Rituximab, Ifosfamide, Carboplatin, Etoposide Research Articles

The Relapse-to-Therapy Interval in Relapsed or Refractory Diffuse Large B Cell Lymphoma Is Associated with Clinical Outcomes

Introduction In newly diagnosed diffuse large B cell lymphoma (DLBCL), the diagnosis-to-treatment (DTI) interval is associated with clinical outcomes: patients who initiated therapy early after DLBCL diagnosis have significantly worse event free survival (EFS) (Maurer JM et al. J Clin Oncol 2018;36:1603-1610). In relapsed or refractory (R/R) DLBCL, the relapse-to-treatment interval (RTI) has gained more relevance with the recent approvals of several novel therapies including chimeric antigen receptor (CAR) T-cell therapies, which require several weeks of manufacturing time, and bispecific antibody therapies that require several weeks of desensitization through dose ramp-up to achieve therapeutic levels. The association between RTI and patient outcomes in R/R DLBCL has not yet been reported. Methods We conducted an IRB-approved retrospective review of r/r DLBCL patients treated with rituximab, ifosfamide, carboplatin, etoposide (R-ICE) as second line treatment at three academic medical centers between 2010-2020. Characteristics at the time of relapse, including RTI and treatment outcomes were collected from the electronic medical record. Outcomes evaluated included disease response to R-ICE, subsequent autologous stem cell transplant (ASCT) and CAR T cell therapy, progression free survival (PFS) and OS. All analyses were done using R and its packages. The optimal cutoff values for RTI were determined using maximally selected rank test from MaxStat and survminer packages. The association between RTI and clinical outcomes was evaluated using Fisher test and Wilcoxon rank-sum test. Survival was calculated using the Kaplan Meier method, comparisons done using log-rank. Results We identified 249 patients treated with second line R-ICE for r/r DLBCL with available RTI data. The median RTI was 18 days (IQR 9-31). The optimal RTI cutoffs calculated with maximally selected rank test were 7 days for PFS and 11 days for OS. An intermediate value of 10 days was chosen. At the time of relapse, age, gender, cell of origin and double expressor / double hit features were comparable among groups, but patients with an RTI of ≤ 10 days were more likely to have B symptoms, elevated lactate dehydrogenase, and intermediate or high IPI scores compared to those with longer RTI (table 1). The RTI had a strong association with patient outcomes. Patients with RTI of 10 days or less had a lower rate of complete remission (20% vs. 45%, p = 0.003). After a median follow up of 53 months (IQR 36-73), median PFS for patients with RTI ≤ 10 days was 5.1 vs. 12.7 months for patients with RTI > 10 days (p <0.001). Four-year PFS estimates were 17.3% for patients with RTI ≤ 10 days vs. 35.3% for patients with RTI > 10 days. Median OS was 26 months for patients with RTI 10 days vs. 85 months for patients with RTI > 10 days (figure 1). Among patients with RTI of ≤ 10 days, 46% went on to receive ASCT, whereas 64% of patients with RTI > 10days had ASCT (p = 0.048). On multivariate Cox proportional hazards analysis including RTI ≤10 days, age > 60 years at time of relapse, elevated LDH, and ECOG ≥ 2, the proportional hazards condition was met for both PFS and OS. Shorter RTI had a statistically significant association with PFS and OS, with hazard ratios (HR) of 1.80 (95% CI 1.27-2.56, p = 0.001) and 1.97 (95% CI 1.29-3.03, p = 0.002), respectively. Conclusions There is a strong association between RTI and the outcomes of R/R DLBCL patients treated with second line R-ICE chemotherapy. Our findings highlight the worse outcomes of patients with rapidly progressive, symptomatic R/R DLBCL and are particularly impactful in the era of CAR T-cells and novel immunotherapies, which can take many weeks to become available or effective. As with the DTI, clinical trials of DLBCL therapies should report RTI whenever possible. More effective and rapidly available treatment approaches should be designed to improve the outcomes of this high-risk patient population.

Outcomes of DLBCL Patients Achieving Complete Remission after R-ICE Chemoimmunotherapy

Introduction Diffuse large B cell lymphoma (DLBCL) patients who are refractory or relapse (r/r) within 12 months of completion of initial therapy (refractory and early relapse, RER) have inferior outcomes than those relapsing 12 months or after (late relapse, LR). Recent trials of anti-CD19 chimeric antigen receptor T (CAR-T) cell therapy have demonstrated improved event-free survival (EFS) in RER-DLBCL when compared with standard chemotherapy with intent to undergo autologous stem cell transplant (ASCT). Due to clinical urgency and logistic factors many patients with r/r DLBCL will receive second line systemic chemotherapy. The optimal treatment for those responding to second line therapy is not yet well defined. Methods We conducted an IRB approved retrospective review of r/r DLBCL patients treated with rituximab, ifosfamide, carboplatin, etoposide (R-ICE) at three academic medical centers between 2010-2020. Baseline characteristics and outcomes were collected from the electronic medical record. Patients having RER-DLBCL were defined as those who had disease that was r/r within 12 months of the end of initial therapy. Outcomes evaluated included disease response to initial and second line therapy, subsequent ASCT and CAR T cell therapy, progression free survival (PFS) and overall survival (OS). Response was assigned by CT scan in 38 (13%) and by PET in 236 (81%) of patients. All analyses were done using R and its packages. Results We identified 291 patients treated with R-ICE for r/r DLBCL, 182 (62.5%) of whom had RER-DLBCL and 109 (37.4%) and LR-DLBCL. Baseline characteristics between RER and LR-DLBCL were comparable (Table 1), with the exception of age. RER-DLBCL patients received a median of 2 cycles vs. 3 cycles of RICE for LR-DLBCL (p = 0.008). Patients with RER-DLBCL had overall (OR) and complete response (CR) rates of 62% and 30%, vs. 86% and 45% among patients with LR-DLBCL, respectively (p < 0.0001). 170 patients underwent ASCT. 79 patients received CAR T cell therapy, 42 (14%) without prior ASCT and 37 (13%) after ASCT. After a median follow up of 53 months (IQR, 36-76), median PFS for ER-DLBCL vs. LR-DLPBCL was 6 months vs. 31 months (HR=1.84 [95%CI 1.36-2.49, p < 0.001), with 4-year PFS estimates of 24% (95% CI 18-32%) vs. 40% (95% CI 31-51%), respectively. Median OS was 36 months for ER-DLBCL vs. 68 months for LP-DLBCL (HR=1.63 [95% CI 1.13-2.36], p = 0.009), with 4-year estimates of 48% (95% CI 40-56%) vs. 66% (95% CI 57-76%), respectively. Among patients achieving CR after R-ICE, median PFS was 43 months for RER-DLBCL vs. not reached for LR-DLBCL (HR=1.43 [95% CI 0.8-2.4], p = 0.2) (Figure 1), with 4-year PFS estimates of 43% (95% CI 31 - 60%) and 50% (95% CI 37 - 68%), respectively. Median OS for patients in CR after R-ICE was 85 months for RER-DLBCL and 102 months for LR-DLBCL (HR = 0.98 [95% CI 0.5 - 1.92], p > 0.9), with 4-year OS estimates of 69% (95% CI 57 - 84%) and 72% (95% CI 60 - 87%), respectively. Patients who underwent ASCT after achieving CR had median PFS of 71 months (95% CI 29 - NR), while median survival was not reached (95% CI 85 months - NR). Four-year PFS and OS estimates of 53% and 77%, respectively. Among patients undergoing ASCT after CR, there was no statistically significant difference in PFS (4-year PFS: RER-DLBCL 48.5% vs. LR-DLBCL 58.6%, p = 0.1) or OS (4-year OS: RER-DLBCL 78.2% vs. LR-DLBCL 74.9%, p = 0.9) On univariate analysis, elevated LDH, RER-DLBCL and failure to achieve CR after R-ICE (i.e. PR or SD/PD) were associated with increased hazards of progression, while age > 70 years, elevated LDH, RER-DLBCL and failure to achieve CR were associated with increased hazards of death (Table 1). On multivariate analysis, however, the effect of early relapse was not statistically significant for risk of progression or death, whereas response to R-ICE retained statistical significance. Conclusions The poor outcomes of RER-DLBCL are the result of a high proportion of patients with chemorefractory disease. However, DLBCL patients who achieve CR after R-ICE salvage can achieve long term disease control, regardless of the time to relapse from initial therapy, in particular if they proceed to ASCT. These results suggest second line chemotherapy, followed by ASCT vs. CAR T for chemosensitive and chemorefractory patients may be a response - adapted approach that can maximize DLBCL patient outcomes, regardless of time to relapse. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

High-dose polychemotherapy with autologous hematopoietic stem cell transplantation in children with non-Hodgkin lymphomas

High-dose polychemotherapy with autologous hematopoietic stem cell transplantation in children with non-Hodgkin lymphomas

50 - Avelumab (A) Plus Utomilumab (U) in Combination with RICE (rituximab, ifosfamide, carboplatin, etoposide) As a Second-Line Therapy for Patients with Relapsed/Refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL) Eligible for Autologous Stem Cell Transplantation (ASCT)

50 - Avelumab (A) Plus Utomilumab (U) in Combination with RICE (rituximab, ifosfamide, carboplatin, etoposide) As a Second-Line Therapy for Patients with Relapsed/Refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL) Eligible for Autologous Stem Cell Transplantation (ASCT)

A Phase I Study of Selinexor and R-ICE in Patients with Relapsed/Refractory Aggressive B-Cell Lymphomas

A Phase I Study of Selinexor and R-ICE in Patients with Relapsed/Refractory Aggressive B-Cell Lymphomas

Phase I/II study of R-ICE (rituximab-ifosfamide-carboplatin-etoposide) with lenalidomide (R2-ICE) in patients with first-relapse/primary refractory diffuse large B-cell lymphoma (DLBCL) in academic and community cancer research united (ACCRU) network.

TPS8073 Background: Response rates to salvage immunochemotherapy in patients with DLBCL relapsing after or refractory (R/R DLBCL) to front line therapy remain unsatisfactory. Lenalidomide (Len) has significant single agent activity in relapsed/refractory DLBCL. The addition of lenalidomide (Len) days 1-7 to rituximab plus ifosfamide-carboplatin-etoposide (RICE) was shown to be feasible with promising efficacy in phase 1b study (Feldman T, et al. BJH, 2014). We developed phase I/II study to evaluate the safety and efficacy of the addition of Len (extended to 14 day schedule) to RICE (R2-ICE) for R/R-DLBCL patients who are candidates for stem cell transplant. Methods: The phase I portion was designed to determine the maximally tolerated dose Len in combination with RICE using the standard cohort 3+3 design. The escalation dose levels were 15 mg and 20 mg daily x 14 days. Prophylactic aspirin and growth factor support is mandatory. After 2 cycles of therapy response is evaluated with a PET/CT scan; the responding patients are eligible for 1-2 additional cycles of R2ICE as a bridging before HDC/SCT. The estimated overall response rate for two cycles of R-ICE in R/R DLBCL to RCHOP was estimated to be approximate 45%. We hypothesize that the addition of lenalidomide in the relapse setting could increase the overall response rate by approximately 20%. The one-stage design with an interim analysis being utilized in phase 2 requires 45 evaluable patients (one sided alpha = 0.09, power 90%). For Phase I, all types of B-cell lymphomas were eligible. For phase II portion only DLBCL patients are eligible per central pathology review. Other eligibility criteria include: received one line of previous anti-lymphoma therapy, ≥ 2 weeks from completion of prior anti-lymphoma therapy, candidate for HDC and SCT, adequate organ (creatinine clearance ≥ 60ml/min by Cockcroft-, total bilirubin ≤ 2 × ULN) and bone marrow function (ANC) ≥1500/mm3; platelet count ≥75,000/mm3). The use of steroids and/or rituximab up to 1 week prior to registration for management of symptoms is allowed. 9 patients cleared phase 1 without DLT and dose of 20 mg days 1 -14 was recommend for phase 2 part (RP2D) of the study. The phase 2 study passed interim futility analysis and accrual continues. Correlatives include cell of origin by Nanostring, Myc/bcl2 expression and by FISH and minimal residual disease. PET scans are centrally reviewed including metabolic tumor volume. Clinical trial information: NCT02628405 .

Utility of Daily Laboratories in Patients with Lymphoma Admitted for Inpatient Chemotherapy

Background: Daily CBC (Complete blood count) and CMP (Complete metabolic profile) have been drawn on our patients with high-grade lymphoma admitted for inpatient chemotherapy with R-EPOCH (Rituximab, Prednisone, Vincristine, Cyclophosphamide, Doxorubicin) which is given over 5 days and R-ICE (Rituximab, Ifosfamide, Carboplatin, Etoposide) which is given over 3 day period. We conducted a retrospective study at our center looking to find if daily laboratory, other than day 1 laboratory, will have an impact on decisions regarding 1) change in chemotherapy dose or schedule 2) requirement of Blood products transfusion 3) cost effectiveness. Methods: We did retrospective review of 101 admissions between 2010-2017. We documented how frequent CBC and CMP were obtained during patient admissions. We documented any change in chemotherapy schedule or dose, or any need for blood product transfusion based on results of laboratory obtained starting day 2 of cycle 2. We excluded day 1 given that its results are required to proceed with chemotherapy. Also we excluded induction cycle 1. We documented cost of laboratory obtained other than day 1. Results: Daily CBC and CMP did not lead to any significant changes in plan of care of chemotherapy regimen and only lead to blood transfusions in 4.1% of patients on R-EPOCH and 6% of patients on R-ICE regimens. The cost associated with daily CBC and CMP was $1725 for R-EPOCH regimen and $1339 for R-ICE regimen. Conclusion: We recommend only day 1 CBC/CMP for patients admitted for R-EPOCH and R-ICE chemotherapy starting cycle 2. Daily CBC/CMP didn't lead to any significant changes on the plan of care and added more cost. Table Disclosures No relevant conflicts of interest to declare.

Interim Circulating Tumor DNA As a Prognostic Biomarker in the Setting of Interim PET-Based Adaptive Therapy for DLBCL

Interim Circulating Tumor DNA As a Prognostic Biomarker in the Setting of Interim PET-Based Adaptive Therapy for DLBCL

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.

A Phase 1 Study of Denintuzumab Mafodotin (SGN-CD19A) in Relapsed/Refactory B-Lineage Non-Hodgkin Lymphoma

BackgroundDenintuzumab mafodotin (SGN-CD19A) is a novel antibody-drug conjugate (ADC) composed of a humanized anti-CD19 monoclonal antibody conjugated to the microtubule-disrupting agent monomethyl auristatin F (MMAF) via a maleimidocaproyl linker. CD19 is a B-cell-specific marker expressed in the vast majority of patients (pts) with B-cell non-Hodgkin lymphoma (NHL).MethodsAn ongoing phase 1, dose-escalation study is investigating the safety, tolerability, pharmacokinetics (PK), and antitumor activity of denintuzumab mafodotin in pts with relapsed or refractory (R/R) B-cell NHL (NCT 01786135). Eligible pts were ≥12 yrs of age and were R/R to ≥1 prior systemic regimens; pts with diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma grade 3 (FL3) also received intensive salvage therapy ± autologous stem cell transplant (ASCT), unless they refused or were ineligible. Denintuzumab mafodotin was administered IV every 3 weeks (q3wk; 0.5-6 mg/kg) for dose escalation and every 6 weeks (q6wk; 3 mg/kg) in a subsequent expansion cohort. A modified continual reassessment method was used for dose allocation and maximum tolerated dose (MTD) estimation in the q3wk dosing schedule. Archived tissue was collected to assess potential biomarkers of response.ResultsTo date, 62 pts have been treated, including 53 pts (85%) with DLBCL (of whom 16 had transformed DLBCL), 5 (8%) with mantle cell lymphoma, and 3 (5%) with FL3. Median age was 65 yrs (range, 28-81). Pts had received a median of 2 prior systemic therapies (range, 1-6); 15 pts (24%) had prior ASCT. Thirty-seven pts (60%) were refractory to the most recent prior therapy. Fifty-two pts were treated in the q3wk schedule (0.5-6 mg/kg), and 10 pts were treated with 3 mg/kg q6wk. Five pts remain on treatment (2 q3wk pts, 3 q6wk pts).Overall, 20 (33%) of 60 efficacy-evaluable pts achieved objective responses, including 13 (22%) with CRs. Eighteen of the 20 objective responses were achieved by the end of Cycle 2 (15 q3wk pts, 3 q6wk pts). TableQ3wk Dosing (N=51)Q6wk Dosing (N=9)RelapsedaN=22RefractorybN=29RelapsedaN=3RefractorybN=6Best clinical response, n (%)Complete remission (CR)7 (32)3 (10)3 (100)-Partial remission (PR)4 (18)3 (10)--Stable disease (SD)6 (27)7 (24)-3 (50)Progression5 (23)16 (55)-3 (50)ORR (CR+PR), % (95% CI)50 (28, 72)21 (8, 40)100 (29, 100)-CR rate, % (95% CI)32 (14,55)10 (2, 27)100 (29, 100)-ORR=objective response rateaBest response of CR/PR with most recent prior therapybBest response of SD/PD with most recent prior therapyMedian duration of objective response in the q3wk schedule was 39 wks for relapsed pts (95% CI: 11.6, - [range, 0.1+ to 73+ wks]) and 41 wks for refractory pts (95% CI: 13.7, 67 [range, 13.7 to 67 wks]); this included 2 pts who maintained their responses for >15 mos. Data for the q6wk schedule are not yet mature.The MTD was not reached at 0.5-6 mg/kg q3wk, and only 1 DLT was observed (G3 keratopathy at 3 mg/kg). Toxicity profiles were similar across both dosing schedules; the most frequently reported adverse events (AEs) were blurry vision (65%), dry eye (52%), fatigue and keratopathy (35% each), constipation (29%), photophobia (27%), and nausea (26%). Ocular symptoms and corneal exam findings consistent with superficial microcystic keratopathy were observed in 52 pts (84%); symptoms were less severe than the associated corneal exam findings. Keratopathy was managed with topical steroids and dose modifications, and improved/resolved within a median of ~5 wks (range, 1-17) in pts for whom there was sufficient follow-up. ADC PK demonstrated a mean terminal half-life of ~2 wks, and accumulation was observed following multiple dose administrations in both schedules.ConclusionsDenintuzumab mafodotin is generally well tolerated and demonstrates encouraging activity with durable responses in heavily pre-treated pts with B-cell NHL. In relapsed pts, 56% achieved objective responses with a CR rate of 40% across both the q3wk and q6wk schedules. The low rate of myelosuppression and neuropathy suggests that denintuzumab mafodotin could be incorporated into novel combination regimens in earlier lines of therapy. A randomized phase 2 trial is being initiated to evaluate RICE (rituximab, ifosfamide, carboplatin, etoposide) ± denintuzumab mafodotin pre-ASCT as second-line treatment for pts with DLBCL. DisclosuresMoskowitz:Seattle Genetics, Inc.: Consultancy, Research Funding; Merck: Research Funding; Genentech: Research Funding. Off Label Use: Denintuzumab mafodotin (SGN-CD19A) is not approved for use.. Fanale:Seattle Genetics, Inc.: Consultancy, Honoraria, Other: Travel expenses, Research Funding. Shah:Janssen: Speakers Bureau; Seattle Genetics: Research Funding; DeBartolo Institute for Personlaized Medicine: Research Funding; Rosetta Genomics: Research Funding; Acetylon Pharmaceuticals, INC: Membership on an entity's Board of Directors or advisory committees; Plexus Communications: Honoraria; Spectrum: Speakers Bureau; Pharmacyclics: Speakers Bureau; Bayer: Honoraria; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SWOG: Consultancy; NCCN: Consultancy. Chen:Genentech: Consultancy, Speakers Bureau; Millennium: Consultancy, Research Funding, Speakers Bureau; Seattle Genetics, Inc.: Consultancy, Other: Travel expenses, Research Funding, Speakers Bureau. Kim:Bayer: Consultancy; Seattle Genetics, Inc.: Consultancy, Research Funding; Eli Lilly: Consultancy. Kostic:Seattle Genetics, Inc.: Employment, Equity Ownership. Liu:Seattle Genetics, Inc.: Employment, Equity Ownership, Other: Travel expenses. Peng:Seattle Genetics, Inc.: Employment, Equity Ownership. Forero-Torres:Seattle Genetics, Inc.: Research Funding.

Abstract 2541: Preclinical results of SGN-CD19A in combination with R-ICE or R-CHOP in non-Hodgkin lymphoma models

Abstract SGN-CD19A is an antibody drug conjugate (ADC) that recognizes CD19, a B-cell specific marker expressed in B-cell malignancies including non-Hodgkin lymphoma (NHL). SGN-CD19A is currently in a phase I clinical trial for adult patients with relapsed refractory B-cell NHL (CT.gov NCT01786135) in which it has shown evidence of single-agent activity (1). This ADC binds CD19, internalizes, and releases cys-mcMMAF, which ultimately induces apoptosis in targeted cells (2). Lymphoma tumor xenografts treated with SGN-CD19A show growth delay in a dose dependent manner. Here we show that SGN-CD19A in combination with standard of care [rituximab/ifosfamide/carboplatin/etoposide (R-ICE), rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone (R-CHOP), or components] exceeds the activity of SGN-CD19A alone and results in impressive anti-tumor activity in multiple xenograft models. It was notable that in some xenograft models, SGN-CD19A + R-CHOP or SGN-CD19A + R-ICE yielded activity that was similar to SGN-CD19A plus rituximab alone. This strong interaction between rituximab and SGN-CD19A was modeled in vitro. SGN-CD19A synergized with rituximab, in the absence of cross-linking, to cause decreased cell viability in NHL cell lines. These data suggest that cell autonomous signaling contributes to the unique interaction between rituximab and SGN-CD19A. Our in vivo and in vitro data support R-CHOP, R-ICE, or rituximab as viable combination therapies for NHL patients with SGN-CD19A. 1) Uma Borate et al. A first-in-human phase 1 study of the antibody-drug conjugate SGN-CD19A in relapsed or refractory B-lineage acute leukemia and highly aggressive lymphoma. Blood 2013 122:1437 2) Che-Leung Law et al. Preclinical characterization of an auristatin-based anti-CD19 drug conjugate, SGN-19A. Abstract number 625. In: Proceedings of the 102th Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Citation Format: Heather A. Van Epps, Kerry Klussman, Martha Anderson, Weiping Zeng, Devra Olson, Maureen Ryan, Tina Albertson, Che-Leung Law. Preclinical results of SGN-CD19A in combination with R-ICE or R-CHOP in non-Hodgkin lymphoma models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2541. doi:10.1158/1538-7445.AM2015-2541

Multifocal Extranodal Involvement of Diffuse Large B-Cell Lymphoma

Endobronchial involvement of extrapulmonary malignant tumors is uncommon and mostly associated with breast, kidney, colon, and rectum carcinomas. A 68-year-old male with a prior diagnosis of colon non-Hodgkin lymphoma (NHL) was admitted to the hospital with a complaint of cough, sputum, and dyspnea. The chest radiograph showed right hilar enlargement and opacity at the right middle zone suggestive of a mass lesion. Computed tomography of thorax revealed a right-sided mass lesion extending to thoracic wall with the destruction of the third and the fourth ribs and a right hilar mass lesion. Fiberoptic bronchoscopy was performed in order to evaluate endobronchial involvement and showed stenosis with mucosal tumor infiltration in right upper lobe bronchus. The pathological examination of bronchoscopic biopsy specimen reported diffuse large B-cell lymphoma and the patient was accepted as the endobronchial recurrence of sigmoid colon NHL. The patient is still under treatment of R-ICE (rituximab-ifosfamide-carboplatin-etoposide) chemotherapy and partial regression of pulmonary lesions was noted after 3 courses of treatment.

R-ICE versus R-ESHAP for salvage therapy in aggressive B-cell non-Hodgkin lymphoma.

e18509 Background: Standard therapy for aggressive Non-Hodgkin’s lymphoma (NHL) consists of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), however the 5 year relapse rate is 20%. Patients with relapsed/refractory (RR) NHL are offered autologous stem cell transplantation (SCT) after salvage chemotherapy demonstrates chemosensitivity and reduces tumor burden. No standard salvage regimen for RR-NHL exists. Frequently used regimens include R-ICE (rituximab, ifosfamide, carboplatin, etoposide) and R-ESHAP (rituximab, etoposide, methylprednisolone, cytarabine, cisplatin). Which regimen provides the greatest efficacy with least toxicity remains unclear. Methods: Patients diagnosed with RR aggressive NHL who received R-ICE or R-ESHAP between 1/1/2000 and 9/30/2011 were identified. Patients may have received either regimen after failure of initial therapy. The primary objective was to determine the overall response rate (ORR) for each regimen. Secondary objectives included determination of overall survival (OS), and proportion of patients able to receive SCT. OS for each regimen was compared using Kaplan-Meier survival curves. Continuous data was compared using the student’s T-test. Results: The median age was 59 years, 27% were female and 90% were described as Caucasian. 78% were diagnosed with diffuse large B cell lymphoma (DLBCL), 13% with transformed follicular lymphoma, 9% with related aggressive NHL subtypes. 55% had a revised International Prognosis Score of 2. Conclusions: No standard of care exists for management of RR-NHL. No regimen has shown superior efficacy or long term outcomes over another. Our trial suggests similar ORR and OS between two commonly used regimens. Although toxicity profiles differ between these regimens, discontinuation rates due to toxicity were similar. The choice of salvage regimen may be determined by ease of administration, toxicity profile and patient/physician preference rather than improved efficacy between R-ICE and R-ESHAP. [Table: see text]

Relapsed Diffuse Large B-Cell Lymphoma: Clinical Utility of Cell of Origin

Relapsed Diffuse Large B-Cell Lymphoma: Clinical Utility of Cell of Origin

A Prospective Phase II Study of RICE Re-Induction, Then High-Dose Fludarabine and Busulfan, Followed by Autologous or Allogeneic Blood Stem Cell Transplantation for Indolent B-Cell Lymphoma. ClinicalTrials.gov ID: NCT00144092

Optimal high dose conditioning and relative roles of autologous stem cell transplantation (autoSCT) or allogeneic (alloSCT) for indolent lymphoma are uncertain. A prospective phase II study evaluated autoSCT and alloSCT depending on availability of sibling donor after uniform rituximab, ifosfamide, carboplatin, etoposide (RICE) re-induction and novel myeloablative fludarabine, busulfan (FluBu) conditioning for patients with mantle cell lymphoma in first remission or first relapse, or indolent lymphoma in first or second relapse. The 68 patients (autoSCT, 36; syngeneic [syn], 1; alloSCT, 31) who were accrued had a 10-month median progression-free survival (PFS) after their last chemotherapy treatment. After RICE, the overall response rate was 69%, and 24 of 39 patients (62%) cleared marrow of lymphoma. Treatment-related mortality at 100 days and 1 year after FluBu were both 0% post-auto/synSCT, but were 6% and 26% post-alloSCT, respectively. At a median follow-up of 60 months, the respective 5-year overall survival and PFS rates were 71% and 46% for auto/synSCT, and were 58% and 47% for alloSCT. Quality of life assessment 1-year post-SCT favoured auto/synSCT. The protocol was feasible, FluBu was well-tolerated, and both auto/synSCT and alloSCT conferred similar 5-year PFS following the RICE-FluBu protocol.

Diffuse large B-cell non-Hodgkin's lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Diffuse large B-cell non-Hodgkin's lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

YM155, a Novel Survivin Suppressant, Improves the Antitumor Effect of Rituximab and Rituximab-Containing Regimens in Diffuse Large B Cell Lymphoma (DLBCL) Xenograft Mouse Models.

Abstract 2718Poster Board II-694 Introduction:Survivin is a member of the inhibitor of apoptosis (IAP) family of proteins, and is highly expressed in many tumor types. Given its preferential expression in tumor cells, and its ability to block apoptosis and regulate cancer cell proliferation, survivin appears to be an attractive novel target for cancer therapy. YM155 is a novel, small molecule survivin suppressant (Nakahara et al., Cancer Research. 2007;67:8014–21). In this study, we evaluated the antitumor activity of YM155 alone and in combination with rituximab, R-ICE (rituximab + ifosfamide + carboplatin + etoposide), or [rituximab + cytarabin + cisplatin] in DLBCL xenograft models. Methods:Antiproliferative effect of YM155 in a panel of human DLBCL cell lines (DB, Pfeiffer, SU-DHL5, SU-DHL8, WSU-DLCL-2, and RL) was evaluated by sulforhodamine B assay. In in vivo studies, WSU-DLCL-2 and DB were subcutaneously implanted into male BALB/c nu/nu mice. When tumors reached a volume of 300 to 600 mm3, YM155 was administered as a 7-day continuous sc infusion, and the other drugs were administered via iv bolus. Dose and schedule of each drug were adjusted to clinical equivalent dose. PET imaging studies were performed using a Inveon PET/CT system (Siemens Medical Solusion). WSU-DLCL-2 xenografted mice were intravenously injected with [18F] FLT, and five-minute static PET scans were accqiured at 1h after injection. For each small-animal PET scan, region of interest was drawn over each tumor and over normal tissue on decay-corrected whole-body sagittal imagies. Results:In in vitro proliferation assays, YM155 showed potent antiproliferative activity against all six DLBCL cell lines, with GI50 values of 0.35 to 3.9 nM. In in vivo studies using WSU-DLCL2 xenograft model, YM155 at 1 and 3 mg/kg induced tumor regression without body weight loss. In combination studies using WSU-DLCL2 xenograft model, YM155 2 mg/kg enhanced antitumor effects of rituximab, R-ICE and [rituximab + cytarabin + cisplatin] without enhancement of the body weight loss. Tumor regression in the combination groups was sustained longer than single treatment groups, and even complete regressions were achievable. Moreover, combination of YM155 1 mg/kg and rituximab induced strong tumor regression in the DB xenograft model, while single-agent treatments did not show significant antitumor effect compared to vehicle control. In [18F]FLT-PET imaging, a significant reduction of FLT uptake in tumor was observed in rituximab combination group, which was more sensitive than the reduction in tumor volume. Conclusions:YM155 improves the antitumor effect of rituximab and rituximab-containing regimens in diffuse large B cell lymphoma (DLBCL) xenograft mouse models. Disclosures:Nakata:Astellas Pharma Inc.: Employment. Nakahara:Astellas Pharma Inc.: Employment. Kita:Astellas Pharma Inc.: Employment. Mitsuoka:Astellas Pharma Inc.: Employment. Yamanaka:Astellas Pharma Inc.: Employment. Kaneko:Astellas Pharma Inc.: Employment. Miyoshi:Astellas Pharma Inc.: Employment. Mori:Astellas Pharma Inc.: Employment. Koutoku:Astellas Pharma Inc.: Employment. Sasamata:Astellas Pharma Inc.: Employment.