Prognostic Factors For Overall Survival In Elderly Patients With Relapsed Acute Myeloid Leukemia – Retrospective Study On Behalf Of The East German Study Group For Hematology and Oncology (OSHO)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1409-1409
Author(s):  
Thomas Heinicke ◽  
Rainer Krahl ◽  
Christian Jakob ◽  
Christoph Kahl ◽  
Hans-Heinrich Wolf ◽  
...  
Keyword(s):  
Overall Survival ◽  
Prognostic Factors ◽  
Myeloid Leukemia ◽  
Univariate Analysis ◽  
Initial Diagnosis ◽  
Prognostic Impact ◽  
Mutational Status ◽  
First Relapse ◽  
Relapsed Acute Myeloid Leukemia ◽  
Median Interval

Abstract Purpose In patients with relapsed acute myeloid leukemia (AML) > 60 years of age we analyzed age at relapse, interval from first complete remission (CR1) to relapse, cytogenetic risk at initial diagnosis, prior allogeneic stem cell transplantation (alloSCT) and FLT3/NPM1 mutational status as possible prognostic factors for overall survival (OS). Introduction After achieving CR1 more than 50% of elderly AML patients eventually relapse. Prognostic factors for OS are poorly defined in this patient population. For younger patients with relapsed AML a risk score has been described including age at relapse, interval from CR1 to relapse, cytogenetic risk at initial diagnosis and prior stem cell transplantation (SCT) as prognostic factors. We sought to investigate whether these are also prognostic factors in elderly patients with relapsed AML. In addition, we assessed the prognostic impact of FLT3- and NPM1 mutational status (wild-type (wt) or mutated (mut)) at diagnosis. Patients and methods In the ongoing multicenter OSHO trial #69 for AML patients > 60 years we evaluated data of all relapsed patients. Overall survival was calculated from the day of first relapse until the day of death using the Kaplan Meier method. Univariate analysis was performed to test for the influence of age at relapse, interval from CR1 to relapse, cytogenetic risk at initial diagnosis, prior alloSCT and FLT3/NPM1 mutational status. Subsequently, independent prognostic factors were defined in a multivariate analysis with age at relapse, time from CR1 to relapse, cytogenetic risk at initial diagnosis and prior alloSCT as covariates. Results From April 2005 until April 2013 904 patients were registered. 733 of these received intensive induction chemotherapy which resulted in CR1 in 447 (61%) pts. In this patient group 260 relapses were observed after a median interval, calculated from the day of CR1, for living patients of 2.7 years (range 0.1 to 7.5). Median age at relapse was 69 years (range 60 – 85) with 129 (49.6%) pts. being 60 to 68 years old, 102 (39.2%) pts. being 69 to 74 years old and 29 (11.1%) pts. being 75 to 85 years old. Median interval from CR1 to relapse was 0.58 years (0.07 – 6.28). 114 (43.8%) relapses occurred up to 6 months after CR1, 119 (45.8%) between 7 and 18 months after CR1 and 27 (10.4%) later than 18 months after CR1. Only five (1.9%) relapsed pts. showed good risk cytogenetics at diagnosis, whereas it was of intermediate risk in 159 (61.1%) pts., of poor risk in 68 (26.2%) pts. and unknown in 28 (10.8%) pts. Forty-one (15.8%) pts. had received prior alloSCT in CR1. Information on FLT3- and NPM1 mutational status at diagnosis was available in 194 (74.6%) pts. 110 (42.3%) pts. had FLT3/NPM1 wt/wt, 48 (18.5%) pts. had FLT3/NPM1 wt/mut, 23 (8.8%) pts. had FLT3/NPM1 mut/wt and 13 (5.0%) pts. had FLT3/NPM1 mut/mut. OS rate at 2 years of all relapsed pts. was 13 ± 2%. For patients younger than 69 years and for those 69 years of age or older OS rate at 2 years was 17 ± 4% and 9 ± 3%, respectively (p=0.03). The interval between CR1 and first relapse also affected 2 year-OS with 7 ± 3%, 15 ± 4% and 36 ± 12% for pts. with relapse up to 6 months, 7 to 18 months and later than 18 months after CR1, respectively ( 18 months: p=0.009). OS rate at 2 years was also influenced by cytogenetic risk at initial diagnosis with 17 ± 3% for pts. having good or intermediate risk cytogenetics and 3 ± 2% for those with poor risk cytogenetics (p< 0.0005). Prior alloSCT had a negative influence on OS. Two-year OS rate was 10 ± 5 and 13 ± 3% (p= .015) for patients with prior alloSCT vs. those without prior alloSCT, respectively. FLT3/NPM1 mutational status at diagnosis had no impact on OS. In univariate analysis age at relapse (p<0.04), interval from CR1 to relapse (p< 0.0005), cytogenetic risk at initial diagnosis (p<0.02) and prior alloSCT (p<0.02) were shown to be prognostic factors for OS, whereas FLT3/NPM1 mutational status was not significant (p=0.82). In multivariate analysis the same factors remained significant but only interval from CR1 to relapse (p<0.0005) and prior alloSCT (p=0.003) were independent. Conclusion In AML patients >60 years in first relapse OS is poor. Longer interval from CR1 to relapse and no prior alloSCT are independent beneficial prognostic factors for OS. FLT3/NPM1 mutational status at diagnosis has no prognostic impact on OS. Disclosures: Wedding: Roche: Speakers Bureau; Amgen: Speakers Bureau; Chugai: Speakers Bureau; Janssen-Cilag: Speakers Bureau; Novartis: Speakers Bureau; Cephalon: Speakers Bureau; Prostarkan: Speakers Bureau; Pfizer: Speakers Bureau. Niederwieser:Novartis: Consultancy.

scholarly journals Neutrophil-lymphocyte ratio in metastatic breast cancer is not an independent predictor of survival, but depends on other variables

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Alejandra Ivars Rubio ◽  
Juan Carlos Yufera ◽  
Pilar de la Morena ◽  
Ana Fernández Sánchez ◽  
Esther Navarro Manzano ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
Prognostic Factors ◽  
Metastatic Breast Cancer ◽  
Performance Status ◽  
Univariate Analysis ◽  
Metastatic Breast ◽  
Prognostic Impact ◽  
Neutrophil Lymphocyte Ratio ◽  
Lymphocyte Ratio

AbstractThe prognostic impact of neutrophil-lymphocyte ratio (NLR) in metastatic breast cancer (MBC) has been previously evaluated in early and metastatic mixed breast cancer cohorts or without considering other relevant prognostic factors. Our aim was to determine whether NLR prognostic and predictive value in MBC was dependent on other clinical variables. We studied a consecutive retrospective cohort of patients with MBC from a single centre, with any type of first line systemic treatment. The association of NLR at diagnosis of metastasis with progression free survival (PFS) and overall survival (OS) was evaluated using Cox univariate and multivariate proportional hazard models. In the full cohort, that included 263 MBC patients, a higher than the median (>2.32) NLR was significantly associated with OS in the univariate analysis (HR 1.36, 95% CI 1.00–1.83), but the association was non-significant (HR 1.12, 95% CI 0.80–1.56) when other clinical covariates (performance status, stage at diagnosis, CNS involvement, visceral disease and visceral crisis) were included in the multivariate analysis. No significant association was observed for PFS. In conclusion, MBC patients with higher baseline NLR had worse overall survival, but the prognostic impact of NLR is likely derived from its association with other relevant clinical prognostic factors.

scholarly journals Prognostic Impact of the Interaction between DNMT3A mutation and Internal Tandem Duplication of the FLT3 Gene (FLT3-ITD) in Patients with De Novo Mutated NPM1 (NPM1mut) acute Myeloid Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1492-1492
Author(s):  
Guadalupe Oñate ◽  
Ana Garrido ◽  
Jordi Esteve ◽  
Rosa Coll ◽  
Montserrat Arnan Sangerman ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Prognostic Impact ◽  
Intermediate Risk ◽  
Mutational Status ◽  
De Novo Aml ◽  
Acute Myeloid

Abstract Introduction The association of NPM1mut and FLT3-ITD in de novo acute myeloid leukemia (AML) with intermediate-risk cytogenetics has different prognostic impact depending on the FLT3 allelic burden. Previous studies published by our cooperative group showed that patients with de novo AML of intermediate-risk cytogenetics with NPM1mut and FLT3-ITD low ratio (<0.5, FLT3low) at diagnosis presented an overall survival and relapse rate similar to those with NPM1mut and FLT3wt. Therefore, in the CETLAM-2012 protocol, patients with FLT3low NPM1mut AML are not considered for allogenic hematopoietic stem cell transplant (allo-HSCT) in first complete remission (CR1). Recent studies suggest that the co-occurrence of DNMT3A mutation in FLT3-ITD NPM1mut AML patients confers a worse prognosis regardless of FLT3-ITD ratio. We analysed our data to determine whether these findings were confirmed in our cohort, specifically in the low FLT3-ITD ratio patients, since this could have therapeutic implications. Methods and patients A total of 163 patients with de novo AML, intermediate-risk cytogenetics and NPM1mut were analysed (median age 53 years (18-72); male:female 72:91 (0.79)). Eighty patients (49%) harboured an FLT3-ITD, with a high allelic ratio in 42 of 76 patients with available ITD/wt ratio (55%). They were included in the AML-2003 (n=49) and AML-2012 (n=114) CETLAM protocols. Proportion of patients undergoing alloHSCT in CR1 is detailed in table 1. Bone marrow samples from diagnosis were studied for DNMT3A mutations as previously described. The definition of complete remission (CR), overall survival (OS), leukemia-free survival (LFS) and risk of relapse (RR) followed recommended ELN criteria. The Kaplan-Meier method was used to estimate the distribution of LFS and OS, for RR cumulative incidence was used. Results Out of the 163 patients with AML of intermediate risk cytogenetics and NPM1mut, 78 presented DNMT3A mutations (48%). Of these, 62 (79%) presented mutations in codon R882 or corresponded to DNA insertions/deletions while 16 (21%) harboured missense mutations. Presence of DNMT3A mutation did not associate with FLT3-ITD (ITD/85 DNMT3Awt vs ITD/78 DNMT3Amut, p=0.394). In the entire cohort, 5-year OS, LFS and RR were 58±4.5%, 59±4.6% and 27±13.9%. FLT3-ITD ratio confirmed its prognostic impact when analysing FLT3wt (n=83) vs FLT3low (n=34) vs FLT3high (n=42) patients (5-year OS of 68±6% vs 62±8.7% vs 37±8.6%; p=0.002; and 5-year RR of 18±9.4% vs 27±16.1% vs 41±23.2%; p=0.023). On the contrary, DNMT3Amut did not exert any effect on overall outcome (5-yr OS DNMT3Awt vs DNMT3Amut 61±6.2% vs 55±6.2%; p=0.234) When DNTM3A mutational status was considered, the impact of FLT3-ITD on outcome was mitigated in wild-type DNMT3A population. Thus, we found that DNMT3Awt patients presented no statistical differences in OS according to FLT3 mutational status or ratio: FLT3wt (n=46) vs FLT3-ITD (n=39) was 67±8.5% vs 57±8.2%; p=0.122, whereas FLT3wt (n=46) vs FLT3low (n=18) vs. FLT3high (n=19) was 67±8.5% vs. 66±11.5% vs 46±11.8%; p=0.088 (image 1A).This was also seen in relation to LFS and RR according to FLT3 ratio: 5-yr LFS of FLT3wt vs FLT3low vs FLT3high was 72±7.9% vs 61±12.6% vs 51±13.4%; p=0.244 and 5-year RR of the same groups: 19±8.8% vs 26±12.5% vs 27±21.9%; p=0.724 (image 2A). In the DNMT3Amut group, patients with FLT3-ITD (n=41) presented shorter OS than those with FLT3wt (n=37) with an OS of 37±10.7% vs 69±7.8%; p=0.028. When FLT3 ratio was considered, FLT3wt (n=37) vs FLT3low (n=16) vs FLT3high (n=23) showed an OS of 69±7.8% vs. 58±13.2% vs 27±13.1%; p=0.038 (image 1B). Similar results were seen in LFS according to FLT3 ratio (FLT3wt (n=29) vs FLT3low (n=16) vs FLT3high (n=20) 71±8.6% vs 53±12.9% vs 18±13.8%; p=0.012). Finally, we observed significant differences in the 5-year RR when considering DNMT3Amut patients in relation to FLT3 ratio (FLT3wt vs FLT3low vs FLT3high 18±10.6% vs 27±20% vs 54±28.8%; p=0.021)(image 2B). Conclusions In this study, patients with NPM1mut and FLT3-ITDlow presented a similar outcome to patients with NPM1mut and FLT3wt regardless of DNMT3A mutational status. These results support the modification of alloHCST policy in CR1 in CETLAM-2012, which do not consider alloHSCT for patients with FLT3low. On the other hand, concurrence of DNMT3A mutation may have an added negative effect in patients with NPM1mut and FLT3-ITDhigh, which should be further confirmed in larger studies. Disclosures No relevant conflicts of interest to declare.

Genomic Aberrations Dramatically Improve The Strong Prognostic Impact Of IGHV Mutational Status In Chronic Lymphocytic Leukemia (CLL)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1370-1370
Author(s):  
Giovanni Del Poeta ◽  
Dario Ragusa ◽  
Francesco Buccisano ◽  
Michele Dal Bo ◽  
Luca Maurillo ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Sanger Sequencing ◽  
Conflicts Of Interest ◽  
Direct Sequencing ◽  
Univariate Analysis ◽  
Intermediate Stage ◽  
Lymphocytic Leukemia ◽  
Prognostic Impact ◽  
Mutational Status ◽  
Genomic Aberrations

Abstract CLL is a heterogeneous disease with patients (pts) experiencing rapid disease progression and others living for years without requiring treatment. Recently, next generation sequencing has revealed new molecular alterations, targeting the NOTCH1 and BIRC3 genes which occur in about 10% CLL at diagnosis and correlate with poor outcome. Given the possibility of targeting NOTCH1 and BIRC3 with drugs currently under development, the primary endpoints of our research were: 1) to determine overall survival (OS) upon IGHV, NOTCH1, TP53 and BIRC3 in univariate analysis; 2) to correlate these genomic aberrations with other biological or clinical prognostic factors, and finally 3) to confirm NOTCH1, BIRC3 and TP53 as independent prognostic factors. We investigated 475 pts with a median age of 65 years (range 33-89), whose 160 had low Rai stage, 301 intermediate stage and 14 high stage. NOTCH1 mutations (mut) were studied by ARMS PCR for c.7544-7545delCT and by Sanger sequencing of NOTCH1 exon 34. Mutations of TP53 were analysed by DNA direct sequencing, while BIRC3 disruption (disr) was studied by Sanger sequencing for mutations and by interphase FISH for deletions. All these alterations were studied at diagnosis or before any chemotherapeutic approach. NOTCH1mut and TP53mut pts were 52 (10.9%) and 36/475 (7.6%), respectively. Thirty four patients were BIRC3mut (7.2%) and 26 BIRC3 deleted (5.5%) for a total of 46 cases (9.7%) BIRC3disr. NOTCH1, TP53 and BIRC3 alterations were mutually exclusive. There were significant correlations between NOTCH1 (P<0.00001), TP53 (P=0.004), BIRC3 status (P=0.00004) and IGHV mutations. Concerning FISH cytogenetics (460 patients), a significant correlation (P<0.0001) was found between NOTCH1mut and trisomy 12 (20/62; 32%). TP53mut were strictly associated with del17p (15/25; 60%; P<0.0001), while BIRC3disr was found mainly within 11q22-q23 deletions subset (22/46;49%; P<0.0001). With regard to clinical outcome, 30 (83%) of 36 TP53mut pts (P=0.00009), 47 (90%) of 52 NOTCH1mut (P<0.00001) and 40 (87%) of 46 BIRC3disr pts had received chemotherapy at the time of analysis. Twenty nine NOTCH1mut (56%), 15 TP53mut (42%) and 18 BIRC3disr (39%) pts underwent at least two lines of treatment (P<0.0001). Noteworthy, shorter OS was observed in IGHV unmutated (UM) patients (12% vs 80% at 18 years, P<0.00001), in NOTCH1mut pts (12% vs 71% at 16 years, P<0.00001), in TP53mut pts (9% vs 76% at 14 years, P<0.00001) and in BIRC3disr pts (29% vs 65% at 16 years, P=0.00001). To further explore the prognostic impact of NOTCH1mut, TP53mut and BIRC3disr, we investigated them within the UM (153 pts) IGHV subset, notoriously at worst prognosis. As a matter of fact, NOTCH1mut (16% vs 45% at 14 years, P=0.012), TP53mut (0% vs 43% at 13 years, P=0.002) and BIRC3disr (0% vs 57% at 11 years, P=0.011) pts showed significant shorter OS [Figure]. Within the mutated IGHV subgroup we obtained similar results. In multivariate analysis of OS, TP53mut (HR 5.2, P<0.00001), age >60 years (HR 3.8, P=0.00002), IGHV UM status (HR 0.30, P=0.0001), intermediate/high Rai stages (HR 2.8, P=0.0002), NOTCH1mut (HR 2.6, P=0.001), and BIRC3disr (HR 2.5, P=0.005) were confirmed to be independent adverse prognostic factors. Noteworthy, here, we demonstrated that genomic aberrations are able to improve the historical prognostic ability of the IgHV mutational status. In conclusion, genomic aberrations, particularly TP53mut, NOTCH1mut and BIRC3disr should be considered as novel important prognostic parameters in CLL and therefore they have to be necessarily considered in updated scoring prognostic systems. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Frequency and prognostic impact of mutations in SRSF2, U2AF1, and ZRSR2 in patients with myelodysplastic syndromes

Blood ◽  
2012 ◽  
Vol 119 (15) ◽  
pp. 3578-3584 ◽  
Author(s):  
Felicitas Thol ◽  
Sofia Kade ◽  
Carola Schlarmann ◽  
Patrick Löffeld ◽  
Michael Morgan ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Confidence Interval ◽  
Myelodysplastic Syndromes ◽  
Myeloid Leukemia ◽  
Univariate Analysis ◽  
Hazard Ratio ◽  
Prognostic Impact ◽  
Wild Type ◽  
Acute Myeloid

Abstract Mutations in genes of the splicing machinery have been described recently in myelodysplastic syndromes (MDS). In the present study, we examined a cohort of 193 MDS patients for mutations in SRSF2, U2AF1 (synonym U2AF35), ZRSR2, and, as described previously, SF3B1, in the context of other molecular markers, including mutations in ASXL1, RUNX1, NRAS, TP53, IDH1, IDH2, NPM1, and DNMT3A. Mutations in SRSF2, U2AF1, ZRSR2, and SF3B1 were found in 24 (12.4%), 14 (7.3%), 6 (3.1%), and 28 (14.5%) patients, respectively, corresponding to a total of 67 of 193 MDS patients (34.7%). SRSF2 mutations were associated with RUNX1 (P < .001) and IDH1 (P = .013) mutations, whereas U2AF1 mutations were associated with ASXL1 (P = .005) and DNMT3A (P = .004) mutations. In univariate analysis, mutated SRSF2 predicted shorter overall survival and more frequent acute myeloid leukemia progression compared with wild-type SRSF2, whereas mutated U2AF1, ZRSR2, and SF3B1 had no impact on patient outcome. In multivariate analysis, SRSF2 remained an independent poor risk marker for overall survival (hazard ratio = 2.3; 95% confidence interval, 1.28-4.13; P = .017) and acute myeloid leukemia progression (hazard ratio = 2.83; 95% confidence interval, 1.31-6.12; P = .008). These results show a negative prognostic impact of SRSF2 mutations in MDS. SRSF2 mutations may become useful for clinical risk stratification and treatment decisions in the future.

The association of pretreatment neutrophil to lymphocyte ratio with overall survival in patients with glioblastoma multiforme (GBM).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 2062-2062 ◽  
Author(s):  
Richard Martin Bambury ◽  
MinYuen Teo ◽  
Anny Yusuf ◽  
Susan Murray ◽  
Jodie E Battley ◽  
...  
Keyword(s):  
Overall Survival ◽  
Prognostic Factors ◽  
Complete Blood Count ◽  
Univariate Analysis ◽  
Significant Proportion ◽  
Cox Proportional Hazards ◽  
Neutrophil To Lymphocyte Ratio ◽  
Published Data ◽  
Prognostic Impact ◽  
Lymphocyte Ratio

2062 Background: GBM is the most common and aggressive primary brain tumor. The neutrophil to lymphocyte ratio (NLR) gives a measure of systemic inflammatory response and lymphopenia, both of which are poor prognostic factors in many malignancies. No published study has assessed the prognostic impact of NLR in GBM. Methods: Patients treated for GBM at our regional referral centre with assessable complete blood count at first presentation (prior to corticosteroid therapy or surgery) were identified. Medical notes were reviewed to extract demographic and treatment data. Survival curves were estimated via Kaplan-Meier method and compared via log-rank method. Multivariate analysis was performed via Cox proportional hazards regression modelling. Results: A total of 86 patients were identified, of which 65(76%) were male. Median age at diagnosis was 58 years (range: 18–76). At the time of analysis all patients still alive had ≥ 2 years follow-up. Median overall survival (OS) was 9.3 months (range: 1-82). 57% completed the standard adjuvant Stupp protocol and 43% discontinued early due to disease progression or treatment toxicity. Median OS was 11.2 months in patients with NLR<4 and 7.5 months in patients with NLR>4 (HR 0.59, p=.04). Other significant prognostic factors based on univariate analysis were consistent with published data (Table). After correcting for known prognostic factors NLR remained a significant predictor of survival (Table). Conclusions: Recent advances in immunotherapy have highlighted the importance of the immune system in the treatment and prognosis of cancer patients. Many GBM patients are on corticosteroids for a significant proportion of their disease course which may abrogate the effects of host immunity on outcome. Nevertheless, we have shown that NLR at diagnosis is an independent predictor of survival in GBM patients. Investigation of therapies which harness the immune response are warranted in this disease. [Table: see text]

scholarly journals Prognostic Factors for Overall Survival in Relapsed Acute Myeloid Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3666-3666
Author(s):  
Thomas Heinicke ◽  
Rainer Krahl ◽  
Christoph Kahl ◽  
Sebastian Scholl ◽  
Hans-Heinrich Wolf ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Prognostic Factors ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
De Novo ◽  
Initial Diagnosis ◽  
Time Interval ◽  
Mutational Status ◽  
Acute Myeloid

Abstract Purpose: To define prognostic factors for overall survival in adult patients (pts) with relapsed acute myeloid leukemia (AML). Introduction: Prognostic factors for overall survival after AML relapse are poorly defined. Here, we investigate patient and disease related factors in terms of their impact on prognosis after AML relapse in a cohort of 495 adult AML relapse patients treated in two prospective AML trials of the East German Society of Hematology and Oncology (OSHO). Patients and methods: We retrospectively evaluated all consecutive relapsed AML pts treated in two OSHO trials (OSHO #61 (pts < 60 years) and OSHO #69 (pts > 60 years)). Age, cytogenetic risk at initial diagnosis, FLT3/NPM1 mutational status, type of AML (de novo versus secondary to myelodysplastic syndrome or myeloproliferative neoplasia (MDS/MPN) versus therapy related), time interval from first complete remission (CR1) to relapse and allogeneic stem cell transplantation (alloSCT) as consolidation in CR1 were evaluated in univariate and multivariate analysis. Results: Between March 2002 and July 2014, a total of 862 and 968 patients (pts) were enrolled in the OSHO #61 and #69 trial, respectively. Five hundred and thirty two of 690 (77%) documented pts achieved first complete remission in the #61 and 501 of 813 (62%) pts in the #69 trial. Of these, 495 pts (252 male, 243 female) experienced AML relapse, 207(39%) pts in #61 and 288(57%) pts in #69. Median age at relapse was 63 years (range 18 to 86 years). Initial diagnoses were de novo AML, secondary AML to MDS/MPN and therapy related AML in 332(67%) pts, 129 (25.9%) pts and 30 (6%) pts, respectively. Time from CR1 to relapse was < = 6 months in 198 (40%) pts, 7 to 18 months in 226 (45.7%) pts and > 18 months in 71 (14.3%) pts. Initial karyotpe was available for 449 pts (90.7 %). It was favorable, intermediate and poor in 20 (4.5%) pts, 301(67%) pts and 128(28.5%) pts, respectively. Sixty two (13.9%) relapsed pts had a monosomal karyotype at initial diagnosis. NPM1/FLT3 mutational status at initial diagnosis was available in 354 (78.8%) pts, 378 (71%) pts in #61 and 370 (74%) pts in #69. One hundred and three (20.8%) had allogeneic stem cell transplantation as consolidation in CR1 (56 pts) in #61 and (47 pts) in #69. Relapse therapy was documented in 450 (91%) pts. Six pts that had immunosuppression withdrawn as the only therapy and nine pts that had received a tyrosine kinase inhibitor as monotherapy were excluded from further analysis due to small numbers. All other treatments were as follows: intensive chemotherapy (INT) n=225, alloSCT with or without prior INT n=50, donor lymphocyte infusions (DLi) with or without prior chemotherapy n=22, palliative mild cytoreductive chemotherapy (mCT) n=66, azacitidine (Aza) n=52, best supportive care (BSC) n=20. With these, CR was achieved in 78 (36%), 34 (68%), 8 (36%), 6 (9%), 1 (2%), 0 (0%), respectively. Median overall survival probability (OS) for all 495 relapsed patients was 6 months. It was 11.3 months, 5.7 months, 4.5 months and 4.6 months for patients aged 18 to 50 years, 51 to 60 years, 61 to 70 years and 71 to 86 years, respectively (p<0.0005). Initial cytogenetics also influenced OS, it was 10.4 months, 7.5 months and 3.8 months for patients with a favorable, intermediate and poor karyotype, respectively (p<0.0005). Having a monosomal karyotype at initial diagnosis was associated with a median OS of only 2.3 months (p<0.001). Initial FLT3/NPM1 mutational status had no impact on OS after relapse. OS was 4 months, 7.1 months and 16.9 months for pts with a time interval from CR1 to relapse of <= 6 months, 7 to 18 months and > 18 months, respectively (p<0.0005). In univariate analysis age (p<0.0005), initial cytogenetic risk (p<0.0005), type of AML (p=0.01), interval from CR1 to relapse (p<0.0005), alloSCT in CR1 (p=0.03) and type of relapse therapy (p<0.0005) had a significant impact on OS. In multivariate analysis favorable prognostic factors for OS were lower age (p<0.0005), favorable initial cytogenetics (p=0.01), longer interval from CR1 to relapse (p<0.0005) and not having undergone alloSCT in CR1. Conclusions: Our study shows that outcome of relapsed AML pts is poor. Younger age, favorable cytogenetics at initial diagnosis, a longer interval from CR1 to relapse and not having undergone alloSCT as consolidation in CR1 are positive prognostic factors, whereas type of AML and FLT3/NPM1 mutational status have no significant impact on survival after relapse. Disclosures Off Label Use: Azacitidine is licensed in Germany for the treatment of adult patients with the following conditions, who are not eligible for haematopoietic stem cell transplantation: • intermediate-2 and high-risk myelodysplastic syndromes (MDS) according to the International Prognostic Scoring System (IPSS), • chronic myelomonocytic leukaemia (CMML) with 10-29% marrow blasts without myeloproliferative disorder, • acute myeloid leukaemia (AML) with 20-30% blasts and multi-lineage dysplasia,according to World Health Organisation (WHO) classification.. Wolf:Bayer: Honoraria; Geo Pharma: Honoraria. Sayer:Takeda: Other; Medac: Other. Al-Ali:Novartis: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding.

ID1 Expression Correlates with CEBPA Mutational Status and Is Not An Independent Risk Factor in Cytogenetically Normal AML,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3554-3554
Author(s):  
Katharina Wagner ◽  
Frederik Damm ◽  
Michael A Morgan ◽  
Felicitas Thol ◽  
Haiyang Yun ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Prognostic Factors ◽  
Prognostic Factor ◽  
Conflicts Of Interest ◽  
Univariate Analysis ◽  
High Expression ◽  
Prognostic Impact ◽  
Mutational Status ◽  
Negative Prognostic Factor ◽  
Cebpa Mutations

Abstract Abstract 3554 Background: Acute myeloid leukemia with normal karyotype (CN-AML) is a heterogenous disease. During the last years, mutations in several genes (e.g. NPM1, FLT3, CEBPA, WT1, IDH1, IDH2) have been identified which are involved in the pathogenesis of AML and affect the prognosis of these patients. Moreover, deregulated expression of genes such as MN1, BAALC, ERG and WT1 was demonstrated to be predictive of outcome in CN-AML. Recently, high expression of the ID1 gene was described as a negative prognostic factor in AML (Tang et al. Blood 2009, 114:2993–3000). Aims: We have shown that C/EBPα, a transcription factor encoded by the CEBPA gene, binds to a regulatory element in the promoter region of the ID1 gene and regulates ID1 expression in leukemic cells (Wagner et al. Proc Natl Acad Sci USA 2006, 103:6338–6343). Therefore, we wanted to analyze the prognostic impact of ID1 expression in CN-AML in the context of other molecular markers, in particular CEBPA mutations. Methods: ID1 expression was quantified normalized to ABL by real time RT-PCR in 269 patients (age 16–60 years) with CN-AML treated with intensive double induction and consolidation therapy within the AMLSG 295 and 0199 trials (NCT00209833). The patients were also analyzed for mutations in the genes NPM1, FLT3, CEBPA, WT1, IDH1 and IDH2. Median follow up was 79 months. Results: Expression of ID1 varied over a 3-log range. High expression of ID1 (ID1high, defined as > median expression level) was significantly associated with the presence of a FLT3 -ITD or an IDH2 mutation and WT1 wildtype. Moreover, ID1 expression was closely associated with CEBPA mutational status. Altogether, 41 patients (15%) harboured a CEBPA mutation (24 monoallelic and 17 biallelic mutations). ID1 expression in the CEBPA wildtype patients was significantly higher than in patients with monoallelic CEBPA mutations and these patients had a significantly higher ID1 expression compared to patients with biallelic CEBPA mutations (p = 0.001). ID1high patients had a trend to a lower complete remission (CR) rate (74% vs. 84%; p = 0.07), but in multivariate analysis only blast clearance on day 15 after induction 1, age and WT1 SNP rs16754 were independent predictors for the achievement of CR. In univariate analysis, ID1high patients had an inferior overall survival (OS) compared to patients with low expression (median OS 29 vs. 78 months, 5 year OS 39% vs. 53%, p = 0.026). ID1high status was an independent negative prognostic factor in multivariate analysis when analyzed together with NPM1, FLT3 -ITD, WT1, IDH1, IDH2, extramedullary disease and platelet counts (HR 1.51; 95% CI 1.06–2.19). However, when also CEBPA mutational status was entered into the model, ID1 expression lost its prognostic impact and the only independent prognostic factors were age, platelets, CEBPA mutations, NPM1 /FLT3 -ITD risk group and WT1 SNP rs16754. Likewise, ID1high patients had a trend to an inferior relapse-free survival (RFS; HR 1.36, 95% CI 0.96–1.93, p = 0.086) in univariate analysis. However, in multivariate analysis including CEBPA mutational status, ID1 expression had no impact on RFS and the only prognostic factors for RFS were NPM1 and CEBPA mutations and WT1 SNP rs16754. In CEBPA wildtype patients, ID1 expression had no impact on CR-rate, OS or RFS in univariate or multivariate analysis. Conclusions: CEBPA mutations seem to deregulate ID1 expression in CN-AML. Therefore, ID1 expression is not an independent prognostic factor in CN-AML. Disclosures: No relevant conflicts of interest to declare.

scholarly journals NPM1+/FLT3- Patients with Acute Myeloid Leukemia (AML) Have Excellent Clinical Outcome Independent of Age When Treated with Cytotoxic Chemotherapy: Mayo Clinic Experience

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5331-5331
Author(s):  
Mehrdad Hefazi Torghabeh ◽  
Mustaqeem A Siddiqui ◽  
Mrinal M. Patnaik ◽  
Alexandra Wolanskyj ◽  
Darci Zblewski ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Elderly Patients ◽  
Myeloid Leukemia ◽  
Cytotoxic Chemotherapy ◽  
Adult Patients ◽  
Prognostic Impact ◽  
Mutational Status ◽  
Significant Difference ◽  
Acute Myeloid

Abstract Background: Molecular profiling has revolutionized the field of hematology, and in particular myeloid neoplasms. NPM1+/FLT3- mutational status has been shown to have a favorable prognostic impact in patients with acute myeloid leukemia (AML). However, little is known about its interaction with age. Methods: We retrospectively analyzed the overall survival (OS) in newly diagnosed AML patients, whose FLT3 and NPM1 data were available, and were treated with cytotoxic chemotherapy at our institution between 2003 and 2013. Patients 18 to 60 years of age were categorized as adult, and those above 60 years were classified as elderly. Each of the elderly or adult groups were further divided according to the presence or absence of combined NPM1+/FLT3- mutational status. Estimated probabilities of overall survival were calculated using the Kaplan-Meier method, with the log-rank test to compare groups. Demographics and continuous variables were compared using the Wilcoxon rank sum test. Appropriate IRB approval was obtained. Results: Out of 835 patients with AML, 86 patients with both known FLT3/NPM1 mutation status and receiving induction chemotherapy were found. NPM1+/FLT3- mutational status was present in 11 elderly (median age 68 yr, hemoglobin (Hb) 8.7 g/dL, white blood cells (WBC) 9.6 x109/L, platelets (PLT) 100 x109/L, peripheral blood blasts percentage (PB%) 31), and in 11 adult patients (median age 49 years, Hb 9.1 g/dL, WBC 14 x109/L, PLT 67 x109/L, and PB% 21). Twenty-eight elderly patients (median age 66 yr, Hb 9.4 g/dl, WBC 15.7 x109/L, PLT 66 x109/L, and PB% 33), and 36 adult patients (median age 49 years, Hb 9.1 g/dL, WBC 14 x109/L, PLT 67 x109/L, and PB% 21) were carrying genotypes other than NPM1+/FlT3-. There was no statistical significant difference in the median age, Hb, WBC, PLT, and PB% at the time of diagnosis. Out of 86 patients, 79 had intermediate, 6 had adverse, and 1 had favorable cytogenetic risk. All elderly and adult patients with NPM1+/FLT3- genotype had intermediate risk cytogenetics. When treated with cytotoxic chemotherapy, elderly patients with NPM1+/FLT3- genotype demonstrated a significantly better overall survival compared to elderly patients without this genotypes (p=0.015), and interestingly also to adult AML carrying other genotypes (p=0.028). Surprisingly, there was not an improved survival in adults with NPM1+/FLT3- genotype compared to adults carrying other genotypes (p=0.14), but this may have been related to the small numbers in each group. No significant difference in the overall survival was observed between elderly and adult patients who were carrying NPM1+/FLT3- mutational status (p=0.4). The estimated 5-year survival rates for elderly with and without NPM1+/FLT3- status were 71% vs. 14%, and for adults with and without this genotype were 49% vs. 19%, respectively. Conclusion: Age does not have an impact on the OS in AML patients with NPM1+/FLT3- mutational status, arguing strongly for intense chemotherapy in this group. Elderly AML patients with NPM1+/FLT3- genotype have a superior OS compared to both adult and elderly patients carrying other genotypes, when treated with cytotoxic chemotherapy. Further validation in large prospective studies is warranted. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

The Concomitant High Expression of the B-Cell Receptor Signaling Inhibitor Molecules CD150, CD305, and CD307b Predicts Longer Overall Survival in the Context of Low-Risk Chronic Lymphocytic Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1720-1720
Author(s):  
Antonella Zucchetto ◽  
Dania Benedetti ◽  
Chiara Caldana ◽  
Erika Tissino ◽  
Michele Dal Bo ◽  
...  
Keyword(s):  
Overall Survival ◽  
Prognostic Factors ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Low Risk ◽  
Prognostic Impact ◽  
Mutational Status ◽  
B Cell Receptor Signaling ◽  
Cell Receptor Signaling

Abstract Background. Risk assessment in chronic lymphocytic leukemia (CLL) is determined by the presence/absence of several negative prognostic factors, including the unmutated (UM) IGHV mutational status, TP53 deregulation by mutation and/or deletion of the 17p (17p-) chromosome, and high CD49d expression. Nevertheless, clinical heterogeneity can be observed also in the context of low-risk CLL, identified according to the absence of the aforementioned negative prognosticators. Thus, identifying novel markers that may predict an indolent clinical course in the context of low-risk CLL cases can be of key clinical relevance. The CD150/SLAMF1, CD305/LAIR1, and CD307b/FCRL2 molecules have been independently reported as molecules associated with a mutated IGHV status, and with longer time to first treatment in CLL. However, the prognostic relevance of the combined CD150/CD305/CD307b expression in predicting overall survival (OS) in the context of low-risk CLL remains to be explored. Aim. To assess the prognostic value of CD150, CD305, CD307b as OS predictors in the context of low-risk CLL, as defined according to the canonical prognostic factors. Methods. The study included 330 CLL cases all characterized for Rai stage (stages 0-I: 254 cases), CD49d expression (CD49d- CLL, <30% of positive cells by flow cytometry: 191), IGHV mutational status (mutated, M: 191), karyotype abnormalities according to the hierarchical stratification (normal/13q-/+12: 206 cases), all tested at diagnosis. Median follow-up of patients was 77 months with 67 deaths. Immunophenotypic analysis was performed in thawed samples using a combination of anti-CD5 FITC, -CD19PE-Cy7, -CD150PE, -CD305PerCPCy5.5, CD307bAPC mAbs, and DAPI to exclude dead cells. Both percent of positive cells and mean fluorescence intensity (MFI) data were recorded. Results. A significantly higher (p<0.0001) CD150, CD305 and CD307b expression in M versus UM CLL was documented, with mean % of expression/MFI of 65%/498MFI vs. 25%/160MFI (CD150), 60%/1208MFI vs. 33%/583MFI (CD305), 87%/495MFI vs. 76%/383MFI (CD307b). The best cut-off levels for OS, calculated using a ROC analysis, were: 50%/290MFI for CD150; 10%/230MFI for CD305; 80%/360MFI for CD307b. Given the overall concordance in the definition of positive cases by using MFI or % values, the latter was chosen for further analyses. Using the % cut-offs, 154 (46.7%), 234 (70.9%) and 212(64.2%) were classified positive for CD150, CD305 and CD307b respectively. The clinical impact of the three markers as OS predictors was confirmed in both univariate (hazard ratio/confidence interval (HR/CI)= 0.20/0.11-0.37; p<0.0001 for CD150; HR/CI= 0.40/0.25-0.65; p=0.0002 for CD305; HR/CI= 0.27/0.16-0.44; p<0.0001 for CD307b), and multivariate (HR/CI=0.34/0.17-0.66; p=0.0015 for CD150; HR/CI=0.47/0.29-0.76; p=0.0023 for CD305;HR/CI=0.42/0.24-0.73; p=0.0022 for CD307b) analyses. Therefore, we combined their expression in a 0 (all the three markers below the cut-off) to 3 (all the three markers above the cut-off) score, and dichotomized CLL cases according to the expression of 3/2 markers (n=205) versus 0/1 markers (n=125). The prognostic impact of this combined markers expression was tested in univariate analysis (HR/CI=0.24/0.14-0.40; p<0.0001 ) and in a multivariate model including: IGHV mutational status, CD49d expression, Rai stage (stage 0-I versus stages II-IV), karyotype abnormalities (normal/del13/+12 versus del11/del17). The combined markers expression retained its prognostic impact (HR/CI=0.47/0.26-0.87; p=0.0172), along with the UM IGHV (HR/CI=2.66/1.44-4.89; p=0.0018), CD49d+ expression (HR/CI=2.14/1.25-3.67; p=0.0058) del11/del17 (HR/CI=2.08/1.23-3.50; p=0.0063). Moreover, expression of ≥2 markers was associated with a better prognosis in the context of the M IGHV (p=0.0042), CD49d- (p=0.0002), Rai 0-I stage (p<0.0001) and normal/del13/+12 karyotype (p=0.0001) groups (see Figure). Conclusions: High expression of at least two of the CD150, CD305 and CD307b molecules predicts longer OS in CLL, also in the context of low-risk prognostic categories. A synergic effect of the CD150, CD305 and CD307b molecules, all inhibitors of the B-cell receptor signaling, may be taken into account to functionally explain this peculiar clinical behavior. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

Quantification of VEGF Isoforms and VEGFR Transcripts by qRT-PCR and Their Significance in Acute Myeloid Leukemia

2009 ◽  
Vol 24 (1) ◽  
pp. 22-31 ◽  
Author(s):  
Samia Mourah ◽  
Raphaël Porcher ◽  
Géraldine Lescaille ◽  
Philippe Rousselot ◽  
Marie-Pierre Podgorniak ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Univariate Analysis ◽  
Prognostic Impact ◽  
Mrna Levels ◽  
Event Free Survival ◽  
Free Survival ◽  
The Impact ◽  
Acute Myeloid

Vascular endothelial growth factor (VEGF) and its receptors are known to play an important role in normal and pathological hematopoiesis but the prognostic impact of VEGF isoform transcripts in acute myeloid leukemia (AML) has not been addressed. We conducted a single-institution prospective study to analyze the impact of these angiogenic factors and the expression of their receptors on the survival of adult patients newly diagnosed with AML. We investigated the levels of VEGF transcript isoforms VEGF121, -145, -165, -189 and -206 and their receptors, VEGFR-1 and VEGFR-2, using quantitative reverse transcriptase polymerase chain reaction assays in peripheral blood mononuclear cells (PBMCs) of 67 consecutive AML patients at diagnosis. VEGF total protein was measured for comparison with mRNA levels in PBMCs. The VEGF121 splice variant transcript in AML PBMCs was significantly higher than in the normal controls. VEGF transcripts were quantified in all samples while its protein was detected in 42/67 (63%) of AML samples. High levels of VEGF121, VEGF165 transcripts and VEGF protein in AML were significantly related to a worse prognosis when analyzing overall survival (p<0.0001, p=0.019 and p=0.012, respectively) or event-free survival (p<0.0001, p=0.010 and p=0.047) using univariate analysis. In multivariable analysis only VEGF121 expression remained an independent prognostic factor for either event-free survival or overall survival [aHR=8.83 (3.48–22.4), p<0.0001, and aHR=9.52 (3.41–26.6), p<0.0001]. No prognostic value was observed for the other isoforms and the two receptors. Our findings show that the level of VEGF121 mRNA in circulating cells from AML patients is a strong independent prognostic parameter, which could be useful in the management of unselected AML patients.

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