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.

Clinicopathological Differences Between Asian and Western Patients with De Novo Diffuse Large B Cell Lymphoma Treated with R-CHOP

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2665-2665
Author(s):  
Natalie Sinclair ◽  
Brady E Beltran ◽  
Moo-Kon Song ◽  
Ivana Ilic ◽  
Sirpa Leppa ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Research Funding ◽  
De Novo ◽  
Cell Lymphoma ◽  
Clinical Stage ◽  
Performance Status ◽  
B Cell Lymphoma ◽  
Advanced Clinical Stage ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Abstract 2665 Introduction: Little is known on the racial differences in characteristics and outcomes of patients with a diagnosis with diffuse large B-cell lymphoma (DLBCL) treated with rituximab-containing regimens. The aim of this retrospective study is to compare the clinicopathological characteristics, prognostic factors and outcomes of Asian and Western patients with a diagnosis of de novo DLBCL treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP). Patients and Methods: Patient-level data was collected from 8 centers (USA, Italy, Sweden, Finland, Croatia, Japan, Korea and China). This study was approved by the Institutional Review Board at each of the participant centers. All patients were diagnosed with de novo DLBCL and treated with R-CHOP administered every 3 weeks. HIV-positive and primary brain DLBCL were excluded. The requested clinical data included age, sex, performance status, lactate dehydrogenase (LDH) levels, number of extranodal sites, clinical stage, expression of CD10, BCL6 and MUM1/IRF4, response to chemotherapy, outcome and overall survival (OS). Patients were divided in Asian and Western, according to the country of report. Comparison between groups was performed with Mann-Whitney and Chi square tests for continuous and categorical variables, respectively. Univariate survival curves were estimated using the Kaplan-Meier method and compared using the log-rank test. Multivariate analysis was performed using the Cox proportional-hazard regression test. P-values of <0.05 were considered statistically significant. Results: A total of 712 patients, 455 Asian and 257 Western patients were included in this study. Western patients were more likely to present with elevated LDH levels (70% vs. 48%; p<0.001), advance clinical stage (58% vs. 49%; p=0.02) and a non-germinal center immunohistochemical profile (53% vs. 43%; p=0.01). Additionally, Western patients were more likely to present with low risk IPI scores (p=0.003 for trend), and had higher complete response (CR) rates (91% vs. 76%; p<0.001). There were no statistical differences between the 2 groups on age at diagnosis, sex distribution, ECOG performance status, number of extranodal sites, overall response rates and proportion of deaths. After a median follow-up of 36 months, there was no difference in median overall survival (OS; not reached in both groups) or estimated 5-year OS (66% vs. 62%; p=0.67) (Figure). In the univariate analyses, ECOG >1, elevated LDH levels and advanced clinical stage were significantly associated with a worse median OS in Westerners (p<0.01 each factor) while ECOG >1, >1 extranodal sites and advanced clinical stage were significant adverse factors for Asians (p<0.01 each factor). In the multivariate analyses, ECOG >1 and advanced clinical stage were independent prognostic factors associated with a worse median OS in Westerners and Asians (p<0.01, p=0.03, and p<0.01, p<0.01, respectively). Elevated LDH level was an adverse independent prognostic factor for Western patients only (p=0.04). Conclusions: Asian and Western patients with de novo DLBCL present with distinct clinical and pathological characteristics, and although the CR rate to standard R-CHOP was higher in Westerners than in Asians, the final outcome, prognostic factors and median and 5-year OS rates are similar in both populations. Disclosures: Castillo: GlaxoSmithKline: Research Funding; Millennium Pharmaceuticals: Research Funding.

Confirmation of the Mantle Cell Lymphoma International Prognostic Index (MIPI) in An Independent Prospective Patient Cohort.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 138-138 ◽  
Author(s):  
Eva Hoster ◽  
Joerg Hasford ◽  
Olivier Hermine ◽  
Hanneke C. Kluin-Nelemans ◽  
Jan Walewski ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Board Of Directors ◽  
Research Funding ◽  
Cox Regression ◽  
Performance Status ◽  
International Prognostic Index ◽  
Prognostic Index ◽  
Hazard Ratio ◽  
Advanced Stage ◽  
Advisory Committees

Abstract Abstract 138 Background: The Mantle Cell Lymphoma (MCL) International Prognostic Index (MIPI) has been recently developed as first prognostic index especially designed for patients with advanced stage MCL (Hoster et al., Blood 2008). The MIPI is based on four easily available prognostic factors (age, ECOG performance status, leukocyte count, and LDH). It was internally validated using a bootstrap strategy, and several authors reported its validity on larger patient cohorts (Salek et al., ASH 2008, Geisler et al., EHA 2009). We evaluated the prognostic relevance of the MIPI using the pooled data of two currently recruiting randomized trials (MCL Younger and MCL Elderly) of the European MCL Network (Dreyling et al., ASH 2007). Methods: Outcome parameters were primarily overall survival (OS) and secondarily time to treatment failure (TTF). Kaplan-Meier curves according to the MIPI prognostic groups were compared by means of the log rank test and univariate Cox regression. We checked the value of the MIPI prognostic factors within multiple Cox regression. We also evaluated the simplified MIPI and exploratively included patients with stage II into the analyses. Since randomization is ongoing, all analyses were blinded for treatment arms. Results: Currently, 606 patients with advanced stage MCL were evaluable, 317 in MCL Younger and 289 in MCL Elderly. Median age was 63 years (range 32 – 87), 6% had an ECOG performance status > 1, median LDH/ULN ratio was 0.95 (0.29 – 12.2), and median leukocyte count 7,600/μl (1,075/μl – 396,000/μl). The MIPI classified 220 patients (36%) into the low risk (LR), 187 (31%) into the intermediate risk (IR) and 199 (33%) into the high risk (HR) group. With a median follow-up of 19 months and 116 events, the probability for OS at 24 months was 91%, 77%, and 58% for LR, IR, and HR (medians not reached in LR, IR vs. 28 months in HR patients, p < 0.0001), corresponding to a hazard ratio of 2.7 for IR vs. LR (95% CI, 1.5 – 4.9, p = 0.001) and 2.6 for HR vs. IR (95% CI, 1.7 – 4.0, p < 0.0001). The four MIPI prognostic factors were independently prognostic for OS (p < 0.0001 each). In MCL Younger, the distribution to LR, IR, and HR groups was 61%, 23%, and 16%, as compared to 9%, 40%, and 51% in MCL Elderly, the difference reflecting the strong prognostic impact of age. According to preliminary subgroup analyses, 2-years OS rates were 92%, 76%, and 58% (p < 0.0001) in MCL Younger, and 85%, 78%, and 58% (p < 0.0001) in MCL Elderly. The MIPI also separated LR, IR, and HR group with respect to TTF, with medians of 49, 36, and 20 months (p < 0.0001) and a hazard ratio of 2.2 for IR vs. LR (95% CI, 1.4 – 3.4, p = 0.0004) and 2.0 for HR vs. IR (95% CI, 1.4 – 2.8, p = 0.0001). The simplified MIPI classified 36%, 32%, and 33% to LR, IR, and HR groups with high concordance to the MIPI (weighted kappa 0.82). Two-years OS rates were 90%, 79%, 58% for LR, IR, HR according to the simplified MIPI (p < 0.0001) with a hazard ratio of 2.4 for IR vs. LR (95% CI, 1.3 – 4.2, p = 0.003) and 2.5 for HR vs. IR (95% CI, 1.7 – 3.8, p < 0.0001). Inclusion of 32 patients with stage II MCL did not essentially change the results. Discussion: We could confirm the prognostic relevance of the MIPI in a large independent patient cohort treated within current randomized trials. Therefore, the MIPI may be used for risk stratification in future clinical trials, for the comparative interpretation of the results of different trials, for the evaluation of new biological prognostic factors, and may finally lead to risk-adapted treatment decisions in advanced stage MCL. Disclosures: Hoster: Roche: travel support. Trneny:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biogen Idec: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Dreyling:Roche: Honoraria, Research Funding. Unterhalt:Roche: travel support.

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.

Equivalent Outcome Between Reduced Intensity Versus Conventional Myeloablative Conditioning Hematopoietic Stem Cell Transplantation for Patients Older Than 35 Years with Acute Myeloid Leukemia.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3103-3103
Author(s):  
Marie Sebert ◽  
Raphaël Porcher ◽  
Marie Robin ◽  
Lionel Ades ◽  
Emmanuel Raffoux ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Research Funding ◽  
Cox Regression ◽  
Karnofsky Performance Status ◽  
Performance Status ◽  
Conditioning Regimen ◽  
Hematopoietic Stem ◽  
Treatment Related Mortality ◽  
Related Mortality

Abstract Abstract 3103 Introduction: Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) provides the best chance of long-term survival for patients with intermediate or high-risk acute myeloid leukemia (AML). The major limitation of this procedure is the risk of treatment related mortality (TRM). Use of reduced intensity conditioning (RIC) regimen has become standard practice among older candidates with comorbidities. Although RIC regimen have been used for over a decade in older patients, the benefit of this approach in younger patients with AML compared with the risk of toxicity of standard regimen (MAC) is still discussed. We compared the outcomes for patients with AML over 35 years using RIC or MAC HSCT. Patients, methods, and transplantation characteristics: From January 2000 to December 2010, 132 consecutive patients older than 35 years with AML (18 secondary AML) received HSCT in our center, either from siblings (n=87) or HLA 10/10 allele-matched donors (n=45). MAC (n=72) and RIC (n=60) regimens were defined as previously described (Bacigalupo, 2009). Seventy-three patients were in first complete remission (CR1); 30% of patients had poor risk cytogenetics (MRC classification). Karnofsky performance status was scored at time of HSCT. Engraftment, acute and chronic graft-versus-host disease (GvHD), transplantation-related mortality (TRM), relapse rate as well as overall survival (OS) at 4 years were compared according to the intensity of the conditioning regimen. First a classical multivariable Cox analysis was conducted. In a second step, baseline confounding factors were adjusted for using inverse probability-of-treatment weighting (IPTW). Results of the comparison: Patient characteristics according to the intensity of the conditioning regimen were similar for AML type (de novo versus secondary), gender, karnofsky performance status, CR#, donor type and number of CD34+ infused. Particularly, cytogenetic risks were comparable in both groups. Patients were younger in the MAC group (median age 44 years [range 35 to 56 years] vs 54[37 to 66] for RIC, p<0,0001), received mainly bone marrow as source of stem cells (54% versus 2% for RIC, p<0,0001) and GvHD prophylaxis using cyclosporine plus methotrexate (89% versus 5% for RIC, p<0,0001). Moreover, ATG in the conditioning regimen (more ATG in RIC: 51 vs. 14%, p<0.0001), donor age (older for RIC: 49 vs. 39 years, p=0.002) and number of nucleated cells infused (higher in RIC: 11 vs. 4 × 108/kg, p<0.0001) were also different. The median follow-up was 47 months (10 to 134), and 25% of patients had a follow-up of at least 74 months. During evolution, all patients engrafted. The cumulative incidence (CIf) of acute GVHD grade II-IV was 49% (35% after RIC vs 61% after MAC, p=0.001). The 5-year CIf of chronic GVHD was 37% (40% after RIC vs 30% after MAC, p=0.32). During FU, 71 patients died. The 5-year CIf of TRM was 21% (13% after RIC vs 28% after MAC, p=0.009). Adjusting for cytogenetic risk, gender donor/recipient mismatch and infused nucleated cells, no difference was observed between RIC and MAC (HR 0.9, p=0.16). The 5-year CIf of relapse was 42% (51% after RIC vs 35% after MAC (p=0.22)). Adjusting for gender donor/recipient mismatch, donor/recipient CMV serostatus and infused CD34+ cells, no marked difference was observed between RIC and MAC (HR 0.8, 95%CI 0.4–1.5, p=0.50). The 5-year OS was 39% (50% after RIC vs 34% after MAC, p=0.38). Using both Cox regression and IPTW to account for imbalance in patients characteristics, similar OS was found after RIC and MAC (Figure 1), with adjusted HRs for MAC vs RIC of 0.9 (95%CI 0.4–1.8, p=0.68) with Cox regression and 0.9 (95%CI 0.4–1.8, p=0.76) with IPTW. Conclusion: In patients with AML over 35 years, MAC regimen lead to a non significant higher rate of treatment related mortality with no benefit in terms of relapse when compared with RIC regimen. Until prospective trials are completed, this study supports the use of a RIC regimen for patients with AML older than 35 years who are transplanted either from siblings or matched unrelated donors. Disclosures: Fenaux: Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; GSK: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.

Gene Mutations and Treatment Outcome in CLL Patients Treated with Chlorambucil (Chl) or Ofatumumab-Chl (O-Chl): Results from the Phase III Study COMPLEMENT1 (OMB110911)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1992-1992 ◽  
Author(s):  
Eugen Tausch ◽  
Christina Galler ◽  
Richard Schlenk ◽  
Peter Hillmen ◽  
Fritz Offner ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Board Of Directors ◽  
Research Funding ◽  
Cox Regression ◽  
Gene Mutations ◽  
Phase Iii ◽  
Response To Treatment ◽  
Prognostic Impact ◽  
Advisory Committees

Abstract BACKGROUND: Genomic aberrations and IGHV mutation status are established prognostic factors in CLL. With TP53, NOTCH1, SF3B1, ATM, MYD88, FBXW7, BIRC3 and POT1 recurrently mutated genes were found in CLL and were discussed to associate with disease characteristics and to affect therapy efficacy and outcome. METHODS: We assessed the incidence and impact of gene mutations in the COMPLEMENT1 trial (1st line Chl vs. O-Chl). Pretreatment samples were available from 376 patients (84.1%) and this cohort was representative of the full trial population. Mutations were analyzed by amplicon-based targeted NGS using Illumina Miseq for all coding exons (TP53, ATM, MYD88, FBXW7, BIRC3 and POT1) or hotspot exons (NOTCH1, SF3B1). Additionally, the exact variant frequency was determined. RESULTS: The incidences of gene mutations were: TP53 8.2%, NOTCH1 14.9%, SF3B1 14.1%, ATM 10.9%, MYD88 2.7%, FBXW7 3.5%, POT1 7.7%, and BIRC3 2.7%. Regarding baseline characteristics, we found significant associations: TP53mut with high ß2MG (p=0.01), 17p- (p<0.01), and unmutated IGHV (p=0.01); ATMmut with high WBC (p=0.02), and 11q- (p<0.01); MYD88mut with mutated IGHV (p=0.02); FBXW7mut with 17p- (p=0.02), and +12q (p<0.01). BIRC3mut was only present in IGHV unmutated cases (p<0.01), was more frequent in 11q- (p<0.01), +12q (p=0.05), and in cases with NOTCH1mut (p=0.05). POT1mut was more frequent in NOTCH1mut cases (p=0.02) without associations with any other baseline parameter. Regarding response to treatment, TP53mut was significantly associated with reduced ORR rate (p<0.01). CR rate was not correlated with mutations in the covered genes. At a median follow-up of 31.7 months, there were 249 (66%) events for PFS and 63 (16.8%) events for OS. O-Chl as compared to Chl resulted in significantly improved PFS (median 22.4 vs. 13.1 months, HR 0.54, p<0.01). In univariate analyses, TP53mut (HR 2.07, p<0.01), NOTCH1mut (HR 1.50, p=0.01) and SF3B1mut (HR 1.66, p=0.01) were associated with shorter PFS, whereas ATM and other candidate genes showed no association (ATMmut: HR 1.40, p=0.07). Analyzing both treatment arms separately, TP53mut had an impact on PFS with Chl and O-Chl treatment (HR 1.92, p=0.04 and HR 2.49, p<0.01). Notably, NOTCH1mut was associated with outcome in O-Chl only (HR 2.01, p<0.01 vs. HR 1.14, p=0.59) resulting in a reduced beneficial effect from the addition of Ofatumumab to Chlorambucil treatment. ATMmut and BIRC3mut mutations were only adverse prognostic factors with Chl monotherapy (ATMmut: HR 1.69, p=0.05 vs. HR 1.35, p=0.27; BIRC3mut: HR 2.84, p=0.04 vs. HR 0.99, p=0.99). OS was reduced significantly only in TP53mut cases (HR 3.69, p<0.01). Of note, none of the MYD88mut cases (n=10) had died within the follow-up period. To identify genomic factors of independent prognostic impact, we performed multivariable Cox regression analyses for PFS and OS including treatment arms, 11q-, +12q, 17p-, IGHV and all candidate gene mutations. For PFS, the following independent prognostic factors were identified: O-Chl (HR 0.46, p<0.01), 17p- (HR 3.14, p<0.01), 11q- (HR 1.57, p=0.01), unmutated IGHV (HR 1.43, p=0.02), TP53mut (HR 1.81, p=0.03), NOTCH1mut (HR 1.63, p<0.01) and SF3B1mut (HR 1.54, p=0.02). Regarding OS, only 17p- (HR 4.07, p<0.01), and unmutated IGHV (HR 1.81, p=0.05) were identified as independent adverse prognostic factors with TP53mut showing a trend (HR 2.14, p=0.10). CONCLUSION: We performed mutational analyses for the 8 most frequent mutated genes in CLL in the COMPLEMENT1 trial evaluating 1st line O-Chl against Chl. An independent prognostic impact was identified for TP53mut, NOTCH1mutand SF3B1mut regarding PFS. Notably, NOTCH1mut affected outcome mainly with O-Chl treatment, whereas ATMmut and BIRC3mut were associated with outcome with Chl monotherapy. In multivariate analysis for OS, none of the gene mutations, but the established parameters IGHV and 17p- had independent prognostic impact. Disclosures Tausch: GlaxoSmithKline: Research Funding, Travel support Other. Hillmen:GSK: Honoraria, Research Funding. Offner:GlaxoSmithKline: Honoraria, Research Funding. Janssens:GSK: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Speakers Bureau; Roche: Speakers Bureau; Mundipharma: Speakers Bureau. Mayer:Glaxo: Research Funding; Roche: Research Funding. Panagiotidis:GlaxoSmithKline: Consultancy, Honoraria. McKeown:GlaxoSmithKline: Employment. Gupta:GlaxoSmithKline: Employment. Stilgenbauer:GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Complete Remissions (CRs) with Azacitidine Regimens Compared to Crs with 7+3 Induction Chemotherapy and the Effect on Overall Survival

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1613-1613 ◽  
Author(s):  
Megan Othus ◽  
Mikkael A Sekeres ◽  
Sucha Nand ◽  
Guillermo Garcia-Manero ◽  
Frederick R. Appelbaum ◽  
...  
Keyword(s):  
Overall Survival ◽  
Prognostic Factors ◽  
Research Funding ◽  
Cox Regression ◽  
Intensive Therapy ◽  
Univariate Analysis ◽  
Multivariable Analysis ◽  
Curative Intent ◽  
Kaplan Meier ◽  
The Impact

Abstract Background: CR and CR with incomplete count recovery (CRi) are associated with prolonged overall survival (OS) for acute myeloid leukemia (AML) patients (pts) treated with curative-intent, induction therapy. For AML pts treated with azacitidine (AZA), response (CR, partial response, marrow CR, or hematologic improvement) is also associated with prolonged OS. We evaluate whether patients given AZA for myelodysplastic syndromes (MDS) or AML had longer OS if they achieved CR. We also compare the effect size of CR on OS between AZA regimens and 7+3. Patients and Methods: We analyzed four SWOG studies: S1117 (n=277) was a randomized Phase II study comparing AZA to AZA+lenalidomide or AZA+vorinostat for higher-risk MDS and CMML pts (median age 70 years, range 28-93); S0703 (n=133) treated AML pts not eligible for curative-intent therapy with AZA+mylotarg (median age 73 years, range 60-88). We analyzed the 7+3 arms of S0106 (n=301 were randomized to 7+3, median age 48 years, range 18-60) and S1203 (n=261 were randomized to 7+3, median age 48 years, range 19-60). CR was defined per 2003 International Working Group criteria. In S1117 CR was assessed every 16 weeks and patients remained on therapy until disease progression. In S0703, S0106, and S1203 CR was assessed following 1-2 induction cycles; patients not achieving CR (S0106) or CRi (S0703 and S1203) were removed from protocol treatment. OS was measured from date of study registration. To avoid survival by response bias, we performed landmark analyses of OS. We present results based on the study-specific landmark date that 75% of pts who eventually achieved a CR had done so (S1117 144 days, S0703 42 days, S0106 44 days, S1203 34 days). Pts who did not achieve CR by this date were analyzed with pts who never achieved CR. Pts who died or were lost to follow-up before this date were excluded from analyses. As a sensitivity analysis we also analyzed based on the 90% date; results were not materially different. Log-rank tests were used to compare survival curves and Cox regression models were used for multivariable modeling including baseline prognostic factors age, sex, performance status, white blood cell count, platelet count, marrow blast percentage, de novo disease (versus antecedent MDS or therapy-related disease), study arm (for S1117 only), and cytogenetic risk (IPSS criteria for S1117, SWOG criteria for S0703, S0106, and S1203). The following analysis considers morphologic CR only. S0106 treated CR with incomplete count recover (CRi) pts as treatment failures (S0703 and S1203 did not) and CRi was not defined for S1117. Hematologic improvement was only defined for S1117 patients. Results: In univariate analysis, CR was significantly associated with prolonged survival among MDS pts treated with azactidine on S1117 (HR=0.55, p=0.017), confirming the results seen in AML pts treated with azacitidine (and mylotarg, S0703, HR=0.60, p=0.054) and 7+3 (S0106 HR=0.44, p<0.001; S1203 HR=0.32, p<0.0001) (Figure 1). For each study this relationship remained significant in multivariable analysis controlling for baseline prognostic factors (S1117 HR=0.25, p<0.001; S0703 HR=0.64, p=0.049; S0106 HR=0.45, p<0.001; S1203 HR=0.41, p<0.001). There was no evidence that the impact of CR varied across the four cohorts (interaction p-value = 0.76). In the full cohort, the effect of CR was associated with a HR of 0.45 (Table 1). Conclusion: Adjusting for pt characteristics, achievement of morphologic CR was associated with a 60% improvement in OS, on average, compared to that seen in pts who don't achieve a CR, regardless of whether pts were treated with 7+3 or AZA containing regimens, and suggesting that value CR is similar of whether pts receive more or less "intensive" therapy for these high grade neoplasms. Support: NIH/NCI grants CA180888 and CA180819 Acknowledgment: The authors wish to gratefully acknowledge the important contributions of the late Dr. Stephen H. Petersdorf to SWOG and to study S0106. Figure 1 Kaplan-Meier plots of landmark survival by response. Figure 1. Kaplan-Meier plots of landmark survival by response. Table 1 Multivariable analysis, N=878 Table 1. Multivariable analysis, N=878 Disclosures Othus: Glycomimetics: Consultancy; Celgene: Consultancy. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees. Erba:Millennium Pharmaceuticals, Inc.: Research Funding; Amgen: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Agios: Research Funding; Gylcomimetics: Other: DSMB; Juno: Research Funding; Daiichi Sankyo: Consultancy; Sunesis: Consultancy; Pfizer: Consultancy; Ariad: Consultancy; Jannsen: Consultancy, Research Funding; Incyte: Consultancy, DSMB, Speakers Bureau; Celator: Research Funding; Astellas: Research Funding; Celgene: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau.

Comorbidity and survival in cancer patients receiving palliative care

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 9066-9066
Author(s):  
V. T. Chang ◽  
N. Sambamoorthi ◽  
B. Zhou ◽  
H. Yan ◽  
M. L. Gonzalez ◽  
...  
Keyword(s):  
Palliative Care ◽  
Cancer Patients ◽  
Advanced Cancer ◽  
Rating Scale ◽  
Cox Regression ◽  
Early Stage ◽  
Karnofsky Performance Status ◽  
Performance Status ◽  
Survival Analyses ◽  
Comorbidity Index

9066 Background: Comorbidity has received increasing attention in the assessment of patients with early stage cancer, or at diagnosis. We studied whether three indices of comorbidity, the Charlson Comorbidity Index (CMI), the Cumulative Illness Rating Scale (CIRS), and the Kaplan Feinstein Index (KFI) add prognostic information for cancer patients receiving palliative care. Methods: In an IRB approved protocol, 103 patients with advanced cancer were seen at the time they were starting palliative care. They had a Karnofsky Performance Status (KPS) determination, and were followed longitudinally. Comorbidity scores were coded from the medical record. At this time, all patients had died and survival analyses were performed. Results: The median age was 69 years (range 41–87), median Karnofsky Performance Status (KPS) was 70% (range 20–90); primary sites were lung 41 pts (40%), prostate 23pts (22%), colorectal 10 pts (10%), other cancers 29 pts (28%). Median survival was 111 days (range 4–1,145 days). Median CMI was 10 (range 4–14), CIRS15 4 (2–5), CIRS16 9 (4–12), CIRS17 2.3 (1.5–3.33), CIRS18 1 (0–3), KFI 2 (0–3). In univariate survival analyses, when bisected by median values, the KPS, age, CMI, and subscales of the CIRS (CIRS 16, CIRS 17, CIRS18) were significantly related to survival, but not the KFI. In multivariate Cox regression analyses that included KPS (p<0.0001) and age (p<0.003) and a comorbidity index, the CMI (p<0.0001), and certain subscales of the CIRS were independently predictive of survival, specifically the CIRS 15 (p<0.0001), CIRS16 (p<0.0001), CIRS 17 (p<0.0001), and CIRS18 (p<0.0001). The primary site was not an independent survival predictor. Conclusion: In patients with advanced cancer receiving palliative care, measures of comorbidity may contribute to refining estimates of prognosis and ultimately to health care resource utilization. The optimal comorbidity measure remains to be determined. These results will be confirmed in larger populations. Supported in part by the Soros Open Society Institute Project Death in America and VA HSRD IIR 02–103 No significant financial relationships to disclose.

Pretreatment prognostic factors associated with outcomes for first-line FCR-based treatments in previously untreated CLL.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 6517-6517
Author(s):  
William G. Wierda ◽  
Susan Mary O'Brien ◽  
Stefan Faderl ◽  
Alessandra Ferrajoli ◽  
Jan Andreas Burger ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
High Risk ◽  
Performance Status ◽  
Absolute Lymphocyte Count ◽  
Patient Characteristics ◽  
Treatment Modalities ◽  
First Line ◽  
Liver Size ◽  
Improved Outcomes ◽  
New Treatment

6517 Background: First-line chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR) demonstrated improved outcomes, including survival, for fit patients (pts) with CLL. Modifications of this regimen, including intensified rituximab (FCR3), addition of mitoxantrone (FCMR) or addition of alemtuzumab fir high-risk CLL (CFAR), were evaluated but did not improve outcomes in historic comparisons. Methods: We correlated outcomes, including complete remission (CR), time-to-treatment failure (TTF) and overall survival (OS), with new and traditional pretreatment prognostic factors to identify high-risk pts. Results: All pts (N=473) had an NCI-WG indication for treatment and received a first-line FCR-based regimen on trial; the intended treatment was 6 courses. Patient characteristics correlated with outcomes are presented in the table. Factors not associated with outcomes included absolute lymphocyte count; platelet count; performance status; spleen size; liver size; and number of involved lymph node sites. Conclusions: We identified the following as high-risk pretreatment features for patients going on first-line FCR-based therapy: advanced age, presence of 17p del, high B2M (≥4mg/l), and unmutated IGHV gene. Pts with these features should be pursued with new treatment modalities and novel agents in order to improve outcomes. [Table: see text]

Patient (pt) characteristics, treatment patterns, outcomes and prognostic factors in plasmacytoid urothelial carcinoma (PUC).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e16007-e16007 ◽  
Author(s):  
Leonidas Nikolaos Diamantopoulos ◽  
Ali Raza Khaki ◽  
Funda Vakar-Lopez ◽  
Maria S. Tretiakova ◽  
John L. Gore ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Cox Regression ◽  
Treatment Patterns ◽  
Treatment Modalities ◽  
Chi Square ◽  
Peritoneal Disease ◽  
Curative Intent ◽  
Positive Margins ◽  
Entire Cohort ◽  
Pn Stage

e16007 Background: PUC is uncommon and highly aggressive, with limited data on treatment patterns, outcomes and prognostic factors. We hypothesized that PUC is associated with clinical under-staging, poor outcomes and lack of chemotherapy (CT) response. Methods: We conducted a retrospective review of pts with UC and plasmacytoid component (PUC), seen in our institution (2000 - 2018). Demographic and clinicopathologic data, treatment modalities, pathologic complete/partial response (pCR, pPR) to neoadjuvant CT (NAC), and overall survival (OS) from diagnosis and surgery (Sx) were captured. T-test, chi-square, and Cox-regression were used to explore potential prognostic associations. OS was estimated with KM method. Results: We identified 63 consecutive pts (51 men) with available data for analysis. Median age at diagnosis was 67 (44-89). During initial diagnostic workup, 32 (51%) pts had extravesical disease (cT3:24, cT4:8) and 23 (36.5%) hydronephrosis at imaging. Overall, 39 (62%) pts underwent Sx with curative intent, 25 (39.6%) were pre-treated with cisplatin-based NAC; adjuvant CT was given to 15 (24%). The remaining pts pursued bladder-sparing and/or palliative approaches. At time of Sx, 17/39 (43.6%) pts had pathologic upstaging, 10 (25.6%) had positive margins and 19 (48.7%) pN+ stage. In the NAC pt subset (25 pts), 5 (20%) had progression on scans, 19 (76%) had Sx; 2 pts had pCR (10.5%), 1 had pPR, 6 (31.5%) had pathologic upstaging. In the entire cohort, median follow-up was 8 months. Median OS was 20.7 months from diagnosis and 23.6 months from Sx. NAC was not significantly associated with longer OS (from Sx) (HR 1.53, 95%CI 0.16-15, p = 0.715) and the same was true for adjuvant CT (HR 0.64, 95%CI 0.1-4, p = 0.630). 15/39 pts recurred after Sx (38.4%), with 9/15 (60%) having peritoneal/retroperitoneal involvement. Conclusions: PUC frequently presented with advanced stage at diagnosis and demonstrated poor NAC response, frequent upstaging, positive margins and pN+ stage at Sx. More than half of patients who recurred after Sx, presented with (retro)peritoneal disease. Studies evaluating molecular biomarkers and drivers in PUC, and prospective clinical trials are being pursued.

scholarly journals Primary Gastric Lymphoma: Conservative Treatment Modality Is Not Inferior to Surgery for Early-Stage Disease

ISRN Oncology ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
Fatih Selçukbiricik ◽  
Deniz Tural ◽  
Olgun Elicin ◽  
Selin Berk ◽  
Mustafa Özgüroğlu ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Conservative Treatment ◽  
Treatment Modality ◽  
Performance Status ◽  
Gastric Lymphoma ◽  
Poor Performance ◽  
Treatment Modalities ◽  
Poor Performance Status ◽  
Advanced Stage ◽  
Primary Gastric Lymphoma

Objectives. The aim of this study was to evaluate clinical characteristics, prognostic factors, survival rates, and treatment modalities in patients with primary gastric lymphoma (PGL). Methods. We retrospectively reviewed and analyzed data from patients treated for PGL in our clinic from 1998 through 2010. Staging was performed using the Lugano Staging System. Overall and disease-free survival (OS and DFS) were calculated from the date of diagnosis. Results. We identified 79 patients. Thirty-seven patients (47%) were male. The median age at presentation was 57 (18–85) years. The median follow-up time was 41 (9–52) months. Thirty patients (38%) underwent surgery, 74 (92%) received chemotherapy, and 18 (23%) received radiotherapy. The five-year OS and DFS rates were 91.2% and 83.9%, respectively, in patients with stage I/II or IIE disease and 70.6% and 65.5%, respectively, in patients with stage IV disease ( for both rates). Treatment modality (surgical or conservative) had no impact on OS or DFS in early stages. In a multivariate analysis, poor performance status, advanced stage, and high LDH levels were significant bad prognostic factors for DFS, while advanced stage, poor performance status, and age > 60 years were significant bad prognostic factors for OS. Conclusion. Surgery provides no advantage for survival over conservative treatment; thus, conservative treatment modalities should be preferred initially at early stages of PGL.

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