NUP98/NSD1 Translocation Further Risk-Stratifies Patients With FLT3/ITD In Acute Myeloid Leukemia: A Report From Children’s Oncology Group and SWOG

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 488-488
Author(s):  
Fabiana Ostronoff ◽  
Megan Othus ◽  
Robert B. Gerbing ◽  
Michael R. Loken ◽  
Susana C Raimondi ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Clinical Outcome ◽  
Myeloid Leukemia ◽  
Prognostic Significance ◽  
Building Blocks ◽  
Nuclear Pore ◽  
Disease Characteristics ◽  
The Impact ◽  
Very High ◽  
Acute Myeloid

Abstract Nucleoporins (NUP) are a family of proteins that form the building blocks of the nuclear pore complex. Translocations involving NUP family members have been reported in acute myeloid leukemia (AML) as predictors of poor outcome. Using whole transcript sequencing we identified NUP98/NSD1 translocations in 2 AML patients; both were cytogenetically normal (CN) and harbored FLT3/ITD. We therefore performed a comprehensive study on the prevalence of NUP98/NSD1 in children and adult AML patients to define the prognostic significance of this translocation and its contribution to clinical outcome. NUP98/NSD1 was evaluated using RT-PCR and the fusion transcripts were verified by Sanger sequencing. Presence of NUP98/NSD1 transcript was initially assessed on all available diagnostic specimens from patients treated in COG AAML03P1. As this transcript was detected only in patients with CN-AML or FLT3/ITD, the remaining evaluations on CCG2961, COG AAML0531 and SWOG0106 were limited to this patient population. Presence of NUP98/NSD1 was correlated with disease characteristics and clinical outcome. We initially assessed the impact of the NUP98/NSD1 in children with FLT3/ITD. Of the 2486 patients treated in 3 pediatric trials (age >1 month to < 30 years), 373 had FLT3/ITD (15%), of whom 16% also harbored NUP98-NSD1. Demographics and disease characteristics of FLT3/ITD patients were compared between those with and without NUP98/NSD1. NUP98/NSD1 was significantly associated with younger age, intermediate risk cytogenetics, higher marrow blast %, white blood and platelet count. Mutations in NPM1 and CEBPA were not detected in those with dual FLT3/ITD and NUP98/NSD1 alterations, whereas WT1 was enriched in these patients as compared to those with FLT3/ITD without NUP98/NSD1 (40.6% vs 17.3%, p=0.004). Patients with FLT3/ITD who also harbored NUP98/NSD1 had significantly worse complete remission (CR) rates (28% vs 69%, p<0.001), overall survival (3-year OS 32% vs 55%, p=0.004) and event-free survival (3-year EFS 16% vs 38%, p<0.001) than those with FLT3/ITD without NUP98/NSD1. Minimal residual disease (MRD) was also significantly higher in patients with dual FLT3/ITD and NUP98/NSD1 alterations as compared to those with FLT3/ITD without NUP98/NSD1 (76% vs 36.5%, p<0.0029). Within the FLT3/ITD cohort, in multivariate analysis including other known prognostic factors (such as cytogenetics, WBC, bone marrow blast %, NPM1, CEBPA and WT1), NUP98/NSD1 remained an independent predictor of poor CR rate. In CN-AML pediatric patients (N=267), the prevalence NUP98/NSD1 was 8%, of which 73% of were also FLT3/ITD. The CR rate for CN-AML harboring NUP98/NSD1 was significantly lower than in those without it (50% vs. 78%, p=0.008) and patients with both NUP98/NSD1 and FLT3/ITD had CR rate of 38% compared to that of 83% in patients with NUP98/NSD1 without FLT3/ITD. We also evaluated NUP98/NSD1 in patients treated on SWOG 0106. Of the 595 patients enrolled (age >18 to <60 years), 133 with either CN-AML or FLT3/ITD had available diagnostic specimens for analysis. Within the FLT3/ITD cohort, 8.5% (5 out of 59) patients also harbored NUP98/NSD1. Four of these 5 patients failed to achieve CR; the only patient with dual FLT3/ITD and NUP98/NSD1 alteration who achieved CR, died within a year of relapsed AML. There was only 1 patient with CN-AML with NUP98/NSD1 who did not harbor FLT3/ITD. This was the only patient who achieved and remained alive at 4.5 years of follow-up. The CR rate among FLT3/ITD patients without NUP98/NSD1 was 69%. In this large cooperative study we demonstrated that NUP98/NSD1 is commonly seen in children and young adults with AML with high association with CN-AML and very high overlap with FLT3/ITD. Although the CR rate is not affected in those with FLT3/ITD, we demonstrated that those with dual FLT3/ITD and NUP98/NSD1 alterations have extremely low CR rate and high post-induction MRD than FLT3/ITD patients without NUP98/NSD1. In contrast, NUP98/NSD1 patients without FLT3/ITD have a more favorable CR rate and survival. Within FLT3/ITD patients, the presence of NUP98/NSD1 can be used to identify those at very high risk for induction failure. The high simultaneous frequency of NUP98/NSD1 and WT1 in FLT3/ITD AML suggests a cooperative mechanism among these genetic lesions into leukemogenesis. Targeted therapy strategies should be developed for this subgroup of patients with highly resistant disease. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Low expression of MN1 associates with better treatment response in older patients with de novo cytogenetically normal acute myeloid leukemia

Blood ◽  
2011 ◽  
Vol 118 (15) ◽  
pp. 4188-4198 ◽  
Author(s):  
Sebastian Schwind ◽  
Guido Marcucci ◽  
Jessica Kohlschmidt ◽  
Michael D. Radmacher ◽  
Krzysztof Mrózek ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Older Patients ◽  
Myeloid Leukemia ◽  
Hox Genes ◽  
De Novo ◽  
Prognostic Significance ◽  
The Impact ◽  
Favorable Group ◽  
Acute Myeloid

AbstractLow MN1 expression bestows favorable prognosis in younger adults with cytogenetically normal acute myeloid leukemia (CN-AML), but its prognostic significance in older patients is unknown. We analyzed pretherapy MN1 expression in 140 older (≥ 60 years) de novo CN-AML patients treated on cytarabine/daunorubicin-based protocols. Low MN1 expressers had higher complete remission (CR) rates (P = .001), and longer overall survival (P = .03) and event-free survival (EFS; P = .004). In multivariable models, low MN1 expression was associated with better CR rates and EFS. The impact of MN1 expression on overall survival and EFS was predominantly in patients 70 years of age or older, with low MN1 expressers with mutated NPM1 having the best outcome. The impact of MN1 expression was also observed in the Intermediate-I, but not the Favorable group of the European LeukemiaNet classification, where low MN1 expressers had CR rates and EFS similar to those of Favorable group patients. MN1 expresser-status-associated gene- and microRNA-expression signatures revealed underexpression of drug resistance and adverse outcome predictors, and overexpression of HOX genes and HOX-gene–embedded microRNAs in low MN1 expressers. We conclude that low MN1 expression confers better prognosis in older CN-AML patients and may refine the European LeukemiaNet classification. Biologic features associated with MN1 expression may help identify new treatment targets.

scholarly journals Prognostic Significance of Expression of a Single MicroRNA,miR-181a, in Cytogenetically Normal Acute Myeloid Leukemia: A Cancer and Leukemia Group B Study

2010 ◽  
Vol 28 (36) ◽  
pp. 5257-5264 ◽  
Author(s):  
Sebastian Schwind ◽  
Kati Maharry ◽  
Michael D. Radmacher ◽  
Krzysztof Mrózek ◽  
Kelsi B. Holland ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Gene Expression Profile ◽  
Expression Profile ◽  
Myeloid Leukemia ◽  
Prognostic Significance ◽  
Comprehensive Cancer Center ◽  
Wild Type ◽  
The Impact ◽  
Acute Myeloid

PurposeTo evaluate the prognostic significance of expression levels of a single microRNA, miR-181a, in the context of established molecular markers in cytogenetically normal acute myeloid leukemia (CN-AML), and to gain insight into the leukemogenic role of miR-181a.Patients and MethodsmiR-181a expression was measured in pretreatment marrow using Ohio State University Comprehensive Cancer Center version 3.0 arrays in 187 younger (< 60 years) adults with CN-AML. Presence of other molecular prognosticators was assessed centrally. A gene-expression profile associated with miR-181a expression was derived using microarrays and evaluated by Gene-Ontology analysis.ResultsHigher miR-181a expression associated with a higher complete remission (CR) rate (P = .04), longer overall survival (OS; P = .01) and a trend for longer disease-free survival (DFS; P = .09). The impact of miR-181a was most striking in poor molecular risk patients with FLT3-internal tandem duplication (FLT3-ITD) and/or NPM1 wild-type, where higher miR-181a expression associated with a higher CR rate (P = .009), and longer DFS (P < .001) and OS (P < .001). In multivariable analyses, higher miR-181a expression was significantly associated with better outcome, both in the whole patient cohort and in patients with FLT3-ITD and/or NPM1 wild-type. These results were also validated in an independent set of older (≥ 60 years) patients with CN-AML. A miR-181a-associated gene-expression profile was characterized by enrichment of genes usually involved in innate immunity.ConclusionTo our knowledge, we provide the first evidence that the expression of a single microRNA, miR-181a, is associated with clinical outcome of patients with CN-AML and may refine their molecular risk classification. Targeted treatments that increase endogenous levels of miR-181a might represent novel therapeutic strategies.

scholarly journals Multilineage Dysplasia as Assessed by Immunophenotype in Acute Myeloid Leukemia: A Prognostic Tool in a Genetically Undefined Category

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3196
Author(s):  
Francesco Mannelli ◽  
Sara Bencini ◽  
Matteo Piccini ◽  
Giacomo Gianfaldoni ◽  
Maria Ida Bonetti ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Prognostic Significance ◽  
World Health ◽  
Erythroid Cell ◽  
Multiparameter Flow Cytometry ◽  
Prognostic Information ◽  
The Impact ◽  
Insight Into ◽  
Acute Myeloid

Acute myeloid leukemia (AML) “with myelodysplasia-related changes (MRC)” is considered a separate entity by the World Health Organization (WHO) classification of myeloid neoplasms. While anamnestic and cytogenetic criteria provide objective attribution to this subset, with clear unfavorable prognostic significance, the actual role of multi-lineage dysplasia (MLD) as assessed by morphology is debated. The aim of our work was to study MLD by a technique alternative to morphology, which is multiparameter flow cytometry (MFC), in a large series of 302 AML patients intensively treated at our Center. The correlation with morphology we observed in the unselected analysis reiterated the capability of the MFC-based approach at highlighting dysplasia. MLD data, estimated through an immune-phenotypic score (IPS), provided no insight into prognosis when considered overall nor within well-defined genetic categories. Of interest, IPS-related dysplasia conveyed significant prognostic information when we focused on genetically undefined patients, triple-negative for NPM1, FLT3 and CEBPA (TN-AML). In this context, the lack of dysplastic features (IPS_0) correlated with a significantly higher CR rate and longer survival compared to patients showing dysplasia in one or both (neutrophil and erythroid) cell lineages. The impact of IPS category maintained its validity after censoring at allogeneic HSCT and in a multivariate analysis including baseline and treatment-related covariates. In a subgroup featured by the lack of genetic determinants, our data could help address the relative unmet needs in terms of risk assessment and treatment strategy, and provide insight into prediction of response in the rapidly evolving therapeutic scenario of AML.

Cryptic NUP98/NSD1 Translocations Are Highly Prevalent in FLT3/ITD-Positive Acute Myeloid Leukemia and Lead to High Rate of Induction Failure. Report From Children's Oncology Group

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 529-529
Author(s):  
Fabiana Ostronoff ◽  
Todd A. Alonzo ◽  
Robert B. Gerbing ◽  
Michael R. Loken ◽  
Laura Pardo ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Adverse Outcome ◽  
Prognostic Significance ◽  
High Rate ◽  
Fusion Transcripts ◽  
Disease Characteristics ◽  
High Prevalence ◽  
Induction Failure ◽  
Very High ◽  
Acute Myeloid

Abstract Abstract 529 The nucleoporins (NUP) are a family of proteins, which form the building blocks of the nuclear pore complex. Translocations involving NUP family members NUP214 and NUP98 have been reported in acute myeloid leukemia (AML). DEK/NUP214 (also known as DEK/CAN, t(6;9)) is a known translocation in AML that is highly associated with FLT3/ITD and adverse outcome (see presentation by Moraleda P. et al). By Whole Transcript Sequencing (RNA Seq) we identified 2 cases of NUP98/NSD1 fusions by patients with cytogenetically normal (CN-) AML, both with FLT3/ITD. Recent studies by Hollink I. et al demonstrated high prevalence of FLT3/ITD in patients with NUP98/NSD1 translocations and its association with adverse outcome. Given the significant overlap between DEK/NUP214, NUP98/NSD1 fusions and FLT3/ITD, we studied the prevalence of these fusion transcripts in patients with FLT3/ITD to define the prognostic significance of genomic alteration and their contribution to clinical outcome. Pretreatment samples from patients with FLT3/ITD (N=117) as well as those with CN-AML (N=166) treated on COG-AAML0531 underwent evaluation for NUP98/NSD1 fusion transcripts RT-PCR. Fusion transcripts, as well as the break point junction was verified by Sanger sequencing. Presence of NUP98/NSD1 transcript was correlated with disease characteristics and clinical outcome in patients with FLT3/ITD. In patients with FLT3/ITD (N=117) NUP98-NSD1 was detected in 15 patients (13%). Demographics and disease characteristics of FLT3/ITD patients were compared between those with and without NUP98/NSD1. There were no significant differences in the median age (11 vs. 13 years, p=0.19) or blast % (85% vs. 80%, p=0.23) at diagnosis between patients with and without NUP98/NSD1. Mutations in NPM1 and CEBPA were not detected in those with dual FLT3/ITD and NUP98/NSD1; however, WT1 was significantly more common in FLT3/ITD patients with NUP98/NSD1 than in those without it (43% vs. 13%, p=0.01). Complete remission (CR) rates were compared in FLT3/ITD patients with and without NUP98/NSD1. CR rate in those with and without NUP98/NSD1 was 28% vs. 73% (p=0.002). Moreover, FLT3/ITD patients harboring NUP98/NSD1 were also more likely to have post-induction minimal residual disease (MRD) than those without NUP98/NSD1 (75% vs. 40.6%, p=0.03). In addition to patients with NUP98/NSD1, eight additional patients had NUP214/CAN translocation (i.e., t(6;9)), and cumulatively, translocations involving these two NUP genes accounted for 20% of patients with FLT3/ITD. CR rates in FLT3/ITD-positive patients with and without NUP translocations was determined. Those with NUP98 or NUP214 translocations had a CR rate of 40% compared to 74% in those without NUP translocations (p= 0.001). Further, the presence and prognostic significance of NUP98/NSD1 was then evaluated in CN-AML. The prevalence NUP98/NSD1 in this patient population was 7.8%. Of note, seventy-nine percent of the CN-AML patients with NUP98/NSD1 harbored FLT3/ITD as well. The CR rate for CN-AML harboring NUP98/NSD1 was significantly lower than in those without it (50% vs. 79.5%, p=0.03). When analyzing CN-AML patients who harbored both NUP98/NSD1 and FLT3/ITD, only 33% achieved CR, whereas all patients who with NUP98/NSD1 without FLT3/ITD achieved CR. Although the CR rate does not appear to be affected, AML patients with FLT3-ITD have higher relapse rates and therefore inferior outcome. We now show that among patients with FLT3/ITD, those with concurrent NUP fusions have a very low-rate of CR and high post-induction MRD than those without this fusion. The high prevalence of FLT3/ITD among NUP patients is likely not random and it is conceivable that NUP and FLT3/ITD have cooperating functional consequences that lead to a distinct leukemic phenotype and enhanced drug resistance. In conclusion, the presence of NUP in FLT3-ITD patients identifies a distinct subgroup of patients with a very high-rate of induction failure. FLT3-ITD patients should be further categorized according to the presence of NUP to improve risk-stratification of pediatric and young adult AML patients and help clinicians to identify those at very high-risk for induction failure. New therapy strategies are needed for this subgroup of patients with highly resistant disease. Disclosures: Loken: Hematologics, Inc: Employment, Equity Ownership. Pardo:Hematologics Inc: Employment.

Overexpression of the ETS-Related Gene, ERG, Predicts a Worse Outcome in Acute Myeloid Leukemia With Normal Karyotype: A Cancer and Leukemia Group B Study

2005 ◽  
Vol 23 (36) ◽  
pp. 9234-9242 ◽  
Author(s):  
Guido Marcucci ◽  
Claudia D. Baldus ◽  
Amy S. Ruppert ◽  
Michael D. Radmacher ◽  
Krzysztof Mrózek ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Clinical Outcome ◽  
Myeloid Leukemia ◽  
Tandem Duplication ◽  
Prognostic Significance ◽  
Related Gene ◽  
Expressed Sequenced Tags ◽  
Group B ◽  
Leukemia Group ◽  
Acute Myeloid

Purpose To test the prognostic significance of ETS-related gene (ERG) expression in cytogenetically normal primary acute myeloid leukemia (AML). Patients and Methods Pretreatment blood samples from 84 cytogenetically normal AML patients aged less than 60 years, who were characterized for BAALC expression, FLT3 internal tandem duplication (ITD), and MLL partial tandem duplication (PTD) and uniformly treated on Cancer and Leukemia Group B 9621 protocol, were analyzed for ERG expression by real-time reverse transcriptase polymerase chain reaction. Patients were divided into quartiles according to ERG levels and were compared for clinical outcome. High-density oligonucleotide arrays were used to identify genes differentially expressed between high and low ERG expressers. Results With a median follow-up of 5.7 years, patients with the upper 25% of ERG expression values had a worse cumulative incidence of relapse (CIR; P < .001) and overall survival (OS; P = .011) than the remaining patients. In a multivariable analysis, high ERG expression (P < .001) and the presence of MLL PTD (P = .027) predicted worse CIR. With regard to OS, an interaction was observed between expression of ERG and BAALC (P = .013), with ERG overexpression predicting shorter survival only in low BAALC expressers (P = .002). ERG overexpression was an independent prognostic factor even when the unfavorable group of FLT3 ITD patients lacking an FLT3 wild-type allele was included. High ERG expression was associated with upregulation of 112 expressed-sequenced tags and named genes, many of which are involved in cell proliferation, differentiation, and apoptosis. Conclusion ERG overexpression in AML patients with normal cytogenetics predicts an adverse clinical outcome and seems to be associated with a specific molecular signature.

scholarly journals Prognostic Significance of IDH1 and IDH2 mutations in Older Patients with Primary Cytogenetically Normal Acute Myeloid Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5058-5058 ◽  
Author(s):  
Jinghan Wang ◽  
Zhixin Ma ◽  
Qinrong Wang ◽  
Mengxia Yu ◽  
Xiufeng Yin ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Older Patients ◽  
Myeloid Leukemia ◽  
Prognostic Significance ◽  
Old Patients ◽  
Multivariable Analyses ◽  
Idh1 Mutations ◽  
Idh1 And Idh2 Mutations ◽  
The Impact ◽  
Acute Myeloid

Abstract IDH1 and IDH2 mutations are frequently identified in older patients with AML.With the development and application of IDH inhibitor, the prognostic significance of these mutations in old patients is of primary importance. To assess the impact on clinic outcome, we analyzed 224 older (> 60 years) patients with primary cytogenetically normal acute myeloid leukemia (CN-AML) similarly treated with intensive induction chemotherapy. Our analysis identified IDH1 and/or IDH2 (IDH1/2), IDH1 or IDH2 mutations in 63(28%), 29(12.9%) and 35(15.6%) patients, respectively. In general, IDH1 and IDH2 mutations were mutually exclusive, with only one patient having both IDH1 R132C and IDH2 R140Q mutations. IDH2 R172 mutations were exclusive with all other mutations analyzed (NPM1, CEBPA, DNMT3A, IDH1 and FLT3-ITD). There was a strong interaction between IDH2 mutation and NPM1 mutational status. Concurrent presence of IDH2 R140 and NPM1 mutations was independently associated with longer overall survival (OS; P=0.038, HR=0.42) and event free survival (EFS; P=0.034, HR=0.46) compared to the wild type counterpart in multivariable analyses. In contrast, IDH1 mutations were independently associated with shorter OS (P=0.004, HR=1.98) and EFS (P=0.014, HR=1.72) in multivariable analyses. Notably, IDH1 R132 mutations harbored higher levels of total 2-hydroxyglutarate compared to IDH2 R140Q mutations. Patients with IDH1 mutations or IDH2 R140 and NPM1 mutations harbored also distinct miRNA-expression signatures. Future studies will establish whether these difference between IDH1 and IDH2 mutations will be relevant with respect to response of the respective subsets of patients to the emerging therapies with IDH1 and IDH2 inhibitors. Disclosures No relevant conflicts of interest to declare.

scholarly journals EXTRAMEDULLARY INVOLVEMENT IN ACUTE MYELOID LEUKEMIA. A SINGLE CENTER TEN YEARS EXPERIENCE

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Luana Fianchi ◽  
Martina Quattrone ◽  
Marianna Criscuolo ◽  
Silvia Bellesi ◽  
Giulia Dragonetti ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Prognostic Significance ◽  
Best Supportive Care ◽  
Monocytic Leukemia ◽  
Trisomy 8 ◽  
Extramedullary Relapse ◽  
Incidence Risk ◽  
The Impact ◽  
Acute Myeloid

The incidence, risk factors and prognostic significance of extramedullary involvement (EMI) in adult patients with acute myeloid leukemia have not been established yet. This study analyzed the clinical and biological characteristics, the impact on prognosis and the cumulative incidence of EMI in a monocentric retrospective study. All consecutive adult pts with a diagnosis of AML observed in our institution between January 2010 and December 2017 were included into the analysis.Overall 346 AMLs were analyzed. The incidence of EMI was 11% (38 pts). The involved sites were: skin (66%), CNS (23%), pleura (7%), lymph nodes (5%), peritoneum (2%), spleen (2%), pancreas (2%), breasts (2%) and bones (2%). Most pts (91%) had only one site of EMI, while 9% had multiple sites affected at the same time. Twenty-four (55%) patients showed signs of EMI at presentation, while extramedullary relapse occurred in 9 pts (24%); 5 pts had EMI both at presentation and at relapse.EMI had a significantly higher frequency in pts with monocytic and myelo-monocytic leukemia subtypes (p<0,0001), MLL rearrangements (p=0.001), trisomy 8 (p=0,02) and a specific cytofluorimetry pattern (CD117-, p= 0,03; CD56-/CD117-, p= 0,04; CD56+/CD117-, p= 0,04).An analysis regarding treatment, OS and DFS was performed only on the 28 patients who experienced EMI at the onset of their disease; one EMI patient received best supportive care and was consequently excluded from OS analysis. The other 27 patients were treated with: conventional chemotherapy (21 pts), hypomethylating agent (5 pts) and low dose citarabine (1 pts); 8 pts (28.5%) received an allogeneic stem cell transplantation (allo-HSCT). Complete remission (CR) rate after induction therapy was 22% with a median DFS of 7.4 months. Median OS of all 27 EMI pts was 11.6 months (range 2-79); this resulted significantly longer for the 8 EMI pts who undergone allo-HSCT than those (19 pts) who didn’t receive this procedure (16.7 vs 8.2 months respectively, p=0.02). Univariate and multivariate analyses showed that undergoing allo-HSCT and achieving CR were the main positive prognostic factors for survival in our population (p<0,0001).This study confirms poor prognosis for EMI pts. Allo-HSCT, applicable however only in some cases, seems to have a crucial role in the therapeutic approach of these patients, being associated with a better prognosis.

scholarly journals The Impact of Diagnosis to Treatment Interval on the Outcome of Patients with Acute Myeloid Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2212-2212
Author(s):  
Samah Nassereddine ◽  
Kimberley Doucette ◽  
Vanya Aggarwal ◽  
Richard Amdur ◽  
Imad A. Tabbara ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
University Hospital ◽  
Advisory Committees ◽  
Disease Characteristics ◽  
Treatment Interval ◽  
Initiation Of Therapy ◽  
The Impact ◽  
Acute Myeloid

Introduction: Acute myeloid leukemia (AML) has historically been considered an oncologic emergency, requiring immediate intervention and initiation of therapy. Although urgency to initiate treatment has been debated, no guidelines exist to address the impact of diagnosis to treatment interval (DTI) in patients with AML. Recent FDA approvals have added treatment options using targeted therapy as monotherapy in older patients (e.g. - ivosidenib), or in combination with chemotherapy in younger patients (e.g.- midostaurin) in the newly diagnosed setting with improved outcomes. Unfortunately, results of molecular mutation testing often return several days after the initial diagnosis of AML has been made. While immediate induction is important to control disease and to minimize disease-related morbidity and mortality (Sekkers et al), molecular testing is becoming increasingly important for treatment decisions, and there may be benefit in waiting for these results. In addition, in 'real world settings', several barriers (e.g., lack of resources, correct diagnostic testing) often delay time to diagnosis, and initiation of therapy. We conducted a retrospective study in two academic centers in a major metropolitan area in the United States to evaluate the impact of DTI on the outcomes of patients with AML. Methods: We collected data from 196 patients who presented to George Washington University Hospital (120 patients) between June 2010 and July 2018 and Georgetown University hospital (76 patients) between January 2014 and December 2018. All patients were older than 18 years. Patients with acute promyelocytic leukemia and those who decided to pursue treatment elsewhere were excluded. Patients characteristics including age, gender, race, smoking past medical history and disease characteristics (Cytogenetics, FISH and NGS when available) were collected using retrospective chart review. Type of treatment received (low intensity vs high intensity), and the time from diagnosis to initiation of therapy were collected. We recorded mortality at day 30 and day 90. Multivariable logistic regression models were used to evaluate the association of DTI with mortality independently from patient age. Chi-square test was used to examine the association of 30- and 90-day mortality with DTI. Results: A total of 140 patients were used in the analysis, 71% of whom were treated within 5 days of diagnosis (DTI <1-5 days), 16% in 6-10 days, and 12% in >10 days. Incidence of 30-day mortality was 15%, 14%, and 0% (p=.24), while 90-day mortality was 28% 18%, and 13% for <1-5, 6-10, and >10 days respectively (p=.33). Neither association was statistically significant, and adjusting for age and type of therapy did not change the findings. Conclusion: Our data does not support that shorter DTI is associated with improved mortality regardless of age or type of therapy. Although there was no statistical significance, there was a numerical trend of improved mortality in patients with delayed DTI (6-10 days) compared to those with a DTI of <1-5 days. Larger prospective studies need to be conducted to investigate DTI in AML patients based on patient's age, disease characteristics, and treatment type. In particular, given the growing importance of knowing molecular mutations at diagnosis, used for both prognosis and incorporation of potential targeted agents, it will be important to understand how long we can safely wait to treat patients without affecting outcomes. Disclosures Lai: Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Speakers Bureau; Astellas: Speakers Bureau; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Implication of Flow Cytometry-Based Maturity Score in Risk Stratification of Acute Myeloid Leukemia in Adult Egyptians

QJM ◽  
2020 ◽  
Vol 113 (Supplement_1) ◽  
Author(s):  
E A M Eldebaky ◽  
H M E Afifi ◽  
S A Pessar ◽  
A M S Ahmed
Keyword(s):  
Acute Myeloid Leukemia ◽  
Clinical Outcome ◽  
Median Survival ◽  
Myeloid Leukemia ◽  
Maturity Score ◽  
Significant Difference ◽  
Mature Group ◽  
Immature Group ◽  
The Impact ◽  
Acute Myeloid

Abstract Background Already for decades, controversy exists as to whether immunophenotyping has a prognostic significance in acute myeloid leukemia (AML). However, the impact of the immunophenotypic assessment of blast maturity is largely unknown. Objectives Studying the influence of the degree of immunophenotypic maturity, via the application of the flow-cytometric based maturity score, on the clinical outcome as well as the laboratory and clinical parameters of patients with AML. Methods This study was conducted on 40 newly diagnosed AML patients with the quantifications of the variable expressions of three early myeloid progenitor markers namely CD34, CD117 and TdT. After that, the estimation of the blast maturity was based on a previous score proposed in a study by Schneider et al. (2015). Results Out of forty patients enrolled, 8 patients (20%) were assigned to the mature group whereas 32 patients were assigned to the immature group. There was no statistically significant difference between both groups in terms of demographics, clinical and laboratory data, cytogenetic risk groups as well as treatment outcome determined by mortality and response to chemotherapy on day 28 and at 6 months. Mature group showed slightly higher median survival in comparison to the immature group. Conclusion There is no evident relationship between maturity score of the blast population of a patient and the clinical outcome despite mild prolongation of median survival of the mature group. Higher sample size is needed to confirm this observation.

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