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

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.

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

Blood ◽

10.1182/blood-2011-06-357764 ◽

2011 ◽

Vol 118 (15) ◽

pp. 4188-4198 ◽

Cited By ~ 40

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.

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The possible significance of trisomy 8 in acute myeloid leukemia

International Journal of Research in Medical Sciences ◽

10.18203/2320-6012.ijrms20172464 ◽

2017 ◽

Vol 5 (6) ◽

pp. 2652 ◽

Cited By ~ 2

Author(s):

Salil N. Vaniawala ◽

Monika V. Patel ◽

Pratik D. Chavda ◽

Shivangi H. Zaveri ◽

Pankaj K. Gadhia

Keyword(s):

Acute Myeloid Leukemia ◽

Chromosomal Aberrations ◽

Myeloid Leukemia ◽

Chromosomal Abnormalities ◽

Prognostic Significance ◽

Chromosomal Translocation ◽

Banding Technique ◽

Trisomy 8 ◽

Increased Risk ◽

Acute Myeloid

Background: Acute myeloid leukemia (AML) is a heterogeneous disorder that results from a block in the differentiation of haematopoietic progenitor cells along with uncontrolled proliferation. Trisomy 8 is the most common recurring numerical chromosomal aberrations in acute myeloid leukemia (AML). It occurs either as a sole anomaly or together with other additional chromosomal aberrations. The prognostic significance of trisomy 8 in presence of other additional chromosomal abnormality depends on clonal cytogenetic changes. The patients with trisomy 8 had shorter survival with significantly increased risk with other chromosomal abnormality.Methods: Total 139 patients were screened between January 2016 to November 2016 who were suspected of AML cases. Bone marrow cultures were set up using conventional cytogenetic methods. Chromosomal preparation was made and subjected to GTG banding technique. Banded metaphases were analysed and karyotyped for further analysis.Results: Cytogenetic evaluation of karyotyped of 139 suspected AML patients showed 52 with t(8;21)(q22;q22), 36 with t(15;17)(q22;q12), and 11 with inv(16)(p13;q22). The rest 40 cases found with additional chromosomal abnormalities, of which 16 were sole trisomy 8 and 24 cases were found with other chromosomal abnormalities In addition, only one person found with t(8;21) and trisomy 8, while three person having t(15;17) with trisomy 8.Conclusions: AML is considered to be one of the most important cytogenetic prognostic determinants. Recurrent chromosomal translocation with trisomy 8 varying 1.9% for t(8;21) and 8.3% for t(15;17). In the present study trisomy 8 in AML with known favourable anomalies is very small. Therefore, it cannot be taken as a prognostic marker.

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

Journal of Clinical Oncology ◽

10.1200/jco.2010.29.2953 ◽

2010 ◽

Vol 28 (36) ◽

pp. 5257-5264 ◽

Cited By ~ 137

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.

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

Cancers ◽

10.3390/cancers12113196 ◽

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.

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Secondary genetic lesions in acute myeloid leukemia with inv(16) or t(16;16): a study of the German-Austrian AML Study Group (AMLSG)

Blood ◽

10.1182/blood-2012-05-431486 ◽

2013 ◽

Vol 121 (1) ◽

pp. 170-177 ◽

Cited By ~ 101

Author(s):

Peter Paschka ◽

Juan Du ◽

Richard F. Schlenk ◽

Verena I. Gaidzik ◽

Lars Bullinger ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Chromosomal Aberrations ◽

Myeloid Leukemia ◽

Jak2 V617f ◽

Tyrosine Kinase Domain ◽

Age Difference ◽

Trisomy 8 ◽

Kit Mutation ◽

The Impact ◽

Acute Myeloid

Abstract In this study, we evaluated the impact of secondary genetic lesions in acute myeloid leukemia (AML) with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11. We studied 176 patients, all enrolled on prospective treatment trials, for secondary chromosomal aberrations and mutations in N-/KRAS, KIT, FLT3, and JAK2 (V617F) genes. Most frequent chromosomal aberrations were trisomy 22 (18%) and trisomy 8 (16%). Overall, 84% of patients harbored at least 1 gene mutation, with RAS being affected in 53% (45% NRAS; 13% KRAS) of the cases, followed by KIT (37%) and FLT3 (17%; FLT3-TKD [14%], FLT3-ITD [5%]). None of the secondary genetic lesions influenced achievement of complete remission. In multivariable analyses, KIT mutation (hazard ratio [HR] = 1.67; P = .04], log10(WBC) (HR = 1.33; P = .02), and trisomy 22 (HR = 0.54; P = .08) were relevant factors for relapse-free survival; for overall survival, FLT3 mutation (HR = 2.56; P = .006), trisomy 22 (HR = 0.45; P = .07), trisomy 8 (HR = 2.26; P = .02), age (difference of 10 years, HR = 1.46; P = .01), and therapy-related AML (HR = 2.13; P = .14) revealed as prognostic factors. The adverse effects of KIT and FLT3 mutations were mainly attributed to exon 8 and tyrosine kinase domain mutations, respectively. Our large study emphasizes the impact of both secondary chromosomal aberrations as well as gene mutations for outcome in AML with inv(16)/t (16;16).

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The Prognostic Significance of Trisomy 8 in Patients With Acute Myeloid Leukemia

Leukemia & Lymphoma ◽

10.1080/10428190290012074 ◽

2002 ◽

Vol 43 (3) ◽

pp. 583-586 ◽

Cited By ~ 12

Author(s):

Michelle A. Elliott ◽

Louis Letendre ◽

Curtis A. Hanson ◽

Ayalew Tefferi ◽

Gordon W. Dewald

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Prognostic Significance ◽

Trisomy 8 ◽

Acute Myeloid

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Frequency, Characteristics and Prognostic Significance of RUNX1 mutations in Patients with Acute Myeloid Leukemia, Not Otherwise Specified

Blood ◽

10.1182/blood.v126.23.3860.3860 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3860-3860

Author(s):

Mi-Hyun Bae ◽

Young-Uk Cho ◽

Bohyun Kim ◽

Dong Hyun Lee ◽

Seongsoo Jang ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Platelet Count ◽

Myeloid Leukemia ◽

Prognostic Significance ◽

Hazard Ratio ◽

Trisomy 13 ◽

Transactivation Domain ◽

Trisomy 8 ◽

Not Otherwise Specified ◽

Acute Myeloid

Abstract Background: Somatic mutations in RUNX1 gene have been identified in a substantial proportion of patients with de novo acute myeloid leukemia (AML). It is suggested as a new candidate molecular marker and, therefore, is suggested to be routinely performed at the diagnostic stage of AML. Despite its clinical importance, however, previous cohorts have been heterogeneous in terms of cytogenetic and molecular subtypes of AML. Here, the aim of this study was to evaluate the frequency, biologic characteristics, and prognostic significance of RUNX1 mutations focusing on patients with AML, not otherwise specified (NOS). Methods: Diagnostic samples from 202 patients with AML were analyzed for RUNX1 mutations. We excluded AML with recurrent genetic abnormalities, AML with myelodysplasia-related changes, and therapy-related AML because these entities have prognostic relevances of their own. RUNX1 mutations were detected using standard PCR techniques and direct sequencing. Results: RUNX1 mutations were found in 27 (13.4%) patients. The mutations were clustered in Runt homology domain (13, 48.1%) and transactivation domain (9, 33.3%). Frameshift mutations were most common (52.9%), followed by missense mutations (35.3%) and nonsense mutations (11.8%). As shown in Table 1, patients with RUNX1 mutations had a lower platelet count (P = 0.03), a higher rate of trisomy 8 (P = 0.02) and trisomy 13 (P = 0.039), and a trend toward older age (P = 0.063) than patients without mutations. Presence of RUNX1 mutations and NPM1 or CEBPA mutations were mutually exclusive. At the median follow-up of 12.1 months, RUNX1 mutations predicted for shorter overall survival (OS; P = 0.007) and relapse-free survival (RFS; P = 0.003). In the multivariate analysis, RUNX1 mutation was a significant marker for inferior OS (hazard ratio, 3.037; P = 0.014) and RFS (hazard ratio, 5.699; P = 0.001). Conclusion: The findings of our study further strengthen the previous data about RUNX1 mutations in AML. Furthermore, AML NOS with RUNX1 mutations is characterized by distinct biology and is associated with adverse clinical outcome. Our study supports the notion that RUNX1 mutational status would be integrated into diagnostic workup of AML, particularly for AML, NOS subgroup. Table 1. Clinical and biologic features of the cohort by RUNX1 mutations RUNX1 mutations P -value Mutated, n (%) Wild type, n (%) Number 27 (13.4) 175 (86.6) Male sex 17 (63.0) 94 (53.7) 0.489 Median age, years (range) 63 (14 - 80) 55 (1 - 83) 0.063 WBC count, ¡¿109/L (median, range) 7.9 (1.1 - 133.3) 14.0 (0.8 - 231.3) 0.636 Hemoglobin, g/dL (median, range) 8.6 (5.0 - 10.6) 8.8 (4.1 - 17.3) 0.376 Platelet count, ¡¿109/L (median, range) 35 (14 - 230) 59 (9 - 900) 0.03 Blood blasts, % (median, range) 29 (0 - 94) 38.5 (0 - 93) 0.312 FAB subtypes M0 3 (11.1) 11 (6.3) 0.609 M1, M2 21 (77.8) 129 (73.7) 0.831 M4, M5 3 (11.1) 27 (15.4) 0.767 M6, M7 0 8 (4.6) 0.546 Cytogenetic abnormalities Normal karyotype (%) 11 (40.7) 104 (59.4) 0.106 Trisomy 8 (%) 5 (18.5) 8 (4.6) 0.02 Trisomy 11 (%) 1 (3.7) 4 (2.3) 0.823 Trisomy 13 (%) 3 (11.1) 3 (1.7) 0.039 Trisomy 21 (%) 1 (3.7) 2 (1.1) 0.866 Distribution of other mutations FLT3 -ITD 5 (18.5) 50 (28.6) 0.39 FLT3 -TKD 1 (3.7) 4 (2.3) 0.823 NPM1 0 55 (31.4) 0.002 CEBPA 0 17 (9.7) 0.187 MLL -PTD 1 (3.7) 14 (8.0) 0.691 Disclosures No relevant conflicts of interest to declare.

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

Blood ◽

10.1182/blood.v122.21.488.488 ◽

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.

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