scholarly journals Excellent Outcome of Young Patients (18-60 years) with Favourable-Prognosis Diffuse Large B-Cell Lymphoma (DLBCL) Treated with 4 Cycles CHOP Plus 6 Applications of Rituximab: Results of the 592 Patients of the Flyer Trial of the Dshnhl/GLA

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 781-781 ◽  
Author(s):  
Viola Poeschel ◽  
Gerhard Held ◽  
Marita Ziepert ◽  
Bettina Altmann ◽  
Mathias Witzens-Harig ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Standard Treatment ◽  
Young Patients ◽  
B Cell Lymphoma ◽  
Advisory Committees ◽  
Bulky Disease ◽  
Favourable Prognosis ◽  
Significant Difference ◽  
To Receive

Abstract Background: 6 cycles CHOP-like chemotherapy plus rituximab (6x R-CHOP) are the standard treatment for young patients with DLBCL. The MInT trial established a subgroup with favourable prognosis as defined as aaIPI=0 and no bulky disease [Pfreundschuh et al., Lancet Oncol 2006; 7: 379-391] with a 3-year EFS of 89%, PFS of 95% and OS of 98%. We hypothesized that 4 cycles of CHOP plus 6 applications of rituximab are non-inferior to the standard treatment of 6x R-CHOP in this population. Patients and Methods: 18 to 60 year-old patients, aaIPI =0 without bulky (≥7.5 cm) disease were randomized to receive 6x R-CHOP or 4x R-CHOP+2xR at 21-day cycles. Radiotherapy was not planned to be given except for prophylactic radiotherapy of the contralateral testis in patients with testicular lymphoma. The primary endpoint was progression free survival (PFS) with events defined as progressive disease, relapse or death. Assuming a 93% 3-years PFS for the 6x R-CHOP arm, it was planned to tolerate an impairment of 5.5% by reducing the number of courses to 4x R-CHOP+2xR to prove non-inferiority with a power of 80% and an alpha-error of 5% (one-sided). Results: Between 12/2005 and 10/2016, 592 patients were randomized in the international multi-center FLYER trial and 588 patients were evaluable for this final analysis. 295 patients were assigned to receive 6x R-CHOP and 293 were assigned to receive 4x R-CHOP+2xR. There were no relevant differences in demographics (median age: 48 years, 99% aaIPI=0, 1% aaIPI=1, 0.3% bulky disease), protocol adherence and toxicity between the two arms. PFS, EFS and OS after 4x R-CHOP+2xR were as good as after 6x R-CHOP. After 66 months median observation, the 3-year PFS rate of the patients receiving 4x R-CHOP+2xR was 96% vs. 94% of patients receiving 6x R-CHOP (p=0.760). The lower limit of the 95% CI of the difference between treatment arms was 0% and excludes -5.5% demonstrating the non-inferiority. The 3-year EFS was identical (89%) in both treatment arms. The 3-years OS was 99% in patients receiving 4x R-CHOP+2xR and 98% in patients receiving 6x R-CHOP. In a multivariable analysis adjusting for strata (stage and E-involvement), the hazard ratio of 4x R-CHOP+2xR compared to 6x R-CHOP was 1.0 (95% CI: 0.7-1.6; p=0.896) for EFS, 0.9 (95% CI: 0.5-1.6; p=0.797) for PFS, and 0.8 (95% CI: 0.4-1.9; p=0.671) for OS. With respect to relapse rate there was also no significant difference between the two treatment arms. 4% (95% CI 2-7%) of the patients in the 4x R-CHOP+2xR arm relapsed vs. 5% (95% CI 3-8%) of the patients in the 6x R-CHOP arm. 33% of relapses occurred in the first two years after study inclusion but continue to be seen with longer follow-up in both arms. Conclusion: In young patients with favourable prognosis DLBCL outcome after 4x R-CHOP+ 2xR is non-inferior compared to the previous standard 6x R-CHOP. Thus, chemotherapy can be spared without compromising prognosis in this population. Supported by Deutsche Krebshilfe Figure. Figure. Disclosures Poeschel: Roche: Other: Travel grants; Amgen: Other: Travel grants. Held:BMS: Consultancy, Other: Travel grants, Research Funding; Amgen: Research Funding; Roche: Consultancy, Other: Travel grants, Research Funding; MSD: Consultancy; Spectrum: Research Funding. Holte:Roche, Norway: Research Funding; Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees. Viardot:Roche: Consultancy, Honoraria; Amgen: Consultancy; Gilead Kite: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Borchmann:Novartis: Consultancy, Honoraria. Keller:Celgene: Research Funding; BMS: Consultancy; Takeda: Consultancy, Research Funding; Janssen-Cilag: Consultancy, Equity Ownership; Roche: Consultancy; MSD: Consultancy. Schmidt:Gilead: Honoraria, Other: Travel Grants; Celgene: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grants. Marks:Merck: Honoraria; BMS: Honoraria; Servier: Honoraria. Stilgenbauer:Boehringer-Ingelheim: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: 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; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmcyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Hoffmann La-Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Schmitz:Riemser: Honoraria, Other: Travel grants; Kite/Gilead: Honoraria, Other: Travel grants; Novartis: Honoraria, Other: Travel grants; Celgene: Other: Travel grants; Roche: Honoraria. Murawski:Takeda: Consultancy; Janssen: Other: Travel grants.

Easix As Prediction Score before CAR-T Cells Vs Allogeneic Hematopoietic Cell Transplantation (alloHCT) for Relapsed/Refractory (r/r) Large B Cell Lymphoma (LBCL)

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 11-12
Author(s):  
Felix Korell ◽  
Thomas Luft ◽  
Michael Schmitt ◽  
Sascha Dietrich ◽  
Anita Schmitt ◽  
...  
Keyword(s):  
T Cells ◽  
Board Of Directors ◽  
Research Funding ◽  
B Cell Lymphoma ◽  
Tumor Board ◽  
Advisory Committees ◽  
Educational Activities ◽  
Bulky Disease ◽  
Car T Cells ◽  
Car T

BACKGROUND: In a previous study we have shown that CD19-directed chimeric antigen receptor (CAR)-T cells do not appear to be inferior to alloHCT when used as standard cellular immunotherapy (CI) for patients with multiply r/r LBCL (EBMT 2020). The purpose of the present follow-up analysis was to further compare the risk profile of the 2 cohorts by applying the EASIX score (lactate dehydrogenase (U/L) × creatinine (mg/dL)/thrombocytes (109 cells per L)), and to assess if EASIX could be used as outcome predictor in patients with r/r LBCL undergoing CAR-T and alloHCT, respectively. METHODS: Eligible were all patients referred to our institution with relapsed/refractory (R/R) DLBCL and a tumor board decision recommending treatment with CAR-T cells between 07/2018 and 02/2020 and those recommending allogeneic donor search between 2004 and 2019. Patients with DLBCL transformed from CLL were excluded. EASIX was evaluated retrospectively using uni- and multivariable analyses (with regards to age, gender and number of failed therapy lines) and mortality using Cox regression analyses. RESULTS: 41 patients intended for CAR-T cells and 60 patients intended for alloHCT were included. In both cohorts nearly all patients had active disease at indication. Cohorts were comparable for sex, time from diagnosis, ZUMA1 eligibility, and PS, but CAR-T patients tended to be older (median 56 vs 51 years, p=0.093), and had more often primary refractory and bulky disease (p=0.004 and p=0.04, respectively). Median EASIX score across both cohorts was 1.50 (0.27-70.5), with significantly higher scores in the CART group both at indication (EASIX-ind; median 1.79 and 1.22 for CAR-T and alloHCT, respectively, p=0.031) and at conditioning for CI (EASIX-pre, median 2.24 vs 1.26, p=0.005). Median OS from indication was 475d for the CAR-T cohort vs 285d for the alloHCT cohort (p=0.88). On multivariate analysis, EASIX-ind was significantly associated with adverse OS if alloHCT was intended (HR per 2fold increase 1.43, 95%CI 1.08-1.90, p=0.013), but not if CAR-T was intended (HR per 2fold increase 1.16, 95%CI 0.88-1.53, p=0.3). After CI, 12-month estimates for NRM, relapse incidence, PFS, and OS for CAR-T vs alloHCT were 3% vs 21% (p=0.04), 59% vs 44% (p=0.12), 39% vs 33% (p=0.97), and 68% vs 54% (p=0.32). EASIX-pre predicted overall survival (OS) in both CAR-T (HR per 2fold increase 2.11, 95%CI 1.21-3.7, p=0.009) and alloHCT (HR per 2fold increase 3.69, 95%CI 1.54-8.31, p=0.003) cohorts. In the alloHCT group, the EASIX effect was largely driven by higher NRM risk with increasing EASIX-pre, while in the CAR-T group poorer OS with increasing EASIX-pre was largely relapse-related. CONCLUSIONS: In patients undergoing CI for r/r LBCL, EASIX measured prior to conditioning can predict mortality after both CAR-T and alloHCT. If applied already at indication for CI, the predictive capacity of EASIX is weaker and no longer significant if CAR-T is intended. Further studies for validation of this data appear to be warrantable. Disclosures Schmitt: MSD: Membership on an entity's Board of Directors or advisory committees, Other: PI of clinical trials on letermovir; TolerogenixX Ltd: Other: Co-Founder and shareholder; Hexal: Other: Travel grants , Research Funding; Apogenix: Research Funding; Kite: Other: Travel grants, educational activities and conferences; Novartis: Other: educational activities and conferences, Research Funding. Dietrich:Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; KITE: Membership on an entity's Board of Directors or advisory committees. Schmitt:Hexal: Other: Travel grants ; TolerogenixX LtD: Other: Co-founder, Part-time employee ; Therakos/Mallinckrodt: Research Funding; Jazz Pharmaceuticals: Other: Travel grants . Dreger:Neovii: Research Funding; Roche: Consultancy, Speakers Bureau; Riemser: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Janssen: Consultancy; Gilead: Consultancy, Speakers Bureau; AstraZeneca: Consultancy; AbbVie: Consultancy, Speakers Bureau.

scholarly journals Does Addition of Rituximab (R) to BEAM Conditioning Improve Outcomes of Patients with Diffuse Large B-Cell Lymphoma (DLBCL) Undergoing Autologous Hematopoietic Cell Transplantation (auto-HCT)?

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 785-785
Author(s):  
Deepa Jagadeesh ◽  
Navneet S. Majhail ◽  
He Yizeng ◽  
Kwang Woo Ahn ◽  
Carlos Litovich ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Cumulative Incidence ◽  
Research Funding ◽  
B Cell Lymphoma ◽  
Older Age ◽  
Disease Stage ◽  
Karnofsky Performance Score ◽  
Advisory Committees ◽  
Significant Difference ◽  
The Impact

Introduction: Rituximab-based high-dose therapy (HDT) is frequently prescribed to DLBCL patients (pts) undergoing auto-HCT. However data supporting the benefit of adding R to auto-HCT conditioning are not available. Herein, we report the impact of R-based conditioning on auto-HCT outcomes of DLBCL pts. Methods: Using the Center for International Blood and Marrow Transplant Research registry, 862 adult (≥18 years) DLBCL pts undergoing auto-HCT, between 2003-2017 were included. Analysis was limited to pts receiving BEAM (BCNU, etoposide, cytarabine, melphalan)-based HDT, as R was infrequently used with non-BEAM conditioning regimens. All pts received R-containing chemoimmunotherapy in the frontline setting and had chemosensitive disease prior to HCT. Early chemoimmunotherapy failure (ECitF) was defined as not achieving a complete remission (CR) after frontline chemoimmunotherapy or relapsing within 1 year of initial diagnosis. Primary outcome was overall survival (OS). Secondary outcomes included non-relapse mortality (NRM), relapse, progression-free survival (PFS) and infectious complications within 100 days post-HCT. Results: The study cohort was divided into 2 groups; BEAM (n=667) and R-BEAM (n=195). The baseline characteristics of the 2 cohorts were comparable including age at auto-HCT, disease stage, Karnofsky performance score, extranodal involvement, time from diagnosis to auto-HCT, number of prior therapies, remission status, and ECitF. However, significantly more R-BEAM cohort patients received R as part of last therapy line before auto-HCT (75% vs. 86%; P=0.001). Median follow-up of survivors was 48 (range 1-171) and 64 (range 3-142) months in the BEAM and R-BEAM cohorts, respectively. On univariate analysis, the 4 year cumulative incidence of relapse (41% vs 44%), NRM (11% vs 9%), PFS (48% vs 47%; Figure 1) and OS (58% vs 61%; Figure 2) were similar in the R-BEAM and BEAM groups, respectively (Table 1). On multivariate analysis, no significant difference was seen in OS (HR 0.81; 95% CI 0.81-1.31; P=0.83) or PFS (HR 0.94; 95% CI 0.76-1.18; P=0.61) (Table 1) between the two cohorts. Addition of R had no impact on risk of relapse (HR 0.83; 95% CI 0.65-1.07; P=0.15) or NRM (HR 1.43; 95% CI 0.909-2.26; P=0.12). Variables independently associated with lower OS included older age (HR 3.05; 95% CI 1.81-5.13; P<0.001), not being in CR at auto-HCT (HR 1.67, 95% CI 1.39-2.07; P<0.001) and presence of ECitF (HR 1.52, 95% CI 0.54-3.26; P<0.001). Older age (HR 2.26, 95% CI 1.48-3.45; P<0.0002) and not being in CR at auto-HCT (HR 1.78, CI 1.47-2.14; P<0.0001) were also associated with inferior PFS. There was no significant difference in the 100-day cumulative incidence of bacterial, viral or fungal infections between the two cohorts. Disease relapse was the main cause of death in both BEAM and R-BEAM cohorts (66% vs 55%). Conclusion: In this large registry analysis of DLBCL pts undergoing auto-HCT, adding R to BEAM conditioning had no impact on transplantation outcomes. Older age, absence of CR and ECitF were associated with inferior survival. Disclosures Majhail: Mallinckrodt: Honoraria; Incyte: Consultancy; Nkarta: Consultancy; Anthem, Inc.: Consultancy; Atara Bio: Consultancy. Sureda:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support; Gilead: Honoraria; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria; BMS: Honoraria; Roche: Honoraria; Sanofi: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kharfan-Dabaja:Daiichi Sankyo: Consultancy; Pharmacyclics: Consultancy. Hamadani:ADC Therapeutics: Consultancy, Research Funding; Merck: Research Funding; Takeda: Research Funding; Pharmacyclics: Consultancy; Celgene: Consultancy; Medimmune: Consultancy, Research Funding; Janssen: Consultancy; Otsuka: Research Funding; Sanofi Genzyme: Research Funding, Speakers Bureau.

The Role of the Rituximab Partner Chemotherapy Regimen In Young Patients with Good-Prognosis Diffuse Large B-Cell Lymphoma (DLBCL): Results of the 6-Year Follow-up of the Mint Study of the Mabthera International Trial (MInT) Group.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2826-2826
Author(s):  
Niels Murawski ◽  
Evelyn Kuhnt ◽  
Sandra Grass ◽  
Wolfgang Hiddemann ◽  
Eva Cavallin-Stahl ◽  
...  
Keyword(s):  
Adverse Events ◽  
Board Of Directors ◽  
Cox Regression ◽  
Young Patients ◽  
Good Prognosis ◽  
Hazard Ratio ◽  
Advisory Committees ◽  
Bulky Disease ◽  
To Receive

Abstract Abstract 2826 Background: The addition of rituximab to CHOP-21 significantly improved clinical outcome in elderly patients with DLBCL (Coiffier et al., 2002). In young patients, the MInT trial, where young good-prognosis patients were randomized to receive a CHOP-like regimen or the same CHOP-like regimen plus rituximab, had to be stopped early because of superiority of the rituximab arm, and results were published with a median follow-up of 34 months (Pfreundschuh et al., Lancet Oncology 2006;379–91). Objective: Because the MInT study was the first study to show a survival benefit of the addition of rituximab to a CHOP-like regimen in young good-prognosis patients, it is important to analyze the effect of different chemotherapy regimens on long-term outcome. Methods: In a phase III intergroup study with participating cooperative groups from 18 countries, previously untreated young (18-60 years) patients with good-prognosis DLBCL (age-adjusted IPI 0 or 1, stages II-IV and stage I with bulky disease) were randomized to receive 6 cycles of a CHOP-like regimen (CHEMO) or the same chemotherapy plus rituximab 375 mg/m2, given on day 1 of each 3-weekly regimen and on days 1, 22, 43, 64, 85 and 106 of the 2-week regimens, respectively (R-CHEMO). Radiotherapy (30-40 Gy) was planned to sites of initial bulky disease and/or extranodal involvement. The primary endpoint was event-free survival (EFS) with events defined as failure to achieve complete remission, progressive disease, relapse, death or additional (unplanned) therapy. Results: Between 05/2000 and 10/2003 a total of 823 patients were recruited of whom 396 were allocated to receive CHOP-21, 361 to CHOEP-21, 34 to MACOP-B, and 32 to PMitCEBO with or without rituximab. Patients`characteristics were not different between the treatment arms with the exception that patients in the MACOP-B and R-MACOP-B arm had a more favorable prognostic profile. Toxicity, incidence of adverse events and severe adverse events in the different CHEMO and the R-CHEMO arms were not significantly different. After a median observation time of 70 (0.03-117) months, the 6-year EFS rates of patients assigned to CHEMO only were 50.4%, 60%, 41.7%, and 78.6% for CHOP-21, CHOEP-21, PMitCEBO, and MACOP-B, respectively. In an adjusted multivariate Cox regression model for EFS restricted to CHEMO patients, only the CHOEP-21 hazard ratio (HR) was significant (HR=0.73; p=0.05) compared to CHOP-21, while the hazard ratios of the different chemotherapies were not significantly different for PFS and OS (6 year PFS-rates: 60.2%, 64.8%, 67.5%, 86.2%; and 6 year OS-rates: 78.8%, 80.2%, 65.5%, and 100.0%, respectively). In patients assigned to R-CHEMO, 6-year EFS rates were 74.9%, 75%, 36.5%, and 86.7% for CHOP-21, CHOEP-21, PMitCEBO and MACOP-B, respectively. Likewise, PMitCEBO patients tended to have lower PFS (6-year rates: 79.1%, 81.9%, 58.9, and 86.7%, respectively) and OS (6-year rates: 91.9%, 89.4%, 80.0 and 94.1%, respectively). The poor outcome after R-PMitCEBO in contrast to R-CHOP was confirmed by multivariable Cox regression restricted to R-CHEMO and adjusting for aaIPI and bulky disease. Hazard ratio of PMitCEBO was significant for EFS (HR 4.35, p<0.001) and PFS (HR 3.62, p=0.002), with a strong trend for OS (HR 3.11, p=0.073). Conclusion: While the addition of rituximab to CHOP-like regimens usually results in reduced differences between chemotherapy regimens (“chemo-equalizer” effect, e.g. disappearance of the superiority of CHOEP over CHOP after the addition of rituximab), combination of rituximab with some regimens might result in an unexpectedly poor outcome. Therefore, rituximab should not be combined with regimens other than CHOP outside randomized trials. Supported by Roche, Deutsche Krebshilfe and KML. Disclosures: Jäger: Roche: Honoraria, Research Funding. Pettengell:Roche: Honoraria. Pfreundschuh:Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees.

A Randomized Phase 3 Trial Of Melphalan-Lenalidomide-Prednisone (MPR) Or Cyclophosphamide-Prednisone-Lenalidomide (CPR) Vs Lenalidomide Plus Dexamethsone (Rd) In Elderly Newly Diagnosed Multiple Myeloma Patients

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 536-536 ◽  
Author(s):  
Antonio Palumbo ◽  
Valeria Magarotto ◽  
Sara Bringhen ◽  
Massimo Offidani ◽  
Giuseppe Pietrantuono ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Research Funding ◽  
Alkylating Agents ◽  
Second Primary ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Significant Difference ◽  
Grade 3 ◽  
To Receive

Abstract Background Rd and MPR are effective treatments in newly diagnosed multiple myeloma (NDMM) patients (pts). In this study we compared a non-alkylating containing regimen (Rd) vs alkylating-based regimens (MPR/CPR) in elderly transplant ineligible NDMM pts. Methods Patients were randomized (2:1) to receive nine 28-day cycles of MPR/CPR or Rd. MPR: lenalidomide 10 mg/day for 21 days; melphalan orally 0.18 mg/Kg for 4 days in pts 65-75 years old and 0.13 mg/Kg in >75 years pts; prednisone 1.5 mg/Kg for 4 days; CPR: cyclophosphamide orally 50 mg/day for 21 days in pts 65-75 years old and 50 mg every other day (eod) in >75 years pts; lenalidomide 25 mg/day for 21 days; prednisone 25 mg every other day. Rd: lenalidomide 25 mg/day for 21 days; dexamethasone 40 mg on days 1,8,15 and 22 in pts 65-75 years old and 20 mg in those >75 years. After induction, patients were randomized to receive maintenance with lenalidomide alone (10 mg/day for 21 days) or with prednisone (25 mg eod on days 1-28), until disease progression. The primary endpoint was progression-free survival (PFS). Results Between October 2009 and October 2012, 659 pts were enrolled ( MPR/CPR:439 and Rd:220), and 641 pts were evaluable (MPR/CPR:430 and Rd:211). Patient characteristics were well balanced in the 2 groups: median age was 73 years in both groups, 38% of pts were older than 75 years, 27% had ISS stage III in both groups, 21% of patients both in the MPR/CPR and in the Rd groups had unfavorable FISH profile [t(4;14) or t (14;16) or del17p]. After induction, the response rates were similar in the 2 groups: at least PR rate was 75% versus 79% (p=0.52) and CR rate was 9% versus 7% (p=0.35), in the MPR/CPR and Rd group, respectively. No significant difference in response rate were reported between two alkylating containing regimens. After a median follow-up of 21 months, the 2-year PFS was 55% in MPR/CPR and 49% in Rd (HR=0.86, 95% CI: 0.66-1.12, p=0.26), and 2-year OS was 84% in MPR/CPR and 80% in Rd (HR= 0.93, 95% CI: 0.60-1.41, p=0.71) At least one grade ≥3 hematological adverse event was reported in 51% with MPR/CPR and 29% with Rd (p<0.001), with a significant difference between the two alkylating agents (67% MPR and 31% CPR, p<0.001). At least one grade ≥3 extra-hematologic toxicities were similar in the two groups (31% with MPR/CPR and 28% with Rd, p=0.77). with no difference between two alkylating agents (31% both in MPR and CPR group). Second primary malignancies (SPM) were reported in 5 MPR patients (1 hematologic and 4 solid) in 1 CPR patient (hematologic) and in 2 Rd patients (both solid). Conclusion In a community-based population, triplet alkylating combinations did not lead to different PFS or OS clinical benefits over doublet therapy. Updated results will be presented at the meeting. Disclosures: Palumbo: Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen Pharmaceuticals: Consultancy, Honoraria; Millenium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria. Bringhen:Celgene: Honoraria. Giuliani:Celgene: Research Funding. Cavallo:Celgene: Honoraria; Celgene: Membership on an entity’s Board of Directors or advisory committees. Hajek:Celgene: Honoraria; Celgene: Consultancy. Boccadoro:Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees.

Randomised Intergroup Trial of First line Treatment for young Low-Risk Patients (<61 years) with Diffuse Large B-Cell Non-Hodgkin's Lymphoma (DLBCL) with a CHOP-like Regimen with or without the Anti-CD20 Antibody Rituximab – 6-Year Follow-up of the Mint Study of the Mabthera International Trial (MInT) Group

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 111-111 ◽  
Author(s):  
Michael Pfreundschuh ◽  
Evelyn Kuhnt ◽  
Lorenz Trümper ◽  
Anders Osterborg ◽  
Marek Trneny ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Survival Benefit ◽  
Research Funding ◽  
Good Prognosis ◽  
Event Free Survival ◽  
Advisory Committees ◽  
Bulky Disease ◽  
Free Survival ◽  
To Receive

Abstract Abstract 111 Background: The addition of rituximab to CHOP-21 significantly improved clinical outcome in elderly patients with DLBCL (Coiffier et al., 2002). The MInT trial, randomized young good-prognosis patients to receive a CHOP-like regimen or the same CHOP-like regimen plus rituximab, and was stopped early because of superiority of the rituximab arm, and results were published with a median follow-up of 34 months (Pfreundschuh et al., Lancet Oncology 2006; 379-91). Objective: Because the MInT study was the first study to show a survival benefit with the addition of rituximab to a CHOP-like regimen in young good-prognosis patients, extended follow-up is important to determine whether the survival benefit is maintained over time and whether a definitive effect on cure rates can be shown. Methods: In a phase III intergroup study with participating cooperative groups from 18 countries, previously untreated patients (18-60 years) with low-risk DLBCL (age-adjusted IPI 0 or 1, stages II-IV and stage I with bulky disease) were randomized to receive 6 cycles of a CHOP-like regimen (CHEMO) or the same chemotherapy plus rituximab 375 mg/m2, given on day 1 of each 3-week regimen and on days 1, 22, 43, 64, 85 and 106 of the 2-week regimens, respectively (R-CHEMO). Radiotherapy (30-40 Gy) was planned to sites of initial bulky disease and/or extranodal involvement. The primary endpoint was event-free survival (EFS) with events defined as failure to achieve complete remission, progressive disease, relapse, death or additional therapy. The trial was powered to show a 10% difference in EFS rate after 3 years. Results: Between 05/2000 and 10/2003 a total of 823 patients were recruited of whom 396 were allocated to receive CHOP-21, 361 to CHOEP-21, 34 to MACOP-B, and 32 to PMitCEBO with or without rituximab. Toxicity, incidence of adverse events and severe adverse events in the CHEMO and the R-CHEMO arms were not significantly different. After a median follow-up of 70 (0.03-117) months, patients assigned to chemotherapy and rituximab had increased 6-year event-free survival compared with those assigned to chemotherapy alone (74.0% [95% CI 69.0–78.3] vs 55.7% [50.3-60.8]; log-rank p<0·0001), increased 6-year progression-free survival (79.9% [75.1 - 83.8%] vs 63.8% [58.2-68.8]; log-rank p<0.001) and increased overall survival (89.8% [86.0-92.6] vs 80.0% [75.3-83.9; log rank p=0.001). In a multivariate analysis event-free survival was affected by the addition of rituximab (hazard ratio [HR] 0.49, p< 0.001), age-adjusted IPI (HR 1.73, p<0.001), and bulky disease (HR 1.43, p=0.004). Similar effects were observed for OS, while PFS was affected by treatment arm (HR 0.49, p<0.001) and age-adjusted IPI (HR 1.8, p<0.001). As a consequence, a very favorable subgroup (aaIPI=0, no bulky) can be distinguished from a less favorable subgroup (aaIPI=1 and/or bulky disease) among good-prognosis patients treated with rituximab. There were 10 late (>60 months) events after CHEMO (61.4 to 96.1 months), including 4 in the very favorable subgroup, while all 8 late events (67.5 to 105.7 months) after R-CHEMO occurred in the less favorable subgroup only, and none in the very favorable subgroup. Conclusion: Addition of rituximab to a CHOP-like regimen leads to a significant improvement of the outcome in young patients with good-prognosis diffuse large B-cell lymphoma, with significant survival benefit maintained during a 6-year follow-up. However, except in the very favorable subgroup after R-CHEMO, late relapses after 5 years occur. While reduction of treatment in a randomized study like the FLYER trial of the DSHNHL is justified, further progress, e.g. by dose densification (UNFOLDER trial of the DSHNHL) and/ or dose escalation is still warranted for the less favorable subgroup. Supported by Roche, Deutsche Krebshilfe and KML. Disclosures: Pfreundschuh: Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Trneny:Roche: Honoraria, Research Funding. Walewski:Roche: Honoraria, Research Funding. Pettengell:Roche: Honoraria. Jäger:Roche: Honoraria, Research Funding. Lopez-Guillermo:Roche: Consultancy.

scholarly journals Treatment Outcomes of Consolidative Radiation in Extranodal Early-Stage Diffuse Large B-Cell Lymphoma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 49-49
Author(s):  
Daniel A. Ermann ◽  
Victoria A. Vardell ◽  
Harsh Shah ◽  
Randa Tao ◽  
David K. Gaffney ◽  
...  
Keyword(s):  
Soft Tissue ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Early Stage ◽  
B Cell Lymphoma ◽  
Nodal Disease ◽  
Advisory Committees ◽  
Large B Cell Lymphoma ◽  
To Receive

Abstract Introduction Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of Non-Hodgkin Lymphoma, with approximately 25-30% of patients presenting as early or limited-stage (stage I and II). Though treatment with chemoimmunotherapy is standard of care, the role of consolidative radiotherapy (RT) in limited-stage (LS) patients is not well defined. Recent studies have attempted to shorten chemotherapy courses and eliminate RT for LS patients. Additionally, recent single institutional data has suggested LS patients with extranodal (EN) disease may have better outcomes if treated with RT. We aimed to investigate whether the addition of RT provided a survival benefit in early-stage DLBCL patients based on primary site at presentation comparing nodal to EN disease. Methods The National Cancer Database was utilized to identify patients diagnosed with LS-DLBCL from 2004 to 2015. Only patients treated with multiagent chemotherapy were included. Patients with international prognostic index (IPI) score available were separated into low (0-1 factors) or high-risk (2-4) groups. Landmark analysis was performed to exclude patients with last contact, including death, within 12 months of diagnosis. Kaplan-Meier survival analysis was used to compare overall survival (OS). Cox regression analysis was used to identify hazard ratios for survival using RT between subgroups. Results Of the 39,745 LS patients identified, 62.9% had nodal disease and 37.1% had EN disease with stage I disease accounting for 51.5% of patients. Only 6,628 patients had reported IPI scores with the majority having low-risk IPI (69.2%). Compared to patients with only nodal disease, patients with EN involvement were more likely to receive consolidative RT (42.9% vs 37.2%; p&lt;0.05). EN patients were most likely to receive RT with primary bone (67.7% of 1526 patients), skin/soft tissue (60.3% of 1353), breast (58.6% of 652), testes (58.4% of 950) and thyroid (56.6% of 1059) involvement (all p&lt;0.05). GI (18.1% of 4652) and lung (23.3% of 614) primaries were least likely to receive RT (p&lt;0.05). With a median follow up of 58.8 months, the addition of RT was associated with improved 5-year OS for all LS patients as compared to those treated with chemotherapy alone (68 vs. 62%, p&lt;0.001). While RT was associated with improved 5-year OS in both the nodal and EN disease patients, nodal patients had a greater benefit of receiving RT as compared to EN patients (nodal: 71% vs. 63%, p&lt;0.001; EN: 64% vs. 62%; p&lt;0.001). Specifically, in EN patients, the addition of RT significantly increased 5-year OS for skin/soft tissue (60% vs. 57%, p&lt;.001), head and neck (63% vs. 60%, p&lt;0.02), testicular (63% vs. 45%, p&lt;.001), and thyroid sites (73% vs. 67%, p &lt;0.02). Furthermore, RT slightly improved 5-year OS outcomes for patients with both low-risk (75% vs. 73%; p&lt;0.01) and high-risk IPI (52% vs. 50%; p&lt;0.04). On multivariate analysis, adjusting for age, stage, and Charlson-Deyo comorbidity score, the addition of RT was an independent factor for improved survival for all LS patients (Hazard Ratio [HR] 0.84, 95% Confidence Interval [CI] 0.81-0.88; p&lt;0.001) along with EN sites of skin/soft tissue (HR 0.72, 95% CI 0.58-0.88; p&lt;0.01), testicle (HR 0.70, 95% CI 0.54-0.90, p&lt;0.01) and thyroid (HR 0.68, 95% CI 0.51-0.90; p&lt;0.01). No significant survival differences were observed in patients with EN involvement of the lung, bone, breast, or GI tract when RT was added to their treatment. Conclusions We report the largest retrospective study on EN outcomes utilizing consolidative RT in early-stage DLBCL. Though there is no consensus on optimal treatment indications for RT in LS-DLBCL, this data shows improved OS in both nodal only disease and within specific EN disease subgroups when RT is added to front-line chemotherapy. As recent studies have attempted to shorten chemotherapy cycles and limit the use of RT, these results suggest caution against omission of RT in select patients. Figure 1 Figure 1. Disclosures Shah: AstraZeneca: Research Funding; Seattle Genetics: Research Funding; Epizyme: Research Funding. Stephens: TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Abbvie: Consultancy; JUNO: Research Funding; Innate Pharma: Membership on an entity's Board of Directors or advisory committees; Adaptive: Membership on an entity's Board of Directors or advisory committees; Arqule: Research Funding; Mingsight: Research Funding; Beigene: Membership on an entity's Board of Directors or advisory committees; Epizyme: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy; CSL Behring: Consultancy; Celgene: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Clinical Relevance of MYC/BCL2 and Cell of Origin in Patients with Relapsed Diffuse Large B-Cell Lymphoma Treated with Autologous Stem Cell Transplantation

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2021-2021
Author(s):  
Yingjun Wang ◽  
Ken H. Young ◽  
Denái R. Milton ◽  
Celina Ledesma ◽  
Elias Jabbour ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Advisory Board ◽  
Cell Of Origin ◽  
Advisory Committees ◽  
Large B Cell Lymphoma ◽  
Significant Difference ◽  
Bcl2 Expression

Purpose: Dual expression of MYC and BCL2 proteins (Double Expressor Lymphoma-[DEL]) and MYC, BCL2 and /or BCL6 translocations (Double Hit Lymphoma-[DHL]) as well as the cell-of-origin (COO) are important prognostic factors in patients (pts) with diffuse large B-cell lymphoma (DLBCL) who are treated with standard chemo-immunotherapy. Data are limited regarding the prognostic impact and interdependence of these biomarkers on outcomes in pts with relapsed DLBCL treated with autologous stem cell transplantation (ASCT). Methods: Data from Pts with relapsed DLBCL who underwent ASCT at our center and in whom archived tumor material was available were analyzed. Cutoff values of 40% for MYC and 70% for BCL2 were established by immunohistochemistry (IHC). FISH cases for MYC and BCL2 were considered for evaluation if at least 200 tumor cell nuclei per core displayed reliable signals in the sections. COO classification was achieved by IHC methods according to both the Visco-Young and Choi algorithms. The majority of pts (81%) underwent chemo-mobilization of stem cells with rituximab for in-vivo purging; rituximab was also given on days+1 and +8 with BEAM conditioning (J Clin Oncol 2005; 23:2240-7; Clin Cancer Res 2018; 24:2304-11). The study was IRB-approved at our center. Results: 303 pts were evaluated; 169 (56%) met the criteria for DEL and 3 (1%) for DHL; 8 (3%) met criteria for both (DEL/DHL) and 97 (32%) for neither (non-DEL/non-DHL). Because of small size, the 3 pts with only DHL were excluded from this analysis. In addition, 8 pts (3%) had atypical DHL and their outcomes were analyzed separately. GCB classification was successful in 269 pts, and 119 pts (44%) were of the GCB subtype. Median age of the whole group was 60 years (range, 18-80); the male gender predominated (65%). The median number of prior lines of therapies was 2. At ASCT, 90% of pts had chemo-sensitive disease (64% CR, 26% PR), and 6% had small volume SD; IPI was ≥ 2 in 17% of pts and PET was positive in 26%. There were no statistically significant differences in pt characteristics between the subgroups of non-DEL/non-DHL, DEL, or DEL/DHL, with the exception of GCB distribution: 46% and 41% of non-DEL/non-DHL and DEL, respectively, were classified to be of the GCB subtype, whereas all 8 DEL/DHL were classified as non-GCB (P=0.002). With a median follow-up time among survivors of 50 months (range, 4-217 months), the 4-year overall survival (OS) rates of non-DEL/non-DHL, DEL and DEL/DHL subgroups were 65%, 59%, and 25%, respectively. There was no significant difference in OS between non-DEL/non-DHL and DEL subgroups (P=0.39), however a significant difference in OS was observed between the two subgroups compared to the DEL/DHL pts (P=0.034; Figure 1). Progression-free-survival (PFS) rates were higher for the non-DEL/non-DHL (4-year rate: 51%) and DEL (4-year rate: 49%) compared to DEL/DHL (4-year rate: 25%) subgroups, though not statistically different (P=0.22). A higher risk of non-relapse mortality was observed in the DEL/DHL group compared to the other 2 groups (hazard ratio [HR]=3.8, P=0.017). The 4-year OS and PFS rates for the atypical DHL were 67% and 33%, respectively. We also evaluated the interaction of COO with BCL-2 protein expression; we found that pts who had BCL2 (+) expression, had worse OS (HR=1.82; P=0.049) and a trend for worse PFS (HR=1.58; P=0.08) compared to BCL2 (-) pts. This interaction was more prominent however in GCB pts. The 4 year OS rates of GCB/BCL2(-) and GCB/BCL2(+) were 87% and 56%, respectively (P=0.030). The 4-year PFS rates were 88% and 47%, respectively (P=0.007) (Figure 2). The OS and PFS rates within non-GCB subgroups were similar regardless of BCL2 expression. Conclusions: Our study shows that pt subgroups who have both DEL/DHL DLBCL have inferior survival. Interestingly, we also found that pts who have DEL and non-DEL/non-DHL have similar outcomes after ASCT. BCL2 expression is an important prognostic factor in GCB lymphoma. Investigational studies combining targeted therapies in this setting are warranted. Disclosures Jabbour: Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Cyclacel LTD: Research Funding. Molldrem:M. D. Anderson & Astellas Pharma: Other: Royalties. Bashir:Imbrium: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; StemLine: Research Funding; Acrotech: Research Funding; Celgene: Research Funding. Kebriaei:Amgen: Research Funding; Pfizer: Honoraria; Jazz: Consultancy; Kite: Honoraria. Popat:Bayer: Research Funding; Incyte: Research Funding; Jazz: Consultancy. Westin:Novartis: Other: Advisory Board, Research Funding; Celgene: Other: Advisory Board, Research Funding; Janssen: Other: Advisory Board, Research Funding; MorphoSys: Other: Advisory Board; Curis: Other: Advisory Board, Research Funding; Genentech: Other: Advisory Board, Research Funding; Unum: Research Funding; Kite: Other: Advisory Board, Research Funding; Juno: Other: Advisory Board; 47 Inc: Research Funding. Qazilbash:Bioclinical: Consultancy; Amgen: Consultancy, Other: Advisory Board; Autolus: Consultancy; Genzyme: Other: Speaker. Champlin:Johnson and Johnson: Consultancy; Actinium: Consultancy; Sanofi-Genzyme: Research Funding.

scholarly journals A Multicenter, Real World Analysis of Primary Central Nervous System Lymphoma in Those with and without Human Immunodeficiency Virus

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1457-1457
Author(s):  
Christopher Dittus ◽  
Natalie S Grover ◽  
Tarsheen Sethi ◽  
Jonathon B. Cohen ◽  
Alfredo Voloschin ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Real World ◽  
Research Funding ◽  
Performance Status ◽  
Advisory Board ◽  
Advisory Committees ◽  
Entire Cohort ◽  
Genetics Research ◽  
Significant Difference ◽  
To Receive

Abstract Introduction: Representing 4% of central nervous system (CNS) tumors, primary CNS lymphoma (PCNSL) is a rare type of extranodal non-Hodgkin lymphoma (NHL) that involves the brain, leptomeninges, eyes, spinal cord or cerebrospinal fluid without evidence of systemic disease. High-dose methotrexate (HD-MTX)-based regimens that incorporate consolidation with reduced dose whole brain radiation therapy (WBRT) or autologous stem cell transplant have shown 2-year overall survival (OS) rates ranging from 69% to 81% (Morris, JCO, 2013; Omuro, Blood, 2015). Although these data are encouraging, patients whose CNS deficits are too severe to receive treatment will die within the first months of diagnosis. HIV PCNSL has been associated with a poorer performance status and worse OS compared to non-HIV PCNSL. With the advent of combination antiretroviral therapy (ART), HIV PCNSL has become less common and by incorporating HD-MTX into HIV PCNSL treatment, outcomes have improved (Gupta, Neuro Oncol, 2017). In this study, we report the real world survival of PCNSL at 3 large academic centers, including those who received HD-MTX versus those who did not. We also compare survival of HIV PCNSL relative to non-HIV PCNSL. Methods: Adult patients (&gt;18 years of age) with PCNSL at 3 medical centers (UNC Chapel Hill, Vanderbilt Medical Center, Emory University) were included in this analysis. Patients were diagnosed between January 2004 and July 2020. Only the diffuse large B-cell lymphoma (DLBCL) histology was included. Cases were excluded if there was any disease outside of the CNS or if they previously had systemic DLBCL. Demographic information was collected from the medical record, as well as disease-related information, HIV status, HD-MTX treatment (defined as &gt;3g/m2) with or without other chemotherapeutic agents, imaging to determine progression, and survival data. Data were analyzed for the entire cohort as well as compared between HIV and non-HIV subjects. Demographic variables were summarized using appropriate statistics (frequencies, mean and standard deviation) and compared between HIV and non-HIV patients using Fisher's exact tests or Wilcoxon rank sum tests. Progression free survival (PFS) and OS were also compared between HIV and non-HIV patients using log-rank tests. Results: We identified 158 cases of PCNSL. The median PFS for the entire cohort was 1.17y and the median OS was 3.24y. Patients who received HD-MTX had an improved PFS (1.69y vs 0.25y; p=0.0016) and an improved OS (4.01y vs 1.05y; p=0.00075) over those who did not receive HD-MTX. Twenty-six of the 158 cases were HIV positive. Table 1 reports clinical features in HIV versus non-HIV PCNSL patients. Patients with HIV PCNSL were significantly younger than those with non-HIV PCNSL (44y vs 75y), and had a worse performance status (PS&gt;2: 57.7% vs 26.8%). Notably, patients with HIV were less likely to receive HD-MTX compared to patients without HIV (53.8% vs 83.3%). Receiving frontline WBRT trended towards significance in favor of the HIV PCNSL group. Other factors such as gender, deep structure involvement, elevated cerebrospinal fluid protein, and elevated lactose dehydrogenase (LDH) were not significantly different between groups. When comparing HIV to non-HIV PCNSL, there was not a statistically significant difference in PFS (0.30y vs 1.34y; p=0.34), but there was a statistically significant difference in OS (0.30y vs 3.65y; p=0.0023) (Figure 1). When comparing those who received HD-MTX in the HIV group vs non-HIV group, there was not a statistically significant difference in PFS (3.39y vs 1.66y; p=0.45) or OS (3.6y vs 4.0y; p=0.43) (Figure 2). Conclusions: Our analysis shows that real-world survival for PCNSL is modest compared to reported outcomes from clinical trials. Patients who are able to receive treatment with HD-MTX had a significantly improved outcome. HIV PCNSL has worse OS than non-HIV PCNSL, and the median PFS and OS were both several months in the HIV PCNSL group, suggesting an unmet need for both frontline and salvage therapies. The survival difference between HIV PCNSL and non-HIV PCNSL decreased when evaluating only those patients who received HD-MTX. Importantly, fewer patients received HD-MTX in the HIV PCNSL group; and these patients had worse PS. These real-world data may serve as the benchmark for survival outcomes in PCNSL and provide valuable information for designing future trials in patients with PCNSL. Figure 1 Figure 1. Disclosures Dittus: Genentech: Research Funding; AstraZeneca: Research Funding; Seattle Genetics: Research Funding; BeiGene: Other: Advisory Board. Grover: Kite: Other: Advisory Board; ADC: Other: Advisory Board; Novartis: Consultancy; Tessa: Consultancy; Genentech: Research Funding. Cohen: Janssen, Adicet, Astra Zeneca, Genentech, Aptitude Health, Cellectar, Kite/Gilead, Loxo, BeiGene, Adaptive: Consultancy; Genentech, BMS/Celgene, LAM, BioINvent, LOXO, Astra Zeneca, Novartis, M2Gen, Takeda: Research Funding. Park: G1 Therapeutics: Consultancy; Takeda: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Teva: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees; Rafael Pharma: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Seattle Genetics: Research Funding, Speakers Bureau; Gilead: Speakers Bureau.

scholarly journals TP53 and MYD88 Mutations As Detected By Liquid Biopsy in the Prediction of Progression-Free Survival in Patients with Diffuse Large B-Cell Lymphoma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4480-4480
Author(s):  
Maher Albitar ◽  
Andrew Ip ◽  
Hong Zhang ◽  
Andrew L. Pecora ◽  
Jeffrey Justin Estella ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Residual Disease ◽  
Progression Free Survival ◽  
B Cell Lymphoma ◽  
Leadership Role ◽  
Advisory Committees ◽  
Free Survival ◽  
Large B Cell Lymphoma ◽  
Significant Difference

Abstract Introduction: Liquid biopsy has been reported to be useful in predicting residual disease in patients with diffuse large B-cell lymphoma (DLBCL). Most of the studies focused on quantifying the level of circulating lymphoma-specific DNA. We explored the clinical relevance of the specific mutated genes in predicting progression in patients with DLBCL. Method: Peripheral blood samples were collected from patients with DLBCL based on their visit to clinic without other specific selection. Median age of patients is 69 (range 28-91), with 51% of the patients being male. These patients were treated on multiple protocols including R-CHOP, R-EPOCH, Magrath, HCVAD, CAR-T (#2 patients), and others. cfDNA was extracted and sequenced by next generation sequencing using 177 gene panel. The panel uses single primer extension (SPE) approach with UMI. Sequencing depth is increased to more than 2000X after removing duplicates. Low level mutations are confirmed by inspecting BAM file. Results: A total of 86 sample from 61 patients were collected post clinical remission at different time points (median 28 weeks, range: 1-994 weeks). Of these samples, 56 (65%) from 46 patients (75%) were positive. However, 6 of these samples from 4 patients had germline mutations or mutations in TET2, ASXL1, or DNMT3A that are consistent with CHIP (clonal hematopoiesis of indeterminate potential). The remaining 50 positive samples from 42 patients had 8 repeats on the same patients collected at different time points. Comparing the 19 negative patients with the 42 positive patients post-remission, patients with residual molecular disease were significantly older than patients without residual disease (P=0.01). However, there was no significant difference between the two groups in gender, ethnic background, LDH, cell of origin classification, or TP53 positivity by IHC. Patients with residual disease showed tendency for short progression-free survival (P=0.08). Focusing on patients with specific mutations detected in the cfDNA showed that 14 (23%) patients had mutations either in TP53 or MYD88. There was no significant difference in age between these two groups or any of the other clinical variables. However, patients with TP53/MYD88 mutations had significantly shorter survival (P=0.04). Conclusion: Post-remission residual disease as measured by circulating cfDNA is an independent predictor of potential relapse in patients with DLBCL. However, presence of it is important to determine the aggressiveness of the residual circulating clone. Residual circulating lymphoma DNA with TP53 or MYD88 mutations is a strong predictor of earlier relapse. Figure 1 Figure 1. Disclosures Pecora: Genetic testing cooperative: Other: equity investor; Genetic testing cooperative: Membership on an entity's Board of Directors or advisory committees. Feldman: Alexion, AstraZeneca Rare Disease: Honoraria, Other: Study investigator. Goy: Bristol Meyers Squibb: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; MorphoSys: Honoraria, Other; AbbVie/Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria; Acerta: Consultancy, Research Funding; Elsevier's Practice Update Oncology, Intellisphere, LLC(Targeted Oncology): Consultancy; Celgene: Consultancy, Honoraria, Research Funding; Michael J Hennessey Associates INC: Consultancy; Elsevier PracticeUpdate: Oncology: Consultancy, Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Medscape: Consultancy; Gilead: Membership on an entity's Board of Directors or advisory committees; Genentech/Hoffman la Roche: Research Funding; AbbVie/Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; OncLive Peer Exchange: Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Xcenda: Consultancy, Honoraria; Vincerx pharma: Membership on an entity's Board of Directors or advisory committees; Rosewell Park: Consultancy; LLC(Targeted Oncology): Consultancy; Genomic Testing Cooperative: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: Leadership role; Xcenda: Consultancy; Hoffman la Roche: Consultancy; Incyte: Honoraria; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Infinity/Verastem: Research Funding; Janssen: Research Funding; Karyopharm: Research Funding; Vincerx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Physicians' Education Resource: Consultancy, Other: Meeting/travel support; COTA (Cancer Outcome Tracking Analysis): Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: Leadership role; Phamacyclics: Research Funding; Constellation: Research Funding; Hackensack Meridian Health, Regional Cancer Care Associates/OMI: Current Employment.

scholarly journals Oral Azacitidine and Cedazuridine Approximate Azacitidine Efficacy in a Murine Model

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1376-1376
Author(s):  
Haley E. Ramsey ◽  
Maria Arrate ◽  
Londa Fuller ◽  
Agnieszka E. Gorska ◽  
Kelli Boyd ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Board Of Directors ◽  
Cell Lines ◽  
Research Funding ◽  
Fixed Dose ◽  
Bone Marrow Toxicity ◽  
Advisory Committees ◽  
Combination Tablet ◽  
Significant Difference ◽  
To Receive

Background: DNA methyltransferase inhibitors (DNMTi) induce remissions and improve survival for patients with MDS and those with AML unable to receive standard cytotoxic chemotherapy. Accordingly, DNMTi therapy is the backbone of SOC treatment for MDS and AML. Given the inconvenience, pain, and general detriments to QOL with SQ or IV therapy daily for 5-7 days every month with azacitidine (AZA) or decitabine (DAC), many have attempted to provide the therapy orally, but encountered difficulties with this method of administration given rapid first-pass clearance via the enzyme cytidine deaminase (CDA) which is ubiquitous in the gut and liver. Recently, DAC was combined with cedazuridine (CDZ), an oral CDA inhibitor, in a fixed-dose (35mg/100mg) combination tablet (ASTX727) to approximate the pharmacokinetics of IV DAC (Savona et al Lancet Haematology 2019). To determine if a similar strategy might be feasible with AZA, we attempted to increase the bioavailability of oral AZA with CDZ in a murine tumor model. Methods: We measured GI50 in AML cell lines treated with vehicle (DMSO), AZA, and AZA/CDZ combination. Although cancer cell lines produce CDA, total levels are negligible in comparison CDA in the gut and liver. For this reason, we then studied CDZ, AZA, and the AZA/CDZ combination in a systemic model of AML in immunocompromised mice. NSGS mice were sub-lethally irradiated and administered MOLM-13 AML cells via tail vein injection. At day seven post-transplant, engrafted mice were randomized to receive 2.5 mpk i.p. AZA(n=8), 2.5 mpk oral AZA(n=8), 3 mpk CDZ + oral AZA(n=6), or CDZ alone at 30 mpk (n=7). All oral AZA and CDZ was administered via oral gavage daily for 7 consecutive days; i.p. therapy was similarly given for 7 consecutive days. During treatment, the kinetics of MOLM-13 expansion was defined by detection of human AML in the blood as detected by flow cytometry. At approximately three weeks after transplant, CDZ-only treated mice became moribund, and all experimental groups were sacrificed for analysis of chimerism. Results: After 72 hour of treatment, no differences were noted in viability of cell lines between AZA and AZA+ CDZ in vitro. In the xenograft model, as expected, i.p. AZA-treated mice had significant decreases in leukemic expansion in the bone marrow and spleen, whereas CDZ alone did not (AZA i.p. vs CDZ, p = 0.004 and &lt;0.001). More importantly, whereas oral AZA alone failed to decrease AML expansion in both the bone marrow and spleen of treated mice (oral AZA vs CDZ., p = 0.677 and 0.249, respectively), the addition of CDZ to oral AZA led to significant decreases in AML in both bone marrow and spleen (Oral AZA + CDZ vs CDZ, p = 0.012 and 0.004, respectively). Likewise, addition of CDZ to oral AZA showed no significant differences in activity against AML compared to traditional AZA i.p. dosing in either bone marrow or splenic tissue (p= 0.204 and 0.224, respectively). Furthermore, in a Kaplan-Meier survival analysis, mice treated with CDZ alone die within 21 days of transplant, but both i.p. AZA and oral AZA + CDZ treated mice had a 50% extended survival with no significant difference in survival between i.p. AZA and oral AZA + CDZ treated mice (p= 0.502). H&E staining revealed no significant bone marrow toxicity in treated mice, suggesting that AZA preferentially effected transplanted MOLM-13 AML cells. Conclusion: Consistent with previous preclinical and clinical studies with ASTX727, the oral AZA approximated AZA anti-tumor activity when co-treated with CDA-inhibitor CDZ. These preliminary data provide rationale for the development of CDZ + oral AZA therapy as a fixed dose combination (ASTX030) in myeloid disease. Clinical trials evaluating ASTX030 are being planned. Figure Disclosures Oganesian: Astex Pharmaceuticals, Inc.: Employment. Azab:Astex Pharmaceuticals, Inc.: Employment. Savona:TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sunesis: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Patents & Royalties; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Selvita: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Sign in / Sign up

Export Citation Format

Share Document