Clinical Useful Prognostic Index for Adult Patients with Acute Myeloid Leukemia in First Relapse.

Abstract The treatment of acute myeloid leukemia (AML) in first relapse is associated with unsatisfactory rates of complete responses that are usually short lived. Previously proposed prognostic classification methods serving therapeutic decisions and evaluation of investigational treatment strategies at relapse of AML have been based on the duration of the relapse free interval and have largely neglected the influence of other known prognostic factors. Here we present an improved clinically useful prognostic index. This index has been developed from a multivariate analysis of 667 AML patients in first relapse among 1540 newly diagnosed non-M3 AML patients of age 15 to 60 years entered into three successive HOVON/SAKK Collaborative Group trials. The score, which has a range of 0 to 14 points, uses four relevant parameters. The parameters are: length of relapse free interval after first complete remission (more than 18 months: 0 points; 7 to 18 months: 3 points; 6 months or less: 5 points), cytogenetics at diagnosis (t(16;16) or inv(16): 0 points; t(8;21): 3 points; other cytogenetics: 5 points), age at relapse (35 years or younger: 0 points; 36 to 45 years: 1 point; older than 45 years: 2 points) and whether or not a previous stem cell transplantation (SCT) has been undertaken in first complete remission (no SCT: 0 points; previous SCT: 2 points). These points were assigned following estimations of the relative values of each of these factors contributing to outcome. Ultimately, three risk groups were defined: a favorable prognostic group A (0 to 6 points; overall survival of 70% at one year and 46% at five years), an intermediate risk group B (7 to 9 points; overall survival of 49% at one year and 18% at five years), and an unfavorable risk group C (10 to 14 points; overall survival of 16% at one year and 4% at five years). Thus, four commonly applied clinical parameters may identify among patients with AML in first relapse those for salvage or investigational therapy.

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Prognostic Index for Older Adult Patients with Newly Diagnosed Acute Myeloid Leukemia: The Edouard Herriot Hospital Experience.

Blood ◽

10.1182/blood.v110.11.4352.4352 ◽

2007 ◽

Vol 110 (11) ◽

pp. 4352-4352

Author(s):

Claudiu Plesa ◽

Quoc-Hung Le ◽

Youcef Chelghoum ◽

Mohamed Elhamri ◽

Isabelle Tigaud ◽

...

Keyword(s):

Overall Survival ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Risk Group ◽

Prognostic Score ◽

Prognostic Index ◽

Disease Free Survival ◽

Newly Diagnosed ◽

Co Morbidity ◽

Acute Myeloid

Abstract The treatment of older adults with acute myeloid leukemia (AML) is associated with unsatisfactory rates of complete responses and long-term overall survival. Therefore, a clinically usefull prognostic index can facilitate therapeutic decision making and evaluation of investigational treatment strategies in this patient population. Overall, 243 of the 432 patients (56%, 95% CI: 51–60%) achieved CR (229 of them after the first induction course and 14 after salvage therapy). The median disease-free survival (DFS) and the median overall survival (OS) of the entire cohort were 8.4 months (95% CI: 7.2–10.1 months) and 8.3 months (95% CI: 7.2–10 months) respectively. A prognostic score is presented based on the multivariate analysis of 432 newly diagnosed non-M3 AML patients aged more than 60 years, selected on the base of their initial performance status and the absence of severe co-morbidity factors, for entering onto five successive clinical trials combining an anthracycline and cytarabine. Four clinically relevant parameters are included in this index: cytogenetics at diagnosis, history of previous hematologic disorder, hematologic features at diagnosis, and LDH level at diagnosis. Using this stratification system, three risk groups were defined: a favorable-risk group A (OS of 39% at 2 years and 21% at 5 years), an intermediate-risk group B (OS of 19% at 2 years and 8% at 5 years), and a poor-risk group (OS of 5% at 2 years and 0% at 5 years). The prognostic index estimates the outcome of elderly AML patients usually selected for intensive chemotherapy trials using four easily determined parameters and might identify patients who are really candidates for this treatment strategy from those for whom investigational therapy or palliation may be most appropriate.

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Prognostic Index for Adult Patients With Acute Myeloid Leukemia in First Relapse

Journal of Clinical Oncology ◽

10.1200/jco.2005.06.027 ◽

2005 ◽

Vol 23 (9) ◽

pp. 1969-1978 ◽

Cited By ~ 315

Author(s):

Dimitri A. Breems ◽

Wim L.J. Van Putten ◽

Peter C. Huijgens ◽

Gert J. Ossenkoppele ◽

Gregor E.G. Verhoef ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Risk Group ◽

Prognostic Score ◽

Treatment Strategies ◽

Prognostic Index ◽

Collaborative Group ◽

Clinical Cancer Research ◽

First Relapse ◽

Acute Myeloid

Purpose The treatment of acute myeloid leukemia (AML) in first relapse is associated with unsatisfactory rates of complete responses that usually are short lived. Therefore, a clinically useful prognostic index can facilitate therapeutic decision making and evaluation of investigational treatment strategies at relapse of AML. Patients and Methods A prognostic score is presented based on the multivariate analysis of 667 AML patients in first relapse among 1,540 newly diagnosed non-M3 AML patients (age 15 to 60 years) entered onto three successive Dutch-Belgian Hemato-Oncology Cooperative Group and the Swiss Group for Clinical Cancer Research Collaborative Group trials. Results Four clinically relevant parameters are included in this index (ie, length of relapse-free interval after first complete remission, cytogenetics at diagnosis, age at relapse, and whether previous stem-cell transplantation was performed). Using this stratification system, three risk groups were defined: a favorable prognostic group A (overall survival [OS] of 70% at 1 year and 46% at 5 years), an intermediate-risk group B (OS of 49% at 1 year and 18% at 5 years), and a poor-risk group C (OS of 16% at 1 year and 4% at 5 years). Conclusion The prognostic index estimates the outcome of AML patients in first relapse using four commonly applied clinical parameters and might identify patients who are candidates for salvage and investigational therapy.

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Results from a randomized trial of salvage chemotherapy followed by lestaurtinib for patients with FLT3 mutant AML in first relapse

Blood ◽

10.1182/blood-2010-08-301796 ◽

2011 ◽

Vol 117 (12) ◽

pp. 3294-3301 ◽

Cited By ~ 265

Author(s):

Mark Levis ◽

Farhad Ravandi ◽

Eunice S. Wang ◽

Maria R. Baer ◽

Alexander Perl ◽

...

Keyword(s):

Overall Survival ◽

Acute Myeloid Leukemia ◽

Complete Remission ◽

Randomized Trial ◽

Myeloid Leukemia ◽

Remission Rate ◽

Platelet Recovery ◽

First Relapse ◽

Acute Myeloid

AbstractIn a randomized trial of therapy for FMS-like tyrosine kinase-3 (FLT3) mutant acute myeloid leukemia in first relapse, 224 patients received chemotherapy alone or followed by 80 mg of the FLT3 inhibitor lestaurtinib twice daily. Endpoints included complete remission or complete remission with incomplete platelet recovery (CR/CRp), overall survival, safety, and tolerability. Correlative studies included pharmacokinetics and analysis of in vivo FLT3 inhibition. There were 29 patients with CR/CRp in the lestaurtinib arm and 23 in the control arm (26% vs 21%; P = .35), and no difference in overall survival between the 2 arms. There was evidence of toxicity in the lestaurtinib-treated patients, particularly those with plasma levels in excess of 20μM. In the lestaurtinib arm, FLT3 inhibition was highly correlated with remission rate, but target inhibition on day 15 was achieved in only 58% of patients receiving lestaurtinib. Given that such a small proportion of patients on this trial achieved sustained FLT3 inhibition in vivo, any conclusions regarding the efficacy of combining FLT3 inhibition with chemotherapy are limited. Overall, lestaurtinib treatment after chemotherapy did not increase response rates or prolong survival of patients with FLT3 mutant acute myeloid leukemia in first relapse. This study is registered at www.clinicaltrials.gov as #NCT00079482.

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Methylation of ESR1 and Tumour Suppressor Genes Together Constitute an Independent Outcome Predictor in Acute Myeloid Leukemia.

Blood ◽

10.1182/blood.v108.11.803.803 ◽

2006 ◽

Vol 108 (11) ◽

pp. 803-803 ◽

Cited By ~ 3

Author(s):

Corine J. Hess ◽

Johannes Berkhof ◽

Fedor Denkers ◽

Gert J. Ossenkoppele ◽

Gerrit Jan Schuurhuis ◽

...

Keyword(s):

Overall Survival ◽

Acute Myeloid Leukemia ◽

Promoter Methylation ◽

Myeloid Leukemia ◽

Total Population ◽

Risk Group ◽

Methylation Status ◽

Methylation Index ◽

Group B ◽

Acute Myeloid

Abstract In acute myeloid leukemia (AML) promoter methylation has been observed for the estrogen receptor (ESR1) as well as for a number of Tumor Suppressor Genes (TSGs). These individual aberrancies were suggested to be part of a general methylation defect in subsets of AML patients, rather than random events. The objective of this study was to assess whether aberrant promoter methylation of multiple genes, as observed in AML samples, are associated and whether such associations render impact on clinical outcome. By Methylation-Specific Multiplex Ligation Probe Amplification (MS-MLPA) the methylation status of 26 TSGs was determined in bone marrow samples of 119 primary AML patients and 5 control individuals. No promoter methylation was detected in any of the controls, while at least one TSG was methylated in 59/119 patients. Methylation was observed in 12 out of 26 assessed sites, most frequently for ER, CDKN2B/p15, and IGSF4 (28–36% of all patients). A substantial intra-class correlation of 0.38 existed between methylation of different TGSs. ESR1 methylation (34/119) strongly predicted concurrent methylation of TSGs, OR 7.33 (95%CI 4.13–12.99). A regression model that included both the ESR1 methylation status and the number of methylated TSGs (methylation index), showed both parameters to be independent oppositely directed predictors for overall survival (OS), HR 0.06 (95%CI 0.01–0.33; p=.001) and HR 1.92 (95%CI 1.19–3.10; p=.007), respectively. In line with this observation, a higher methylation index was found to yield a significant negative effect on patient OS in both the ESR1 methylated (ESR1+) and ESR1 unmethylated (ESR1−) subgroups. Combining ESR1 methylation status with the absence or presence of promoter methylation of other TSGs (TSG+ or TSG−); yielded 4 patient subgroups with large differences in OS in univariate analysis (p=.0001, figure 1A). In multivariate analysis that included, FLT3-status, age at diagnosis, cytogenetics and achievement of CR, the predictive impact of the 4-group division on OS was maintained, HR 2.12 (95%CI 1.04–4.29; p=.037). Moreover, the combination identified a good prognostic patient subgroup (n=15, median OS 39 month) within the intermediate cytogenetic risk group (n=54, median OS 8.3 month), figure 1B. In conclusion, concurrent methylation occurs frequent in AML and is best predicted by ESR1 methylation. Methylation of ESR1 and methylation of other TSGs represent processes with independent predictivity. When combined, they constitute a unique and powerful factor for predicting overall survival, both in the total AML population as well as within the intermediate cytogenetic risk group. Figure 1. Overall Survival based on the methylation status of ER (ER+/ER) combined with the absence or presence of methylation of TSGs (TSG+/TSG−) for the total population (A) and confined to the intermediate cytogenetic risk group (B) Figure 1. Overall Survival based on the methylation status of ER (ER+/ER) combined with the absence or presence of methylation of TSGs (TSG+/TSG−) for the total population (A) and confined to the intermediate cytogenetic risk group (B)

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Clinical Characterization of Acute Myeloid Leukemia with Myelodysplasia-Related Changes as Defined by the 2008 WHO Classification System.

Blood ◽

10.1182/blood.v112.11.922.922 ◽

2008 ◽

Vol 112 (11) ◽

pp. 922-922

Author(s):

Olga K Weinberg ◽

Mahesh Seetharam ◽

Li Ren ◽

Lisa Ma ◽

Katie Seo ◽

...

Keyword(s):

Flow Cytometry ◽

Overall Survival ◽

Acute Myeloid Leukemia ◽

Clinical Outcome ◽

Myeloid Leukemia ◽

Who Classification ◽

Risk Group ◽

Who Criteria ◽

Multilineage Dysplasia ◽

Acute Myeloid

Abstract Background: Although some studies have validated the 2001 WHO classification of acute myeloid leukemia (AML), including the importance of multilineage dysplasia, others have suggested that multilineage dysplasia correlates with unfavorable cytogenetics but has no independent impact on prognosis. In 2008, the revised WHO classification system has expanded this category into “AML with myelodysplasia-related changes” (AML-MRC) that now includes 1) AML arising from myelodysplastic syndrome (MDS), 2) AML with MDS-related cytogenetic abnormalities, and 3) AML with multilineage dysplasia. An individual case may fall into this category by meeting any of the criteria. The goal of the current study is to clinically characterize this newly defined AML-MRC subgroup. Methods: One-hundred consecutive AML patients diagnosed at Stanford University Hospital between 2005 and 2007 with adequate material for mutation analysis were studied. Cases were classified using the 2008 WHO criteria. Diagnostic cytogenetic findings were reviewed and patients were stratified into risk groups using Southwest Oncology Group criteria. Available flow cytometry immunophenotyping results were reviewed and all samples were tested for NPM, FLT3 (ITD and D835) and CEBPA mutations. Clinical parameters including hemogram data at time of diagnosis were reviewed. Clinical follow-up including overall survival (OS), progression free survival (PFS) and complete remission (CR) rates were retrospectively determined. Kaplan-Meier methods and univariate and multivariate Cox proportional hazards regression analysis were used to compare the clinical data. Results: The cases included 57 males and 43 females with a median age of 56 (range 17–81). Cytogenetic risk-group stratification resulted in 9 patients with favorable, 65 with intermediate and 19 with unfavorable risk status. Using the 2008 WHO criteria, there were 48 AML-MRC, 40 AML not otherwise specified (AML-NOS), 9 AML with either t(8;21), inv(16) or t(15;17), and 3 therapy related AMLs. Overall, 26 patients had a NPM1 mutation (16 of which were FLT3 mutated), 25 had FLT3-ITD, 8 had FLT3-D835 and 9 had a CEBPA mutation (3 of which were FLT3 mutated). Compared to AML-NOS, patients with AML-MRC were significantly older (59 vs 51 years, p=0.014) and presented with lower hemoglobin (9 vs 11.2 g/dL, p=0.044), lower platelets (47 vs 54 K/uL, p=0.059), unfavorable cytogenetics (14/46 vs 3/36, p=0.014) and exhibited a decreased frequency of CEBPA mutation (0/46 vs 7/40, p=0.001) as compared to AML-NOS. Based on the flow cytometry immunophenotyping, the blasts from patients with AML-MRC more frequently expressed CD14 compared to AML-NOS (10/46 vs 4/36, p=0.048). Clinical outcome data showed that patients with AML-MRC had a significantly worse OS, PFS and CR compared to AML-NOS (Figure, all p<0.0001). Even after excluding the 14 patients with unfavorable cytogenetics from the AML-MRC group, the remaining patients with AML-MRC (defined solely by the presence of multilineage dysplasia) had worse outcomes compared to all AML-NOS patients (OS, p=0.013; PFS, p=0.012; CR, p=0.0076). Among 65 patients with intermediate risk cytogenetics, the outcome difference between the AML-MRC and AML-NOS groups remained significant (OS, p=0.0292; PFS, p=0.0232), also indicating prognostic significance of multilineage dysplasia. Within the AML-MRC group, univariate analysis showed that low platelets (<20,000/mm3), FLT3-D835 mutation and MDS-related cytogenetics correlated with OS (p=0.0456, p=0.0265, p=0.002 respectively) and PFS (p=0.0478, p=0.0626, p=0.001). A multivariate Cox proportional hazard analysis, performed on the entire group, identified unfavorable cytogenetic risk group, advanced age (> 60), FLT3-ITD and AML-MRC status as significant predictors of worse OS with the following respective hazard ratios: 2.82 (95% CI, 1.52–5.26), 2.11 (1.01–4.42), 1.98 (1.01–3.90), 1.92 (1.01–3.65). Conclusion: The newly defined WHO category of AML-MRC exhibits a significantly worse clinical outcome compared to AML-NOS and is predictive of worse overall survival in the multivariate analysis of AML patients, independent of age or cytogenetic risk group. These findings support the clinical, morphologic and cytogenetic criteria for this 2008 WHO AML category. Figure Figure

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Comparable Disease-Free and Overall Survival After “Well-Matched” Unrelated Donor and Matched Sibling Donor Transplantation in Acute Myeloid Leukemia with Adverse Risk Karyotype in First Complete Remission: A Report From the Acute Leukemia Working Committee of the Centre for International Blood and Marrow Transplant Research.

Blood ◽

10.1182/blood.v114.22.526.526 ◽

2009 ◽

Vol 114 (22) ◽

pp. 526-526

Author(s):

Vikas Gupta ◽

Martin S. Tallman ◽

Wensheng He ◽

Brent Logan ◽

John F. DiPersio ◽

...

Keyword(s):

Overall Survival ◽

Acute Myeloid Leukemia ◽

Complete Remission ◽

Myeloid Leukemia ◽

Unrelated Donor ◽

Allogeneic Hsct ◽

Matched Sibling ◽

Disease Free ◽

First Complete Remission ◽

Acute Myeloid

Abstract Abstract 526 In patients with acute myeloid leukemia (AML) in first complete remission (CR1), the indications for matched sibling donor (MSD) transplants and unrelated donor (URD) haemopoietic stem cell transplantation (HSCT) are different. We sought to determine the prognostic impact of donor type on the outcomes of AML with adverse risk karyotype in CR1, a high-risk AML population considered as a standard indication for MSD and URD HSCT. We evaluated the outcomes of 584 patients undergoing allogeneic HSCT for AML with adverse risk karyotype in CR1 between 1995 and 2006, reported to the CIBMTR. Adverse risk karyotype was defined according to SWOG/ECOG classification. Cytogenetics abnormalities were further classified as: complex karyotype (3 or more abnormalities), 32%; and Non-complex divided as abnormal chromosome 7, 25%; chromosome 5, 9%; MLL gene rearrangements, 18%; t (6;9), 5%; and others, 10%. 226 patients underwent MSD and 358 URD. URD were classified based on high resolution typing as:” well matched” [n=254 (71%)] with no known disparity at HLA A, B, C, DRB1; and, “partially matched” [n=104 (29%)] with one locus known or likely mismatched. Previous MDS was present in 19% and 14% had therapy-induced (t-AML). Conditioning regimens were myeloablative and reduced intensity in 74% and 26%, respectively. At 3 years treatment-related mortality (TRM) incidence was 28% (95% CI 24-31); relapse 36%(32-40); disease-free survival (DFS) 36%(32-41) and overall survival (OS) 39%(35-44). Multivariate analyses are summarized in the table. “Well matched” URD and MSD yielded similar DFS and OS, while outcomes were significantly inferior for “partially matched” URD. Cytogenetically defined subsets had similar outcomes. Evaluated as a time-dependent covariate, chronic GVHD had a significantly lower risk of relapse (RR 0.68, p=0.046), while acute GVHD had no effect (RR 0.99, p=0.96). “Well matched” URD and MSD lead to similar DFS and OS in AML CR1patients with adverse risk karyotype. The pool of patients who may benefit from graft-vs-leukemia effect generated with allogeneic HSCT may be considerably expanded with “well-matched” URD HSCT. If a suitable MSD is not availabel, “well-matched” URD should be strongly considered where a MSD HSCT would otherwise be undertaken. Disclosures: No relevant conflicts of interest to declare.

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Acute Myeloid Leukemia with Myelodysplasia-Related Changes (MRC) Did Not Show Inferior Outcomes Compared to Those without MRC,

Blood ◽

10.1182/blood.v118.21.3563.3563 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3563-3563

Author(s):

Jee Hyun Kong ◽

Hyun Ae Jung ◽

Hee Kyung Ahn ◽

Silvia Park ◽

Hee-Jin Kim ◽

...

Keyword(s):

Overall Survival ◽

Acute Myeloid Leukemia ◽

Induction Chemotherapy ◽

Myeloid Leukemia ◽

Risk Group ◽

Univariate Analysis ◽

Group A ◽

Group B ◽

Group D ◽

Acute Myeloid

Abstract Abstract 3563 The distinctive features of the World Health organization (WHO) classification compared to French-America-British Co-operative group (FAB) classification of acute myeloid leukemia is the new morphological entity “AML with multilineage dysplasia (MLD)”, and now this subgroup has been renamed as 'AML with myelodysplasia-related change (MRC)”. It generally accepted that dysplasia was most frequently noted in older individual, is often associated with an unfavorable cytogenetic profiles and unfavourable response to therapy. However it is still controversial. Therefore, we evaluated the impact of MRC on overall survival (OS) and leukemia free survival (LFS) in acute myeloid leukemia patients. A total of 644 adult AML patients diagnosed at Samsung Medical Center (SMC) between Sep.1994 and Oct. 2010 were enrolled. We reviewed their medical histories, clinical parameters, hemogram data, bone marrow aspirate and cytogenetic studies, and reclassified them into AML with of MRC and without MRC groups. Of 664 patients, 543 patients were received induction chemotherapy, among them, 84 patients demonstrated MRC and 451 patients did not. Median age was 50 (15–88) years old, and 57.1% of patients were male. Median follow up period was 77.3 [0–191] months. AML without MRC group had more favorable cytogenetic risk, higher WBC counts and LDH levels than those with MRC. However, other variable such as age, sex, hemoglobin level, absolute neutrophil, and peripheral blast count, induction chemotherapy regimen, hematopoietic stem cell transplantation, CR1 (complete response after induction chemotherapy), CRp (complete recovery of platelet), and relapse rate were not different between two groups. Since FLT3-ITD and NPM1 tests were introduced into laboratory work after 2005, results of these tests were available only in 158 and 75 patients respectively, and these were not different between two groups. In univariate analysis, advanced age (>65 years) predicted worse LFS (median LFS [95% C.I.]; ° Â65 years vs >65 years; 9.3[7.2–11.4] vs 5.9[4.6–7.2] months, p =0.014). In terms of OS, young age (p=0.000), female (p=0.000), favorable cytogenetic risk (p=0.000), CR1 (p=0.000), CRp (p=0.000), absence of relapse (p=0.000), and HSCT (p=0.000) showed a higher probability of longer OS (Table 1). The presence of MRC, FLT3-ITD, and NPM1 did not affect OS (Table 1).Table 1.Summary of univariate analysis for overall survival.Median OS (months) [95% C.I.] or mean OS ± SD (months)pAge°Â65 years47.9 [17.1 – 78.6]0.000>65 years13.1 [5.9 – 20.4]SexMale23.2 [16.5 – 30.0]0.000¢Female112.2 [ – ]Cytogenetic risk¢Favorable107.0±7.40.000Intermediate28.0 [19.0 – 36.9]Unfavorable10.8 [7.8 – 13.7]Unknown17.5 [6.8 – 28.1]MRCAbsence35.9 [6.6 – 65.2]0.081Presence19.0 [6.9 – 31.0]CR1¢Yes112.2 [–]0.000No3.6 [1.1 – 6.1]CRp¢Yes70.9±4.40.000No54.8 [18.5 – 91.1]RelapseYes21.5 [17.2 – 25.9]0.000No17.5 [–]HSCT¢Auto86.2±5.60.000¢Allo83.8±6.5Not done17.5 [10.8 – 24.1]FLT3-ITDPositive8.2 [0–26.1]0.595Negative29.5 [20.9–38]NPM1¢Positive104.1±11.00.978¢Negative78.9±15.0¢“median survival not reached Next, we analyzed MRC effect in each variable to OS. The presence MRC did not affect OS of each group which divided according to the age (Figure 1. A and B), sex, cytogenetic risk groups (Figure 1. C and D), relapse, CR1, HSCT, and FLT3-ITD, though AML with MRC group had tendancy to have poor survival rate in intermediate cytogenetic risk group (Figure 1. C). However in patients who did not acheived CRp or showed NPM1, the presence of MRC correlated with shorter OS.Figure 1.Overall survival (OS) according to the presence of MRC in age ° Â65 group (A), age>65 group (B), intermediate cytogenetic risk group (C)), and unfavorable cytogenetic risk group (D).Figure 1. Overall survival (OS) according to the presence of MRC in age ° Â65 group (A), age>65 group (B), intermediate cytogenetic risk group (C)), and unfavorable cytogenetic risk group (D). In this study, patients with MRC did not show inferior outcomes than those without MRC. Therefore it is not necessary to decide different treatment strategy according to the presence of MRC Disclosures: No relevant conflicts of interest to declare.

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Patients with FLT3 Negative Acute Myeloid Leukemia and Normal Cytogenetic who Have the Combination Mutations (NPM1-/CEBPA-) Have Better Survival Than Patients Who Have the Combination Mutations (NPM1+/CEBPA+)

Blood ◽

10.1182/blood.v118.21.4874.4874 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4874-4874

Author(s):

Shamail Butt ◽

Pascal Akl ◽

Himanshu Bhardwaj ◽

Samer A Srour ◽

Terry Dunn ◽

...

Keyword(s):

Bone Marrow ◽

Overall Survival ◽

Acute Myeloid Leukemia ◽

Mutation Analysis ◽

Myeloid Leukemia ◽

Risk Group ◽

Intermediate Risk ◽

Cebpa Mutations ◽

Normal Cytogenetics ◽

Acute Myeloid

Abstract Abstract 4874 Introduction: Acute Myeloid Leukemia (AML) is the most common type of acute leukemia in adults. About 50% of patients with AML have normal karyotype, and are categorized as intermediate risk group. However, the clinical behavior and response to treatment in this group is heterogeneous. As a result, there is strong interest in characterizing molecular genetic features in the intermediate-risk AML patients that might rectify their stratification risk. In this group, FLT3-ITD (Internal Tandem Duplication) and FLT3-TKD (Tyrosine Kinase Domain) mutations are known to confer unfavorable risk whereas NPM1 and CEBPA mutations are known to be favorable risk markers. The purpose of this study is to analyze the combination of NPM1 and CEBPA mutations in presence or absence of FLT3 mutations on prognosis of AML patients referred to the State's largest tertiary care center over a period of 10 years for the treatment of leukemia. Patients and Method: We performed a retrospective chart review of all patients with AML evaluated at University of Oklahoma Health Sciences Center between January 2000 and December 2010. Patient's age, gender, race, laboratory and clinical data as well as bone marrow biopsy and aspirate findings were reported. PCR and Fragment Analysis were conducted on all available DNA preserved bone marrow materials to test the FLT3, NPM1 and CEBPA mutations. For statistical analysis, Kaplan-Meyer curve was used. Results: A total of 239 patients were evaluated. Male to female ratio was 2/1. Median age at diagnosis was 46y. 21 out of the 239 patients were less than 18 year old. DNA samples were present on 132 patients and mutation analysis for FLT3, CEBPA and NPM1 was performed. Correlation between mutations and AML prognosis was determined. 67/132 (50.8 %) patients were categorized into intermediate risk group (majority of patients had normal cytogenetics). 14/67 (20.9%) pts were FLT3+ (FLT3-ITD or FLT3-TKD mutation). 17/67 (23.9%) were NPM1+. 7/67 (10.4%) were CEBPA +. Kaplan-Meier curve was used to identify cumulative proportion surviving over time. FLT3 presence or absence itself was not identified to be statistically significant (p 0.416) in terms of overall survival. Interestingly, presence or absence of combined NPM1/CEBPA mutation in FLT3 negative patients, among intermediate risk group, was found to be statistically significant (p<0.05) in determining overall survival. In this subgroup, presence of NPM1/CEBPA combination (NPM1+/CEBPA+) was associated with poor prognosis (figure 2, lower curve), while absence of NPM1/CEBPA combination (NPM1-/CEBPA-) carries a better prognosis (figure 2, upper curve). Conclusion: Results of our study highlight the importance of performing combinations of mutation analysis in evaluation of overall prognosis in AML patients. FLT3-/NPM1+ profile in patients with normal cytogenetics is thought to confer a favorable prognosis. We demonstrated in this study that using combination mutation analysis in patients with FLT3- can change the risk stratification in patients with intermediate risk group and might affect therapeutic interventions in this patient population. Larger prospective studies are needed in the future for further validation of our findings. Disclosures: No relevant conflicts of interest to declare.

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Mitoxantrone and etoposide for acute myeloid leukemia in first relapse.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.6563 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 6563-6563

Author(s):

Annie P. Im ◽

Brian Thomas McLaughlin ◽

Yan Lin ◽

Anastasios Raptis ◽

Mounzer E. Agha ◽

...

Keyword(s):

Overall Survival ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Hematopoietic Cell Transplantation ◽

Survival Duration ◽

Study Cohort ◽

Platelet Recovery ◽

First Remission ◽

First Relapse ◽

Acute Myeloid

6563 Background: Achievement of complete remission (CR) for relapsed acute myeloid leukemia (AML) is crucial for improving prognosis and survival. However, there are no established standard therapies for AML in first relapse. Our purpose was to evaluate the efficacy and toxicity of a regimen of mitoxantrone and etoposide for relapsed AML and assess factors that may be predictive of response. Methods: Patients were identified from a database of patients with AML treated at the University of Pittsburgh Cancer Institute from 1999-2011. Subjects were patients with AML in first relapse treated with mitoxantrone 10mg/m2 and etoposide 100mg/m2 daily on days 1-5. An exploratory analysis was performed to determine CR rate, overall survival, toxicities, and predictive factors. Results: The study cohort consisted of 66 patients with AML in first relapse, median age 56.5 years (range 21-75). At time of relapse, 12 were classified as having poor cytogenetics, 39 had intermediate cytogenetics, and 5 had favorable cytogenetics (9 patients did not have karyotype analysis). 34.8% (23/66) of patients achieved CR, and 16 went on to have allogeneic hematopoietic cell transplantation. Patients with favorable, intermediate, and poor cytogenetics had CR rates of 60% (3/5), 35.9% (14/39) and 50% (6/12), respectively. Median survival was 8.1 months (95% CI 5.1-11.9). Patients who achieved CR had significantly improved survival compared to those who did not (20.0 months vs. 5.2 months, p<0.0001). Median days to neutrophil and platelet recovery were 37.5 (range 19-81) and 40 (range 21-81), respectively. There were no grade 3/4 hepatic toxicities. The 4-week and 8-week mortality rates were 4.5% and 13.6%, respectively. Duration of first remission greater than 12 months was predictive of CR (p<0.001), whereas age, cytogenetics, bone marrow blast percentage, and white blood cell count at relapse were not. Conclusions: In an unselected heterogeneous patient population with relapsed AML, mitoxantrone and etoposide was an effective regimen with acceptable toxicity, and those who achieved CR had significantly improved overall survival. Duration of first remission greater than 12 months was the only predictive factor, and response was seen among all cytogenetic risk groups.

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