scholarly journals Five Gene Probes Carry Most Of The Discriminatory Power Of The 70-Gene Risk Model In Multiple Myeloma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 125-125
Author(s):  
Christoph Heuck ◽  
Pingping Qu ◽  
Frits van Rhee ◽  
Sarah Waheed ◽  
Saad Z Usmani ◽  
...  
Keyword(s):  
High Risk ◽  
Research Funding ◽  
Risk Model ◽  
Progression Free Survival ◽  
Dna Probes ◽  
Low Risk ◽  
Free Survival ◽  
The Us ◽  
Risk Patients ◽  
Total Therapy

Abstract Gene expression profiling (GEP) reliably predicts overall and progression free survival in multiple myeloma. Driven by the concept that therapy will reveal biology, we applied the GEP70 risk model to 56 patients enrolled in Total Therapy 6 (TT6), a phase 2 trial for previously treated patients. One year survival estimates were 62% vs.97%, p<0.0001, Figure 1A). To investigate whether fewer than the 70 genes could predict this difference in outcomes, the probe sets of the GEP70 risk model were ranked by p-values, based on univariate Cox regression analysis for OS. The five probe sets with the smallest P values (corresponding to genes ENO1, FABP5, TRIP13, TAGLN2, and RFC4) were combined to create a continuous score (Figure1B). Association of several of these genes with different cancers has previously been reported by others. We re-trained this 5 gene model (GEP5) on a dataset of 275 uniformly treated patients on Total Therapy 3A (TT3A) and identified a new optimal cutoff of 10.68. We validated this new cutoff with patients enrolled in Total Therapy 2 (TT2) (n=351) and Total Therapy 3B (TT3B) (n=166). For TT2 patients, the dataset from which the GEP70 model was developed, clinical outcomes of the GEP5defined low risk patients were very similar to the GEP70 defined low risk patients. Survival estimates were higher for GEP5-defined high risk than for GEP70 high risk patients (5-year estimated OS: 40%, GEP5; 28%, GEP70; 5-year estimated PFS: 26%, GEP5; 15%, GEP70) (Figure 2A and 2B). This was also seen in both TT2 treatment arms. For the second validation cohort (TT3B), GEP5 and GEP70 risk distinction were similar to the TT3A discovery cohort (Figures 2C and 2D). On multivariate analysis, the GEP5-defined high-risk designation was the most adverse variable for PFS, with an estimated hazard ratio of 3.44 (95% CI: 2.02-5.86), whereas the GEP70 model was selected first for OS. (Table 1).Table 1.Multivariate stepwise Cox regression analysis performed on the TT3B validation setOverall survivalProgression-free survivalVariablen/N (%)HR (95% CI)P-valueHR (95% CI)P-valueMultivariateGEP70 high-risk36/159 (23%)4.45 (2.47, 8.02)<.001B2M > 5.5 mg/L49/159 (31%)1.73 (1.01, 2.95)0.045GEP5 high-risk42/159 (26%)3.44 (2.02, 5.86)<.001 Applied to the publicly available dataset from the HOVON group, GEP5 identified a high risk group with a 3-year estimate OS survival of 52% compared to 75% for the low risk group (p<0.001). TT4 and TT5 are phase 2 trials for previously untreated GEP70 defined low-risk and high-risk patients, respectively. GEP5 identified in TT4 a subset (17/303) of high risk patients with significantly worse 3-year estimated OS (69% vs. 86%, p=0.03), and in TT5 GEP5 identifies a low-risk subset (22/57) of patients with significantly better 3-year estimate OS (94% vs. 59%, p=0.01). Recently a large-scale proteomics experiment involving 85 patients with MM identified ENO1, FABP5, and TAGLN2 among a set of 24 proteins that are associated with short OS. It was further shown that gene expression levels correlated closely with protein abundance. In summary, we have identified 5 genes that have the greatest influence on GEP defined risk. The GEP5 score maintains prognostic power even in patients who have been risk stratified using other risk models. The correlation of expression at both mRNA and protein levels indicate that the genes identified in GEP5 are not simply an artifact of the microarray methodology, but rather supports their biologic relevance. This simplified risk model with a reduced number of genes has the potential to open molecular risk testing to a larger audience. Figure 1. Figure 1. Overall Survival in TT6 according to A) GEP70 risk score and B) GEP5 risk score Figure 2. Figure 2. Overall survival (left panels) and progression-free survival (right panels) according to GEP5 risk score in A) TT3A training set set, B) TT2 test set and C) a second test set TT3B Figure 3. Figure 3. Overall survival (left panels) and progression-free survival (right panels) according to GEP5 in A) the publicly available HOVON dataset B) TT4, for previously untreated GEP70 defined low-risk myeloma and C) TT5, for previously untreated GEP70 defined high-risk myeloma Disclosures: van Rhee: Jansen & Jansen: Research Funding. Usmani:Celgene: Consultancy, Research Funding, Speakers Bureau; Onyx: Research Funding, Speakers Bureau. Epstein:University of Arkansas for Medical Sciences: Co-inventor of the DNA probes for FISH of IGHC/IGHV (14q32), MMSET/FGFR3 (4p16), CCND3 (6p21), CCND1 (11q13), MAF (16q23), and MAFB (20q12) loci, sub. to the US Patent & Trademark Office as Prov. App# 61/726,327: Methods of Detecting 14q32 Translocations, Co-inventor of the DNA probes for FISH of IGHC/IGHV (14q32), MMSET/FGFR3 (4p16), CCND3 (6p21), CCND1 (11q13), MAF (16q23), and MAFB (20q12) loci, sub. to the US Patent & Trademark Office as Prov. App# 61/726,327: Methods of Detecting 14q32 Translocations Patents & Royalties. Zhang:University of Arkansas for Medical Sciences: Co-inventor of the DNA probes for FISH of IGHC/IGHV (14q32), MMSET/FGFR3 (4p16), CCND3 (6p21), CCND1 (11q13), MAF (16q23), and MAFB (20q12) loci, sub. to the US Patent & Trademark Office as Prov. App# 61/726,327: Methods of Detecting 14q32 Translocations, Co-inventor of the DNA probes for FISH of IGHC/IGHV (14q32), MMSET/FGFR3 (4p16), CCND3 (6p21), CCND1 (11q13), MAF (16q23), and MAFB (20q12) loci, sub. to the US Patent & Trademark Office as Prov. App# 61/726,327: Methods of Detecting 14q32 Translocations Patents & Royalties. Barlogie:Celgene: Consultancy, Honoraria, Research Funding; Myeloma Health, LLC: Patents & Royalties.

scholarly journals A Novel Epigenetic Machine Learning Model to Define Risk of Progression for Hepatocellular Carcinoma Patients

2021 ◽  
Vol 22 (3) ◽  
pp. 1075
Author(s):  
Luca Bedon ◽  
Michele Dal Bo ◽  
Monica Mossenta ◽  
Davide Busato ◽  
Giuseppe Toffoli ◽  
...  
Keyword(s):  
Machine Learning ◽  
Hepatocellular Carcinoma ◽  
High Risk ◽  
Progression Free Survival ◽  
Low Risk ◽  
Functional Enrichment ◽  
Free Survival ◽  
High Risk Patients ◽  
Risk Of Progression ◽  
Risk Patients

Although extensive advancements have been made in treatment against hepatocellular carcinoma (HCC), the prognosis of HCC patients remains unsatisfied. It is now clearly established that extensive epigenetic changes act as a driver in human tumors. This study exploits HCC epigenetic deregulation to define a novel prognostic model for monitoring the progression of HCC. We analyzed the genome-wide DNA methylation profile of 374 primary tumor specimens using the Illumina 450 K array data from The Cancer Genome Atlas. We initially used a novel combination of Machine Learning algorithms (Recursive Features Selection, Boruta) to capture early tumor progression features. The subsets of probes obtained were used to train and validate Random Forest models to predict a Progression Free Survival greater or less than 6 months. The model based on 34 epigenetic probes showed the best performance, scoring 0.80 accuracy and 0.51 Matthews Correlation Coefficient on testset. Then, we generated and validated a progression signature based on 4 methylation probes capable of stratifying HCC patients at high and low risk of progression. Survival analysis showed that high risk patients are characterized by a poorer progression free survival compared to low risk patients. Moreover, decision curve analysis confirmed the strength of this predictive tool over conventional clinical parameters. Functional enrichment analysis highlighted that high risk patients differentiated themselves by the upregulation of proliferative pathways. Ultimately, we propose the oncogenic MCM2 gene as a methylation-driven gene of which the representative epigenetic markers could serve both as predictive and prognostic markers. Briefly, our work provides several potential HCC progression epigenetic biomarkers as well as a new signature that may enhance patients surveillance and advances in personalized treatment.

scholarly journals Rituximab Maintenance Benefits Less for Follicular Lymphoma Patients with Low Risk of the Follicular Lymphoma International Index

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3544-3544
Author(s):  
Tingyu Wang ◽  
Ru Li ◽  
Rui Lv ◽  
Ying Yu ◽  
Jiawen Chen ◽  
...  
Keyword(s):  
High Risk ◽  
Follicular Lymphoma ◽  
Progression Free Survival ◽  
Risk Groups ◽  
Low Risk ◽  
Control Group ◽  
Intermediate Risk ◽  
Free Survival ◽  
Rituximab Maintenance ◽  
Risk Patients

Abstract Background Follicular lymphoma (FL) is an incurable indolent disease with a heterogeneous course. The Follicular Lymphoma International Prognostic Index (FLIPI) is the most commonly used prognostic system to predict survival. Rituximab-based immunochemotherapy is now the standard choice for the first-line therapy of FL, followed by rituximab maintenance (RM) in patients with response, which prolongs the progression-free survival (PFS). However, the role of RM in different FLIPI risk groups has never been studied as we know. In this study, we aimed to illustrate the effect of RM in FLIPI risk groups. Methods Newly diagnosed FL patients at our center were enrolled in this analysis. All the patients received the rituximab-based chemoimmunotherapy induction regimens. Response assessments were determined according to Lugano's 2014 criteria. Patients who didn't respond to induction were excluded. Categorical variables were compared using Fisher's exact test. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method and compared with the log-rank test. Results From May 2003 to September 2020, 203 newly diagnosed FL were included. 192 patients (95.0%) achieved remission (complete response, CR/partial response, PR) after immunochemotherapy induction, of whom 96 patients continued rituximab maintenance therapies every 3 months for 1-2 years (RM group) (median 7 times，range 4 to 12). 96 patients received no maintenance or fewer than 4 times (control group) (median 0 times, range 0-3). There were no significant differences in baseline characteristics other than the Ann Arbor stage and pathological grade. The RM group patients were more likely to be at low grade (71.8% vs 54.9%, P = 0.042) and advanced stage (90.6% vs 78.7% , P = 0.027) (Table 1). After a median follow-up of 36.4 months (95% confidence interval [CI], 32.2 to 40.6), median OS and PFS were not reached. The 5-year OS rates and PFS rates were 95.1% (95%CI, 90.2%-100%) and 83.0% (95%CI, 75%-91%)(Fig 1). And RM significantly prolonged the PFS, with 5-year PFS rates 92.2% (95%CI, 85.1%-99.3%) and 70.3%(95%CI, 55%-85.6%) (P = 0.0003) (Fig 2). According to FLIPI risk stratification, patients were classified into low-risk, intermediate-risk, and high-risk groups. The 5-year PFS rates were 97.7% (95%CI, 93.2%-100%), 84.7% (95%CI, 70.4%-99%), and 67.8% (95%CI, 49%-86.6%), respectively (Fig 3). For low-risk patients, there was no significant difference in PFS for the RM group vs the control group. However, for both intermediate risk and high-risk patients, PFS was significantly longer in the RM group compared to the control group (P &lt; 0.0001). The PFS rates at 5 years in intermediate-risk patients were 100% and 77.8% (95%CI, 40.8%-92.6%), for the RM group vs control group, high risk 76.4% (95%CI, 54.3%-98.5%), and 54.9% (95%CI, 21.6%-88.2%), respectively (Fig 4). Conclusion Standard rituximab maintenance significantly prolongs progression-free survival in FLIPI intermediate risk and high-risk patients with FL, but not in the FLIPI low risk group. Figure 1 Figure 1. Disclosures Wang: AbbVie: Consultancy; Astellas Pharma, Inc.: Research Funding.

scholarly journals Novel Prognostic Scoring System for Autologous Hematopoietic Cell Transplantation (AHCT) in Multiple Myeloma (MM)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 783-783 ◽  
Author(s):  
Binod Dhakal ◽  
Raphael Fraser ◽  
Zhubin Gahvari ◽  
Aric C. Hall ◽  
Natalie Scott Callander ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Scoring System ◽  
Research Funding ◽  
Validation Cohort ◽  
Progression Free Survival ◽  
Low Risk ◽  
Advisory Committees ◽  
Final Model ◽  
Free Survival

Background: Novel agent induction and AHCT remains the preferred initial therapeutic strategy for transplant-eligible MM patients. Current prognostic tools in MM focus solely on disease-specific factors at diagnosis to determine patient prognosis-International Staging System (ISS) and revised-ISS (R-ISS). A major limitation to both, the ISS and R-ISS, is that they are not specific for HCT-eligible patients and do not take into account other patient factors that may enter into a decision to pursue AHCT. The data used to generate these staging systems were from broad populations with varying upfront treatment strategies and included patients who were ineligible for intensive therapy. Additionally, there is considerable interest in identifying the population that relapses early despite modern induction/AHCT approaches who are candidates for novel approaches for maintenance/consolidation. To address these problems, we used data from the Center for Blood and Marrow Transplant Research (CIBMTR) registry to identify disease-, patient-, and transplantation-specific variables that are associated with progression-free survival (PFS) in patients undergoing upfront AHCT (within 12 months of diagnosis). Methods: We used the outcomes of 2528 MM patients undergoing upfront AHCT from 2008-2017 reported to the CIBMTR. Patients were divided into training and validation sets with a 50% random split. High risk cytogenetics was defined as the presence of one or more of the following: t(4;14), t (14;16), t (14;20), del 13q, del 17p, 1q gain, or 1p deletion. We used a Cox multivariable model to identify factors prognostic of progression free survival (PFS) in a training subset. The regression coefficients of the final model was transformed into a risk score with an appropriate transformation. A weighted score using these factors was assigned to the training cohort (n = 917) and validation cohort (n=897) using subset that had all values that entered the final model. Kaplan-Meier estimates of the individual scores were used to classify patients into risk groups for both cohorts. Results: Baseline characteristics of these patients are shown in Table 1. No cytogenetic abnormality, VRD induction, pre-AHCT bone marrow plasma cells (BMPCs) &lt;10% and 1 line of induction chemotherapy were assigned 0 points. Pre-AHCT BMPCs ≥10% (hazard ratio HR, 1.47; 95% CI, 1.19-1.83), use of ≥2 lines of induction chemotherapy prior to AHCT (HR 1.32; 95% CI 1.06-1.64), standard cytogenetic risk vs. no abnormality (HR 1.41; 95% CI 1.13-1.77) and induction regimens (non-VRD regimens vs. VRD) (HR 1.4, 95% CI 1.17-1.74) were associated with increased hazard of progression and assigned 1 point in the scoring system. Presence of high-risk cytogenetics vs. no abnormality (HR 1.87; 95% CI 1.45-2.42) was assigned 2 points, and the use of thalidomide and dexamethasone (TD) as an induction regimen (HR 2.19; 95% CI 1.48-3.2) was assigned 3 points. A two-category system was created based on the scoring: low risk (0-3) and high risk (4-6). The scoring system was prognostic for PFS when applied to both cohorts. High-risk group was found to have significantly higher risk of progression and/or death compared to low risk in training (HR 2.2; 95% CI 1.74-2.86; p&lt;0.0001) and validation cohort (HR 1.7, 95% CI 1.30-2.22; p=0.0001) respectively (Table 2). The 3-year PFS in the training cohort was 60% (95% CI 56%-64%) in low risk and 27% (95% CI 17%- 36%) in high risk while in the validation cohort was 51% (95% CI 47%-55%) in low risk and 28% (95% CI 16%- 39%) in high risk (Figure 1A and 1B). Conclusions: We describe a prognostic model specifically for patients undergoing upfront AHCT in MM which can identify patients at very high risk for early relapse/progression. These patients should be ideal candidates for studies of immunotherapy or other interventions after AHCT aimed at reducing relapse. Disclosures Dhakal: Sanofi: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees. Kumar:Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding. Shah:Genentech, Seattle Genetics, Oncopeptides, Karoypharm, Surface Oncology, Precision biosciences GSK, Nektar, Amgen, Indapta Therapeutics, Sanofi: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Nkarta: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees; Teneobio: Consultancy, Membership on an entity's Board of Directors or advisory committees; University of California, San Francisco: Employment; Poseida: Research Funding; Indapta Therapeutics: Equity Ownership; Celgene, Janssen, Bluebird Bio, Sutro Biopharma: Research Funding. Qazilbash:Amgen: Consultancy, Other: Advisory Board; Autolus: Consultancy; Bioclinical: Consultancy; Genzyme: Other: Speaker. D'Souza:EDO-Mundapharma, Merck, Prothena, Sanofi, TeneoBio: Research Funding; Prothena: Consultancy; Pfizer, Imbrium, Akcea: Membership on an entity's Board of Directors or advisory committees. Hari:AbbVie: Consultancy, Honoraria; Cell Vault: Equity Ownership; Sanofi: Honoraria, Research Funding; Spectrum: Consultancy, Research Funding; Amgen: Research Funding; Kite: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; BMS: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding.

EUTOS Score Identifies Cases with Poor Outcome in Patients with Early Chronic Phase Chronic Myeloid Leukemia, Though Not Predictive for Optimal Response to Imatinib

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3778-3778 ◽  
Author(s):  
Mario Tiribelli ◽  
Massimiliano Bonifacio ◽  
Elisabetta Calistri ◽  
Gianni Binotto ◽  
Elena Maino ◽  
...  
Keyword(s):  
High Risk ◽  
Risk Group ◽  
Progression Free Survival ◽  
High Risk Group ◽  
Low Risk ◽  
Molecular Response ◽  
Free Survival ◽  
Optimal Response ◽  
Risk Patients ◽  
Eutos Score

Abstract Abstract 3778 Introduction. The EUTOS score has recently been developed by the European Leukemia-Net (ELN) to predict the achievement of an 18-month complete cytogenetic response (CCyR) and progression-free survival in imatinib-treated early chronic phase (ECP) chronic myeloid leukemia (CML) patients. The score uses the percentage of basophils and spleen size to divide patients in 2 groups of low- and high-risk. Since its publication in 2011, however, there have been conflicting reports about the efficacy of EUTOS score. Moreover, scanty data are available on the power of this scoring system to foresee optimal response to imatinib, as defined by ELN recommendations. Aims and Methods. To test the power of EUTOS score in predicting achievement of optimal response to imatinib, as defined by ELN, time to imatinib failure (TTF) and progression-free survival (PFS), we evaluated 265 ECP CML patients treated with front-line standard dose imatinib (400 mg daily) at 5 major hematology centres in the north-eastern area of Italy. Partial cytogenetic response (PCyR) and CCyR were defined as 1–35% and 0% Ph+ metaphases, respectively; major molecular response (MMR) was defined as BCR-ABL <0.1%IS. TTF was measured from the start of imatinib to the date of any of the following events: progression to accelerated or blastic phase, death for any cause at any time, imatinib dose increase (≥ 600 mg/day) for primary or secondary hematologic or cytogenetic resistance. PFS was measured from the start of imatinib to the date of progression to accelerated or blastic phase or death for any cause at any time. Survival probabilities were estimated by the Kaplan-Meier method and compared by log rank test; differences among variables were evaluated by the Fisher's exact test or by Student's t-distribution. Results. A total of 265 consecutive patients with ECP CML were included in this study. The median age was 55 years (range 19–84), with 149 males and 116 females. The median follow-up was 61 months (range 6–136). The median time from diagnosis to imatinib therapy was 0.7 months (range 0 – 7.6). The distribution according to the EUTOS score was: 248 patients (93.6%) in the low risk group and 17 patients (6.4%) in the high risk group. The “optimal response” endpoints to imatinib (i.e. PCyR at 6th months, CCyR at 12th months and MMR at 18th months) were higher in low-risk patients, but did not achieve statistical significance. Specifically, the values were as following: PCyR 86% vs 67% (p=0.055), CCyR 80% vs 63% (p=0.117) and MMR 61% vs 36% (p=0.126). Cumulative incidence of CCyR was comparable in the two groups (88%% in low-risk and 80% in high risk), but time to CCyR was shorter in low-risk patients (6 months) compared to the one in high-risk patients (9 months) (p=0.048) [figure 1]. More importantly, EUTOS score was able to predict long term response to therapy. Indeed, 59% of patients in the high-risk group experienced imatinib failure, compared to 30% in the low-risk group (p=0.027). Moreover also TTF was significant shorter in the high-risk group [figure 2]. Fifty-three patients in the low-risk group (21%) were switched to 2nd-generation TKIs (29 dasatinib, 22 nilotinib, 1 bosutinib, 1 ponatinib), compared to six (35%) in the high-risk group (4 dasatinib, 2 nilotinib). Also PFS rate was significantly worse in patients with high EUTOS score, with 11/248 events (4%) in the low-risk group and 4/17 (23%) in the high-risk cases (p=0.01) [figure 3]. Conclusions. In our study group, the EUTOS score was predictive for long-term outcome of imatinib therapy, both in terms of treatment failure and of progression-free survival. Taking into consideration the ELN definitions of optimal response, there was a trend toward better cytogenetic and molecular response in low-risk patients; the lack of statistical significance could be due to the relatively small number of high-risk cases. Disclosures: No relevant conflicts of interest to declare.

Haploidentical Transplantation Using T-Cell Replete Peripheral Blood Stem Cells and Myeloablative Conditioning in Patients with High-Risk Hematologic Malignancies Who Lack Conventional Donors Is Well Tolerated and Produces Excellent Relapse-Free Survival: Results of A Prospective Phase II Trial

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 889-889
Author(s):  
Connie A. Sizemore ◽  
Asad Bashey ◽  
Melissa Sanacore ◽  
Karen Manion ◽  
H. Kent Holland ◽  
...  
Keyword(s):  
T Cell ◽  
High Risk ◽  
Research Funding ◽  
Low Risk ◽  
Peripheral Blood Stem Cells ◽  
Free Survival ◽  
Haploidentical Transplantation ◽  
Preparative Regimen ◽  
Blood Stem Cells ◽  
Risk Patients

Abstract Abstract 889 Introduction: Haploidentical hematopoietic stem cell transplantation (HSCT) provides an opportunity for nearly all patients to benefit from HSCT when a human leukocyte antigen (HLA) genotypically matched donor is not available. Initial approaches to mismatched allografting using ex-vivo T-cell depletion and intense preparative regimens were associated with high rates of graft rejection, severe graft-versus-host disease (GVHD) and infectious complications, resulting in an unacceptable treatment-related morbidity and mortality. More promising outcomes have been recently demonstrated by a new approach to haploidentical transplantation, utilizing a nonmyeloablative preparative regimen, followed by a T cell-replete bone marrow infusion and post-transplantation immunosuppression with high dose Cyclophosphamide (Cy), tacrolimus, and mycophenolate mofetil (MMF). However, relapse represents the major cause of treatment failure in these patients, particularly with high-risk myeloid malignancies. Methods: In order to decrease relapse risk in patients with high-risk malignancies, we initiated a trial between January 2009 and March 2011, of haploidentical allografting using a myeloablative preparative regimen and peripheral blood stem cells (PBSC) instead of bone marrow as the graft source. Eligibility was limited to patients perceived to be at prohibitively high risk of relapse following nonmyeloablative haploidentical BMT. Initial conditioning (n=5) consisted of Fludarabine 30 mg/m2 on days −7 to −2, IV Busulfan 130 mg/m2 on days −7 to −4, and Cy 14.5 mg/kg on days −3 and −2 followed by an unmanipulated PBSC infusion in all patients. In response to increased rates of mucositis, fludarabine and busulfan doses were decreased by 30% and 15%, respectively, in subsequent patients. Post-grafting immunosuppression consisted of Cy 50mg/kg/day on days 3 and 4, MMF, and tacrolimus. Results: A total of twenty patients were enrolled in the study: median age 44 years (25–56); diagnoses AML=12, ALL= 2, HD=1, CML=3, CLL=1, NHL=1; allograft from 5/10 locus matched (n=14), 6/10 locus matched (n=2), 7/10 locus matched (n=3), or 8/10 locus matched (n=1). CIBMTR disease risk-high risk =7 (35%), intermediate risk = 4 (20%) or low risk = 9 (45%). Of the 9 low risk patients, seven were cytogenetically poor-risk AML and/or required ≥2 induction cycles to induce complete response. Donor engraftment occurred in all 20 patients, with a median time to neutrophil and platelet recovery of 16 and 27 days, respectively. All evaluable patients achieved complete donor T cell and myeloid chimerism by Day +30. The cumulative incidence of grades II–IV and grades III–IV aGVHD was 30% and 20%, respectively. The cumulative incidence of cGVHD at one year was 42%. Non-relapse mortality (NRM) at 100 days and 1 yr was 10% for all patients and 0% for low-risk patients. Non-infectious fever (median tmax 103.9; 101.2–106.8), possibly related to cytokine release from proliferating alloreactive cells, developed in 90% of patients within a median of 2.5 days (1–5) of transplant and resolved by day 6 (5-7) following post-transplant Cy. BK virus-associated cystitis occurred in 75% of patients, and was severe (requiring hospital admission for bladder irrigation and/or pain management) in 35%. Other severe infections were not seen at increased frequency compared to conventional donor myeloablative transplants at our center. With a median follow-up of 14 months, the estimated 1 year overall and disease-free survival was 74% and 51%, respectively for all patients; 100% and 76%, respectively for low-risk patients. Conclusion: HLA haploidentical HSCT using this myeloablative regimen with T-cell replete PBSC and post-transplant Cy is associated with excellent rates of engraftment, GVHD, NRM and DFS, it is therefore a valid option in patients with high-risk malignancies who lack timely access to a conventional donor. Disclosures: Sizemore: Otsuka America Pharmaceuticals, Inc.: Research Funding. Bashey:Otsuka America Pharmaceuticals, Inc.: Research Funding. Sanacore:Otsuka America Pharmaceuticals, Inc.: Research Funding. Manion:Otsuka America Pharmaceuticals, Inc.: Research Funding. Holland:Otsuka America Pharmaceuticals, Inc.: Research Funding. Morris:Otsuka America Pharmaceuticals, Inc.: Research Funding. Brown:Otsuka America Pharmaceuticals, Inc.: Research Funding. Solomon:Otsuka America Pharmaceuticals, Inc.: Research Funding.

A Clinicogenetic Risk Model (m7-FLIPI) Prospectively Identifies One-Half of Patients with Early Disease Progression of Follicular Lymphoma after First-Line Immunochemotherapy

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 333-333 ◽  
Author(s):  
Jurinovic Vindi ◽  
Robert Kridel ◽  
Annette M Staiger ◽  
Monika Szczepanowski ◽  
Heike Horn ◽  
...  
Keyword(s):  
High Risk ◽  
Research Funding ◽  
Risk Model ◽  
Low Risk ◽  
First Line ◽  
Free Survival ◽  
Therapy Initiation ◽  
Line Therapy ◽  
Progression Of Disease

Abstract Background: Follicular lymphoma (FL) is the second most common nodal lymphoma worldwide and remains incurable for most patients (pts). FL is recognized to be a highly heterogeneous disease and a subset of pts experience remarkable poor outcome. In a recent study, 19-26% of pts receiving first-line R-CHOP experienced progression of disease (POD) within 24 months after diagnosis and had a 5-year (yr) overall survival (OS) of only 34-50%, as compared to a 5-yr OS of 90-94% for pts without POD within 24 months (Casulo et al., J Clin Oncol 2015). Consequently, event-free survival at 12 (EFS12) and 24 months (EFS24) have been suggested as novel surrogate endpoints for poor overall survival in clinical trials and useful for patient counseling (Maurer et al., ASH 2014). We have previously shown that a clinicogenetic risk model (m7-FLIPI) that includes the mutation status of seven genes (EZH2, ARID1A, MEF2B, EP300, FOXO1, CREBBP, and CARD11), the FL International Prognostic Index (FLIPI), and the Eastern Cooperative Oncology Group (ECOG) performance status, improves risk stratification for failure-free survival (FFS) and OS in pts with FL receiving first-line immunochemotherapy (Pastore et al., Lancet Oncology 2015). An online tool is available at: http://www.glsg.de/m7-flipi. It would be advantageous to determine prognosis prior to front-line therapy rather than after POD. Thus, we aimed to investigate the predictive utility of the m7-FLIPI for early POD. Patients and Methods: Clinical and mutation data were available from two independent cohorts: 151 pts who received R-CHOP and IFN maintenance as part of a randomized trial of the German Low-Grade Lymphoma Study Group (GLSG), and 107 pts from a population-based registry of the British Columbia Cancer Agency (BCCA) who received R-CVP. Among the latter, 93 (87%) received R-maintenance by intention to treat. All pts had symptomatic, advanced stage or bulky disease considered ineligible for curative radiotherapy, and a biopsy specimen obtained </=12 months prior to the initiation of first-line therapy. POD was defined as progression, relapse, or death due to any cause. POD12 and POD24 were defined based on POD status at 12 and 24 months after therapy initiation, respectively. Logistic regression analysis was performed to assess if m7-FLIPI was predictive of early POD using the statistical software R (version 3.1.2). Results: In the GLSG cohort, median age was 57 yrs (range 27-77), 51% had high-risk FLIPI, and 5-yr failure-free survival (FFS) and OS rates were 66% and 83%, respectively (median follow-up for OS 7.7 yrs). In the BCCA cohort, median age was higher (62 yrs, 37-83), but high-risk FLIPI was similarly frequent (50%); 5-yr FFS and OS rates were 58% and 74%, respectively (median follow-up for OS 6.7 yrs). A total of 43 GLSG (28%) and 24 BCCA pts (22%) were classified as high-risk by m7-FLIPI, with a 5-yr OS of 65% and 42%, respectively. In the GLSG cohort, 8 (5%) and 29 pts (19%) had POD within 12 and 24 months, respectively, 4 and 10 pts were censored before POD12 and POD24 (table). High-risk m7-FLIPI pts were significantly more likely to experience early POD with an Odds Ratio (OR) of 20.80 (95% confidence interval (CI) 3.53-395.96; p=0.0052) for POD12 and 6.33 (95% CI 2.67-15.69; p<0.0001) for POD24. Likewise, in the BCCA cohort, 16 (15%) and 28 pts (26%) experienced POD12 and POD24, respectively (table). The OR for high-risk m7-FLIPI pts was 4.69 (95% CI 1.52-14.65; p=0.0068) for POD12, and 5.36 (95% CI 2.03-14.60; p=0.0008) for POD24. In the GLSG and BCCA cohorts, the m7-FLIPI had a sensitivity of 88% and 50%, a specificity of 75% and 82%, a positive predictive value (PPV) of 16 and 33%, and a negative predictive value (NPV) of 96% and 90% to predict POD12. For POD24, sensitivity was 62% and 46%, specificity 79% and 86%, PPV 42% and 54%, and NPV 82% and 82%, respectively. Conclusion: We conclude that patients classified as high-risk m7-FLIPI are highly enriched among those with early progression of disease. However, approximately one-half of patients with progression by 24 months after therapy initiation are classified as low-risk m7-FLIPI. Thus, further efforts are needed to refine the m7-FLIPI and thereby capture additional cases that may benefit from innovative first-line approaches. Table. Population m7-FLIPI N POD12 POD24 GLSG Total 151 8/147* 29/141* High-risk 43 7 18 Low-risk 108 1 11 BCCA Total 107 16/107 28/107 High-risk 24 8 13 Low-risk 83 8 15 *Pts censored were removed Disclosures Ansell: Bristol-Myers Squibb: Research Funding; Celldex: Research Funding.

EUTOS Score Is Also Valid in CML Patients Not Involved in Clinical Studies

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3759-3759 ◽  
Author(s):  
Verena S Hoffmann ◽  
Jiri Mayer ◽  
Anna G. Turkina ◽  
Andrzej Hellmann ◽  
Karel Indrak ◽  
...  
Keyword(s):  
High Risk ◽  
Research Funding ◽  
Progression Free Survival ◽  
Study Data ◽  
Observation Time ◽  
High Risk Group ◽  
Advisory Committees ◽  
Free Survival ◽  
Risk Patients ◽  
Eutos Score

Abstract Abstract 3759 Data of 2060 patients from the in-study registry of the European Outcome and Treatment Study (EUTOS) for CML were used to develop and validate the EUTOS score [1]. All these patients were included in prospective controlled clinical trials. The EUTOS score aims to support clinical decision making within the first 18 months after initiation of treatment with imatinib. Patients who did not achieve complete cytogenetic remission (CCyR) within 18 months had a lower probability of achieving CCyR in the further course of therapy and were more likely to suffer from progressive disease. The EUTOS score is calculated by multiplying the percentage of basophiles by seven and the spleen size measured in centimeters below costal margin by four and adding both values. Both parameters have to be assessed before any therapy is started. If the resulting value is higher than 87 the patient is at high risk of not being in CCyR after 18 months of therapy, otherwise he is a low risk patient. In the In-study data the EUTOS score showed a sensitivity of 21%, a specificity of 92% and a positive predictive value of 34%. So every third patient in the high risk group eventually did not achieve CCyR. As the development and validation of the EUTOS score used patient data from prospective clinical studies we now wanted to assess the score's performance on CML-patients in routine health care. The EUTOS Out-Study registry provides data of 1547 patients from Spain, Poland, Czech Republic, Romania, Slovakia, and Russia. Information on the EUTOS score and the status of CCyR at 18 months (+/− 3 months) was available for 316 patients. The patients in the In-study registry were slightly older than in the Out-study registry (median (range): 52 years (18–83) vs 48 years (18–85)) and more men were involved (61% vs 52%). The Out-study data support the timeline of 18 months as patients without CCyR at 18 months progress more often than patients with CCyR (progression free survival after 36 months 99.2% vs 90.8%, p<0.0001). As 316 of 1547 datasets might lead to a selection bias we compared the characteristics of both groups but medians of age, spleen size, platelets, percentage of blast cells, percentage of eosinophils, white blood cell count, hemoglobin and percentage of basophils were almost equal. So no selection bias is evident. In the Out-study data the EUTOS score reached a sensitivity of 16%, a specificity of 90%, and a positive predictive value of 41%. These results were similar to the results of the In-study data and confirmed that the score defines a small high risk group with a high probability of not reaching CCyR. The cumulative incidence curve showed that high risk patients achieve CCyR significantly later and less often than low risk patients (Median 34.0 months vs 20.4 months, 32.6% vs 43.4% after 18 months of therapy, p<0.0001). In addition high risk patients have a significantly higher risk of progression (progression free survival after 5 years: 88.8% vs 80.7%, p=0.0235, median observation time 66 months) and death (overall survival after five years 89.9% vs 82.0%, p=0.0103, median observation time 66 months). The results show that the EUTOS score is also valid in Out-study patients and is able to identify patients with a significantly higher risk of not achieving CCyR and of progression, after 18 months of therapy. As the score is easy to calculate with only two variables needed that are routinely measured it is a simple way to alert physicians to the need for closer monitoring of the patient. Disclosures: Hoffmann: Novartis Pharma: Research Funding. Turkina:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Baccarani:Bristol Myers Squibb: Honoraria; Novartis Pharma: Research Funding.

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

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

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

ABVD Versus Escalated Beacopp in Advanced Stage Hodgkin's Lymphoma: Results from a Retrospective, Multicenter European Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1565-1565 ◽  
Author(s):  
Patrizia Mondello ◽  
Irene Dogliotti ◽  
Jan-Paul Bohn ◽  
Federica Cavallo ◽  
Simone Ferrero ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Advanced Stage ◽  
Advisory Committees ◽  
Free Survival ◽  
High Risk Patients ◽  
Risk Patients

Purpose: Hodgkin's lymphoma (HL) is a highly curable disease even in advanced-stage, with &gt;90% of long-term survivors. Currently, the standard of care is ABVD (doxorubicin, etoposide, vinblastine and dacarbazine), as it is less toxic and as effective as other more intensive chemotherapy regimens. Alternatively, BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone) has been proposed as front-line intensified regimen with a better initial disease control and prolonged time to relapse when compared to ABVD. However, this advantage is associated with higher rates of severe hematologic toxicity, treatment-related deaths, secondary neoplasms and infertility. To date, the debate regarding which regimen should be preferred as first line for advanced-stage HL is still ongoing. To shed some light on this open question we compared efficacy and safety of both regimens in clinical practice. Patients and Methods: From October 2009 to October 2018, patients with HL stage III-IV treated with either ABVD or BEACOPP escalated (BEACOPPesc) were retrospectively assessed in 7 European cancer centers. Results: A total of 372 consecutive patients were included in the study. One-hundred and ten patients were treated with BEACOPPesc and 262 with ABVD. The baseline characteristics of the two groups did not differ significantly, except for a higher rate of high-risk patients in the BEACOPPesc group in contrast to the ABVD one (47% vs 18%; p= 0.003). Complete response rate (CR) assessed by PET imaging at the end of the second cycle was 67% and 78% for the ABVD and BEACOPPesc group (p= 0.003), respectively. Thirteen patients of the ABVD group achieved stable disease (SD) and 6 had a progression disease (PD). On the other hand, 4 of the patients in the BEACOPPesc group progressed, another 2 interrupted therapy because life-threatening toxicity. At the end of the therapy, CR was 76% in the ABVD group and 85% in the BEACOPPesc group (p= 0.01). A total of 20% patients in the ABVD group and 14% patients in the BEACOPPesc group received consolidation radiotherapy on the mediastinal mass at the dose of 30Gy. After radiotherapy, the number of patients with CR increased to 79% and 87% in the two groups (p= 0.041), respectively. Thirty-nine patients (35%) in the BEACOPPesc group required dose reduction of chemotherapy due to toxicity compared to 12 patients (5%; p= &lt;0.001) in the ABVD group. Overall, the rate of severe toxicities was higher in the BEACOPPesc group in comparison with the ABVD cohort. In particular, there was a significant increased frequency of acute grade 3-4 hematologic adverse events (neutropenia 61% vs 24%; anemia 29% vs 4%; thrombocytopenia 29% vs 3%), febrile neutropenia (29% vs 3%), severe infections (18% vs 3%). Myeloid growth factors were administered to 85% and 59% of patients in the BEACOPPesc group compared to the ABVD group. Blood transfusions were required in 51% and 6% of patients in the BEACOPPesc group compared to the ABVD cohort. Progression during or shortly after treatment occurred in 5 patients in the BEACOPPesc group (4%) and in 16 patients in the ABVD group (6%; p= 0.62). Among the 96 patients who achieved a CR after BEACOPPesc and radiotherapy, 8 relapsed (8%), compared to 29 of 208 patients in the ABVD group (14%; p= 0.04). At a median follow-up period of 5 years, no statistical difference in progression free survival (PFS; p=0.11) and event-free survival (EFS; p=0.22) was observed between the BEACOPPesc and ABVD cohorts. Similarly, overall survival (OS) did not differ between the two groups (p=0.14). The baseline international prognostic score (IPS &lt;3 vs ≥ 3) significantly influenced the EFS with an advantage for the high-risk group treated with BEACOPPesc (Figure 1A; p=0.03), but not the PFS (Figure 1B; p=0.06) and OS (Figure 1C; p=0.14). During the follow-up period, in the BEACOPPesc group one patient developed myelodysplasia and one acute leukemia. Second solid tumors developed in one patient in the ABVD group (lung cancer) and one in BEACOPPesc group (breast cancer). Conclusion: We confirm that the ABVD regimen is an effective and less toxic therapeutic option for advanced-stage HL. Although BEACOPP results in better initial tumor control especially in high-risk patients, the long-term outcome remains similar between the two regimens. Disclosures Ferrero: EUSA Pharma: Membership on an entity's Board of Directors or advisory committees; Servier: Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Speakers Bureau. Martinelli:BMS: Consultancy; Pfizer: Consultancy; ARIAD: Consultancy; Roche: Consultancy; Novartis: Consultancy. Willenbacher:European Commission: Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Myelom- und Lymphomselbsthilfe Österreich: Consultancy, Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead Science: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; IQVIA: Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees; oncotyrol: Employment, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Fujimoto: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Celgene: 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; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tirol Program: Research Funding; Abbvie: Consultancy, Honoraria; Sandoz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Sequential Treatment with Rituximab and CHOP Chemotherapy in B-Cell PTLD - Moving Forward to a First Standard of Care: Results From a Prospective International Multicenter Trial.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 100-100 ◽  
Author(s):  
Ralf Trappe ◽  
Sylvain Choquet ◽  
Stephan H.K. Oertel ◽  
Veronique Leblond ◽  
Daan Dierickx ◽  
...  
Keyword(s):  
High Risk ◽  
Complete Remission ◽  
Risk Stratification ◽  
Disease Progression ◽  
Early Treatment ◽  
Interim Analysis ◽  
Research Funding ◽  
Low Risk ◽  
Sequential Treatment ◽  
Risk Patients

Abstract Abstract 100 Purpose: This trial aimed to investigate the efficacy and safety of sequential treatment with rituximab and CHOP-21 in patients with PTLD unresponsive to reduction of immunosuppression. Methods: An ongoing prospective, multicenter, international phase II trial was initiated in January 2003. Initially patients were treated with a fixed sequence of rituximab at days 1, 8, 15 and 22 (4R) followed by four cycles of CHOP-21 combined with G-CSF support starting 4 weeks after the last dose of rituximab (sequential treatment, ST). Based on the results of an earlier interim analysis showing that the response to rituximab predicts OS the trial was amended in 2007 introducing risk stratification according to the response to 4R (risk stratified sequential treatment, RSST). In RSST patients achieving a complete remission after 4R (low risk) continue with four 3-weekly courses of rituximab monotherapy while patients in PR, SD or PD (high risk) are followed by four cycles of R-CHOP-21 + G-CSF. Results: This is a scheduled interim analysis after inclusion of a total of 104 patients. The median follow up is 34.0 months for ST (64 pts.) and 9.1 months for RSST (40 pts.). 61 ST and 35 RSST patients were diagnosed with monomorphic PTLD, 3/5 with polymorphic PTLD. 27/23 patients were kidney, 3/0 kidney+pancreas, 15/8 liver, 13/6 heart, 6/3 lung or heart+lung transplant recipients. Median age at diagnosis of PTLD was 53/60 years (mean age: 48/56 years). 59%/58% of patients had an advanced stage of disease (Ann Arbor III/IV) and 49%/47% of tumors were EBV positive. 75%/75% of patients had late PTLD (i.e. later than 1 year after transplantation). LDH was elevated in 71%/64% of patients, respectively. The overall response rate (ORR) to 4 initial courses of rituximab monotherapy (4R, N=104) was 54% with a CR-rate of 32% and the subsequent completion of treatment with CHOP or R-CHOP allowed a clear increase of the response (p<0.0001, Fig. 1). With ST the final ORR was 89% (CR rate: 69%). 86%, 75% and 75% of patients were without disease progression at one, two and three years, respectively (Fig. 2a). Disease free survival was 87%, 78% and 70% at one, two and three years. There were 6 early treatment associated deaths (9%) resulting from infections (1 from CMV-colitis, 1 from PcP-pneumonia, 1 from fulminant hepatitis, 3 from sepsis) and 2/64 patients died from refractory PTLD. Two further patients died due to hemorrhage during treatment. With RSST the ORR was 90% and 73% achieved a complete remission. 90% of patients were without disease progression at one year (Fig. 2a). There was one early treatment related death due to infection (2.5%). This patient died from sepsis secondary to intestinal perforation in response to R-CHOP treatment. 2/40 patients died from refractory PTLD. With 1 event in 16 patients in both, the ST and the RSST-arms, subsequent consolidation with rituximab monotherapy (RSST) seems not to be inferior to consolidation with 4 cycles of CHOP (ST) in patients with a CR after 4R. Up to now there is no difference in toxicity between CHOP and R-CHOP in ST/RSST. Patients failing to achieve a complete remission with 4R (72 patients) seem to benefit from the subsequent escalation from CHOP to R-CHOP (Fig. 2b). Conclusions: This is the largest prospective study in PTLD. Sequential treatment with rituximab and CHOP-21 + G-CSF is well tolerated and highly effective with a treatment related mortality of less than 10% and an efficacy of up to 90%. In comparison to historic series of rituximab monotherapy, significantly more patients achieve a CR with sequential treatment and time to progression (TTP) is very much prolonged. In comparison to historic series of CHOP, sequential treatment is much better tolerated. This may result from a lower tumor burden and a better patient fitness at the time chemotherapy is applied. Introduction of risk stratification according to the response to 4 courses of rituximab monotherapy might further improve these results restricting chemotherapy related toxicity to high risk patients while these data suggest that low risk patients can effectively be treated with extended rituximab monotherapy. Thus, risk stratified sequential treatment (RSST) might further improve OS in this difficult to treat disease. Disclosures: Trappe: Hoffmann La Roche Ltd.: Consultancy, Honoraria, Research Funding; AMGEN GmbH: Research Funding. Choquet:Hoffmann La Roche Ltd.: Consultancy, Honoraria. Oertel:Hoffmann La Roche Ltd.: Employment, Equity Ownership. Leblond:Hoffmann La Roche Ltd.: Consultancy, Honoraria, Research Funding. Ekman:Hoffmann La Roche Ltd.: Honoraria. Dührsen:Hoffmann La Roche Ltd.: Honoraria, Research Funding. Salles:Hoffmann La Roche Ltd.: Consultancy, Honoraria, Research Funding. Morschhauser:Hoffmann La Roche Ltd.: Honoraria. Riess:Hoffmann La Roche Ltd.: Consultancy, Honoraria, Research Funding; AMGEN GmBH: Consultancy, Honoraria, Research Funding.

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