Refractory Aggressive B-cell Lymphoma Research Articles

Efficacy and safety of pixantrone for the treatment of multiply relapsed or refractory aggressive non-Hodgkin B-cell lymphomas.

Few treatment options exist for patients with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (NHL) who fail first- and second-line therapies. Pixantrone is a novel aza-anthracenedione agent with reduced potential for cardiotoxicity but maintained anti-tumour activity relative to anthracyclines. The current retrospective, observational, real-life study was undertaken in 79 patients who received pixantrone monotherapy for multiply R/R aggressive B-cell NHL in Spain and Italy. Before pixantrone, patients had received a median of 3 prior therapies and 84.6% of them were refractory to the last regimen. Median progression-free survival (mPFS) was 2.8months (95% confidence interval [CI] 2.1-3.6) and median overall survival (mOS) was 4.0months (95%CI 5.6-7.9), with an objective response rate (ORR) of 29% (complete remission [CR]: 13.2%, partial remission [PR]: 15.2%). Patients receiving ≥2 cycles of pixantrone showed mPFS and mOS of 3.1 and 6.0months, respectively, and an ORR of 36.8% (CR: 17.5%, PR: 19.3%). Overall, 63.3% of patients reported ≥1 adverse event (AE), most commonly haematological AEs. One patient developed grade 2 sinus tachycardia. Pixantrone was effective and well tolerated in a real-world population of multiply R/R patients with aggressive B-cell NHL, many of whom had very poor prognostic factors.

Phase 2 Study of Alemtuzumab Added to Dose-Adjusted EPOCH-R in Relapsed and Refractory Aggressive B-Cell Lymphomas

Introduction: Relapsed and refractory aggressive B-cell lymphomas can be cured with hematopoietic stem cell transplant (HSCT), but effective salvage regimens are required. Anthracyclines are the most effective agents in lymphoma and dose-adjusted doxorubicin, etoposide, vincristine, cyclophosphamide, prednisone with rituximab (DA-EPOCH-R) was originally developed in relapsed/refractory lymphomas. Gene-expression profiling of diffuse large B-cell lymphoma (DLBCL) identified stromal signatures associated with inferior survival and targeting the tumor microenvironment may block important survival signals. Alemtuzumab is a humanized monoclonal antibody targeting CD52, present on both B and T-cells. We hypothesized that targeting CD52 could overcome treatment resistance. We report the safety and activity of alemtuzumab added to DA-EPOCH-R in relapsed/refractory aggressive B-cell lymphomas, including Hodgkin lymphoma (HL). Methods: Adult pts with relapsed/refractory aggressive B cell lymphomas and adequate organ function were eligible. Pts with HIV or CNS involvement were ineligible. Pre-treatment evaluation included laboratory investigations, computed tomography (CT) scans, bone marrow aspirate/biopsy, and brain MRI/CT if indicated. Alemtuzumab 30 mg was infused first on day 1 over 12 hours before rituximab. EPOCH was infused over 5 days and dose-adjusted based on neutrophil nadir for up to 6 cycles. Responding pts were allowed to receive consolidation. Infective prophylaxis included trimethoprim-sulfamethoxazole, acyclovir, and fluconazole in all pts, and lamivudine for pts at risk of HBV reactivation. PCR for cytomegalovirus (CMV) was done at baseline and with every cycle. Tumor response was assessed per the revised 2014 International Working Group guidelines. CT scans were performed after cycles 4 and 6, and every 3 months for year 1, 4 months for year 2 and 6 months for years 3-5. Positron-emission tomography scans were performed after cycle 4 and 6. The primary endpoint of the study was overall response rate. Results: 50 pts were enrolled from November 2009 to March 2014. Two pts did not receive any chemotherapy due to congestive heart failure and rapid disease. 48 pts received 1 cycle and were included in the analysis. Median age was 45 years (range, 18-72) and 29 (60%) pts were male. Twenty-one (44%) pts had DLBCL (T-cell-histiocyte rich DLBCL (THRLBCL) in 4), 16 (33%) HL, 6 (13%) primary mediastinal B-cell lymphoma, 4 (8%) mediastinal grey zone lymphoma and 1 (2%) B-cell lymphoma NOS. Median lines of prior treatment was 2 (range 1-10). All pts received prior anthracycline and 10 (20%) received prior ASCT. Thirty-five (72%) were primary refractory to chemotherapy. In 46 pts evaluable for response, overall response rate (ORR) was 65% including a complete response (CR) rate of 33%. Of 30 responding pts, 13 (44%) received consolidation therapy (5 allogeneic HSCT, 7 radiation, 1 ASCT) and 17 received no further therapy with 7 long-term remissions. In 20 evaluable DLBCL pts, the ORR was 65% including a 30% rate of CR. All 4 THRLBCL responded and 3 had durable remissions after consolidative XRT (2) and allogeneic HSCT (1). In 15 evaluable HL pts, the ORR was 80% including a CR rate of 60%. After a median potential follow up of 84.6 months, median PFS and OS were 6.7 months (CI95: 4.1 - 10.4) and 18.1 months (CI95: 11.5 - not estimable), respectively. In DLBCL, the 2-year PFS and OS were 23% (CI95 9%-47%) (Figure 1A) and 41% (CI95 19%-66%), respectively, while in HL, the 2-year PFS and OS were 36% (CI95 15%-63%) (Figure 1B) and 60% (CI95 33%-82%), respectively. Febrile neutropenia, grade 4 thrombocytopenia, and CMV reactivation without infection occurred in 18%, 26%, and 53% of cycles, respectively. Grade 3 infection occurred in 18% of pts and included BK (3), HSV (1), and CMV (1). Overall, 27 deaths occurred, 3 during therapy (2 of sepsis, 1 of congestive heart failure) and 24 post-therapy (9 of PD, 5 of sepsis, 1 of hemorrhage, 1 of PTLD, and 8 of unknown causes). Conclusion: Alemtuzumab can safely be added to DA-EPOCH-R in relapsed/refractory aggressive B-cell lymphomas without a significant increase risk of opportunistic infections or unexpected toxicity. Nearly half of patients were successfully bridged to consolidation therapy; however, selected pts, particularly those with significant T-cell infiltration, experience long-term durable remission. Figure 1 Disclosures Dunleavy: Pharmacyclics: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Alemtuzumab is not standard of care treatment of lymphoma. We have studied Alemtuzumab in combination with EPOCH in this study

Retrospective Analysis of Gemcitabine and Oxaliplatin (GemOx)-Based Treatment in Patients with Relapsed/Refractory Aggressive B-Cell Non-Hodgkin Lymphoma

Retrospective Analysis of Gemcitabine and Oxaliplatin (GemOx)-Based Treatment in Patients with Relapsed/Refractory Aggressive B-Cell Non-Hodgkin Lymphoma

CTLA4Ig-based reduced intensity conditioning and donor lymphocyte infusions for haploidentical transplantation in refractory aggressive B-cell lymphoma relapsing after an autograft: Early results from a pilot study

CTLA4Ig-primed donor lymphocyte infusions (DLIs) have been found to promote natural killer (NK) cell-mediated anti-leukemia effect following haploidentical hematopoietic cell transplantation (HCT). Incorporation of CTLA4Ig in conditioning aided long-term remission in myeloma probably by blocking the CD28-CD86 pro-survival pathway when combined with CTLA4Ig-primed DLI. We explored a similar approach in 12 patients (8-65 years) who had refractory aggressive B-cell lymphoma (R-ABCL) following autologous HCT. They received CTLA4Ig-based reduced-intensity conditioning and sequential CTLA4Ig-primed DLIs on days +7, +21, and +35. None developed acute graft-versus-host disease (GVHD). Two patients developed chronic GVHD. Only 3 patients had disease-progression at 100 days posttransplant with a progression-free and GVHD-free survival at 2 years of 75%. A higher expression of CD80 in tumor cells and a greater proliferation of CD56dim CD16+ NK cells were observed at days +30 and +60 in patients with progression-free survival. We hypothesize that CTLA4Ig, with a greater avidity for CD80, probably interferes with the anti-apoptotic effect mediated through this pathway, and together with early proliferation of mature NK cell when used in conjunction with DLI, this approach might provide a curative option for patients with R-ABCL.

L’émergence des traitements par cellules CAR-T dans les lymphomes

Emerging therapies using CAR-T cells in lymphomaAfter the promising results obtained in North American academic centers suggesting the curative potential of these treatments, the development of T cells carrying a chimeric antigen receptor (CAR-T) directed against the CD19 antigen has experienced rapid developments in recent years. Three major trials (each involving about 100 patients with relapsed or refractory aggressive B-cell lymphoma) were conducted and evaluated the efficacy of these treatments (Zuma-1, Juliet and Transcend). Tumor responses are observed in 52% to 82% of patients, with a best complete response (CR) rate of 40% to 58%. Although some patients with early CR may relapse rapidly, the quality of the response appears to improve over time for other patients in partial response, all of which result in a proportion of patients with prolonged CR by approximately 30% to 40% (up to more than one year after treatment). Toxicities (mostly early and reversible) are mainly represented by the cytokine release syndrome (severe in 1% to 22% of patients) and neurological disorders sometimes severe (in 12% to 31% of patients), while other patients develop cytopenias or hypogammaglobulinemia. The updating of these studies over time and the new developments (in the improvement of their conception and in their use) of the CAR-T will allow to better defining the place of these innovative and promising treatments in the therapeutic strategy of patients with lymphoma.Cet article fait partie du numéro supplément Les cellules CAR-T : une révolution thérapeutique ? réalisé avec le soutien institutionnel des partenaires Gilead : Kite et Celgene.

Procalcitonin As a Potential Biomarker for Differentiating Bacterial Infectious Fevers from Cytokine Release Syndrome

Procalcitonin As a Potential Biomarker for Differentiating Bacterial Infectious Fevers from Cytokine Release Syndrome

Possible Factors on Efficacy and Safety of CAR-T Therapy in Relapsed or Refractory Aggressive B-Cell Lymphoma

Background:Recent advances have improved the treatment of B-cell malignancies, but patients who have disease resistant to primary or salvage treatment or who relapse after transplantation have an extremely poor prognosis. Studies of chimeric antigen receptor T-cell (CAR-T) therapy have shown high response rates and long response duration in refractory B-cell lymphomas after the failure of conventional therapy, which suggest that this therapy may be potentially curative. To explore the possible factors on efficacy and safety of CAR T-Cell therapy in relapsed or refractory aggressive B-cell lymphomas, we conducted the clinical trial of CAR-T Cell Treating Relapsed/Refractory B-cell lymphomas (NCT03196830).Methods:From March 2017 to April 2018, 25 patients were enrolled into our clinical trial. According to the surface expression of tumor cells by either flow cytometry or immunohistochemistry, different targets of CAR T-cells were infused, ionly anti-CD19 (n=11), sequential infusion of anti-CD22 and anti-CD19 (n=8), and sequential infusion of anti-CD20 and anti-CD19 (n=6). Patients received conditioning treatment (low-dose cyclophosphamide, 300 mg/m² per day, and fludarabine, 30 mg/m² per day) on days -5, -4, and -3 before the administration of autologous CAR T-cells. The primary endpoint was the proportion of patients with an objective response. Secondary endpoints included safety and biomarker assessments.Results:Among the 25 patients who were enrolled, response was successfully evaluatedfor 24. The objective response rate was 75%, and the complete response rate was 33%. With a median follow-up of 3.2 months, 54% of the patients continued to have a response, with 25% continuing to have a complete response. Grade 3 or higher cytokine release syndrome (CRS) and neurologic events occurred in 24% and 16% of the patients, respectively. One of the patients died during treatment. Serum biochemical index analysis confirmed the associations of peak serum interleukin-2, -6, -10, INF-γ, ferritin, C-reactive protein (CRP) concentrations and the level of lactate dehydrogenase (LDH) before therapy with the grade 3 or higher CRS, as well as peak serum interleukin-6, -10, INF-γ, CRP, ferritin and the level of LDH before therapy with grade 3 or higher neurologic events.Conclusion:Our study demonstrates the efficacy and safety of CAR-T therapy relapsed or refractory aggressive B-cell lymphoma. The level of LDH before therapy was higher in patients who developed grade 3 or serious CRS, which suggest that we should improve safety by reducing tumor burden before CAR T-cells infusion. Due to the small number of enrolled cases, no significant improvement of efficacy was observed, this result needs to be further confirmed by expanding the number of study cases. DisclosuresNo relevant conflicts of interest to declare.

R-ICE Chemotherapy with or without Autologous Transplantation for Elderly Patients with Relapsed or Refractory Aggressive B-Cell Lymphomas

For patients aged 60 years or older, the treatment of relapsed aggressive B-cell lymphomas remains challenging. The purpose of this retrospective analysis was to evaluate the results of the R-ICE (rituximab, ifosfamide, carboplatin, etoposide) protocol alone as compared to R-ICE followed by high-dose chemotherapy with autologous transplantation. The 3-year progression-free survival (PFS) and overall survival (OS) rates in 17 patients receiving R-ICE without transplantation were 32% (95% confidence interval (CI): 8.48-55.52) and 35% (95% CI: 11.48-58.52), respectively. Median PFS and OS times were 9 months (95% CI: 2-22) and 12 months (95% CI: 5-19), respectively. In 17 age-matched transplanted patients the respective survival rates were 18% (95% CI: 0.36-35.64) and 24% (95% CI: 4.4-43.6). Median PFS and OS times were 11 months (95% CI: 6-16) and 16 months (95% CI: 13-19), respectively. Thus, R-ICE alone is a reasonable treatment option for elderly patients with relapsed or refractory aggressive B-cell lymphomas.

Safety and efficacy of GVD and anti-PD-1 (SHR-1210) regimen with or without low-dose decitabine priming for refractory bulky and aggressive primary mediastinal large B-cell lymphoma.

7556Background: Relapsed/refractory PMBCL (rrPMBCL) generally has limited treatment options and dismal prognosis. Recently, monotherapy of anti-PD-1 was reported to induce an effective and durable ...

Evaluation of the Effectiveness and Safety of Pixantrone for the Treatment of Multiply Relapsed or Refractory Aggressive Non Hodgkin B-Cell Lymphoma in an Ongoing International Registry

Abstract Introduction:There is an unmet need for rescue treatment of Non-Hodgkin Lymphoma (NHL) patients who are refractory to initial treatment or relapse after immuno-chemotherapy or after receiving a transplant. Pixantrone is a novel aza-anthracenedione structurally different to anthracyclines and anthracenediones which is thought to be associated with reduced anthracycline-related cardiotoxicity due to a purported reduction in free-radical formation and cardiotoxic alcohols. Due to the lack of Real World Data in patients treated with pixantrone, we perform this study with the objective to evaluate the effectiveness and safety of the drug in a patient's population from Spain and Italy. Methods: An observational retrospective registry of patients was designed. Data were collected from across all centres that have treated at least one patient with pixantrone (one cycle or more) in Spain and from selected centres in Italy. Eligible patients were at least 18 years old, had histologically proven relapsed or refractory aggressive B-cell NHL and had to be treated according to pixantrone product information (SmPC). Informed consent was obtained from patients still alive when the study was initiated. Pixantrone was administered as monotherapy (50 mg/m2 on days 1, 8 and 15 of a 28 days cycle). Clinical baseline characteristics at the time of starting pixantrone were collected: age, gender, international prognostic index (IPI), Eastern Cooperative Oncology Group (ECOG) performance status, extranodal disease, B symptoms and Ann Arbor stage. Details on prior therapy before pixantrone were collected, including transplantation, radiotherapy, and chemotherapy. Type of regimen, duration, best Overall Response Rate (ORR) and rituximab use were registered for the last therapeutic treatment received. Pixantrone treatment specifications as treatment duration, dose delays and dose reductions, ECOG and best outcome were collected. Follow up data after pixantrone treatment and safety information were also requested. Primary endpoint was the Progression Free Survival (PFS). Secondary endpoints included: the proportion of patients who reached a complete response (CR) after pixantrone treatment; ORR and OS. This study is ongoing and recruiting patients in Spain and Italy. Results: In this preliminary analysis 49 patients were included in 31 centers. It is expected to include 90 patients until final database closure. The key baseline characteristics of analyzed patients are outlined in Table 1. The mean age at diagnosis was 65 years (95% CI 61-70). The median number of cycles of treatment with pixantrone was 2 (range, 1-6). Twenty seven patients (58.7%) died in the follow-up up to date. Data on ORR, PFS, and OS will be detailed in the final report, expected in December, 2017. Until now, related or possibly related to pixantrone adverse reactions (AR) were reported in 28 of 38 patients (73.7%). The most common reported adverse reactions were hematological (58.7%), being gastrointestinal adverse reactions the most common non-hematological toxicity reported (10.7%). and administration-site reactions (10.7%). Regarding the ARs severity, Grade 2 were the most frequently reported (36%), followed by Grade 3 (21.3%) and Grade 4 (18.6%).No cardiotoxicity has been reported. Conclusion: These preliminary results of pixantrone treatment in real world clinical practice showed that pixantrone was well tolerated with no evidence of cardiac toxicity. The effectiveness of pixantrone in this study will be confirmed with the future final registry results. Download : Download high-res image (197KB) Download : Download full-size image Disclosures Zinzani: Janssen: Consultancy; Lundbeck: Consultancy; Gilead Sciences: Consultancy; Roche: Consultancy; Celgene: Consultancy; Mundipharma: Consultancy; Takeda: Consultancy; Verastem: Consultancy; Sandoz: Consultancy; Bristol-Myers Squibb: Consultancy; Merck: Consultancy; Servier: Consultancy; Nordic Nanovector: Consultancy; Astellas: Consultancy. Navarro: Laboratorios Servier: Consultancy. Sancho: Celgene: Honoraria; Gilead: Honoraria; Laboratorios Servier: Consultancy; Janssen: Honoraria; Mundipharma: Honoraria; Roche: Honoraria; Kern Pharma: Honoraria. Soler: Laboratorios Servier: Consultancy. Grasso Cicala: Laboratorios Servier: Employment. Yapur: Laboratorios Servier: Employment. Spione: Servier Italy: Employment.

A Phase II LYSA Study of Obinutuzumab Combined with Lenalidomide for Relapsed or Refractory Aggressive B-Cell Lymphoma

A Phase II LYSA Study of Obinutuzumab Combined with Lenalidomide for Relapsed or Refractory Aggressive B-Cell Lymphoma

Outcomes in refractory aggressive diffuse large b-cell lymphoma (DLBCL): Results from the international SCHOLAR-1 study.

7516Background: Patients with relapsed/refractory DLBCL have heterogeneous outcomes to subsequent therapy. The subgroup of these patients with refractory disease (r-DLBCL) have a worse prognosis. A multi-cohort study, SCHOLAR-1 (Retrospective Non-Hodgkin Lymphoma Research) was performed to evaluate outcomes for patients with r-DLBCL and serve as a benchmark for future clinical trials in this population. Methods: Eligible subjects had r-DLBCL defined as progressive disease (PD) or stable disease (SD) as best response to chemotherapy (duration of SD <12 mos and at least 4 cycles of first-line or 2 cycles of later line therapy) or relapse ≤12 mos of ASCT. Patients must have received an anti-CD20 monoclonal antibody (unless CD20-) and an anthracycline as one of their prior regimens. Data from 2 phase 3 studies (LYSARC-CORAL and Canadian Cancer Trials Group-LY.12), and 2 observational cohorts (MD Anderson Cancer Center (MDACC), and Mayo Clinic / University of Iowa (MC/IA) Specialized Program of Research Excell...

Lenalidomide Plus Rituximab for Relapsed or Refractory Diffuse Large B-Cell, Follicular and Transformed Lymphoma: Final Data Analysis of a Phase 2 Trial

Background: We have previously reported the favorable safety and efficacy of lenalidomide plus rituximab in relapsed or refractory (R/R) aggressive B-cell lymphoma, including diffuse large B-cell lymphoma (DLBCL), grade 3 follicular lymphoma (FLG3) and transformed lymphoma (TL) (Wang et al, Leukemia 2013). Here we report results of the final data analysis of this phase 2 trial after an extended follow-up.Methods: Patients with R/R DLBCL, FLG3 and TL were enrolled in this single arm trial. Lenalidomide (20 mg daily) was administered orally on days 1-21 of each 28-day cycle, and rituximab (375 mg/m2 weekly) was administered intravenously during the first cycle only. Treatment was continued with dose-reduction allowance until disease progression, stem-cell transplantation or severe toxicity. The primary endpoint was overall response rate (ORR), and the secondary endpoint was survival. Analysis was by intention to treat.Results: In total, 45 patients were enrolled, with 32 DLBCL, 4 FLG3 and 9 TL. 29 were male and 16 were female. The median age was 66 years (range 23-84). Median ECOG PS was 1 (range 0-3). 41 patients (91.1%) were stage 3-4. Median number of prior lines of therapy was 3 (range 1-4). The median follow-up time was 9.8 months (range 0.8-77.7). Overall, 10 patients (22.2%) achieved CR, and 5 patients (11.1%) achieved PR, with an ORR of 33.3%. An additional 11 patients (24.4%) achieved SD. The ORR was 28.1% for DLBCL, 25.0% for FLG3, and 55.6% for TL. In Chi-square test, lower IPI score (0-2) was associated with higher ORR (P = 0.043). Patients with fewer prior lines of therapy tended to respond better (P = 0.118). In multivariate logistic regression, lower IPI was predictive of better ORR (P = 0.023). Median time to initial and best response was 1.8 months (range 0.8-2.1) and 1.8 months (range 0.8-20.1), respectively. Median duration of response was 10.2 months (95% CI 0.0-24.7). The median progression-free survival (PFS) was 3.7 months (95% CI 1.8-5.6), and the median overall survival (OS) was 10.8 months (95% CI 6.5-15.1). The 6- and 12-month PFS rates were 22.5% and 11.3%, respectively. The 1-, 2- and 5-year OS rates were 43.5%, 38.9% and 15.4%, respectively. Median OS was 50.3 months (95% CI 42.8-57.8) in responders and 6.6 months (95% CI 4.0-9.1) in non-responders (P < 0.001). In multivariate Cox regression, lower IPI was significantly predictive of longer OS (HR = 0.323, 95% CI = 0.157-0.668, P = 0.002) and showed a clear trend in predicting longer PFS (HR = 0.495, 95% CI 0.234-1.048, P = 0.066). Gender, Ki67 at registration and number of prior lines of therapy were not predictive of PFS or OS.Conclusions: Lenalidomide plus rituximab is an efficacious treatment regimen for relapsed or refractory aggressive B-cell lymphoma. IPI is strongly predictive of ORR and OS in this setting. Ki-67 and number of prior lines of therapy are not predictive of ORR, PFS or OS. DisclosuresNeelapu:Celgene: Consultancy, Research Funding. Shah:Celgene: Consultancy, Research Funding. Thomoas:Celgene: Research Funding. Wang:Celgene: Research Funding.

Pixuvri&lt;sup&gt;®&lt;/sup&gt; (Pixantrone Dimaleate, BBR 2778): From Lab to Market

This review will trace the steps in the development of pixantrone dimaleate (initial code BBR 2778, Pixruvi®), an anthracenedione chemotype, as a chemotherapeutic agent. This drug exhibits reduced cardiotoxicity in comparison to anthracyclines and mitoxantrone. Synthetic pathways, biological evaluations and mechanistic considerations will be discussed. On May 10, 2012, the European Medicines Agency granted a conditional marketing approval to CTI Biopharma for pixantrone dimaleate for the treatment of adults suffering from multiple relapsed or refractory aggressive non-Hodgkin B-cell lymphomas (NHL). Potential applications of pixantrone dimaleate for the treatment of multiple sclerosis and other maladies will be presented. Keywords: BBR-2778, cardiotoxicity, non-Hodgkin, lymphoma, pixantrone, Pixuvri®.

High Response Rate and Acceptable Toxicity of R-P-Imvp-16/CBDCA for Relapsed or Refractory Aggressive B-Cell Lymphoma

BACKGROUND: The optimal management of relapsed or refractory aggressive B-cell lymphoma is not standardized. We previously reported the salvage chemotherapy with P-IMVP-16/CBDCA consisting of methylprednisolone (mPSL), carboplatin (CBDCA), etoposide (VP-16), ifosfamide (IFM), and methotrexate (MTX) for patients (pts) with aggressive non-Hodgkin’s lymphoma who had previously received CHOP consisting of cyclophosphamide (CPA), doxorubicin (DOX), Vincristine (VCR) and prednisolone (PSL) (Sawada M; Eur J Haematol 2002). The purpose of this study is to determine the efficacy and safety of salvage chemotherapy with rituximab (R) combined with P-IMVP-16/CBDCA (R-P-IMVP-16/CBDCA) for relapsed or refractory aggressive B-cell lymphoma.PATIENTS AND METHODS: We retrospectively analyzed 66 pts with relapsed or refractory aggressive B-cell lymphoma who had received R-P-IMVP-16/CBDCA (R: 375mg/m2 on day1, mPSL: 1000mg/body on days 2-4, IFM: 1000mg/m2 on days 2-6, MTX: 30mg/m2 on day 4 and 11, VP-16: 80mg/m2 on days 2-4, and CBDCA 300mg/m2 on day 2, with granulocyte colony-stimulating factor every 21 days in 5 institutes of Gifu Hematology Study Group between July 2004 and January 2014. The pts who had responded to R-P-IMVP-16/CBDCA underwent autologous transplantation or received 3 additional R-P-IMVP-16/CBDCA cycles. Pts aged 70 or older were given 75% or less of the standard dose. All patients received R-CHOP or R-THP-COP regimen as a first-line chemotherapy. THP (pirarubicin), a derivative of DOX, is an anthracyclin with less cardiotoxicity than DOX. THP-COP has an equivalent efficacy to CHOP (Turumi H; JCRCO 2004).RESULTS: Enrolled 66 pts had a median age of 64.5 years [range 25-83] and were 65% male. The pathology of underlying lymphoma comprised diffuse large-B cell lymphoma (n=51), follicular lymphoma grade 3 (n=11), intravascular large B-cell lymphoma (n=1), primary mediastinal B cell lymphoma (n=1) and mantle cell lymphoma (n=2). The response rate [complete response (CR/CRu) plus partial response (PR)] was 60.6% (40/66), including 28 (42.4%) CR/CRu and 12 (18.2%) PR. Another 5 pts had stable disease and 21 pts progressed. Median overall survival (OS) and progression-free survival (PFS) were 47.1 months and 9.2 months, respectively. The OS rate for the 66 pts was 65.1% at 1 yr and 57.3% at 2 yr. The PFS rate for the 66 pts was 45.6% at 1 yr and 31.2% at 2 yr. The survival rate for the 40 responders was 97.4% at 1 yr and 88.1% at 2 yr, and the survival rate for the 26 non-responders was 15.0% at 1 yr (P<0.001). Common toxicity criteria grade ≥ 3 drug-related adverse events included: neutropenia, anemia, thrombocytopenia and febrile neutropenia. Although the major toxicities were neutropenia and febrile neutropenia, only one DLBCL pt with common variable immunodeficiency died of sepsis related to neutropenia. Non-hematological adverse effects were predominantly mild and tolerable.CONCLUSIONS: The R-P-IMVP-16/CBDCA regimen displayed a significant activity in relapsed or refractory aggressive B-cell lymphoma, with acceptable toxicity and should be considered a candidate for combination chemotherapy. Futher clinical studies should be required. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

A Phase 2 Study from Spanish Geltamo Group Investigating the Efficacy and Safety of Bendamustine As Part of Conditioning Regimen for Autologous Stem-Cell Transplantation in Patients with Aggressive Lymphomas: Second Interim Analysis

INTRODUCTIONHigh-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is the standard treatment for patients with relapsed or refractory aggressive B-cell lymphoma, and is frequently used as part of first-line therapy in patients with peripheral T-cell lymphoma (PTCL). However, long-term remission rates with this strategy are inferior to 50%, so novel approaches are required. We have designed a prospective multicenter phase II study to evaluate the safety and efficacy of bendamustine as part of conditioning regimen in patients with aggressive lymphomas undergoing ASCT. METHODSInclusion criteria were: histologic diagnosis of i) relapsed or refractory diffuse large B-cell lymphoma (DLBCL) or grade 3B follicular lymphoma (FL) in partial response (PR) or complete remission (CR) after salvage therapy, or ii) transformed DLBCL or peripheral T-cell lymphoma (PTCL) in first or subsequent PR or CR. Conditioning regimen consisted of bendamustine (200 mg/m2, days -7 and -6), etoposide (200 mg/m2, days -5 to -2), cytarabine (400 mg/m2, days -5 to -2), and melphalan (140 mg/m2, day -1) (BendaEAM regimen). Primary endpoint was progression-free survival (PFS) at 3 years. Secondary endpoints were toxicity, response to transplant at 3 months, and overall survival (OS). This trial was registered at EMEA (EUDRACT number 2010-020926-17). RESULTSSixty patients (median age 54 years, range 27-70) from 22 Spanish hospitals were included since May 2011 to November 2012. Histologies were: 40 DLBCL, 3 grade 3B FL, 13 transformed DLBCL, and 7 PTCL. 82% of patients have received ³2 lines of treatment prior to ASCT. 37 patients (62%) were in CR at the time of transplant and 23 (38%) in PR. A median number of 4.05 x 106/Kg (range: 1.69-19.80) CD34+ cells were reinfused. All patients (except one who died early) engrafted after a median of 11 (range: 9 to 72) and 14 (range: 4 to 53) days, respectively, to achieve >0.5 x109/L neutrophils and >20 x109/L platelets. 39 serious adverse events (SAEs) were reported before day +100, including 14 infectious episodes, 2 of them resulting in respiratory failure and death (3.3% of transplant related mortality). Another major SAE was renal toxicity developed by 5 patients (8.3%) after bendamustine administration, reversible in all cases (3 of these patients had developed mild renal failure during previous salvage therapy). Non-relapse mortality after day +100 was 3.3% (1 patient died because of Wernicke’s encephalopathy, and 1 patient from infectious complications). Concerning response to transplant, 44 patients (73.3%) achieved CR, 7 (11.7%) PR, and 6 patients (10%) did not respond. Univariate analysis showed that patients who received more than 2 lines of treatment prior to transplant (1 line: 100% of CR post-transplant; 2 lines: 71%; >2 lines: 50%; p=0.013), and those who were in PR at transplant (48% vs 89%, p<0.001) had lower CR rates after ASCT (day +100), although only disease status at transplant retained the significant influence in the multivariate analysis (RR: 0.11, 95% CI: 0.03-0.42, p=0.001). Histological diagnosis had no significant influence on CR rates after ASCT (DLBCL: 73%; transformed DLBCL: 69%; PTCL: 86%; p>0.1). At the time of analysis, 13 patients (22%) had disease progression and 8 patients (13%) have died (4 from lymphoma, and 4 from other causes). With a median follow-up of 18.9 (9.5 to 32.3) months, the estimated 2-year PFS and OS were 73% and 88%, respectively. CONCLUSIONSThe BendaEAM conditioning regimen is feasible and active in patients with aggressive lymphomas. Toxicity profile is similar to that commonly observed in the ASCT setting, but renal toxicity can occur and should be carefully monitored, especially in patients with prior history of renal failure. Longer follow-up is needed to assess the long-term toxicity and the efficacy of this regimen, although patients who are not in CR before transplant seem to have poorer outcomes. DisclosuresNo relevant conflicts of interest to declare.

O2-1-5 - Efficacy and Safety of Rituximab Combined with P-Imvp-16/Cbdca for Refractory or Relapsed Aggressive B-Cell Lymphoma

Background: We previously reported the efficacy of salvage chemotherapy with P-IMVP-16/CBDCA consisting of methylprednisolone (mPSL), carboplatin (CBDCA), etoposide (VP-16), ifosfamide (IFM), and methotrexate (MTX) for patients with aggressive non-Hodgkin's lymphoma who had previously received CHOP (Eur J Haematol 2002). The purpose of this study was to determine the efficacy and safety of salvage chemotherapy with rituximab (R) combined with P-IMVP-16/CBDCA (R-P-IMVP-16/CBDCA) for refractory or relapsed aggressive B-cell lymphoma.Methods: We retrospectively analyzed 32 patients with relapsed or refractory aggressive B-cell lymphoma who had received R-P-IMVP-16/CBDCA (R: 375mg/m2 on day1, mPSL: 1000mg/body on days 2-4, IFM: 1000mg/m2 on days 2-6, MTX: 30mg/m2 on day 4 and 11, VP-16: 80mg/m2 on days 2-4, and CBDCA 300mg/m2 on day 2, with granulocyte colony-stimulating factor every 21 days) between June 2004 and June 2013. Patients aged 70 or older were given 75% of the standard dose. All patients received R-CHOP or R-THP-COP regimen as a first-line chemotherapy. The overall response rate (ORR), survival, and toxicity were analyzed.Results: The pathology of underlying lymphoma comprised diffuse large-B cell lymphoma (n = 26), follicular lymphoma grade 3 (n = 3), intravascular large B-cell lymphoma (n = 1) and mantle cell lymphoma (n = 1). ORR was 53.1% (17 pts), including 28.1% (9 pts) CR. Median overall survival (OS) and progression-free survival were 19.1 months and 3.5 months, respectively. Nine patients (28.1%) proceeded to autologous stem cell transplantation and their 2-year OS was 87.5%. Although the major toxicity was neutropenia, no patient died of infection related to neutropenia. Non-hematological adverse effects were predominantly mild and tolerable.Conclusions: R-P-IMVP-16/CBDCA chemotherapy for patients with refractory or relapsed aggressive B-cell lymphoma might be effective as a salvage therapy.

Lenalidomide plus R-CHOP21 in elderly patients with untreated diffuse large B-cell lymphoma: results of the REAL07 open-label, multicentre, phase 2 trial

Up to 40% of elderly patients with untreated diffuse large B-cell lymphoma (DLBCL) given a regimen of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone every 21 days (R-CHOP21) relapse or develop refractory disease. Lenalidomide has high activity in relapsed or refractory aggressive B-cell lymphomas. In phase 2 of the REAL07 trial, we aimed to establish the safety and efficacy of the combination of lenalidomide and R-CHOP21 in elderly patients with untreated DLBCL. REAL07 was an open-label, multicentre trial that was done in 13 centres in Italy and one in Germany. Eligible patients were aged 60-80 years; had newly diagnosed, untreated, CD20-positive, Ann Arbor stage II-IV DLBCL or grade 3b follicular lymphoma; had an Eastern Cooperative Oncology Group performance status of 0-2; had an International Prognostic Index (IPI) risk of low-intermediate, intermediate-high, or high; and were fit according to comprehensive geriatric assessment. Participants were to receive 15 mg oral lenalidomide on days 1-14 of six 21-day cycles, and standard doses of R-CHOP21 chemotherapy (375 mg/m(2) intravenous rituximab, 750 mg/m(2) intravenous cyclophosphamide, 50 mg/m(2) intravenous doxorubicin, and 1·4 mg/m(2) intravenous vincristine on day 1, and 40 mg/m(2) oral prednisone on days 1-5). The primary endpoint was frequency of overall response (complete response [CR] and partial response [PR]), which was assessed by (18)F-fluorodeoxyglucose ((18)F-FDG) PET at the end of the treatment. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00907348. 49 patients were included in phase 2: nine had been enrolled into phase 1 between Oct 23, 2008, and June 4, 2009, and had received the maximum tolerated dose of 15 mg lenalidomide; and 40 were enrolled into phase 2 between April 28, 2010, and June 3, 2011. 45 patients (92%, 95% CI 81-97) achieved a response (42 [86%] CR; three [6%] PR). Three patients (6%) did not respond and one (2%) died for reasons unrelated to treatment or disease. 277 (94%) of 294 planned cycles of lenalidomide and R-CHOP21 were completed. Grade 3-4 neutropenia was reported in 87 cycles (31%), grade 3-4 leukopenia in 77 (28%), and grade 3-4 thrombocytopenia in 35 (13%). No grade 4 non-haematological adverse events were reported. No patients died during the study as a result of toxic effects. Lenalidomide with R-CHOP21 is effective and safe in elderly patients with untreated DLBCL. Fondazione Italiana Linfomi and Celgene.

Pixantrone for the treatment of adult patients with relapsed or refractory aggressive non-Hodgkin B-cell lymphomas

Treatment of patients with relapsed or refractory aggressive non-Hodgkin B-cell lymphoma remains an unmet clinical need, and the progressive myocardial toxicity related to cumulative, dose-dependent damage induced by anthracyclines represents a tricky issue in the planning of therapy. Pixantrone is a promising aza-anthracenedione with reduced cardiotoxicity and significant antineoplastic activity, and has been investigated in solid and hematologic tumors in several Phase I, II, and III trials. The aim of this review is to summarize the data reported so far on pixantrone as a salvage therapy in relapsed/refractory non-Hodgkin B-cell lymphoma.

Impact of prior rituximab on outcomes of autologous stem-cell transplantation in patients with relapsed or refractory aggressive B-cell lymphoma: a multicentre retrospective Spanish group of lymphoma/autologous bone marrow transplant study

The use of highly effective rituximab-containing therapy for treating diffuse large B-cell lymphoma (DLBCL) makes it more difficult to salvage relapsed or refractory patients. Autologous stem-cell transplantation (ASCT) is the reference treatment for these patients, but the impact of previous exposure to rituximab on the subsequent results of ASCT remains unknown. We analysed 248 patients with relapsed or refractory DLBCL or grade 3B follicular lymphoma pre-treated with rituximab as part of first-line therapy (R+ group) who received ASCT, in comparison with a control group of 127 patients without previous exposure to rituximab (R- group). The complete remission (CR) rates were similar in both groups. Multivariate analysis identified age-adjusted International Prognostic Index at diagnosis, extranodal involvement and disease status at transplant, and the number of previous chemotherapy lines as independent factors with a negative influence on CR rate. Compared with R- patients, those in the R+ group had a significantly better progression-free survival (63% vs. 48% at 5years) and overall survival (72% vs. 61% at 5years). This observation was independent of other prognostic factors that affected these outcomes. In conclusion, ASCT is no less effective in patients with relapsed or refractory aggressive B-cell lymphoma pre-treated with first-line rituximab-containing therapy than in rituximab-naive patients.