Acute Myeloid Leukemia: Pretreatment Biochemical and Clinical Variables Predictive For Risk Status Based On Validated Cytogenetic and Molecular Abnormalities

Abstract Introduction Insurance status has been found to affect treatment outcomes in various solid tumors. However, less data is available in patients with acute myeloid leukemia (AML). We conducted a comprehensive retrospective analysis to further investigate whether insurance status affects treatment outcomes in AML patients. Our analyses evolved to explore the role potential biochemical and clinical pre-treatment variables play in affecting treatment outcomes and predicting known cytogenetic risk groups. Methods From 2000 to 2011 we identified 269 patients with AML at The University of Oklahoma Health Sciences Center. A total of 217 patients with usable medical records were included in the final analysis. In the study, 28 pretreatment variables were examined to assess their effect on prognosis in terms of treatment outcomes and their ability to predict cytogenetic/molecular risk status. Cytogenetic risk groups were created based on the National Comprehensive Cancer Network (NCCN) guidelines algorithm. Primary outcomes were complete remission (CR), relapse, and overall survival (OS) rates. In order to assess survival, Kaplan-Meier curves and log rank tests of equality were performed on categorical variables. Cox proportional hazard models were used to assess continuous variables. A multivariate Cox proportional hazard model was created to explore associations between overall survival times with all covariates. Pre-treatment variables were then used to predict cytogenetic risk status using a multinomial logistic regression. Results Of the 217 patients (52.2% males, 47.8% females) included in the study, 81.5% were white, 9.0% African American, and 6.2% Native American. Median age at diagnosis was 51.0 years. 36.3% had private insurance, 45.8% had public insurance, and 17.3% were uninsured. There was no significant association found between insurance status and treatment outcomes (CR, OS, and relapse rates). Cytogenetic risk status was independently associated with insurance status (table 1). Cytogenetic risk status was also significantly related to complete remission (p=0.0007), status at last follow up (p = 0.0405), and overall survival (p = 0.0002 for better-risk and p < 0.0001 for intermediate-risk, compared to poor-risk group). Among 28 tested variables, we found 3 factors significantly predict cytogenetic/molecular risk status. Having the better-risk group as the reference group, diabetes (OR-12.7, 95% CI = 1.44-111.7) and elevated creatinine (OR- 0.07, 95% CI = 0.0-0.95) were predictive for intermediate-risk, where as diabetes (OR-6.9, 95% CI = 1.07-44.8) and elevated uric acid (OR- 0.60, 95% CI = 0.39-0.91) were predictive for poor-risk group. Conclusion Based on cytogenetic and molecular classification, our results on survival analysis are consistent with previous reported studies (figure 1). There was no association between treatment outcomes and insurance status. Among the 28 pretreatment variables studied, we found that diabetes, uric acid, and creatinine might be useful markers in predicting cytogenetic risk category. This could aid in risk-adaptive treatment plans before cytogenetic tests become available or tests prove to be unfeasible to be done. Larger studies are needed to corroborate our findings. Disclosures: No relevant conflicts of interest to declare.

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Incorporating molecular markers in standard prognostic models for DLBCL patients using real-world data.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e19251 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e19251-e19251

Author(s):

Shivam Mathura ◽

Vicki Kay Fung ◽

Keshava Dilwali ◽

Ashwin Subramanian Lakshmanan

Keyword(s):

Monoclonal Antibody ◽

Molecular Markers ◽

Risk Group ◽

Risk Groups ◽

Cox Proportional Hazard Model ◽

Proportional Hazard ◽

Proportional Hazard Model ◽

Real World Data ◽

Cox Proportional Hazard ◽

The Relationship

e19251 Background: NCCN-IPI is a prognostic scoring system that outperforms other risk classification mechanisms in diffuse large B-cell lymphoma (DLBCL) but does not consider the molecular profile of patients. We evaluated the predictive value of NCCN-IPI and clinically relevant molecular markers on the overall survival (OS) of patients with diagnosed DLBCL in real-world data (RWD). Methods: Patients diagnosed with DLBCL were identified in the COTA RWD population, and then subset to those with sufficient attributes to calculate NCCN-IPI at diagnosis (age, stage, LDH ratio, performance status, extranodal disease) and those who received a monoclonal antibody targeting CD20 (n = 383). This population was further filtered to patients tested for BCL-2, BCL-6, and C-MYC (n = 176). Disease characteristics were summarized using descriptive statistics and chi-square tests of independence were performed to assess the relationship between NCCN-IPI Risk-Group and molecular marker results. A Cox proportional hazard model was used to identify prognostic features of OS. Results: There were statistically significant relationships between NCCN-IPI Risk-Group and both BCL-2 (p = 0.007) and C-MYC (p < 0.001) after Bonferroni correction for the number of molecular markers tested. A Cox proportional hazard model with the three molecular markers as covariates revealed a statistically significant correlation between the presence of C-MYC alteration and decreased OS (HR = 2.02, CI: 1.24-3.32, p = 0.005). However, when NCCN-IPI Risk-Group was added as a covariate, the relationship between C-MYC and OS was no longer significant. The hazard ratios associated with high-intermediate and high risk groups were larger than that of the low-intermediate group. All three of these risk groups were statistically significant in the model (p < 0.038). Conclusions: The inclusion of molecular markers to the NCCN-IPI prognostic model did not increase predictive power in this RWD cohort. We validated the NCCN-IPI model and found it to be a robust tool for classifying risk and estimating OS in patients who have received a CD20 monoclonal antibody. A larger sample size would increase power to further explore the impact of molecular markers on overall survival. [Table: see text]

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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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Curability of Patients With Acute Myeloid Leukemia Who Did Not Undergo Transplantation in First Remission

Journal of Clinical Oncology ◽

10.1200/jco.2011.40.5977 ◽

2013 ◽

Vol 31 (10) ◽

pp. 1293-1301 ◽

Cited By ~ 119

Author(s):

Alan K. Burnett ◽

Anthony Goldstone ◽

Robert K. Hills ◽

Donald Milligan ◽

Archie Prentice ◽

...

Keyword(s):

Overall Survival ◽

Complete Remission ◽

Myeloid Leukemia ◽

Risk Group ◽

Risk Groups ◽

Salvage Treatment ◽

Cell Transplant ◽

Delayed Entry ◽

Risk Patients ◽

First Remission

Purpose The aims of this study were to quantify the prospects of salvage treatment of patients who did not undergo transplantation in first complete remission (CR1) and to assess the contribution of allograft in second complete remission (CR2) with respect to major risk groups. This evaluation can inform the decision whether to offer a transplant in CR1. Patients and Methods Of 8,909 patients who entered the Medical Research Council AML10, AML12, and AML15 trials, 1,271 of 3,919 patients age 16 to 49 years who did not receive a transplant in CR1 relapsed. Of these patients, 19% are alive beyond 5 years compared with 7% of patients who relapsed after an allograft in CR1. Overall survival and the contribution of a transplant in CR2 were assessed overall and by cytogenetic risk group by using Mantel-Byar analysis. Results Fifty-five percent of patients who relapsed entered CR2. This percentage varied by risk group as follows: favorable (82%), intermediate (54%), adverse (27%), and unknown (53%), which resulted in 5-year survivals of 32%, 17%, 7%, and 23%, respectively. Sixty-seven percent of remitters received an allotransplant that delivered superior survival compared with patients who did not receive a stem-cell transplant (42% v 16%). A more-stringent assessment of a transplant by using delayed-entry (Mantel-Byar) analysis confirmed the benefit of transplant overall and within intermediate and adverse risk groups but not the favorable subgroup. Conclusion Successful salvage treatment of patients who do not undergo transplantation in CR1 and relapse can be achieved in 19% of patients, which is improved by a transplant except in favorable risk disease. This result suggests that, for intermediate-risk patients in particular, equivalent overall survival can be achieved by delaying transplantation until after relapse, which would require many fewer transplants.

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

Journal of the National Comprehensive Cancer Network ◽

10.6004/jnccn.2018.7116 ◽

2019 ◽

Vol 17 (3.5) ◽

pp. CGE19-065

Author(s):

Zin W. Myint ◽

Rani Jayswal ◽

Ranjana Arora ◽

Gregory P. Monohan ◽

Amit Goldberg ◽

...

Keyword(s):

Overall Survival ◽

Myeloid Leukemia ◽

Somatic Mutations ◽

Cox Regression ◽

Risk Group ◽

Risk Groups ◽

Intermediate Risk ◽

Poor Risk ◽

Baseline Characteristics ◽

Clinically Significant

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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Prognostic nomogram for patients with non-metastatic HER2 positive breast cancer in a prospective cohort

The International Journal of Biological Markers ◽

10.1177/1724600818824786 ◽

2019 ◽

Vol 34 (1) ◽

pp. 41-46 ◽

Cited By ~ 2

Author(s):

Chuanxu Luo ◽

Xiaorong Zhong ◽

Zhu Wang ◽

Yu Wang ◽

Yanping Wang ◽

...

Keyword(s):

Breast Cancer ◽

Overall Survival ◽

Prognostic Factors ◽

Prospective Cohort ◽

Proportional Hazard ◽

Her2 Positive ◽

Her2 Positive Breast Cancer ◽

Cox Proportional Hazard ◽

Cox Proportional Hazard Regression ◽

Positive Breast Cancer

Purpose: A nomogram is a reliable tool to generate individualized risk prediction by combining prognostic factors. We aimed to construct a nomogram for predicting the survival in patients with non-metastatic human epidermal growth factor receptor 2 (HER2) positive breast cancer in a prospective cohort. Methods: We analyzed 1304 consecutive patients who were diagnosed with non-metastatic HER2 positive breast cancer between January 2008 and December 2016 in our institution. Independent prognostic factors were identified to build a nomogram using the COX proportional hazard regression model. The prediction of the nomogram was evaluated by concordance index (C-index), calibration and subgroup analysis. External validation was performed in a cohort of 6379 patients from the Surveillance, Epidemiology, and End Results (SEER) database. Results: Through the COX proportional hazard regression model, five independent prognostic factors were identified. The nomogram predicting overall survival achieved a C-index of 0.78 in the training cohort and 0.74 in the SEER cohort. The calibration plot displayed favorable accordance between the nomogram prediction and the actual observation for 3-year overall survival in both cohorts. The quartiles of the nomogram score classified patients into subgroups with distinct overall survival. Conclusion: We developed and validated a novel nomogram for predicting overall survival in patients with non-metastatic HER2 positive breast cancer, which presented a favorable discrimination ability. This model may assist clinical decision making and patient–clinician communication in clinical practice.

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Mortality calculator as a possible prognostic predictor of overall survival after gastrectomy in elderly patients with gastric cancer

World Journal of Surgical Oncology ◽

10.1186/s12957-020-02052-x ◽

2020 ◽

Vol 18 (1) ◽

Author(s):

Hidenori Akaike ◽

Yoshihiko Kawaguchi ◽

Suguru Maruyama ◽

Katsutoshi Shoda ◽

Ryo Saito ◽

...

Keyword(s):

Gastric Cancer ◽

Overall Survival ◽

Prognostic Factors ◽

Elderly Patients ◽

Performance Status ◽

Proportional Hazard ◽

Proportional Hazard Model ◽

Clinical Database ◽

National Clinical Database ◽

Cox Proportional Hazard

Abstracts Background The number of elderly patients with gastric cancer has been increasing. Most elderly patients have associated reduced physiologic functions that can sometimes become an obstacle to safe surgical treatment. The National Clinical Database Risk Calculator, which based on a large Japanese surgical database, provides predicted mortality and morbidity in each case as the surgical-related risks. The purpose of this study was to investigate the clinical significance of the risk for operative mortality (NRC-mortality), as calculated by the National Clinical Database Risk Calculator, during long-term follow-up after gastrectomy for elderly patients with gastric cancer. Methods We enrolled 73 patients aged ≥ 80 years and underwent gastrectomy at our institution. Their surgical risk was evaluated based on the NRC-mortality. Several clinicopathologic factors, including NRC-mortality, were selected and analyzed as the possible prognostic factors for elderly patients who have undergone gastrectomy for gastric cancer. Statistical analysis was performed using the log-rank test and Cox proportional hazard model. Results NRC-mortality ranged from 0.5 to 10.6%, and the median value was 1.7%. Dividing the patients according to mortality, the overall survival was significantly worse in the high mortality group (≥ 1.7%, n = 38) than in the low mortality group (< 1.7%, n = 35), whereas disease-specific survival was not different between the two groups. In the Cox proportional hazard model, multivariate analysis revealed NRC-mortality, performance status, and surgical procedure as the independent prognostic factors for overall survival. For disease-specific survival, the independent prognostic factors were performance status and pathological stage but not NRC-mortality. Conclusion The NRC-mortality might be clinically useful for predicting both surgical mortality and overall survival after gastrectomy in elderly patients with gastric cancer.

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

Blood ◽

10.1182/blood.v104.11.2011.2011 ◽

2004 ◽

Vol 104 (11) ◽

pp. 2011-2011

Author(s):

Dimitri A. Breems ◽

Wim L.J. Van Putten ◽

Bob Lowenberg

Keyword(s):

Overall Survival ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Risk Group ◽

Prognostic Index ◽

Free Interval ◽

First Relapse ◽

One Year ◽

First Complete Remission ◽

Acute Myeloid

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

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Intensive Care Unit Admissions in Patients with Hematologic Malignancies: Outcomes and Prognostic Indicators.

Blood ◽

10.1182/blood.v106.11.752.752 ◽

2005 ◽

Vol 106 (11) ◽

pp. 752-752 ◽

Cited By ~ 1

Author(s):

Diana Rubin-Superfin ◽

Timothy Albertson ◽

Carol M. Richman

Keyword(s):

Confidence Interval ◽

Risk Group ◽

Hazard Analysis ◽

Hematologic Malignancies ◽

Hazard Ratio ◽

Prognostic Indicators ◽

Proportional Hazard ◽

Icu Stay ◽

Cox Proportional Hazard ◽

Life Threatening

Abstract With intensification in treatments of hematologic malignancies (HM), the number of life-threatening complications requiring intensive care unit (ICU) admissions has increased. In general, cancer patients requiring ICU care are considered to have a poor prognosis, but it is a common belief among intensivists that patients with HM have an exceptionally grave prognosis. The aim of the current study was to assess outcomes in patients with HM admitted to the ICU for life-threatening complications. In addition, this study intended to identify early prognostic indicators that would be helpful in determining outcomes of ICU stay in this patient population. We performed a retrospective chart review of 185 consecutive critically ill patients with HM admitted to the ICU at a tertiary university hospital during a 5.5-year period. We collected variables ar admission and during admission and identified predictors of in-hospital mortality by Cox proportional hazard analysis. 88.7% patients had active disease, and 36.2% were bone marrow transplant (BMT) recipients. 24.3% were leukopenic (leukocyte count,<1.0x109/L) at admission. Sepsis (30.3%), respiratory failure (17.3%), and post-surgical complications (16.2%) were the major reasons for ICU admissions. 22.2% required vasopressors at admission. 38.4% required mechanical ventilation (MV) and 9.2% needed hemodialysis during ICU stay. Crude ICU, in-hospital, and 6-month mortality rates were 19.5%, 8.1%, and 9.7%, respectively. MV (hazard ratio, 2.75), blood urea nitrogen (BUN)>22 (hazard ratio, 1.81), pre-existent COPD/Asthma (hazard ratio, 3.24), urine output (UOP)<400 ml/24hr (hazard ratio, 2.8) were associated with poor outcome, while high albumin (hazard ratio, 0.54) was associated with better prognosis in multivariate Cox proportional hazard analysis. Using an univariate logistic regression model, diagnosis of acute leukemia (odds ratio, 2.42; 95% confidential interval, 1.23–4.75) or allogeneic BMT (odd ratio, 4.33; 95% confidence interval, 1.17–16.06) were associated with poor outcome, whereas diagnosis of lymphoma (odd ratio, 0.34; 95% confidence interval, 0.16–0.72) or APACHE II<22 (odd ratio, 0.33; 95% confidence interval, 0.17–0.65) were associated with better prognosis. Using these variables, we categorized our population into 4 groups: a very low risk group (lymphoma or other non-leukemia in combination with no need for MV and good UOP/normal BUN), a low risk group (lymphoma or other non-leukemia in combination with either MV, or low UOP/high BUN, or both), an intermediate risk group (leukemia or post-BMT in combination with either MV, or low UOP/high BUN, or neither negative factors), and a high risk group (leukemia or post-BMT in combination with MV and low UOP/high BUN). Survival probabilities at 6 months were 85%, 50%, 47%, and 16%, respectively (p<0.0001). The survival of patients with HM in the ICU was compatible with overall ICU survival at our institution, contrary to prevailing opinion. However, we identified several early predictors of outcome that may be important in deciding on prolonged ICU stay.

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

Blood ◽

10.1182/blood.v108.11.803.803 ◽

2006 ◽

Vol 108 (11) ◽

pp. 803-803 ◽

Cited By ~ 3

Author(s):

Corine J. Hess ◽

Johannes Berkhof ◽

Fedor Denkers ◽

Gert J. Ossenkoppele ◽

Gerrit Jan Schuurhuis ◽

...

Keyword(s):

Overall Survival ◽

Acute Myeloid Leukemia ◽

Promoter Methylation ◽

Myeloid Leukemia ◽

Total Population ◽

Risk Group ◽

Methylation Status ◽

Methylation Index ◽

Group B ◽

Acute Myeloid

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

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