Favorable outcome of patients with acute myeloid leukemia harboring a low-allelic burden FLT3-ITD mutation and concomitant NPM1 mutation: relevance to post-remission therapy

Key Points In intermediate-risk AML, effect of FLT3 burden is modulated by NPM1 mutation, especially in patients with a low ratio. Combined evaluation of NPM1 mutation and FLT3-ITD burden might contribute to identify patients who benefit from early allogeneic HSCT.

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A novel prognostic model in elderly patients with acute myeloid leukemia: results of 909 patients entered into the prospective AML96 trial

Blood ◽

10.1182/blood-2010-01-267302 ◽

2010 ◽

Vol 116 (6) ◽

pp. 971-978 ◽

Cited By ~ 102

Author(s):

Christoph Röllig ◽

Christian Thiede ◽

Martin Gramatzki ◽

Walter Aulitzky ◽

Heinrich Bodenstein ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Risk Model ◽

Cox Model ◽

Prognostic Significance ◽

Disease Free Survival ◽

Intermediate Risk ◽

Npm1 Mutation ◽

Prognostic Groups ◽

Acute Myeloid

Abstract We present an analysis of prognostic factors derived from a trial in patients with acute myeloid leukemia older than 60 years. The AML96 trial included 909 patients with a median age of 67 years (range, 61-87 years). Treatment included cytarabine-based induction therapy followed by 1 consolidation. The median follow-up time for all patients is 68 months (5.7 years). A total of 454 of all 909 patients reached a complete remission (50%). Five-year overall survival (OS) and disease-free survival were 9.7% and 14%, respectively. Multivariate analyses revealed that karyotype, age, NPM1 mutation status, white blood cell count, lactate dehydrogenase, and CD34 expression were of independent prognostic significance for OS. On the basis of the multivariate Cox model, an additive risk score was developed that allowed the subdivision of the largest group of patients with an intermediate-risk karyotype into 2 groups. We are, therefore, able to distinguish 4 prognostic groups: favorable risk, good intermediate risk, adverse intermediate risk, and high risk. The corresponding 3-year OS rates were 39.5%, 30%, 10.6%, and 3.3%, respectively. The risk model allows further stratification of patients with intermediate-risk karyotype into 2 prognostic groups with implications for the therapeutic strategy. This study was registered at www.clinicaltrials.gov as #NCT00180115.

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Next-generation sequencing–based posttransplant monitoring of acute myeloid leukemia identifies patients at high risk of relapse

Blood ◽

10.1182/blood-2018-04-848028 ◽

2018 ◽

Vol 132 (15) ◽

pp. 1604-1613 ◽

Cited By ~ 25

Author(s):

TaeHyung Kim ◽

Joon Ho Moon ◽

Jae-Sook Ahn ◽

Yeo-Kyeoung Kim ◽

Seung-Shin Lee ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

High Risk ◽

Myeloid Leukemia ◽

Relevant Information ◽

Longitudinal Tracking ◽

Key Points ◽

Generation Sequencing ◽

Allelic Burden ◽

Risk Of Relapse ◽

Acute Myeloid

Key Points Higher allelic burden at day 21 of post-HCT is associated with higher risk of relapse and mortality. Longitudinal tracking of AML patients receiving HCT is feasible and provides clinically relevant information.

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Addition of the Anti-CD33 Monoclonal Antibody Mylotarg to Fludarabine/High Dose Cytarabine - Based Induction Significantly Improves Outcome in Patient Affected By FLT3-ITD Positive Cytogenetically Normal Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2019-131420 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1365-1365

Author(s):

Paola Minetto ◽

Anna Candoni ◽

Fabio Guolo ◽

Marino Clavio ◽

Maria Elena Zannier ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Favorable Effect ◽

High Dose ◽

Intermediate Risk ◽

Npm1 Mutation ◽

Mutational Status ◽

High Dose Cytarabine ◽

Risk Patients ◽

Acute Myeloid

Background: The addition of the anti-CD33 targeting antibody Mylotarg (MY) to conventional "3+7" induction has been shown to improve the outcome of patients affected by acute myeloid leukemia (AML) without adverse cytogenetic alterations. Early reports suggested that MY was particularly effective among low risk patients, such as core binding factor AML, particularly if included in a high dose cytarabine-based induction therapy. The role of MY for intermediate risk patients appears to be less clear. Cytogenetically defined intermediate risk patients may be further stratified considering two frequent molecular aberrations: FLT3 "internal tandem duplication" (FLT3-ITD) mutation, associated with poor prognosis and NPM1 mutation (NPM1-mut), associated with a good prognosis. The concomitant presence of NPM1-mutpartially overcomes the negative prognostic impact of FLT3-ITD, which is also modulated by FLT3-ITD/wild type allelic ratio. NPM1 and FLT3 mutational status assessment is strongly recommended for risk stratification at diagnosis by the last ELN 2017 guidelines. Aims: To investigate the efficacy of MY added to an intensive fludarabine, high dose cytarabine and Idarubicin-based induction regimen (FLAI) as frontline treatment for younger (<65 years), cytogenetically normal AML patients according to NPM1 and FLT3-ITD mutational status. Methods:One-hundred and forty eight consecutive AML patients, treated in 3 Italian Hematology centersbetween 2008 and 2018and harboring at least one molecular alteration among NPM1-mut and FLT3-ITD, were included in the analysis. Thirty three patients carried isolated FLT3-ITD, 50patients showed concomitant FLT3-ITD and NPM1-mut and 65 isolated mutated NPM-1.Median age was 50 years(range: 18-65). All patients received FLAI induction (fludarabine 30 mg/sqm and ARA-C 2g/sqm on days1 to 5 plus idarubicin 10 mg/sqm on days 1-3-5), with or without low dose MY(3 mg/sqm, added in 42 patients), followed by a second induction without fludarabine and with idarubicin at the increased dose of 12 mg/sqm. Before 2017, patients with isolated FLT3-ITD mutation were scheduled for allogeneic stem cell transplantation (HSCT), if an HLA-matched sibling donor was available, whereas after 2017 only patients with high allelic burden isolated FLT3-ITD mutation received HSCT in first CR. The other patients received conventional high dose cytarabine consolidation for a total of 3 cycles. Results: Overall, 60-days mortality was 3%, and was not significantly influenced by receiving or not MY during induction. After one induction cycle, 126 patients achieved CR (85%) with no difference between patients receiving or not MY. After a median follow up of 70months, 3-year overall survival (OS) was 59.5% (median not reached). OS duration was significantly longer in NPM1 mutated patients (p <0.05).Patients with isolated FLT3-ITD mutation had a significantly worse prognosis (3-year OS 38.3%, p<0.05). The addiction of MY did not significantly improve outcome in the whole cohort but did show a significant positive effect on survival among FLT3-ITD patients (3-year OS 66.7% vs 46.6% for FLT3-ITD patients receiving or not MY, respectively, p<0.03, Fig. 1). This effect was more evident among the 33 NPM1 negative/FLT3-ITD patients: in this subgroup, patients who received MY had an overall good outcome that was similar to patients with double mutation who received the same therapy(median OS not reached in both groups, p=n.s.). On the contrary, among patients who did not receive MY, NPM1 negative/FLT3-ITD positive patients had a poor outcome, significantly inferior to double positive patients receiving the same regimen(3-Year OS 39.8% and 57.3%, respectively, p<0.05). The favorable effect of MY among FLT3-ITD patients was not influenced by FLT3-ITD allelic burden.Of note, the proportion of patients receiving HSCT in first CR, as expected, was higher among patients harboring isolated FLT3-ITD mutation, but there was no significant difference among patients receiving or not MY. Conclusions: Despite the potential bias due to the retrospective nature of the analysis, our data seem to indicate that Mylotarg, added to an intensive fludarabine/high dose cytarabine-based induction, provides a significant improvement in anti-leukemic efficacy in patients carrying FLT3-ITD mutation, especially if concomitant NPM1 mutation is not present. Disclosures Candoni: Gilead: Honoraria, Speakers Bureau; Celgene: Honoraria; Pfizer: Honoraria; Janssen: Honoraria; Merck SD: Honoraria, Speakers Bureau. Bocchia:Novartis: Honoraria; Incyte: Honoraria; BMS: Honoraria.

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

Journal of Cancer Research and Clinical Oncology ◽

10.1007/s00432-021-03761-w ◽

2021 ◽

Author(s):

Cécile Pochon ◽

Marie Detrait ◽

Jean-Hugues Dalle ◽

Gérard Michel ◽

Nathalie Dhédin ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Acute Myeloid Leukemia ◽

Young Adults ◽

Retrospective Study ◽

Myeloid Leukemia ◽

Chronic Gvhd ◽

Intermediate Risk ◽

Allogeneic Hsct ◽

Acute Myeloid

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

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Molecular Markers Predicting Clinical Outcome in Patients with Intermediate-Risk Acute Myeloid Leukemia Receiving Autologous Stem Cell Transplantation.

Blood ◽

10.1182/blood.v110.11.604.604 ◽

2007 ◽

Vol 110 (11) ◽

pp. 604-604

Author(s):

Jordi Esteve ◽

Susana Kalko ◽

Montserrat Torrebadell ◽

Mireia Camos ◽

Pedro Jares ◽

...

Keyword(s):

Gene Expression ◽

Acute Myeloid Leukemia ◽

Stem Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Autologous Stem Cell Transplantation ◽

Myeloid Leukemia ◽

Intermediate Risk ◽

Npm1 Mutation ◽

Acute Myeloid

Abstract Post-remission therapy in patients with acute myeloid leukemia (AML) is assigned according to the predictable biological risk of the disease, mainly based on cytogenetics. Nonetheless, optimal post-remission strategy for the intermediate-risk subtype, given the prognostic heterogeneity of this category, is currently undefined. Analysis of potentially relevant molecular features within this subgroup might contribute to clarify the role of autologous stem cell transplantation (autoHSCT) in these patients. Thirty seven patients (age: 53, 15–66; 51% female) diagnosed with intermediate-risk de novo AML during the period 1994–2006 who received an autoHSCT in first complete response were included in the study. Pre-transplant therapy was similar in all patients, consisting of standard induction chemotherapy (ICE, n=8, IDICE, n=29) and one cycle of high-dose ara-C-based consolidation chemotherapy. Internal tandem duplication of flt-3 (flt-3 ITD) and exon 12 NPM1 mutations were studied by either PCR or RT-PCR following standard methods. Gene expression profiling was examined in 28 patients with oligonucleotide HGU133 Plus 2.0 arrays (Affymetrix). Gene expression measures were normalized using RMA methodology (Affy package), and dChip v1.3 and Limma software (Bioconductor) were used for unsupervised and supervised analyses. In order to identify genes with prognostic value, a supervised analysis based on patients’ outcome (relapsed patients vs. long-term responders, i.e. >2-year duration) was performed. The combined results of NPM mutation and flt-3 ITD defined three subgroups of patients with different outcome: group 1 (n=12), constituted by patients with mutated NPM1 without flt-3 ITD; group 2 (n=20), which included patients with neither NPM1 mutation or flt-3 ITD; and group 3 (n=5), defined by flt-3 ITD regardless NPM1 mutational status. Thus, 5-year survival of these 3 subgroups of patients was 91%±9%, 52%±12%, and 20%±18%, respectively (p=0.02; see figure). Preliminary results of multiple gene profile comparisons between subgroups of patients with different outcome disclosed a cluster of genes with differential expression. Thus, in the most significant balanced comparison, 1238 genes were found to vary significantly in the unsupervised analysis, and 109 differentially expressed genes were identified in the supervised analysis. Interestingly, overexpression of genes such as TNF, RETN, CFLAR, SLC16A7, ENG, CD48, PLCR1, and SULTB1 correlated with a high relapse risk, whereas increased expression of YY1, FBXL12 and EXOSC6 were associated with a favorable outcome. In conclusion, presence of NPM1 mutation and flt-3 ITD are strong predictors of the outcome after autoHSCT in patients with intermediate-risk AML. Furthermore, genome-wide analysis may contribute to further define gene clusters with prognostic significance in patients with cytogenetically intermediate-risk AML receiving autoHSCT as consolidation therapy. Figure Figure

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The Role of Cytogenetic Abnormalities in Acute Myeloid Leukemia with NPM1 mutations and No FLT3 Internal Tandem Duplication.

Blood ◽

10.1182/blood.v114.22.1594.1594 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1594-1594

Author(s):

Jean-Baptiste Micol ◽

Nicolas Boissel ◽

Aline Renneville ◽

Sylvie Castaigne ◽

Claude Gardin ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Tandem Duplication ◽

Favorable Outcome ◽

Internal Tandem Duplication ◽

Npm1 Mutation ◽

Molecular Abnormalities ◽

Flt3 Internal Tandem Duplication ◽

Acute Myeloid

Abstract Abstract 1594 Poster Board I-620 Background Nucleophosmin (NPM1) gene mutations are observed in almost one-third of adult acute myeloid leukemia (AML). If the favorable genotype defined by the presence of NPM1 mutations without fms-like tyrosine kinase 3 (FLT3) internal tandem duplication (ITD) is known to be associated with favorable outcome in patients with cytogenetically normal (CN) acute myeloid leukemia (AML), impact of these molecular abnormalities are still debated in those with cytogenetically abnormal (CA) AML. Patients and Methods We analyzed the role of these factors in newly diagnosed AML patients homogeneously treated in the Acute Leukemia French Association (ALFA) trials between 1990 and 2006 (ALFA 9000, 9801, 9802). Among 1529 patients (15-70 years of age), 554 patients were screened for NPM1 mutation, FLT3-ITD and have informative karyotype. Mutations screening were centrally performed according to previously described procedures. Karyotype was considered as normal if at least 20 normal marrow metaphases were present without any abnormal marrow metaphases. Favorable core binding factor (CBF) AML (74 patients) were excluded from this analysis. Results Among the 480 remaining patients, 137 (29%; median age 48 years, range 17-68) were NPM1 mutated, 22 of them (16%) having CA-AML. We found no difference between NPM1 mutated CN-AML patients (n=115) and NPM1 mutated non-CBF CA-AML patients (n=22) in term of complete remission rate (88% vs 83%; P= .49), overall survival (OS) (39% vs 38 % at 5 years, P= .85), event-free survival (EFS) (33% vs 25% at 5 years, P= .39). However, in the context of the favorable genotype, EFS was significantly longer in the 79 CN- than in the 16 CA-AML patients (41% vs 19% at 5 years ; P= .04) with a trend to better OS (51% vs 31% at 5 years ; P= .12). No significant differences were observed in patients with NPM1 mutated AML but FLT3-ITD (5-year EFS, 12% vs 40%; 5-year OS, 20% vs 60%; P= .47 and .27, respectively), even if the numbers of patients were here very low (35 CN- vs 5 CA-AML). More importantly, the favorable genotype was predictive of a longer EFS and OS in the 267 patients with CN-AML (5-year EFS, 41% vs 19%; 5-year OS, 51% vs 30%; P= .0001 and .001, respectively), while no differences were observed in the 213 patients with non-CBF CA-AML (5-year EFS, 19% vs 16%; 5-year OS, 31% vs 27%; P= .38 and .36, respectively). Conclusion As shown, patients with the favorable genotype but CA-AML had an outcome relatively similar to those with a non favorable genotype and either CA- or CN-AML. The favorable outcome associated with NPM1 mutation in the absence of FLT3-ITD might thus depend on the presence of a normal karyotype. We thus think that larger studies or overviews are needed to definitely answer this question. Disclosures Dombret: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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Prognostic impact of low allelic ratio FLT3-ITD and NPM1 mutation in acute myeloid leukemia

Blood Advances ◽

10.1182/bloodadvances.2018020305 ◽

2018 ◽

Vol 2 (20) ◽

pp. 2744-2754 ◽

Cited By ~ 35

Author(s):

Masahiro Sakaguchi ◽

Hiroki Yamaguchi ◽

Yuho Najima ◽

Kensuke Usuki ◽

Toshimitsu Ueki ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Gene Mutation ◽

Myeloid Leukemia ◽

Favorable Outcome ◽

Prognostic Impact ◽

Cell Transplant ◽

Allele Ratio ◽

Hematopoietic Stem ◽

Npm1 Mutation ◽

Acute Myeloid

Abstract In the opinion of the European LeukemiaNet (ELN), nucleophosmin member 1 gene mutation (NPM1 mut)–positive acute myeloid leukemia (AML) with an fms-like kinase 3-internal tandem duplication (FLT3-ITD) allele ratio (AR) <0.5 (low AR) has a favorable prognosis, and allogeneic hematopoietic stem cell transplant (allo-HSCT) in the first complete remission (CR1) period is not actively recommended. We studied 147 patients with FLT3-ITD gene mutation–positive AML, dividing them into those with low AR and those with AR of ≥0.5 (high AR), and examined the prognostic impact according to allo-HSCT in CR1. Although FLT3-ITD AR and NPM1 mut are used in the prognostic stratification, we found that NPM1 mut–positive AML with FLT3-ITD low AR was not associated with favorable outcome (overall survival [OS], 41.3%). Moreover, patients in this group who underwent allo-HSCT in CR1 had a significantly more favorable outcome than those who did not (relapse-free survival [RFS] P = .013; OS P = .003). Multivariate analysis identified allo-HSCT in CR1 as the sole favorable prognostic factor (RFS P < .001; OS P < .001). The present study found that prognosis was unfavorable in NPM1 mut–positive AML with FLT3-ITD low AR when allo-HSCT was not carried out in CR1.

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Autologous Versus Related Versus Unrelated Hematopoietic Stem Cell Transplantation for Adult Patients with NPM1 Mutated/FLT3-ITD Negative Acute Myeloid Leukemia in First Remission: A Study from the Acute Leukemia Working Party (ALWP) of the European Society of Blood and Marrow Transplantation (EBMT)

Blood ◽

10.1182/blood.v128.22.2279.2279 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2279-2279

Author(s):

Xavier Poiré ◽

Myriam Labopin ◽

Didier Blaise ◽

Patrice Chevallier ◽

Johan Maertens ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Stem Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Myeloid Leukemia ◽

Research Funding ◽

Intermediate Risk ◽

Npm1 Mutation ◽

First Remission ◽

Acute Myeloid

Abstract Introduction: Acute myeloid leukemia (AML) in first remission (CR1) with intermediate-risk cytogenetics and isolated NPM1 mutation carries a good prognosis. There is not a clear benefit to perform allogeneic stem cell transplantation (allo-SCT) in CR1, and this procedure is not usually recommended in these patients. High dose chemotherapy followed by autologous stem cell transplantation (auto-SCT) is a good therapeutic alternative in good-risk AML in CR1 associated with lower toxicity. Nevertheless, relapse remains as high as 40% in this subgroup. To evaluate the best consolidation strategy in AML with isolated NPM1 mutation, we retrospectively compared auto-SCT, related (MRD) and fully matched (10/10) unrelated (MUD) allo-SCT within the EBMT registry. Methods: We selected de novo adult AML with intermediate-risk cytogenetics harbouring an isolated NPM1 mutation without FLT3-ITD and transplanted in CR1 between 2005 and 2015. Results: Two hundred and fifty-six patients have been allocated. One hundred and twenty-five patients received an auto-SCT, 72 a MRD and 59 a MUD. Median age at SCT was 52.5-year-old (range, 18.9-77) and median follow-up was 30 months (range, 1.6-109.7). A normal karyotype was found in 86% of auto-SCT and 74% of allo-SCT (p=0.02). Molecular status was available in 55% of patients, with a higher proportion of complete molecular remission (CMR) before auto-SCT than before allo-SCT (84% versus 63%, respectively, p=0.005). There was no difference in the number of induction courses to reach CR1 between groups. The majority of patients have a good performance status at the time of SCT. Peripheral blood was more frequently used as stem cell source in auto-SCT compared to allo-SCT (97% versus 77%, respectively, p<0.01). Total body irradiation was administered in 23% of allo-SCT and in 3% of auto-SCT (p<0.01). Among allo-SCT, a myeloablative conditioning regimen was administered in 57% of the patients. In vivo T-cell depletion was more frequently in MUD than in MRD (70 versus 40%, respectively, p=0.001). The 2-year leukemia-free survival (LFS) was 62% in auto-SCT, 69% in MUD and 81% in MRD (p=0.02 for MRD versus auto-SCT or MUD). The 2-year overall survival (OS) was not significantly different among auto-SCT, MUD and MRD, reaching 82%, 81% and 85%, respectively (p=0.88). The 2-year non-relapse mortality (NRM) was 2.5% in auto-SCT and 7.5% in allo-SCT (p=0.04), without any difference between MRD and MUD. The 2-year cumulative incidence of relapse (RI) was significantly higher after auto-SCT (30%) than after MUD (22%) and MRD (12%, p=0.01). Among patients transplanted in CMR, RI was higher after auto-SCT and LFS was superior after allo-SCT (RI: 21 vs. 11 vs 4%; LFS: 61 vs 74 vs. 91 after auto-SCT, MUD, and MRD, respectively, p=0.04), although this difference did not translate into a different OS (82 vs. 77 vs. 90 after auto-SCT, MUD, and MRD, respectively). In the 28 patients not transplanted in CMR who received an allo-SCT, 2-year RI, LFS and OS were 33% (15-53), 63 (43-83), and 81 (65 - 96%), whereas only 10 patients with persistant MRD received an auto-SCT precluding firm conclusions. In multivariate analysis, MRD versus auto-SCT but not MUD versus auto-SCT was significantly associated with a lower RI (p<0.01 and p=0.13, respectively) and a better LFS (p=0.01 and p=0.31, respectively). Age correlated significantly with higher NRM (p<0.01). Donor type, and age were not significantly associated with OS. Conclusion: Allo-SCT using a sibling donor appears as a good consolidation therapy to prevent relapse for young patients with AML and isolated NPM1 mutation in CR1. Auto-SCT was followed by higher relapse risk and inferior LFS, but similar OS to both allo-SCT modalities. In patients with molecular persistence, allo-SCT was followed by a relatively favourable outcome, but the low number of patients with molecular data included in this series precludes more firm conclusions. The strategy for patients not transplanted in CMR remains to be further evaluated. Disclosures Maertens: Pfizer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy; Astellas: Consultancy, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; Merck Sharp & Dohme: Consultancy, Honoraria, Research Funding, Speakers Bureau. Baerlocher:Geron: Research Funding; Novartis: Research Funding; Janssen: Research Funding.

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Clonal evolution in relapsed NPM1-mutated acute myeloid leukemia

Blood ◽

10.1182/blood-2013-01-479188 ◽

2013 ◽

Vol 122 (1) ◽

pp. 100-108 ◽

Cited By ~ 149

Author(s):

Jan Krönke ◽

Lars Bullinger ◽

Veronica Teleanu ◽

Florian Tschürtz ◽

Verena I. Gaidzik ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

High Risk ◽

Myeloid Leukemia ◽

Clonal Evolution ◽

Npm1 Mutation ◽

Key Points ◽

Primary Leukemia ◽

Acute Myeloid

Key Points Relapsed AML with NPM1 mutation is genetically related to the primary leukemia and characterized by an increase in high-risk aberrations. DNMT3A mutations show the highest stability and thus may precede NPM1 mutations.

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TET2 mutation is an unfavorable prognostic factor in acute myeloid leukemia patients with intermediate-risk cytogenetics

Blood ◽

10.1182/blood-2011-02-339747 ◽

2011 ◽

Vol 118 (14) ◽

pp. 3803-3810 ◽

Cited By ~ 176

Author(s):

Wen-Chien Chou ◽

Sheng-Chieh Chou ◽

Chieh-Yu Liu ◽

Chien-Yuan Chen ◽

Hsin-An Hou ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Prognostic Factor ◽

Myeloid Leukemia ◽

Negative Impact ◽

Intermediate Risk ◽

Npm1 Mutation ◽

Disease Evolution ◽

Unfavorable Prognostic Factor ◽

Tet2 Mutation ◽

Acute Myeloid

Abstract The studies concerning clinical implications of TET2 mutation in patients with primary acute myeloid leukemia (AML) are scarce. We analyzed TET2 mutation in 486 adult patients with primary AML. TET2 mutation occurred in 13.2% of our patients and was closely associated with older age, higher white blood cell and blast counts, lower platelet numbers, normal karyotype, intermediate-risk cytogenetics, isolated trisomy 8, NPM1 mutation, and ASXL1 mutation but mutually exclusive with IDH mutation. TET2 mutation is an unfavorable prognostic factor in patients with intermediate-risk cytogenetics, and its negative impact was further enhanced when the mutation was combined with FLT3-ITD, NPM1-wild, or unfavorable genotypes (other than NPM1+/FLT3-ITD− or CEBPA+). A scoring system integrating TET2 mutation with FLT3-ITD, NPM1, and CEBPA mutations could well separate AML patients with intermediate-risk cytogenetics into 4 groups with different prognoses (P < .0001). Sequential analysis revealed that TET2 mutation detected at diagnosis was frequently lost at relapse; rarely, the mutation was acquired at relapse in those without TET2 mutation at diagnosis. In conclusion, TET2 mutation is associated with poor prognosis in AML patients with intermediate-risk cytogenetics, especially when it is combined with other adverse molecular markers. TET2 mutation appeared to be unstable during disease evolution.

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