Minority Health Disparities in Acute Myeloid Leukemia: A Metropolitan, Single-Center Retrospective Analysis

Abstract Background: Acute myeloid leukemia (AML) is an aggressive bone marrow cancer affecting 20,000 adults in the United States yearly. Five-year relative survival remains poor at 29.5%, though this has been steadily increasing. There are no known differences in diagnostic rates between racial and ethnic groups. Previous work has shown being African American is an independent predictor of poorer survival - particularly in impoverished areas and those with Medicaid. We aimed to identify potential racial disparities amongst our AML population - with special attention to insurance coverage, access to care, disease biology, regimen selection, toxicities, referral for allogeneic hematopoietic stem cell transplant (alloHSCT), and overall survival with non-Hispanic Whites as a control. Methods: This study is a retrospective analysis of patients diagnosed with AML and treated at Virginia Commonwealth University/Massey Cancer Center identified by our data analytics core from June 2018 to December 2020. Data were extracted and manually verified from the electronic medical record into an AML database instrument created in RedCap. Race was determined by self-report. Statistical analysis was performed using GraphPad Prism. Descriptive and inferential statistics were performed with comparisons between groups using an unpaired t-test with Welch's correction or with Fischer's exact test. Overall survival rates were evaluated using Kaplan-Meier analyses and compared using log-rank test. The event date was death and patients were otherwise censored at the date of last contact. Results: Our cohort consisted of 160 patients: 26.3% African Americans, 68.8% Whites, 1.9% Hispanic/Latinos, 1.9% other or declined to state, and 1.3% were unknown. To analyze the impact of minority populations, Hispanic/Latino and "other" categories were combined with African American into a "Non-White" cohort (N = 48) and compared to the "White" cohort (N = 110). There was no baseline difference in age (p= 0.212), Charleson Comorbidity Index (CCI) at presentation (p = 0.692), or ECOG status (p = 0.920) at presentation (Table 1). Assessment of disease biology, including European Leukemia Network risk stratification (p = 0.507), presence of complex karyotype (p = 0.366) and presence of TP53 mutations (p = 0.776) did not detect a statistically significant difference between the two groups (Table 1). Choice of intensive (vs non-intensive) induction based on physician's discretion was also similar (62.5% in non-White, 68.2% in Caucasians, p = 0.583). Toxicity analysis such as ICU during induction (p = 0.519) and death within 60 days of induction (p = 0.8) showed no difference between groups. In parameters assessing access to care, non-Whites were more likely than Whites to have either Medicaid or no insurance coverage, opposed to private insurance or Medicare (p = 0.0166). Despite this, there was no difference in overall survival assessed by log-rank test (p = 0.068) across all cytogenetic cohorts or with respect to the adverse risk cohort (p = 0.143), though the non-White cohort had a mOS of 286 days (9.4 months) compared to 764 days (25.1 months) in the White cohort. Rates of being lost to follow up were not different between the two groups (p = 0.34). However, rates of alloHSCT were approaching significance with p = 0.0528 favoring Caucasians. Discussion: Our data suggest similar disease biology at presentation amongst racial and ethnic groups, as well as similar comorbidities, performance status at diagnosis, and choice of induction regimen. As previous research has shown, our minority cohort was more likely to have no insurance or Medicaid than the Caucasian population. However, this did not lead to a statistically significant overall survival difference. Rates of alloHSCT were approaching statistical significance between the groups. This suggests that improving access to transplant might be one of the more effective tools for improving outcomes in this group. Additionally, demographics in the Richmond metro area demonstrate a population of 47% African American and 48% Whites, whereas our data showed 26% African Americans and 69% Whites, with no known strong racial predilection of AML based on SEER data (46% vs 54%, respectively). Thus, concern remains that there may be a significant number of patients with AML who either do not seek care, or present in a condition where treatment is no longer possible. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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Recombinant Human Thrombomodulin in the Treatment of Acute Myeloid Leukemia Patients Complicated by Disseminated Intravascular Coagulation: Retrospective Analysis of the Outcomes Between the Patients with Heparin and with Recombinant Human Thrombomodulin Therapy

Blood ◽

10.1182/blood.v118.21.1247.1247 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1247-1247

Author(s):

Naoki Takezako ◽

Naohiro Sekiguchi ◽

Akihisa Nagata ◽

Satoshi Noto ◽

Akiyoshi Miwa

Keyword(s):

Overall Survival ◽

Acute Myeloid Leukemia ◽

Continuous Infusion ◽

Myeloid Leukemia ◽

Laboratory Data ◽

Heparin Therapy ◽

Rank Test ◽

Dalteparin Sodium ◽

Log Rank Test ◽

Acute Myeloid

Abstract Abstract 1247 Introduction: Thrombomodulin is a thrombin receptor on the endothelial cell surface that plays an important role as a regulator of coagulation. Recombinant human thrombomodulin (rTM) is a promising anticoagulant that activates protein C, which leads to inactivation of factor (F) Va and FVIIIa and decreased thrombin formation. In addition, rTM is a novel anticoagulant with a long half-life. When compared with heparin therapy, rTM therapy more significantly improves DIC and alleviates bleeding symptoms in DIC patients. However, it is unknown as to whether or not the treatment with rTM affects patient's outcome. Therefore, we retrospectively analyzed 103 patients with acute myeloid leukemia (AML) (except adult acute promyelocytic leukemia), and compared the outcomes between the patients with heparin therapy and with rTM. Methods: The diagnosis of de novo AML patients was based on the morphology, histopathology, cytogenetics, expression of leukocyte-differentiation antigens, and the French-American-British (FAB) classification. The patients examined in the current study (aged 18–84 years) were diagnosed with AML from January 2004 to March 2010. Patients younger than 65 years of age were treated with idarubicin (12 mg/m2 per day) for 3 days (days 1–3) and cytarabine (100 mg/m2 per day) by continuous infusion for 7 days (days 1–7). Patients 65 years of age or older were treated with daunorubicin (40 mg/m2 per day) for 3 days (days 1–3) and 200 mg/m2 per day behenoyl cytarabine for 8 days (days 1–8). The continuous infusion of dalteparin sodium (75 IU/kg per day) or recombinant human thrombomodulin (380 U/kg per day) was used to treat DIC. The diagnostic criteria for DIC previously proposed by the Japanese Ministry of Health and Welfare (JMHW) were employed in this study. The criteria are based on a scoring system including the presence of underlying disease (0 or 1 points), organ failure (0 or 1 points), and the results of coagulation tests of fibrinogen (0 to 2 points), fibrin/fibrinogen degradation products (FDP, 0 to 3 points), and the prothrombin time (0 to 2 points). DIC is diagnosed when the DIC score is greater than 4. Comparisons between the qualitative variables were carried out using the χ2 test. The survival probabilities were estimated by the Kaplan-Meier method, and differences in the survival distributions were evaluated using the log-rank test. These statistical analyses were performed with the software package Stata version 11 (StataCorp LP, College Station, TX, USA). For all analyses, the P values were 2-tailed, and a P value less than.05 was considered to be significant. Results: DIC developed in 45 patients. 31 patients were treated with dalteparin sodium and 14 patients were treated with recombinant human thrombomodulin. The FAB subtypes, age distribution, major laboratory data (CBC, LDH, and CRP) were not significantly different between two groups. No patient died within 4 weeks after diagnosis who were treated with rTM. On the other hand, 3 patients died within 4 weeks after diagnosis who were treated with dalteparin sodium because of bleeding. The DIC resolution rates for the rTM and dalteparin sodium groups were 85.7 %( 12/14) and 67.7 %( 21/31). The overall survival was worse in the DIC group compared with the non- DIC group on the log-rank test (P=0.003). The overall survival was superior in the rTM group compared with dalteparin sodium group (P=0.016). Conclusion: We conclude that treatment with rTM is safe and efficient, when compared with dalteparin sodium. Based on this retrospective study, randomized control study could be attempted in the future. Disclosures: No relevant conflicts of interest to declare.

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Gene Expression Profiling Identifies Distinct Subclasses in Core Binding Factor Acute Myeloid Leukemia.

Blood ◽

10.1182/blood.v106.11.673.673 ◽

2005 ◽

Vol 106 (11) ◽

pp. 673-673

Author(s):

Lars Bullinger ◽

Stephan Kurz ◽

Konstanze Dohner ◽

Claudia Scholl ◽

Stefan Frohling ◽

...

Keyword(s):

Gene Expression ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Expression Patterns ◽

The Other ◽

Rank Test ◽

Core Binding Factor ◽

Log Rank Test ◽

Binding Factor ◽

Acute Myeloid

Abstract Recurrent cytogenetic aberrations have been shown to constitute markers of diagnostic and prognostic value in acute myeloid leukemia (AML). However, even within well-defined cytogenetic AML subgroups with an inv(16) or a t(8;21) we see substantial biological and clinical heterogeneity which is not fully reflected by the current classification system. Therefore, we profiled gene expression in a large series of adult AML patients with core binding factor (CBF) leukemia [inv(16) n=55, t(8;21) n=38] using a whole genome DNA microarray platform in order to better characterize this disease on the molecular level. By unsupervised hierarchical clustering based on 8556 filtered genes we observed that our CBF leukemia samples separated primarily into three different subgroups. While two of the subgroups were characterized by inv(16) and t(8;21) cases, respectively, the third subgroup contained a mixture of both cytogenetic groups. There was no obvious correlation with known secondary aberrations or molecular marker like FLT3-ITD, NRAS and KIT mutations between the cases in the mixed subgroup and the others. However, the newly defined inv(16)/t(8;21)-subgroup (n=35) was characterized by distinct clinical behavior with shorter overall survival times (P=0.029; log rank test) compared to the other two groups. Unsupervised analyses within the inv(16) and t(8;21) cases also revealed corresponding inv(16) and t(8;21) subgroups with a strong trend towards inferior outcome (P=0.11 and P=0.09, respectively; log rank test). Since the primary translocation/inversion events themselves are not sufficient for leukemogenesis, distinct patterns of gene expression found within each of these cytogenetic groups may suggest alternative cooperating mutations and deregulated pathways leading to transformation. Therefore, we performed a supervised analysis to determine the characteristic gene expression patterns underlying the cluster-defined subgroups. We identified 528 genes significantly differentially expressed between the newly defined inv(16)/t(8;21)-subgroup and the other CBF cases (significance analysis of microarrays, false discovery rate < 0.001). Potential candidates for cooperating pathways characterizing the mixed inv(16)/t(8;21)-subgroup included e.g. AVO3, a member of the mTOR pathway, oncogene homologs like LYN and BRAF, as well as FOXO1A and IL6ST which have been previously identified to correlate with outcome in AML (Bullinger et al., N Engl J Med350:1605, 2004). In conclusion, while the observed signatures remain to be validated for their functional relevance, both supervised and unsupervised methods provide numerous insights into the pathogenesis of CBF AML, identifying clinically significant patterns of gene expression, as well as candidate target genes involved in leukemogenesis.

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Cytogenetics As a Prognostic Factor Of The Overall Survival (OS) Of Mexican Patients With Myelodysplastic Syndrome (MDS)

Blood ◽

10.1182/blood.v122.21.5236.5236 ◽

2013 ◽

Vol 122 (21) ◽

pp. 5236-5236

Author(s):

Maria Guadalupe Rodriguez-Gonzalez ◽

Yaneth Martinez-Ibarra ◽

Jorge Vela-Ojeda ◽

Kevin Nacho-Vargas ◽

Luis Meillon ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Multivariate Analysis ◽

Myeloid Leukemia ◽

Cytogenetic Study ◽

Rank Test ◽

Test Figure ◽

Poor Risk ◽

Log Rank Test ◽

The Poor ◽

Acute Myeloid

Abstract Introduction MDS are a heterogeneous group of acquired clonal diseases, characterized by an increase of the apoptosis and several grades of cytopenias. They originate in hematopoietic stem cells with cytogenetic and molecular abnormalities, having the risk of evolving into an acute myeloid leukemia (AML). There are no clinical data of the characteristics of the patients with MDS in Mexico, thus we consider necessary to know the behavior of this disease in our population, also to evaluate the cytogenetic alterations, and to investigate whether they are associated with the OS. Methods A longitudinal-observational study was performed at the MDS clinic of the Hematology Department of the Specialties Hospital of the Centro Médico Nacional La Raza of the Instituto Mexicano del Seguro Social (IMSS), from January 25, 2005 to January 25, 2013. The primary objective was to evaluate the epidemiological characteristics and the cytogenetic findings of the patients with MDS in our population, establishing its correlation with the OS. We included patients >16 y.o., male and female, with diagnosis of newly diagnosed MDSs with a cytogenetic testing available (GGT-band analysis performed at Quest Diagnostics and Genetica Pre y Post Natal). SPSS version 20 was used for statistical analysis. Survival was evaluated through KM curve. A Multivariate analysis with logistic regression was performed in order to know the OR and 95% CI and a p<0.05 was accepted as statistically significant. Results A total of 92 patients were included, 44 (47.8%) men, and 48 (52.2%) women. The cytogenetic study was normal in 72 (78.3%) of the patients and 20% (21.7%) had an abnormal cytogenetic study. The cytogenetic abnormalities were as follows: 5 (25%) had complex karyotype, 3 (15%) had –Y, 2 (10%) hypodiploidy, 2 (10%) del9, 1 (5%) del7, 1 (5%) +9, 1 (5%) t 1;5, 1 (5%) 17p-, 1 (5%) del21, 1 (5%) +19, 1(5%) del5q y 1(5%) +8. 77 patients (83.7%) had favorable cytogenetic risk; 8 (8.7%) intermediate cytogenetic risk; and 7 (7.6%) poor risk. The IPSS risk stratification was: low risk in 33 (35.9%) of the patients, intermediate-1 risk in 39 (53.3%), intermediate 2 risk in 5 (5.4%), and high risk in 5 (5.4%). The median OS was 85 months (figure 1), with a median follow-up of 35 months (2-96 months). The median survival for the favorable cytogenetic risk was 82.7 months 95% CI; 74.7-90.6), for the intermediate cytogenetic risk 73.6 months (95% CI; 49.06-98.1), and for the poor cytogenetic risk, 46.8 months (95% CI; 10.6-18.4). The patients with favorable cytogenetic risk had a better survival than those with intermediate or poor cytogenetic risk (P= .001 Log-rank test). (Figure 2) Of the 92 patients, 10 (10.08%) progressed to acute myeloid leukemia the cytogenetic risk of these patients was as follows: 5 had a favorable risk karyotype and 5 had poor risk karyotype. The patients with favorable cytogenetic risk had a lower risk of progression in comparison with those with poor risk karyotype (P= 0.000). The median PFS to AML was 18.7 months (95 CI 4.1-33.2). Survival per cytogenetic risk group: for the favorable cytogenetic risk the median survival was 22.2 months 95% CI (.76-43), and for the poor cytogenetic risk it was 15.2 months, 95% CI (.0-36.8). (P= .362 Log-rank test). (Figure 3). The performance of the cytogenetic study to classify the patients and to estimate the IPSS is statistically associated with mortality (P 0.006). In the multivariate analysis was found that there is an association, independently of the cytogenetic study with favorable risk according to the IPSS, with the protection against mortality, with an OR=0.141, (95% CI 0.042-0.47). This confered a protection factor of 86% for the survival, independently of the treatment and the MDS type. Conclusion Cytogenetic alterations in MDS patients differs importantly from other reports, since only a 21.7% of our patients had an abnormal cytogenetic finding. Nevertheless cytogenetic evaluation was very important for this population since it confirmed its prognostic importance for the OS of the Mexican MDS patients. Disclosures: Nacho-Vargas: Novartis Oncologia Mexico: Employment. Romero-Salas:Novartis Oncologia Mexico: Employment.

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Serum Albumin As a Prognostic Factor for Overall Survival at 6-Months in Acute Myeloid Leukemia (AML)

Blood ◽

10.1182/blood-2021-154138 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1226-1226

Author(s):

Ashley D Fox ◽

Chijioke Okereke ◽

Thuy Le ◽

Anand P Jillella ◽

Locke J. Bryan ◽

...

Keyword(s):

Overall Survival ◽

Acute Myeloid Leukemia ◽

Multivariate Analysis ◽

African Americans ◽

Serum Albumin ◽

Myeloid Leukemia ◽

Independent Predictor ◽

Univariate Analysis ◽

Normal Albumin ◽

Acute Myeloid

Abstract Introduction: The role of serum albumin as a prognostic factor has been well established in various medical conditions including some hematologic malignancies such as multiple myeloma and myelodysplastic syndromes . In this retrospective analysis, we examined the prognostic value of serum albumin at diagnosis prior to any therapy in a cohort of patients with acute myeloid leukemia (AML) irrespective of treatment modality. Methods: Data were collected retrospectively in a cohort of 257 AML patients who received treatment between 2002 to 2019. The cohort included patients who received conventional 7+3 induction, patients who were not candidates for induction receiving lower intensity chemotherapy +/- targeted drug, and patients who were placed on clinical trials. Patients under the age of 17 were excluded, as well as patients who received their initial diagnosis and induction at an outside hospital whose initial laboratory data for albumin were not available. We excluded patients who were not identified as Caucasian or African American in our final analysis. 46 patients were lost to follow up before 6-months and were excluded from all analysis. Analysis were performed with Epi Info software. Our patients were dichotomized by serum albumin ≥3.5 (normal albumin) and <3.5 (hypoalbuminemia [HA]). Chi-square test was performed for univariate analysis of categorical variables and logistic regression was performed for multivariable analysis. Results: Of the 211 patients, the median age was 59.4 years (17 - 83.4) with 1:1 male to female ratio. 171 patients survived to 6 months and were included in our analysis. There was no significant age difference between normal albumin and HA groups (median age 59 and 59.7 respectively, p=0.854). There was an equal distribution of patients with HA with respect to sex (33.0% male and 36.9% female, p=0.560). With regards to race, more African Americans were found to have hypoalbuminemia compared to Caucasians (46% African Americans vs. 30% Caucasians, p=0.027). Patients with HA had an overall survival rate of 72.2% at 6 months while those with normal albumin levels had a survival rate of 85.1% (p=0.027). Multivariate logistic regression analysis including age, race, sex and albumin levels showed that age, sex and albumin levels were statistically significant independent predictors of survival at 6 months [Table 1]. Patients with albumin ≥3.5 were significantly more likely to survive controlling for age, race, and sex (OR=2.16, p=0.044). Multivariate analysis additionally showed that age was inversely associated with survival at 6-months (p=0.003) and males were more likely to survive than females (p=0.034). Though African Americans were shown to have a higher incidence of HA in univariate analysis, race was not an independent predictor for survival in the multivariate analysis when controlling for age, sex, and albumin level. Conclusions: In this cohort of AML patients, we found that hypoalbuminemia is an independent predictor survival. Serum albumin <3.5 was associated with a significantly decreased overall survival at 6-months. Age and sex were additional independent predictors of 6-month survival. This data suggests that hypoalbuminemia, defined as albumin <3.5, has prognostic utility in AML patients. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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High expression of CD52 mRNA predicts poor prognosis for cytogenetic normal acute myeloid Leukemia patients

10.21203/rs.2.22823/v2 ◽

2020 ◽

Author(s):

Ping Cai ◽

Wenzhi Cai ◽

Xiaoyu Xu ◽

Xiaofei Yang ◽

Yemin Wang ◽

...

Keyword(s):

Gene Expression ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Rank Test ◽

Dna Hypomethylation ◽

Log Rank Test ◽

Pathological Mechanism ◽

High Level ◽

Acute Myeloid

Abstract Background: The prognosis of cytogenetic normal acute myeloid leukemia (CN-AML) varies. Finding new biomarkers affecting the prognosis of these patients may bring a new strategy for precise classification and treatment. CD52 plays a significant role in chronic lymphocytic leukemia (CLL). However, the potential role of CD52 in CN-AML remains largely elusive. Methods: We analyzed the prognostic role of different expression levels of CD52 in 58 CN-AML from The Cancer Genome Atlas (TCGA) dataset and validated these results with 345 CN-AML patients from Gene Expression Omnibus (GEO) dataset. Results: CN-AML patients with high CD52 mRNA expression had a poorer prognosis compared to low CD52 expression ( event-free survival [EFS], P =0.056; overall survival [OS], P=0.043; log-rank test) and the results was verified by GSE12417 (OS, P=0.020; log-rank test) and GSE71014 (OS, P=0.020; log-rank test). Hematopoietic stem cell transplantation (HSCT) may improve prognosis of patients with CD52 high . Regression analysis shows that the expression level of CD52 (HR=1.503; 95%CI:1.158-1.949 ; P=0.002) is a prognostic factor independent of age (HR=3.045; 95%CI:1.524-6.086; P=0.002) and FLT3 mutation status (HR=2.219; 95%CI:1.123-4.382; P=0.022). CD52 gene expression shows a predictive effect on EFS (1-year survival- area under the curve [AUC]:0.685, 2-year survival-AUC:0.752) and OS (1-year survival-AUC: 0.717, 2-year survival-AUC:0.770). Besides, we also found that there is a significant negative correlation between CD52 mRNA expression and DNA methylation . Accordingly, we speculated that CD52 DNA hypomethylation may responsible for the high level of CD52 mRNA. Functional enrichment analysis of differentially expressed genes in CD52 high and CD52 low suggests that adhesion molecule deregulation maybe also the potential pathological mechanism of CD52. Conclusions: CD52 gene mRNA overexpression is an independent adverse prognostic factor for CN-AML. CD52 DNA hypomethylation may responsible for the high level of CD52 mRNA. Adhesion molecule deregulation maybe potential pathological mechanism of CD52. Whether CD52 monoclonal antibodies play a role in high risk patients need further research.

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Evolutionary Patterns of Cytogenetically Normal Acute Myeloid Leukemia Correlate with Time to Relapse

Blood ◽

10.1182/blood.v128.22.288.288 ◽

2016 ◽

Vol 128 (22) ◽

pp. 288-288

Author(s):

Sebastian Vosberg ◽

Luise Hartmann ◽

Klaus H Metzeler ◽

Daniela Schumacher ◽

Friederike Pastore ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Complete Remission ◽

Myeloid Leukemia ◽

Rank Test ◽

Resistant Clone ◽

Log Rank Test ◽

Sensitive Clone ◽

Somatic Alterations ◽

Time To Relapse ◽

Acute Myeloid

Abstract Even though two-thirds of acute myeloid leukemia (AML) patients respond to induction chemotherapy and achieve complete remission (CR), the majority of these patients will eventually relapse. The time from CR to relapse is an important clinical indicator of disease aggressiveness, as patients relapsing within the first 6 months after initial diagnosis have a poorer prognosis in terms of response to salvage therapy and overall survival compared to patients with a later relapse. To learn about the evolution during the course of disease, we analyzed the somatic mutation patterns from initial diagnosis to relapse in 50 cytogenetically normal (CN) AML patients. Based on the ELN classification, 38% of the patients (n=19) were assigned as "favorable" at diagnosis, all other patients were classified as "intermediate-I". ELN classification was associated with time to relapse as "intermediate-I" patients relapsed earlier than "favorable" patients (median 9.3 months vs. 16.1 months, p=0.008, log-rank test). Somatic alterations were detected by exome sequencing and confirmed by targeted amplicon sequencing of matched diagnostic, remission and relapse samples. FLT3-ITD and NPM1 mutation status were obtained from routine diagnostic tests as the reliable detection of these markers by NGS remains challenging. The vast majority of somatic alterations were present both at diagnosis and at relapse, hereafter referred to as stable mutations (70%, Fig. 1A). All patients in our cohort had ≥1 stable mutation with DNMT3A being the most stably altered gene. In 47 out of 50 patients (94%), we observed mutations that were only found at diagnosis or only at relapse. Based on the mutation patterns, four distinct 'evolutionary' subgroups of patients were defined (Fig. 1B): (I) patients with an identical mutation profile at diagnosis and at relapse ("stable", n=3, 6%), (II) patients who gained mutations at relapse ("stable + gain", n=24, 48%), (III) patients that lost mutations at relapse ("stable + loss", n=8, 16%), and (IV) patients with both loss and gain of mutations at relapse ("mixed", n=15, 30%). Mutations that were lost during the course of the disease were detected in e.g. PTPN11 or NRAS. Relapse-specific mutations were identified in e.g. IDH1/2, WT1, KPNB1 or KDM6A. Evolutionary subgroups showed differences in time to relapse (Fig. 1C). Patients with "stable + loss" relapsed earlier (median 4.1 months) than patients with gain of mutation at relapse (groups "stable + gain" and "mixed", median 12.2 months). All patients in the category "stable + loss" developed relapse within the first year after complete remission. The "stable" group of 3 patients showed an intermediate time to relapse (median 9.6 months), but was too small for a statistically valid comparison. Ultimately, the genetic evolution of CN-AML patients without gain of new mutations at relapse (categories "stable" and "stable + loss") was associated with significantly earlier relapse compared to patients that gained mutations at relapse (categories "stable + gain" and "mixed", Fig. 1D, p=0.001, log-rank test). Distinct predominant patterns of clonal evolution were observed in the ELN genetic groups, as only one patient of the "stable + loss" group was initially classified as "favorable". Interestingly, applying the ELN classification on relapse samples revealed a switch from "favorable" to "intermediate-I" in six patients, all with gain of mutations at relapse. This points towards more aggressive genetic profiles at relapse in these patients. The acquisition of mutations and/or the outgrowth of a resistant clone during/after chemotherapy might require a longer time or is per se associated with a longer time to relapse and a more favorable prognosis. Loss of mutations at relapse suggest the presence of two clones at diagnosis, with a chemotherapy resistant clone expanding after the eradication of a chemotherapy sensitive clone. As both clones share mutations and only the sensitive clone contains specific alterations, the resistant clone might be an ancestor of the sensitive clone. Taken together, in some patients the AML cells may require additional genetic alterations to become chemotherapy resistant, whereas in other patients the selective eradication of a sensitive clone is a potential mechanism underlying disease progression. Understanding the evolution of AML under selective pressure of chemotherapy is essential to cure or prevent AML relapse. Disclosures Hiddemann: Roche: Other: Grants; Genentech: Other: Grants; Roche: Membership on an entity's Board of Directors or advisory committees.

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Clinical Prognostic Factors and Outcomes of Essential Thrombocythemia When Transformed to Myelodysplastic Syndrome and Acute Myeloid Leukemia

Blood ◽

10.1182/blood.v124.21.1821.1821 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1821-1821

Author(s):

Yaman Suleiman ◽

Samir Dalia ◽

Jijun Liu ◽

Jeremy W Bowers ◽

Eric Padron ◽

...

Keyword(s):

Overall Survival ◽

Acute Myeloid Leukemia ◽

Prognostic Factors ◽

Myelodysplastic Syndrome ◽

Median Time ◽

Essential Thrombocythemia ◽

Myeloid Leukemia ◽

Jak2 V617f ◽

Disease Biology ◽

Acute Myeloid

Abstract Introduction: Essential Thrombocythemia (ET) is a common myeloproliferative neoplasm (MPN) that usually has an indolent disease course. Over the long term, ET can progress into myelofibrosis, acute myeloid leukemia (AML), or myelodysplastic syndrome (MDS). Incidence rate of transformation to MDS or AML is 1-5% with median time to transformation reported between 84 and 138 months. Although transformation of ET to MDS or AML has been reported previously, there is little information on prognosis in these patients and if specific ET related therapy may lead to increased risk of transformation to MDS or AML. Our study aims to investigate a cohort of ET patients who transformed to MDS or AML in order to better understand their clinical course and identify prognostic factors that may impact overall survival. Methods: After obtaining institutional review board approval, cases of ET between 1990 and 2014 with pathological confirmed transformation to MDS or AML were identified through our pathology database. Patient demographic data, pathological data, and therapy information were recorded. Pathology slides were reviewed by two hematopathologists in order to confirm the diagnosis. Kaplan Meier estimates were used for overall survival assessment and Cox regression modeling for univariate analysis. Results: A total of 40 patients were identified who met the study criteria. Nineteen (48%) were male, and the median age at time off ET diagnosis was 59 years (19-72 years). Sixteen patients (40%) transformed to MDS, 13 (33%) to AML, and 11 (27%) to MDS followed by AML. Median time from ET diagnosis to transformation was 76 months (26-481). Overall, with time to transformation to MDS being 69 months (69-223) and to AML being 88 months (39-481), respectively. After a median follow up of 15 years (10.1-19.9 years), the median OS from ET diagnosis was 10 years (7.4-12.6 years). The median OS from time of transformation was 14 months (5-22.9 months). Patients who had MDS showed longer OS from time of transformation than those who had AML, 35 months (14.2-55.7) versus 10 months (4.4-15.6). Jak2 V617F-negative patients (12 pts) had a better OS from time of diagnosis of ET than Jak2 V617F-positive positive patients (14 pts) (20 yrs vs 8 yrs P = 0.05) but the OS did not differ from time of transformation (P = 0.5). Nine of 40 pts (33%) had normal cytogenetics and 31/40 pts (77%) had abnormal cytogenetics at the time of transformation to MDS or AML. More than half of them had complex cytogenetic 18/31 (58%). At the time of transformation, complex versus non-complex cytogenetic abnormalities did not have an impact on patients’ survival from disease evolution (P = 0.67). The use of hydoxyurea or anagrelide did not have an impact on transformation (P = 0.96, P = 0.58), nor did either impact OS from transformation (P = 0.54, and P = 0.67, respectively). Patients with a grade 2-3 fibrosis identified in the bone marrow at time of transformation had worse OS from transformation than those with grade 0-1 fibrosis (P = 0.05). A higher white blood cell count, but not platelet count, hemoglobin (Hgb) or blast count, at transformation to AML was associated with worse overall survival (P=0.04). Advanced age was also associated with worse OS at transformation of all patients (P = 0.01). Conclusions: Little is known about prognostic factors in ET transformed to MDS or AML. In our forty patients there was no difference in OS from transformation based on having received hydroxyurea or anagrelide therapy for ET. Patients with moderate to severe myelofibrosis (grade 2 - 3 fibrosis) or a higher WBC count at time of transformation had worse overall survival from transformation likely indicating a more aggressive MDS or AML disease biology. Interestingly, OS from diagnosis of ET was 8 years versus 20 years in patients with JAK2 V617F-positive versus JAK2 V617F-negative ET indicating different disease biology in Jak2 negative ET patients. Collaborative multi institutional efforts are needed to further assess prognostic factors in this rare transformation and establish a genetic link especially in JAK 2 negative patients. Disclosures No relevant conflicts of interest to declare.

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Clinical Characteristics and Outcomes in Patients with t(8;21) Acute Myeloid Leukemia in Japan.

Blood ◽

10.1182/blood.v110.11.4269.4269 ◽

2007 ◽

Vol 110 (11) ◽

pp. 4269-4269

Author(s):

Hiroto Narimatsu ◽

Toshiya Yokozawa ◽

Hiroatsu Iida ◽

Motohiro Tsuzuki ◽

Masaya Hayakawa ◽

...

Keyword(s):

Overall Survival ◽

Myeloid Leukemia ◽

Clinical Characteristics ◽

Survival Rates ◽

Japanese Patients ◽

Rank Test ◽

High Dose ◽

Log Rank Test ◽

High Dose Cytarabine ◽

Acute Myeloid

Abstract Clinical characteristics of Japanese patients with t(8;21) acute myeloid leukemia (AML) have not been well described. From January 2000 to December 2005, a total of 147 Japanese adult de novo AML (FAB: M2) patients were newly diagnosed with t(8;21) AML (n=46) or without t(8;21) AML (n=101) in collaborating hospitals. Patients with t(8;21) (median age, 49.5 years; range, 18–86 years) were significantly younger than AML(M2) patients without t(8;21) (median age, 60 years; range 17–90 years) (p<0.001). Three-year overall survival rate in patients with t(8;21) was 70% (95% confidence interval (CI), 51–83%), significantly better than that in AML (M2) patients without t(8;21) (log-rank test, p=0.005) (Figure). Among patients <60-years-old, overall survival rates of patients with t(8;21) AML and patients with non-t(8;21) AML(M2) were 71% (95%CI, 47–86%) and 58% (95%CI, 41–72%), respectively (log-rank test, p=0.28). Of the 40 patients who achieved complete remission, 21 patients received high-dose cytarabine-containing consolidation therapy. Event-free survival rates at 3 years after diagnosis in patients with and without high-dose cytarabine were 60% (95%CI, 36–78%) and 57% (95%CI, 26–79%), respectively (log-rank, p=0.87). In multivariate analysis, age and white blood cell count at diagnosis represented significant predictors of overall survival. For the 147 AML(M2) patients, presence of t(8;21) was not a significant predictor of overall survival after adjusting for age (hazard ratio, 0.65; 95%CI, 0.34–1.24; p=0.19). Japanese patients with t(8;21) AML display more favorable survival rates than those in Western countries. Efficacy of high-dose cytarabine might differ between Japanese and Western patients. Clinicians must be aware of potential differences among different ethnicities. Figure Figure

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A randomized phase 3 study of tipifarnib compared with best supportive care, including hydroxyurea, in the treatment of newly diagnosed acute myeloid leukemia in patients 70 years or older

Blood ◽

10.1182/blood-2009-01-198093 ◽

2009 ◽

Vol 114 (6) ◽

pp. 1166-1173 ◽

Cited By ~ 100

Author(s):

Jean-Luc Harousseau ◽

Giovanni Martinelli ◽

Wieslaw W. Jedrzejczak ◽

Joseph M. Brandwein ◽

Dominique Bordessoule ◽

...

Keyword(s):

Overall Survival ◽

Acute Myeloid Leukemia ◽

Supportive Care ◽

Myeloid Leukemia ◽

Best Supportive Care ◽

Rank Test ◽

P Value ◽

Newly Diagnosed ◽

Phase 3 ◽

Acute Myeloid

AbstractThis phase 3, multicenter, open-label study evaluated the efficacy and safety of tipifarnib compared with best supportive care (BSC), including hydroxyurea, as first-line therapy in elderly patients (≥70 years) with newly diagnosed, de novo, or secondary acute myeloid leukemia. A total of 457 patients were enrolled with 24% 80 years of age or older. Tipifarnib 600 mg orally twice a day was administered for the first 21 consecutive days, in 28-day cycles. The primary endpoint was overall survival. The median survival was 107 days for the tipifarnib arm and 109 days for the BSC arm. The hazard ratio (tipifarnib vs BSC) for overall survival was 1.02 (P value by stratified log-rank test, .843). The complete response rate for tipifarnib in this study (8%) was lower than that observed previously, but with a similar median duration of 8 months. The most frequent grade 3 or 4 adverse events were cytopenias in both arms, slightly more infections (39% vs 33%), and febrile neutropenia (16% vs 10%) seen in the tipifarnib arm. The results of this randomized study showed that tipifarnib treatment did not result in an increased survival compared with BSC, including hydroxyurea. This trial was registered at www.clinicaltrials.gov as #NCT00093990.

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Improved Treatment Results in High-Risk Pediatric Acute Myeloid Leukemia Patients After Intensification With High-Dose Cytarabine and Mitoxantrone: Results of Study Acute Myeloid Leukemia–Berlin-Frankfurt-Münster 93

Journal of Clinical Oncology ◽

10.1200/jco.2001.19.10.2705 ◽

2001 ◽

Vol 19 (10) ◽

pp. 2705-2713 ◽

Cited By ~ 143

Author(s):

U. Creutzig ◽

J. Ritter ◽

M. Zimmermann ◽

D. Reinhardt ◽

J. Hermann ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

High Risk ◽

Myeloid Leukemia ◽

Rank Test ◽

High Dose ◽

Free Survival ◽

Log Rank Test ◽

Risk Patients ◽

Standard Risk ◽

Acute Myeloid

PURPOSE: To improve outcome in high-risk patients, high-dose cytarabine and mitoxantrone (HAM) was introduced into the treatment of children with acute myelogenous leukemia (AML) in study AML-BFM 93. Patients were randomized to HAM as either the second or third therapy block, for the purpose of evaluation of efficacy and toxicity. PATIENTS AND METHODS: A total of 471 children with de novo AML were entered onto the trial; 161 were at standard risk and 310 were at high risk. After the randomized induction (daunorubicin v idarubicin), further therapy, with the exception of HAM, was identical in the two risk groups and also comparable to that in study Acute Myeloid Leukemia–Berlin-Frankfurt-Münster (AML-BFM) 87. RESULTS: Overall, 387 (82%) of 471 patients achieved complete remission, and 5-year survival, event-free survival (EFS), and disease-free survival rates were 60%, 51%, and 62%, respectively. Idarubicin induction resulted in a significantly better blast cell reduction in the bone marrow on day 15. Estimated survival and probability of EFS were superior in study AML-BFM 93 compared with study AML-BFM 87 (P = .01, log-rank test). This improvement, however, was restricted to the 310 high-risk patients (remission rate and probability of 5-year EFS in study AML-BFM 93 v study AML-BFM 87: 78% v 68%, P = .007; and 44% v 31%, P = .01, log-rank test). Probability of 5-year EFS among standard-risk patients in study AML-BFM 93 was similar to that in study AML-BFM 87 (65% v 63%, P = not significant). Whether HAM was placed as the second or third therapy block was of minor importance. However, patients who received the less intensive daunorubicin treatment during induction benefited from early HAM. CONCLUSION: Improved treatment results in children with high-risk AML in study AML-BFM 93 must be attributed mainly to the introduction of HAM.

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