An Effective Salvage Treatment Using Rituximab, Ifosfamide, Etoposide, Cytarabine, and Dexamethasone (R-IVAD) for Patients with Relapsed or Refractory Aggressive B-Cell Lymphoma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1759-1759
Author(s):  
Katsuhiro Miura ◽  
Kazuhiro Takei ◽  
Sumiko Kobayashi ◽  
Yujin Kobayashi ◽  
Toshitake Tanaka ◽  
...  
Keyword(s):  
Stem Cell ◽  
B Cell ◽  
Conflicts Of Interest ◽  
Cell Lymphoma ◽  
Performance Status ◽  
B Cell Lymphoma ◽  
Complete Response ◽  
High Dose ◽  
Salvage Regimen ◽  
Aggressive B Cell Lymphoma

Abstract Abstract 1759 Background The prognosis of patients with relapsed or refractory aggressive B-cell lymphoma after the conventional first line chemotherapy is still disappointing. Although several rituximab combined salvage regimens were reported, the optimal treatment has not yet been established. We therefore evaluated the efficacy and toxicity of a non-anthracycline based salvage regimen, consisting of rituximab, ifosfamide, etoposide, cytarabine and dexamethasone (R-IVAD) in patients with relapsed or refractory aggressive B-cell lymphoma. Patients and methods Patients with relapsed or refractory CD20-positive diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma grade 3 (FL G3) were consecutively enrolled in this treatment. R-IVAD consisted of rituximab (375 mg/m2 on day -2), ifosfamide (1500 mg/m2 on day 1–5), etoposide (150 mg/m2 on day 1–3), cytarabine (100 mg/m2 on day 1–3) and dexamethasone (40 mg/body on day 1–3). Treatment was given every 3 weeks up to a total of 3 courses with support of granulocyte colony stimulating factor. For responders under 65 years old with good performance status (PS), we planed peripheral stem cell collection after the third cycle of R-IVAD and consolidating high-dose chemotherapy (HDC) with cycrophosphamide (60 mg/kg on day -7,-6), etoposide (500 mg/m2 on day -6, -5, -4) and ranimustine (250 mg/m2 on day -3, -2) followed by autologous stem cell transplantation (ASCT). Results Thirty-two patients (25 DLBCL and 7 FL G3) with a median age of 64 years old (range 38–79) participated in this study and received an average of 2.6 cycles of R-IVAD. There were 21 relapsed and 11 primary refractory patients. The overall response (OR) and the complete response (CR) rate were 72% and 56% respectively. The OR rate of relapsed patients was significantly higher than that of primary refractory patients (86% vs. 45%, p=0.035). With a median 16 months (range 2–99) of follow up, the 2-year overall survival (OS) and the event-free survival (EFS) for all patients were 55% and 36% respectively. Of the 11 eligible patients, 10 successfully proceeded to HDC/ASCT with an average of 5.5 × 106/kg of harvested CD34-positive cells, resulting in the 2-year OS of 90%. No treatment related death was observed during the investigation. Multivariate analysis revealed that the age > 60 years, PS ≥ 2, extranodal sites ≥ 2, and primary refractory disease were independently associated with worse survival. Conclusion R-IVAD regimen, which efficiently mobilizes peripheral stem cells, is a safe and efficacious alternative for patients with relapsed or refractory aggressive B-cell lymphoma. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Obinutuzumab Plus Gemcitabine, Dexamethasone and Cisplatin (O-GDP) As Salvage Chemotherapy Prior to Autologous Stem Cell Transplant in Aggressive B Cell Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2027-2027
Author(s):  
Michael D. Jain ◽  
Anca Prica ◽  
Ryan D. Morin ◽  
Vishal Kukreti ◽  
Robert Kridel ◽  
...  
Keyword(s):  
Stem Cell ◽  
B Cell ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Cell Transplant ◽  
Cell Of Origin ◽  
Salvage Regimen ◽  
Grade 3 ◽  
Aggressive B Cell Lymphoma

Background: CCTG LY.12 defined GDP (gemcitabine, dexamethasone and cisplatin) (GDP) as an effective outpatient salvage chemotherapy regimen in relapsed/refractory (R/R) patients with aggressive lymphomas who are candidates for autologous stem cell transplant (ASCT) (Crump et al. JCO 2014). Obinutuzumab (O) is an alternative anti-CD20 that may produce responses in rituximab-refractory lymphomas. Head-to-head, O did not improve efficacy compared to R when combined with CHOP as initial therapy (Vitolo JCO 2017). However, salvage therapy differs from initial therapy in that patients have been previously exposed to, and have relapsed after, prior R. We therefore performed a single centre, single arm clinical trial of O-GDP to assess safety and efficacy in R/R aggressive B cell lymphoma as a salvage regimen prior to consolidation with ASCT. Methods: Transplant eligible patients with DLBCL and transformed indolent lymphoma were treated with O-GDP for two cycles, followed by response assessment by CT. Non-progressers received a third cycle of O-GDP for stem cell mobilization and final response assessed by CT-PET prior to ASCT. O was given at 1000 mg weekly during the first cycle of GDP and then on day 1 of cycles 2 and 3. Responses were determined by Lugano criteria using investigator assessment. The primary outcome is ORR by CT imaging after 2 cycles. The pre-specified statistical analysis stated that the trial will be declared positive if the ORR is >60%, negative if the ORR is <40% and indeterminate if in-between. Secondary outcomes included complete metabolic response rate after 3 cycles of O-GDP and the rate of proceeding to ASCT. Exploratory outcomes included measurements of circulating tumor (ct) DNA during protocol therapy, and analysis of individual mutations. Double-hit score and cell of origin assessments were as previously described (Ennishi et al. JCO 2019). Outcomes: 30 patients were enrolled with a median age of 59.5 years (range 30 - 70). 20 patients had DLBCL, 9 had transformed indolent lymphoma (TRIL; all but one patient having transformed follicular lymphoma) and 1 patient had follicular lymphoma grade 3B. IPI at diagnosis was 0-1 (20% of patients), 2 (30%) or 3+ (50%). Dose delays of O during cycle 1 occurred in 10% of patients due to toxicity with delays in cycle 2 or 3 of O-GDP in 30% of patients. 87% of patients had a dose reduction of chemotherapy with 46% of day 8 gemcitabine doses being held or reduced. Grade 3-4 AEs were seen in 87% of patients (grade 3-4 neutropenia: 77% [febrile neutropenia: 13%]; grade 3 anemia: 13%; grade 3-4 thrombocytopenia: 43%). The ORR (CR + PR) by CT imaging after 2 cycles of study therapy was 60% (95% CI 41-77%). The best ORR (by Lugano criteria including PET/CT) after 3 cycles of study therapy was 70% (51-85%; CMR in 33%) of patients. Of all enrolled patients, 67% (47-83%) proceeded to ASCT. With a median follow up 1.3 years for all enrolled patients, the estimated 1 year OS was 76% (62-93%) and PFS was 59% (44-80%). The OS and PFS in transplanted patients at 1 year was 90% (77-100) and 70% (53-93%) respectively with a median follow-up of 1 year. In post hoc subset analysis, de novo DLBCL had a best ORR of 55% while TRIL/FL3B had an ORR of 100%. The presence of the double hit (DHIT) signature and cell of origin (COO) by gene expression was analyzed in 26/30 patients. Best ORR for DHIT positive was 3/4 patients (75%), DHIT negative was 11/16 (69%) and DHIT indeterminate was 5/6 (83%). Best ORR for ABC-type was 7/10 (70%), GCB-type was 9/13 (69%), unclassified was 1/1 (100%) and PMBL was 1/2 (50%). Conclusions: O-GDP is a feasible outpatient salvage regimen that enables ASCT in patients with R/R aggressive B cell lymphoma across histological and molecular subtypes. Higher rates of cytopenias with O-GDP contributed to treatment delays and dose reductions or holds. Further mutational analysis will be presented. The ORR of 60% met the study primary endpoint and the 1 year OS and PFS are encouraging. Disclosures Jain: Kite/Gilead: Consultancy. Prica:Celgene: Honoraria; Janssen: Honoraria. Kukreti:Amgen: Honoraria; Takeda: Honoraria; Celgene: Honoraria. Kridel:Gilead Sciences: Research Funding. Crump:Servier: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Kite/Gilead: Consultancy. Scott:Roche/Genentech: Research Funding; Celgene: Consultancy; Janssen: Consultancy, Research Funding; NanoString: Patents & Royalties: Named inventor on a patent licensed to NanoSting [Institution], Research Funding. Kuruvilla:Abbvie: Consultancy; Seattle Genetics: Consultancy; Merck: Consultancy; Janssen: Honoraria; Karyopharm: Honoraria; Celgene: Honoraria; Gilead: Honoraria; Seattle Genetics: Honoraria; Roche: Honoraria; Roche: Consultancy; Karyopharm: Consultancy; Novartis: Honoraria; Gilead: Consultancy; Janssen: Research Funding; Roche: Research Funding; BMS: Consultancy; Merck: Honoraria; BMS: Honoraria; Astra Zeneca: Honoraria; Amgen: Honoraria. OffLabel Disclosure: Obinutuzumab is an anti-CD20 antibody being tested here in a prospective clinical trial for relapsed/refractory aggressive B cell lymphomas

Treosulfan-Based Tandem High-Dose Chemo-Immuno- Therapy with Autologous Stem Cell Transplantation for Relapsed and Refractory Aggressive B-Cell Lymphomas.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5488-5488 ◽  
Author(s):  
Albrecht Reichle ◽  
Ernst Holler ◽  
Anna Berand ◽  
Reinhard Andreesen
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
B Cell ◽  
Cell Transplantation ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
High Dose ◽  
Unrelated Donor ◽  
B Cell Lymphomas ◽  
Poor Risk

Abstract Feasibility and high efficacy of repetitive dose-intensive chemo-immuno-therapy in relapsed and refractory aggressive B-cell lymphoma (adjusted IPI at relapse 2 and 3) was proven by double-induction followed by tandem high-dose chemo-immuno-therapy with stem cell transplantation including a treosulfan-based conditioning regimen. For cytoreduction and stem cell mobilisation, 2 cycles of a cisplatin-based chemotherapy plus rituximab (R), R-VIPE or R-DHAP, were applied followed by two identical cycles of high-dose chemotherapy (HD-CT) consisting of treosulfan 14 g/m2 iv day −4 to day -2, carboplatin 300 mg/m2 iv day −4 to day −2 and etoposide 500 mg/m2 iv day −2 to day −4. Each HD-CT was combined with rituximab 375 mg/m2. Thirty patients (pts), mean age 53 years (range 35–68), stage III: n=9, stage IV: n=21, have been enrolled. 80% of the pts suffered from early relapse within 6 months (n=6) or refractory disease and no available matched related or unrelated donor (n=18), 6 pts had a late relapse (≥ 6 months). All patients received previously CHOP-based CTs. Histology revealed diffuse-large cell lymphoma (n=19), follicular lymphoma Grade 3 (n=6), immunoblastic lymphoma (n=3), and mantle cell lymphoma (n=2). In 7 pts both, low- and high-grade lymphomas were observed. Only one stem cell mobilization was necessary to collect sufficient CD34+ cells for two transplantations. Median hematologic recovery (&gt; 1.0 leukocytes/nl and platelets &gt;20/nl) after 1st and 2nd HD-CT was achieved by day 10 (8–11). No therapy-related death occurred. CTC °III and °IV non-hematologic toxicities were as follows: 11 of 29 pts after 1st HD-CT had °III toxicities (infection, vomiting, enteritis, stomatitis, diarrhea), after 2nd HD-CT 10 of 27 pts, respectively. Complete remission (CR 3 months post transplantation) was achieved in 22 of 30 pts (73%). CR was documented after double-induction (n=2), 1st HD-CT (n=9), and 2nd HD-CT (n=11), PR in 6 pts, and 2 pts had progressive disease during induction CT and HD-CT, respectively. At a median observation time of 19 months (range 3.6 to 4.6 months) 26 pts (87%) are alive. Sequential R-HD-CT results (in poor risk pts) in a median PFS of 14.0 months (CI 8.7 to 19.3 months), median overall survival (OS, intent-to-treat analysis) has not been reached (at 4 years 72%). In conclusion, treosulfan-based tandem R-HD-CT is feasible with a manageable toxicity profile. CR and continuous CR rates argue for a dose-response relationship even in high-risk patients with aggressive B-cell lymphomas. Some poor risk pts seem to be cured with the treosulfan-based HD-chemo-immuno-therapy. In cases of progression rescue therapies may be successfully administered as shown by the favorable OS rate. This study has now been extended as a multicenter trial.

Treatment of Diffuse Large B-Cell Lymphoma with Rituximab, Intensive Induction and High-Dose Consolidation: The Final Analysis of the Czech Lymphoma Study Group (CLSG) R-MegaCHOP-ESHAP-BEAM (R-MEB) Trial.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 21-21
Author(s):  
Marek Trneny ◽  
Robert Pytlik ◽  
David Belada ◽  
Katerina Kubackova ◽  
Ingrid Vasova ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
Performance Status ◽  
Bone Marrow Involvement ◽  
B Cell Lymphoma ◽  
High Dose ◽  
Cell Transplant ◽  
Bulky Disease ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Background. Combined immunochemotherapy with CHOP and rituximab have improved the outcome of patients with diffuse large B-cell lymphoma (DLBCL). and related diseases. However, the cure rate of patients with IPI 3–5 or aaIPI 3 is still only about 50% with this regimen. Given the feasibility of previous CLSG regimens based on high-dose CHOP-ESHAP induction and BEAM consolidation, we have conducted a phase II trial combining this approach with rituximab immunotherapy. Patients and methods. Patients aged 18–65 years with DLBCL and age-adjusted IPI (aaIPI) 2–3 were treated with three cycles of high-dose CHOP (MegaCHOP - cyclophosphamide, 3 g/m2, vincristine 2 mg, adriamycin, 75 mg/m2, and prednisone, 300 mg/m2) with G-CSF every 3 weeks, followed by three cycles of ESHAP (etoposide, 240 mg/m2, cisplatin, 100 mg/m2, methylprednisolone, 2000 mg and Ara-C 2000 mg/m2) every 3 weeks. Four to six doses of rituximab 375 mg/m2 were administered on day 1 of each cycle of induction therapy. High-dose therapy (BEAM) followed by autologous stem cell transplant (ASCT) was used as consolidation. Radiotherapy was given to residual masses or sites of bulky disease. Primary endpoint was progression-free survival (PFS), while secondary endpoints were overall survival (OS) and feasibility of the treatment. Results. From April 2002 to October 2006, 105 consecutive patients from 10 centers were recruited. 58% were men and 42% women with median age 46 years (19–63 years). 74% of patients had stage IV disease, 92% had elevated LDH, 53% had performance status &gt;1, 55% had B symptoms and 19% had bone marrow involvement. aaIPI was 2 in 62% of patients and 3 in 38% of patients. 68% of patients received the whole treatment according to the protocol, including ASCT and radiotherapy. Stem cells mobilization according to the protocol was performed in 90% of patients and was successful in 86% of mobilized patients (77% of all patients). 73% of patients ultimately received ASCT (including 3 patients transplanted after ammended treatment) and 51% of patients received planned radiotherapy. Complete remission (CR) was achieved in 83% of all patients and partial remission (PR) in 2%. Early toxic death rate was 6% and 9% patients had primary refractory disease. Of patients who achieved CR or PR, only 6 subsequently relapsed (7%) and two suffered late toxic death (2%). With a median follow-up of 32 months for living patients, the estimated 2-year PFS is 77% and 2-year OS is 81%. Age less than median (46 years) was strongest predictor of favorable outcome (p = 0,00006 for PFS and p = 0,00013 for OS), while there was no effect of stage, LDH, performance status or aaIPI (2-year PFS 79% for aaIPI 2 and 77% for aaIPI 3, 2-year OS 81% for aaIPI 2 and 80% for aaIPI 3). Delivery of ASCT or radiotherapy did not significantly affected PFS in patients who did not suffered early progression or early toxic death, but radiotherapy modestly improved OS of these patients (p = 0,03). Conclusion. R-MEB has proved to be an effective treatment strategy for younger patients with high-risk aggressive B-cell lymphoma. Currently, CLSG is testing whether utilization of early PET scan may decrease toxicity and improve treatment tolerance while maintaining the efficacy of this regimen.

Comparison of salvage therapies for relapsed or refractory diffuse large B-cell lymphoma (DLBCL): Network meta-analysis.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e19037-e19037 ◽  
Author(s):  
Venkata Vosuri ◽  
Ravi Kaisreddy ◽  
Somasekhar Bandi
Keyword(s):  
Adverse Events ◽  
B Cell ◽  
Cell Lymphoma ◽  
Meta Analysis ◽  
B Cell Lymphoma ◽  
Complete Response ◽  
High Dose ◽  
Large B Cell Lymphoma ◽  
High Dose Cytarabine ◽  
Large B Cell

e19037 Background: Salvage chemotherapy followed by autologous stem cell transplantation(ASCT) is the standard second-line treatment for relapsed or refractory diffuse large b-cell lymphoma(DLBCL). Rituximab plus ifosfamide, carboplatin, and etoposide(R-ICE) and rituximab plus dexamethasone, high dose cytarabine, cisplatin(R-DHAP) are the two widely used regimens worldwide but quest for optimal regimen continues. Our objective is to compare currently available salvage therapies based on complete response and adverse events. Methods: Pubmed, EMBASE and Clinicaltrials.gov were queried for salvage therapies in relapsed or refractory DLBCL. Only randomized clinical trials including phase 2 and 3 trials involving salvage therapies for relapsed or refractory DLBCL were selected. Data was extracted based on meta-analysis guidelines by two independent reviewers. Network meta-analyses of treatment effects and adverse outcomes were calculated with a frequentist approach. Results: Overall, 5 studies(1480 patients) were included. The salvage therapies investigated were rituximab plus ifosfamide, carboplatin, and etoposide(R-ICE), rituximab plus dexamethasone, high dose cytarabine, cisplatin(R-DHAP), rituximab plus gemcitabine, dexamethasone, cisplatin(R-GDP), ofatumumab plus dexamethasone, cytarabine, and cisplatin(O-DHAP), ifosfamide plus ofatumunab, carboplatin, and etoposide(O-ICE), dacetuzumab plus rituximab, ifosfamide, carboplatin and etoposide(DR-ICE). Of the 6 regimens in the network, treatment with R-DHAP (OR:0.36,95%CI:0.24-0.54), R-GDP(OR:0.37,95%CI: 0.21-0.65), O-ICE(OR:0.16,95%CI: 0.05-0.53), O-DHAP(OR:0.30,95%CI:0.17-0.52), DR-ICE(OR:0.77,95%CI:0.40-1.49) were not superior against network placebo(R-ICE) in achieving complete response. Higher odds of occurring severe adverse events was observed in R-DHAP(OR:2.02,95%CI: 1.35-3.01) and O-DHAP(OR:2.15,95%CI: 1.24-3.72) salvage regimens when compared to R-ICE. Conclusions: R-DHAP, R-GDP, O-ICE and O-DHAP were found to have no difference in treatment effect in achieving complete response in comparison to R-ICE. R-DHAP and O-DHAP are associated with higher number of severe adverse events in comparison with R-ICE. Outcomes mentioned above should be interpreted in the context of drugs and other factors involved in the disease.

scholarly journals Rituximab Maintenance Therapy After Autologous Stem-Cell Transplantation in Patients With Relapsed CD20+ Diffuse Large B-Cell Lymphoma: Final Analysis of the Collaborative Trial in Relapsed Aggressive Lymphoma

2012 ◽  
Vol 30 (36) ◽  
pp. 4462-4469 ◽  
Author(s):  
Christian Gisselbrecht ◽  
Norbert Schmitz ◽  
Nicolas Mounier ◽  
Devinder Singh Gill ◽  
David C. Linch ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Salvage Chemotherapy ◽  
High Dose ◽  
Large B Cell Lymphoma ◽  
Relapsed Disease ◽  
Large B Cell

Purpose The standard treatment for relapsed diffuse large B-cell lymphoma (DLBCL) is salvage chemotherapy followed by high-dose therapy and autologous stem-cell transplantation (ASCT). The impact of maintenance rituximab after ASCT is not known. Patients and Methods In total, 477 patients with CD20+ DLBCL who were in their first relapse or refractory to initial therapy were randomly assigned to one of two salvage regimens. After three cycles of salvage chemotherapy, the responding patients received high-dose chemotherapy followed by ASCT. Then, 242 patients were randomly assigned to either rituximab every 2 months for 1 year or observation. Results After ASCT, 122 patients received rituximab, and 120 patients were observed only. The median follow-up time was 44 months. The 4-year event-free survival (EFS) rates after ASCT were 52% and 53% for the rituximab and observation groups, respectively (P = .7). Treatment with rituximab was associated with a 15% attributable risk of serious adverse events after day 100, with more deaths (six deaths v three deaths in the observation arm). Several factors affected EFS after ASCT (P < .05), including relapsed disease within 12 months (EFS: 46% v 56% for relapsed disease after 12 months), secondary age-adjusted International Prognostic Index (saaIPI) more than 1 (EFS: 37% v 61% for saaIPI < 1), and prior treatment with rituximab (EFS: 47% v 59% for no prior rituximab). A significant difference in EFS between women (63%) and men (46%) was also observed in the rituximab group. In the Cox model for maintenance, the saaIPI was a significant prognostic factor (P < .001), as was male sex (P = .01). Conclusion In relapsed DLBCL, we observed no difference between the control group and the rituximab maintenance group and do not recommend rituximab after ASCT.

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