scholarly journals Functional Classification of TP53 Mutations in Acute Myeloid Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2725-2725
Author(s):  
Sayantanee Dutta ◽  
Gudrun Pregartner ◽  
Frank G. Rücker ◽  
Ellen Heitzer ◽  
Armin Zebisch ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Myeloid Leukemia ◽  
Scoring Systems ◽  
Advisory Board ◽  
Low Risk ◽  
Missense Mutations ◽  
Tp53 Mutations ◽  
The Impact ◽  
Acute Myeloid

In more than 50% of human cancers, somatically acquired aberrations of the tumor suppressor gene TP53 are encountered. Approx. 10% of patients with acute myeloid leukemia (AML) reveal TP53 mutations with higher incidences in therapy-related subtypes and erythroleukemias. These mutations are regarded early events of leukemogenesis. In contrast to mere deletions at the TP53 locus, TP53 mutations confer an exceedingly adverse prognosis in AML even when occurring at a subclonal level. However whether different TP53 mutations in AML exhibit a different functional impact on disease progression or outcome remains unknown. In the present study, we have investigated this issue using four TP53 specific, functional scoring systems in a large cohort of patients of the German-Austrian AML study group (AMLSG). The AMLSG cohort consisted of a total of 1537 patients with newly diagnosed AML who were intensively treated within three multicenter, clinical trials. A total of 108 TP53 mutations were detected in 98 patients using targeted amplicon sequencing - 88 (81.4%) missense, 8 (7.4%) nonsense and 6 (5.6%) splice site mutations as well as 6 small insertions and deletions. For each of the four functional TP53 scores, we have assessed their impact on overall survival (OS) and event-free survival (EFS). First, we compared the impact of TP53 missense mutations in 84 patients with all other types of mutations (n= 14). In a next approach, TP53 mutations were grouped into disruptive (n=42) and non-disruptive (n=56) ones, based on the impact of the particular mutations on the protein structure predicted from the crystal structure of p53-DNA complexes (Poeta et al. New Engl J Med 2007). We then classified missense TP53 mutations (n=84) based on their "Evolutionary Action Scores (EAp53)" (Neskey et al. Cancer Res 2015). This algorithm takes evolutionary sensitivity and amino acid conservation into account and scores missense TP53 mutations from 0 to 100. Mutations with the high EAp53 score are considered high risk whereas wild type TP53 has an EAp53 score of zero. We extracted the EAp53 score of those AMLSG patients showing missense mutations from the respective server (http://mammoth.bcm.tmc.edu/EAp53) and used the threshold of 75 from the initial publication to divide the patients into low-risk (<75, n=49) and high-risk groups (≥75, n=35). However, with these three functional scoring systems, no difference regarding OS and EFS could be shown between the mutational groups. The "Relative Fitness Score (RFS)" was recently developed for the TP53 DNA binding domain (DBD) mutants as an indicator of their functional impact (Kotlar et al. Molecular Cell 2018). A catalogue of 9833 TP53 DBD mutants were generated and their selective growth was assessed in p53 null cancer cell lines. The RFS score for each mutant is the median of its relative enrichment or depletion in culture, calculated at 3 time points and depicted as a log (base 2) value. A high RFS indicates selective growth of the mutant corresponding to its higher fitness. We extracted the RFS for the TP53 DBD mutations of the AMLSG cohort (n=83) using the online data resource (GSE115072) and performed a receiver-operating characteristics (ROC) analysis to calculate the optimal threshold of RFS separating deceased from survivors most efficiently. Thereby, the best RFS cut-off value according to the Youden index was -0.135. Applying this threshold (low-risk RFS ≤ -0.135, n=25; high-risk RFS > -0.135, n= 58) we demonstrated a significantly better OS (P=0.009) and EFS (P=0.037) for patients with a low-risk RFS in multivariable analyses adjusting for age, white blood cell count, cytogenetics and type of AML. Using the AML-specific TP53 RFS score, we could show that more than 30% of patients with TP53 mutations (25/83) reveal a significantly better survival indicating that this score is of prognostic value. Based on these findings, we propose that - along with clinical parameters - RFS values of TP53 mutations should also be considered for a comprehensive risk assessment of TP53 mutated AML patients. Disclosures Zebisch: Celgene: Honoraria; Novartis: Honoraria, Other: Advisory board; AbbVie: Other: Advisory board; Roche: Honoraria. Bullinger:Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Daiichi Sankyo: Honoraria; Gilead: Honoraria; Hexal: Honoraria; Menarini: Honoraria; Novartis: Honoraria; Astellas: Honoraria; Pfizer: Honoraria; Sanofi: Honoraria; Seattle Genetics: Honoraria; Bayer: Other: Financing of scientific research; Abbvie: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Jazz Pharmaceuticals: Honoraria. Döhner:Daiichi: Honoraria; Jazz: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Janssen: Honoraria; CTI Biopharma: Consultancy, Honoraria. Sill:Novartis: Other: Advisory board; AbbVie: Other: Advisory board; Astellas: Other: Advisory board; Astex: Other: Advisory board.

scholarly journals TP53 Action and the Consequences of TP53 Mutation in Acute Myeloid Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. SCI-13-SCI-13
Author(s):  
Scott W. Lowe
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Tp53 Mutation ◽  
P53 Mutation ◽  
Tp53 Mutations ◽  
Genomic Analyses ◽  
Equity Ownership ◽  
Myeloid Neoplasia ◽  
The Impact ◽  
Acute Myeloid

p53 action and the consequences of p53 mutation in acute myeloid leukemia TP53 mutations are common in treatment associated myeloid neoplasia (tMN) and complex karyotype acute myeloid leukemia (CK-AML), where they are associated with chemoresistance and one of the worst prognoses of any leukemia genotype. To understand the impact of TP53 mutations on AML biology, we are performing arge scale genomic analyses of p53 mutant AML and have produced a series of animal models that appear to faithfully reflect molecular and biological features of the human disease. We have gone on to explore the biology of particular TP53 mutational configurations drive AML initiation and maintenance, and to identify and understanding the events that cooperate with p53 mutations during leukemogenesis. Disclosures Lowe: Blueprint Medicines: Consultancy, Equity Ownership; ORIC pharmaceuticals: Consultancy, Equity Ownership; Mirimus: Consultancy, Equity Ownership; Constellation Pharma: Consultancy, Equity Ownership; Petra Pharmaceuticals: Consultancy, Equity Ownership; PMV Pharmaceuticals: Consultancy, Equity Ownership; Faeth Therapeutics: Consultancy, Equity Ownership.

Elderly Patients with Acute Myeloid Leukemia Are Not All the Same: Results of the Prospective DSIL AML96 Trial.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1840-1840
Author(s):  
Markus Andreas Schaich ◽  
Walter E. Aulitzky ◽  
Heinrich Bodenstein ◽  
Martin Bornhaeuser ◽  
Thomas Illmer ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Prognostic Factors ◽  
High Risk ◽  
Elderly Patients ◽  
Induction Therapy ◽  
Myeloid Leukemia ◽  
Low Risk ◽  
Severe Toxicity ◽  
Elderly Aml ◽  
Acute Myeloid

Abstract The majority of patients with acute myeloid leukemia (AML) are older than 60 years at diagnosis. However, treatment results for these elderly patients are still unsatisfactory. This is thought to be due to a more aggressive disease, preexisting co-morbidities or a decreased tolerance for intensive treatment approaches. As for younger patients there is growing evidence that elderly AML patients may be divided into prognostic subgroups. So far data on prognostic factors in this group of patients are still sketchy. Between February 1996 and March 2005 a total of 827 elderly AML patients with a median age of 67 (61–87) years were treated within the prospective AML96 trial of the German Study Initiative Leukemia (DSIL). 643 patients had de novo and 184 patients secondary disease. All patients were scheduled to receive a double induction therapy with Daunorubicin and Ara-C (DA3+7). The consolidation therapy consisted of one course of m-Amsacrine and intermediate-dose (10g/m2) Ara-C. 265 (32%) patients reached CR criteria after double induction therapy. Forty-two patients (5%) had only a PR, 307(37%) displayed refractory disease, 126(15%) died during induction therapy and 77(10%) received only one course of induction therapy due to severe toxicity. Out of the 265 patients in CR 120 (45%) patients received the consolidation course. The strongest independent prognostic factors for achieving a CR were less than 10% blasts in the day 15 bone marrow, the presence of a NPM mutation or a low-risk karyotype (p&lt;0.0001 each). The 3-year overall (OS) and relapse-free survival (RFS) rates were 18% for all patients and 17% for all patients in CR, respectively. In the multivariate analysis the strongest prognostic factors for survival were age, LDH and cytogenetics (p&lt;0.0001 each). Using these three parameters a prognostic model for survival was established. Patients older than 70 years with intermediate- or high-risk cytogenetics and a high LDH level at diagnosis (n=213) had a 3-year OS of only 9%, whereas patients with low-risk cytogenetics or patients with intermediate-risk cytogenetics, younger than 70 years and a low LDH level (n=237) had a 3-year OS of 32%. All other patients (n=377) had an intermediate 3-year OS of 15% (p&lt;0.0001). In conclusion, elderly AML patients can be stratified into prognostic groups. AML patients older than 70 years with high LDH levels and intermediate- or high-risk cytogenetics at diagnosis do not profit from conventional chemotherapy.

scholarly journals A three-gene signature might predict prognosis in patients with acute myeloid leukemia

2020 ◽  
Vol 40 (6) ◽  
Author(s):  
Xin Zhu ◽  
Qian Zhao ◽  
Xiaoyu Su ◽  
Jinming Ke ◽  
Yunyun Yi ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Transcription Factor ◽  
High Risk ◽  
Myeloid Leukemia ◽  
Cox Regression ◽  
Risk Group ◽  
White Blood Cells ◽  
Gene Signature ◽  
Low Risk ◽  
Acute Myeloid

Abstract The identification of effective signatures is crucial to predict the prognosis of acute myeloid leukemia (AML). The investigation aimed to identify a new signature for AML prognostic prediction by using the three-gene expression (octamer-binding transcription factor 4 (OCT4), POU domain type 5 transcription factor 1B (POU5F1B) and B-cell-specific Moloney murine leukemia virus integration site-1 pseudogene 1 (BMI1P1). The expressions of genes were obtained from our previous study. Only the specimens in which three genes were all expressed were included in this research. A three-gene signature was constructed by the multivariate Cox regression analyses to divide patients into high-risk and low-risk groups. Receiver operating characteristic (ROC) analysis of the three-gene signature (area under ROC curve (AUC) = 0.901, 95% CI: 0.821–0.981, P&lt;0.001) indicated that it was a more valuable signature for distinguishing between patients and controls than any of the three genes. Moreover, white blood cells (WBCs, P=0.004), platelets (PLTs, P=0.017), percentage of blasts in bone marrow (BM) (P=0.011) and complete remission (CR, P=0.027) had significant differences between two groups. Furthermore, high-risk group had shorter leukemia-free survival (LFS) and overall survival (OS) than low-risk group (P=0.026; P=0.006), and the three-gene signature was a prognostic factor. Our three-gene signature for prognosis prediction in AML may serve as a prognostic biomarker.

Impact of allogeneic hematopoietic stem cell transplantation on pediatric acute myeloid leukemia of FAB subtypes M4 and M5

2020 ◽  
Author(s):  
Yu-juan Xue ◽  
Pan Suo ◽  
Yi-fei Cheng ◽  
Ai-dong Lu ◽  
Yu Wang ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
High Risk ◽  
Myeloid Leukemia ◽  
Risk Groups ◽  
Low Risk ◽  
Intermediate Risk ◽  
Hematopoietic Stem ◽  
Pediatric Acute Myeloid Leukemia ◽  
Acute Myeloid

Abstract Background: FAB-M4 and M5 are unique subgroups of pediatric acute myeloid leukemia. However, for these patients, few studies have demonstrated the clinical and biological characteristics and efficacy of hematopoietic stem cell transplantation (HSCT), and especially haplo-HSCT. Procedure: We retrospectively evaluated the outcomes of 70 children with FAB-M4/M5 enrolled in our center from January 2013 to December 2017. Results: Of the patients, 32, 23, and 15 were in low-risk, intermediate-risk, and high-risk groups, respectively. T(16;16), inv16/CBFB-MYH11 was the most frequent cytogenetic abnormality. Among detected genetic alterations, WT1 was mutated at the highest frequency, followed by FLT3-ITD, NPM1, and CEBPA. Thirty-three patients received HSCT (haplo-HSCT = 30), of which four, 18, and 11 were in low-risk, intermediate-risk, and high-risk groups, respectively. For all patients, the 3-year overall survival (OS), event-free survival (EFS), and cumulative incidence of relapse (CIR) were 85.3 ± 4.3%, 69.0 ± 5.7%, and 27.9 ± 5.2%, respectively. By multivariate analysis, low-risk stratification predicted superior OS, EFS, and PLT ≤ 50 × 109/L at diagnosis, with FLT3-ITD mutations predicting higher CIR and poorer EFS. In intermediate- and high-risk groups, HSCT was independently associated with higher EFS and lower CIR. With a median post-transplant observation time of 30.0 months, the 3-year OS, EFS, CIR, and non-relapse mortality in the haplo-HSCT group were 74.2 ± 8.6%, 68.3 ± 8.9, 24.6 ± 7.6%, and 6.6 ± 4.1%, respectively. Conclusions: Risk-oriented treatment is important for pediatric FAB-M4/M5. For intermediate- and high-risk groups, HSCT significantly improved survival and haplo-HSCT might be a viable alternative approach.

TP53 Mutations In Patients With High-Risk Acute Myeloid Leukemia Treated With Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 711-711
Author(s):  
Jan Moritz Middeke ◽  
Silvia Herold ◽  
Elke Rücker-Braun ◽  
Brigitte Mohr ◽  
Wolfgang E. Berdel ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
High Risk ◽  
Myeloid Leukemia ◽  
Tp53 Mutation ◽  
Chromosome 17 ◽  
Hematopoietic Stem ◽  
Tp53 Mutations ◽  
Donor Type ◽  
Acute Myeloid

Abstract Purpose The treatment success in patients (pts) with acute myeloid leukemia (AML) is very heterogeneous. Cytogenetic and molecular alterations present at diagnosis are strong prognostic factors, which have been used to individualize treatment. As shown by several groups, the subgroup of pts with deletion of the short arm of chromosome 17 are at high risk for treatment failure (e.g. Seifert, Leukemia 2009), which persists even after allogeneic hematopoietic stem cell transplantation (HSCT) (Middeke, Blood 2012; Mohr, Br J Haematol 2013). Besides allelic loss of TP53 located on the short arm of chromosome 17, other mechanisms of inactivation have been shown for this key tumor suppressor gene, most importantly missense point mutations or small deletions. These alterations have also been linked to poor outcome in AML after chemotherapy (Grossmann, Blood 2012). Here, we studied the impact of TP53 mutations on the outcome of AML pts with adverse cytogenetic risk treated with HSCT. Patients and Methods We selected AML pts with complex karyotype (CK), monosomy 7, monosomy 5/del5q and/or abnl(17p) who had received HSCT within 3 randomized controlled trials (NCT numbers 00180115, 00180102, and 00180167). All pts were treated with intensive induction chemotherapy and HSCT according to a risk adapted strategy. Complete sequencing of the TP53coding region was done using next generation sequencing (NGS) on a 454 GS Junior instrument (Roche) using the IRONII-study amplicon panel. Amplicons were generated from genomic DNA isolated at the time of diagnosis. Data analysis was done using the Sequence Pilot software package (JSI Medical Systems), a 10% cut-off was used for mutation calling. Nonsynonymous mutations were classified into bi-allelic TP53 mutations if detected allelic frequency as determined by NGS was >50% and mono-allelic TP53 mutations for frequencies between 10% and 50%. All samples with synonymous mutations or no detectable mutations according to the predefined cut-off of 10% were classified as TP53wild type (wt). Overall survival (OS), event-free survival (EFS), cumulative incidence of relapse (CIR) and non-relapse-mortality (NRM) after HSCT were analyzed according to the mutational status. Results Samples from 97 pts with AML were analysed, the median age was 51 years (range 18 to 67), 83% suffered from de novo AML, while 13% had sAML and 3% therapy-related myeloid neoplasms. CK and monosomal karyotype (MK) were present in 61% and 42% of the pts, respectively. Twenty-nine pts (30%) had abnl(17p) detected by conventional karyotyping or FISH analysis. Twenty-six pts (27%) were treated with standard myeloablative conditioning (MAC) regimens while the remaining pts received reduced intensity conditioning (RIC). Donors were siblings in 36 pts (37%) and matched or mismatched unrelated donors in all other pts. Overall, TP53 mutations were found in 40 pts (41%). Twenty-eight (29%) pts had a bi-allelic TP53 mutation while 12 (12%) pts had a mono-allelic TP53 mutation. We identified 15 pts with TP53 mutations without abnl(17p). Four pts with abnl(17p) had wt TP53. Pts with TP53 mutations were significantly older than pts with wt TP53 AML (median age 55 vs. 43, p=.004). Donor type, type of conditioning and the rate of transplantation in first complete remission were not statistically different among pts with or without TP53mutations. With a median follow up of 67 months the three-year probabilities of OS and EFS for pts with wt TP53 were 33% (95% CI, 21% to 45%) and 24% (95% CI, 13% to 35%) compared to 10% (95% CI, 0% to 19%) and 8% (95% CI, 0% to 16%) (p=.002 and p=.007) for those with mutated TP53, respectively. CIR at three years was 42% for pts with wt TP53 and 60% for those with mutated TP53 (p=.05). NRM was not different in both groups. In multivariate analysis including age, donor type (sibling vs. all other), type of conditioning (RIC vs. MAC) and disease status (CR1 vs. advanced disease) only the TP53-mutation status had a significant influence on EFS (HR=1.72; p=.03). In our analysis, classification according to MK did not significantly influence OS, EFS, CIR or NRM. Conclusion In this cohort of pts with cytogenetic adverse risk abnormalities, who had received HSCT, TP53 mutations were present in 41% of the pts. OS and EFS were significantly worse in pts with mutated TP53. Mutational analysis of TP53 might be an important additional tool to predict outcome after HSCT in pts with adverse karyotype AML. Disclosures: No relevant conflicts of interest to declare.

Early immunophenotypical evaluation of minimal residual disease in acute myeloid leukemia identifies different patient risk groups and may contribute to postinduction treatment stratification

Blood ◽  
2001 ◽  
Vol 98 (6) ◽  
pp. 1746-1751 ◽  
Author(s):  
Jesús F. San Miguel ◽  
Marı́a B. Vidriales ◽  
Consuelo López-Berges ◽  
Joaquı́n Dı́az-Mediavilla ◽  
Norma Gutiérrez ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Minimal Residual Disease ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Response To Therapy ◽  
Low Risk ◽  
Prognostic Impact ◽  
Minimal Residual ◽  
Acute Myeloid

Abstract Early response to therapy is one of the most important prognostic factors in acute leukemia. It is hypothesized that early immunophenotypical evaluation may help identify patients at high risk for relapse from those who may remain in complete remission (CR). Using multiparametric flow cytometry, the level of minimal residual disease (MRD) was evaluated in the first bone marrow (BM) in morphologic CR obtained after induction treatment from 126 patients with acute myeloid leukemia (AML) who displayed aberrant phenotypes at diagnosis. Based on MRD level, 4 different risk categories were identified: 8 patients were at very low risk (fewer than 10−4 cells), and none have relapsed thus far; 37 were at low risk (10−4 to 10−3 cells); and 64 were at intermediate risk (fewer than 10−3 to 10−2 cells), with 3-year cumulative relapse rates of 14% and 50%, respectively. The remaining 17 patients were in the high-risk group (more than 10−2 residual aberrant cells) and had a 3-year relapse rate of 84% (P = .0001). MRD level not only influences relapse-free survival but also overall survival (P = .003). The adverse prognostic impact was also observed when M3 and non-M3 patients with AML were separately analyzed, and was associated with adverse cytogenetic subtypes, 2 or more cycles to achieve CR, and high white blood cell counts. Multivariate analysis showed that MRD level was the most powerful independent prognostic factor, followed by cytogenetics and number of cycles to achieve CR. In conclusion, immunophenotypical investigation of MRD in the first BM in mCR obtained after AML induction therapy provides important information for risk assessment in patients with AML.

scholarly journals Development and validation of a novel survival model for acute myeloid leukemia based on autophagy-related genes

PeerJ ◽  
2021 ◽  
Vol 9 ◽  
pp. e11968
Author(s):  
Li Huang ◽  
Lier Lin ◽  
Xiangjun Fu ◽  
Can Meng
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Tumor Growth ◽  
Risk Score ◽  
Myeloid Leukemia ◽  
Low Risk ◽  
Tumor Cell Death ◽  
Score Model ◽  
Acute Myeloid

Background Acute myeloid leukemia (AML) is one of the most common blood cancers, and is characterized by impaired hematopoietic function and bone marrow (BM) failure. Under normal circumstances, autophagy may suppress tumorigenesis, however under the stressful conditions of late stage tumor growth autophagy actually protects tumor cells, so inhibiting autophagy in these cases also inhibits tumor growth and promotes tumor cell death. Methods AML gene expression profile data and corresponding clinical data were obtained from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, from which prognostic-related genes were screened to construct a risk score model through LASSO and univariate and multivariate Cox analyses. Then the model was verified in the TCGA cohort and GEO cohorts. In addition, we also analyzed the relationship between autophagy genes and immune infiltrating cells and therapeutic drugs. Results We built a model containing 10 autophagy-related genes to predict the survival of AML patients by dividing them into high- or low-risk subgroups. The high-risk subgroup was prone to a poorer prognosis in both the training TCGA-LAML cohort and the validation GSE37642 cohort. Univariate and multivariate Cox analysis revealed that the risk score of the autophagy model can be used as an independent prognostic factor. The high-risk subgroup had not only higher fractions of CD4 naïve T cell, NK cell activated, and resting mast cells but also higher expression of immune checkpoint genes CTLA4 and CD274. Last, we screened drug sensitivity between high- and low-risk subgroups. Conclusion The risk score model based on 10 autophagy-related genes can serve as an effective prognostic predictor for AML patients and may guide for patient stratification for immunotherapies and drugs.

scholarly journals Prognostic Significance of 11q23/MLL Fusion Partners in Children with Acute Myeloid Leukemia (AML) - Results from the Children's Oncology Group (COG) Trial AAML0531

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1211-1211 ◽  
Author(s):  
Erin M. Guest ◽  
Betsy A. Hirsch ◽  
E. Anders Kolb ◽  
Todd A. Alonzo ◽  
Robert Gerbing ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Myeloid Leukemia ◽  
Chromosome 1 ◽  
Prognostic Impact ◽  
Fusion Partner ◽  
Complex Karyotype ◽  
Free Survival ◽  
The Impact ◽  
Acute Myeloid

Abstract Background: Rearrangement of chromosome 11q23 at KMT2A (MLL+) occurs in ~20% of childhood acute myeloid leukemia (AML) cases and is the most common recurrent cytogenetic abnormality in childhood AML. More than 80 fusion partners of MLL have been characterized and the prognostic impact varies by partner and additional cytogenetic aberrations (ACAs). We previously reported superior event-free-survival (EFS), overall survival (OS), relapse risk (RR) and disease free survival (DFS) for patients with MLL+ on AAML0531 treated with gemtuzumab ozogamicin (GO). The impact of fusion partners has not been described for this trial cohort. Objective: To determine the impact of 11q23/MLL+ fusion partners on outcomes for children with AML who were treated uniformly on AAML0531. Methods: AAML0531 (2006 - 2010) was a randomized phase 3 trial of GO with conventional chemotherapy for children, adolescents, and young adults, ages 0 to 29 years, with de novo AML. The trial enrolled 1022 eligible patients without Down syndrome, and cytogenetic data was available for 988 patients. Of those, 215 (21.8%) were classified as 11q23/MLL+ after central cytogenetic review. The majority of patients with 11q23/MLL+ AML (n=200, 93%) were classified as intermediate risk (IR) and a minority (n=15, 7%) were classified as high risk (HR) based upon high FLT3 internal tandem duplication allelic ratio (FLT3-ITD-AR), monosomy 5/5q deletion, monosomy 7, or >15% blasts by morphology following Induction (Ind) I. HSCT was performed for 30 patients (14%). We defined 11q23/MLL+ subgroups for partners identified in ≥5 cases. Partners in <5 cases were grouped as "other"; unidentified fusions were classified as "unknown". Outcomes of minimal residual disease (MRD) at end of Ind I and complete remission (CR) at end of Ind II, 5-yr EFS and OS from study entry, and 5-yr RR from end of Ind II for patients in CR were compared across subgroups. Univariable and multivariable analyses were performed. Results: The median age for the 11q23/MLL+ cohort was 2.5 years and the distribution was equally male and female. The majority of cases (n=175, 81%) were classified into 8 specific partner subgroups, and the remaining cases were classified as other (n=30, 14%) or unknown (n=10, 5%). The most common translocation was t(9;11)(p22;q23) (n= 82, 38%). Central nervous system involvement was rare (<10% overall and in every subgroup). While extramedullary chloromas were rare (7% overall), chloromas were reported in 83% (n=5) of t(10;11)(p11.2;q23), 40% (n=16) of t(10;11)(p12;q23), and 27% (n=4) of t(6;11)(q27;q23). ACAs were observed in 86 of 211 cases (41%) that underwent central review. ACAs were numerical in 54 cases (26%), most commonly trisomy 8 (n=30, 14%) and structural + numerical in 32 cases (15%), most commonly involving chromosome 1 (n=11, 34%). Molecular findings for 3 studied genes were rare: High FLT3-ITD-AR n=4; NPM1 n=1; CEBPA n=0. Clinical outcomes varied significantly by fusion partner and poorer OS was primarily due to relapse (Table 1). CR rate was 86% overall and did not vary by subgroups. MRD was detected in 21% overall and was most common in t(1;11)(q21;q23) and t(6;11)(q27;q23). Complex karyotype (≥3 abnormalities) was seen in 52 cases (25%) and predicted inferior outcome compared to <3 abnormalities (5-yr EFS 29% vs. 41%, p=0.02; 5-yr OS 44% vs. 63%, p=0.001, respectively). Chromosome 1 abnormalities were associated with very poor outcomes, 5-yr EFS 19% and 5-yr OS 29%. The most unfavorable partners for EFS were t(6;11)(q27;q23), t(10;11)(p11.2;q23), t(10;11)(p12;q23), and t(11;19)(q23;p13.3)(Figure 1). In multivariable comparison to patients with t(9;11)(p22;q23), the former 3 groups maintained inferior EFS (HR 2.51, p=0.006; HR 3.10, p<0.001; HR 2.15, p=0.002, respectively) and OS (HR 2.56, p=0.017; HR 4.8, p=0.006; HR 2.14, p=0.016, respectively). Conclusions: Fusion partners critically impact the prognosis of 11q23/MLL+ AML. In this large, uniformly treated cohort, t(6;11)(q27;q23), t(10;11)(p11.2;q23) and t(10;11)(p12;q23) were independently associated with inferior EFS and OS. Children with these unfavorable partners are at high risk for relapse and allogeneic HSCT should be considered in first CR. Complex karyotype, chromosome 1 aberrations, and extramedullary chloromas were additional adverse prognostic factors. Work is ongoing to confirm these results in the subsequent COG trial, AAML1031. Disclosures No relevant conflicts of interest to declare.

Remission Rates In Childhood Acute Myeloid Leukemia (AML) Utilizing a Dose-Intensive Induction Regimen with or without Gemtuzumab Ozogamicin (GO): Initial Results From the Children's Oncology Group Phase III Trial, AAML0531

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 182-182 ◽  
Author(s):  
Alan S Gamis ◽  
Todd A Alonzo ◽  
Robert B Gerbing ◽  
Richard Aplenc ◽  
Lillian Sung ◽  
...  
Keyword(s):  
Risk Factors ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Low Risk ◽  
Phase Iii ◽  
Phase Iii Trial ◽  
Diagnostic Characteristics ◽  
Significant Difference ◽  
The Impact ◽  
Acute Myeloid

Abstract Abstract 182 Acute Myeloid Leukemia - Therapy, excluding Transplantation: Pediatric and Adult AML Therapy Therapy for childhood AML has evolved in North America over the past decade by pursuing a dose-intensive rather than an intensive-timing strategy. COG AAML0531 was a recently completed Phase III trial that was based upon the MRC AML 12 dose-intensive regimen which reported a complete remission (CR) rate of 93% in their ADE arm with 3% induction (Ind) deaths (Gibson, Blood 100:35a, 2002). While survival outcomes remain “blinded” as the last patients (pts) complete therapy, remission (REM) outcomes can now be examined. Utilizing a data cutoff of March 31, 2010, 1009 non-M3 AML pts were enrolled and after excluding 36 ineligible and 5 DS pts 968 eligible de novo AML were examined. Pts were randomized to standard therapy with or without GO at 3 mg/m2 given on Ind I day 6 and intensification II day 7. Induction consisted of 2 therapy courses (Ind I: ADE10 & Ind II: ADE8), cytarabine 100 mg/m2/dose bid × 10 days (8 days for Ind II), etoposide 100 mg/m2/day on days 1–5, and daunomycin 50 mg/m2/day on days 1–3-5. Pts remained on the trial regardless of REM status after Ind I; however pts not in CR after Ind II were taken off protocol. There were 968 pts that began Ind I and 851 pts that began Ind II, with 25 & 7 withdrawals, 50 & 29 who were still in Ind or had not yet submitted data, and 19 & 4 deaths in each course, respectively. CR (defined in the protocol as <5% morphologic blasts (blasts) & extramedullary disease (EMD) resolved) was achieved in 70% (628/900) & 86% (731/854) by the end of each Ind course, respectively. This is similar to that seen in the intensively-timed CCG-2961 after 2 Ind courses. The impact of REM status after Ind I upon CR rates after Ind II was then assessed. After Ind I (ADE10), partial REM (PR) (5-15% blasts) was seen in 12% (104/900) and persistent disease (PD) (>15% blasts) was seen in 14% (126/900) of whom 81% (79/98) & 60% (65/109) entered CR after Ind II (ADE8), respectively. The extent of PD after Ind I and its impact upon CR after Ind II was then examined. For those whose PD was defined by only residual EMD and whose marrow was in PR or CR, 97% achieved a CR after Ind II. For those whose PD was defined by marrow blasts >15%, 42% achieved CR following Ind II. We examined whether the degree of marrow disease (15-30% vs >30% blasts) impacted CR in the PD pts but found no significant difference in CR by amount of PD (52% vs 36%, p=.234). Among the 25 pts who withdrew from Ind I, response after Ind I was assessable in 19 (4 CR, 1 PR, 14 PD) although no impact upon Ind II outcome could be ascertained. Diagnostic characteristics were analyzed for CR rate after Ind II with selected risk factors listed in the table. Significant prognostic factors for REM after 2 courses were found by univariate analysis to include WBC>100,000 (OR=2.7, p<.001), FLT3-ITD (OR=2.9, p<.001), low risk cytogenetics (OR=0.2, p<.001). In a multivariate model in 464 pts who had all three risk factors reported to date, the same risk factors were independently predictive of outcome: WBC (OR=2.5, p=.002), FLT3-ITD (OR = 2.0, p=.034), and low risk cytogenetics (OR = 0.24, p=.007). FLT3 analysis for this abstract includes only those clinically available (after a trial amendment in the 3rd year). This will be updated with the FLT3 research sample analyses for those pts enrolled prior to the amendment. Overall toxic mortality by the end of Ind II of 2.7% (2.1% in ADE10, and 0.5% in ADE8) are similar to reported outcomes in the COG pilot trial, AAML03P1, (2.6%) and better than that seen in CCG-2961 (14.1% & 10%, pre-& post-amendment). These data provide an important background for the next COG Phase III trial utilizing this same standard Ind due to open soon and provides a platform for an early comparison between outcomes of the MRC trials and those in COG with identical Ind courses. Disclosures: Smith: Pfizer, Inc: Member, Medical Advisory Committee (for bosutinib—not GO).

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