The Impact of Rituximab and Radiotherapy On Treatment Outcome of Patients with DLBCL and Skeletal Involvement

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 690-690
Author(s):  
Gerhard Held ◽  
Samira Zeynalova ◽  
Niels Murawski ◽  
Marita Ziepert ◽  
Barbara Kempf ◽  
...  
Keyword(s):  
Overall Survival ◽  
Board Of Directors ◽  
Cox Regression ◽  
Multivariable Analysis ◽  
Event Free Survival ◽  
Advisory Committees ◽  
Free Survival ◽  
Skeletal Involvement ◽  
The Impact

Abstract Abstract 690 Background: There is limited information on the role of skeletal involvement in DLBCL patients treated with rituximab. Methods: In a retrospective subgroup analysis patients with aggressive B-cell lymphomas with and without skeletal involvement were compared with respect to clinical presentation, event-free and overall survival. Results: Of 3840 patients 292 (7.6%) had skeletal involvement. In a multivariable analysis of patients treated within the randomized MInT and RICOVER-60 trials, the two largest randomized trials addressing the role of rituximab in DLBCL to date, skeletal involvement was associated with a reduced hazard ratio (HR) of 0.8 (p=0.181) for event-free survival and 0.7 (p=0.083) for overall survival for patients treated without, but with an increased HR (1.5; p=0.048) for event-free and (1.1; p=0.828) for overall survival in patients treated with rituximab. This was due to the failure of rituximab to improve the outcome of patients with skeletal involvement. In the MInT trial, the 3-year EFS rates were 64% without and 63% with rituximab (p=0.680) and the 3-year OS rates were 83% without and 90% with rituximab (p=0.542). similarly, in the RICOVER-60 trial, the 3-year EFS rates were 45% without and 50% with rituximab (p=0.593) and the 3-year OS rates were 68% without and 68% with rituximab. In a Cox regression model for event-free survival adjusted for the IPI risk factors a relevant interaction (HR 1.5; p=0.056) term between rituximab and skeletal involvement was observed. In contrast to rituximab, additive radiotherapy to sites of skeletal involvement was associated with a better outcome: 3-year EFS rates were 40% without and 75% with radiotherapy (p<0.001), 3-year OS rates were 70% without and 86% with radiotherapy to sites of skeletal involvement (p=0.064). In a multivariable analysis radiotherapy reduced the risk for an event in EFS by 70% (HR=0.3; p=0.001) and by 50% in OS (HR=0.5; p=0.111). Conclusion: Addition of rituximab failed, but radiotherapy to sites of skeletal involvement did improve the outcome of DLBCL patients with skeletal involvement. Radiotherapy to sites of skeletal involvement, though abandoned by many cooperative groups world-wide, is recommended in the rituximab era, unless prospective trials demonstrate that it might be omitted in cases with a negative PET after immunochemotherapy. Disclosures: Dreyling: Roche: Membership on an entity's Board of Directors or advisory committees. Hallek:Roche: Membership on an entity's Board of Directors or advisory committees. Schmitz:Chugai: Membership on an entity's Board of Directors or advisory committees. Pfreundschuh:Roche: Membership on an entity's Board of Directors or advisory committees; Chugai: Consultancy.

25-OH-Vitamin-D Deficiency Impairs Rituximab-Mediated Cellular Cytotoxicity and Is Associated With An Inferior Outcome Of Elderly DLBCL Patients Treated With Rituximab

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1819-1819 ◽  
Author(s):  
Joerg Thomas Bittenbring ◽  
Bettina Altmann ◽  
Frank Neumann ◽  
Marina Achenbach ◽  
Joerg Reichrath ◽  
...  
Keyword(s):  
Vitamin D ◽  
Overall Survival ◽  
Vitamin D Deficiency ◽  
Multivariable Analysis ◽  
Serum Levels ◽  
Event Free Survival ◽  
Free Survival ◽  
Vitamin D Levels ◽  
25 Oh Vitamin D ◽  
The Impact

Abstract Background To investigate the impact and underlying mechanisms of vitamin-D-deficiency (VDD) on outcome of elderly (61 to 80 year-old) DLBCL patients. Methods Pretreatment 25-OH-vitamin-D serum levels from 359 patients treated in the prospective multicenter RICOVER-60 trial with 6 or 8 cycles of CHOP-14 with and without 8 cycles rituximab and 63 patients in the RICOVER-noRT study treated with 6xCHOP-14 + 8xR were determined determined by LIASION®, a commercially available chemoluminescent immunoassay. Results RICOVER-60 patients with VDD (defined as serum levels ≤8 ng/m l) and treated with rituximab had a 3-year event-free survival of 59% compared to 79% in patients with >8 ng/ml; 3-year overall survival was 70% and 82%, respectively. These differences were significant in a multivariable analysis adjusting for IPI risk factors with a hazard ratio of 2.1 [p=0.008] for event-free survival and 1.9 [p=0.040] for overall survival. In patients treated without rituximab 3-year EFS was not significantly different in patients with vitamin-D levels ≤8 and >8 ng/ml (HR 1.2; p=0.388). These results were confirmed in an independent validation set of 63 patients treated within the RICOVER-noRT study. Rituximab-mediated cellular toxicity (RMCC) against the CD20+ cell line Daudi as determined by LDH release assay increased significantly (p<0.005) in 5/5 vitamin-D-deficient individuals after vitamin-D substitution and normalization of their vitamin-D levels. Conclusions VDD is a significant risk factor for elderly DLBCL patients treated with rituximab. Our results show that VDD impairs RMCC and that RMCC can be improved by vitamin-D substitution. This together with the differential effect of VDD in patients treated with and without rituximab suggests that vitamin-D substitution might result in a better outcome of these patients when treated with CHOP plus rituximab. Supported by a grant from Deutsche Krebshilfe. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Increased Monocytic Myeloid-Derived Suppressor Cells in the Marrow of Relapsed/Refractory Acute Myeloid Leukemia Patients Following Induction Chemotherapy

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5270-5270
Author(s):  
Amanda Przespolewski ◽  
Paul K. Wallace ◽  
Tara Cronin ◽  
Eunice S. Wang
Keyword(s):  
Overall Survival ◽  
Board Of Directors ◽  
Induction Chemotherapy ◽  
Myeloid Leukemia ◽  
Potential Role ◽  
Suppressor Cells ◽  
Advisory Committees ◽  
Free Survival ◽  
Relapsed Disease

Abstract Background: Acute myeloid leukemia (AML) is an aggressive malignancy associated with poor long-term outcomes. This malignancy arises in the context of an immunosuppressive milieu, which fosters immune escape and tumor growth. Myeloid-derived suppressor cells (MDSCs) represent a heterogeneous group of immature myeloid cells with immunosuppressive activity, the most potent of which are the monocytic MDSCs (mMDSCs). The presence of mMDSCs within the bone marrow microenvironment of patients with AML, along with their impact on disease relapse and overall survival has yet to be fully characterized. Therefore, we sought to address this unanswered question through a retrospective analysis of a cohort of AML patients (pts) at Roswell Park Comprehensive Cancer Center. Methods: Medical records were retrospectively reviewed under an IRB approved protocol in order to identify pts aged 18-70 years old with normal karyotype (NK) AML treated with standard cytarabine and anthracycline based chemotherapy with refractory or subsequent relapsed disease. Demographics, disease-specific variables, baseline clinical characteristics, treatment response, and adverse events were analyzed using descriptive statistics. Overall survival and relapse-free survival were estimated utilizing Kaplan-Meier (KM) analysis. Detailed analysis of previously collected clinical multiparameter flow cytometric data was performed utilizing WinList software to identify mMDSCs at serial clinical time points (diagnosis, after induction chemotherapy, and relapse). A mononuclear gate was created utilizing CD45 vs. SSC (blasts excluded), followed by FSC vs. SSC to eliminate dead cells and aggregates. Based on the scientific literature, mMDSCs were defined as the subset of marrow cells co-expressing CD14+ and HLA-DR dim, and was reported as the percentage of total monocytes in the marrow aspirate sample. Results: Six pts with NK-AML who received induction chemotherapy with cytarabine, daunorubicin, and etoposide (ADE) were identified. Mean age was 56 years (range 35 - 67), with 3/6 male pts (50%) (Table 1). NPM1 was mutated in 2/6 pts at diagnosis, with no FLT3-ITD mutations identified. In addition, 2 pts had an elevated WBC at presentation. Following induction therapy, 2 pts had primary refractory disease with four achieving complete remission (CR). Furthermore, each of the 6 pts relapsed. All 6 pts had marrow aspirate samples containing detectable mMDSCs by flow cytometry at multiple time points. Of note, 5 of 6 pts had elevated mMDSCs (average 76.2%; range 72.8% - 82.6% of total marrow monocytes) detected at time of response assessment following induction. Median relapse-free survival was 48 months (Figure 1). Overall survival not yet been reached. Mean duration of follow up was 85 months (range 61 - 119 months). Conclusions: This retrospective analysis suggests that high numbers of marrow mMDSCs (>72%) are associated with relapsed/refractory AML in a small patient cohort. Of note, other risk factors for refractory/relapsed disease (i.e. elevated WBC at presentation and FLT3 mutation) were not consistently present in our cohort, thus supporting a potential role of mMDSCs in promoting disease recurrence. Additional studies to further quantify and delineate the biological role of mMDSCs in a larger pt cohort are needed to corroborate these findings and determine the potential role of these immune cells in therapy resistant AML. Disclosures Wang: Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Jazz: Speakers Bureau; Amgen: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Novartis: Speakers Bureau; Jazz: Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Event-Free Survival at 24 Months Following Autologous Stem Cell Transplant in Diffuse Large B-Cell Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2896-2896
Author(s):  
Seth M Maliske ◽  
Matthew J. Maurer ◽  
Carrie A. Thompson ◽  
Luis Porrata ◽  
Ivana Micallef ◽  
...  
Keyword(s):  
Overall Survival ◽  
Board Of Directors ◽  
Research Funding ◽  
Salvage Chemotherapy ◽  
Newly Diagnosed ◽  
Event Free Survival ◽  
Advisory Committees ◽  
Free Survival ◽  
Genetics Research

Introduction: Front-line immunochemotherapy (IC) with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is expected to cure 60-70% of newly diagnosed DLBCL. Up to one third of newly diagnosed DLBCL patients will have relapsed or refractory (r/r) disease.1 Current standard of care for these patients is salvage chemotherapy and, if chemosensitive, to be followed by high dose chemotherapy with hematopoietic cell rescue (autoHCT).2,3 Event-free survival at 24 months (EFS24) after frontline IC is associated with excellent long-term outcomes with overall survival (OS) similar to that of age- and sex-matched controls.4 In comparison, those achieving EFS24 following autoHCT for relapsed or refractory disease may have increased risk for late-mortality compared to the general population with advanced age and intensive salvage therapy contributing to the risk of late complications.5 We sought to better characterize EFS24 after autoHCT to determine the utility of this end-point for informed clinical decisions, patient management, and future clinical trials. Methods: Patients were prospectively enrolled onto the Molecular Epidemiology Resource (MER) of the University of Iowa/ Mayo Clinic Specialized Program of Research Excellence (SPORE). Patients were followed for relapse, retreatment, and death; all events were validated by medical record review. For this analysis patients were included if they were consented within 9 months of initial diagnosis of DLBCL between 2002-2012, had received anthracycline-based IC (R-CHOP, or similar), and eventually had undergone autoHCT for r/r DLBCL. Patients with primary central nervous system (CNS) lymphoma or post-transplant lymphoproliferative disorders (PTLD) were excluded. Overall survival (OS) was defined as time from autoHCT until death due to any cause. Event-free survival (EFS) was defined as time from autoHCT until progression, relapse, retreatment, or death due to any cause. OS from achieving EFS24 after autoHCT was compared to age- and sex-matched general US population. Results: 108 patients underwent autoHCT for relapsed DLBCL between 2002 and 2017. Median age at autoHCT of the patients was 60 years (range 20-78) and 72 (67%) were male. The most common transplant conditioning regimen was BEAM (82%). At a median follow-up after autoHCT of 85 months (range 1-171), 72 patients (67%) had an event and 64 patients (59%) had died. Kaplan-Meier estimates for EFS and OS at 24 months from the time of autoHCT were 49% (95% CI: 40-59) and 61% (95% CI: 52-71), respectively. 52 patients had a progression within 24 months of autoHCT; OS from progression was poor (median OS=2.8 months, 95% CI: 1.8-6.0; 5 year OS = 9%, 95% CI: 2-22). 48 patients achieved EFS24 after autoHCT; median OS from achieving EFS24 was 136 months (95% CI: 92-NE) and 5 year OS was 79% (95% CI: 68-93). This was inferior to the background population (Figure 1, SMR=3.64, 95% CI: 2.11-6.27, p<0.0001). Eight patients had a progression after achieving EFS24 from autoHCT. OS from progression in these 8 patients (median OS=27.3 months, 95% CI: 14.4-NE; 5 year OS = 16%, 95% CI: 3-93) was improved compared to progression within 24 months of autoHCT (p=0.072, figure B). Cause of death (COD) in EFS24 achievers was progression of lymphoma (n=6), infection (n=1), secondary malignancy related to therapy (n=3), heart disease (n=1), and unknown (n=1). Conclusions: Patients achieving EFS24 after salvage chemotherapy and autoHCT have a favorable long-term prognosis; however, overall survival remained inferior to the general population. Most common COD after achieving EFS24 was progression of lymphoma. In spite of this, EFS24 remains a valuable end-point for informed clinical decisions, patient management, and future clinical trials. Figure 1 Disclosures Maurer: Morphosys: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Nanostring: Research Funding. Ansell:Mayo Clinic Rochester: Employment; Bristol-Myers Squibb: Research Funding; Affimed: Research Funding; Trillium: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Mayo Clinic Rochester: Employment; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Trillium: Research Funding; LAM Therapeutics: Research Funding. Cerhan:Celgene: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; NanoString: Research Funding. Farooq:Celgene: Honoraria; Kite Pharma: Research Funding.

scholarly journals The Prognostic Significance of Monocytopenia in Patients with Myelodysplastic Syndrome

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5427-5427
Author(s):  
Panagiotis T Diamantopoulos ◽  
Vassiliki Pappa ◽  
Nora-Athina Viniou ◽  
Ioannis Kotsianidis ◽  
Alexandra Kourakli ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Cox Regression ◽  
Univariate Analysis ◽  
Prognostic Significance ◽  
Prognostic Impact ◽  
Advisory Committees ◽  
Free Survival ◽  
Very High

Background: The currently used prognostic systems for myelodysplastic syndromes (MDS) do not consider the prognostic role of monocytopenia, although monocytes may participate in the prognosis of the disease as part of the host immunity. Aim: We studied the prognostic significance of monocytopenia in patients with MDS registered in the Hellenic National MDS registry. Methods: We analyzed clinicopathological data from patients with MDS recorded in a large retrospective national registry. Patients with MDS/MPN were excluded, while patients treated with allogeneic hematopoietic cell transplantation were censored for overall survival (OS) and leukemia-free survival (LFS). IBM SPSS statistics, version 23.0 (IBM Corporation, North Castle, NY, USA) was used for the analysis of the results. Kaplan-Meier survival analysis and Cox regression analysis were performed for LFS and OS. Results: The study comprised 1719 patients with MDS per the 2008 WHO classification for MDS. The main characteristics of the patients are shown in Table 1. At the time of data cut-off, 818 patients were deceased and the median follow-up for the remaining 901 patients was 23.0 months. The median absolute monocyte count (AMC) was 0.30 x 109/L (0.00 - 0.99 x 109/L). Patients with excess blasts (RAEB1/2) tended to have lower AMCs (median 0.19 versus 0.32 for patients without excess blasts, p<0.0001) and lower AMCs were found in higher IPSS-R categories (very low, 0.37 x 109/L; low, 0.30 x 109/L; intermediate, 0.25 x 109/L; high, 0.16 x 109/L; very high, 0.20 x 109/L) while there was a highly significant difference between lower risk (very low and low) and higher risk (intermediate, high, very high) MDS (0.33 x 109/L vs 0.21 x 109/L, p<0.0001). In univariate analysis, patients with AMCs below 0.2 x 109/L had a median OS of 34.0 months vs 63.0 months for patients with higher AMCs (p<0.0001) with a hazard ratio (HR) for death of 1.57 (95% CI 1.37 - 1.81, p<0.0001). In a multivariate Cox regression model including hemoglobin below 10 g/dL, absolute neutrophil count (ANC) below 1.0 x 109/L, and platelet count below 100 x 109/L (all of them being prognostic for OS in univariate analysis), monocytopenia retained its prognostic significance (HR, 1.16; 95% CI, 1.00 - 1.36, p=0.049). There was a positive correlation between the AMC and the ANC (Pearson Correlation 0.393, p<0.0001). Nevertheless, in a model comprising of AMC and ANC, both variables were independently correlated to OS. Moreover, in a model including AMC below 0.2 x 109/L, the cytogenetic risk score per the IPSS-R, the number of cytopenias, and bone marrow blasts (categorized per the IPSS-R), no additional prognostic impact was found for AMC (HR, 1.01; 95% CI, 0.86 - 1.17; p=0.957). After stratification per the IPSS-R categories, low AMC was prognostic for low OS only in patients with low IPSS-R (median OS, 57 months for patients with low AMC vs 75 months for those with high AMC, p=0.039), but there was no additional prognostic impact after multivariate analysis. Moreover, AMC was prognostic for LFS, since patients with low AMCs (<0.2 x109/L) had a median LFS of 57.0 months, while the median LFS for patients with higher AMCs was not reached (HR, 2.47, 95% CI, 2.01 - 2.47, p<0.0001). In a Cox regression model including the above stated factors (cytopenias, bone marrow blasts, cytogenetic risk, and AMC), AMC retained its prognostic significance for LFS (HR, 1.27; 95% CI, 1.02 - 1.58; p=0.031). In a subgroup of 162 patients treated with hypomethylating agents (HMAs), monocytopenia was not predictive or response to treatment, but low AMC was correlated to a shorter median progression free survival (27.0 months vs not reached for patients with higher AMC, p=0.001). This correlation was not translated into a survival benefit (survival after HMA initiation, 27.0 vs 28.0 months respectively, log rank p=0.213). Conclusions: Based on a large patient cohort, we found that patients with MDS with excess blasts as well as higher risk patients per the IPSS-R have low AMCs. Moreover, we showed that low AMCs are prognostic of lower OS in univariate analysis and of lower LFS in both univariate and multivariate analysis, highlighting a possible pathogenetic role for AMCs in MDS. Further analysis is needed to define the exact prognostic role of AMC in MDS. Disclosures Pappa: Amgen: Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene / GenesisPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Research Funding; Abbvie: Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kotsianidis:Celgene: Research Funding. Symeonidis:MSD: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding; Tekeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Vassilakopoulos:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; WinMedica: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene / GenesisPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Hematopoietic Cell Transplantation with or without Sorafenib Maintenance for Patients with FLT3-ITD Acute Myeloid Leukemia in CR1

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 864-864 ◽  
Author(s):  
Andrew M. Brunner ◽  
Shuli Li ◽  
Amir T. Fathi ◽  
Vincent T Ho ◽  
Richard M. Stone ◽  
...  
Keyword(s):  
Overall Survival ◽  
Board Of Directors ◽  
Research Funding ◽  
Multivariable Analysis ◽  
Control Group ◽  
Advisory Committees ◽  
Landmark Analysis ◽  
Median Date ◽  
The Impact ◽  
Disease Free

Abstract Introduction: Patients with acute myeloid leukemia (AML) with internal tandem duplications in the fms-like tyrosine kinase 3 receptor (FLT3-ITD) are at high risk for relapse despite allogeneic hematopoietic cell transplantation (HCT) in first remission (CR1).We have previously shown sorafenib, an oral FLT3/multikinase inhibitor, to be safe as maintenance therapy after HCT (BBMT 2014;20:2042). We performed a retrospective study to evaluate the impact of sorafenib maintenance on outcomes of adult patients with FLT3-ITD AML undergoing HCT in CR1. Methods: We identified consecutive patients (n=80) at 2 institutions with AML between 2008 and 2014, with FLT3-ITD at diagnosis, who underwent HCT in CR1. Patients given sorafenib in remission after HCT were in the "sorafenib" group, and others were the "control" group. We identified the median date of sorafenib initiation, and performed a landmark analysis including only controls alive without relapse at that date. The primary outcome was overall survival (OS). We performed multivariable analysis, accounting for age >60, conditioning intensity, NPM1 status, cytogenetic risk, and donor type, to estimate the impact of sorafenib maintenance on OS, disease-free survival (DFS), non-relapse mortality (NRM), and time to relapse from the estimated date of sorafenib initiation. Cumulative incidence of grade 2-4 acute GVHD (aGVHD) and chronic GVHD (cGVHD) requiring systemic immunosuppression were estimated from date of transplant. Results: We identified 26 sorafenib patients and 54 control patients. Median follow up was 22.1 mo. (range, 6.3-49.8) for survivors in the sorafenib group, and 37.5 mo. (range, 12.4-88.9) in the control group (p=0.020). The median time to sorafenib was 68 days after transplant; subsequent analysis therefore included 26 sorafenib patients and 41 control patients alive without relapse at day +68. There were no significant differences in patient characteristics (Table 1). Two patients in the control group had concomitant FLT3-TKD mutations. Patients on sorafenib had improved 2-year OS compared to controls in the landmark analysis (83% vs. 58%, p=0.019, Figure 1). In multivariable analysis, sorafenib maintenance significantly improved OS (HR for death 0.146, p=0.0047) and DFS (HR 0.091, p=0.0005). Of patients alive without relapse at d+68, sorafenib maintenance was associated with improved 2-year DFS (85% vs. 52%, p=0.0047) and lower 2-year cumulative incidence of relapse (9.5% vs. 41%, p=0.0065). After 68 days, 2 sorafenib patients and 4 controls developed aGVHD. There was no difference in 2-year NRM (5.7% vs. 7.6%, p=0.61) or cumulative cGVHD at 1 year (50% vs. 37%, p=0.31). Conclusions: Sorafenib maintenance after HCT is associated with significantly improved DFS and OS among patients with FLT3-ITD AML undergoing HCT in CR1, with no difference in GVHD or NRM. These findings suggest a potential benefit of sorafenib and possibly other FLT3 inhibitors after HCT for FLT3-ITD AML, and support a randomized controlled trial of FLT3 inhibition after HCT. Table 1. Patient Demographics Control n=41 Sorafenib n=26 P-value Age (median, range) 53 (25,72) 54.5 (20,74) 0.39 HCT Age (median, range) 53 (25,73) 55 (20,74) 0.44 Gender (male, %) 12 (29%) 12 (46%) 0.20 Race (white, %) 35 (85%) 24 (92%) 1.00 ECOG at Diagnosis* 0.43 0 7 (39%) 7 (50%) 1 7 (39%) 7 (50%) 2 3 (17%) 0 3 1 (6%) 0 Antecedant Disease 0.58 De Novo 32 (78%) 22 (85%) tAML 4 (10%) 3 (12%) Prior MDS or MPN 5 (12%) 1 (4%) Cytogenetic Risk 1.00 Favorable 2 (5%) 1 (4%) Intermediate 35 (88%) 23 (88%) Adverse 3 (8%) 2 (8%) NPM1 mut# 20 (74%) 14 (56%) 0.25 CEBPA mut (n) 0 2 1.00 Induction Treatment 0.37 7+3 based induction 39 (95%) 23 (88%) Other induction 2 (5%) 3 (12%) TKI prior to HCT 10 (24%) 7 (27%) 1.00 ECOG at HCT+ 0.63 0 13 (32%) 6 (25%) 1 18 (44%) 14 (58%) 2 10 (24%) 4 (17%) HCT Intensity 1.00 Myeloablative 23 (56%) 14 (54%) Reduced intensity 18 (44%) 12 (46%) Donor Type 0.49 Matched 36 (88%) 21 (81%) Mismatched 5 (12%) 5 (19%) aGVHD prophylaxis 0.61 CNI and Methotrexate 24 (59%) 17 (65%) *Diagnosis ECOG missing in 23 control and 12 sorafenib patients #NPM1 testing performed on 27 control and 25 sorafenib patients +HCT ECOG missing in 2 sorafenib patients Figure 1. Disease-free and Overall Survival for FLT3-ITD AML patients, with or without sorafenib maintenance after HCT. Landmark analysis was performed from median date of sorafenib initiation (d+68). Figure 1. Disease-free and Overall Survival for FLT3-ITD AML patients, with or without sorafenib maintenance after HCT. Landmark analysis was performed from median date of sorafenib initiation (d+68). Figure 2. Figure 2. Disclosures Off Label Use: Sorafenib for FLT3-ITD AML. Fathi:Takeda Pharmaceuticals International Co.: Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees; Exelexis: Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees; Ariad: Consultancy; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Stone:Celator: Consultancy; Karyopharm: Consultancy; Pfizer: Consultancy; Celgene: Consultancy; AROG: Consultancy; Novartis: Research Funding; Abbvie: Consultancy; Sunesis: Consultancy, Other: DSMB for clinical trial; Amgen: Consultancy; Roche/Genetech: Consultancy; Merck: Consultancy; Juno: Consultancy; Agios: Consultancy. Soiffer:Gentium SpA/Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Chen:Bayer: Consultancy, Research Funding.

scholarly journals Low Dose Rituximab Plus High Dose Dexamethasone As First-Line Treatment for Autoimmune Hemolytic Anemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 13-14
Author(s):  
Carlos Saúl Rodríguez-Roque ◽  
Andres Gomez-De Leon ◽  
Michelle Morcos-Sandino ◽  
Nelson Josafat López-Flores ◽  
David David Galindo-Calvillo ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Hemolytic Anemia ◽  
Autoimmune Hemolytic Anemia ◽  
Low Dose ◽  
Complete Response ◽  
Event Free Survival ◽  
First Line ◽  
Advisory Committees ◽  
Free Survival ◽  
Loss Of Response

Introduction Corticosteroids are the first line therapy for autoimmune hemolytic anemia (AIHA), but are associated with significant adverse events, dependency and frequent relapses. Rituximab is reserved for severe or steroid-resistant disease. Low-dose rituximab is also effective, but its efficacy in the first line has been poorly described. We report our results with this combination. Methods Adults older than 16 years newly diagnosed with warm antibody AIHA either primary or secondary were included. Patients systematically received dexamethasone 40 mg for 4 days followed by a 1 mg/kg rapid prednisone taper plus rituximab 100 mg weekly for 4 doses. Our primary outcome was response at day 28 based on the First International Consensus Meeting (complete response: normalization of Hb, no evidence of hemolysis and absence of transfusions; response: increase of Hb by &gt;2g/dl, or normalization of biochemical resolution of hemolysis or absence of transfusion in 7 days), secondary outcome was event-free survival with an event defined as a laboratory or clinical relapse or loss of response. Results Sixteen patients were treated with low-dose rituximab during the study period, ten women (62.5%), six men (37.5%). The median age was 34 years (range, 17-78). Three (18.75%) were secondary to lupus erythematosus. The median follow-up was 20 months (range, 0.4-66). Most received 4 doses of rituximab (87.5%). All patients responded at day 28, (100%) 31.2% achieved a complete response (CR). Subsequently, 81.3% achieved CR. Ten (62.5%) were considered steroid-dependent, however, most discontinued treatment without loss of response (75%). The event-free survival was 63.8% to 5 years. Conclusion Low-dose rituximab therapy as a first-line in AIHA showed encouraging results as most patients were able to discontinue treatment without relapse. Disclosures Gomez-Almaguer: Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

scholarly journals Ponatinib and Chemotherapy in Young Adults with De Novo Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia. Results of Ponalfil Clinical Trial after Completion of Recruitment

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 29-30
Author(s):  
Josep-Maria Ribera ◽  
Olga García ◽  
Pau Montesinos ◽  
Pilar Martinez ◽  
Jordi Esteve ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Molecular Response ◽  
Event Free Survival ◽  
Advisory Committees ◽  
Free Survival ◽  
Allogeneic Hsct ◽  
Central Artery

Background and objective. The combination of tyrosine kinase inhibitors (TKI) and chemotherapy (intensive, attenuated or minimal) has improved the prognosis of patients (pts) with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL). The combination of HyperCVAD and ponatinib has improved the molecular response and survival compared with other combinations of chemotherapy with first or second generation TKI (Jabbour E, et al, Lancet Haematol. 2018; 5:e618-e627). The Spanish PETHEMA group conducted the phase 2 PONALFIL trial, which incorporates ponatinib to the same induction and consolidation schedule of the ALL Ph08 trial (Ribera JM et al. Cancer 2019;125:2810-2817) The results of this trial after completed recruitment are herein reported. Patients and method. The PONALFIL trial (NCT02776605) combined ponatinib (30 mg/d) and induction chemotherapy (vincristine, daunorubicin and prednisone) followed by consolidation (high-dose methotrexate, ARA-C, mercaptopurine, etoposide) and allogeneic HSCT. TKI use as maintenance was only scheduled for pts with persistence or reappearance of MRD. By July 2020 the 30 scheduled pts were recruited. The response to therapy (complete morphological [CR], molecular [complete, CMR or major, MMR] after induction and before allogeneic HSCT) (assessed by centralized BCR-ABL/ABL ratio),event-free survival (EFS), overall survival [OS]) and toxicity are herein analyzed. Results. Median age was 50 (20-59) years and 14/30 pts were female. One pt showed CNS involvement at diagnosis. ECOG score at diagnosis was &lt;2 in 86% of pts. Median of WBC count was 6.4 (0.6-359.3) x109/L, Hb 90 (63-145) g/L, platelets 38 (11-206) x109/L. The immunologic phenotype was common in 26 cases, with molecular isoform p190 in 20 patients (67%), p210 in 9 (30%) and p230 in 1 (3%). CR was attained 26/26 patients (100%) (4 are still on induction therapy), with CMR in 11/26 cases (42%), MMR in 6/26 (23%) and no molecular response in 9/26 (35%)).Two patients withdrew the trial (thrombosis of the central retina artery and severe intestinal infection, one case each). Consolidation was given to 24 patients, 2/24 are receiving consolidation and 22 patients received allogeneic HSCT (14 in CMR, 6 in MMR, 2 without molecular response). No relapses before HSCT were detected. No transplant-related mortality was observed to date, but 1 patient withdrew the trial by severe GVHD. Ponatinib was given after HSCT in 4 pts due to loss of molecular response. Three pts relapsed after HSCT, one of them after documented loss of molecular response. All pts are alive (median follow-up of 4.5 months, range 0.5-26.2.2). The EFS probability at 30 months was 91% (79%, 100%) (Figure 1). One hundred and two adverse events (AE) have been registered in 20 patients, 25 of whom were severe (SAE) and occurred in 14 patients, prompting to withdrawn of the trial in 3 (thrombosis of the central artery of the retina, severe bowel infection, grade IV aGVHD, one case each). The most frequent AE were hematologic (26%), gastrointestinal (15%), infections (10%), hepatic (8%) and cutaneous (5%). Cardiovascular events occurred in 2 patients (angor pectoris and thrombosis of central artery of the retina, one case each). Conclusions. The preliminary results of the PONALFIL trial after recruitment completed show a high short-term antileukemic efficacy with acceptable toxicity profile. Supported in part by grant 2017 SGR288 (GRC) Generalitat de Catalunya and "La Caixa" Foundation. Figure 1. Event free survival (EFS) of the whole series. Figure 1 Disclosures Ribera: Pfizer, Amgen, Ariad, Novartis: Consultancy, Speakers Bureau; Pfizer, Amgen: Research Funding. Martinez-Lopez:Incyte: Consultancy, Research Funding; Novartis: Consultancy; BMS: Consultancy, Research Funding; Janssen-cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria. Garcia-Sanz:Amgen: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Gilead: Honoraria, Research Funding; Incyte: Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria; Pharmacyclics: Honoraria; Takeda: Consultancy, Research Funding.

Maintaining Imatinib ≥600 Mg Daily in the First 12 Months of Chronic Phase CML Treatment Is Associated with Superior Event-Free Survival at 5 Years.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1125-1125 ◽  
Author(s):  
Michael P Osborn ◽  
Susan Branford ◽  
Deborah L White ◽  
John F Seymour ◽  
Ruth Columbus ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Event Free Survival ◽  
Advisory Committees ◽  
Free Survival ◽  
Event Rates

Abstract Abstract 1125 Poster Board I-147 The Australasian Leukaemia and Lymphoma Group conducted a trial (TIDEL I) in 103 patients with newly diagnosed chronic phase CML, using imatinib 600 mg/day with dose escalation to 800 mg/day for suboptimal response. This was defined as failure to achieve (1) complete haematological response (CHR) at 3 months, (2) major cytogenetic response (MCR) at 6 months, (3) complete cytogenetic response (CCR) or molecular equivalent at 9 months, or (4) less than 0.01% (IS) BCR-ABL by RQ-PCR at 12 months. Here we report the outcomes with all surviving patients having been treated for at least 60 months. We aimed to determine whether the patient outcome at 60 months was predicted by the molecular response within the first 18 months of imatinib therapy. The outcomes for patients maintaining a dose of imatinib of ≥600 mg/day in the first 12 months was compared to those who were on a reduced dose for at least part of this time. Event-free survival (EFS) was defined as death from any cause, accelerated phase/blast crisis (AP/BC), and loss of CHR, MCR or CCR. The 103 patients included 66 males and 37 females with a median (±SD) age of 49 (±14) years. All patients had an ECOG performance status of 0-2 at enrolment. The 5-year EFS was 71%, transformation (AP/BC) free survival (TFS) was 95%, and overall survival was 87%. Of the 14 patients who died, 3 died in blast crisis, 2 from transplant-related complications, 8 from CML-unrelated causes, and the cause of death of 1 patient was unavailable. The annual rates of progression to AP/BC over 5 years were 3%, 1%, 0%, 1%, and 0%, while annual event rates were 13%, 8%, 8%, 1%, and 4%. CCR was achieved by 89% of patients by 60 months, while 72% achieved a major molecular response (MMR) by this time. In the first 12 months of treatment, 55% of patients maintained an imatinib dose of ≥600 mg/day (mean ±SD dose = 604 ±10 mg/day), while 45% were on <600 mg/day for at least part of this time (mean ±SD dose = 511 ±100 mg/day). EFS at 60 months was significantly higher in patients taking ≥600 mg/day compared with those who had been dose-reduced to <600 mg/day (89% vs 56%, P<0.001). Annual event rates for the ≥600 mg/day group were 6%, 2%, 2%, 0%, and 2%, while annual event rates for those on <600 mg/day were 14%, 16%, 16%, 8%, and 4%. By 60 months, 96% of patients who had been on ≥600 mg/day within the first 12 months had achieved CCR, while only 80% of those who had been on <600 mg/day had achieved this milestone (P<0.001). Log rank analysis of the achievement of MMR was also significant (P=0.03). Overall survival and TFS after 12 months were both similar between the dosing groups. There was no difference between the dosing groups' median age (50 vs 48 years, P=0.36) or Sokal score (1.04 vs 0.94, P=0.33) that may otherwise account for these results. The outcome was also determined for all patients dependent on the BCR-ABL levels at various assessment timepoints. Patients with a BCR-ABL level of <10% (IS) at 6 months (n=92) had an EFS of 78% at 60 months, while all of those with a level >10% (IS) (n=8) had an event (P<0.001). Patients with a level of ≤1% (IS) at 12 months (equivalent to CCR) (n=81) had an EFS of 75% compared with 25% (n=13) for those with levels >1% (IS) (P<0.001). At 18 months, a level ≤0.1% (IS) (n=58) conferred an EFS of 88%, while those who had failed to attain this depth of response (n=30) had an EFS of 60%. There was a significant difference in EFS between those who had achieved an MMR at 18 months and those who had achieved a CCR, but no MMR (88% vs 67%, P=0.03). In conclusion, our data suggest that patients maintaining a dose of ≥600mg in the first 12 months of imatinib therapy are more likely to achieve CCR and MMR, and superior EFS compared to those with a lower dose. This study also confirms that achieving an MMR by 18 months is associated with improved EFS. This emphasises the value of achieving a molecular response early in the treatment course, as well as adding weight to the evidence supporting the role of molecular monitoring in CML. Disclosures Branford: Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. White:Novartis and Britol-Myers Squibb: Research Funding. Seymour:Bayer Schering: Consultancy, Membership on an entity's Board of Directors or advisory committees, Travel grants; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Travel Grants. Catalano:Roche: Honoraria, Research Funding, Travel grants. Mills:Celgene Pty Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hughes:Bristol-Myers Squibb: Advisor, Honoraria, Research Funding; Novartis: Advisor, Honoraria, Research Funding.

Allogenic Transplantation in Lymphomas: A Focused Analysis On Aggressive Lymphomas and Factors Predictive of Outcome in a Series of 179 Pts Treated At John Theurer Cancer Center.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3120-3120
Author(s):  
Anthony R Mato ◽  
Kathryn Waksmundzki ◽  
Tania Zielonka ◽  
Ewelina A Protomastro ◽  
Theresa Amatucci ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Board Of Directors ◽  
Cox Regression ◽  
Cancer Center ◽  
Advisory Committees ◽  
Stem Cell Source ◽  
Cell Source ◽  
Refractory Lymphoma ◽  
Donor Source

Abstract Abstract 3120 Introduction: Chemo-immunotherapy (i.e. rituximab combinations) has clearly had a significant impact on the outcome of all B-cell NHL both in terms of PFS and OS. However in the relapse/refractory setting a large proportion of pts still do very poorly especially in aggressive subtypes including DLBCL and MCL. Salvage therapy followed by HDT-ASCT in relapsed DLBCL remains the standard, though pts with early failures (<1y) and/or prior exposure to rituximab still show dismal results (CORAL data). In MCL the use of HDT-ASCT in the relapse setting is debated given the frequency of chemo-resistance leading to poor results even in second CR. The use of allogeneic transplantation was developed based on observations c/w with a clear GVL effect in NHL as illustrated by pts going into remission after DLI injections. The development of non-myeloablative approaches has allowed expansion of use of allogeneic BMT in relapsed/refractory NHL. We report here one of the largest series (179 consecutive pts) with relapsed/refractory lymphoma focusing on overall survival and outcome predictors. Methods: Utilizing Kaplan-Meier survival and Cox regression methods, we report on the outcome of 179 consecutive pts with relapsed/refractory lymphoma who underwent allogeneic stem cell transplantation at the John Theurer Cancer Center between 1995–2012. The primary study endpoint was overall survival (OS) assessed by chart and SSDI database review. Secondary study endpoints included examination of the association between overall survival and allogeneic stem cell source, donor source, development of GVHD, pre-transplant chemo-sensitivity and prior failure to HDT-ASCT (second transplant). The proportional hazards assumption was met for this analysis. Results: Survival data on 179 pts (median age 48, range 20–71) were analyzed, representing 86 deaths and 5720 total months at risk (median follow up=12.3 months). Baseline characteristics included: ECOG PS (med 1, range 0–2), diagnosis (25% DLBCL, 21% HD, 20% MCL, 13% FCL, 13% PTCL, 8% other), donor source (50% matched SIB, 31% MUD, 19% mismatched MUD), stem cell source (73% PB, 23% BM, 6% Cord) and prior autologous SCT (38%). The median OS for the entire cohort was 31.2 months. OS KM curves by selected aggressive NHL subtypes are represented in Figure 1. We performed COX regression analyses to address outlined secondary endpoints. In univariate analyses statistically significant inferior outcomes were associated with the use of mismatched unrelated donor (HR 1.4, p=.01, Figure 2), bone marrow donor stem cells vs. PBSCT (HR=1.7 p=.04), pre-transplant stable/refractory disease (HR 1.8, p=.03), absence of cGVHD (HR=4.7, p<.001) and presence of acute GVHD (HR 2.8, p=.001). No difference in OS was detected whether pts had undergone allogeneic SCT as a second transplant (med time between auto/allo=20.9 months) following relapse after auto SCT (HR 1.14, CI .75–1.73, p=.5). Conclusions: This series represents a large cohort of poor risk, relapsed/refractory lymphoma pts treated consecutively with allogeneic stem cell transplantation over a > 10-year period at our institution with the following observations: Disclosures: Mato: Celgene: Speakers Bureau; Millennium: Speakers Bureau; Seattle Genetics: Speakers Bureau; Genentech: Speakers Bureau. Goldberg:Eisai: Speakers Bureau. Feldman:Allos: Speakers Bureau; celgene: Speakers Bureau; Seattle Genetics: Speakers Bureau; Merck: Speakers Bureau. Goy:Milennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; J & J: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees.

Early Versus Deferred Treatment With Combined Fludarabine, Cyclophosphamide and Rituximab (FCR) Improves Event-Free Survival In Patients With High-Risk Binet Stage A Chronic Lymphocytic Leukemia – First Results Of a Randomized German-French Cooperative Phase III Trial

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 524-524 ◽  
Author(s):  
Carmen D Schweighofer ◽  
Florence Cymbalista ◽  
Carolin Müller ◽  
Raymonde Busch ◽  
Raphael Porcher ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Early Stage ◽  
Phase Iii ◽  
Event Free Survival ◽  
Advisory Committees ◽  
Phase Iii Trial ◽  
Free Survival ◽  
Risk Patients ◽  
Binet Stage

Abstract Introduction Patients with asymptomatic early Rai or Binet stage chronic lymphocytic leukemia (CLL) do not benefit from mono-chemotherapy. Therefore, clinical observation without treatment (watch&wait; W&W) has been the gold standard for the management of these patients. Chemoimmunotherapy with FCR improves the outcome of patients with advanced CLL, but its efficacy in early stage disease has not been investigated. Several clinical and biological variables identify those patients who have a high risk of an aggressive disease course and who might benefit from early interventions. Consequently, this trial was conducted to test the value of FCR treatment in patients with early stage, high-risk CLL. Methods This report represents the endpoint and safety analysis of a randomized German-French cooperative phase III trial comparing the efficacy of early versus deferred FCR therapy in treatment-naïve Binet stage A CLL patients with a high risk of disease progression. Risk assessment was performed using 4 prognostic markers: Lymphocyte doubling time <12 months, serum thymidine kinase >10 U/L, an unmutated immunoglobulin heavy chain variable region gene (IGHV) status, and presence of unfavorable cytogenetics (del11q, del17p, trisomy 12) by fluorescence-in-situ hybridization. Presence of at least 2 versus less than 2 of these factors defined “high-risk” versus “low-risk” CLL. High-risk CLL patients were further randomized to receive either 6 cycles FCR (HR-FCR) or to be followed by a W&W strategy (HR-W&W). Patients with low-risk CLL were observed only (LR-W&W). Results Between 2005 and 2010, a total of 824 patients was enrolled, 423 patients in 69 centers of the German CLL Study Group and 401 patients in 25 centers of the French Cooperative Group on CLL. The diagnosis of CLL needed to be established no longer than 12 months prior to enrollment and patients were required to present with previously untreated stage Binet A CLL at the time of inclusion. Overall, 800 patients (97.1%) were stratified, 201 of them categorized as high-risk CLL (25.1%). There was no significant difference between high-risk patients from the two study groups regarding common baseline characteristics (e.g., age, sex, comorbidity, immunophenotype) and the distribution of risk factors used for stratification. 100 out of 201 high-risk patients were randomized to receive FCR therapy (HR-FCR), while 101 patients were allocated to the HR-W&W arm. 18 out of 100 patients (18%) withdrew consent for FCR therapy before treatment was started. 71 (86.6%) of 82 treated patients completed ≥4 cycles. The most common of 228 CTC grade III/IV adverse events reported within 12 months after treatment initiation were hematotoxicity (73.2% of patients) and infections (19.5% of patients). Three patients (3.7%) developed fatal CTC grade V infections (2 septic bacteremias, 1 of them with pulmonary aspergillosis; 1 encephalitis). Out of 79 patients available for response assessment until month 12 after treatment start, 76 showed a complete or partial remission (ORR 96.2%), 2 patients had stable disease (2.5%) and 1 patient had progressed (1.3%). After a median follow up of 46 months (range 0-88 months), HR-FCR patients demonstrated a significantly improved event-free survival (EFS) compared to HR-W&W patients (median EFS not reached versus 24.5 months, respectively, P<0.0001, Fig. 1). Overall survival was not significantly different between HR-FCR and HR-W&W with 181 high-risk patients (90%) being alive at last follow up. Both, HR-FCR and HR-W&W patients exhibited a significant shorter event-free and overall survival than LR-W&W patients, demonstrating an efficient prognostic segregation of patients by the risk assessment used for this trial (analysis based on the German LR-W&W cohort only, complete German-French LR-W&W data will be presented at the meeting). Conclusion This is the first randomized phase III trial investigating the efficacy of FCR chemoimmunotherapy in early stage CLL. So far, the study has revealed two major results: 1. A combination of clinical and biological factors can be used to identify early stage CLL patients who experience a rapid disease progression with unfavorable outcome, 2. FCR chemoimmunotherapy substantially improves event-free survival in early stage high-risk CLL. Disclosures: Langerbeins: Roche: travel grants Other. Cazin:roche: meeting invitation Other, Membership on an entity’s Board of Directors or advisory committees; GSK: meeting invitation, meeting invitation Other, Membership on an entity’s Board of Directors or advisory committees. Fischer:Mundipharma: Travel grants, Travel grants Other; Roche: Travel grants Other. Stilgenbauer:Roche: Consultancy, Research Funding, Travel grants Other; Mundipharma: Consultancy, Research Funding. Leblond:Roche : Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Mundipharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Hallek:F. Hoffmann-La Roche: Consultancy, Honoraria, Research Funding.

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