Outcome of Patients (pts) with Low and Intermediate-1 Risk Myelodysplastic Syndrome (MDS) After Hypomethylating Agent (HMA) Failure.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2824-2824
Author(s):  
Elias J. Jabbour ◽  
Naval G. Daver ◽  
Tina (Xiao Qin) Dong ◽  
Tapan M. Kadia ◽  
Susan O'Brien ◽  
...  
Keyword(s):  
Overall Survival ◽  
Growth Factors ◽  
High Risk ◽  
Lower Risk ◽  
Risk Model ◽  
Survival Rates ◽  
Low Risk ◽  
Intermediate Risk ◽  
High Risk Disease ◽  
Overall Survival Rates

Abstract Abstract 2824 Background: HMA are standard of care in pts with high-risk MDS and commonly used in pts with lower risk. Pts with high-risk disease post HMA failure have a poor prognosis with a median survival of 4 months (Jabbour et al. Cancer. 2010;116:3830–4). The prognosis of patients with low and intermediate-1 risk MDS after HMA failure is not known. Aims: To assess survival in patients with low and intermediate-1 risk disease at the time of HMA failure that might benefit from specific strategies or investigational agents. Methods: Data from 699 patients with MDS (n=397) and chronic myelomonocytic leukemia (n=302) treated with HMA at one institution between 2000 and 2011 were reviewed. 126 (18%) of them were of low and intermediate-1 risk disease by IPSS score. Results: A total of 30 (24%) patients with MDS (n=26) and CMML (n=4) who had failed HMA therapy and remained of low and intermediate-1 risk disease were analyzed. These included 6 patients with low- and 24 intermediate-1 risk disease. Eleven patients had secondary disease. At the start of HMA, 22 patients were low-risk and 8 were intermediate-1 risk disease. Seventeen patients had a diploid cytogenetic analysis. Seven and 23 patients received azacitidine and decitabine, respectively. These patients had discontinued HMA because of primary resistance in all patients. The characteristics of the study group are shown in Table 1. Upon HMA failure, 24 (80%) were low-risk disease and 6 (20%) intermediate-1-risk disease. A total of five (17%) patients transformed subsequently into acute myeloid leukemia. After a median of 18 months from HMA failure, 12 (40%) patients remained alive. The median overall survival was 22 months with estimated 1- and 2-year overall survival rates of 65% and 45%, respectively. Considering overall survival from the start of HMA therapy, the median survival was 29.5 months with estimated 1- and 2-year overall survival rates of 80% and 60%, respectively. The 30 patients with HMA failure were subsequently assessed by the lower-risk MDACC risk model (Garcia-Manero et al. Leukemia. 2008;22:538–43): 8 (27%) had low-risk, 8 (27%) intermediate-risk, and 14 (46%) high-risk disease. Their 1-year survival rates were 66%, 73%, and 86%, respectively. Considering survival from the time of the initiation of HMA therapy, the estimated 1-year survival rates were 60%, 70%, and 100%, respectively, for patients with high-risk, intermediate-risk, and low-risk disease according to the MDACC risk model. After HMA failure, 11 (37%) patients received salvage investigational therapy, of whom 3 responded with 2 achieving hematologic improvement for a median of 12 months (range, 5–19) and one patient achieving a complete remission for 14 months that was lost thereafter, 1 (3%) received immunotherapy, 1 (3%) received growth factors only, and 17 (57%) elected not to receive any further treatment. No response was observed in the 2 patients who received subsequent immunotherapy or growth factors. Conclusion: The outcome of patients with low and intermediate-1 risk MDS after HMA failure is poor and appears to be predictable. Disclosures: Ravandi: Genzyme/Sanofi: Honoraria. Faderl:Genzyme: Advisory Board Other, Research Funding.

Development of a prognostic risk model for small cell lung cancer: Identification of high-, intermediate-, and low-risk cohorts based on clinical-genomic data.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 8554-8554
Author(s):  
Fatemeh Ardeshir-Larijani ◽  
Gary Wildey ◽  
Pingfu Fu ◽  
Afshin Dowlati
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Risk Model ◽  
Cox Regression ◽  
Cox Model ◽  
Prognostic Index ◽  
Low Risk ◽  
Intermediate Risk ◽  
Entire Cohort ◽  
Clinical Genomic

8554 Background: Although many clinical prognostic factors for SCLC outcome have been described, there are no models that incorporate the combination of clinical and genomic details into a risk model defining high and low risk patients. Methods: From a total of 791 SCLC patients seen between 2013-2018, 91 were evaluated by exome sequencing. Using the univariate Cox regression model, 19 genes were prognostic for survival and included RET, ERBB4 MAP3K1, ABL1, CCND1, TSC1, PRKCI, FGFR3, JAK3, ZNF217, BRCA1, GPR124, LRP1B, GNAS, TAF1, FGF3, STAT3, CD79A and FLT. LASSO, elastic-net Cox and traditional Cox model with stepwise selection along with traditional clinical factors (age and stage) were further used to build the final model. The final risk groups were defined based upon the prognostic index from multivariable Cox model involving age, stage (extensive/limited) and 6 genes ( MAP3K1, ABL1, CCND1, PRKCI, BRCA1, GNAS). Results: The overall survival (OS) for the entire cohort was 11.2 (95% CI: 9 – 13.4) months and the median age was 65 (range: 39 - 90) years. Eighty percent (N = 74) of evaluated patients had extensive stage (ES) disease. The HR for death of age and stage (ES/LS) was 1.06 (CI: 1.03-1.08, p < 0.0001) and 4.33 (CI: 2.23-8.41, p < 0.0001) respectively. ABL1 demonstrated the highest HR of 10.14 (2.81-36.6, p = 0.0004) followed by PRKCI (HR: 5.05, CI: 1.43-17.8 , p < 0.012), CCND1 (HR: 4.52, CI: 1.23-16.57, p < 0.023), MAP3K1 (HR: 3.38, CI: 1.37- 8.33, p = 0.008) and GNAS (HR: 2.21, CI: 1.11-4.43, p < 0.025). Interestingly, BRACA1 mutation was protective as patients with BRACA1 mutation had significantly better overall survival (HR: 0.3, CI: 0.1- 0.85, p < 0.023). Our model categorized patients into three groups of low risk ( N= 31), intermediate risk ( N= 30) and high risk ( N= 30) with significantly different survival outcomes ( p < 0.0001). Those with low risk had the median OS of 27.4 (95% CI: 16.8-55.5) months, intermediate risk with median OS of 10.8 (95% CI: 7 – 14.7) months and high risk with median OS of 5.4 (95% CI: 3.9- 9) months. Conclusions: This clinical-genomic risk group stratification represents a useful model to estimate SCLC survival outcome and may have value in future clinical trials.

Initial Results of a Randomized Phase II Study of Low Dose Decitabine (DAC) Versus Low Dose Azacitidine (AZA) in Patients with Low- or Intermediate-1-Risk Myelodysplastic Syndromes (MDS)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4640-4640 ◽  
Author(s):  
Elias Jabbour ◽  
Koji Sasaki ◽  
Naval Daver ◽  
Naveen Pemmaraju ◽  
Courtney D. DiNardo ◽  
...  
Keyword(s):  
High Risk ◽  
Phase Ii ◽  
Lower Risk ◽  
Low Dose ◽  
Survival Rates ◽  
Low Risk ◽  
Standards Of Care ◽  
Improvement Rate ◽  
Median Response ◽  
High Risk Disease

Abstract Background: The prognosis of patients with lower-risk MDS is heterogeneous; many have poor survival (Leukemia. 2008;22:538-543). Hypomethylating agents (HMA) improve the outcomes of patients with higher-risk MDS. Recent Phase I/II studies suggested that HMA doses below current standards of care retain activity in MDS, potentially with a better toxicity profile (JCO. 2009;27:1850-1856). We hypothesized that lower doses of HMA may be active and well tolerated in patients with lower-risk MDS. Aim: This is a phase II randomized trial to evaluate the efficacy and tolerability of low-dose regimens of either DAC or AZA in patients with low- or intermediate-1-risk MDS. Materials and Methods: Eligible patients were adults older than 18 years with de novo or secondary IPSS low- or intermediate-1-risk MDS, including CMML, with normal organ function. Patients were randomized on a Bayesian design to receive DAC 20 mg/m2 IV or AZA 75 mg/m2 IV/SC per day for 3 consecutive days every 28 days. The primary efficacy end point is overall improvement rate (OIR: complete remission [CR], partial remission [PR], marrow CR [mCR], or hematologic improvement [HI]). Secondary end points are HI, transfusion independence, cytogenetic response, overall survival (OS), and time to acute myeloid leukemia or death. Chi-square test and independent t-test were performed to evaluate differences of patients’ characteristics. OS was estimated with the Kaplan-Meier method. A log-rank test was used for statistical analysis, and p<0.05 was considered statistically significant. Results: Between 11/2012 and 4/2014, 68 patients were enrolled. Eleven patients have not been on-study long enough for response assessment. Fifty-seven patients are currently evaluable in this study; 28 patients received DAC, and 29 patients received AZA. Median duration of follow-up is 9 months (range, 0-18+). Median age at enrollment was 71 years (33-85). Median time from diagnosis to therapy was 1.5 months (range, 0.2-63.4). Baseline patient demographic and clinical characteristics did not differ significantly between groups. Of the 28 patients in the DAC arm, 13 (46%) had diploidy, and 2 (7%) had complex karyotypes; 3 (11%) were low-risk and 25 (89%) were intermediate-1-risk by IPSS. Of the 29 patients in the AZA arm, 17 (59%) had diploidy, and 1 (3%) had complex karyotype; 5 (17%) were low-risk and 24 (83%) were intermediate-1-risk by IPSS (2006). Six (21%) patients in the DAC arm and 7 (24%) in the AZA arm received growth factor support prior to therapy. Overall, 19 (33%) patients achieved CR, 2 (4%) CRp, 6 (11%) mCR, and 5 (9%) HI. In the DAC arm, 15 (54%) achieved OIR, 10 (36%) CR, 1 (4%) CRp, 3 (11%) mCR, and 1 (4%) HI. In the AZA arm, 16 (56%) achieved OIR, 9 (31%) CR, 1 (3%) CRp, 3 (10%) mCR, and 3 (10%) HI. Median response duration is 13 months (range, 0-16+). In the DAC group, 1 (8%) out of 12 initially RBC-dependent patients became RBC independent, 3 of 5 RBC/platelet-dependent patients became RBC/platelet-independent, and 1 (7%) of 14 transfusion-independent patients became RBC-dependent. In the AZA group, 3 (27%) of 11 initially RBC-dependent patients became RBC-independent, and 1 (7%) of 14 transfusion-independent patients became dependent. The median number of courses is 7 (range, 2-17+). Treatment has been well tolerated, and only 3 (5%) patients had dose reduction due to grade 3-4 myelosuppression. No death is observed during therapy but 9 deaths in total (16%) were observed after HMA failure; 3 (10%) in AZA and 1 (3%) in DAC in patients who failed to respond and discontinued therapy before death; 2 (7%) in AZA and 3 (11%) in DAC in patients who progressed to higher grade of MDS and changed therapy before death. The 1-year survival rates for the DAC and AZA were 80% and 67%, respectively (p=0.478). Median OS has not been reached, and no difference was noted between groups. Analyzing survival by the MDA lower-risk scoring system (Leukemia. 2008;22:538-543), the median survival was not reached for patients with low-risk disease, not reached for patients with intermediate-risk disease, and 272 days for patients for high-risk disease. The 1-year survival rates were 100%, 82%, and 64% for patients with low-, intermediate-, and high-risk disease, respectively. Conclusion: Low-dose HMA shows promising results in patients with low- or intermediate-1- risk MDS, with an OIR of 53%. The study continues to accrue patients, and results will continue to be updated as they are analyzed. Disclosures No relevant conflicts of interest to declare.

scholarly journals A Novel Autophagy-Related lncRNA Gene Signature to Improve the Prognosis of Patients with Melanoma

2020 ◽  
Author(s):  
Yi Ding ◽  
Tian Li ◽  
Min Li ◽  
Tuersong Tayier ◽  
MeiLin Zhang ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Risk Model ◽  
Risk Group ◽  
Clinical Information ◽  
Low Risk ◽  
Gene Set Enrichment Analysis ◽  
Positive Regulation ◽  
Risk Patients ◽  
Cox Analysis

Abstract Background: Autophagy and long non-coding RNAs (lncRNAs) have been the focus of research on the pathogenesis of melanoma. However, the autophagy network of lncRNAs in melanoma has not been reported. The purpose of this study was to investigate the lncRNA prognostic markers related to melanoma autophagy and predict the prognosis of patients with melanoma.Methods: We downloaded RNA-sequencing data and clinical information of melanoma from The Cancer Genome Atlas. The co-expression of autophagy-related genes (ARGs) and lncRNAs was analyzed. The risk model of autophagy-related lncRNAs was established by univariate and multivariate COX regression analyses, and the best prognostic index was evaluated combined with clinical data. Finally, gene set enrichment analysis was performed on patients in the high- and low-risk groups.Results: According to the results of the univariate COX analysis, only the overexpression of LINC00520 was associated with poor overall survival, unlike HLA-DQB1-AS1, USP30-AS1, AL645929, AL365361, LINC00324, and AC055822. The results of the multivariate COX analysis showed that the overall survival of patients in the high-risk group was shorter than that recorded in the low-risk group (p<0.001). Moreover, in the receiver operating characteristic curve of the risk model we constructed, the area under the curve (AUC) was 0.734, while the AUC of T and N was 0.707 and 0.658, respectively. The Gene Ontology was mainly enriched with the positive regulation of autophagy and the activation of the immune system. The results of the Kyoto Encyclopedia of Genes and Genomes enrichment were mostly related to autophagy, immunity, and melanin metabolism.Conclusion: The positive regulation of autophagy may slow the transition from low-risk patients to high-risk patients in melanoma. Furthermore, compared with clinical information, the autophagy-related lncRNAs risk model may better predict the prognosis of patients with melanoma and provide new treatment ideas.

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

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.

scholarly journals The preoperative prognostic value of the radiomics nomogram based on CT combined with machine learning in patients with intrahepatic cholangiocarcinoma

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Youyin Tang ◽  
Tao Zhang ◽  
Xianghong Zhou ◽  
Yunuo Zhao ◽  
Hanyue Xu ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Intrahepatic Cholangiocarcinoma ◽  
Prognostic Value ◽  
Survival Rates ◽  
Low Risk ◽  
Liver Carcinoma ◽  
Incidence And Mortality ◽  
Significant Difference ◽  
Prognostic Prediction

Abstract Background Intrahepatic cholangiocarcinoma is an aggressive liver carcinoma with increasing incidence and mortality. A good auxiliary prognostic prediction tool is desperately needed for the development of treatment strategies. The purpose of this study was to explore the prognostic value of the radiomics nomogram based on enhanced CT in intrahepatic cholangiocarcinoma. Methods In this retrospective study, 101 patients with pathological confirmation of intrahepatic cholangiocarcinoma were recruited. A radiomics nomogram was developed by radiomics score and independent clinical risk factors selecting from multivariate Cox regression. All patients were stratified as high risk and low risk by a nomogram. Model performance and clinical usefulness were assessed by calibration curve, ROC curve, and survival curve. Results A total of 101patients (mean age, 58.2 years old; range 36–79 years old) were included in the study. The 1-year, 3-year, and 5-year overall survival rates were 49.5%, 26.6%, and 14.4%, respectively, with a median survival time of 12.2 months in the whole set. The least absolute shrinkage and selection operator (LASSO) method selected 3 features. Multivariate Cox analysis found three independent prognostic factors. The radiomics nomogram showed a significant prognosis value with overall survival. There was a significant difference in the 1-year and 3-year survival rates of stratified high-risk and low-risk patients in the whole set (30.4% vs. 56.4% and 13.0% vs. 30.6%, respectively, p = 0.018). Conclusions This radiomics nomogram has potential application value in the preoperative prognostic prediction of intrahepatic cholangiocarcinoma and may facilitate in clinical decision-making.

MDM2 SNP309 and TP53 SNPArg72Pro Polymorphisms in Myelodysplastic Syndrome.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1745-1745
Author(s):  
João Agostinho Machado Neto ◽  
Fabiola Traina ◽  
Paula Melo Campos ◽  
Marilisia Andreoli ◽  
Irene Lorand Metze ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Myelodysplastic Syndrome ◽  
Disease Progression ◽  
Low Risk ◽  
Healthy Controls ◽  
Mdm2 Snp309 ◽  
P53 Pathway ◽  
Hematopoietic Stem ◽  
High Risk Disease

Abstract Abstract 1745 Poster Board I-771 Introduction Myelodysplastic syndrome (MDS) encompasses a heterogeneous group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis, refractory cytopenia and a tendency to progress towards acute myeloid leukemia (AML). The progression of the disease may be associated with genetic or epigenetic alterations and a possible change in protein function. MDM2/P53 pathway plays an important role in the control of apoptotic and proliferation mechanisms. Single nucleotide polymorphisms (SNPs) were identified in the TP53 and MDM2 genes. MDM2 SNP309 results in higher levels of MDM2 and attenuates p53 pathway. The SNP in codon 72 of the TP53 gene results in either a C or G nucleotide and leads to either Proline (Pro) or Arginine (Arg), respectively. The Arg variant has been shown to be more potent in apoptosis induction and the Pro variant has been shown to be better in inducing cell-cycle arrest and to have a greater ability to repair damaged-DNA. The aim of the present study was to investigate the incidence of MDM2 and TP53 polymorphisms in MDS patients and to correlate the frequency of these SNPs with age, neutrophis and platelets at diagnosis, low risk versus high risk disease according to FAB (RA and RARS versus AREB and AREBt) and IPSS (Low and Int-1 versus Int-2 and high), cytogenetic risk (low versus intermediate and high risk), disease progression and overall survival. Patients and Methods We studied 103 healthy controls and 63 patients with MDS. According to FAB, patients were distributed as follows: 43 RA, 10 RARS, 7 RAEB, 1 RAEBt and 2 CMML. The median follow-up time was 40 months (range 2 – 159 months). Samples were obtained from peripheral blood or bone marrow and were screened for the presence of polymorphisms MDM2 SNP309 and TP53 SNPArg72Pro, by PCR analysis with specific primers and appropriate restriction enzyme. Appropriate statistical analyses were used for each test. Results The frequencies of genotypes for MDM2 SNP309 and TP53Pro7Arg were similar between MDS and healthy controls; MDM2 SNP309: 51% vs 53%, for TT, 38% vs 32% for TG, and 11% vs 15% for GG, TP53Pro7Arg: 47.5% vs 44%, for Arg/Arg, 47,5% vs 42% for Pro/Arg, and 5% vs 14% for Pro/Pro. No differences were observed between MDS patients with presence or absence of the polymorphisms in relation to age, neutrophis and platelets at diagnosis, low risk versus high risk disease according to FAB, IPSS and cytogenetic risk, disease progression and overall survival. Conclusions MDM2 and TP53 polymorphisms have been described to affect the risk for cancer, onset age and overall survival in solid tumors and leukemias. This was the first study to report these SNPs in MDS and leads to believe that these polymorphisms are not associated with risk for the disease and with clinical data. Keywords: MDM2, p53, myelodysplasia, polymorphisms Disclosures No relevant conflicts of interest to declare.

Outcome Of Patients (pts) With Low and Intermediate-1 Risk Myelodysplastic Syndrome (MDS) After Hypomethylating Agent (HMA) Failure

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 388-388 ◽  
Author(s):  
Elias Jabbour ◽  
Guillermo Garcia-Manero ◽  
Lianchun Xiao ◽  
Al Ali Najla ◽  
Asmita Mishra ◽  
...  
Keyword(s):  
High Risk ◽  
Scoring System ◽  
Lower Risk ◽  
Research Funding ◽  
Complete Response ◽  
Low Risk ◽  
International Prognostic Scoring System ◽  
Cancer Center ◽  
Primary Resistance ◽  
High Risk Disease

Abstract Background HMA are standard of care in pts with high-risk MDS and commonly used in pts with lower risk. Pts with high-risk disease post HMA failure have a poor prognosis with a median survival of 4-6 months. The prognosis of pts with low and intermediate-1 risk MDS by the International Prognostic Scoring System (IPSS) after HMA failure is not known. Aims To assess outcome of pts with low and intermediate-1 risk disease post HMA failure that might benefit from specific strategies or investigational agents. Methods Data from 423 pts with low (n= 141, 33%) and intermediate-1 risk disease (n=282, 67%) by IPSS score treated with HMA at MD Anderson Cancer Center (MDACC; n=144) and Moffitt Cancer Center (MCC; n=279) between 2000 and 2011 were analyzed. Results Median age was 69 years. 294 (69%) pts had a diploid cytogenetic analysis. 63 (15%) pts had therapy-related MDS. 282 (67%) pts received azacitidine, 87 (21%) decitabine, and 54 (12%) both. Median number of cycles of HMA administered was 6 (range, 1-64) for a median duration of therapy of 7 months (range, 1- 74). Best response to HMA was complete response (CR) in 39 (9%) pts, partial response (PR) in 13 (3%), a bone marrow CR in 6 (1%), and hematologic improvement (HI) in 90 (21%) pts. Pts had discontinued HMA because of primary resistance in 198 (47%) pts, loss of response in 141 pts (33%), intolerance in 13 pts (3%) and other reasons in 71 pts (17%). At the time of HMA failure, 81 (19%) pts transformed into acute myeloid leukemia (AML). Of the 302 remaining pts evaluable by IPSS, 67 (22%) pts were of low-risk, 158 (53%) of intermediate-1 risk, 48 (16%) of intermediate-2 risk, and 29 (9%) of high-risk disease. By the revised IPSS (R-IPSS), the percentage of pts with low, very low, intermediate, high, and very high risk disease were 11%, 29%, 30%, 20%, and 10%, respectively. By the MDACC global prognostic scoring system (MDGPSS) 18%, 35%, 29%, and 18%, of the pts were of low-risk, intermediate-1, intermediate-2, and high-risk disease, respectively. After a median follow-up of 16 months from HMA failure, 117 (28%) pts remained alive. The median overall survival (OS) was 15 months (95% CI: 12-18) with estimated 1- and 3-year OS rates of 55% and 27%, respectively. Both, the R-IPSS and the MDGPSS were predictive of survival post HMA failure (Table 1 ). Conclusion In the largest cohort of lower risk MDS pts treated with HMA, the outcome after HMA failure is poor. Treatment of those patients remains an unmet medical need. OS is a reasonable primary endpoint for clinical studies targeting this population. Disclosures: Lancet: Celgene: Research Funding. Sekeres:Celgene: Consultancy; Amgen: Consultancy. List:Celgene: Research Funding. Komrokji:Celgene: Research Funding, Speakers Bureau.

Update on Supportive Care and New Therapies: Immunomodulatory Drugs, Growth Factors and Epigenetic-Acting Agents

Hematology ◽  
2005 ◽  
Vol 2005 (1) ◽  
pp. 161-166 ◽  
Author(s):  
Eva Hellström-Lindberg
Keyword(s):  
Growth Factors ◽  
High Risk ◽  
Survival Rates ◽  
Low Risk ◽  
New Drugs ◽  
Refractory Anemia ◽  
Negative Consequences ◽  
Phase Ii Trials ◽  
Leukemic Transformation ◽  
Transfusion Therapy

Abstract Patients with “low-risk” myelodysplastic syndrome (MDS) are mostly treated with approaches aiming to reduce the negative consequences of ineffective hematopoiesis. Transfusion therapy should be tailored to allow adequate oxygenation and optimal quality of life, and may lead to the need for iron chelation therapy. Growth factors (erythropoietin and granulocyte colony-stimulating factor [G-CSF]) may induce long-lasting improvement of hemoglobin levels and does not increase the risk for leukemic transformation. Growth factors should be offered to defined subgroups of patients. Immunosuppression with anti-thymoglobulin or cyclosporine A may be an alternative for younger patients with refractory anemia (RA). The new immunomodulating compound lenalidomide, CC5013, is very active in the 5q– syndrome and is under evaluation for other low-risk MDS subtypes. “High-risk” MDS is associated with poor survival and high risk for leukemic transformation. The DNA hypomethylating compounds azacytidine and decitabine may offer improved long-term outcomes in this group of patients, although there has so far been no effect on survival rates. The efficacy of farnesyl transferase inhibitors has been evaluated in a series of phase II trials. The overall response rate was low, but the majority of responses were CRs. Finally, a number of new drugs directed to various biological and genetic targets are entering clinical trials.

Early Mortality in Acute Promyelocytic Leukemia May Be Higher Than Previously Reported.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1015-1015 ◽  
Author(s):  
Ash A Alizadeh ◽  
James S. McClellan ◽  
Jason R. Gotlib ◽  
Steven Coutre ◽  
Ravindra Majeti ◽  
...  
Keyword(s):  
Overall Survival ◽  
Clinical Trials ◽  
High Risk ◽  
Early Death ◽  
Promyelocytic Leukemia ◽  
Early Mortality ◽  
Low Risk ◽  
Intermediate Risk ◽  
Risk Patients

Abstract Abstract 1015 Poster Board I-37 Background: Early mortality, mostly from hemorrhagic complications, occurs in less than 10% of patients currently treated in clinical trials for acute promyelocytic leukemia (APL). However, data about the proportion of patients developing such complications prior to clinical trial enrollment are scarce in the literature (Sanz M, et al Blood 2009). Approximately 5% of newly diagnosed patients with APL have been reported not to be eligible for participation in clinical trials due to very poor clinical condition, and their outcome has never been reported. However, enrollment on clinical trials may be difficult in specific clinical situations, such as after hours/weekend admissions and/or emergent requirement for therapy. This study reports the incidence, time of occurrence and clinical features of APL patients with a focus on early mortality. Methods: 150 consecutive APL patients treated at Stanford University between 8/1986 and 7/2009 were identified. Thirteen patients were excluded for lack of appropriate clinical information. Clinical features of patients with APL were analyzed for factors that might be relate to prognosis, including age, gender, white blood cell count, platelet count, fibrinogen, PTT, and INR. Continuous variables were compared with the t-test and categorical variables by Fisher's exact test or X-square statistic. The Kaplan–Meier method was applied to assess overall survival time. Results: Of the 137 patients included in this analysis, the median age at diagnosis was 45 (1-93) years and 78 (57%) were females. Using the PETHEMA criteria, there were 37, 46 and 20 patients with high-, intermediate- and low-risk disease (34 patients could not be classified based on partial/missing data). With a median follow-up time of 748 (0-6,235) days for the entire cohort, 52 (38%) have died. 19 (14%) and 11 (8%) of these patients died within 7 and 3 days of presentation, respectively. Patients with high-risk features had a 13% and 24% chance of dying with 3 and 7 days of presentation, respectively, with significantly inferior outcomes (p=0.045) when compared to those with intermediate-risk patients (6% and 13%) and low-risk disease (5% and 5%). Patients with unknown risk category faired similarly to low-risk patients. The most common cause of early mortality in these 19 patients was intracranial hemorrhage (n=11). Patients with early death (ED) (either <=3 or <=7 days) tended to be older than APL patients with non-early deaths (>7d), or APL patients alive as of their last follow-up (median age 54 years vs. 50 years vs. 39 years), and were more likely to have higher risk disease, though coagulopathy appeared not significantly different amongst the groups. Median fibrinogen, PTT and INR for each individual group are presented on Table 1. The 3-year overall survival (% +/- SE) of the low, intermediate, and high risk patients was 90+/-7, 74+/-7, and 64+/-8, respectively, though early mortality (death within 7 days) was a major determinant of this stratification (p=0.045). Conclusions: Risk of early death in APL patients appears to be higher than previously reported in clinical trials, where trial registration may exclude patients requiring urgent therapeutic interventions. In this cohort, 25% and 13% patients with high- and intermediate-risk APL died within 7 days of presentation, respectively. Risk group stratification was very predictive of risk of early death. Disclosures: No relevant conflicts of interest to declare.

Association of CD33 Expression Level with Disease Risk-Group Classification and Induction Response In Pediatric AML: A Report From the Children's Oncology Group

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2732-2732
Author(s):  
Jessica A. Pollard ◽  
Todd A. Alonzo ◽  
Robert B. Gerbing ◽  
Phoenix A. Ho ◽  
Rhonda Ries ◽  
...  
Keyword(s):  
High Risk ◽  
Disease Risk ◽  
Risk Group ◽  
Group Classification ◽  
Low Risk ◽  
Intermediate Risk ◽  
Oncology Group ◽  
High Risk Disease ◽  
Pediatric Aml ◽  
Cebpa Mutations

Abstract Abstract 2732 Our previous analysis of diagnostic AML bone marrow (BM) samples from a subset of patients enrolled on Children's Oncology Group (COG) AAML03P1, a pilot study in which conventional chemotherapy was used in combination with the CD33 targeted therapeutic gemtuzumab ozogamicin (GO), demonstrated that CD33 expression is highly variable in pediatric AML and that low or absent CD33 expression was not associated with inferior clinical response. Moreover, patients with the highest CD33 expression did not have superior outcomes. Low CD33 expression was associated with low risk disease [core binding factor (CBF) AML e.g. t(8;21), inv(16) or t(16;16), CEBPA mutated AML, NPM1 mutated AML] whereas the highest CD33 expression levels were seen in patients with high-risk disease [FLT3/ITD+ disease with allelic ratio >0.4, high risk cytogenetics e.g. -7, -5, -5q]. These findings refute previous adult AML data in which CD33 expression is directly correlated with response to single agent GO and suggest, within AAML03P1, that clinical response is linked to underlying disease biology. In this larger analysis, we prospectively evaluated CD33 expression levels of AML blasts isolated from 676 pediatric diagnostic BM samples (238/340 and 438/968 patients enrolled on COG AAML03P1 and COG AAML0531 respectively) to determine whether this association persists in a larger cohort. CD33 expression, as defined by mean fluorescent intensity (MFI) of the blast population, varied over 2-log fold, and a median MFI of 128 was observed (range 3–1550.07). The study population was divided into quartiles (Q) based on CD33 expression (n= 169 patients per quartile). Median MFI was 37.49 (range 3–62) for Q1, 90 (range 62.21–128) for Q2, 171 (range 128–245) for Q3 and 349 (range 245.52–1550.07) for Q4. Samples were also screened for disease-relevant molecular mutations: 89/650 (14%) were FLT3/ITD positive; 69/587 (12%) were positive for NPM1 mutations; and 35/585 (6%) positive for CEBPA mutations. FLT3/ITD prevalence significantly increased with increasing CD33 quartile (Q1 7%, Q2 10%, Q3 17%, Q4 20%; p<0.001), whereas no definitive trend in prevalence was observed for NPM1 (Q1 7%, Q2 14%, Q3 15%, Q4 12%; p=0.158) or CEBPA mutations (Q1 6%, Q2 8%, Q3 6%, Q4 4%; p=0.307). Cytogenetic data was available for 613 (91%) samples; 177 (29%) CBF AML samples were identified and their prevalence declined with increasing quartile (Q1 51%, Q2 40%, Q3 20%, Q4 6%; p<0.001). There was no apparent association between CD33 expression and high-risk cytogenetics; however, analysis was limited by the small number of patients (9/613, 1.4%) with such mutations. For risk-group classification, complete cytogenetic and molecular data were available for 535 (79%) samples: 204/535 (38%) were classified as low-risk and 64/535 (12%) were defined as high-risk. There was an inverse association between CD33 expression and prevalence of low-risk AML (Q1 59%, Q2 50%, Q3 27%, Q4 17%; p<0.001). In contrast, the prevalence of high-risk disease increased with each quartile (Q1 5%, Q2 8%, Q3 17%, Q4 18%; p<0.001). We observed a higher median CD33 MFI with high-risk disease (median MFI 195.315; range 12–720) than with low-risk (median MFI 80.5; range 5–1550.07) or intermediate-risk (i.e., neither low- nor high-risk) disease (median MFI 163.06; range 7–1351) (p<0.001). Response from end of induction I (CR) was also determined for our patient cohort. Rates of CR were similar across CD33-expression quartiles (Q1 78%, Q2 75%, Q3 75%, Q4 72%; p=0.581). Moreover, CR rates for each risk group did not vary across quartiles (low-risk: Q1 84%, Q2 85%, Q3 88%, Q4 82%; p=0.917; intermediate-risk: Q1 77%, Q2 65%, Q3 72%, Q4 71%; p=0.594; high-risk: Q1 57%, Q2 67%, Q3 60%, Q4 72%; p=0.801). This large scale analysis supports our earlier finding that CD33 expression in pediatric AML is heterogeneous and associated with conventional risk-group criteria. As outcome data matures from COG AAML0531, the phase III counterpart of AAML03P1 in which patients are randomized to GO treatment, we will determine whether the addition of GO improves survival of patients with low versus high CD33 expression and whether this finding translates into enhanced outcomes for associated disease-risk groups. Disclosures: Franklin: Amgen : Employment, Equity Ownership.

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