CGE19-065: Number of Somatic Mutations Is an Independent Predictor of Overall Survival in Acute Myeloid Leukemia

Purpose: Acute myeloid leukemia (AML) is characterized by multiple somatically acquired mutations that affect genes of different functional categories. It has been well established in myelodysplastic syndrome (MDS) that the cumulative number of somatic mutations has an impact on overall survival. However, no such data exist for AML. In this study, we sought to determine the number of clinically significant somatic mutations for each cytogenetically defined risk group of AML and to determine whether this had an impact on overall survival (OS). Methods: In this retrospective, single-center study, all adult patients diagnosed with AML from August 2016–December 2017 were reviewed. Baseline characteristics, somatic mutations in the diagnostic bone marrow as detected by Next Generation Sequencing (NGS), and survival outcomes were analyzed. NGS panel was done in-house and could identify 94 genes. Patients were divided into favorable, intermediate, and poor risk groups based on cytogenetics, and molecular abnormalities using NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for AML, version 1.2018. Kaplan-Meier plots and Cox regression analyses were utilized. Results: A total of 105 AML patients were included; baseline characteristics and frequency of identified clinically significant (CS) mutations are described in the presentation. The FLT3 mutation occurred in the highest frequency (22%) followed by DNMT3A & ASXL1 (15%). 17 (16%) patients were favorable risk, 33 (31%) intermediate risk, and 55 (52%) were poor risk. 67.6% of patients were male, and the median age was 64 (20–79) years. There was a difference in the number of CS mutations between the intermediate risk group and favorable risk group (P=.007), but not between the favorable risk and poor risk groups (P=.221) or between the intermediate risk group and poor risk group (P=.093). Increased number of CS mutations (≥ 5) was seen with equal frequency across risk groups and predicted for shorter overall survival in both univariate (HR=2.80; P=.039) and by multivariate Cox regression analysis (P=.001) independently from assigned risk group. There were no differences in age, gender, smoke, geographic, and different risk groups by multivariate analyses. Conclusion: Our study shows that ≥ 5clinically significant somatic mutations were associated with adverse outcomes and decreased survival, independent of risk groups and induction regimen. Thus, it may be a useful prognostic factor. This finding needs to be validated using a larger sample size.

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A Novel Risk Classification Model Predicts Overall Survival and Locoregional Surgery Benefit in Colorectal Patients with Distant Metastasis at the Initial Diagnosis

10.21203/rs.3.rs-117490/v1 ◽

2020 ◽

Author(s):

Mo Chen ◽

Tian-en Li ◽

Pei-zhun Du ◽

Junjie Pan ◽

Zheng Wang ◽

...

Keyword(s):

Overall Survival ◽

High Risk ◽

Distant Metastasis ◽

Cox Regression ◽

Risk Group ◽

Risk Groups ◽

Risk Classification ◽

Low Risk ◽

Classification Model ◽

Intermediate Risk

Abstract Background and aims: In this research, we aimed to construct a risk classification model to predict overall survival (OS) and locoregional surgery benefit in colorectal cancer (CRC) patients with distant metastasis.Methods: We selected a cohort consisting of 12741 CRC patients diagnosed with distant metastasis between 2010 and 2014, from the Surveillance, Epidemiology and End Results (SEER) database. Patients were randomly assigned into training group and validation group at the ratio of 2:1. Univariable and multivariable Cox regression models were applied to screen independent prognostic factors. A nomogram was constructed and assessed by the Harrell’s concordance index (C-index) and calibration plots. A novel risk classification model was further established based on the nomogram.Results: Ultimately 12 independent risk factors including race, age, marriage, tumor site, tumor size, grade, T stage, N stage, bone metastasis, brain metastasis, lung metastasis and liver metastasis were identified and adopted in the nomogram. The C-indexes of training and validation groups were 0.77 (95% confidence interval [CI] 0.73-0.81) and 0.75 (95% CI 0.72-0.78), respectively. The risk classification model stratified patients into three risk groups (low-, intermediate- and high-risk) with divergent median OS (low-risk: 36.0 months, 95% CI 34.1-37.9; intermediate-risk: 18.0 months, 95% CI 17.4-18.6; high-risk: 6.0 months, 95% CI 5.3-6.7). Locoregional therapies including surgery and radiotherapy could prognostically benefit patients in the low-risk group (surgery: hazard ratio [HR] 0.59, 95% CI 0.50-0.71; radiotherapy: HR 0.84, 95% CI 0.72-0.98) and intermediate risk group (surgery: HR 0.61, 95% CI 0.54-0.68; radiotherapy: HR 0.86, 95% CI 0.77-0.95), but not in the high-risk group (surgery: HR 1.03, 95% CI 0.82-1.29; radiotherapy: HR 1.03, 95% CI 0.81-1.31). And all risk groups could benefit from systemic therapy (low-risk: HR 0.68, 95% CI 0.58-0.80; intermediate-risk: HR 0.50, 95% CI 0.47-0.54; high-risk: HR 0.46, 95% CI 0.40-0.53).Conclusion: A novel risk classification model predicting prognosis and locoregional surgery benefit of CRC patients with distant metastasis was established and validated. This predictive model could be further utilized by physicians and be of great significance for medical practice.

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Risk Classification for Overall Survival by the Neutrophil–Lymphocyte Ratio and the Number of Metastatic Sites in Patients Treated with Pembrolizumab—A Multicenter Collaborative Study in Japan

Cancers ◽

10.3390/cancers13143554 ◽

2021 ◽

Vol 13 (14) ◽

pp. 3554

Author(s):

Taizo Uchimoto ◽

Kazumasa Komura ◽

Wataru Fukuokaya ◽

Takahiro Kimura ◽

Kazuhiro Takahashi ◽

...

Keyword(s):

Overall Survival ◽

Risk Model ◽

Risk Group ◽

Objective Response ◽

Collaborative Study ◽

Risk Groups ◽

Intermediate Risk ◽

Neutrophil Lymphocyte Ratio ◽

Poor Risk ◽

Metastatic Sites

Pembrolizumab has emerged as the new standard of care in patients with platinum-refractory metastatic urothelial carcinoma (mUC), whereas the optimal risk stratification to predict survival outcomes is still controversial. We examined a risk model for overall survival (OS) in mUC treated with pembrolizumab using our multi-institutional dataset (212 patients). The median age was 72 years old. Median OS from the initiation of pembrolizumab treatment was 11.7 months. The objective response rate (ORR) was 26.4%. On multivariate analysis, multiple metastatic sites and an NLR > 3.50 at the initiation of pembrolizumab treatment were identified as independent predictors for OS. We next developed a risk model using those two predictors. Patients without any factors were assigned to the favorable-risk group (26.5%). Patients with either factor and both factors were assigned to the intermediate-risk group (44.3%), and poor-risk group (29.2%), respectively. Kaplan–Meier curves showed clear discrimination of OS among the risk groups (p < 0.001). The ORR in each group was 35.7% in the favorable-risk group, 27.7% in the intermediate-risk group, and 17.7% in the poor-risk group. Given that the model can be concisely determined at the initiation of pembrolizumab treatment, physicians may be encouraged to consider the risk group for daily practice.

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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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Palliative prognostic tools for the terminally ill patients with gastric cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.31_suppl.120 ◽

2014 ◽

Vol 32 (31_suppl) ◽

pp. 120-120 ◽

Cited By ~ 1

Author(s):

Beodeul Kang ◽

Hye Jin Choi ◽

Sun Young Rha

Keyword(s):

Gastric Cancer ◽

Survival Time ◽

Cancer Patients ◽

Risk Group ◽

Terminally Ill ◽

Risk Groups ◽

Low Risk ◽

Intermediate Risk ◽

Poor Risk ◽

Gastric Cancer Patients

120 Background: Terminally ill patients with gastric cancer have specific gastrointestional symptoms and signs related with cancer progression. To estimate accurate survival expectancy of gastric cancer patients is important for timely decision making of their end of life issues. Methods: We reviewed the 276 patients with terminally ill gastric cancer who were treated at Yonsei Cancer Center between January 2007 and December 2011 and eventually were died. Retrospectively, we conducted the data of clinical signs, symptoms, and laboratory results at the time of cessation of the active treatment. Then, we established the palliative survival estimation model by stratification of risk group. Results: Median palliative survival time from the decision to stop further treatment to death was 42days. In the multivariate Cox regression analysis, 5 parameters were identified as prognostically significant factors: anorexia, dyspnea, hypoalbuminemia, elevated blood urea nitrogen, and elevated serum alkaline phosphatase. We scored each variables as 1-3 for symptom(1:asymptomatic, 2:symptomatic, 3:symptomatic requiring intervention) and 1-2 for lab results(1:normal, 2:abnormal) and summed up each scores. Using the total score, patients were divided into 3 risk groups: low-risk(5-7points), intermediate-risk(8-11points), and poor-risk patients(12point). As a result, median palliative survival for low-risk group(n=110) was 87.0±7.4days, intermediate-risk group(n=158) and poor-risk group(n=8) were 31.0±2.1days and 6.0±2.1days, respectively (p<0.0001). Conclusions: Using multivariate analysis and summation of each prognostic factor score, 3 risk groups were determined. After validation by prospective multicenter trial, this palliative survival time estimation tool will be helpful to inform the accurate survival for terminally ill gastric cancer patients.

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Subclassification of the intermediate-risk group in patients with advanced renal cell carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e16537 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e16537-e16537

Author(s):

Maria Zapata-Garcia ◽

Maria Zurera Berjaga ◽

Alba Moratiel Pellitero ◽

Marta Gascon Ruiz ◽

Andrea Sesma Goñi ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Prognostic Factors ◽

Cell Carcinoma ◽

Renal Cell ◽

Cox Regression ◽

Risk Group ◽

Intermediate Risk ◽

First Line ◽

Poor Risk ◽

Prognosis Group

e16537 Background: Renal cell carcinoma (RCC) have low prevalence but it incidence is increasing. For a correct therapeutic approach, it is important to carry out a correct prognostic stratification. Several prognostication systems have been proposed. One of the most commonly used is the one developed by Heng. It is based on IMDC database. This classification includes six prognostic factors (hemoglobin, neutrohils, platelets, serum calcium, Karnosky Performance Status and time from diagnosis to initiaton treatment) to divide patients into three gorups. The relevance of IMDC prognostic criterio, in the era of immunotherapy, remains to be established. In the absence of alternative criteria, these prognostication system continue to be used. A great prognostic disparity has been observed in the intermediate prognosis group. This raises the need to divide this group into two. Thus, patients included in it would be better selected. Methods: Observational, single-center, retrospective study, based on a cohort of 107 patients with advanced RCC, recruited from January 2006 to December 2019. Main objective: Evaluate whether survival of patients with intermediate prognosis (treated with antiangiogenic in first-line) is different depending on the presence of one or two prognostic factors. Descriptive and survival analysis (OS and PFS) were performed. In addition, the influence of prognostic factors on OS and PFS were compared using the log-rank test and Cox regression. Results: In the overall population, median overall survival (OS) was 26.86 months (95% CI: 21.09-32.63) and median PFS was 18.41 months (95% CI: 14.02-22.79). Median OS were, in favorable-risk 42.24 months (95% CI: 29.62-54.62), in intermediate-risk 27,24 (95% CI: 19.44-35-03) and in poor-risk 8.00 (95% CI: 4.54-11.45). Median PFS were in favorable-risk 30.53 months (95% CI:20.92-40.13), in intermediate-risk 17,16 (95% CI:11.54-22.78) and poor-risk 6.13 (95% CI:3.02-9.25). Median OS and PFS, in patients with intermediate-risk, with a single risk factor were 33.79 (95% CI 23.17-44.41) and 20.97 months (95% CI 13.35-28.59), compared to 14.88 (95% CI 8.80-20.95) and 10.59 months (95% CI 4.87-16.32) in those with two risk factors. The results were statistically significant in OS (p = 0.01) and PFS (p = 0.037). Conclusions: The differences in median OS and PFS, within the intermediate prognosis group (1 or 2 RF), confirm the existence of two subgroups of patients. Patients with 1 RF are similar to those with favorable-risk. These results are important since, the presence of 1 or 2 RF, would condition the choice of TKIs as part of the first-line treatment combination. More studies are needed to better subclassify the intermediate risk group when optimizing the best treatments for each patient.

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Pretreatment Cytogenetic Abnormalities Are Predictive of Induction Success, Cumulative Incidence of Relapse and Overall Survival in Patients >60 Years of Age with Newly Diagnosed Acute Myeloid Leukemia.

Blood ◽

10.1182/blood.v106.11.3293.3293 ◽

2005 ◽

Vol 106 (11) ◽

pp. 3293-3293

Author(s):

Richard F. Schlenk ◽

Sabine Kayser ◽

Martina Morhardt ◽

Konstanze Döhner ◽

Hartmut Döhner ◽

...

Keyword(s):

Overall Survival ◽

High Risk ◽

Myeloid Leukemia ◽

Risk Group ◽

Normal Karyotype ◽

Risk Groups ◽

High Risk Group ◽

Newly Diagnosed ◽

Balanced Translocations ◽

Acute Myeloid

Abstract Purpose: Karyotype at diagnosis provides the most important prognostic information in younger adults with acute myeloid leukemia (AML). However, there are few data available looking in particular at patients (pts.) above 60 years of age. We prospectively analyzed 361 elderly pts. with newly diagnosed AML. All pts. were treated within the AMLHD98B treatment trial and received intensive induction and consolidation therapy. Pts. exhibiting a t(15;17) received an age-adjusted AIDA-regimen. Median follow-up time was 48 months. The median age was 67 years (range 60–85 years). Results: 160 pts. had a normal karyotype (44%); 48 pts. (13%) exhibited the balanced translocations t(8;21) (n=12), inv(16) (n=14), t(15;17) (n=11), or t(11q23) (n=11); in the absence of these balanced translocations, 73 pts. exhibited a single aberration, 179 pts. two aberrations, and 61 pts. a complex karyotype (≥3 aberrations; including 44 pts. with 5 or more aberrations). Analyses were normalized to the complete remission (CR) rate (52%), cumulative incidence of relapse (CIR) (77%) and overall survival (OS) (13%) after 4 years of pts. with normal karyotype. Pts. exhibiting a t(15;17) showed a significantly better CIR (29%) and OS (55%), whereas pts. with the other balanced translocations [t(8;21), inv(16)/t(16;16) and t(11q23)] did not differ from pts. with normal karyotype. The limited backward selected Cox-model for OS [t(15;17) excluded] revealed two risk groups: standard-risk [normal karyotype, t(8;21), inv(16), t(11q23), +8 and +11 in absence of a complex karyoytpe] and high-risk [all other aberrations]. The CR rates were 56% and 18%, and the OS-rates after 4 years for the standard- (n=223) and the high-risk group (n=127) were 15% and 0%, respectively. The MRC risk classification system for patients >55 years applied to our patients revealed CR- and OS-rates after 4 years of 73% and 19%, 47% and 12%, as well as 7% and 0% for the low (n=26), intermediate (n=282) and high risk groups (n=44), respectively [t(15;17) excluded]. In conclusion, our risk classification system identified a large high-risk group (36%) of elderly patients with AML who did not benefit from intensive chemotherapy.

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A Sensitive Risk Score for Directing Treatment in Younger Patients with AML.

Blood ◽

10.1182/blood.v108.11.18.18 ◽

2006 ◽

Vol 108 (11) ◽

pp. 18-18 ◽

Cited By ~ 7

Author(s):

Alan K. Burnett ◽

Robert K. Hills ◽

Keith Wheatley ◽

Anthony H. Goldstone ◽

Archie G. Prentice ◽

...

Keyword(s):

Risk Score ◽

Cox Regression ◽

Risk Group ◽

Experimental Therapy ◽

Intermediate Risk ◽

Total Risk ◽

Younger Patients ◽

Cox Regression Analysis ◽

Poor Risk ◽

Secondary Disease

Abstract Treatment strategies for younger patients (<60 years) with AML who enter complete remission (CR) are frequently decided on a risk assessment based on cytogenetic characterisation. Most collaborative groups have devised prognostic cytogenetic groupings of favourable, intermediate or poor risk which have relapse risks of 25–35%, 50–60%, and 80–85% respectively. The precise lesions in each group might vary by study group, but the overall discrimination is consistent. Favourable and possibly intermediate risk cases may not receive transplantation, whereas poor risk cases will. Outcomes for poor risk cases have failed to improve over the years, and if not transplanted these patients are candidates for experimental therapy. There is concern that cytogenetic segregation may not on its own be sufficiently sensitive on an individual patient level, and the inclusion of other factors may better customise risk. We performed a Cox regression analysis on 1937 non-APL cases with complete data who entered CR in the MRC AML10 and 12 trials. Increasing age, cytogenetic risk group higher WBC, male sex, secondary disease, and incomplete response to course 1 were all identified as significantly (p= 0.05) associated with poorer survival. These respectively contributed 0.013 per year, 0.651 per cytogenetic group, 0.002 per WBC unit (/nl), 0.170 for males, 0.221 for secondary disease, and 0.195 for PR/ 0.390 for resistant disease following course 1 to an individual’s total risk score. The groups were separated into scores of <2.00 (good risk), 2.00–2.667 (standard) and >2.667 (poor risk) which gave excellent discrimination for survival from CR at 5 years of 63%, 47% and 24% (p<0.00001). The score was prospectively validated in 897 patients who entered the MRC AML15 trial and was confirmed to be predictive with survivals from CR of 69%, 61% and 42% (p<0.00001). The value of the new score was to move patients out of the old cytogenetic category. The major effect was to move 274 patients from intermediate risk to poor risk and 42 poor risk patients to intermediate risk (table). This score has implications for treatment approach since, relatively, 60% more patients were identified as high risk and are therefore candidates for experimental therapy, or may, from Mantel-Byar analysis, benefit from transplantation. MRC Risk Group Total Good Standard Poor Crosstabulation of old and new risk group classification New Risk Classification Good 309 28 0 337 (14%) Standard 51 1288 42 1381 (59%) Poor 2 274 353 629 (27%) Total 362 (15%) 1590 (68%) 395 (17%) 2347

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Validation of the European Leukemia Net (ELN) Genetic Classification of Acute Myeloid Leukemia: Inclusion of Monosomal Karyotype Improves Prognostic Discrimination

Blood ◽

10.1182/blood.v116.21.1712.1712 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1712-1712

Author(s):

Montserrat Hoyos ◽

Salut Brunet ◽

Josep F. Nomdedeu ◽

Jordi Esteve ◽

Rafael F. Duarte ◽

...

Keyword(s):

Overall Survival ◽

Myeloid Leukemia ◽

Risk Groups ◽

Intermediate Risk ◽

Genetic Classification ◽

Prognostic Stratification ◽

Monosomal Karyotype ◽

Acute Myeloid ◽

Intermediate Dose

Abstract Abstract 1712 The study of chromosome alterations helps to classify acute myeloid leukemia (AML) into three prognostic groups, favorable, intermediate and adverse. The prognostic value of favorable risk and adverse risk abnormalities is well defined; in contrast, the outcome of intermediate-risk group is heterogeneous. Molecular characterization of patients with intermediate-risk AML has identified subcategories with diverse prognosis. All this knowledge has translated into a recent ELN proposal for the genetic classification of AML. Additionally, the intermediate and particularly the cytogenetically adverse groups have been refined by the HOVON group by introducing the concept of “monosomal karyotype” (MK), consisting of at least two autosomal monosomies or one monosomy plus a structural abnormality. Objective: To validate the recent ELN classification in a large series of AML patients and to investigate if the inclusion of MK improved the prognostic stratification. Patients and methods: 804 consecutive patients treated under the CETLAM AML-99 (n=353) and CETLAM-03 (n=451) trials were analyzed. The two protocols included idarubicin, intermediate-dose cytarabine and etoposide as induction and mitoxantrone and intermediate-dose cytarabine as consolidation. G-CSF priming was given in the CETLAM-03 trial. Following, risk-adapted treatment with chemotherapy or hematopoietic transplantation was administered. Parameters analyzed were relapse rate (REL), leukemia-free survival (LFS) and overall survival (OS). Results: Median age of the series was 46 years (range 16–60). Median follow-up of patients alive was 15 months. The ELN classification resulted in different prognostic risk groups. At 5 years, ELN favorable risk category had an OS of 60±4%, intermediate-I of 32±%, intermediate-II of 46±% and adverse of 17±3% (p<0.001). REL was comparable in the intermediate-I and adverse groups, 59±6% and 63±6% respectively, which translated into similar LFS. In contrast to the partial predictive value of the ELN proposal in our series, particularly in the intermediate categories, modified criteria identified 5 significantly different genetic risk groups: a) patients with RUNX1-RUNX1-T1 or CBFB-MYH11, b) patients with CEBPA or NPM1 mutations without FLT3-ITD, c) patients with intermediate cytogenetics of the MRC classification without mutations in CEBPA, NPM1 nor FLT3-ITD, and with FLT3-ITD, d) adverse MRC cytogenetics without MK and, e) patients with MK. Overall survival at 5 years for the 5 groups was 66±5%, 59±5%, 32±4%, 15±5%, and 4±4%, respectively (p<0.001). Conclusion: In the present study, the ELN genetic classification did not discriminate the prognosis of patients in the intermediate-I and intermediate-II categories. In contrast, genetic grouping that considered CBF AML, favorable mutations in the intermediate cytogenetics category and that separated adverse karyotype with or without MK translated into significantly different OS. This classification, together with the study of mutations recently described and the expression of certain genes may contribute to a more precise prognostic stratification and risk-adapted therapy. Disclosures: No relevant conflicts of interest to declare.

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Comparison of Matched/Mismatched Unrelated Donor Stem Cell Transplantation to Autologous Stem Cell Transplantation for Acute Myeloid Leukemia in First Complete Remission: A Study from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT)

Blood ◽

10.1182/blood.v126.23.3216.3216 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3216-3216

Author(s):

Francesco Saraceni ◽

Myriam Labopin ◽

Norbert Claude Gorin ◽

Didier Blaise ◽

Reza Tabrizi ◽

...

Keyword(s):

Stem Cell ◽

Myeloid Leukemia ◽

Risk Group ◽

Unrelated Donor ◽

Cell Transplant ◽

Intermediate Risk ◽

Poor Risk ◽

Risk Patients ◽

Matched Sibling ◽

Good Risk

Abstract Background. Optimal post-remission strategy for patients with acute myeloid leukemia (AML) is still matter of debate. Allogeneic Stem Cell Transplant (allo-HSCT) is the most effective treatment to prevent leukemia relapse, and for patients who lack a sibling donor transplantation from a matched or mismatched unrelated donor (URD) is usually the preferred alternative. However, increase in donor-recipient HLA mismatch, patient age and comorbidity scores lead to higher non relapse mortality (NRM) rates; moreover incidence of chronic GVHD is rather high after transplant from unrelated donors. Autologous Stem Cell Transplant (ASCT) has several advantages compared to allo-HSCT including low NRM, no GVHD risk, less late effects and better quality of life. The aim of the current study was to compare the outcome of allo-HSCT from matched (10/10 URD) or mismatched unrelated donor at a single HLA-locus (9/10 URD) to ASCT in patients with AML in first CR. Patients and methods. We performed a retrospective analysis of 2689 AML patients receiving 10/10 URD (n=1260), 9/10 URD-HSCT (n=356) or ASCT (n=1073) in first CR between 2005 and 2013 and reported to the ALWP of the EBMT. Results. Median FU was 35, 27 and 27 months for ASCT, 10/10 and 9/10 URD, respectively (p<10-4); median age was 48.7, 50.8, 48.7 years, respectively (p=10-3). Time from diagnosis to transplant was longer for URD compared to ASCT (p<10-4); patients who received URD had more frequently poor risk cytogenetics (p<10-4), were more likely to get a TBI-based conditioning (p<10-4) and were transplanted more recently (p<10-4), compared to patients who received ASCT. The 2-year cumulative incidence of relapse (RI) for ASCT, 10/10 and 9/10 URD were 46.3±3%, 24.9±3% and 27.7±5%, respectively (p<10-5), while the 2-year NRM rates were 3.1±2%, 16.4±4% and 20.5±4%, respectively (p<10-5). The 2-year KM estimates of leukemia-free survival (LFS) were 50.6±3% for ASCT, 58.7±3% for 10/10 URD and 51.8±6% for 9/10 URD (p=0.002), while the 2-year overall survival (OS) rates were 68.2±3, 63.6±3% and 55.1±6%, respectively (p<10-4). ASCT showed significantly higher RI compared to URD independently of cytogenetic risk (good risk: p<10-4, intermediate and poor risk: p<10-5); accordingly, 2y LFS was significantly better for URD compared to ASCT in all risk groups (good risk: p=0.034, intermediate risk: p=0.0007, poor risk: p=0.021). ASCT and URD showed similar OS in good and poor risk patients, while in intermediate risk group ASCT resulted in similar OS compared to 10/10 URD and better OS compared to 9/10 URD (66.2±4% for ASCT, 65.8±5% for 10/10 URD, 55.4±7% for 9/10 URD, p=0.012) (Fig 1). Within intermediate cytogenetic risk group, FLT3-ITD mutational status affected outcome; in patients harboring FLT3-ITD 10/10 URD showed the best LFS and OS (LFS: 36.3±11% for ASCT, 58.4±7% for 10/10 and 34±13% for 9/10 URD, p=10-3; OS: 51.7±12%, 62.2±7% and 41.4±14%, respectively, p=0.02). Conversely, in patients with wild type FLT3-ITD URD showed better LFS compared to ASCT (51.3±8% for ASCT, 66.7±7% for 10/10 URD, 64±13% for 9/10 URD, p=0.008), while no difference was observed in OS. Multivariate analysis confirmed significantly lower RI for 10/10 (HR 0.36, p<10-5, 95% CI:0.29-0.44) and 9/10 URD (HR 0.43, p<10-5, 95% CI:0.32-0.57) and higher NRM for 10/10 URD (HR 3.88, p<10-5, 95% CI:2.37-6.33) and 9/10 URD (HR 4.89, p<10-5, 95% CI:2.84-8.43) compared to ASCT. URD-SCT was associated with better LFS compared to ASCT (HR 0.57, p<10-5, 95%, CI:0.47-0.67 for 10/10 URD; HR 0.69, p=0.002, 95% CI:0.55-0.87 for 9/10 URD). 10/10 URD was associated with better OS compared to ASCT (HR 0.81, p=0.031, 95% CI:0.66-0.98) but no difference in OS was observed between 9/10 URD and ASCT (HR 1.02, p=0.87, 95% CI:0.79-1.31). Conclusion. In AML patients lacking an HLA-matched sibling donor URD-HSCT significantly reduces relapse risk and improves LFS. 10/10 URD showed better OS compared to ASCT in MV analysis in our series, while 9/10 URD impact on LFS didn't translate in better OS. In intermediate risk patients, in the absence of an HLA fully matched sibling or unrelated donor, autologous transplant may be considered as a valid option as ASCT results seem to overlap 10/10 URD outcome and to provide better survival compared to mismatch URD. Analysis is ongoing to better define which subpopulation of patients might benefit from each approach. Figure 1. OS in patients with intermediate risk cytogenetics. Figure 1. OS in patients with intermediate risk cytogenetics. Disclosures Craddock: Celgene: Consultancy, Honoraria, Research Funding; Pfizer: Speakers Bureau; Sunesis: Honoraria; Johnson and Johnson: Consultancy.

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Clinical relevance of high–intermediate risk endometrial cancer according to European risk classification

International Journal of Gynecological Cancer ◽

10.1136/ijgc-2020-001693 ◽

2020 ◽

Vol 30 (10) ◽

pp. 1528-1534

Author(s):

Agnieszka Rychlik ◽

Ignacio Zapardiel ◽

Laura Baquedano ◽

María Ángeles Martínez Maestre ◽

Denis Querleu ◽

...

Keyword(s):

Overall Survival ◽

Multivariate Analysis ◽

Endometrial Cancer ◽

Lymph Node ◽

European Society ◽

Risk Group ◽

Risk Groups ◽

Intermediate Risk ◽

Nodal Metastases ◽

Disease Free

ObjectiveRisk models in endometrial cancer define prognosis and indicate adjuvant therapy. One of the currently used classifications was designed in 2016 in collaboration with the European Society of Medical Oncology (ESMO), the European Society of Gynecologic Oncology (ESGO), and the European Society of Radiotherapy (ESTRO). A high–intermediate risk group was introduced within the intermediate risk group. The purpose of this study was to evaluate the clinical relevance of this subclassification.MethodsA multicenter retrospective study was carried out at five international tertiary institutions. Patients diagnosed with intermediate risk endometrial cancer on the basis of definitive pathology findings were included. Patients were stratified into intermediate and high–intermediate risk groups. Incidence of nodal metastases, and disease free and overall survival were compared between the two risk groups in univariate and multivariate analysis.Results477 patients were included: 325 (68%) patients were identified as intermediate and 152 (32%) as high–intermediate endometrial cancer patients. Nodal metastases were found in 18 patients (11.8%) in the high–intermediate risk endometrial cancer group and 16 patients (4.9%) in the intermediate risk group. Lymphovascular space invasion was found to be a strong predictive factor of lymph node involvement. High–intermediate risk was found to be an independent factor of disease free survival (hazard ratio (HR) 1.76; 95% confidence interval (CI) 1.00 to 3.08; p=0.050) and overall survival (HR 1.99; 95% CI 1.10 to 3.60; p=0.022) in the multivariate analysis.ConclusionsThe study validates the clinical significance of the intermediate risk endometrial cancer subclassification. Prognosis for high–intermediate risk endometrial cancer was significantly poorer. The prevalence of lymph node metastases was higher in this group of patients.

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