification in CN-AML patients. Study registered at www.clinicaltrials.gov as #NCT00209833.

scholarly journals Prospective Identification of Acute Myeloid Leukemia Patients Who Benefit from Gene-Expression Based Risk Stratification

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1397-1397
Author(s):  
Diego Chacon ◽  
Ali Braytee ◽  
Yizhou Huang ◽  
Julie Thoms ◽  
Shruthi Subramanian ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Risk Stratification ◽  
Genetic Risk ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Risk Groups ◽  
High Fidelity ◽  
Improve Outcome ◽  
Acute Myeloid

Background: Acute myeloid leukemia (AML) is a highly heterogeneous malignancy and risk stratification based on genetic and clinical variables is standard practice. However, current models incorporating these factors accurately predict clinical outcomes for only 64-80% of patients and fail to provide clear treatment guidelines for patients with intermediate genetic risk. A plethora of prognostic gene expression signatures (PGES) have been proposed to improve outcome predictions but none of these have entered routine clinical practice and their role remains uncertain. Methods: To clarify clinical utility, we performed a systematic evaluation of eight highly-cited PGES i.e. Marcucci-7, Ng-17, Li-24, Herold-29, Eppert-LSCR-48, Metzeler-86, Eppert-HSCR-105, and Bullinger-133. We investigated their constituent genes, methodological frameworks and prognostic performance in four cohorts of non-FAB M3 AML patients (n= 1175). All patients received intensive anthracycline and cytarabine based chemotherapy and were part of studies conducted in the United States of America (TCGA), the Netherlands (HOVON) and Germany (AMLCG). Results: There was a minimal overlap of individual genes and component pathways between different PGES and their performance was inconsistent when applied across different patient cohorts. Concerningly, different PGES often assigned the same patient into opposing adverse- or favorable- risk groups (Figure 1A: Rand index analysis; RI=1 if all patients were assigned to equal risk groups and RI =0 if all patients were assigned to different risk groups). Differences in the underlying methodological framework of different PGES and the molecular heterogeneity between AMLs contributed to these low-fidelity risk assignments. However, all PGES consistently assigned a significant subset of patients into the same adverse- or favorable-risk groups (40%-70%; Figure 1B: Principal component analysis of the gene components from the eight tested PGES). These patients shared intrinsic and measurable transcriptome characteristics (Figure 1C: Hierarchical cluster analysis of the differentially expressed genes) and could be prospectively identified using a high-fidelity prediction algorithm (FPA). In the training set (i.e. from the HOVON), the FPA achieved an accuracy of ~80% (10-fold cross-validation) and an AUC of 0.79 (receiver-operating characteristics). High-fidelity patients were dichotomized into adverse- or favorable- risk groups with significant differences in overall survival (OS) by all eight PGES (Figure 1D) and low-fidelity patients by two of the eight PGES (Figure 1E). In the three independent test sets (i.e. form the TCGA and AMLCG), patients with predicted high-fidelity were consistently dichotomized into the same adverse- or favorable- risk groups with significant differences in OS by all eight PGES. However, in-line with our previous analysis, patients with predicted low-fidelity were dichotomized into opposing adverse- or favorable- risk groups by the eight tested PGES. Conclusion: With appropriate patient selection, existing PGES improve outcome predictions and could guide treatment recommendations for patients without accurate genetic risk predictions (~18-25%) and for those with intermediate genetic risk (~32-35%). Figure 1 Disclosures Hiddemann: Celgene: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Bayer: Research Funding; Vector Therapeutics: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding. Metzeler:Celgene: Honoraria, Research Funding; Otsuka: Honoraria; Daiichi Sankyo: Honoraria. Pimanda:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Beck:Gilead: Research Funding.

scholarly journals BCOR Mutations in Acute Myeloid Leukemia: Clonal Evolution and Prognosis

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 4-4
Author(s):  
Ashley Zhang ◽  
Yuntao Liu ◽  
Shuning Wei ◽  
Benfa Gong ◽  
Chunlin Zhou ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Risk Stratification ◽  
Myeloid Leukemia ◽  
Statistical Difference ◽  
Tp53 Mutation ◽  
Clonal Evolution ◽  
Normal Karyotype ◽  
Abnormal Karyotype ◽  
Acute Myeloid

Background BCOR gene is a transcription repressor that may influence normal hematopoiesis and is associated with poor prognosis in acute myeloid leukemia (AML) with normal karyotype. However, due to the rare mutation frequency in AML (3.8%-5%), clinical characteristics and prognosis of AML patients with BCOR mutation including abnormal karyotype are still unknown. In addition, the clonal evolution of AML patients with BCOR mutation has not been fully investigated. Methods By means of next generation of sequencing, we performed sequencing of 114 genes related to hematological diseases including BCOR on 509 newly diagnosed AML patients (except for acute promyelocytic leukemia) from March 2017 to April 2019. The 2017 European Leukemia Net (ELN) genetic risk stratification was used to evaluate prognosis. Overall survival (OS) was defined as the time from diagnosis to death or last follow-up. Relapse-free survival (RFS) was measured from remission to relapse or death. Clonal evolution was investigated through analyzing bone marrow samples at diagnosis, complete remission (CR) and relapse from the same patient. Result Among 509 AML patients, we found BCOR mutations in 23 patients (4.5%). BCOR mutations were enriched in patients with mutations of RUNX1 (p = 0.008) and BCORL1 (p = 0.0003). Patients with BCOR mutation were more at adverse ELN risk category compared to patients without BCOR mutation (p = 0.007). Besides, there was a larger proportion of patients with normal karyotype in BCOR mutation group but it had not reached statistical difference (62.5% vs 45.5%, p = 0.064). The abnormal karyotype in patients with BCOR mutations included trisomy 8, t(9;11), inv(3), -7 and complex karyotype.There were no significant differences in age, sex, white blood cell count, hemoglobin or platelet count between the two groups. More patients died during induction (13.0% vs 3.5%, p = 0.56) and fewer patients achieved CR after 2 cycles of chemotherapy when patients had BCOR mutations (69.6% vs 82.5%, p = 0.115) but the difference had not reached statistical difference . Patients with BCOR mutations had inferior 2-year OS (52.1% vs 70.7%, p = 0.0094) and 2-year RFS (29.8% vs 61.1%, p = 0.0090). After adjustment for ELN risk stratification, BCOR mutation was still remain a poor prognostic factor. However, the adverse prognostic impact of BCOR mutation is overcome by hematopoietic stem cell transplantation (HSCT), in which there was no difference between BCOR mutation group and wild type group (p = 0.474) (Figure 1). Through analysis of paired bone marrow sample at diagnosis, remission and relapse, we revealed the clonal evolution that BCOR mutation was only detected at diagnosis sample as a subclone and diminished at CR and relapse while TP53 mutation was only detected at relapse with a variant allele frequency (VAF) of 25.5%. We also found BCOR mutation at another patient's diagnosis and relapse sample while TP53 mutation was detected at relapse with VAF of 11.8%. Conclusion BCOR is associated with RUNX1 mutation and higher ELN risk. AML patients with BCOR mutation including normal and abnormal karyotype conferred a worse impact on OS that can be overcome by HSCT. BCOR mutation is a subclone at diagnosis or relapse in some patients, in which TP53 mutation clone occurred at relapse. Disclosures No relevant conflicts of interest to declare.

Clinicopathologic Characterization of Acute Myeloid Leukemia and Myelodysplastic Syndrome with Inv(3)(q21q26.2)/t(3;3)(q21;q26.2) Reveals That Complex Karyotype but Not Blast Percentage Is Associated with Poor Survival; A Bone Marrow Pathology Group Study

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3847-3847
Author(s):  
Heesun J. Rogers ◽  
James W. Vardiman ◽  
John Anastasi ◽  
Gordana Raca ◽  
Natasha M Savage ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Who Classification ◽  
Risk Group ◽  
Risk Groups ◽  
Complex Karyotype ◽  
Genetic Abnormalities ◽  
Very High ◽  
Acute Myeloid

Abstract Abstract 3847 Acute myeloid leukemia (AML) with inv(3)(q21q26.2)/t(3;3)(q21;q26.2); RPN1-EVI1 [inv3/t3] is a distinct type of AML with recurrent genetic abnormalities (RGA) in the 2008 WHO classification, with poor response to therapy and poor prognosis. The resulting dysregulation of EVI1 plays an important role in stem cell self-renewal and leukemogenesis. Although myelodysplastic syndrome (MDS) with inv3/t3 has a high risk of progression to AML, inv3/t3 is not among the genetic abnormalities sufficient for diagnosis of AML, irrespective of blast percentage (%) in the WHO classification. The revised International Prognostic Scoring System (IPSS-R) includes comprehensive cytogenetic subgrouping to better define prognosis in MDS patients. In this system, inv3/t3 is included in a poor risk karyotype group. The objective of this multicenter study was to evaluate a series of patients with MDS/AML and inv3/t3 in order to characterize their clinicopathologic features and outcome, and to apply the IPSS-R to inv3/t3 MDS patients. 111 patients (40 MDS and 71 AML with inv3/t3) were gathered from 8 medical centers. The median age at diagnosis was 56.5 years and was significantly older in MDS than AML with inv3/t3 patients (65 vs 54.5, p=0.03). Patients typically presented with normocytic anemia, thrombocytopenia and mild leukopenia (median Hb 9.1 g/dL, platelet 91 x109/L, WBC 3.6 x109/L). MDS with inv3/t3 patients had lower WBC than AML with inv3/t3 (median 3.1 vs 5.5, p<0.001). 19% of patients had hepatosplenomegaly. The median bone marrow (BM) blast% was 4% in MDS and 50% in AML with inv3/t3 and BM cellularity was higher in AML (70%) than MDS (40%) with inv3/t3 (both p<0.001). 88% of patients showed dysmegakaryopoiesis with characteristic small uni/bilobated forms. Dysgranulopoiesis (46%) and dyserythropoiesis (56%) were common and 59% of patients displayed multilineage dysplasia. The cytogenetics showed isolated inv3/t3 in 41% of patients, one additional abnormality in 33% and complex karyotype in 26%. −7/del7q (37%) was a frequent additional abnormality. Philadelphia chromosome (Ph) was noted in 10% of AML with inv3/t3. Overall 83% of patients (75% of MDS and 87% of AML with inv3/t3) expired (median follow up of 7.9 months (mo)). Most patients received therapy including 54% with chemotherapy (CTX; topoisomerase II inhibitors and/or antimetabolites) alone, 27% with CTX and allogeneic stem cell transplant (SCT) and 19% with supportive care. 16% of patients (10 MDS and 8 AML with inv3/t3) were associated with prior therapy for solid tumors and lymphomas. 57% of MDS with inv3/t3 patients subsequently evolved to AML. There was no significant difference in overall survival (OS) between MDS and AML with inv3/t3 (12.9 vs 8.0 mo, Cox PH p=0.11, Figure 1). There was no OS difference between MDS and AML after excluding Ph+ cases (Cox PH p=0.17) nor between de novo and therapy related MDS/AML with inv3/t3 (Cox PH p=0.89). Patients with isolated inv3/t3, one additional cytogenetic abnormality, and a complex karyotype showed progressively shorter OS (12.9, 10.0 and 4.3 mo, Cox PH p<0.001, Figure 2). The patients who received CTX and SCT showed superior OS to patients receiving CTX alone or supportive care only (15, 7 and 5 mo, respectively, Cox PH p=0.02). In multivariate analysis, choice of therapy and complex karyotype retained independent prognostic significance (Cox PH p= 0.02 and p<0.001, respectively). MDS with inv3/t3 patients were classified into IPSS Intermediate (Int)-1 (21), Int-2 (13), and high (6) risk groups. IPSS-R categorized MDS patients into low (3), Int (6), high (14) and very high (17) risk groups. 57% of IPSS Int-1 risk group patients (expected OS 3.5 year) were reclassified to high or very high risk group in IPSS-R (expected OS <1.6 year). Thus, the IPSS-R scores were higher relative to IPSS score (signed rank test, P<0.001). However, 72.5% and 77.5% of MDS with inv3/t3 patients had shorter OS than expected OS by IPSS-R and IPSS scores. The IPSS-R better reflects the OS of inv3/t3 than IPSS but may not fully reflect the generally dismal prognosis. Patients with MDS and AML with inv3/t3 follow a similarly aggressive clinical course, supporting classification of MDS with inv3/t3 as an AML with RGA irrespective of blast%. Additional cytogenetic abnormalities are associated with shorter OS in AML/MDS with inv3/t3 and our data suggest that aggressive therapy with SCT should be considered in these patients. Disclosures: Vardiman: Celgene Corporation: review of slides for clinical trials not relevant to this abstract Other. Foucar:e. Honoraria–Scientific Symposium Pathology Education: ASCP Press; ARP, Amirsys, ASCP Press; ARP, Amirsys Patents & Royalties, Honoraria, Not relevant to this abstract Other.

Study AML-BFM 2004: Improved Survival In Childhood Acute Myeloid Leukemia without Increased Toxicity

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 181-181 ◽  
Author(s):  
Ursula Creutzig ◽  
Martin Zimmermann ◽  
Michael Dworzak ◽  
Jean-Pierre Bourquin ◽  
Christine Neuhoff ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Myeloid Leukemia ◽  
Risk Group ◽  
Risk Groups ◽  
High Risk Group ◽  
Therapeutic Window ◽  
Liposomal Daunorubicin ◽  
Off Label ◽  
Acute Myeloid

Abstract Abstract 181 Acute Myeloid Leukemia - Therapy, excluding Transplantation: Pediatric and Adult AML Therapy Study AML-BFM 2004 was designed to improve outcome of children and adolescents with AML without increasing toxicity. Patients were stratified into a standard- (SR)* or high-risk (HR)** group according to morphology, cyto-/molecular genetics including FLT3-ITD, and therapy response on day 15. Notably, reclassification of SR patients to the HR group in case of FLT3-ITD positivity was newly established in this study. Improvement of prognosis was attempted by intensification of chemotherapy: (1) Randomized introduction of liposomal daunorubicin (L-DNR) in a higher equivalent dose than idarubicin during induction in both risk groups (L-DNR 80mg/m2/day/3x) in comparison to standard induction using idarubicin 12mg/m2/day/3x, each combined with cytarabine and etoposide (L-DNR may offer an increased therapeutic window due to lower cardiotoxicity) and (2) randomised introduction of 2-chloro-2-deoxyadenosine (2-CDA, 2×6mg/m2) as intensification during the cytarabine/idarubicin (AI) consolidation in HR patients only. Overall results improved compared to the previous study AML-BFM 98: Survival estimates at 5 year (pOS) in patients (excluding Myeloid leukemia in Down syndrome) were 72% + 3% vs. 64% + 2% (AML-BFM 04 n=566 vs. AML-BFM 98 n=472), plogrank=0.02; the 5-year event-free survival (pEFS): was 54% + 3% vs. 50% + 2%, plogrank=.40. Results in the 197 SR patients were excellent: pOS 88% + 3% vs. 78% + 3% (n=182), plogrank=.01, EFS 69%, + 4% vs. 64% + 4%, plogrank=.40. Results in the 368 HR patients also improved: pOS 63% + 4% vs. 56% + 3% (n=290), plogrank=.07, EFS 46%, + 3% vs. 41% + 3%, plogrank=.43. OS improvement was partly due to better results after treatment of relapse or nonresponse (3-year pOS after nonresponse/relapse in 171 patients of study 2004 40% + 5% vs. 32% + 4% in 198 patients in AML-BFM 98, plogrank=.017). Results for the 1st randomization L-DNR vs. idarubicin during induction were similar (pOS 78% + 4% vs. 70% + 4%, plogrank=.15, pEFS 60% + 4% vs. 54% + 4%, plogrank=.17). There were less early deaths (4 vs. 8 patients) and less treatment related deaths in remission in the L-DNR group (2 vs. 5 patients). The rate of severe infection was slightly lower with L-DNR (pFisher 0.15). Two L-DNR vs. 6 idarubicin patients showed grade III/IV cardiotoxicity after induction. Results of the 2nd randomization in HR patients (AI/2-CDA vs. AI) were also similar: p=OS 75% + 5% vs. 65% + 5%, plogrank=.18, pEFS 51% + 5% vs. 51% + 5%, plogrank=.98. Toxicity rates of the intensification with 2-CDA were tolerable. In conclusion, compared to the previous study AML-BFM 98, results of study AML-BFM 2004 show significant improvement in both risk groups. This appears attributable to a combination of factors including therapy intensification, better supportive care and improved treatment of patients with relapse or nonresponse. Given the reduced toxicity of L-DNR and a trend towards better survival rates by adding L-DNR during induction and 2-CDA during HR consolidation, these agents will be further used in the forthcoming AML-BFM study. *Standard risk group definition: FAB M1/M2 with Auer rods, FAB M4eo or favorable cytogenetics [t(8;21) or inv(16)] and blasts in the bone marrow on day 15 <5%, and FAB M3 (all patients) **High-risk group definition: all others. Disclosures: Off Label Use: liposomal daunorubicin is used, which is off label for pediatric AML. It was used because it offers a possibility to increase cumulative dosages of anthracyclines with lower cardiotoxicity.

The Prognostic Impact of the Revised IPSS Cytogenetic Scoring System for Patients with MDS Allows a Risk-Stratification for Patients with MDS-Derived Acute Myeloid Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1715-1715
Author(s):  
Friedrich Stölzel ◽  
Michael Kramer ◽  
Brigitte Mohr ◽  
Martin Wermke ◽  
Martin Bornhäuser ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Risk Stratification ◽  
Scoring System ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Risk Groups ◽  
Prognostic Impact ◽  
Poor Risk ◽  
The Impact ◽  
Acute Myeloid

Abstract Abstract 1715 Besides cytopenias and the medullary blast count, cytogenetic risk groups (good vs. intermediate vs. poor) according to IPSS are of main prognostic relevance for overall survival (OS) in patients with myelodysplastic syndrome (MDS). Recently, the revised IPSS (rIPSS) was introduced involving 5 (very good vs. good vs. intermediate vs. poor vs. very poor) instead of 3 cytogenetic risk groups, which better predict disease progression to MDS-derived acute myeloid leukemia (mdsAML) and OS of MDS patients receiving supportive care only. We analyzed the impact of the rIPSS-based cytogenetic scoring systems on the outcome of patients with AML undergoing intensive chemotherapy within the AML96, AML2003, and AML60+ trials of the Study Alliance Leukemia (SAL). This was done in an intention to compare its general prognostic influence as well as between patients with mdsAML and those with a de novo disease (dnAML). A total of 258 patients (median age 63 years, range 24 – 82) with mdsAML were identified and 258 patients with dnAML were matched with regards to age, gender, clinical trial, induction and consolidation therapy, respectively. Distributions of the cytogenetics in both groups according to MRC, IPSS and rIPSS score are shown in Table 1. Expectedly, the MRC cytogenetic scoring system revealed a stratification into two risk groups for patients with mdsAML with intermediate (3-year OS 27%) and adverse (3-year OS 10%), p=.004, and stratification into three groups for dnAML with favorable (3-year OS 50%), intermediate (3-year OS 32%) and adverse (3-year OS 10%), p=.001. When using the new rIPSS, this allowed a stratification of mdsAML patients with a 3-year OS of 28% for good+intermediate, 12% for poor, and 2% for very poor, p<.001, compared to 28% for good, 22% for intermediate, and 7% for poor risk cytogenetics according to the IPSS, p=.002. Importantly, the rIPSS allowed for a refined subdivision of patients within the poor and very poor group. By applying the rIPSS in dnAML patients we observed a 3-year OS of 34% for good+intermediate, 22% for poor, and 11% for very poor, p<.001, compared to 37% for good, 23% for intermediate, and 19% for poor risk cytogenetics according to the IPSS, p=.028. In conclusion, the rIPSS and IPSS-based classifications are feasible for prognostic risk stratification of patients with both dnAML and mdsAML. Interestingly, the rIPSS-based good and intermediate risk groups do not separate patients in both groups sufficiently. Furthermore, the rIPSS as compared to the current MRC-based cytogenetic scoring system allowed for a more concise distribution of mdsAML patients with the detection of a very poor (rIPSS) risk group with a dismal outcome. Table 1. dnAML, n=258 (%) mdsAML, n=258 (%) Cytogenetics MRC AML Good 16 (7) 0 Intermediate 210 (81) 179 (69) Poor 32 (12) 79 (31) Cytogenetics IPSS Good 158 (61) 121 (47) Intermediate 59 (23) 79 (31) Poor 41 (16) 58 (22) Cytogenetics rIPSS Very good 0 0 Good 167 (65) 131 (51) Intermediate 47 (18) 53 (20) Poor 18 (7) 34 (13) Very poor 26 (10) 40 (15) Disclosures: Platzbecker: Novartis: Consultancy; Celgene: Consultancy; GlaxoSmithKline: Consultancy; Amgen: Consultancy.

scholarly journals Impact of NPM1/FLT3-ITD genotypes defined by the 2017 European LeukemiaNet in patients with acute myeloid leukemia

Blood ◽  
2020 ◽  
Vol 135 (5) ◽  
pp. 371-380 ◽  
Author(s):  
Konstanze Döhner ◽  
Christian Thiede ◽  
Nikolaus Jahn ◽  
Ekaterina Panina ◽  
Agnes Gambietz ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Hematopoietic Cell Transplantation ◽  
Risk Group ◽  
Cox Model ◽  
Risk Groups ◽  
Mutational Status ◽  
Genetic Features ◽  
Poor Outcomes ◽  
Acute Myeloid

Abstract Patients with acute myeloid leukemia (AML) harboring FLT3 internal tandem duplications (ITDs) have poor outcomes, in particular AML with a high (≥0.5) mutant/wild-type allelic ratio (AR). The 2017 European LeukemiaNet (ELN) recommendations defined 4 distinct FLT3-ITD genotypes based on the ITD AR and the NPM1 mutational status. In this retrospective exploratory study, we investigated the prognostic and predictive impact of the NPM1/FLT3-ITD genotypes categorized according to the 2017 ELN risk groups in patients randomized within the RATIFY trial, which evaluated the addition of midostaurin to standard chemotherapy. The 4 NPM1/FLT3-ITD genotypes differed significantly with regard to clinical and concurrent genetic features. Complete ELN risk categorization could be done in 318 of 549 trial patients with FLT3-ITD AML. Significant factors for response after 1 or 2 induction cycles were ELN risk group and white blood cell (WBC) counts; treatment with midostaurin had no influence. Overall survival (OS) differed significantly among ELN risk groups, with estimated 5-year OS probabilities of 0.63, 0.43, and 0.33 for favorable-, intermediate-, and adverse-risk groups, respectively (P &lt; .001). A multivariate Cox model for OS using allogeneic hematopoietic cell transplantation (HCT) in first complete remission as a time-dependent variable revealed treatment with midostaurin, allogeneic HCT, ELN favorable-risk group, and lower WBC counts as significant favorable factors. In this model, there was a consistent beneficial effect of midostaurin across ELN risk groups.

scholarly journals RUNX1 Mutation Is Associated with Poor Outcome in Patients with Acute Myeloid Leukemia Receiving Allogeneic Stem Cell Transplantation

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2052-2052
Author(s):  
Onyee Chan ◽  
Chetasi Talati ◽  
Hannah H Asghari ◽  
Jinming Song ◽  
Mohammad Hussaini ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Risk Group ◽  
Intermediate Risk ◽  
Advisory Committees ◽  
Kaplan Meier ◽  
Risk Patients ◽  
Acute Myeloid

Background: Runt-related transcription factor 1 (RUNX1) is a key regulator of hematopoiesis, and aberrant expression of this gene can facilitate leukemogenesis. RUNX1 mutations (RUNX1mut) are thought to carry a poor prognosis and have been recently incorporated into the risk stratification systems for acute myeloid leukemia (AML) by European LeukemiaNet (ELN) (Dohner et al. 2017) and National Comprehensive Cancer Network (NCCN et al. 2019). However, the clinical significance of this mutation after allogeneic stem cell transplantation (allo-SCT) is controversial with a recent study suggesting that allo-SCT may reverse the unfavorable influence of RUNX1mut(Qin et al. 2017). In this study, we describe the prognostic impact of RUNX1mutin patients with AML undergoing allo-SCT and compare the outcomes to ELN-defined adverse risk, RUNX1wtAML patients and patients with intermediate risk AML. Methods: We retrospectively reviewed our database of 407 patients who received allo-SCT at the Moffitt Cancer Center between 2013 and 2018. Only AML patients undergoing allo-SCT during first complete remission that had molecular information prior to transplant were included. This cohort was divided into three subgroups: 1) RUNX1mutAML 2) ELN-defined adverse risk, RUNX1wtAML and 3) ELN-defined intermediate risk AML. We utilized clinical data captured by BMT Research and Analysis Information Network (BRAIN). Univariate and multivariate analyses were conducted using log-rank and Cox regression, respectively. Cumulative incidence function was performed as defined by the Fine and Gray model. Kaplan-Meier analysis with log-rank test was used to estimate median overall survival (mOS) from the time of diagnosis. Results: Among 407 AML patients reviewed, we identified 28 patients with RUNX1mut, 71 adverse risk RUNX1wtpatients, and 69 intermediate risk patients. Of the 28 patients (18 males/10 females) with RUNX1mut, 53.6% were under age 60, two-thirds had de novo AML (dAML), and 92.9% had intermediate risk cytogenetics as defined by ELN 2017 at diagnosis. Baseline characteristics are described in Table 1. Univariate analysis identified RUNX1mutto be predictive of inferior OS compared to the intermediate risk cohort (HR 2.29, 95% CI 1.12-4.64, p=0.022). Subsequent multivariate regression using covariates of age, sex, AML type, lines of therapy prior to allo-SCT, and conditioning regimen confirmed RUNX1mutas an independent covariate for reduced OS (HR 2.51, 95% CI: 1.18-5.33, p=0.016). At a median follow-up of 29.3 months for the entire cohort, Kaplan-Meier analysis confirmed an inferior mOS in patients with RUNX1mutcompared to the intermediate risk group (25.7 months vs. 59.8 months, p=0.029) and was not different from RUNX1wtadverse risk group (25.7 months vs. 45.7 months, p=0.872) (Figure 1A). Cumulative incidence of relapse after allo-SCT for patients with RUNX1mutis significantly higher than intermediate risk patients (p=0.005, Figure 1B); however, there was no difference compared to RUNXwtadverse risk AML (p=0.295). There was no difference in non-relapse mortality (NRM) between RUNX1mutand intermediate risk patients (p=0.789, Figure 1B) or RUNX1mutand RUNX1wtadverse risk AML (p=0.323). When impact of concomitant somatic mutations on disease recurrence in RUNX1mutcohort was assessed, no discernible trends were identified. RUNX1mutwas mutually exclusive with NPM1 and frequently co-occurred with DNMT3A (21.4%), IDH2 (17.9%), and SRSF2 (17.9%) (Figure 2). Interestingly, 92.9% of the patients with RUNX1muthad ELN-defined intermediate risk cytogenetics and only 7.1% of the cohort had ELN-defined adverse risk cytogenetics. Conclusions: Our findings indicate that allo-SCT AML patients with RUNX1muthave poor outcomes analogous to RUNX1wtadverse risk AML. Disclosures Talati: Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Pfizer: Honoraria; Astellas: Honoraria, Speakers Bureau; Celgene: Honoraria; Daiichi-Sankyo: Honoraria; Agios: Honoraria. Kuykendall:Incyte: Honoraria, Speakers Bureau; Janssen: Consultancy; Abbvie: Honoraria; Celgene: Honoraria. Sallman:Celyad: Membership on an entity's Board of Directors or advisory committees. Komrokji:Novartis: Speakers Bureau; Agios: Consultancy; Incyte: Consultancy; JAZZ: Speakers Bureau; JAZZ: Consultancy; celgene: Consultancy; pfizer: Consultancy; DSI: Consultancy. List:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lancet:Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Other: fees for non-CME/CE services ; Agios, Biopath, Biosight, Boehringer Inglheim, Celator, Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm, Novartis: Consultancy. Sweet:Astellas: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; Celgene: Speakers Bureau; Incyte: Research Funding; Stemline: Consultancy; Agios: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Uncommon cytogenetic abnormalities identifying high-risk acute myeloid leukemia in children

2020 ◽  
Vol 16 (33) ◽  
pp. 2747-2762
Author(s):  
Riccardo Masetti ◽  
Salvatore Nicola Bertuccio ◽  
Vanessa Guidi ◽  
Sara Cerasi ◽  
Annalisa Lonetti ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Myeloid Leukemia ◽  
Large Scale ◽  
Risk Groups ◽  
Prognostic Impact ◽  
Treatment Protocols ◽  
Genomic Landscape ◽  
Pediatric Aml ◽  
Acute Myeloid

Pediatric acute myeloid leukemia (AML) represents an aggressive disease and is the leading cause of childhood leukemic mortality. The genomic landscape of pediatric AML has been recently mapped and redefined thanks to large-scale sequencing efforts. Today, understanding how to incorporate the growing list of genetic lesions into a risk stratification algorithm for pediatric AML is increasingly challenging given the uncertainty regarding the prognostic impact of rare lesions. Here we review some uncommon cytogenetic lesions to be considered for inclusion in the high-risk groups of the next pediatric AML treatment protocols. We describe their main clinical characteristics, biological background and outcome. We also provide some suggestions for the management of these rare but challenging patients and some novel targeted therapeutic options.

scholarly journals Validation and refinement of the revised 2017 European LeukemiaNet genetic risk stratification of acute myeloid leukemia

Leukemia ◽  
2020 ◽  
Vol 34 (12) ◽  
pp. 3161-3172 ◽  
Author(s):  
Tobias Herold ◽  
Maja Rothenberg-Thurley ◽  
Victoria V. Grunwald ◽  
Hanna Janke ◽  
Dennis Goerlich ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Risk Stratification ◽  
Induction Chemotherapy ◽  
Genetic Risk ◽  
Myeloid Leukemia ◽  
Risk Group ◽  
Prognostic Significance ◽  
Risk Classification ◽  
Age Range ◽  
Acute Myeloid

AbstractThe revised 2017 European LeukemiaNet (ELN) recommendations for genetic risk stratification of acute myeloid leukemia have been widely adopted, but have not yet been validated in large cohorts of AML patients. We studied 1116 newly diagnosed AML patients (age range, 18–86 years) who had received induction chemotherapy. Among 771 patients not selected by genetics, the ELN-2017 classification re-assigned 26.5% of patients into a more favorable or, more commonly, a more adverse-risk group compared with the ELN-2010 recommendations. Forty percent of the cohort, and 51% of patients ≥60 years, were classified as adverse-risk by ELN-2017. In 599 patients <60 years, estimated 5-year overall survival (OS) was 64% for ELN-2017 favorable, 42% for intermediate-risk and 20% for adverse-risk patients. Among 517 patients aged ≥60 years, corresponding 5-year OS rates were 37, 16, and 6%. Patients with biallelic CEBPA mutations or inv(16) had particularly favorable outcomes, while patients with mutated TP53 and a complex karyotype had especially poor prognosis. DNMT3A mutations associated with inferior OS within each ELN-2017 risk group. Our results validate the prognostic significance of the revised ELN-2017 risk classification in AML patients receiving induction chemotherapy across a broad age range. Further refinement of the ELN-2017 risk classification is possible.

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