scholarly journals JAK2, Calr and MPL Mutation Status Predicts the Survival Outcome of Patients with Primary Myelofibrosis

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1829-1829
Author(s):  
Uri Rozovski ◽  
Taghi Manshouri ◽  
Vilma Dembitz ◽  
Ksenija Bozinovic ◽  
Sherry Pierce ◽  
...  
Keyword(s):  
Overall Survival ◽  
Triple Negative ◽  
Primary Myelofibrosis ◽  
Risk Groups ◽  
Survival Outcome ◽  
Janus Kinase ◽  
Survival Outcomes ◽  
Rapid Progression ◽  
Mutation Status ◽  
Substitution Mutation

Abstract Background Patients with primary myelofibrosis survive for a median of 5-7 years after diagnosis. However, survival outcomes markedly vary; some patients experience rapid progression and others survive for 10 years or more. The international prognostic scoring system (IPSS) stratifies patients into 4 risk groups on the basis of clinical features (age and constitutional symptoms) and blood counts (hemoglobin, white blood cells, and the presence of circulating blasts). Most patients with primary myelofibrosis harbor mutually exclusive somatic mutations in 1 of 3 genes. In 60% of patients, a substitution mutation is detected in the Janus Kinase 2 (JAK2) gene (JAK2V617F). In another 30% of patients, a frameshift mutation is identified in the Calreticulin (CALR) gene. In 5% of patients, a substitution mutation is found in the gene that codes for the thrombopoietin receptor (MPL). Although patients with mutated CALR generally have more indolent disease than patients with JAK2V617F, the prognostic significance of harboring JAK2V617F is confounded by the observation that low JAK2V617F allele burden is associated with aggressive disease and shortened overall survival (OS) duration. Aim To develop a prognostic model based on the mutation status of the JAK2, CALR, and MPL genes and to determine whether JAK2, CALR, and MPLmutation status provides additional prognostic value to the IPSS. Patients and methods Bone marrow samples were collected and processed from 344 patients with primary myelofibrosis at The University of Texas MD Anderson Cancer Center between 2000 and 2013 (157 months), at the initial visit. All samples were screened for JAK2V617F and for exon9 deletion or insertion mutations in CALR. We used quantitative PCR to quantify the levels of wild-type and mutated JAK2 and determine the JAK2V617F burden. Patients who did not have a mutation in either gene (n = 73) were also screened for an exon10 substitution mutation in MPL. Results Of the 344 patients screened for JAK2V617F and mutations in CALR, 226 (66%) had JAK2V617F and 43 (13%) had mutations in CALR. Of the 75 patients who did not have JAK2 or CALR mutations, 16 (21%) had mutated MPL. In 59 patients (17%), we did not identify mutations in any of the genes (“triple negative”). In the 226 patients who harbored the JAK2V617F mutation, a cut-point of 50% dichotomized patients into those with a high JAK2V617F burden (≥50%) and a favorable survival outcome (median OS: 80 months, 95% confidence interval [CI]: 51-109 months) and those with a low JAK2V617F burden and an adverse survival outcome (median OS: 50 months, 95% CI: 40-60 months; Figure 1). Clinically, patients with a high JAK2V617F burden had larger spleens than those with a low JAK2V617Fburden (P < .0001). We then classified patients according to mutation status into 5 groups: mutated CALR, mutated MPL, high JAK2V617F burden, low JAK2V617F burden, or triple negative) and used mutation status and the IPSS to fit a multivariate model to predict OS. In this model, the IPSS and mutation status independently predicted OS, and as implicated by the higher p-value of the Wald chi-square test, the mutation status was a superior estimate of OS. On the basis of this analysis, patients were stratified according to mutation status into 3 groups with different survival outcomes. Patients had a favorable outcome if they harbored CALR or MPL mutations or if they had a high JAK2V617F burden (n = 170, OS: 104 months, 95% CI: 86-122 months). Patients who were triple negative had an intermediate survival outcome (n = 59, OS: 56 months, 95% CI: 35-77 months). Patients with a low JAK2V617F burden had an adverse outcome (n = 115, OS: 45 months, 95% CI: 38-52 months; Figure 2). The risk of transformation to acute myeloid leukemia was similar across groups except that patients with a low JAK2V617Fburden had a lower risk of transformation (hazard ratio = 0.27, 95% CI: 0.1-0.8). Conclusion On the basis of mutation status in JAK2, CALR, and MPL, we stratified patients into 3 groups with good (CALR or MPL mutation or high JAK2V617F burden), intermediate (triple negative), or adverse (low JAK2V617Fburden) survival outcomes. Our results indicate that prognostication based on mutation status is independent of and superior to the IPSS. Figure 1: Overall survival in patients with primary myelofibrosis with a high or low JAK2V617Fburden Figure 1:. Overall survival in patients with primary myelofibrosis with a high or low JAK2V617Fburden Figure 2: Overall survival in patients with primary myelofibrosis, stratified by mutation status into 3 risk groups Figure 2:. Overall survival in patients with primary myelofibrosis, stratified by mutation status into 3 risk groups Disclosures No relevant conflicts of interest to declare.

scholarly journals Evaluation of Ruxolitinib versus Best Available Therapy in Treating Primary Myelofibrosis

2021 ◽  
Author(s):  
Kawa M. Hasan ◽  
Ahmed Y. Elmeshhadany ◽  
Nazar P. Shabila
Keyword(s):  
Overall Survival ◽  
Kinase Inhibitor ◽  
Laboratory Data ◽  
Primary Myelofibrosis ◽  
Risk Groups ◽  
Janus Kinase ◽  
Response To Treatment ◽  
International Prognostic Scoring System ◽  
Janus Kinase Inhibitor ◽  
Treatment Groups

Objectives: Ruxolitinib is a Janus kinase inhibitor (JAK) that is approved for the treatment of myelofibrosis. The therapeutic protocol has changed after the introduction of Ruxolitinib. The aim of this study was to evaluate the effectiveness of Ruxolitinib and to compare it with best available therapy in patients with primary myelofibrosis. Methods: In this retrospective study, 72 patients with primary myelofibrosis were scrutinized in the period from 2012 to 2018 at Nanakali hemato-oncology teaching center, Erbil, Iraqi Kurdistan. The patients were divided into 2 cohorts, 26 of them were treated with Ruxolitinib and 46 others received best available therapy. The patients’ characteristics, their response to treatment, and the outcomes were evaluated. The efficacy of treatment in both arms was compared. Results: The majority our studied patients (46, 63.8%) were in the high and intermediate-2 risk groups according to international prognostic scoring system. At time of diagnosis, there were no noticeable differences in the clinical characteristics and laboratory data among the Ruxolitinib and best available treatment groups of patients. Ruxolitinib was found to be effective in reducing the size of spleen and improving the overall survival when compared to best available treatment group (p<0.001, p= 0.008 respectively). The patients’ performance state had a significant effect on the overall survival in both treatment groups (p=0.003). Conclusion: Ruxolitinib has a significant role in reduction of spleen size, and potentially affect the survival outcomes in patients with myelofibrosis. Keywords: Ruxolitinib, Myelofibrosis, Splenomegaly, Outcomes.

Quantitative Gene Expression Analysis of Surrogate Markers for Genetic Risk Groups and Survival in CLL

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4170-4170
Author(s):  
Dirk Kienle ◽  
Axel Benner ◽  
Dirk Winkler ◽  
Manfred Hensel ◽  
Riccardo Dalla-Favera ◽  
...  
Keyword(s):  
Gene Expression ◽  
Overall Survival ◽  
Survival Analysis ◽  
Genetic Risk ◽  
Proportional Hazards ◽  
Risk Groups ◽  
Cox Proportional Hazards ◽  
Surrogate Markers ◽  
Mutation Status ◽  
Binet Stage

Abstract In CLL, a variety of surrogate markers for individual genetic features, mostly the VH mutation status, were proposed from gene expression analyses. However, their detailed relation to specific genetic subsets such as V3-21 usage, del11q22-q23 (11q−), and del17p13 (17p−), and their prognostic value in relation to established factors is not elucidated yet. Gene expression markers (ADAM29, ATM, CLLU1, DMD, GLO1, HS1, KIAA0977, LPL, MGC9913, PCDH9, PEG10, SEPT10, TCF7, TP53, Vimentin, ZAP-70, ZNF2) were evaluated using real-time quantitative RT-PCR (RQ-PCR) in purified samples of 151 patients. VH sequencing and FISH screening for genomic aberrations were carried out for all cases, survival information was available for 133 cases. Logistic regression was performed to test the predictive value of gene expression for genetic risk groups, Cox proportional hazards statistics for survival analysis. VH mutation status was best assigned by LPL and ZAP70, followed by TCF7, a marker with a characteristic overexpression in VH mutated CLL patients (correct VH prediction in 83%, 83%, and 75% of the patients, respectively). A similar rate of correct VH assignments was achieved in the subgroup of patients with 11q− or 17p− when using these markers (88%, 86%, and 79%, respectively). In contrast to LPL and TCF7, most of the patients with V3-21 usage were recognized as risk patients by ZAP70 independently of the VH status. Therefore, ZAP70 yielded the best results for the overall recognition of patients with a genetic risk constellation (VH unmutated or V3-21 usage or 11q− or 17p−). Comparison of ZAP-70 determination by RQPCR and flow cytometry was performed for 72 patients and revealed 30% of discordant cases. Thereof, the majority was VH unmutated (including several cases with 11q− or 17p−) showing ZAP-70 negativity by FACS and positivity by RQ-PCR. In multivariate analysis of time to first treatment (TFT), ADAM29 was an independent prognostic factor besides the VH status and Binet stage. In overall survival analysis including the gene expression variables only, LPL was the strongest predictor for overall survival. When genetic and clinical factors were added to this analysis, V3-21 usage, 17p−, age, binet stage, and expression of ATM, ADAM29, SEPT10, and TCL1 were identified as significant prognostic factors. In conclusion, novel gene expression markers allow screening for patients at risk but can not fully substitute for the genetic factors, which should therefore at present remain the basis for risk stratification approaches. Some of the novel markers appear to have a prognostic relevance independently of the established factors, which points to relevant biologic and clinical implications demanding further investigation.

Prognostic model based on JAK2, CALR and MPL mutation status and age predicts the survival outcome of patients with primary myelofibrosis

2015 ◽  
Vol 15 ◽  
pp. S235
Author(s):  
Uri Rozovski ◽  
Taghi Manshouri ◽  
Vilma Dembitz ◽  
Ksenija Bozinovic ◽  
Sherry Pierce ◽  
...  
Keyword(s):  
Prognostic Model ◽  
Primary Myelofibrosis ◽  
Survival Outcome ◽  
Mutation Status ◽  
Model Based

scholarly journals Quantification of Ki67 Change as a Valid Prognostic Indicator of Luminal B Type Breast Cancer After Neoadjuvant Therapy

2021 ◽  
Vol 27 ◽  
Author(s):  
Shirong Tan ◽  
Xin Fu ◽  
Shouping Xu ◽  
Pengfei Qiu ◽  
Zhidong Lv ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
Multivariate Analysis ◽  
Neoadjuvant Chemotherapy ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Survival Outcomes ◽  
Luminal B ◽  
Medical University ◽  
Disease Free

Introduction: Ki67 value and its variation before and after neoadjuvant chemotherapy are commonly tested in relation to breast cancer patient prognosis. This study aims to quantify the extent of changes in Ki67 proliferation pre- and post-neoadjuvant chemotherapy, confirm an optimal cut-off point, and evaluate its potential value for predicting survival outcomes in patients with different molecular subtypes of breast cancer.Methods: This retrospective real-world study recruited 828 patients at the Department of Breast Surgery of the First Affiliated Hospital of China Medical University and the Cancer Hospital of China Medical University from Jan 2014 to Nov 2020. Patient demographic features and disease pathology characteristics were recorded, and biomarkers were verified through immunohistochemistry. Various statistical methods were used to validate the relationships between different characteristics and survival outcomes irrespective of disease-free and overall survival.Results: Among 828 patients, statistically significant effects between pathological complete response and survival outcome were found in both HER2-enriched and triple-negative breast cancer (p &lt; 0.05) but not in Luminal breast cancer (p &gt; 0.05). Evident decrease of Ki67 was confirmed after neoadjuvant chemotherapy. To quantify the extent of Ki67 changes between pre- and post-NAC timepoints, we adopted a computational equation termed ΔKi67% for research. We found the optimal cut-off value to be “ΔKi67% = −63%” via the operating characteristic curve, defining ΔKi67% ≤ −63% as positive status and ΔKi67% &gt; −63% as negative status. Patients with positive ΔKi67% status were 37.1% of the entire cohort. Additionally, 4.7, 39.9, 34.5 and 39.6% of patients with Luminal A, Luminal B, HER2-enriched and triple negative breast cancer were also validated with positive ΔKi67% status. The statistically significant differences between ΔKi67% status and prognostic outcomes were confirmed by univariate and multivariate analysis in Luminal B (univariate and multivariate analysis: p &lt; 0.05) and triple negative breast cancer (univariate and multivariate analysis: p &lt; 0.05). We proved ΔKi67% as a statistically significant independent prognostic factor irrespective of disease-free or overall survival among patients with Luminal B and triple-negative breast cancer.Conclusions:ΔKi67% can aid in predicting patient prognostic outcome, provide a measurement of NAC efficacy, and assist in further clinical decisions, especially for patients with Luminal B breast cancer.

A New Prognostic Model for Extranodal Natural Killer/T Cell Lymphoma, Nasal Type

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1769-1769
Author(s):  
Qingqing Cai ◽  
Xiaolin Luo ◽  
Ken H. Young ◽  
Huiqiang Huang ◽  
Guanrong Zhang ◽  
...  
Keyword(s):  
Overall Survival ◽  
Prognostic Factors ◽  
High Risk ◽  
Prognostic Model ◽  
Cell Lymphoma ◽  
Prognostic Index ◽  
Roc Curves ◽  
Risk Groups ◽  
Survival Outcomes ◽  
Nasal Type

Abstract Background Extranodal natural killer (NK)/T–cell lymphoma, nasal type (ENKTL) is an aggressive disease with a poor prognosis. A better risk stratification is beneficial for clinical management in affected patients. Our recent study has shown that fasting blood glucose (FBG) was a novel, prognostic factor, (Cai et al, British Journal of Cancer, 108: 380–386,2013). This finding has not been integrated in the previous prognostic models for ENKTL Therefore, we aimed to design a new prognostic model, including FBG, for ENKTL which supports to identify high–risk patients eligible for advanced or more aggressive therapy. Patients and methods 158 newly diagnosed patients with ENKTL were analyzed between January 2003 and January 2011 at Sun Yat–sen University Cancer Center, China. Overall survival (OS) and progression free survival (PFS) were estimated using the Kaplan–Meier method. The significance of differences between survival was tested using the Log–rank test. Significant variables in the univariate analysis were selected as variables for the multivariate analysis of survival. The latter was performed by the Cox regression mode. We constructed receiver operating characteristic (ROC) curves and compared the areas under the ROC curves of total protein (TP), FBG, Korean Prognostic Index (KPI) and their combinations in comparison to the survival outcome. Results Of 158 patients, 156 patients had complete clinical information for the parameters of the International Prognostic Index (IPI) model and KPI model. The estimated 5–year overall survival rate in 158 patients was 59.2%. Independent prognostic factors included TP < 60 g/L, FBG > 100 mg/dL, KPI score ≥ 2. A new prognostic model was constructed by combining these prognostic factors: Group 1 (64 cases, 41.0%), no adverse factors; Group 2 (58 cases, 37.2%), one adverse factor; and Group 3 (34 cases, 21.8%), two or three adverse factors. The 5–year overall survival of these groups were 88.9%, 35.6% and 12.7%, respectively (p < 0.001). The survival curves according to the new prognostic model are shown in Fig. 1. The new model categorized three groups with significantly different survival outcomes. The new prognostic model was also efficient in discriminating the patients with low to low–intermediate risk IPI group and high–intermediate to high risk IPI group into three subgroups with different survival outcomes (p < 0.001). The KPI model balanced the distribution of patients into different risk groups better than IPI prognostic model (score 0: 12 cases, 7.7%; score 1: 38 cases, 24.4%; score 2: 42 cases, 26.9%; score 3–4: 64 cases, 41.0%), and it was able to differentiate patients with different survival outcomes (p < 0.001). In addition, the new prognostic model had a better prognostic value than did KPI model alone (p < 0.001), suggesting that TP and FBG reinforced the prognostic ability of KPI model (Table 1). Conclusions The new prognostic model we proposed for ENKTL, including the new prognostic indicator total protein and FBG, demonstrated balanced distribution of patients into different risk groups with better prognostic discrimination as compared to KPI model alone. Disclosures: No relevant conflicts of interest to declare.

From Janus kinase 2 to calreticulin: the clinically relevant genomic landscape of myeloproliferative neoplasms

Blood ◽  
2014 ◽  
Vol 123 (24) ◽  
pp. 3714-3719 ◽  
Author(s):  
Mario Cazzola ◽  
Robert Kralovics
Keyword(s):  
Essential Thrombocythemia ◽  
Myeloproliferative Neoplasms ◽  
Jak2 V617f ◽  
Primary Myelofibrosis ◽  
Janus Kinase ◽  
Driver Mutations ◽  
Mutation Status ◽  
Genomic Landscape ◽  
Exon 10 ◽  
Stat Pathway

Abstract Our understanding of the genetic basis of myeloproliferative neoplasms began in 2005, when the JAK2 (V617F) mutation was identified in polycythemia vera, essential thrombocythemia, and primary myelofibrosis. JAK2 exon 12 and MPL exon 10 mutations were then detected in subsets of patients, and subclonal driver mutations in other genes were found to be associated with disease progression. Recently, somatic mutations in the gene CALR, encoding calreticulin, have been found in most patients with essential thrombocythemia or primary myelofibrosis with nonmutated JAK2 and MPL. The JAK-STAT pathway appears to be activated in all myeloproliferative neoplasms, regardless of founding driver mutations. These latter, however, have different effects on clinical course and outcomes. Thus, evaluation of JAK2, MPL, and CALR mutation status is important not only for diagnosis but also for prognostication. These genetic data should now also be considered in designing clinical trials.

scholarly journals Academic Centers Are Associated with Improved Survival Outcomes in High Risk Diffuse Large B-Cell Lymphoma Patients

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4747-4747
Author(s):  
Daniel A. Ermann ◽  
Victoria Vardell Noble ◽  
Avyakta Kallam ◽  
James O. Armitage
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Median Survival ◽  
Risk Score ◽  
B Cell Lymphoma ◽  
Risk Groups ◽  
Low Risk ◽  
Survival Outcomes ◽  
Intermediate Risk ◽  
Hazard Ratios

Abstract Background: Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma, and is characterized as a heterogenous disease associated with varying outcomes. The International Prognostic Index (IPI) has been the standard for baseline prognostic assessment in these patients. In this study we aimed to determine the impact of treatment facility (academic versus non-academic centers) on overall survival outcomes in DLBCL patients stratified by IPI score risk groups, with a focus on high risk disease as this is associated with poorer outcomes. Methods: The 2018 National Cancer Database (NCDB) was utilized for patients diagnosed with DLBCL between 2004-2015. Patients were then stratified based on IPI risk score from low to high risk. Four risk groups were formed: low (0-1), low-intermediate (2), high-intermediate (3), and high (4-5). Overall survival was calculated using Kaplan-Meyer analysis with bivariate cox proportional hazard ratios to compare survival by facility type (academic or community centers) within these risk groups. Results: A total of 160,137 patients were identified. Of these cases 31.8% were classified as low risk, 21.9% were low-intermediate risk, 22.2% were high-intermediate risk, and 24% were high risk. 59.3% of patients were treated at a community center and 40.7% were treated at academic centers. Treatment at academic centers was associated with a significantly improved overall survival (OS) for each risk category. Median survival (in months) for high risk IPI score DLBCL was 47.9 months in community and 61.1 months in academic centers (p<.0001). Median survival for high-intermediate risk score was 48.3 months in community and 87.3 months in academic centers (p<.0001). Median survival for low-intermediate score was 90.3 months in community and 122.8 months in academic centers (p<.0001). Median survival for low risk score was 132 months in community and 148 months in academic centers (p<.0001). Hazard ratios for academic center versus community center for high risk, high-intermediate, low-intermediate and low risk are 0.768, 0.71, 0.848 and 0.818 respectively (p<.0001). Conclusions: Facility type is significantly associated with improved survival outcomes across all IPI based risk groups for DLBCL. This benefit is especially significant in higher risk disease where positive outcomes are less common, suggesting treatment at academic centers may be particularly beneficial in these patients. Some of the possible reasons for this difference may include provider experience, increased access to resources, and opportunity for clinical trials. Further investigations into the factors contributing to such disparities should be done to help standardize care and improve outcomes. Disclosures No relevant conflicts of interest to declare.

Survival outcomes in Egyptian patients with triple-negative breast cancer: Single institute experience.

2015 ◽  
Vol 33 (28_suppl) ◽  
pp. 158-158 ◽  
Author(s):  
Mona Kamal Jomaa ◽  
Ahmed Aly Nagy
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
Triple Negative Breast Cancer ◽  
Median Overall Survival ◽  
Triple Negative ◽  
Disease Free Survival ◽  
Survival Outcomes ◽  
Free Survival ◽  
Disease Free ◽  
Grade Iii

158 Background: Triple-negative breast cancer (TNBC) is a unique subtype and consider as an aggressive disease without established targeted treatment options. This study conducted to determine the incidence, characteristics, and survival outcomes of TNBC patients in an Egyptian cancer institute. Methods: Medical records of 520 patients treated between 2010-2011 in Clinical Oncology Department-Ain Shams University-Egypt were analyzed. Cox proportional hazards models were used to evaluate the association between TNBC and DFS and OS after adjusting for other covariates. Results: Among the 520 patients, 139 were TNBC .The median age was 50 years (SD±11.767, Range 20-80 ) versus 52 years (SD±12.134, Range 20-80), median tumor diameter was 5 cm (SD± 1.408, Range 1-7) versus was 5 cm (SD± 1.401, Range 1-7) , and median number of positive axillary LN was 3 (SD± 4.779, Range 0-37) versus 3 (SD± 4.832, Range 0-25) in non TNBC and TNBC respectively . Median disease-free survival was 24 months (SD± 14.128, Range 1-69 ) versus 15 months (SD± 8.811, Range 1-43 ) and median overall survival was 41 months (SD± 16.249, Range 3-60) versus 31 months (SD± 12.184, Range 7-60 ) in non TNBC and TNBC respectively. About 85.6 % of the TNBC tumors were IDC, 4.4 % were ILC and 5% were mixed. About 1.4 % of the TNBC tumors were grade I, 70.5 % were grade II and 28.1% were grade III. Median disease-free survival was 24 months (95%CI 21.679- 26.321) versus 15 months (95%CI 12.587-17.413) (p< 0.001) and median overall survival was 44 months (95%CI 41.396-46.604) versus 31 months (95%CI 29.460-32.540) (p< 0.001) in non TNBC and TNBC respectively. In TNBC cohort , DFS was 12 months (95%CI 11.464-12.536) in patients with grade III tumors versus 25 months (95%CI 22.359-27.641 )in patients with other grades (p< 0.001), this was also reflected in OS as 29 months (95%CI 25.129-32.871 ) versus 44 months (95%CI 41.238-46.762 ) (p< 0.001). Conclusions: Multivariate analyses supported a conclusion that TNBC subtype was an independent adverse prognostic factor for survival along with other known risk factors such as tumor grade.

scholarly journals Clinical characteristics of essential thrombocythemia patients depend on the mutation status

2020 ◽  
Vol 51 (4) ◽  
pp. 230-235
Author(s):  
Witold Prejzner ◽  
Andrzej Mital ◽  
Maria Bieniaszewska ◽  
Aleksandra Leszczyńska ◽  
Agata Szymańska ◽  
...  
Keyword(s):  
Essential Thrombocythemia ◽  
Lower Risk ◽  
Clinical Characteristics ◽  
Triple Negative ◽  
Clinical Course ◽  
Janus Kinase ◽  
Overall Survival Rate ◽  
Mutation Status ◽  
Thrombopoietin Receptor ◽  
The Impact

AbstractThe impact of the mutation status on the clinical course and the outcome of essential thrombocythemia (ET) patients has not yet been completely established. A total of 171 patients with diagnosed ET were tested and subsequently grouped, according to their mutation status – Janus Kinase 2 (JAK2) – 112 patients, calreticulin (CALR) – 36 patients, and thrombopoietin receptor (MPL) – 5 patients. Moreover, 18 individuals were triple-negative (with non-mutated JAK2, CALR, and MPL). CALR-mutated patients preferentially were male, with higher platelets (PLT) counts (mean PLT = 1 002.3) and lower hemoglobin and hematocrit levels at the diagnosis, compared to the JAK2 (mean PLT = 933.6), MPL (mean PLT = 940.8) and triple-negative patients (mean PLT = 822.6) (p = 0.0035). The patients with CALR mutated, and the triple-negative ones had a lower risk of arterial and venous thrombosis (3% and 5.6% cases at the time of diagnosis, respectively) than the patients with JAK2 mutation (7.2%) (p = 0.9210). The overall survival rate did not differ statistically between the groups.

High Dose Daunorubicin Improves Survival in AML up to Age 60, Across All Cytogenetic Risk Groups Including Patients with Unfavorable Cytogenetic Risk, and FLT3-ITD Mutant AML: Updated Analyses from Eastern Cooperative Oncology Trial E1900

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 373-373 ◽  
Author(s):  
Marlise R. Luskin ◽  
Ju-Whei Lee ◽  
Hugo F Fernandez ◽  
Hillard M. Lazarus ◽  
Jacob M. Rowe ◽  
...  
Keyword(s):  
Overall Survival ◽  
Induction Therapy ◽  
Risk Group ◽  
Multivariable Analysis ◽  
Risk Groups ◽  
Prognostic Impact ◽  
Npm1 Mutation ◽  
Mutation Status ◽  
The Impact

Abstract Background: Eastern Cooperative Oncology Group trial E1900 (E1900) showed that induction therapy with a high daily dose of daunorubicin (90 mg/m2) (DNR 90) improves survival in younger patients (pts) (<50 yrs) and intermediate (int) cytogenetic risk AML, but at 2 years of follow-up no benefit was seen in older pts (50-60 yrs), or in those with unfavorable cytogenetic risk or FLT3-ITD mutant AML (Fernandez et al. N Engl J Med 2009). Here we update results of E1900 with longer follow-up, focusing on the benefit of DNR 90 in cytogenetic and common molecular subgroups. Methods: Overall survival (OS) was measured from randomization for induction therapy to death from any cause (censored at last contact). Hazard ratios (HR) for death were computed using univariate and multivariable Cox proportional hazards models; multivariable Cox models were adjusted for sex, age, hemoglobin level, leukocyte count, platelet count, and cytogenetic profile. All conclusions regarding the impact of DNR 90, unless noted, are similar based on univariate and multivariable analysis. Results: Overall, 657 pts were enrolled with a median follow-up of 80.1 months. The HR for death in the DNR 90 group as compared with the standard-dose daunorubicin (45 mg/m2) (DNR 45) group was 0.74 (p=0.001). Pts <50 yrs benefited from DNR 90 (p = 0.002) while those >=50 yrs were not proven to benefit (p = 0.12). Pts with favorable (fav) and int. cytogenetic risk benefited from DNR 90 (p = 0.03 and p = 0.02, respectively). A benefit for pts with unfavorable cytogenetic risk was seen on multivariable analysis (p = 0.04). Impact of DNR 90 by mutation status: The 3 most common mutations were FLT3-ITD (24%), NPM1 (26%), and DNMT3A (24%). AML pts with any of these 3 mutations benefited from DNR 90 (p = 0.009, p = 0.002, and p = 0.02, respectively). FLT3-ITD pts who received DNR 90 had a 4-yr OS of 31%. Benefit was seen in pts age 50-60 with FLT3-ITD or NPM1 mutation (p = 0.02 and p = 0.04, respectively). No benefit of DNR 90 was seen in a small cohort of pts with MLL-PTD (p = 0.06). Benefit of DNR 90 in FLT3-ITD, NPM1, and DNMT3A mutant AML was confirmed in the int. cytogenetic risk group. Impact of DNR 90 on prognostic impact of NPM1: The presence of an NPM1 mutation conferred an improvement in OS in the DNR 90 group which was not seen in the DNR 45 group (p = 0.01 vs p = 0.3). This finding was confirmed in the int. cytogenetic risk group. Conclusion: With median follow-up of over 6 years on E1900, we confirm that DNR 90 improves outcome in pts with fav/int cytogenetic risk, DNMT3A or NPM1 mutant AML, or age < 50 (Patel et al. N Engl J Med 2012). Additionally, we now demonstrate that DNR 90 additionally benefits pts with FLT3-ITD AML, and pts with unfavorable cytogenetic risk, regardless of age. Moreover, we show that the favorable prognostic impact of the NPM1 mutation is only present when pts receive DNR 90. Given the benefit of DNR 90 across all cytogenetic risk groups as well as common molecularly defined subgroups of AML, DNR 90 should be the standard for all pts up to age 60 who are candidates for induction chemotherapy. Table HR for death by AML cohort. Subgroup N Univariate Model DNR 45 DNR 90 HR (DNR 90/DNR 45) & 95% CI Wald P All patients (n=657) Overall 330 327 0.74 (0.61, 0.89) 0.001 Age < 50 yrs³ 50 yrs 188 142 172 155 0.66 (0.50, 0.85) 0.81 (0.62, 1.06) 0.002 0.12 Cytogenetic Favorable Intermediate Unfavorable 38 232 59 51 212 63 0.51 (0.28, 0.93) 0.76 (0.61, 0.96) 0.79 (0.54, 1.16) 0.03 0.02 0.22 FLT3-ITD WT MUT 215 83 241 64 0.74 (0.59, 0.92) 0.61 (0.42, 0.89) 0.008 0.009 MLL-PTD WT MUT 290 16 296 15 0.70 (0.58, 0.86) 0.46 (0.21, 1.04) 0.0004 0.06 NPM1* WT MUT 180 65 192 65 0.70 (0.55, 0.89) 0.50 (0.32, 0.78) 0.003 0.002 DNMT3A WT MUT 177 61 194 58 0.66 (0.52, 0.85) 0.62 (0.41, 0.94) 0.001 0.02 * Statistically significant test of interaction (p<0.2) Figure 1A: Overall Survival by NPM1 Mutation Status and Treatment Arm Figure 1A:. Overall Survival by NPM1 Mutation Status and Treatment Arm Figure 1B: Overall Survival of FLT-ITD Mutant AML Patients by Treatment Arm Figure 1B:. Overall Survival of FLT-ITD Mutant AML Patients by Treatment Arm Disclosures No relevant conflicts of interest to declare.

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