A Prognostic Score for Overall Survival (OS) with Azacitidine (AZA) In Higher Risk MDS Based on 282 Patients (pts), and Validated In 175 Pts From the AZA 001 Trial

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3996-3996
Author(s):  
Raphael Itzykson ◽  
Sylvain Thepot ◽  
Bruno Quesnel ◽  
Francois Dreyfus ◽  
Odile Beyne-Rauzy ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
High Risk ◽  
Risk Score ◽  
Research Funding ◽  
Missing Values ◽  
De Novo ◽  
Prognostic Score ◽  
Continuous Variable ◽  
Ecog Ps ◽  
Rbc Transfusion

Abstract Abstract 3996 Background: AZA significantly improves OS in higher-risk MDS (including RAEB-t/AML) compared to conventional treatments (AZA 001 trial, Lancet Onc, 2009), but prognostic factors of response and OS to AZA remain largely unknown. We designed a prognostic score for OS in a cohort of AZA treated higher-risk MDS in a patient-named compassionate program (French ATU), and validated it in patients from the AZA 001 trial. Methods: Between Sept 2004 and Jan 2009, prior to AZA approval in Europe, IPSS int-2/high risk MDS (including RAEB-t) not previously treated with intensive chemotherapy (IC), allo SCT, or a hypomethylating agent were included in a compassionate program (ATU), and received AZA (planned schedule 75 mg/m2/d ×7 d every 28 d for ≥4 cycles). Independent prognostic factors of OS were individualized in a Cox model. A prognostic score was then developed based on those factors. After validation of the score as a continuous variable, pts were grouped in three distinct risk categories. We subsequently tried to validate this score in the 175 higher risk MDS pts treated with AZA at the same schedule in AZA 001 trial (4 of the 179 pts randomized to AZA in that trial did not start AZA). Results: The ATU cohort included 282 pts with de novo (74%) or therapy related (t) (26%) higher-risk MDS (IPSS int-2 in 54% high in 43%, at least int-2 in 2%). ECOG PS ≥2, RBC transfusion dependence ≥4 units/8 weeks and circulating blasts were present in 21%, 46% and 46% of pts respectively (resp). Cytogenetic risk was good, int, and poor in 31%, 17% and 47% (unknown in 5%). 10% pts had previously been treated with LD araC for their MDS. Multivariate analysis of survival retained PS ≥2 (HR= 2.0 [95% CI: 1.4–2.9]), RBC transfusion dependence ≥4 units/8 weeks (HR=1.9 [1.4-2.6]), presence of circulating blasts (HR=2.0 [1.5-2.7]), and IPSS cytogenetic risk (intermediate: HR=1.4 [0.8-2.3], poor: HR=3.0 [2.0-4.3]) as independent prognostic factors (all p<10-4). We designed a simple prognostic score attributing 1 and 2 points for intermediate and poor risk cytogenetics, resp, and 1 point for each other adverse prognostic factor. As a continuous variable, an increasing score was associated to poorer OS (HR=1.9 [1.6-2.1], p<10-4). Patients were grouped as “low risk” (score=0), intermediate risk (score=1-3) and high risk (score=4-5). Due to missing values, a prognostic group could be attributed to 269 of the 282 pts: 30 (11%), 191 (71%), and 48 (18%) pts were considered low, intermediate and high risk resp. With a median follow-up of 26 months, median OS were not reached, 15.0 and 6.1 months in patients with low, intermediate, and high risk score respectively (p<10-4). The validation cohort included 175 pts of the AZA-001 trial with higher-risk MDS. Apart from the presence of 5 (3%) int-1 pts in AZA-001 cohort (their removal did not affect conclusions), IPSS (int-2 in 42% high in 46%, at least int-2 in 9% vs 54%, 43%, 2% resp., p=0.15) was comparable to the ATU cohort, as well as RBC transfusion dependence ≥4 units/8 weeks (46 vs 45%, p=0.8), presence of circulating blasts (51 vs 45%, p=0.4), whereas all AZA-001 pts were de novo (vs 74% in the ATU cohort), had not been pretreated (vs 10% pretreated by LD AraC in the ATU cohort), had better PS (7% PS ≥2 vs 21% in the ATU cohort, p<10-4) and better cytogenetics (47%, 21% and 27% 5%, good, int, poor, unknown cytogenetics vs 31%, 17%, 47%, 5% resp., p<10-4). The score was validated as a continuous variable on OS (HR=1.4 [1.2-1.7], p=0.0005). Due to missing values, a prognostic group could be attributed to 166 (95%) of pts of the AZA 001 cohort: 27 (16%), 123 (74%), and 16 (10%) pts were classified in the low, intermediate and high risk respectively. Median follow-up was 21 months. Median OS were not reached, 21.4 and 14.3 months respectively in patients with low, intermediate, and high risk score (p=0.004). Conclusion: Our compassionate cohort scoring system based on conventional prognostic factors (ECOG PS, RBC transfusion requirement, circulating blasts and karyotype) was prognostic for survival. Additionally, it was successfully validated in a more selected cohort of higher-risk MDS from a prospective multicenter trial. Prognostic factors of outcome with AZA based on more refined biological studies (including gene methylation status) will probably emerge. In particular, we found in a more recent patient cohort (Itzykson, abstract also submitted to ASH 2010), that TET2 mutations may predict better response to AZA in higher risk MDS. Disclosures: Beach: Celgene: Employment. Fenaux:Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen Cilag: Honoraria, Research Funding; ROCHE: Honoraria, Research Funding; AMGEN: Honoraria, Research Funding; GSK: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Cephalon: Honoraria, Research Funding.

Proposal of A Prognostic Score for Previously Untreated Patients with Chronic Lymphocytic Leukemia Based on An Overall Survival Analysis of Three German CLL Study Group Phase III Trials

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2831-2831
Author(s):  
Jasmin Bahlo ◽  
Natali Pflug ◽  
Thomas Elter ◽  
Kathrin Bauer ◽  
Barbara Eichhorst ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Risk Score ◽  
Research Funding ◽  
Prognostic Score ◽  
Phase Iii ◽  
Mutational Status ◽  
Phase Iii Trials ◽  
Binet Stage ◽  
Very High

Abstract Abstract 2831 Introduction Prognosis and need of treatment in CLL is currently determined by clinical staging systems of Binet and Rai. Recent research has focused on prognostic factors that may predict a poor prognosis independent of the clinical stage. Markers which have shown independent prognostic information are serum parameters and genetic factors (genomic aberrations, IgHV and p53 mutational status). To investigate the relevance of these different factors, we performed a pooled analysis using the data of three multicenter German CLL Study Group phase III trials (CLL1, CLL4 and CLL8). Based on this analysis we propose a prognostic score for previously untreated patients with early and advanced CLL. Material and Methods Patients were recruited between 1997 and 2006 into three phase III trials: 715 in CLL1 (“watch and wait” versus fludarabine (F)), 362 in CLL4 (F versus F and cyclophosphamide (FC)) and 817 patients in the CLL8 trial (FC versus FC and rituximab (FCR)). Serum parameters and genetic factors were centrally analyzed prior to treatment. The main end point of all statistical analyses was overall survival. First, univariate analyses were performed including variables of different groups such as baseline characteristics, stage of disease, laboratory results, molecular cytogenetics, mutational status and serum parameters. Next, multivariate Cox regressions were applied including all parameters that showed a significant association with overall survival in univariate analyses. To create a prognostic score we developed a weighted grading algorithm for independent factors based on ranges of hazard ratios. Finally, a prognostic score was defined as the sum of single ratings of adverse factors. According to this score, four different risk groups for overall survival could be identified. Results In total 1948 patients were eligible for the pooled analysis with a median age of 60 years (range, 30 to 81 years). After a median observation time of 63.4 months 485 deaths were reported. At study entry, 799 patients (42.4%) were at Binet stage A, 717 (38.0%) at Binet stage B and 370 (19.6%) at Binet stage C. Almost all considered variables were significantly associated with outcome and therefore included in the multivariate analysis. Based on the data of 1223 patients for whom all parameters were available, multivariate Cox regressions were performed and identified gender, age, ECOG score, del(17p), del(11q), IgHV mutational status, serum β2-microglobulin and serum thymidine kinase as independent factors for overall survival. Deletion 17p was the strongest adverse factor. Neither the clinical staging (Rai, Binet) nor the treatment modality were independent prognostic factors for overall survival. Similarly, the time interval between first diagnosis and study entry was not an independent prognostic factor. Due to the great differences between hazard ratios of independent factors, we developed a weighted grading system based on a simple algorithm to assign an individual grade to each adverse factor. By using this weighted grading, four different prognostic groups could be separated: low risk (score 0 – 2), intermediate risk (score 3 – 5), high risk (score 6 – 10) and very high risk (score 11 – 14) (figure 1). Overall survival rates were significantly different for these four groups with 95.2%, 86.9%, 67.7% and 18.7% survival after 5 years for the low, intermediate, high and very high risk group, respectively (p<0.0001). Moreover, within the group of patients showing a deletion 17p the score could distinguish patients of a high risk and a very high risk group (p<0.0001). Finally, the score could predict the individual risk for short overall survival independent of and within the different Binet or Rai stages (p<0.0001) (figure 2). Conclusion While Binet and Rai staging systems may remain important for the initial clinical assessment due to their simplicity, our prognostic score using a weighted combination of genetic and serum markers is superior to predict the overall survival of CLL patients. Disclosures: Pflug: Hoffmann-la Roche: Travel grant; Mundipharma: Travel grant. Eichhorst:Hoffmann La Roche: Honoraria, Research Funding, Travel Grants; Mundipharma: Research Funding, Travel Grants; Gilead: Consultancy. Bergmann:Celgene: Honoraria. Döhner:Hoffmann-la Roche: Research Funding. Stilgenbauer:Hoffmann La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Travel Grants. Fischer:Hoffmann La Roche: Travel Grants. Hallek:Hoffmann-la Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Externally Validated Predictive Clinical Model For Untreated Del(17p13.1) Chronic Lymphocytic Leukemia Patients

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4128-4128
Author(s):  
Deborah M Stephens ◽  
Amy Stark ◽  
William G. Wierda ◽  
Jeffrey A. Jones ◽  
Jennifer A. Woyach ◽  
...  
Keyword(s):  
High Risk ◽  
Risk Score ◽  
Predictive Power ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Cancer Center ◽  
Multivariable Model ◽  
Ecog Ps ◽  
The Impact

Abstract CLL patients (pts) with del(17p13.1) (17p-) karyotype are typically refractory to therapy. There are limited data on clinical outcomes of large groups of these pts treated at a single institution. We aimed to develop a risk score to classify pts with de novo 17p- CLL at high risk of early treatment or death. We retrospectively reviewed records of 114 CLL pts with 17p- and no prior therapy seen at OSU from 2002-2012. Treatment free survival (TFS) was calculated from date of 1st visit until date of 1st treatment or death, censoring pts alive and treatment-free at last follow-up. Overall survival (OS) was calculated from date of 1st visit until date of death or last follow-up. TFS/OS estimates were calculated using the Kaplan-Meier method. Proportional hazards models were fit using backwards selection to identify variables significantly associated with TFS & OS. A risk score (RS) was calculated based on the variables and regression coefficients of the model. A simplified risk score (SRS) to be used in clinical practice was based on the strength of associations with clinical outcome when all variables had been categorized. To externally validate the SRS, a dataset of 129 de novo 17p- pts was obtained from MD Anderson Cancer Center (MDA). Consistency in model coefficients used to derive the SRS and predictive power of the SRS using Harrell’s c-index (c) were compared between the sets. In the OSU set, median age was 62 yrs, 33% had Rai Stage 0, 61% had ECOG performance status (PS) 0 and 11% had ECOG PS >2. Around 35% and 10% of pts had white blood cell count (WBC) >50 x109/L and lactate dehydrogenase at least 2 x the upper limit of normal (LDH x2 ULN), respectively. Only 14% had concomitant 11q- and 36% had complex karyotype with >3 aberrations. None of these variables were significantly different between the OSU and MDA sets (p>0.15), nor were TFS and OS (p>0.10). Median TFS estimates were 16 mos (95%CI 6-27) and 6 mos (95%CI 3-12) for the OSU and MDA sets, respectively, while median OS estimates were 5.2 yrs (95%CI 3.4-7.8) and 6.4 yrs (95%CI 4.7-not reached). Using the OSU set, a multivariable model for TFS included ECOG PS, Rai Stage, WBC and 11q- (all p<0.017, c=0.84). A RS used the formula: 0.794 x (ECOG PS1, no=0,1=yes) + 1.686 x (ECOG PS≥2, no=0,1=yes) + 1.485 x (Rai I/II/III/IV, no=0,1=yes) + 0.053 x (age in yrs) + 0.0045 x (WBC) + 0.881 x (11q-, no=0,1=yes). A SRS used the formula: 1 x (ECOG PS1, no=0,1=yes) + 2 x (ECOG PS≥2, no=0,1=yes) + 2 x (Rai Stage I/II/III/IV, no=0,1=yes) + 1 x (age≥65yrs) + 1 x (WBC>50) + 1 x (11q-, no=0,1=yes), with possible scores ranging from 0 to 7. TFS estimates at 2 yrs for SRS=0/1, 2/3, and >4 were 85% (95%CI=0.60-0.95), 51% (95%CI=0.32-0.67), and 0%, respectively (Figure 1A). In the MDA set, Rai Stage and WBC contributed significantly to the SRS, followed by ECOG PS, with little consistency in the impact of age or 11q- compared with the OSU set, leading to a loss in predictive power (c=0.66). Still, the SRS was significantly associated with TFS (p<0.0001), with 2-yr estimates of 63% (95%CI=0.39-0.79), 26% (95%CI=0.15-0.39), and 16% (0.06-0.29) for SRS=0/1,2/3, and >4 (Figure 1B). Using the OSU set, a multivariable model for OS included ECOG PS, age, and LDH (all p<0.025, c=0.76). A RS used the formula: 0.783 x (ECOG PS1, no=0,1=yes) + 1.637 x (ECOG PS≥2, no=0,1=yes) + 0.042 x (age in yrs) + 0.445 x (LDH relative to ULN). A SRS used the formula: 1 x (ECOG PS1, no=0,1=yes) + 2 x (ECOG PS≥2, no=0,1=yes) + 1 x (age≥65yrs) + 1 (LDH x2ULN, no=0,1=yes), with possible scores ranging from 0 to 4. The SRS was associated with OS (p<0.0001, c=0.73), with 2-yr estimates of 89% (95%CI=0.74-0.96), 64% (95%CI=0.39-0.81) and 0% for those with SRS=0, 2, and 4, respectively (Figure 2A). In the MDA set, with the exception of ECOG PS 1, the strength in association of all variables with OS was similar to what had been observed in the OSU set. The predictive ability of the SRS decreased in the MDA set (c=0.68), but remained associated with OS, with the highest score showing early, inferior OS (Figure 2B). Estimates at 2 yrs ranged from 95% (95%CI=0.83-0.99), to 80% (95%CI=0.55-0.92) to 20% (95%CI=0.01-0.58) with an SRS of 0, 2, and 3, respectively; no one had a SRS=4. In conclusion, pretreatment clinical characteristics can be used in a simplified score for de novo CLL pts with 17p- to predict TFS and OS. These scores, particularly the very highest, can be utilized to identify high-risk pts for expedient enrollment on clinical trials. Disclosures: No relevant conflicts of interest to declare.

A Risk Score Combined Clinical and Molecular Profiles Identifies a High-Risk Subgroup within Intermediate-Risk Acute Myeloid Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2713-2713
Author(s):  
Xiaoxia Hu ◽  
Aijie Huang ◽  
Qi Chen ◽  
Ying Zhang ◽  
Lixia Liu ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Prognostic Factors ◽  
High Risk ◽  
Signaling Pathway ◽  
Risk Score ◽  
Myeloid Leukemia ◽  
Intermediate Risk ◽  
Concordance Index ◽  
Scoring Model ◽  
Acute Myeloid

Introduction Acute myeloid leukemia (AML) is categorized into favorable-, intermediate- and adverse-risk groups according to European LeukemiaNet (ELN) risk stratification. The intermediate-risk AML comprises a substantial proportion of AML, and even within the intermediate-risk AML, the biology and prognosis are highly different, which suggests that more prognostic factors are needed to be identified. Method A total of 265 newly diagnosed AML patients treated between January 2010 and January 2019 who had cryopreserved DNA for mutational analyses diagnosed and treated in Changhai Hospital were included. 121 patients were aged ≤ 65y, and classified as intermediate-risk (IR)-AML. A Custom Amplicon panel targeting exons of 210 genes was used for deep sequencing at diagnosis. We used a LASSO Cox regression model to achieve shrinkage and variable selection from prognostic factors (P<0.1 in log-rank tests) to build risk score for predicting overall survival. A nomogram was constructed to display the risk of death in individuals. The discrimination of the risk score was measured by the concordance index (C-index) and areas under time-dependent receiver-operating characteristics (ROC) curves (AUCs), and the calibration of the risk score was explored graphically by calibration plots. Patients with IR-AML and aged ≤ 65y in The Cancer Genome Atlas (TCGA) data (n= 41) was used as a validation cohort. Results The median age was 44 (11-75) years, and 54% had normal karyotype. NRAS and CEBPA were the most recurrently mutated genes (both 26%), followed by KIT (24%), DNMT3A (23%), ARID1B (20%), FLT3-ITD (19%), PCLO (17%), and TET2 (17%). In univariate analyses, age ≥ 55 years, WBC ≥ 10×109/L , PLT > 40×109/L, high LDH counts at diagnosis, DNMT3A and Signaling Pathway genes mutations and the number of mutated genes ≥ 8 were significantly associated with poor OS (P < 0.05), and age ≥ 55 years, WBC≥ 10×109/L, DNMT3A and FLT3-ITD mutations were associated with worse relapse free survival(RFS, P < 0.05). Three variables were incorporated in our scoring model by LASSO, including Signaling Pathway genes mutations (including NRAS, KIT, FLT3, KRAS etc), DNMT3A mutation and WBC≥ 10×109/L. A risk scoring model was developed incorporating the weighted coefficients of these variables:0.6749 × Signaling Pathway + 1.1147 × DNMT3A + 0.7829 × WBC. The risk score grouped IR-AML patients into two subgroups: intermediate-low risk (ILR, score < 1, n= 48) and intermediate-high risk (IHR, score ≥ 1, n= 62) groups (Table1). Concordance index[OS: 0.703, 95% CI (0.643, 0.763); RFS: 0.681, 95%CI (0.620, 0.741)] demonstrated well discrimination power and calibration plots showed that the nomograms did well compared with an ideal model. The 3-year OS for ILR and IHR groups were 72.3% and 29.4% (P < 0.0001), and 3-year RFS were 63.9% and 19.4% (P < 0.0001), respectively (Figure 1A-B). The similar results were also observed in TCGA cohort (3-year OS 57.7% vs. 26.2%, P= 0.019; Figure 1C). The survival was equivalent for patients with ILR when treated with chemotherapy and allogeneic hematopoietic stem cell transplantation (alloHSCT, 3-year OS: 74.7% vs. 70.8%, P= 0.936, RFS: 76.4% vs. 55.0%, P= 0.225; Figure 2A-B). However, alloHSCT benefited patients with IHR. Patients who received alloHSCT had survival advantages over those who treated with chemotherapy only (3-year OS: 51.6% vs. 20.7%, P= 0.022; 3-year RFS: 38.1% vs. 7.8%, P= 0.008; Figure 2C-D). The prognosis of patients with IHR was as poor as those with adverse-risk AML (n=65 , 3-year OS: 29.5% vs. 33.3%, P= 0.794; 3-year RFS: 19.4% vs. 39.1, P= 0.294). Conclusions In this study, we developed and validated a novel scoring model that incorporated molecular and clinical profiles. According to our score model, IR-AML patients could be further stratified into two subgroups with distinct clinical outcomes. And the prognosis of patients with IHR was similar with patients with adverse-risk. Moreover, alloHSCT would override the poor outcome of patients with IHR. In summary, our scoring model might help identify patients with IR-AML who are most likely to benefit from alloHSCT. The results are needed to be validated in other independent cohorts and prospective studies before implementation into clinics. Disclosures No relevant conflicts of interest to declare.

A New Prognostic Disease Specific Model To Predict Survival after Intensive Antileukemic Treatment for Young Patients with Poor-Risk MDS and AML: Results of the CRIANT and AML-10 Studies Conducted by the EORTC/GIMEMA/SAKK/HOVON/EBMT Groups.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2020-2020
Author(s):  
M. Oosterveld ◽  
S. Suciu ◽  
P. Muus ◽  
M. Delforge ◽  
A. Belhabri ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
High Risk ◽  
Prognostic Value ◽  
De Novo ◽  
Survival Rates ◽  
White Blood Count ◽  
Poor Risk ◽  
Prognostic Importance ◽  
De Novo Aml ◽  
Disease Specific

Abstract The use of intensive antileukemic treatment is less widely accepted in high-risk MDS pts compared to de novo AML, due to the reported inferior results. It is questionable whether the poorer outcome reflects an intrinsic property of the involved stem cell or a higher frequency of poor prognostic factors. The purpose of this analysis is to identify disease-specific prognostic factors for outcome of young (aged <56 years) MDS and AML pts. This analysis combines the data of 591 pts in the AML-10 study and 203 pts with high-risk MDS or secondary AML (sAML) in the CRIANT study. Both groups received identical remission-induction therapy (idarubicin, cytarabine and etoposide), followed by one consolidation course with intermediate dose of cytarabine and idarubicin (IDIA). In both studies post-consolidation therapy consisted of alloSCT if an HLA-identical sibling donor was available. The remaining pts received autoSCT (ASCT) in AML-10 or were randomized between ASCT and a 2nd consolidation course in CRIANT. The CR rate was 68% (AML-10) vs. 59% (CRIANT) (p=0.02). The 4-year survival rates were 35% vs. 33% (p=0.80). DFS at 4 years was 43% (AML-10) vs. 35% (CRIANT) (p=0.18). For overall survival (OS) in both studies, study was not of importance (HR=1.09, p=0.45), but the following variables showed independent prognostic value: cytogenetic risk group (the HR for poor vs intermediate risk was 1.68, 95% CI 1.24–2.27, p=0.0008), white blood count (WBC) ≥ 100 x 109/l (HR=2.02, 95% CI 1.53–2.68, p<0.0001), age 46–55 yrs (HR=1.39, 95% CI 1.16–1.67, p=0.0004) and performance status (PS) (HR=1.32, 95% CI 1.17–1.49, p <0.0001). For DFS, the following factors were of an independent prognostic importance: cytogenetics (p<0.0001), age 46–55 (HR=1.23, p=0.05), WBC >100 (HR=1.67, p=0.02) and donor availability (HR=0.77, p=0.04). Some variables were of prognostic value for OS in only one of the studies: in the CRIANT study number of cytopenias (3 vs 0–2) and AHD >6 months appeared of prognostic importance for OS, wherease FAB subtype M2/M4 and cytogenetics inv(16)/t(8;21) were prognostic in AML-10. Therefore a specific prognostic score for OS was established for each study, AML-10 (based on cytogenetics, PS, FAB, WBC and age) and CRIANT (based on cytogenetics, nr of cytopenias, age, AHD and WBC). The AML-10 study distinguished 5 groups with an estimated 4-year survival rate of 69%, 40%, 45%, 26% and 17%, resp. The prognostic value of this score has been validated on patients treated in the AML-10 study with mitoxantrone instead of idarubicin: the 4-year survival were 76%, 46%, 41%, 33% and 18%, resp. The CRIANT study distinguished 5 groups with a 4-year survival rates of 72%, 44%, 39%, 12% and 0%, resp. In conclusion: the prognostic scores identify a group of 26% AML and 42% MDS pts, with a 4-year survival less than 20%. Apparently current treatment modalities are unsatisfactory for these poor-risk pts and novel treatment strategies should be offered to these pts in the context of clinical trials. Our finding that different variables are of prognostic importance in MDS/sAML and de novo AML pts supports the hypothesis that these are intrinsically different disorders. The CRIANT-derived score is a valuable alternative for the IPSS in intensively treated high-risk MDS pts.

Is Longer MDS Duration Prior to Non-Intensive AML Treatment a Favorable Prognostic Factor? Results of the 00331 Multicenter Phase II Decitabine Trial

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2185-2185
Author(s):  
Michael Lubbert ◽  
Claudia Schmoor ◽  
Björn Rüter ◽  
Mathias Schmid ◽  
Ulrich Germing ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Research Funding ◽  
Disease Duration ◽  
Cox Regression ◽  
De Novo ◽  
Performance Status ◽  
Treatment Modalities ◽  
White Blood Count ◽  
Large Trial ◽  
Comorbidity Index

Abstract Abstract 2185 Background: Secondary (s)AML from MDS is more frequent in older AML patients, and associated with an overall worse outcome with standard chemotherapy than de novo AML, particularly after MDS of longer duration (1). The azanucleoside hypomethylating agents 5-azacytidine (Vidaza) and 5-aza-2′-deoxycytidine (Decitabine, DAC) are active in MDS and, as recently shown, also AML. Compared to other predictors of response to these drugs, MDS duration prior to treatment thus far has received only limited attention, with two recent publications reporting conflicting results (2, 3). To independently validate our finding that shorter duration of MDS prior to DAC treatment may be a novel predictor of poor outcome (2, 4), we now applied this parameter to a large trial of low-dose DAC in AML pts (aged >60 years and judged ineligible for standard induction chemotherapy), about half of them with sAML from MDS with variable disease duration. Patients and Methods: Comparisons of response rate (RR, i.e. CR or PR) and overall survival (OS) from start of treatment according to MDS duration (pre-specified categorization according to quartiles) were performed post-hoc in 109 patients (pts) with previously untreated sAML (median age 72 years) treated with DAC (given over 72 hours, every 6 weeks, for up to 4 courses, followed by “maintenance” with 3 daily 1-hour infusions of DAC 20 mg/m2 every 4–6-weeks). Median WBC prior to treatment was 5.200/μl, median serum LDH 279U/l, 31.2% of pts had adverse cytogenetics, 82.6% had a performance status > 1, and 80.7% had a comorbidity index (HCT-CI) >=1. Comparisons by logistic regression and Cox regression (univariate and multivariate, adjusted for other prognostic factors showing an effect in this population of sAML pts) were performed. Results: Of the 227 AML patients treated within the 00331 trial, 109 (48%) had prior MDS with known MDS duration, with a median duration of 8 (25% quartile 3, 75% quartile 25, range 1–101) mths. The overall RR in these pts was 26/109 (24%), the overall 1 yr OS rate was 31% (94 deaths). A comparison of RR according to MDS duration revealed a trend to an increase in RR with longer duration of MDS [<3: 4/25 (16%), 3–8: 5/29 (17%), 8–25: 7/27 (26%), >=25 mths: 10/28 (36%), test for heterogeneity p=0.29, test for trend p=0.06]. Similarly, when OS from start of DAC was analyzed according to this parameter, for pts with previous MDS of longer duration there was a trend to better outcome [<3: 1 yr OS rate 23%, 3–8: 28%, 8–25: 26%, >=25 mths: 46%, test for heterogeneity p=0.17, test for trend p=0.16]. When these analyses were adjusted for other prognostic factors showing an effect in this population of sAML pts (comorbidity index, sLDH with respect to RR, and performance status, comorbidity index, and white blood count with respect to OS), the results were similar (effect of MDS duration with respect to RR: test for heterogeneity p=0.35, test for trend p=0.06, and effect of MDS duration with respect to OS: test for heterogeneity p=0.04, test for trend p=0.11). Conclusion: In this large cohort of uniformly treated pts with sAML, MDS of longer duration appeared to be associated with a better outcome, even after adjusting for important other prognostic factors. These results are supported by a similar analysis of MDS pts randomized in the 06011 EORTC intergroup trial (which compares DAC to Best Supportive Care), where MDS patients with longer (>=3 mths) disease duration prior to treatment also had better outcome (4). They warrant application of this discriminator in the evaluation also of other non-intensive AML treatment modalities. References 1. Estey et al., Blood 90:2969-77, 1997 2. Wijermans et al., Ann. Hematol. 84 Suppl 1:9-14, 2005 3. Kantarjian et al., Cancer 109:265-73, 2007 4. Lübbert, Suciu et al., Abstract submitted, ASH 2010 Disclosures: Off Label Use: decitabine is FDA-approved for treatment of MDS and AML with up to 30% blasts. In the present study, patients with AML and higher blast percentage were treated. Platzbecker: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Döhner: Pfizer: Research Funding.

Consolidation with High Dose Therapy and Autologous Stem Cell Transplant Improves Survival for Patients with Mantle Cell Lymphoma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2006-2006
Author(s):  
Loretta Nastoupil ◽  
Pareen J Shenoy ◽  
Alex Ambinder ◽  
Miray Seward ◽  
Ajay K. Nooka ◽  
...  
Keyword(s):  
Stem Cell ◽  
Prognostic Factors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
High Dose ◽  
High Dose Therapy ◽  
Mantle Cell ◽  
Induction Regimen ◽  
Baseline Characteristics ◽  
Ecog Ps

Abstract Abstract 2006 Background: Mantle cell lymphoma (MCL) comprises 5–7% of all non-Hodgkin lymphomaand remains incurable with conventional chemotherapeutic approaches. Some clinical series and trials suggest that outcomes are improved with intensive induction containing cytarabine (Ara-C) and/or the use of high dose therapy (HDT) and autologous stem-cell transplantation (ASCT) once patients (pts) achieve remission. What is not apparent are the contributions of each and which prognostic factors influence outcomes. We examined our single center experience with initial management strategies for pts diagnosed with MCL between 1995 and 2011 and compared outcomes of CHOP±R (rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone), an intensive induction regimen HCVAD±R (rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate/cytarabine) in patients who subsequently underwent observation or HDT/ASCT. Methods: To examine the effectiveness of CHOP±R, HCVAD±R and HDT/ASCT, and the contributions of each to overall survival (OS), we conducted an IRB-approved retrospective review of consecutive cases of MCL identified from our database. Responsesfollowing the first management strategy were retrospectively assessed using International Working Group Criteria (JCO 1999). Descriptive statistics for the baseline characteristics of pts who received CHOP±R and HCVAD±R were compared using Chi-square tests. Kaplan–Meier estimation was used to evaluate OS and the treatment regimens were compared with the log-rank test. Toevaluate prognostic factors and the effects of treatment on OS, Cox proportional hazards models were used controlling for sex, race, stage, presence of B-symptoms, MIPI score, and those who underwent consolidation with HDT/ASCT. Results: 103 ptswere identified with a median age of 58 (range 32–79 years), 27% were ≥65 years of age, 80% were male, 77% were white, 96% had an ECOG PS ≤1, 93% were advanced stage (III/IV), and the majority had a low risk MIPI score (53%). 43% (N=44) received CHOP±R (mean # of cycles 5.3, median 6, range 1–8) and the remaining 57% received HCVAD±R (N=59, mean # of cycles 4.5, median 4, range 1–12). 65% of HCVAD pts and 27% of CHOP pts received R. No significant differenceswere observed in the baseline characteristics of the two groups: age (59 years CHOP±R vs. 57 HCVAD±R, p=0.06), presence of B symptoms (32% vs. 31%, p=0.77), stage (III/IV, 91% vs. 95%, p=0.69), or MIPI score (low 50% vs. 56%, p=0.97). Of the pts who were consolidated with a transplant (N=47), median age was 58, 85% were male, 32% had B-symptoms, all had an ECOG PS ≤1, 26% had an LDH>ULN, 51% had a low MIPI, and 81% received HCVAD±R as induction. In comparison to those observed, the only significant differences were ECOG PS (8% ≥2, p=0.05) and induction regimen (63% CHOP±R, p<0.001). There were no significant differences in 5-year OS for CHOP±R: 64% (95% CI 44–79%) and HCVAD±R:68% (52–80%). There was a significant difference in 5-year OS for patients who underwent HDT/ASCT vs. those who did not consolidate with transplant (74% vs. 59%, p=0.03). 5-year OS for those treated with HCVAD±R + HDT/ASCT was not significantly different from the rest of the pts74% vs. 61% (p=0.19). After controlling for clinical confounders including sex, race, stage, presence of B-symptoms, consolidation with HDT/ASCT was associated with superior OS (HR 0.46 95% CI 0.22–0.93) while having a high MIPI score was associated with inferior OS (HR 3.79, 95% 1.59–9.01). Conclusions: Our single institution experience for untreated MCL pts demonstrates favorable 5-year OS independent of induction chemotherapy. Patients who underwent consolidation with HDT/ASCT had superior OS compared to those who did not. Disclosures: Flowers: Genentech/Roche (unpaid): Consultancy; Millennium (unpaid): Consultancy; Celgene: Consultancy; Celgene: Research Funding; Spectrum: Research Funding; Millennium: Research Funding; Gilead: Research Funding; Janssen: Research Funding.

Ublituximab, a Novel Glycoengineered Anti-CD20 Monoclonal Antibody (mAb), in Combination with TGR-1202, a Next Generation Once Daily PI3kδ Inhibitor, Demonstrates Activity in Heavily Pre-Treated and High-Risk Chronic Lymphocytic Leukemia (CLL) and B-Cell Lymphoma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 801-801 ◽  
Author(s):  
Matthew A. Lunning ◽  
Julie M. Vose ◽  
Marshall T. Schreeder ◽  
Nathan Fowler ◽  
Loretta J. Nastoupil ◽  
...  
Keyword(s):  
High Risk ◽  
Research Funding ◽  
Next Generation ◽  
Employment Equity ◽  
Once Daily ◽  
Richter's Transformation ◽  
Equity Ownership ◽  
Anti Cd20 ◽  
Ecog Ps ◽  
11Q Deletion

Abstract Introduction: Ublituximab (UTX) is a novel chimeric mAb targeting a unique epitope on the CD20 antigen, glycoengineered to enhance affinity to FcγRIIIa receptors, thereby demonstrating significantly greater ADCC than rituximab. UTX monotherapy in patients (pts) with rituximab relapsed/refractory NHL and CLL has reported a 43% ORR (ASCO 2014). TGR-1202 is a next generation, once daily, oral PI3Kδ inhibitor which notably lacks the hepatotoxicity associated with other PI3Kδ inhibitors, and is active in pts with relapsed and refractory hematologic malignancies (EHA 2014). UTX and TGR-1202 have shown synergistic activity in-vitroin various lymphoid cell lines (Lugano 2013). This Phase 1 trial evaluates safety and efficacy of the combination of a glycoengineered anti-CD20 (UTX) and a PI3Kδ inhibitor (TGR-1202) in pts with heavily pre-treated relapsed or refractory CLL and NHL. Methods: Eligible pts have relapsed/refractory CLL or NHL with an ECOG PS ≤ 2. A 3+3 design evaluates cohorts of CLL and NHL pts independently with UTX dosed on Days 1, 8, 15 of Cycles 1 & 2 followed by maintenance therapy. UTX starts at 600 mg in Cohort 1 and increases to 900 mg for pts with CLL and is fixed at 900 mg for pts with NHL. TGR-1202 starts at 800 mg QD in Cohort 1 and is increased in subsequent cohorts. An amendment in July 2014 was introduced to include an improved micronized formulation of TGR-1202, starting at 400 mg once daily and increasing in subsequent cohorts. There are no limits on prior therapy, and patients with Richter’s Transformation or who are refractory to prior PI3Kδ inhibitors or BTK inhibitors are eligible. Primary endpoints: Safety and Dose Limiting Toxicities (DLT). Secondary endpoints: Efficacy (ORR, CR rate). Results: As of August 2014, 21 pts have been enrolled: 8 CLL/SLL, 7 DLBCL, 5 Follicular Lymphoma, and 1 patient with Richter’s Transformation. Median age is 64 years (range 35-82); 12 male/9 female. Median prior Tx = 3 (range 1-9); median ECOG PS = 1. All pts are evaluable for safety. Adverse events have been manageable with no safety concerns noted. Day 1 infusion related reactions (IRR) were the most common treatment related adverse event (48%), with all but one event Grade 1 or 2 in severity, followed by neutropenia (38%), diarrhea (29%), and nausea (29%). Notably, no events of TGR-1202 related hepatotoxicity have been reported to date. All IRR and neutropenia events have been manageable with dose delays. One neutropenia related dose delay in a CLL patient at UTX 600 mg + TGR 800 mg met the criteria for a DLT, necessitating enrollment of additional pts into this cohort. No other DLTs have been reported, including at higher dose levels. Fifteen pts were evaluable for efficacy with 6 pts too early for response assessment. Among evaluable pts, 80% displayed a reduction in tumor burden at first efficacy assessment, despite pts exhibiting a number of high-risk characteristics, including 3/5 CLL pts having 17p/11q deletion and a median of 6 prior lines of therapy amongst pts with FL. Objective responses are summarized below: Table TypePts (n)PRn (%)ORRn (%)PD(n)% pts ≥ SD for 12 wksMedian Prior Rx CLL/SLL54 (80%)4 (80%)-5 (100%)2 (1 – 3) Richter’s1---1 (100%)1 FL4---4 (100%)6 (3 – 8) DLBCL52 (40%)2 (40%)14 (80%)3 (1 – 6) Total156 (40%)6 (40%)114 (93%)3 (1 – 8) Amongst pts with CLL, 2/2 pts with normal cytogenetics achieved a PR including a patient with prior treatment with a BTK inhibitor, while 2/3 pts with presence of 17p/11q deletion achieved a PR, with the remaining patient having SD with a 44% nodal reduction at first assessment. Conclusions: Preliminary data suggests the combination of UTX + TGR-1202 is well tolerated with early signs of clinical activity in heavily pre-treated and high-risk patient subsets. Enrollment is ongoing with at least 30 patients anticipated. Disclosures Lunning: Onyx: Consultancy; Alexion: Consultancy; Gilead: Consultancy; Spectrum Pharmaceuticals: Consultancy. Schreeder:TG Therapeutics, Inc.: Research Funding. Pauli:TG Therapeutics, Inc.: Consultancy. Miskin:TG Therapeutics, Inc.: Employment, Equity Ownership. Sportelli:TG Therapeutics: Employment, Equity Ownership. Weiss:TG Therapeutics, Inc.: Employment, Equity Ownership. Vakkalanka:Rhizen: Employment, Equity Ownership. Viswanadha:Incozen: Employment. O'Brien:Amgen, Celgene, GSK: Consultancy; CLL Global Research Foundation: Membership on an entity's Board of Directors or advisory committees; Emergent, Genentech, Gilead, Infinity, Pharmacyclics, Spectrum: Consultancy, Research Funding; MorphoSys, Acerta, TG Therapeutics: Research Funding.

Sequential Intensified Conditioning Regimen Allogeneic Hematopoietic Stem Cell Transplantation in Adult Patients with High-Risk AML in Complete Remission: A Survey from the ALWP of the EBMT

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3105-3105
Author(s):  
Florent Malard ◽  
Myriam Labopin ◽  
Gernot Stuhler ◽  
Johanna Tischer ◽  
Joerg Thomas Bittenbring ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
High Risk ◽  
Research Funding ◽  
Antithymocyte Globulin ◽  
De Novo ◽  
Conditioning Regimen ◽  
Secondary Aml ◽  
Off Label ◽  
Advisory Boards ◽  
De Novo Aml

Abstract Introduction. Allogeneic hematopoietic cell transplant (HCT) is an established treatment modality that is potentially curative for many patients with acute myeloid leukemia (AML). The development of reduced intensity conditioning (RIC) allows performing HCT in elderly and/or in heavily pretreated patients and in those with comorbidities precluding the use of standard myeloablative conditioning. Post-transplant relapse remains a challenge after RIC, particularly in patients with adverse prognosis factors.The so-called "sequential" transplant approach (e.g. FLAMSA regimen combining both intensive chemotherapy and RIC HCT within the same procedure) initially developed in patients with refractory AML, could be a promising strategy to improve disease control and decrease the risk of relapse in high-risk AML patients in complete remission (CR). Patients and methods. In the current study we analyzed transplantation outcomes in a cohort of 411 adults AML patients in CR at time of transplant, treated between 2002 and 2013. Patients received a "sequential" conditioning regimen based on Fludarabine 30 mg/m2/d, high-dose aracytine 1-2 g/m2/d, amsacrine 100 mg/m2/d for 5 days and after a 3 days rest, total body irradiation (TBI) 4Gy, cyclophosphamide 50-120 mg/kg, and antithymocyte globulin (ATG) for 2 to 3 days (TBI group, n=269 [65%]). In 142 (35%) patients, TBI was substituted by IV Busulfan 3.2 mg/kg/d for 2 days, or orally equivalent dose (Bu group). 323 patients (79%) had de-novo AML and 88 (21%) had a secondary AML (with prior myelodysplastic syndrome). At time of transplant, 300 (73%) patients were in CR1 and 111 (27%) in CR2. Cytogenetic study in de novo AML was favorable in 19 patients (6%), intermediate in 102 (32%) and poor in 41 (13%). Cytogenetic data were missing in 161 (50%). 104 (25%) patients received matched related donors (MRD) and 307 (75%) unrelated donor (URD) HCT. Majority of patients (94%) received mobilized peripheral blood stem cells graft. Results. Median follow-up of surviving patients was 28 months and median age at transplant was 54 years (18-76). ANC>500/μL was achieved at a median of 17 (range, 9-74) days after HCT. Sixteen patients (4%) failed to engraft. Two year cumulative incidence of relapse (RI) and non-relapse mortality (NRM) were 22% (95%CI, 18-26%) and 22% (95%CI, 18-27%), respectively. The Kaplan-Meier estimate of overall (OS) and leukemia-free survival (LFS) at 2 years were 59% (95%CI, 54-65%) and 56% (95%CI, 50-61%), respectively. Acute GVHD (grade II-IV) occurred in 109 (28%) patients. The 2-year cumulative incidence of chronic GVHD was 31% (95%CI, 26-36), extensive in 17% (95%CI, 12-21). Two years RI, NRM, LFS and OS in TBI vs. Bu patients were 21.8% vs 21.7% (p=0.69), 29.4% vs 18.3% (p=0.008), 48.8% vs 59.6% (p=0.045) and 51.2% vs 64.0% (p=0.013), respectively. In multivariate analysis adjusted for variable with different distribution between Bu and TBI groups, the type of conditioning (TBI vs Bu) has no impact on RI, NRM, LFS and OS. Age over 55 at transplant was an independent adverse prognostic factor in multivariate analysis for NRM (hazard ratio (HR: 1.61, 95% CI: 1.00-2.61, p=0.05)), LFS (HR: 1.39, 95% CI: 1.00-1.92, p=0.05) and OS (HR: 1.55, 95% CI: 1.11-2.18, p=0.01). Being treated in an experienced center (defined as having including 10 or more transplants in the study) was associated with a significant lower RI (HR: 0.84, 95% CI: 0.75-0.93, p=0.001) and better LFS (HR: 0.91, 95% CI: 0.84-0.98, p=0.01) and OS (HR: 0.91, 95% CI: 0.84-0.98, p=0.02). Finally, transplantation from an URD was associated with a significant increase in NRM (HR: 2.11, 95% CI: 1.14-3.91, p=0.02). Of note, CR1 vs. CR2 and de novo vs. secondary AML had no impact on patients' outcome. Conclusions. These results in a rather large cohort of patients with AML suggest that a FLAMSA "sequential" regimen provided an efficient disease control in high-risk AML patients including in CR2 and secondary AML. Furthermore Busulfan and TBI based FLAMSA "sequential" regimens provide a similar outcome. These results should be confirmed in a multicenter well design randomized study. Disclosures Off Label Use: off-label drug use: antithymocyte globulin (ATG) for allo-SCT conditioning. Tischer:Sanofi-Aventis: Other: advisory board. Schmid:Neovii: Consultancy; Janssen Cilag: Other: Travel grand. Mayer:Janssen: Research Funding. Hallek:Pharmacyclics: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Janssen: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Boehringher Ingelheim: Honoraria, Other: Speakers Bureau and/or Advisory Boards; Mundipharma: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Celgene: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Gilead: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Roche: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; AbbVie: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding.

Red Cell Distribution Width (RDW) at Diagnosis of Diffuse Large B-Cell Lymphoma (DLBCL) Is Associated to Higher Mortality and Worse Overall Survival

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5398-5398
Author(s):  
Leyre Bento ◽  
Juan Sarmentero ◽  
Ana Ortuño ◽  
Marta García-Recio ◽  
Bernardo Lopez ◽  
...  
Keyword(s):  
Overall Survival ◽  
Prognostic Factors ◽  
High Risk ◽  
Roc Curves ◽  
Red Cell Distribution Width ◽  
Red Cell ◽  
Cell Distribution ◽  
Distribution Width ◽  
Ecog Ps

Abstract Red cell distribution width (RDW) is an indicator of the variability in the size of circulating erythrocytes (anisocytosis); different conditions can increase the RDW levels; such as hemolysis, ineffective erythropoiesis and blood transfusions. Recently, different studies have shown an association between increased levels of RDW and inflammation in different diseases, being proposed as a surrogate marker of inflammation and a strong predictor of adverse outcome. The proposed mechanism of this association departs from the finding that Inflammatory cytokines like TNFand IL-6 (part of the classic inflammatory cascade), have been found to inhibit erythropoietin-induced erythrocyte maturation, which is reflected in the RDW increase. Some reports have found a relationship between RDW and mortality related to age or several malignant or non-malignant conditions. However, there is no information about the role of RDW in overall survival (OS) of patients with DLBCL. We aim to evaluate the prognostic role of RDW levels in DLBCL patients at diagnosis. METHODS We retrospectively evaluated 83 patients with DLBCL homogenously treated in frontline with R-CHOP from 2002 to 2013 in the Son Espases University Hospital. To avoid selection bias patients were obtained from Pharmacy and Pathology Departments registries. Main clinical and prognostic factors at diagnosis were obtained from medical records. Cheson criteria were used for response assessment. The RDW was collected from the hemogram at diagnosis. The IBM SPSS STADISTICS program was used for all statistical analyses. PFS (time to progression/relapse) and overall survival (OS) (time to death) were measured from the date of ABVD onset, and were estimated according to the Kaplan-Meier method. We performed the comparisons between those interest variables with the log-rank test. A comparison between categorical variables was made with the chi-square of Fisher's exact test, as appropriate. All reported P-values were two-sided, and statistical significance was defined at P<0.05. For selecting cutoff values in RDW we used ROC curves. RESULTS: Main characteristics of patients were as follows: median age was 62 (20-86) years, 24% had ECOG PS>1, 64% advanced III-IV Ann Arbor (AA) stage, 39% B-symptoms, 51% adjusted-International Prognostic Index (a-IPI) and 39% belong to the high risk (3-5) subgroups of R-IPI Median RDW was 14.6 (11.1-21.1). Using ROC curves we selected the cutoff 14.05 for the death event. We evaluated the association of increased RDW with main prognostic factors at diagnosis. RDW >14.05 at diagnosis was associated with a more advanced age, worse ECOG PS, a more advanced AA stage, higher incidence of B symptoms and IPI>2. However, RDW was not related to disease control in terms of response to therapy (p=0.39) or relapse/progression (p=0.21) rates. Inversely, RDW>14.05 was in fact associated to a higher mortality (47%) compared to only 17% in patients with RDW≤14.05 (p=0.008). Median follow-up was 77 (20-137) months. Univariate survival analysis showed age>60 years (p=0.001), ECOG PS>1 (p=0.036), high risk R-IPI (p=0.005), a higher than 15% reduction in relative dose-intensity (RDI) (p=0.026) and RDW>14.05 (p=0.008) were significantly related to worse OS. By contrast, RDW did not significantly influence progression-free survival (p=0.19). CONCLUSIONS: Higher RDW at diagnosis in this series of DLBCL patients was related with older age, worse ECOG PS and more advanced disease but this was not translated into a worse control of disease in terms of only a small non statistically significant impact in response or PFS. By contrast higher RDW was linked to a significantly higher mortality and worse OS possibly related to a higher proinflammatory basal status and comorbidities. Patients with higher RDW may be at risk of reduction in RDI. These findings could justify including RDW in scores of comorbidities in DLBCL as well as in other malignant and non-malignant conditions. Disclosures No relevant conflicts of interest to declare.

scholarly journals Iron Overload in Patients Aged 60 Years and Older with Acute Myeloid Leukemia May Impact Adversely on Overall Survival

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3982-3982
Author(s):  
Colleen A. C. Wong ◽  
Chantal Leger ◽  
Heather A. Leitch
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Clinical Outcomes ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Low Dose ◽  
De Novo ◽  
Iron Stores ◽  
Baseline Characteristics ◽  
Ecog Ps

Abstract Background: Analyses in myelodysplastic syndromes (MDS) and other acquired anemias suggest an association between iron overload and inferior clinical outcomes. There are minimal data examining iron levels in patients with acute myeloid leukemia (AML) and its relation to clinical outcomes. Patients with AML aged 60 years or older have inferior outcomes in general and no studies examine iron load and clinical outcomes in these patients. We wished to determine whether iron levels might contribute to the prognosis of these patients. Methods: We performed a retrospective analysis of patients with AML aged ≥60 years diagnosed from 2002-2018. Patients were identified from the clinical database and charts reviewed. Clinical data extracted included baseline characteristics (demographics; AML presentation; ECOG performance status [PS]; comorbidities [Charlson Comorbidity Index (CI) and Hematopoietic Stem Cell Transplantation CI]; predisposing conditions; prior transfusions; blood counts; bone marrow findings; cytogenetic analysis) AML treatment received, status at last follow up and cause of death (COD). Serum ferritin level (SF) and bone marrow iron stores (BMIS) at AML diagnosis were recorded. BMIS were: absent, 0; reduced, 1; normal, 2; increased, 3; and markedly increased, 4. Elevated iron was: SF>750ng/mL or BMIS ≥3. Statistical analyses were performed using SPSS for Windows, version 25. Results: Of 369 AML patients, 101 were ≥60 years and had adequate data for analysis. The median age at AML diagnosis was 70 (range 60-93) years and 60 (59.4%) were male. ECOG PS was 0, 1, 2, 3 and 4 in 7 (6.9%), 17 (16.8%), 48 (47.5%), 23 (22.8%) and 4 (4%) patients, respectively. 51 (50.5%) were de novo AML, and 49 (48.5%) had predisposing conditions, including MDS (n=39; 38.6%), MPN (n=7; 6.9%), and prior chemotherapy (CT) or radiation (n=3; 3.0%). Cytogenetic risk group was intermediate in 47 (46.5%) and adverse in 33 (32.7%). Treatment received included supportive care in 41 (40.6%), low dose chemotherapy (hydroxyurea, n=18; low dose cytarabine, n=4) in 22 (21.8%), induction CT in 18 (17.8%), and azacitidine in 20 (19.8%). Infection or inflammation were documented in 8 (7.9%). Comorbidities were present in 43 (42.6%) patients, and the median (range) number of comorbidities per patient was 1 (1-3). SF was available in 55 (54.5%), BMIS in 68 (67.3%), and both in 22 (21.8%). There was a significant correlation between SF >750ng/mL and BMIS ≥3 (r=0.555, p=0.008). A composite score including SF and BMIS revealed elevated iron stores (ELFE) in 39 (38.6%) and normal to decreased iron stores in 62 (61.4%). In univariate analysis, factors significant for overall survival (OS) included ECOG PS, p<0.0001; de novo versus secondary AML, p=0.02; neutrophil count, p<0.0001; platelet count, p<0.0001; bone marrow blast %, p=0.04; cytogenetic risk group, p=0.02; and AML treatment received, p<0.0001. Factors with a trend toward significance included the presence of dysplasia, p=0.07; and ELFE, p=0.07. In pairwise comparisons, dysplasia and AML treatment received lost significance, p=0.09. Factors remaining significant for OS when paired with ELFE included ECOG PS, p=0.02; and AML treatment (trend), p=0.05. In a multivariate analysis including ELFE, ECOG PS and AML treatment, ELFE and ECOG PS were significant for OS: p=0.046, hazard ratio (HR) for death 2.5, 95% confidence intervals (CI) 1.02-6.14, and p=0.006, HR=4.1, 95% CI=1.50-11.36, respectively. The median OS for patients receiving induction CT with no ELFE was 18 (range 0.2-82) months versus 10.1 (0.1-18.2) months with ELFE (p=0.05, see Figure). Baseline characteristics in the subgroup receiving induction CT were not significantly different between ELFE non-ELFE patients, with the exception of hemoglobin (p=0.008). COD in all patients were: AML progression, n=72 (71.3%); infection, n=4 (4.0%); and bleeding, n=4 (4.0%); with no significant difference in COD between patients with and without ELFE (p=0.4). Conclusions: In this retrospective, non-controlled analysis, for patients aged ≥60 years with a new diagnosis of AML, elevated iron appears to be associated with inferior overall survival, particularly in those receiving induction chemotherapy. To our knowledge, these are the first data examining clinical outcomes in AML patients ≥60 years of age according to iron status. These results should be confirmed in larger, prospective analyses. Disclosures Leitch: AbbVie: Research Funding; Alexion: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau.

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