scholarly journals Fludarabine, High Dose Cytarabine and Idarubicin-Based Induction Is Highly Effective in Young AML Patients with Concomitant NPM1 and FLT3-ITD Mutation Irrespectively of FLT3-ITD Allelic Burden

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3828-3828
Author(s):  
Paola Minetto ◽  
Anna Candoni ◽  
Fabio Guolo ◽  
Marino Clavio ◽  
Maria Elena Zannier ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Leukemic Cells ◽  
High Dose ◽  
Prognostic Impact ◽  
Allogeneic Bone ◽  
Wild Type ◽  
Npm1 Mutation ◽  
Mutational Status ◽  
High Dose Cytarabine ◽  
Allelic Burden

Background: The presence of FLT3 "internal tandem duplication" (FLT3-ITD) mutation is associated with poor prognosis in acute myeloid leukemia (AML). However, the concomitant presence of NPM1 mutation (NPM1-mut) partially 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 stratificationat diagnosis by the last European Leukemia Net (ELN) guidelines. Aims: To investigate the efficacy of an intensive fludarabine-containing induction regimen (FLAI) for fit, de novo AML patients according to NPM1 and FLT3-ITD mutational status. Methods: One-hundred and sixteen consecutive AML patients, treated in 3 Hematology Italian centers from January 2008 to January 2018, were included in this analysis. Twenty five patients showed isolated FLT3-ITD, 39 concomitant FLT3-ITD and NPM1-mutation and 52 isolated NPM-1-mutation.Median age was 52 yrs (range: 18-65 years). All patients received fludarabine, high dose cytarabine-based induction (fludarabine 30 mg/sqm and ARA-C 2g/sqm ondays 1 to 5 plus idarubicin 10 mg/sqm on days 1-3-5). For patients achieving CR fludarabine was omitted on II induction course and idarubicin dose was increased to 12 mg/sqm. Before2017 patients with isolated FLT3-ITD mutation were scheduled to receive allogeneic bone marrow transplantation (BMT) in first complete remission regardless of allelic burden whereas after 2017 only patients with high allelic burden received BMT in 1st CR. Minimal residual disease was evaluated on marrow samples using multicolor flow-cytometry (MFC)or NPM1 expression levels. Negative MFC-MRD wasdefined by the presence of less than 25 clustered leukemic cells/105 total events (threshold of 0.025% residual leukemic cells, Minetto et. al, BJH 2019). NPM1mutation (NPM1-A, B and D) was measured using Muta Quant Kit Ipsogen from Qiagen. FLT3-ITD allelic burden was available in31/64 of FLT3-ITD patients. Results: Overall 60-days mortality was 4%. After two induction cycles, 101 patients achieved CR (87%). Thirty-three/101 (33%) CR patients underwent BMT in first CR. After a median follow up of 61 months, 3-year overall survival (OS) was 56.8% (median not reached). In univariate analysis OS duration was favorably affected by age <55 yrs (p<0.05), MRD-negative status after induction (both MFC and NPM1 based MRD) (p<0.001) and wild-type FLT3(p<0.05). However, in multivariate analysis only MRD status significantly affected OS (p<0.003). The probability of achieving a molecular MRD negative CR after first cycle among NPM1-mut patients was similar between patients with or without concomitant FLT3-ITD mutation (61% and 66%, respectively, p=n.s.). Interestingly, in younger patients (< 55yrs) OS was comparable in case of isolated NPM1 mutation or concomitant NPM1/FLT3-ITD mutation (3-year OS 68.4% and 62.3%, respectively, p= n.s, Figure 1), regardless of FLT3-ITD allelic burden.Patients with isolated FLT3-ITD mutation had a significantly worse prognosis (3-year OS 34.4%, p<0.05). Again, multivariate analysis showed that persistence of MRD (by any method, p <0.05) was the strongest predictor of outcome. Moreover, performing BMT infirst CR did not impact OS neither in univariate or multivariate analysis. Conclusion: Despite the potential bias due to the retrospective nature of the analysis, our data indicate that intensive fludarabine-high dose cytarabine-based induction exerts a strong anti-leukemic efficacy in younger AML patients carrying NPM1 mutation irrespectively of FLT3 mutational status.Thus, the synergism of fludarabine and cytarabine seems to affect the intrinsic chemosensitivity of NPM1-mut leukemic cells, overcoming the negative impact of FLT3-ITD. Moreover, our data suggest the strong prognostic impact on survival of MRD clearance and question the role of BMT in I CR in this setting of patients. Figure 1 Disclosures Candoni: Gilead: Honoraria, Speakers Bureau; Celgene: Honoraria; Pfizer: Honoraria; Janssen: Honoraria; Merck SD: Honoraria, Speakers Bureau. Bocchia:Incyte: Honoraria; Novartis: Honoraria; BMS: Honoraria.

scholarly journals Intensive Fludarabine, High Dose Cytarabine and Idarubicin-Based Induction for Younger NPM1-Mutated AML Patient: Overcoming the Negative Prognosis of FLT3-ITD Mutation

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 32-33
Author(s):  
Paola Minetto ◽  
Anna Candoni ◽  
Fabio Guolo ◽  
Marino Clavio ◽  
Maria Elena Zannier ◽  
...  
Keyword(s):  
High Risk ◽  
Risk Stratification ◽  
High Dose ◽  
Prognostic Impact ◽  
Allogeneic Bone ◽  
Npm1 Mutation ◽  
Mutational Status ◽  
High Dose Cytarabine ◽  
Allelic Burden

NPM1 and FLT3 mutational status assessment is recommended in acute myeloid leukemia (AML) at diagnosis by European Leukemia Net (ELN) risk stratification. The presence of NPM1 mutation (NPM1-mut) partially overcomes the negative prognostic impact of FLT3-ITD, which is also modulated by FLT3-ITD/wild-type allelic ratio. Targeted drugs are available for FLT3-mutated AML but no data are available so far on the efficacy of intensified front-line regimens in overcoming the negative prognostic role of FLT3-ITD mutation. We investigated the efficacy of an intensive fludarabine, high dose cytarabine (ARA-C) and Idarubicin (IDA) induction regimen (FLAI) as frontline treatment for fit, de novo AML patients according to NPM1 and FLT3-ITD mutational status. One-hundred and forty-nine consecutive AML patients, treated in 3 Hematology Italian centers from January 2008 to January 2018, were included in this analysis. Twenty nine patients had isolated FLT3-ITD, 59 concomitant FLT3-ITD and NPM1-mut and 61 isolated NPM1-mut. Median age was 51 yrs (range: 18-65). All patients received FLAI induction (fludarabine 30 mg/sqm and ARA-C 2g/sqm on days 1 to 5 plus IDA 10 mg/sqm on days 1-3-5). For patients achieving CR fludarabine was omitted on II induction and IDA dose was increased to 12 mg/sqm. Before ELN 2017 risk stratification was adopted, patients with isolated FLT3-ITD mutation were scheduled to receive allogeneic bone marrow transplantation (allo-BMT) in first CR regardless of allelic burden. For patients with AML with NPM1 mutation and concomitant FLT3-ITD indication to allo-BMT in 1st complete remission was mainly based on minimal residual disease (MRD) status. MRD was evaluated on marrow samples using multicolor flow-cytometry (MFC) or NPM1 expression levels. Negative MFC-MRD was defined by the presence of less than 25 clustered leukemic cells/105 total events (threshold of 0.025%, Minetto et. al, BJH 2019). NPM1-mut (NPM1-A, B and D) was measured using Muta Quant Kit Ipsogen from Qiagen. FLT3-ITD allelic burden was available in31/64 of FLT3-ITD patients. Overall, 60-days mortality was 4.7%. After first induction cycles, 129 patients achieved CR (86.6%). Thirty-five/129 (25.5%) CR patients underwent BMT in first CR. After a median follow up of 68 months, 3-year overall survival (OS) was 58.6% (median not reached). In univariate analysis OS duration was affected by NPM1, FLT3 mutational status and ELN risk score. However, NPM1-mutated patient was not negatively affected by the presence of FLT3-ITD, regardless of allelic burden. This observation was even more evident in patients younger than 55 yrs (3 yy OS 64% and 68% for NPM1-mutated with or w/o FLT3-ITD, respectively (p=n.s, Figure 1), regardless of FLT3-ITD allelic burden. ELN 2017 high risk patients displayed the worst prognosis (3-year OS 35.2%). Multivariate analysis showed that NPM1 mutation was the strongest predictor of survival. In order to assess the impact of allo-BMT in 1st CR we performed a Landmark Analysis including patients alive and in CR at day 90. Interestingly, performing allo-BMT in 1st CR did not impact OS in the whole cohort of patients and irrespectively of NPM1 and FLT3 mutational status. The only subgroup who benefit from allo-BMT in first CR was high risk ELN2017 (p&lt;0.05). Despite the potential bias due to the retrospective nature of the analysis, our data indicate that intensive fludarabine-high dose cytarabine-based induction exerts a strong anti-leukemic efficacy in younger AML patients carrying NPM1 mutation irrespectively of FLT3 mutational status. Our data potentially question the role of BMT in first CR in this setting. Figure Disclosures Bocchia: CELGENE: Honoraria; Incyte: Honoraria.

scholarly journals Fludarabine, High-Dose Cytarabine and Idarubicin-Based Induction May Overcome the Negative Prognostic Impact of FLT3-ITD in NPM1 Mutated AML, Irrespectively of FLT3-ITD Allelic Burden

Cancers ◽  
2020 ◽  
Vol 13 (1) ◽  
pp. 34
Author(s):  
Paola Minetto ◽  
Anna Candoni ◽  
Fabio Guolo ◽  
Marino Clavio ◽  
Maria Elena Zannier ◽  
...  
Keyword(s):  
Allogeneic Transplantation ◽  
High Dose ◽  
Prognostic Impact ◽  
Npm1 Mutation ◽  
High Dose Cytarabine ◽  
Genetic Aberration ◽  
Risk Patients ◽  
Allelic Burden

The mutations of NPM1 and FLT3-ITD represent the most frequent genetic aberration in acute myeloid leukemia. Indeed, the presence of an NPM1 mutation reduces the negative prognostic impact of FLT3-ITD in patients treated with conventional “3+7” induction. However, little information is available on their prognostic role with intensified regimens. Here, we investigated the efficacy of a fludarabine, high-dose cytarabine and idarubicin induction (FLAI) in 149 consecutive fit AML patients (median age 52) carrying the NPM1 and/or FLT3-ITD mutation, treated from 2008 to 2018. One-hundred-and-twenty-nine patients achieved CR (86.6%). After a median follow up of 68 months, 3-year overall survival was 58.6%. Multivariate analysis disclosed that both NPM1mut (p < 0.05) and ELN 2017 risk score (p < 0.05) were significant predictors of survival. NPM1-mutated patients had a favorable outcome, with no significant differences between patients with or without concomitant FLT3-ITD (p = 0.372), irrespective of FLT3-ITD allelic burden. Moreover, in landmark analysis, performing allogeneic transplantation (HSCT) in first CR proved to be beneficial only in ELN 2017 high-risk patients. Our data indicate that FLAI exerts a strong anti-leukemic effect in younger AML patients with NPM1mut and question the role of HSCT in 1st CR in NPM1mut patients with concomitant FLT3-ITD.

scholarly journals 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 ◽  
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 (&lt;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 &lt;0.05).Patients with isolated FLT3-ITD mutation had a significantly worse prognosis (3-year OS 38.3%, p&lt;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&lt;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&lt;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.

Incidence and Prognostic Impact of Gene Mutations in Older Patients with AML Treated in the ALFA-9801 Study.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1525-1525
Author(s):  
Aline Renneville ◽  
Sylvie Castaigne ◽  
Sylvie Chevret ◽  
Laura Llopis ◽  
Nathalie Philippe ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Older Patients ◽  
Gene Mutations ◽  
Significant Prognostic Factor ◽  
Prognostic Impact ◽  
Npm1 Mutation ◽  
Younger Patients ◽  
Mutational Status ◽  
Cebpa Mutations ◽  
The Impact

Abstract Introduction: The impact of gene mutations, i.e. poor-prognosis FLT3 internal tandem duplications (ITDs) and good-prognosis NPM1 or CEBPA mutations, has been welldocumented in several recent reports dealing with younger patients with acute myeloid leukemia (AML). As these mutations were associated with cytogenetically normal (CN) AML, most of these reports focused on CN-AML patients. Both FLT3-ITD and NPM1 mutations were also associated with higher WBC. The objective of the present study was to evaluate the incidence, correlations, and prognostic value of these mutations in older patients with the disease. Methods: The French ALFA group has screened a total of 583 patients, including 333 younger patients (15–50 years) treated in the ALFA-9802 trial and 250 older patients (50–70 years) treated in the ALFA-9801 trial. The older ALFA-9801 trial included 468 patients with previously untreated de novo AML and studied the role of idarubicin (IDA) as compared to high-dose daunorubicin (DNR) as well as interleukine-2 as a maintenance therapy (C. Pautas et al. ASH 2007, abstract #162). Comparison between the 250 patients tested for mutations in that trial and the 218 patients not tested showed no differences in age, sex ratio, FAB classification, bone marrow blasts percentage, randomization arm, and performance status at entry in the study. There was, however, a higher rate of patients with intermediate cytogenetics (p=.01) or increased WBC (p=.01) in the former subgroup. Results: Median age of the 250 patients tested was 60 years. Cytogenetics was studied in 232 patients (12 favorable, 174 intermediate, 46 unfavorable). One hundred twenty-two patients (49%) had CN-AML. CR rate was 67.5% and estimated 4-year OS was 26% (95% CI, 20–33). Incidences of FLT3-ITD, NPM1, and CEBPA mutations were 37/250 (15%), 64/249 (26%), and 20/249 (8%), respectively. These incidences were very similar than in the younger ALFA-9802 population [50/329 (15%), 76/321 (24%), and 24/316 (8%), respectively]. In these older AML patients, the correlation between increased WBC and FLT3-ITD (p&lt;.001) or NPM1 mutation (p&lt;.001) was still observed. Conversely, NPM1 mutations only (p&lt;.001), but not FLT3-ITDs (p=.10) or CEBPA mutations (p=.99), were significantly associated with CN-AML. In the whole group of 249 patients with either normal or abnormal karyotype tested for all mutations, 46 were NPM1+/FLT3-ITDwt, 19 FLT3-ITD+/NPM1wt, 18 FLT3-ITD+/NPM1+, and 166 NPM1wt/FLT3-ITDwt. CR rate was 87%, 84%, 56%, and 75% and median OS was 20.5, 18.6, 6.0, and 14.6 months, respectively. In the 20 CEBPA+ patients, CR rate was 80% and median OS was 22.8 months. In the group of 122 CN-AML patients tested for all mutations, 36 were NPM1+/FLT3-ITDwt, 8 FLT3-ITD+/NPM1wt, 15 FLT3-ITD+/NPM1+, and 63 NPM1wt/FLT3- ITDwt. CR rate was 92%, 87.5%, 60%, and 78% and median OS was 20.5, 16.9, 7.0, and 16.8 months, respectively. In the 10 CEBPA+ patients, CR rate was 80% and median OS was not reached. In multivariate analysis including age, WBC, cytogenetics (favorable versus others), and gene mutational status (NPM1+ or CEBPA+ if FLT3-ITDwt versus others), a pejorative effect of age (p=.02) and WBC (p&lt;.001), but a protective effect of mutational status (HR= 0.66, p=.05) and favorable cytogenetics (HR=0.43, p=.06) was observed in the whole patient population. Nevertheless, estimated 4-year OS was only 37% (95% CI, 23–50) in patients with a favorable mutational status. In those with CNAML and a favorable mutational status, estimated 4-year OS reached only 40% (95% CI, 23–56). In this subgroup of patients with CN-AML, WBC was the only significant prognostic factor identified in multivariate analysis (p&lt;.001). Conclusion: This study conducted in a large cohort of patients aged 50 to 70 years and prospectively treated in the same trial showed that gene mutational status still affect the outcome of older patients with AML. Mutation incidences are in the same range than in younger patients. Nevertheless, their impact on OS appeared to be less marked than in younger patients, probably due to the worse general outcome observed in these older patients.

scholarly journals Impact of FLT3-ITD Mutational Burden in 469 Acute Myeloid Leukemia (AML) Patients

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1033-1033 ◽  
Author(s):  
Pierre Hirsch ◽  
Myriam Labopin ◽  
Christophe Marzac ◽  
Anne-Claire Mamez ◽  
Ruoping Tang ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
High Resolution ◽  
Leukocyte Count ◽  
Npm1 Mutation ◽  
Allelic Ratio ◽  
High Burden ◽  
Mutational Burden ◽  
Mutational Status ◽  
Therapeutic Decisions ◽  
Allelic Burden

Abstract Background: FLT3-ITD mutational status is a well known prognostic factor in AML patients. However, its prognostic value in case of low mutational burden is currently under debate, especially in patients with intermediate karyotype and NPM1 mutations. Indeed some studies suggested that patients with an allelic ratio (i.e FLT3-ITD/FLT3 WT) lower than 50 % might have the same prognosis as unmutated patients. Patients and methods: Four hundred and sixty nine (469) patients diagnosed with AML in a single center from 1995 to 2014 and who received intensive chemotherapy based on anthracycline and cytarabine were included. Patients with t(15;17)(q24;q21) or t(9;22)(q34;q11) translocations were excluded. 134 patients underwent allogeneic stem cell transplantation. FLT3-ITD allelic burden was determined using fresh or frozen cells drawn at time of diagnosis in all patients. The mutational status for FLT3-ITD was determined using high-resolution sizing of fluorescent dye-labeled PCR amplification of exons 14-15. Beyond its contribution to mutation detection, high-resolution sizing also allows to estimate the allelic burden by measuring peak height ratios (mutant/wild type) on a fluorescence scale. Low allelic burden was defined by an allelic ratio lower than 50%. NPM1 and CEBPA mutational status were determined in most patients (n=409 and n=349 respectively). Median follow-up time for patients who were still alive was 37 months. Results: Median age was 56 years (range 16-81). Karyotype was unfavorable in 110 (24%) patients, favorable in 45 (10%), intermediate in 298 (63%) patients and normal in 229 (48 %). Overall, FLT3-ITD was detected in 83 (17%) patients. Twenty three patients (5%) had a low allelic ratio and 60 (13%) had a high allelic ratio. NPM1 mutation was found in 100 (24%) patients and bi-allelic CEBPA mutations in 21 (6%). In the overall population, patients with FLT3-ITD had poorer outcome compared to other patients (OS at 3 years: 33+/-5% vs. 52 +/-3%, p =0.02). There was no difference between patients with low allelic burden or patients with high allelic burden for leukemia-free survival (7+/-7% vs. 38+/-8%, p=0.12), overall survival (25+/-5% vs. 37+/-6%, p=0.67) or CR reaching (70% in the two groups). In multivariate analysis, factors independently associated with OS were cytogenetic risk group, age, leukocyte count at diagnosis, NPM1 status, CEBPA status and FLT3-ITD status. There were no difference between patients with high vs. low allelic burden (HR=1.20 [0.59-2.42]). Results were the same when focusing on patients with intermediate karyotype. FLT3-ITD was associated with lower survival (p=0.003), but the mutational burden was not (OS at 3 years 30+/-12% vs. 36+/-7%, for low or high burden respectively, p=0.86). In multivariate analysis, factors independently associated with OS were age, leukocyte count, NPM1 status, CEBPA status and FLT3-ITD status. Again, there were no difference between patients with high versus low allelic burden (HR=0.98[0.45-2.08]. Conclusions: In this series, low FLT3-ITD allelic burden had a similar prognostic significance compared to a higher allelic burden. Therefore, patients with low FLT3-ITD allelic burden should likely be considered as having the same prognosis as patients with high burden, and FLT3-ITD detection, but not FLT3-ITD allelic burden, should be the major factor to be considered for therapeutic decisions. Disclosures No relevant conflicts of interest to declare.

Prognostic Impact of the Amount of CD34+ CD38- CD123+ Cells at Diagnosis In Acute Myeloid Leukemia: a Study From the GOELAMS

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 951-951
Author(s):  
François Vergez ◽  
Alexa Green ◽  
Jérôme Tamburini ◽  
Nathalie Gallay ◽  
Murielle Roussel ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Disease Free Survival ◽  
Complete Response ◽  
Leukemic Cells ◽  
Prognostic Impact ◽  
Npm1 Mutation ◽  
Number Of Patients ◽  
Wbc Count

Abstract Abstract 951 AML cells with CD34+CD38-CD123+ phenotype represent a subset enriched in leukemic stem cells. Moreover, this subpopulation has been described to be resistant to genotoxic agents as compared with leukemic bulk. However, the clinical impact of the amount of CD34+CD38-CD123+ remains poorly described. In this study we evaluated the prognostic impact of the amount of CD34+CD38-CD123+ cells detected at diagnosis in a series of AML patients treated by intensive chemotherapy according to trials from the French GOELAMS group. Quantification of blast cells with the CD34+CD38-CD123+ phenotype was achieved by flow cytometry in 111 patients less than 66 years old with de novo AML treated by 3+7-like chemotherapy. The characteristics of the patients are shown in table 1. Age, WBC count, NPM1 mutation and FLT3-ITD had no impact on achievement of complete response (CR) whereas, CD34+CD38-CD123+ (>15%) and unfavourable karyotype were significantly correlated with lack of CR. By logistic regression, CD34+CD38-CD123+ (>15%) retains significance for CR achievement with an OR of 0.3 (0.11-0.84) (p=0.02). For the 91 complete responders, age, WBC count, karyotype, NPM1 mutation had no impact on disease-free survival (DFS).Interestingly, patients with <1%, 1–15%, >15% CD34+CD38-CD123+ had a median DFS of 57.6 (SE 6.6), 11.2 (SE 7.5) and 9.2 (SE 13.4) months, respectively (p<0.0001, figure 1). FTL3-ITD was also significantly associated with a shorter DFS. In multivariate analysis, CD34+CD38-CD123+<1% was significantly associated with a longer DFS (p=0.00025). Age, %CD34+CD38-CD123+, karyotype, NPM mutation and FLT3-ITD significantly influenced overall survival (OS) whereas WBC count had no impact. Median OS was particularly impressive for patients with CD34+CD38-CD123+<1%. Indeed, median OS was 78.2 (SE 10.7), and 15.3 (SE 5.8) months for CD34+CD38-CD123+<1% vs others, respectively (p<0.0001, figure 1). Multivariate analysis for OS retains two significant factors: adverse karyotype (95%CI, 1.19–4.02, p=0.012) and CD34+CD38-CD123+<1% (95%CI, 0.12–0.52, p=0.00018). Moreover, although the number of patients was low in favourable karyotype (CBF), CD34+CD38-CD123+<1% had a major impact on both DFS, median 57.6 vs 10.2 months for >1% (HR, 0.19, 0.06–0.59, p=0.0038) and OS, median not reached vs 18.5 months (p=0.0025). This study emphasizes the prognosis impact of the CD34+CD38-CD123+ cell burden in AML patients, which is predictive for shorter OS and DFS when representing more than 1% of the leukemic cells, regardless of the usual prognosis categories. We provide here a new prognosis marker that may be easily translated to the clinical practice in AML although it remains to be validated on a large prospective cohort of patients. Moreover, new therapies targeting this subpopulation could help to improve outcome in AML patients.TableCharacteristics of patients.All patients N=111CD34+CD38-CD123+< 1 % N=40CD34+CD38-CD123+ 1-15% N=20CD34+CD38-CD123+> 15% N=20Gender, M/F50/6219/2124/276/14Age, median48 (20–65)47 (20–65)51 (20–64)50 (21–65)WBC,median (G/L)33.2 (1–254)13.8 (1–237.7)41 (1.3–254)32.9 (2.3–193.2)Favourable caryotype231184Intermediate caryotype6924378Unfavourable caryotype19568NPM1 mutation28/957/3116/455/19FLT3-ITD33/1007/3421/475/19Complete Response91 (82%)36 (90%)42 (81.4%)13 (65%)Relapse53 (58.2%)13 (36.1%)30 (71.4%)10 (76.9%)Allogeneic-SCT33 (36.3%)11 (30.6%)15 (35.7%)7 (53.8%) Disclosures: No relevant conflicts of interest to declare.

scholarly journals Varying intensity of postremission therapy in acute myeloid leukemia

Blood ◽  
1992 ◽  
Vol 79 (8) ◽  
pp. 1924-1930 ◽  
Author(s):  
PA Cassileth ◽  
E Lynch ◽  
JD Hines ◽  
MM Oken ◽  
JJ Mazza ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Mortality Rate ◽  
Maintenance Therapy ◽  
Myeloid Leukemia ◽  
High Dose ◽  
Allogeneic Bone ◽  
Consolidation Therapy ◽  
High Dose Cytarabine ◽  
Postremission Therapy ◽  
Acute Myeloid

The Eastern Cooperative Oncology Group (ECOG) conducted a randomized trial in patients less than or equal to 65 years old (median, 44 years) to determine whether increasing the intensity of postremission therapy in acute myeloid leukemia (AML) would improve the outcome. After uniform induction therapy, patients in complete remission (CR) who were less than 41 years old and who had a histocompatible sibling underwent allogeneic bone marrow transplantation (alloBMT) (54 patients). The remainder of patients in CR were randomized to receive either 2 years of continuous outpatient maintenance therapy with cytarabine and 6- thioguanine (83 patients) or a single course of inpatient consolidation therapy consisting of 6 days of high-dose cytarabine plus 3 days of amsacrine (87 patients). The median duration of follow-up is now 4 years, and patients are included in the analyses of outcome regardless of whether they relapsed before starting the intended treatment. Four- year event-free survival (EFS) was 27% +/- 10% for consolidation therapy versus 16% +/- 8% for maintenance therapy (P = .068) and 28% +/- 11% versus 15% +/- 9% (P = .047) in patients less than 60 years old. The outcome for patients receiving alloBMT was compared with the subset of patients less than 41 years old who received consolidation therapy (N = 29) or maintenance therapy (N = 21). Four-year EFS was 42% +/- 13% for alloBMT, 30% +/- 17% for consolidation therapy, and 14% +/- 15% for maintenance therapy. AlloBMT had a significantly better EFS (P = .013) than maintenance therapy, but was not different from consolidation therapy. In patients less than 41 years old, 4-year survival after alloBMT (42% +/- 14%) did not differ from consolidation therapy (43% +/- 18%), but both were significantly better than maintenance therapy (19% +/- 17%), P = .047 and .043, respectively. The mortality rate for maintenance therapy was 0%, consolidation therapy, 21%; and alloBMT, 36%. Consolidation therapy caused an especially high mortality rate in the patients greater than or equal to 60 years old (8 of 14 or 57%). The toxicity of combined high-dose cytarabine and amsacrine is unacceptable, especially in older patients, and alternative approaches to consolidation therapy such as high-dose cytarabine alone need to be tested. In AML, a single course of consolidation therapy or alloBMT after initial CR produces better results than lengthy maintenance therapy. Although EFS and survival of alloBMT and consolidation therapy do not differ significantly, a larger number of patients need to be studied before concluding that they are equivalent.

NPM-1, but Not FLT3-ITD Mutations Predict Early Blast Cell Clearance and CR Rate in Patients with Normal Karyotype AML or High-Risk Myelodysplastic Syndrome (MDS).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 805-805 ◽  
Author(s):  
Karsten Spiekermann ◽  
Annika Dufour ◽  
Gudrun Mellert ◽  
Evelin Zellmeier ◽  
Jan Braess ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Prognostic Factors ◽  
De Novo ◽  
Blast Cell ◽  
High Dose ◽  
Bone Marrow Blast ◽  
Npm1 Mutation ◽  
Free Survival ◽  
Cell Clearance ◽  
High Dose Cytarabine

Abstract Background: Mutations in the NPM1 gene represent the most frequent alterations in patients with AML and are associated with a favourable clinical outcome. Patients and Methods: We analyzed 803 patients that were treated in the AMLCG2000 study. Patients with de novo or secondary AML or high-risk myelodysplastic syndrome (MDS) were randomly assigned upfront for induction therapy containing one course with standard dose and one course with high-dose cytarabine, or two courses with high-dose cytarabine, and in the same step received postremission prolonged maintenance or busulfan/cyclophosphamide chemotherapy with autologous stem-cell transplantation. At diagnosis mutations in the NPM1 and FLT3 gene were analyzed by routine molecular techniques. Results: The median age of all patients was 60 years and the median observation time 23 months. Results of the mutations status of FLT3 (FLT3-ITD) and NPM1 were available in 761/803 (94,8 %) and 690/803 (85,9 %) patients, respectively. NPM1 and FLT3-ITD mutation were found in 352 (51,1%) and 199 (28,9%), respectively. On the basis of these two molecular markers, patients were grouped in 4 subgroups: 1. NPM1+/FLT3−, N=214 (31%), 2. NPM1+/FLT3+, N=138 (20%); 3. NPM1−/FLT3−, N=276 (40%); NPM1−/FLT3+ (9%). The CR-rates were significantly higher in NPM1+ (74,4%) than in NPM1− (55,9%) patients, but were unaffected by the FLT3-ITD status. Overall survival (OS), event-free survival (EFS) and relapse free survival (RFS) was significantly higher in NPM1 positive and FLT3-ITD negative patients. In a multivariate analysis age, WBC, the presence of the NPM1 mutation and de novo AML were independent prognostic factors for the CR-rate. The NPM1− and FLT3 mutation status, age and LDH were identified as independent prognostic factors for RFS. To further characterize the biological effects of NPM1 and FLT3 mutations, we analyzed the in vivo blast cell clearance measured by the residual bone marrow blast cells one week after the end of the first induction cycle (d+16 blasts). The percentage of patients with adequate blast cell reduction (residual bone marrow blast &lt;10%) was significantly higher in NPM1+ patients (87,3%) compared to NPM1− (65,7%) patients. The presence of a FLT3-ITD mutation had no effect on early blast cell clearance. Conclusions: The presence of a NPM1 mutation represents an independent positive prognostic factor for the CR-rate and RFS/OS. In contrast, FLT3-ITD mutations do not affect the CR-rate, but have a negative prognostic impact on RFS and OS. The higher sensitivity of NPM1-positive blasts towards the induction therapy point to a central role of NPM1 in the regulation of apoptotic cell death in AML.

Prognostic Implications of the IDH1 synonymous SNP rs11554137 In Pediatric and Adult AML: a Children's Oncology Group and Southwest Oncology Group Study

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2737-2737
Author(s):  
Phoenix A. Ho ◽  
Todd A. Alonzo ◽  
Kenneth J. Kopecky ◽  
Kristen L. Miller ◽  
Julia Kuhn ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Expression Profiling ◽  
Prognostic Significance ◽  
Normal Karyotype ◽  
Prognostic Impact ◽  
Wild Type ◽  
Bone Marrow Blast ◽  
Free Survival ◽  
Cytogenetic Abnormalities ◽  
Pediatric Aml

Abstract Abstract 2737 Synonymous SNPs may directly impact gene function through various translational or post-translational mechanisms. Further, such “silent” SNPs in the mutational hotspots of AML-associated genes have recently been reported to carry prognostic impact. We aimed to determine the prevalence, clinical associations, and prognostic significance of a known SNP in exon 4 of IDH1, near the location of the frequently-mutated R132 codon. Diagnostic marrow specimens from 253 pediatric AML patients (treated on the COG trial AAML03P1) and 274 adult AML patients (treated on SWOG trials S9031, S9333, or S9500) were analyzed for the presence of SNP rs11554137 via direct sequencing. In the pediatric cohort (median age 9.8 years), SNP rs11554137 was present in 27 of 253 (10.7%) patients. SNP+ pediatric patients did not differ significantly from wild-type patients in terms of sex, racial distribution (African American patients accounted for 23% of SNP+ patients vs. 14% of wild-type patients, P=0.24), bone marrow blast percentage, or age distribution, except in patients aged 0–2 years, who accounted for 44% of SNP+ patients vs. 23% of wild- type patients (P=0.013). Recurrent cytogenetic abnormalities occurred with similar frequencies in both the SNP+ and wild-type pediatric populations, as did FLT3/ITD, NPMc, and CEBPA mutations. Miscellaneous cytogenetic abnormalities accounted for 33% of SNP+ patients vs. 14% of wild-type patients, P=0.033. IDH1 SNP status had no prognostic impact on survival in the pediatric cohort, as SNP+ and wild-type patients had similar rates of five-year overall survival (OS, 76% vs. 63%, P=0.50), disease-free survival (DFS, 48% vs. 53%, P=0.97), and relapse rate (RR, 39% vs. 39%, P=0.94). In the adult cohort (median age 63 years), the IDH1 SNP was present in 30 of 274 (10.9%) patients. A slight female predominance for the SNP (63% vs. 37%, P=0.052) occurred among adult patients. The SNP was more prevalent in African American patients, who accounted for 30% of the SNP+ patients vs. 7% of wild-type patients, P=0.0046. SNP+ patients also had somewhat higher diagnostic bone marrow blast percentages (medians 80% vs. 70%, P=0.025). The normal karyotype subset accounted for similar proportions of SNP+ vs. wild-type patients (42% vs. 46%, P=0.83). Notably, SNP rs11554137 was not present in adult core-binding factor AML. Miscellaneous cytogenetic abnormalities were significantly more common in SNP+ patients (46% vs. 22%, P=0.022). SNP status was not significantly associated with FLT3/ITD status when all adult patients were considered (P=0.14). However, within the normal karyotype subset, FLT3/ITD was present in 90% of SNP+ patients vs. 59% of wild-type patients (P=0.0053). SNP+ patients had somewhat poorer 5 year OS (10% vs. 18%, hazard ratio [HR]=1.17) though this difference was not statistically significant (P=0.44). Among the 142 patients who achieved complete remission (CR), however, 5-year relapse-free survival (RFS) was significantly worse for SNP+ patients (0% vs. 25%, HR = 2.89, P=0.0014). Of the 14 SNP+ patients who achieved CR, 13 relapsed and the 14th patient died of sepsis in remission after 61 days. In multivariate analysis, after adjusting for the effects of age and cytogenetic group, SNP rs11554137 retained an independent prognostic effect (P=0.0062) regarding RFS. Notably, when FLT3/ITD status is included in multivariate analysis, SNP positivity loses independent prognostic significance (HR=1.72, P=0.18). Genome-wide expression profiling was performed on 134 pediatric AML specimens in whom IDH1 SNP status was known. By comparing SNP+ patients with wild-type patients, we derived a distinct gene-expression signature for patients with SNP rs11554137. Among the most upregulated probe sets in the SNP+ cohort were those representing PEX6 and NFYA, both of which interact with the TGF-beta/SMAD signaling network; the retinoid × receptor beta gene RXRB; and the FER gene, a tyrosine kinase critical to FLT3 signaling. The IDH1 SNP rs11554137 is present in approximately 11% of pediatric and adult AML patients, and gene expression profiling data suggests that leukemia in SNP+ patients may have unique biologic features. The SNP was an independent predictor of decreased RFS in adult AML in univariate analysis, but not in multivariate analysis when adjusting for FLT3/ITD status. Disclosures: No relevant conflicts of interest to declare.

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