Rituximab (R) Maintenance Versus Observation After Short Term Chemoimmunotherapy R-FND as First Line Treatment in Elderly Patients with Advanced Follicular Lymphoma (FL): Updated Results and Safety of the Maintenance of An Intergruppo Italiano Linfomi (IIL) Randomized Trial.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1706-1706 ◽  
Author(s):  
Umberto Vitolo ◽  
Carola Boccomini ◽  
Marco Ladetto ◽  
Enrica Gamba ◽  
Isabel Alvarez ◽  
...  
Keyword(s):  
Research Funding ◽  
Line Treatment ◽  
Cardiac Events ◽  
First Line ◽  
Short Term ◽  
Off Label ◽  
Rituximab Maintenance ◽  
End Of Treatment ◽  
Grade 3 ◽  
First Line Treatment

Abstract Abstract 1706 Poster Board I-732 Introduction in order to maintain efficacy and reduce toxicity of the treatment in elderly follicular lymphoma (FL) patients, we designed a study with a short chemo-immunotherapy R-FND with Rituximab consolidation followed by randomization between R maintenance or observation. Material and methods: From January 2004 to December 2007, 242 patients (age 60-75) with untreated advanced stage FL were enrolled by 33 IIL centres. Treatment plan was: 4 courses of R-FND (standard doses of Rituximab, Fludarabine, Mitoxantrone, Dexamethasone) every 28 days followed by 4 weekly Rituximab infusions as consolidation; responding (CR+CRu+PR) patients were randomized between Rituximab maintenance, one dose every 2 months for a total of 4 doses or observation. Qualitative and quantitative PCR monitoring for IgH/Bcl-2 rearrangement on bone marrow (BM) was performed at diagnosis, after R-FND and R consolidation and during maintenance/observation. Results 234 patients were eligible for the study: median age was 66 yrs; advanced stage II 14%, stage III 21% and stage IV 65%; BM involvement and B symptoms were documented in 55% and 18% respectively. FLIPI score was: Low 11%, Intermediate 34%, High 55%. One and 2 or more comorbidities were present in 36% and 23% of the patients respectively. Qualitative PCR analysis for IgH/Bcl-2 was performed in 223 patients at diagnosis and 51% were positive. Two hundred and two (86%) patients completed the induction treatment and were randomized between maintenance or observation; 32 were not because of: stable/progressive disease (16), adverse events (10) or other causes (6). Overall response at the end of treatment was 86% with 69% CR and 18% PR; PCR negativity at the end of treatment was 75%. Rituximab consolidation was able to induce CR in 37/90 (41%) partial responders and to increase PCR negativity from 61% to 75%. With a median follow-up of 22 months, two-years OS and PFS were 92% (95% CI 87%-95%) and 75% (95% CI 68%-81%), respectively (see Figure). Two-years PFS rates according to FLIPI score were 85% for low/intermediate risk and 65% for high risk (p < 0.001); 2-years PFS rates were 57% and 79% respectively in patients with and without B symptoms (p < 0.001). The patients in more advanced decade (> 70 years) or those with 2 or more comorbidities did as well as younger ones or those with one or no comorbidities: 2-yr PFS rates for patients more or less seventy were 73% vs 76% (p = 0.39); for patients with ≥2 comorbidities or one or none were 84% vs 67% vs 76%, respectively (p = 0.82). A total of 1119 courses were delivered; the most frequent CTC grade 3-4 toxicity was neutropenia in 25% of the courses, with only 13 serious infections. One patients developed acute myelogenous leukaemia during treatment and died. Two toxic deaths during treatment (0.8%) occurred: 1 HBV reactivation and 1 Steven Johnson syndrome. So far 212 patients are alive; besides the above mentioned deaths, 15 patients died of lymphoma, 2 died of cardiac failure, 1 died of stroke and 1 died of drowning. So far too few events occurred to proper analyse the efficacy of the Rituximab maintenance. In the maintenance/observation phase the following severe (WHO grade 3-4) toxicities were recorded: 15 patients experienced neutropenia, seven cardiac events, four infections; no other relevant toxicities were recorded. The cumulative incidences of toxic events accounting for competing events at 18 months for maintenance arm (Arm A) versus observation arm (Arm B) were as follows: neutropenia 17% vs 1% (p<0.001); infections 2% vs 2% (p = 0.586); cardiac events 4% vs 4% (p= 0.627). Conclusions a short term chemo-immunotherapy R-FND + Rituximab consolidation is safe and effective with a good 2-yr PFS rate also in patients with high risk FLIPI score or in patients in more advanced decade or with comorbidities. Rituximab maintenance is safe with a more frequent neutropenia that was not associated with an increased risk of infections. Final results of the study will provide insights on the role of Rituximab maintenance after R-chemotherapy. Disclosures Vitolo: Roche: Lecture fees; Mundipharma: Lecture fees. Off Label Use: Study was supported by Roche: Rituximab maintenance in first line treatment is off-label. Boccomini:Roche: Lecture fees. Ladetto:Roche Italy: Research Funding; Amgen: Honoraria, Research Funding.

An Open-Label, Randomized Study of Bendamustine and Rituximab (BR) Compared with Rituximab, Cyclophosphamide, Vincristine, and Prednisone (R-CVP) or Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (R-CHOP) in First-Line Treatment of Patients with Advanced Indolent Non-Hodgkin's Lymphoma (NHL) or Mantle Cell Lymphoma (MCL): The Bright Study

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 902-902 ◽  
Author(s):  
Ian W. Flinn ◽  
Richard H. Van der Jagt ◽  
Brad S. Kahl ◽  
Peter Wood ◽  
Tim E. Hawkins ◽  
...  
Keyword(s):  
Respiratory Failure ◽  
Board Of Directors ◽  
Research Funding ◽  
Standard Treatment ◽  
Line Treatment ◽  
First Line ◽  
Advisory Committees ◽  
Pharmaceutical Industries ◽  
Grade 3 ◽  
First Line Treatment

Abstract Abstract 902 Background Bendamustine (B) is an active agent for relapsed and refractory indolent NHL, both as monotherapy and combined with rituximab (R), results recently updated by the StiL study group. This study compared efficacy and safety of BR with standard treatment regimens of R-CHOP and R-CVP as first-line treatment for indolent NHL or MCL. Methods Patients were randomized to 6–8 cycles of BR or R-CHOP/R-CVP (R-CHOP or R-CVP determined by investigator prior to randomization). BR regimen was B 90 mg/m2/day on days 1 and 2 plus R 375 mg/m2on day 1 of a 28-day cycle. Standard dosing and 21 day cycles were used for R-CHOP and R-CVP. Primary objective was to demonstrate noninferiority of complete response (CR) rate of BR vs standard treatment (noninferiority margin [ratio] 0.88). Secondary measures included overall response rate (ORR), progression-free survival, and overall survival. Tumor response was determined by a blinded independent review committee (IRC) using International Working Group revised response criteria for malignant lymphoma. Investigator assessments were compared with those of the IRC. Results Of 447 randomized patients, 436 received treatment (BR n=221; R-CHOP/R-CVP n=215 [R-CHOP n=99; R-CVP n=116]) and were evaluable for safety. Of these, 419 patients (BR n=213; R-CHOP/R-CVP n=206 [R-CHOP 97; R-CVP n=109]) were evaluable for efficacy. The randomized groups were well matched for age (median 60 and 58 years), sex (male, 61% and 59%), ECOG status (64% performance status 0, both groups), lymphoma type (83% indolent NHL, both groups), and Ann Arbor stage (62% stage IV, both groups). Among randomized patients and efficacy evaluable patients, the IRC-assessed CR rate was numerically higher for BR than R-CHOP/R-CVP and statistically noninferior (Table). In the randomized groups, CR rates for indolent NHL were numerically similar between BR and R-CHOP/R-CVP; however, in MCL, BR was statistically superior (P=0.018) (Table). Investigator-assessed response in randomized patients found superiority of BR vs R-CHOP/R-CVP (P=0.0013). IRC and investigator assessments differed mainly in quality of response (CR vs partial) rather than in whether a patient was a responder. For randomized patients, the ORR was 94% for BR and 84% for R-CHOP/R-CVP. Time-to-event data are immature and will be analyzed later. At time of data cut-off, 8% of the BR group had progressed, relapsed, or died, compared with 4% of R-CHOP/R-CVP group. Most patients completed 6 cycles (92% for BR and 91% for R-CHOP/R-CVP), with high relative dose intensity (>96%). Dose delays were more common for BR-treated patients (35% vs 19%), and dose reductions were less common (22% vs 29%). Most common AEs for BR and R-CHOP/R-CVP, respectively, were nausea (139 vs 102 patients), fatigue (113 vs 107), neutropenia (76 vs 85), constipation (65 vs 90), and alopecia (8 vs 74). Laboratory grade 3/4 hematologic toxicities for BR and R-CHOP/R-CVP were lymphopenia (137 vs 64), neutropenia (98 vs 151), leukopenia (84 vs 116), thrombocytopenia (16 vs 15), and anemia (6 vs 9), respectively. The most frequent investigator-reported nonhematologic grade 3/4 AEs for BR and R-CHOP/R-CVP were infusion-related reaction (13 vs 8 patients). Granulocyte colony stimulating factors were given at investigator discretion (per ASCO recommendations) to 29% of the BR group and 43% of the R-CHOP/R-CVP group. Fatal AEs occurred in 6 BR patients (pneumonia, respiratory failure, and sepsis; acute respiratory failure; cardiac arrest; pneumonia; chronic obstructive pulmonary disease; lung cancer) and 1 R-CHOP/R-CVP patient (sepsis). Conclusion In patients with advanced indolent NHL and MCL, BR produces a CR rate that is noninferior to that of R-CHOP/R-CVP. In the subgroup of patients with MCL, BR produces a significantly higher CR rate (51% vs 24%). High ORRs were attained in both treatment groups. The AE profile of BR was distinct from that of R-CHOP/R-CVP. Support: Teva Pharmaceutical Industries Ltd. Disclosures: Flinn: Teva Pharmaceuticals : Research Funding. Off Label Use: Bendamustine is FDA-approved for adults with chronic lymphocytic leukemia or indolent B-cell non-Hodgkin's lymphoma that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen. Van der Jagt:Celgene: Consultancy, Research Funding, Sponsorship Other; Novartis: Consultancy, Research Funding, sponsorship, sponsorship Other; Roche: Consultancy, sponsorship, sponsorship Other; Cephalon: Consultancy, Research Funding; Incyte: Research Funding; Xanthus: Research Funding; Bristol-Myers Squibb : Consultancy. Kahl:Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Teva Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. MacDonald:Lundbeck: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding. Munteanu:Teva Pharmaceutical Industries Ltd.: Employment. Clementi:Teva Pharmaceutical Industries Ltd.: Employment. Chen:Teva Pharmaceutical Industries Ltd.: Employment. Burke:Spectrum Pharmaceuticals: Consultancy.

Impact Of Rituximab Maintenance Schedule On Prognosis In First Line Treatment Of Follicular Lymphoma. Retrospective Analysis From Czech Lymphoma Group (CLG) Database

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4387-4387
Author(s):  
Andrea Janikova ◽  
Zbynek Bortlicek ◽  
Vit Campr ◽  
Leos Kren ◽  
David Belada ◽  
...  
Keyword(s):  
Overall Survival ◽  
Follicular Lymphoma ◽  
Retrospective Analysis ◽  
Research Funding ◽  
Statistical Significance ◽  
Induction Treatment ◽  
Line Treatment ◽  
First Line ◽  
Rituximab Maintenance ◽  
First Line Treatment

Abstract Introduction Results of randomized studies showed benefit of maintenance therapy with monoclonal anti-CD20 antibody (rituximab) in terms of time to progression (PFS) and overall survival (OS) in follicular lymphoma (FL). General recommendation, based on large clinical trial, is to give 2 years of rituximab maintenance á 375mg/m2every 2 months (12 doses) in first line setting. On the other hand, there are various rituximab maintenance schedules; however, the clear comparison of clinical efficacy is missing. Our retrospective analysis compared two different schedule of rituximab maintenance in first-line treatment of FL used in university centers participating on CLG registry. Methods Data were recruited from 1702 FL patients registered in the prospectively maintained multicentric database (Czech Lymphoma Group; CLG). For the analysis, patients with stage II-IV of new diagnosed FL (grade 1-3a) responding (complete or partial remission) to 6-8 cycles first-line RCHOP (rituximab, cyclophosphamide, doxorubicine, vincristine and prednisone) followed with rituximab maintenance (RM) were included. Completed planned maintenance was inclusion criterion. Patients with previous watch and wait or additional first line therapy (radiotherapy, other chemotherapy, transplant therapy) were excluded. Results Totally, 168 evaluable FL patients with median age 57ys (range 28-82) including 70 (41.7%) men treated with RCHOP + RM were found in CLG database. 52/168 patients received totaly 8 doses of rituximab maintenance every 3 months for 2 years (RM8 arm), whereas 47/168 patients were treated with totaly 12 doses (RM12 arm) of rituximab maintenance every 2 months for 2 years. All patients in both subgroups completed planned RM therapy. There was no difference in distribution of age, gender, FLIPI, grade, B-symptoms, bone marrow involvement, performance status, LDH and beta2microglobuline level between both arms. Induction treatment in terms of administered cycles CHOP (6xCHOP in 41/52 and 35/45 pts., for RM8 and RM12 arm) and rituximab doses (8xR in 48/52 and 41/45 pts., for RM8 and RM12 arm) was similar between arms (ns). There were 4/52 (7.7%) and 5/47 (10.6%) relapses in subgroups RM8 and RM12, with no statistical significance. Median PFS was 3.8 (2.1-5.8) years vs. 3.9 (2.4-7.8) years in RM8 and RM12 arms (not significant), and median OS 3.91 (2.2-6.94) years vs. 3.1 (2.48-8.6) years also with no statistical significance. Conclusion Our results show, that rituximab maintenance given every 2 or every 3 months for two years in first line treatment brings similar benefit to the FL patients in terms of remission duration and overall survival. Despite the fact, that presented data are retrospective observation, this is the first report comparing two different rituximab maintenance regimens in FL. Further prospective study and longer follow up are needed to confirm our preliminary data. This work was supported by grant NT/12193-5 and MHCZ-DRO (FNBr 65269705) Disclosures: Mayer: Roche: Consultancy, Research Funding; Glaxo: Consultancy, Research Funding. Trneny:Roche: Honoraria, Research Funding.

scholarly journals Secondary Central Nervous System (CNS) Involvement in Patients Diagnosed with Diffuse Large B-Cell Lymphoma (DLBCL) during the First Line R-CHOP Treatment and after the End of Treatment

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5040-5040
Author(s):  
Joanna Romejko-Jarosinska ◽  
Michal Osowiecki ◽  
Beata Ostrowska ◽  
Martyna Kotarska ◽  
Katarzyna Domanska-Czyz ◽  
...  
Keyword(s):  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Line Treatment ◽  
Cns Involvement ◽  
First Line ◽  
Large B Cell Lymphoma ◽  
End Of Treatment ◽  
Secondary Central Nervous System ◽  
First Line Treatment

Abstract Background: Secondary central nervous system (CNS) involvement is an unfavorable risk factor with an impact on overall survival (OS) in malignant lymphoma. Methods: We conducted a retrospective analysis of secondary CNS involvement in patients diagnosed with Diffuse Large B-Cell lymphoma (DLBCL) on the first line treatment and after the end of treatment. We collected data on 361 patients diagnosed with DLBCL. Results: The median age (range) was 66 (17-91) years. All patients received first-line R-CHOP21 (rituximab, cyclophosphamide, vincristine, doxorubicin, prednisone) between 2006-2011. Patients with primary involvement of testis, nasopharynx, orbit and CNS received CNS prophylaxis with 15 mg methotrexate intrathecally (IT). Secondary CNS involvement was confirmed in 18 (4.9%) patients which stands for 24.6% (18/73) patients with relapsed lymphoma. Median time from first R-CHOP to lymphoma relapse was 10 months (range 3-33). CNS involvement in first 12 months of treatment was 3.9% (95% CI: 1.8%, 5.8%). Median (range) OS from diagnosis of CNS involvement was 3 (3-79) months. Clinical stage III/IV, IPI 4, breast, 2 or more extranodal sites and NCCN-IPI unfavorable site involvement increased the risk of CNS involvement. Three patients who had received methotrexate IT prophylaxis had CNS involvement at relapse. No patient with primary testis involvement had CNS relapse. Conclusion: Less than 5% of patients had secondary CNS involvement on first line treatment and after end of treatment. Advanced stage, high-risk IPI, 2 or more extranodal sites of involvement increased the risk of CNS involvement after first-line treatment for DLBCL. CNS prophylaxis appears effective in patients with primary testicular lymphoma Disclosures Walewski: Karyopharm: Consultancy; Roche: Consultancy, Honoraria, Other: travel, accommodation, Research Funding; Celgene: Honoraria, Other: travel, accommodation, Research Funding; Gilead: Consultancy, Honoraria, Other: travel, accommodation; Takeda: Consultancy, Honoraria, Other; Ariad: Consultancy; Janssen-Cilag: Consultancy; Mundipharma: Consultancy, Honoraria, Research Funding; Genetics: Other: travel, accommodation; Teva: Consultancy, Honoraria; Seattle: Other: travel, accommodation; GSK/Novartis: Research Funding; Boehringer Ingelheim: Consultancy; Sanofi: Honoraria, Other: travel, accommodation; Servier: Consultancy.

Update on a Prospective Study Evaluating the Safety and Efficacy of Combination Therapy with Fludarabine, Mitoxantrone and Rituximab Followed by Yttrium-90 Ibritumomab Tiuxetan and Maintenance Rituximab as Front Line Therapy for Patients with Indolent Lymphomas

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3946-3946
Author(s):  
Reem Karmali ◽  
Mohamad Kassar ◽  
Antonio M. Jimenez ◽  
Parameswaran Venugopal ◽  
Jamile M. Shammo ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Adverse Effects ◽  
Alternative Treatment ◽  
Research Funding ◽  
First Line ◽  
Ibritumomab Tiuxetan ◽  
Off Label ◽  
Rituximab Maintenance ◽  
Grade 3 ◽  
Indolent Lymphomas

Abstract Abstract 3946 Background: The First Line Indolent Trial (FIT) recently reported the superiority of consolidation therapy with 90Y-ibritumomab tiuxetan (Zevalin) versus observation in patients with advanced stage follicular lymphoma (FL) after induction with chemotherapy. The benefit of rituximab maintenance has also been shown in indolent lymphomas. We report the updated results of a single institution phase II clinical trial using a combination of the above in indolent lymphomas, namely chemo-immunotherapy followed by radioimmunotherapy and rituximab maintenance. Patients and Method: Patients with previously untreated indolent lymphomas including FL and marginal zone lymphomas (MZL), age ≥ 18, PS 0–2, measurable disease, with adequate bone marrow, liver and kidney function were eligible. Previous treatment with rituximab alone was allowed. Initial treatment consisted of 4–6 cycles of FM (fludarabine 25 mg/m2 on days 1–3, mitoxantrone 12 mg/m2 on day 1 of each 28-day cycle). The protocol was amended after enrolling the first four patients to include rituximab 375 mg/m2 on day 1 of each cycle. After 6 to 8 weeks, responding patients received Zevalin followed by maintenance rituximab (375 mg/m2 weekly × 4, repeated every 6 months for 2 years). Results: 22 patients were enrolled between July 2003 and May 2007. The median age was 55 years (range 32–79 years). 11 patients were men. One patient had stage II, 7 had stage III, and 14 had stage IV disease. 20 patients had FL and 2 had MZL. In the FL group, 18 (90%) patients were intermediate or high risk. All but one patient had 4 or more cycles of chemotherapy with an ORR of 100%, a CR of 45% (n=10), a PR of 50% (n=11) and stable disease in one patient. 19 patients underwent therapy with Zevalin. With Zevalin, 6 patients with PR post chemotherapy converted to CR, resulting in an improved CR of 79% (n=15) and a PR of 21% (n=4). Of the 19 patients that underwent Zevalin, 16 proceeded to rituximab maintenance. Of those excluded from rituximab maintenance, one patient refused maintenance, one had prolonged cytopenias after Zevalin and one transformed to DLBCL just prior to rituximab maintenance, requiring alternative treatment. The decision was made to give rituximab maintenance on a different schedule at 375 mg/m2, 1 dose every 3 months, to 2 patients for mild cytopenias. With rituximab maintenance, 2 patients in PR converted to CR. All patients who received chemotherapy and Zevalin were included in the survival analysis (n=19). At a median follow up of 47.7 months, median PFS was 47.2 months and median OS was not reached. 7 patients relapsed and 1 patient transformed to DLBCL, with 6 patients requiring alternative treatment. 3 of these relapses occurred while on rituximab maintenance and one occurred 2 months after receiving Zevalin prior to the initiation of immunotherapy maintenance. Of all relapses/transformations, 2 patients are deceased. In the remainder of patients, 4 (24%) are in stable relapse and 13 (76%) in CR. The most common adverse effects of this regimen were hematological. With chemotherapy, 7 patients had grade 3/4 neutropenia and 4 patients had grade 3/4 thrombocytopenia. Post Zevalin, 11 patients experienced one or more grade 3/4 cytopenias: 8 patients had neutropenia, 8 had thrombocytopenia, and 4 had anemia with time to recovery of counts ranging between 2–4 weeks. 8 of these patients had bone marrow involvement at the start of treatment. One patient developed treatment related MDS that evolved to AML 4 years after the start of therapy. This patient died. Other grade 3/4 adverse effects included: grade 3 hypoxia and pneumonia post chemotherapy in a patient with grade 1 neutropenia and grade 2 cellulitis after Zevalin in a patient with grade 3/4 neutropenia. Conclusion: Chemoimmunotherapy followed by consolidation with radioimmunotherapy and rituximab maintenance is well tolerated and able to improve complete remission rates and maintain durable responses in patients with untreated indolent lymphomas. The use of this approach in indolent NHL patients may become a new standard of care. Disclosures: Off Label Use: Both radioimmunotherapy consolidation with zevalin and rituximab (immunotherapy) maintenance have been used in indolent lymphomas first line post chemo-immunotherapy. However, in this study, we looked at the combination of chemo-immunotherapy followed by zevalin consolidation and rituximab maintenance. This combination is off-label. Kassar:Alexion: Honoraria. Gregory:Amgen: Consultancy; Astellas: Research Funding; Celgene: Research Funding; Cephalon: Research Funding, Speakers Bureau; Genentech (Roche): Consultancy, Research Funding, Speakers Bureau; Glaxo-Smith-Kline: Research Funding; Immunomedics: Research Funding; NCIC CTG: Research Funding; Novartis: Consultancy, Research Funding; Onyx (Proteolix): Research Funding; Spectrum Pharmaceuticals: Consultancy.

Bendamustine, Bortezomib, and Rituximab in Patients with Previously Untreated Low Grade Lymphoma: A Phase II Trial of the Sarah Cannon Research Institute

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1624-1624 ◽  
Author(s):  
Ian W. Flinn ◽  
Dana S. Thompson ◽  
Ralph V. Boccia ◽  
Gerald Miletello ◽  
Andrew Lipman ◽  
...  
Keyword(s):  
Cell Lymphoma ◽  
Phase Iii ◽  
Low Grade ◽  
Line Treatment ◽  
First Line ◽  
Off Label ◽  
Mantle Cell ◽  
Grade 3 ◽  
First Line Treatment

Abstract Abstract 1624 Background: Rituximab and bendamustine combination regimens have demonstrated high activity in non-Hodgkin's lymphoma (NHL). A phase III trial compared bendamustine plus R-CHOP as first-line treatment for follicular, indolent, and mantle cell lymphoma (Rummel ASH 2009). Bendamustine plus rituximab had an overall response rate of 94% and a complete remission rate of 40% compared to 94% and 31%, respectively, for R-CHOP. Phase III trials evaluating bendamustine plus rituximab as first-line therapy for patients (pts) with indolent and mantle cell lymphoma have shown equivalent or superior results when compared to R-CHOP or R-CVP as first-line treatment for indolent lymphoma. Bortezomib is a small molecule proteasome inhibitor that has shown substantial activity in multiple myeloma and lymphoma. Pre-clinical studies demonstrate significant synergy and/or ability to overcome resistance to a variety of current and investigational treatments for lymphoma. This trial evaluated the activity of bendamustine, bortezomib, and rituximab (BBR) in patients with previously untreated low-grade lymphoma. Methods: Eligible patients had histologically-confirmed follicular center cell (FCC) lymphoma (grade 1 or 2), marginal zone lymphoma (MZL), small lymphocytic lymphoma (SLL), or lymphoplasmacytic lymphoma (LPL); lymph node biopsy containing CD20+ B-cells; Ann-Arbor Stage 2, 3, or 4 disease; no previous systemic treatment for lymphoma; bi-dimensional measurable disease with at least 1 lesion measuring > 2.0 cm in a single dimension; ECOG PS 0–2. Treatment for all patients was given in 28-day cycles for a maximum of 6 cycles. Patients received rituximab 375 mg/m2 IV on days 1, 8, and 15 of cycle 1 (cycles 2–6, rituximab only on day 1); bendamustine 90 mg/m2 IV on days 1 and 2; and bortezomib 1.6 mg/m2IV on days 1, 8, and 15. Response evaluations were performed after cycle 3 and cycle 6. Patients were permitted to begin maintenance treatment with rituximab 6 months after completion of study treatment and after 6-month follow-up assessments have been conducted. Results: Between 1/2010 and 11/2011, 55 patients were enrolled with a median age of 62 years (range 30–89). Fifty one percent were male, 85% stage III or IV. Diagnoses were: FCC, 38pts (69%); MZL, 8pts (15%); SLL, 5pts (9%) and LPL, 4pts (7%). The median follow-up is 13 months (range: 6–26). At the time of this analysis, 78% of pts had completed 6 cycles of BRR, and 56% had continued to maintenance rituximab. Two pts remain in the first 6 cycles of BRR. Five pts (9%) discontinued treatment due to toxicity (1pt G2 neuropathy, 1 pt G2 atrial fibrillation, 1 pt G3 pancreatitis, 1 pt G3 diarrhea, 1pt G2 rash). The remaining 5 pts discontinued prematurely (1pt death due to stroke, 1pt wound complication, 1 pt lost to follow-up, 2 pts off due to request). Objective response was achieved in 89% of pts; 26pts (47%) complete response, 23pts (42%) partial response, 2pts (4%) stable disease, and 4pts (7%) unevaluable at the time of this analysis. Related grade 3/4 hematologic toxicities were: neutropenia (25%), febrile neutropenia (2%), thrombocytopenia (5%), and anemia (4%). We observed no grade 4 treatment related non -hematologic adverse events, the most common grade 3 were neuropathy (9%), diarrhea (7%), fatigue (7%), constipation (5%), and rash (5%). Time-to-event data are immature and will be the subject of a later analysis. At the time of data cut-off, 3 pts (5.5%) had progressed or relapsed and 3pts (5.5%) had died. Conclusion: BBR was well tolerated and produced high CR and OR rates. Toxicities including neuropathy were modest. Further study of this regimen in patients with previously untreated lymphoma is warranted. Disclosures: Off Label Use: Off-label bendamustine and bortezomib in first-line treatment for lymphoma. Boccia:Cephalon: Research Funding.

scholarly journals Real World Treatment Patterns and Toxicity Among Elderly Patients with Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5571-5571
Author(s):  
Jesus D Gonzalez-Lugo ◽  
Ana Acuna-Villaorduna ◽  
Joshua Heisler ◽  
Niyati Goradia ◽  
Daniel Cole ◽  
...  
Keyword(s):  
Side Effects ◽  
Real World ◽  
Research Funding ◽  
Treatment Patterns ◽  
Line Treatment ◽  
Event Free Survival ◽  
First Line ◽  
Treatment Change ◽  
Free Survival ◽  
First Line Treatment

Introduction: Multiple Myeloma (MM) is a disease of the elderly; with approximately two-thirds of cases diagnosed at ages older than 65 years. However, this population has been underrepresented in clinical trials. Hence, there are no evidence-based guidelines to select the most appropriate treatment that would balance effectiveness against risk for side effects in the real world. Currently, guidelines advise that doublet regimens should be considered for frail, elderly patients; but more detailed recommendations are lacking. This study aims to describe treatment patterns in older patients with MM and compare treatment response and side effects between doublet and triplet regimens. Methods: Patients diagnosed with MM at 70 years or older and treated at Montefiore Medical Center between 2000 and 2017 were identified using Clinical Looking Glass, an institutional software tool. Recipients of autologous stem cell transplant were excluded. We collected demographic data and calculated comorbidity burden based on the age-adjusted Charlson Comorbidity Index (CCI). Laboratory parameters included cell blood counts, renal function, serum-protein electrophoresis and free kappa/lambda ratio pre and post first-line treatment. Treatment was categorized into doublet [bortezomib/dexamethasone (VD) and lenalidomide/dexamethasone (RD)] or triplet regimens [lenalidomide/bortezomib/dexamethasone (RVD) and cyclophosphamide/bortezomib/dexamethasone (CyborD)]. Disease response was reported as VGPR, PR, SD or PD using pre-established criteria. Side effects included cytopenias, diarrhea, thrombosis and peripheral neuropathy. Clinical and laboratory data were obtained by manual chart review. Event-free survival was defined as time to treatment change, death or disease progression. Data were analyzed by treatment group using Stata 14.1 Results: A total of 97 patients were included, of whom 46 (47.4%) were males, 47 (48.5%) were Non-Hispanic Black and 23 (23.7%) were Hispanic. Median age at diagnosis was 77 years (range: 70-90). Median baseline hemoglobin was 9.4 (8.5-10.5) and 14 (16.1%) had grade 3/4 anemia. Baseline thrombocytopenia and neutropenia of any grade were less common (18.4% and 17.7%, respectively) and 11 patients (20%) had GFR ≤30. Treatment regimens included VD (51, 52.6%), CyborD (18, 18.6%), RD (15, 15.5%) and RVD (13, 13.4%). Overall, doublets were more commonly used than triplets (66, 68% vs 31, 32%). Baseline characteristics were similar among treatment regimen groups. There was no difference in treatment selection among patients with baseline anemia or baseline neutropenia; however, doublets were preferred for those with underlying thrombocytopenia compared to triplets (93.8% vs 6.2%, p<0.01). Median first-line treatment duration was 4.1 months and did not differ among treatment groups (3.9 vs. 4.3 months; p=0.88 for doublets and triplets, respectively). At least a partial response was achieved in 47 cases (63.5%) and it did not differ between doublets and triplets (61.7% vs 66.7%). In general, first line treatment was changed in 50 (51.5%) patients and the change frequency was higher for triplets than doublets (71% vs 42.4%, p<0.01). Among patients that changed treatment, 17(34.7%) switched from a doublet to a triplet; 15 (30.6%) from a triplet to a doublet and 17 (34.7%) changed the regimen remaining as doublet or triplet, respectively. There was no difference in frequency of cytopenias, diarrhea, thrombosis or peripheral neuropathy among groups. Median event-free survival was longer in patients receiving doublet vs. triplet therapy, although the difference was not statistically significant (7.3 vs 4.3 months; p=0.06). Conclusions: We show a real-world experience of an inner city, elderly MM cohort, ineligible for autologous transplantation. A doublet combination and specifically the VD regimen was the treatment of choice in the majority of cases. In this cohort, triplet regimens did not show better response rates and led to treatment change more often than doublets. Among patients requiring treatment, approximately a third switched from doublet to triplet or viceversa which suggest that current evaluation of patient frailty at diagnosis is suboptimal. Despite similar frequency of side effects among groups, there was a trend towards longer event-free survival in patients receiving doublets. Larger retrospective studies are needed to confirm these results. Disclosures Verma: Janssen: Research Funding; BMS: Research Funding; Stelexis: Equity Ownership, Honoraria; Acceleron: Honoraria; Celgene: Honoraria.

scholarly journals Clinical and Biological Characteristics and Outcomes of Richter Transformation : A French Multicenter Study from the Filo Group

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4112-4112
Author(s):  
Charline Moulin ◽  
Romain Morizot ◽  
Thomas Remen ◽  
Hélène Augé ◽  
Florian Bouclet ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Intermediate Risk ◽  
Line Treatment ◽  
First Line ◽  
Advisory Committees ◽  
Long Term Survivors ◽  
First Line Treatment

Introduction: About 2 to 10% of patients (pts) diagnosed with Chronic Lymphocytic Leukemia (CLL) develop diffuse large B-cell lymphoma (DLBCL, so-called Richter transformation (RT)) over long-term follow-up. The outcomes of pts with RT are variable and poorly understood and there is no consensus on the best therapeutic approach. The aim of this study was to analyze the clinical characteristics, outcomes and factors predictive of survival in a large series of RT from the French Innovative Leukemia Organization (FILO). Methods: Biopsy-confirmed RT (limited to DLBCL and excluding Hodgkin lymphoma) diagnosed from 2001 to 2018 were identified from eight FILO centers. Clinical and biological characteristics of CLL and RT at diagnosis, including cytogenetics, clonal relation with the pre-existing CLL, Epstein-Barr virus (EBV) status, cell of origin (COO) analyzed by immunohistochemistry and RT score (Tsimberidou AM et al, J Clin Oncol, 2006) were analyzed as well as treatment and outcomes. Overall survivals (OS) were defined as time from CLL and RT diagnosis to death from any cause and analyzed using the Kaplan-Meier method. Statistical analyses were performed with SAS version 9.4. Results: A total of 70 CLL pts who developed RT were identified. The median age at CLL diagnosis was 62 years old (range 35-82), and 50 (71.4 %) were male. The median time to transformation was 5.5 years (range 0 to 22 years), with 12 simultaneous diagnosis of CLL and RT. Prior to RT, 20 (29%) pts had not been treated for CLL, 50 received one (n=21) or more (n= 29) line of treatment ; 6 pts had received a novel agent (ibrutinib, idelalisib or venetoclax). The median age at RT diagnosis was 68 years old (range 42-88). All biopsies were centrally reviewed; 38/58 pts (66%) had elevated LDH (>1.5N) ; 35/65 pts (54 %) had bulky disease (≥ 5 cm); 10/54 (18.5%) pts had del(17p) or TP53 mutation ; 9/42 pts (21%) had a complex karyotype (at least 3 abnormalities). The CLL and RT were clonally related in 27/27 (100%) tested pts. COO by Hans algorithm was non germinal center B cell-like (GCB) in 26/28 pts (93%). EBV was positive or detected in 5/40 (12.5%) pts. The median of Ki67 positivity was 70% (range 30% to 100%). The RT score (based at RT diagnosis on ECOG performance status 2-4, LDH >1.5 x normal, platelets<100 x 109/L, tumor size >5 cm and >1 prior therapy for CLL) was : low risk in 17 pts (31%), low-intermediate risk in 10 pts (19%), high-intermediate risk in 14 pts (25%) and high risk in 14 pts (25%). The most common first-line treatment of RT was immunochemotherapy (n=57, 87%) including R-CHOP-like regimen (n=48, 73%). Autologous or allogeneic transplantation was performed for 7 pts (11%). Response to first-line treatment was complete or partial response in 26 pts (40%), and stable disease or progression in 39 pts (60%). After a median follow-up of 8 years, 51/64 pts (80%) have died. The main causes of death were progressive DLBCL (n=36, 71%), infection (n=8, 16%) or progressive CLL (n=2, 4%). The median OS of the cohort from CLL and RT diagnosis (Figure 1) were 7.8 years and 9.5 months, respectively. In univariate analysis, patients with TP53 disruption at CLL stage, low platelets count, elevated LDH, elevated beta2-microglobulin, high ECOG score, high RT score, EBV positivity and absence of response to first-line RT treatment had worse OS. The ECOG score, platelets count and TP53 disruption remain significant in multivariate Cox-regression. Last, we compared the clinical and biological parameters of two Richter groups defined as: (i) short-term survivors (<12 months, n = 34) and (ii) long-term survivors (>48 months, n = 18). Long survival was significantly associated with elevated platelets count, low LDH, low ECOG, low RT score and response to RT first-line treatment. Discussion: The clinical outcomes of RT patients is poor and novel treatment options are needed. However, a group of long-term survivors was identified, characterized by elevated platelets count, low LDH, low ECOG, low RT score and response to immunochemotherapy. Disclosures Leblond: Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Thieblemont:Roche: Honoraria, Research Funding; Gilead: Honoraria; Novartis: Honoraria; Kyte: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Cellectis: Membership on an entity's Board of Directors or advisory committees. Cymbalista:Janssen: Honoraria; Gilead: Honoraria; AstraZeneca: Honoraria; Sunesis: Research Funding; Roche: Research Funding; Abbvie: Honoraria. Guièze:Abbvie: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Roche: Honoraria. Broseus:Janssen: Honoraria; Gilead: Honoraria; Novartis: Research Funding. Feugier:gilead: Honoraria, Research Funding, Speakers Bureau; janssen: Honoraria, Research Funding, Speakers Bureau; abbvie: Honoraria, Research Funding, Speakers Bureau; roche: Honoraria, Research Funding, Speakers Bureau.

Phase III Multicenter Randomized Trial of Oxaliplatin Added to Chronomodulated Fluorouracil–Leucovorin as First-Line Treatment of Metastatic Colorectal Cancer

2000 ◽  
Vol 18 (1) ◽  
pp. 136-136 ◽  
Author(s):  
S. Giacchetti ◽  
B. Perpoint ◽  
R. Zidani ◽  
N. Le Bail ◽  
R. Faggiuolo ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Objective Response ◽  
Sensory Neuropathy ◽  
Phase Iii ◽  
Line Treatment ◽  
Survival Times ◽  
First Line ◽  
Grade 3 ◽  
First Line Treatment

PURPOSE: To study how adding oxaliplatin (l-OHP) to chronomodulated fluorouracil (5-FU)–leucovorin (LV) affected the objective response rate, as first-line treatment of metastatic colorectal cancer. PATIENTS AND METHODS: Two hundred patients from 15 institutions in four countries were randomly assigned to receive a 5-day course of chronomodulated 5-FU and LV (700 and 300 mg/m2/d, respectively; peak delivery rate at 0400 hours) with or without l-OHP on the first day of each course (125 mg/m2, as a 6-hour infusion). Each course was repeated every 21 days. Response was assessed by extramural review of computed tomography scans. RESULTS: Grade 3 to 4 toxicity from 5-FU–LV occurred in ≤ 5% of the patients (≤ 1% of the courses). Grade 3 to 4 diarrhea occurred in 43% of the patients given l-OHP (10% of the courses), and less than 2% of the patients had severe hematotoxicity. Thirteen percent of the patients had moderate functional impairment from peripheral sensory neuropathy. Sixteen percent of the patients receiving 5-FU–LV had an objective response (95% confidence interval [CI], 9% to 24%), compared with 53% of those receiving additional l-OHP (95% CI, 42% to 63%) (P < .001). The median progression-free survival time was 6.1 months with 5-FU–LV (range, 4.1 to 7.4 months) and 8.7 months (7.4 to 9.2 months) with l-OHP and 5-FU–LV (P = .048). Median survival times were 19.9 and 19.4 months, respectively. CONCLUSION: By chronomodulating 5-FU–LV, we were able to add l-OHP without compromising dose-intensities. l-OHP significantly improved the antitumor efficacy of this regimen.

JUPITER-02: Randomized, double-blind, phase III study of toripalimab or placebo plus gemcitabine and cisplatin as first-line treatment for recurrent or metastatic nasopharyngeal carcinoma (NPC).

2021 ◽  
Vol 39 (18_suppl) ◽  
pp. LBA2-LBA2
Author(s):  
Rui-hua Xu ◽  
Hai-Qiang Mai ◽  
Qiu-Yan Chen ◽  
Dongping Chen ◽  
Chaosu Hu ◽  
...  
Keyword(s):  
Interim Analysis ◽  
Locally Advanced ◽  
Progression Free Survival ◽  
Final Analysis ◽  
Phase Iii ◽  
Line Treatment ◽  
First Line ◽  
Double Blind ◽  
Grade 3 ◽  
First Line Treatment

LBA2 Background: Gemcitabine-cisplatin (GP) chemotherapy is the standard 1st line treatment for locally advanced, recurrent or metastatic (r/m) NPC. Toripalimab, a humanized IgG4K monoclonal antibody specific for PD-1, provided durable responses in patients (pts) with r/m NPC as monotherapy in the ≥2nd line setting (POLARIS-02 study). The results of JUPITER-02, a randomized, placebo-controlled, double-blinded Phase III trial of toripalimab in combination with GP chemotherapy as first-line treatment for r/m NPC are summarized. Methods: Pts with advanced NPC with no prior chemotherapy in the r/m setting were randomized (1:1) to receive toripalimab 240 mg or placebo d1 in combination with gemcitabine 1000 mg/m2 d1, d8 and cisplatin 80 mg/m2 d1 every 3 weeks (Q3W) for up to 6 cycles, followed by monotherapy with toripalimab or placebo Q3W until disease progression, intolerable toxicity, or completion of 2 years of treatment. Stratification factors were ECOG PS (0 vs. 1) and extent of disease (recurrent vs. primary metastatic) at enrollment. Progression-free survival (PFS) and response were assessed by independent review committee (IRC) per RECIST v1.1. The primary endpoint was PFS by IRC in the ITT population. Secondary end points included ORR, DOR and OS. There was one prespecified interim analysis of PFS at 130 PFS events with a planned final analysis at 200 PFS events. Results: 289 pts were randomized: 146 to the toripalimab arm and 143 to the placebo arm. By May 30, 2020 as the interim analysis cutoff date, the median treatment duration was 39 weeks in the toripalimab arm and 36 weeks in the placebo arm. A significant improvement in PFS was detected for the toripalimab arm compared to the placebo arm (HR = 0.52 [95% CI: 0.36-0.74] two-sided p = 0.0003), with median PFS of 11.7 vs. 8.0 months. The 1-year PFS rates were 49% and 28% respectively. An improvement in PFS was observed across relevant subgroups, including all PD-L1 subgroups. The ORR was 77.4% vs. 66.4% (P = 0.033) and the median DOR was 10.0 vs. 5.7 months (HR = 0.50 [95% CI: 0.33-0.78]). As of Jan 15, 2021, OS was not mature, with 25 deaths in the toripalimab arm and 35 in the placebo arm (HR = 0.68 [95% CI: 0.41-1.14], P = 0.14). The incidence of Grade ≥3 adverse events (AEs) (89.0% vs 89.5%); AEs leading to discontinuation of toripalimab/placebo (7.5% vs 4.9%); and fatal AEs (2.7% vs 2.8%) were similar between two arms; however, immune-related (irAEs) (39.7% vs. 18.9%) and Grade ≥3 irAEs (7.5% vs. 0.7%) were more frequent in the toripalimab arm. Conclusions: The addition of toripalimab to GP chemotherapy as 1st-line treatment for pts with advanced NPC provided superior PFS and ORR and longer DOR than GP alone with a manageable safety profile. These results support the use of toripalimab with GP chemotherapy as the new standard care for this population. Clinical trial information: NCT03581786.

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