Rituximab-containing Chemoimmunotherapy Research Articles

High-Dose Chemotherapy and Autologous Stem Cell Transplantation for Relapsed or Refractory Primary Mediastinal Large B-Cell Lymphoma

Primary mediastinal large B-cell lymphoma (PMBCL) is an uncommon, aggressive type of non-Hodgkin lymphoma. Rituximab-containing chemoimmunotherapy with or without radiation therapy (RT) is standard first-line treatment. Relapsed or refractory (R/R) disease has long been treated with salvage chemotherapy followed by high-dose chemotherapy (HDC), with autologous stem cell transplantation (ASCT) in appropriate patients. We retrospectively analyzed all patients with R/R PMBCL treated with HDC/ASCT at our center between January 2000 and August 2022. The 60 study patients received either rituximab-BEAM (n=37) or rituximab-gemcitabine/busulfan/melphalan (R-GemBuMel) with or without vorinostat (n=23), followed by ASCT. Forty-six patients received mediastinal RT, either as prior consolidation of frontline therapy or following ASCT. At median follow-up of 6 years (range, .3 to 21 years), the 5-year progression-free survival (PFS) and overall survival (OS) rates of the whole group were 58% and 77%, respectively, for the entire cohort, 51% and 65% for the R-BEAM recipients, and 69% and 82% for R-vorinostat/GemBuMel recipients. Multivariable analyses showed that a negative positron emission tomography scan at ASCT (hazard ratio [HR], .28) and involvement of only 1 organ (HR, .33) were independently associated with improved PFS. In addition, receipt of R-vorinostat/GemBuMel (HR, .23) was an independent favorable predictor of OS. Our data indicate that HDC/ASCT is effective in R/R PMBCL, with improved outcomes in patients receiving R-vorinostat/GemBuMel.

Rituximab Treatment of Primary Cutaneous Follicle Center Lymphoma: A Retrospective Review.

Primary cutaneous B-cell lymphoma (PCBCL) presents only in the skin at the time of diagnosis with no evidence of extracutaneous disease, and primary cutaneous follicle center lymphoma (PCFCL) is the most common subtype. There is currently a lack of prospective randomized control trials and large retrospective studies investigating the efficacy of different treatment options for PCFCL. This retrospective study was conducted to describe our local clinical experience and outcomes of patients treated with rituximab-containing regimens. To describe our local clinical experience and treatment outcomes of patients treated with rituximab-containing regimens. A retrospective study consisting of 25 PCFCL patients treated with different modalities. Patient records were reviewed and analyzed using a Kaplan-Meier estimation and SAS 9.4 software. After the initial treatment, all patients had CR except for 1 patient in the observation group. Further, 60% of patients in surgery, 20% in chemoimmunotherapy, 67% in rituximab monotherapy, 33% in steroid injection/systemic prednisone, and 33% in observation experienced a relapse. Although no significant difference was found between treatment groups due to the small sample size, time to relapse trends provides insight into treatment responses. Chemoimmunotherapy had the lowest relapse rate in the first 5 years post-treatment, whereas surgery had a higher tendency to relapse. Despite the potential for rituximab-containing chemoimmunotherapy to yield adverse effects, it is effective in achieving a prolonged clinical remission in patients with PCFCL. It remains a reasonable treatment option for diffuse, extensive, or treatment-resistant disease.

Hepatitis B surface antigen positivity is associated with progression of disease within 24months in follicular lymphoma.

Studies have reported a positive association between hepatitis B surface antigen (HBsAg)-positive hepatitis B virus (HBV) infection and follicular lymphoma (FL). Nevertheless, clinical information concerning chronic HBV infection in FL is sparse. This retrospective cohort study investigated the prognostic impact of HBsAg in immunocompetent patients with FL treated with frontline rituximab-containing chemoimmunotherapy in an HBV-endemic area between 2006 and 2016. Among the 149 analyzed patients, 32 (21.5%) were HBsAg-positive. HBsAg positivity was positively associated with symptomatic splenomegaly, significant serous effusions, and peritreatment hepatic dysfunction. HBsAg-positive patients had a trend of lower complete remission rate (59.4% vs. 76.9%, P = 0.07), significantly poorer overall survival (hazard ratio for death, 2.68; 95% confidence interval, 1.21-5.92), and shorter progression-free survival than had HBsAg-negative patients. Multivariate analysis revealed that HBsAg is an independent adverse prognostic factor for overall survival. Intriguingly, HBsAg-positive patients had a higher incidence of progression of disease within 24months (POD24) than had HBsAg-negative patients (cumulative incidence rate, 25.8% vs. 12.4%, P = 0.045). This study revealed that patients with FL and chronic HBV infection represent a distinct subgroup with a markedly poor prognosis. HBsAg was positively associated with POD24 and might serve as a new prognostic predictor of the survival of FL patients in endemic regions for HBV infection.

Efficacy of Ibrutinib-Rituximab versus Real-World (RW) Treatments for Patients with Waldenström's Macroglobulinemia (WM): Adjusted Comparison of iNNOVATE and the Lyon-Sud RW Database

IntroductionIbrutinib, a first-in-class, oral, covalent inhibitor of Bruton's tyrosine kinase, is approved in several countries as monotherapy for adults with WM, based on the high response rate (90.5%) observed in a phase 2, single-arm trial of symptomatic patients who had received ≥ 1 prior therapy (NCT01614821; Treon SP, et al. N Engl J Med. 2015;372:1430-1440). In the phase 3 iNNOVATE trial (NCT02165397; Dimopoulos MA, et al. N Engl J Med. 2018;378:2399-2410), adding rituximab to ibrutinib (IR) led to a statistically significant improvement in progression-free survival (PFS) compared with placebo-rituximab, in both treatment-naïve (TN) patients and those with disease recurrence. This analysis examined the relative treatment effect of IR versus other RW treatment regimens used in daily clinical practice in TN and relapsed/refractory (R/R) WM. An adjusted comparison was conducted using patient-level data from the iNNOVATE trial and the Lyon-Sud RW database in France.MethodsThe Lyon-Sud database holds medical records for patients with WM diagnosed between 1980 and 2017 from the Centre Hospitalier Lyon-Sud. PFS and overall survival (OS) outcomes were compared between the IR arm of iNNOVATE and RW physicians' choice (PC) treatment in Lyon-Sud (excluding RW ibrutinib). Kaplan-Meier survival curves by patient cohort were generated for both end points. A multivariate Cox proportional hazards model was fitted on the pooled patient-level data from both sources to estimate adjusted hazard ratios (HRs) for effect of IR on PFS and OS versus RW treatment, with age, sex, and treatment line as covariates. The unit of observation for the RW databases was the treatment line (rather than the patient) number, whereby RW patients receiving multiple treatment lines contributed to multiple observations, and baseline was defined as the line-specific treatment start date.ResultsOverall, 242 treatment lines from patients with WM were identified from the Lyon-Sud database; 224 were analyzed. Baseline characteristics were comparable between the IR arm of iNNOVATE (n = 75) and the RW cohort: 62.7% versus 66.5% ≥ 65 years of age; line of therapy, 45.3% versus 48.7% TN [1L], 25.3% versus 25.0% second-line [2L], and 29.3% versus 26.3% third-line or later [3L+]. Median follow-up was 26.7 months for iNNOVATE and 68.5 months for the RW cohort.Non-ibrutinib PC regimens in the RW cohort included rituximab (n = 51 treatment lines), chemotherapy (n = 66; including chlorambucil, n = 31), rituximab-cyclophosphamide-dexamethasone (n = 35), rituximab-CHOP/CHOP-like (n = 21), rituximab-chlorambucil (n = 15), fludarabine-cyclophosphamide-rituximab (n = 14), bendamustine-rituximab (n = 10), other rituximab-containing chemoimmunotherapy (n = 10), and rituximab-targeted agent (n = 2). Two ibrutinib lines were excluded from the RW cohort analysis.Figures A and B show the observed 1L+ Kaplan-Meier curves for IR versus RW PC therapy for all analyzed patients with WM (unadjusted HRs: 0.32 [95% confidence interval (CI), 0.19-0.55] for PFS and 0.38 [95% CI, 0.13-1.09] for OS). After adjusting for differences in patient characteristics, HRs (1L+ therapy) became 0.28 (95% CI, 0.16-0.48; p < 0.001) for PFS and 0.29 (95% CI, 0.09-0.93; p = 0.037) for OS. Restricting the analysis to 1L treatment only (Lyon-Sud n = 109; iNNOVATE n = 34), the adjusted HRs were 0.25 (95% CI, 0.09-0.70; p < 0.009) for PFS and 0.20 (95% CI, 0.02-2.00; p = 0.170) for OS; respective unadjusted HRs were 0.31 (95% CI, 0.12-0.78) and 0.30 (95% CI, 0.04-2.34). In the 2L+ setting (Lyon-Sud n = 115; iNNOVATE n = 41), the adjusted HRs were 0.28 (95% CI, 0.15-0.56; p < 0.001) for PFS and 0.34 (95% CI, 0.08-1.35; p = 0.126) for OS; respective unadjusted HRs were 0.31 (95% CI, 0.16-0.61) and 0.39 (95% CI, 0.12-1.31).ConclusionsIn the absence of randomized controlled trial data for ibrutinib versus other treatment regimens for WM, these adjusted comparisons of clinical trial and RW patient-level data suggest that IR significantly improves both PFS and OS versus RW PC regimens as 1L+ therapy. These results help inform physicians on the standard of care for WM in clinical practice.Funding Source:This project was sponsored by Janssen Pharmaceutica NV, and Pharmacyclics LLC, an AbbVie Company. The real-world databases are independently owned. Writing assistance was provided by Emma Fulkes of PAREXEL and funded by Janssen Pharmaceutica NV. [Display omitted] DisclosuresKarlin:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support. Besson:Janssen Pharmaceutica NV: Employment. Tapprich:Janssen Pharmaceutica NV: Employment. Garside:Janssen Pharmaceutica NV: Employment. Salles:Roche: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; AbbVie: Honoraria; Acerta: Honoraria; Amgen: Honoraria; Novartis: Consultancy, Honoraria; Merck: Honoraria; Pfizer: Honoraria; Takeda: Honoraria; Servier: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Epizyme: Honoraria; Morphosys: Honoraria.

Rituximab maintenance therapy of follicular lymphoma in clinical practice.

Standard of care for patients with symptomatic, advanced‐stage follicular lymphoma (FL) is rituximab‐containing chemoimmunotherapy followed by rituximab maintenance. This prospective, multicenter, noninterventional study analyzed how efficacy and safety data from randomized controlled trials translate into clinical practice in Germany. Both treatment‐naïve and relapsed/refractory patients with FL, who responded to rituximab‐containing induction and were scheduled for rituximab maintenance, were observed for 24 months. Effectiveness was measured by response and Kaplan‐Meier survival analysis. In addition, treatment patterns of induction and maintenance, as well as adverse events, were documented. The evaluable study population consisted of 310 first‐line patients and 173 relapsed/refractory patients, including 116 patients with initial Ann‐Arbor stage I/II and 20 patients with FL grade 3B. Regarding first‐line induction, a shift from R‐CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) to R‐bendamustine was observed over time, as well as a decline in radiotherapy. 2‐year progression‐free survival rates were 88.3% (95% confidence interval [CI] 84.0‐92.6) for first‐line patients and 76.0% (95% CI: 68.8‐83.3) for relapsed/refractory patients. Conversion from partial to complete remission (PR, CR) occurred in 53.4% of analyzed first‐line patients with PR, resulting in 69.4% CRs at study end (relapsed/refractory: conversion in 42.9%, final CRs 57.9%). Safety results were consistent with the known safety profile of rituximab in this setting. Both treatment‐naïve and relapsed/refractory patients with FL show favorable 2‐year PFS rates and improvements in the remission status with postinduction rituximab monotherapy as maintenance and consolidation therapy.

Rituximab in combination with chemotherapy for the treatment of chronic lymphocytic leukaemia in clinical practice.

This study was conducted to investigate the real-world effectiveness and tolerability of rituximab-containing chemoimmunotherapies, which have become the standard of care for chronic lymphocytic leukaemia (CLL), particularly for physically fit patients. Furthermore, current treatment patterns in clinical practice were documented, and an unselected real-life population was compared with older, comorbid patients. Prospective, multicentre, observational study with rituximab-containing chemoimmunotherapy in CLL patients. Of 681 patients in total, 485 were enroled in cohort 1 (unselected) and 196 in cohort 2 (comorbid "slow-go" patients). The median patient age was higher than in most randomised controlled trials (cohort 1: 70years and cohort 2: 75years). The most common treatment regimen in both first-line and relapsed patients was rituximab-bendamustine. Two-year progression-free survival rate for first-line therapy was 84.1% for cohort 1 and 69.8% for cohort 2 (with best overall response rate 81.8% for cohort 1 and 76.6% for cohort 2). General and B-symptoms declined during treatment and remained at low level or decreased further until study end. The safety profile observed in randomised clinical trials was confirmed. Chemoimmunotherapy with rituximab is feasible and safe in a wide variety of clinical settings in CLL, including the treatment of older patients with comorbidities (ClinicalTrials.gov NCT01178086).

Clinical outcomes in patients with diffuse large B cell lymphoma with a partial response to first-line R-CHOP chemotherapy: prognostic value of secondary International Prognostic Index scores and Deauville scores.

After introducing a rituximab-containing chemoimmunotherapy (R-CHOP) for diffuse large B cell lymphoma (DLBCL), a partial response (PR) which is regarded as treatment failure is still observed. To investigate the prognostic factors for the DLBCL patients with a PR to R-CHOP, we retrospectively evaluated 758 newly diagnosed DLBCL patients. After R-CHOP, 88 (11.6%) achieved a PR. Three-year progression-free and overall survival rates measured from the date of PR achievement (PFS2 and OS2) were 57.4 and 67.8%, respectively. The secondary International Prognostic Index (IPI2) scores after R-CHOP were low (0-1) in 68.2% and high (2-3) in 31.8% of the patients. The Deauville scores from 18-fluorodeoxyglucose positron emission tomography after R-CHOP showed low (2-3) in 58.0% and high (4) in 42.0% of the patients. High IPI2 and high Deauville scores were associated with worse PFS2 (P<0.001 and P=0.009) and OS2 (P=0.013 and P=0.067). The high-risk group defined by the IPI2 and Deauville scores, whose scores were both high, showed significantly lower 3-year PFS2 (P<0.001) and OS2 (P=0.006) rates compared with those of the other groups. In multivariate analyses, the IPI score of ≥ 3 at diagnosis and bone marrow involvement at diagnosis were independent prognostic factors. In addition, high IPI2-Deauville score after R-CHOP was significantly associated with poor PFS2 (P=0.009) and demonstrated a trend toward inferior OS2. In conclusion, DLBCL patients who partially responded to R-CHOP are still a heterogeneous group, for which IPI2 and Deauville scores should be evaluated for prediction of prognosis.

Clinical Outcomes in Patients with Diffuse Large B Cell Lymphoma with Partial Responses to First-Line R-CHOP Chemotherapy: Prognostic Value of Secondary IPI Scores and FDG-PET

Background: Rituximab-containing chemoimmunotherapy (R-CHOP) is a standard treatment for patients with diffuse large B cell lymphoma (DLBCL), with a high response rate. Achievement of only a partial response (PR) was regarded as treatment failure, but data on their prognosis are limited to date. Distinguishing PR from CR is not always clear because of controversies in interpreting 18-fluorodeoxyglucose positron emission tomography (FDG-PET) in rituximab-era. Recent advances have prompted a revision in the response criteria, as recently suggested at the 12th International Conference of Malignant Lymphomas (ICML), emphasizing the prognostic significance of FDG-PET results interpreted using the five-point Deauville score. Based on such changes, the prognosis of PR patients should be re-evaluated.Patients and Methods: We conducted a retrospective multicenter study on behalf of the Consortium for Improving Survival of Lymphoma (CISL), to investigate survival outcomes and to define prognostic factors for PR patients after first-line treatment. A total of 758 patients with histologically proven DLBCL, who received the R-CHOP regimen between January 2005 and December 2013, were assessed. Among them, patients who achieved a PR defined by both computed tomography (CT) and FDG-PET at the end of R-CHOP were included in further analysis. Clinical information at diagnosis and after treatment was collected to determine the prognostic factors affecting the clinical outcome of PR patients. FDG-PET scans were reviewed by physicians and nuclear medicine experts in each institution and interpreted using the Deauville five-point scale. The prognostic role of secondary International Prognostic Index after R-CHOP (IPI2), assessed by restaging, age, performance status, residual multiple extranodal involvements and lactate dehydrogenase (LDH) levels, was evaluated. Progression-free survival (PFS2) and overall survival (OS2), measured from the date of the response assessment after R-CHOP to further progression or death, were determined by Kaplan-Meier methods with log-rank test. We also performed t-tests, χ2 tests, and Cox proportional hazard analysis. Statistical significance was accepted when two-sided p values were <0.05.Results: In total, 88 (11.6%) patients partially responded to R-CHOP with a median age of 53.5 years were searched. Over a median follow-up of 47.8 months, 3-year PFS2 and OS2 rates were 58.8% and 69.4%, respectively. The IPI2 scores were 0-1 (low) in 68.2% and ≥2 (high) in 31.8% of patients. The Deauville scores after R-CHOP were 2-3 (low) in 57.9% and 4 (high) in 42.0% of patients. High (≥2) and low (0-1) IPI2 groups represented 28% and 72% of 3-year PFS2 rates (p <0.001). Patients with Deauville score 4 were also associated with worse 3-year PFS2 rates than those with a lower score (2-3) (40.4% vs. 71.1%, p=0.009). For OS2, IPI2 (47.6% vs. 77.7%, p=0.013) and Deauville score (57.5% vs. 75.3%, p=0.067) were prognostic, although the effect of the Deauville score was not statistically significant. A high-risk group, defined by the IPI2-Deauville index (Table 1), showed significantly lower 3-year rates of PFS2 (17.1% vs. 69.3%, p<0.001) and OS2 (43.4% vs. 75.1%, p=0.006) compared with other groups (Figure 1). In a multivariate analysis, the IPI2-Deauville index was an independent prognostic factor for disease progression (HR 1.76, 95% CI 1.15-2.69, p=0.009), adjusted with initial IPI score and bone marrow involvement at diagnosis. For OS2, the index did not remain significant in a multivariate analysis.Conclusion: Our data shows that patients with DLBCL who achieved a PR to R-CHOP is still a heterogeneous group, and IPI2 and Deauville scores can be useful prognostic factors in addition to initial IPI at diagnosis. Validation through future prospective study would be valuable. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Maintenance therapy in CLL: resolving the controversy

The standard of care for chronic lymphocytic leukaemia is fast changing. For younger patients, frontline chemoimmunotherapy with regimens such as fludarabine, cyclophosphamide, and rituximab 1 Thompson PA Tam CS O'Brien SM et al. Fludarabine, cyclophosphamide, and rituximab treatment achieves long-term disease-free survival in IGHV-mutated chronic lymphocytic leukemia. Blood. 2016; 127: 303-309 Crossref PubMed Scopus (381) Google Scholar , 2 Hallek M Fischer K Fingerle-Rowson G et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet. 2010; 376: 1164-1174 Summary Full Text Full Text PDF PubMed Scopus (1545) Google Scholar are still appropriate standard-of-care, whereas kinase inhibitors such as ibrutinib are commonly used in older patients, and in those with relapsed disease. 3 Byrd JC Furman RR Coutre SE et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013; 369: 32-42 Crossref PubMed Scopus (1742) Google Scholar Attempts to intensify the regimen of fludarabine, cyclophosphamide, and rituximab with addition of drugs such as mitoxantrone 4 Faderl S Wierda W O'Brien S Ferrajoli A Lerner S Keating MJ Fludarabine, cyclophosphamide, mitoxantrone plus rituximab (FCM-R) in frontline CLL <70 years. Leuk Res. 2010; 34: 284-288 Summary Full Text Full Text PDF PubMed Scopus (39) Google Scholar resulted in additional toxicity and no improvement in therapeutic efficacy. Thus, current efforts are directed towards the use of less toxic drugs such as monoclonal antibodies and lenalidomide as post-induction therapy, commonly referred to as maintenance therapy. Rituximab maintenance versus observation alone in patients with chronic lymphocytic leukaemia who respond to first-line or second-line rituximab-containing chemoimmunotherapy: final results of the AGMT CLL-8a Mabtenance randomised trialRituximab maintenance therapy prolongs progression-free survival in patients achieving at least a PR to induction with rituximab plus chemotherapy, and the treatment is well tolerated overall. Although it is associated with an increase in infections, there is no excess in infection mortality, suggesting that remission maintenance with rituximab is an effective and safe option in the management of chronic lymphocytic leukaemia in early treatment phases. Full-Text PDF

Rituximab maintenance versus observation alone in patients with chronic lymphocytic leukaemia who respond to first-line or second-line rituximab-containing chemoimmunotherapy: final results of the AGMT CLL-8a Mabtenance randomised trial

In many patients with chronic lymphocytic leukaemia requiring treatment, induction therapy with rituximab plus chemotherapy improves outcomes compared with chemotherapy alone. In this study we aimed to investigate the potential of rituximab maintenance therapy to prolong disease control in patients who respond to rituximab-containing induction regimens. In this randomised, international, multicentre, open-label, phase 3 clinical trial, we enrolled patients who had achieved a complete response (CR), CR with incomplete bone marrow recovery (CRi), or partial response (PR) to first-line or second-line rituximab-containing chemoimmunotherapy and randomly assigned them in a 1:1 ratio (central block randomisation in the electronic case report form system) to either intravenous rituximab 375 mg/m(2) every 3 months, or observation alone, for 2 years. Stratification was by country, line of treatment, type of chemotherapy added to the rituximab backbone, and degree of remission following induction. The primary endpoint was progression-free survival. Efficacy analysis was done in the intention-to-treat population. This is the final, event-triggered analysis. Final analysis was triggered by the occurrence of 92 events. This trial is registered with ClinicalTrials.gov, number NCT01118234. Between April 1, 2010, and Dec 23, 2013, 134 patients were randomised to rituximab and 129 to observation alone. Median observation times were 33·4 months (IQR 25·7-42·8) for the rituximab group and 34·0 months (25·4-41·9) for the observation group. Progression-free survival was significantly longer in the rituximab maintenance group (47·0 months, IQR 28·5-incalculable) than with observation alone (35·5 months, 95% CI 25·7-46·3; hazard ratio [HR] 0·50, 95% CI 0·33-0·75, p=0·00077). The incidence of grade 3-4 haematological toxicities other than neutropenia was similar in the two treatment groups. Grade 3-4 neutropenia occurred in 28 (21%) patients in the rituximab group and 14 (11%) patients in the observation group. Apart from neutropenia, the most common grade 3-4 adverse events were upper (five vs one [1%] patient in the observation group) and lower (three [2%] vs one [1%]) respiratory tract infection, pneumonia (nine [7%] vs two [2%]), thrombopenia (four [3%] vs four [3%]), neoplasms (five [4%] vs four [3%]), and eye disorders (four [3%] vs two [2%]). The overall incidence of infections of all grades was higher among rituximab recipients (88 [66%] vs 65 [50%]). Rituximab maintenance therapy prolongs progression-free survival in patients achieving at least a PR to induction with rituximab plus chemotherapy, and the treatment is well tolerated overall. Although it is associated with an increase in infections, there is no excess in infection mortality, suggesting that remission maintenance with rituximab is an effective and safe option in the management of chronic lymphocytic leukaemia in early treatment phases. Arbeitsgemeinschaft Medikamentöse Tumortherapie gemeinnützige GmbH (AGMT), Roche.

A new prognostic score for AIDS-related lymphomas in the rituximab-era.

While the International Prognostic Index is commonly used to predict outcomes in immunocompetent patients with aggressive B-cell non-Hodgkin lymphomas, HIV-infection is an important competing risk for death in patients with AIDS-related lymphomas. We investigated whether a newly created prognostic score (AIDS-related lymphoma International Prognostic Index) could better assess risk of death in patients with AIDS-related lymphomas. We randomly divided a dataset of 487 patients newly diagnosed with AIDS-related lymphomas and treated with rituximab-containing chemoimmunotherapy into a training (n=244) and validation (n=243) set. We examined the association of HIV-related and other known risk factors with overall survival in both sets independently. We defined a new score (AIDS-related lymphoma International Prognostic Index) by assigning weights to each significant predictor [age-adjusted International Prognostic Index, extranodal sites, HIV-score (composed of CD4 count, viral load, and prior history of AIDS)] with three risk categories similar to the age-adjusted International Prognostic Index (low, intermediate and high risk). We compared the prognostic value for overall survival between AIDS-related lymphoma International Prognostic Index and age-adjusted International Prognostic Index in the validation set and found that the AIDS-related lymphoma International Prognostic Index performed significantly better in predicting risk of death than the age-adjusted International Prognostic Index (P=0.004) and better discriminated risk of death between each risk category (P=0.015 vs. P=0.13). Twenty-eight percent of patients were defined as low risk by the ARL-IPI and had an estimated 5-year overall survival (OS) of 78% (52% intermediate risk, 5-year OS 60%; 20% high risk, 5-year OS 50%).

Early Failure of Frontline Rituximab-Containing Chemo-immunotherapy in Diffuse Large B Cell Lymphoma Does Not Predict Futility of Autologous Hematopoietic Cell Transplantation

The poor prognosis for patients with diffuse large B cell lymphoma (DLBCL) who relapse within 1 year of initial diagnosis after first-line rituximab-based chemo-immunotherapy has created controversy about the role of autologous transplantation (HCT) in this setting. We compared autologous HCT outcomes for chemosensitive DLBCL patients between 2000 and 2011 in 2 cohorts based on time to relapse from diagnosis. The early rituximab failure (ERF) cohort consisted of patients with primary refractory disease or those with first relapse within 1 year of initial diagnosis. The ERF cohort was compared with those relapsing >1 year after initial diagnosis (late rituximab failure [LRF] cohort). ERF and LRF cohorts included 300 and 216 patients, respectively. Nonrelapse mortality (NRM), progression/relapse, progression-free survival (PFS), and overall survival (OS) of ERF versus LRF cohorts at 3 years were 9% (95% confidence interval [CI], 6% to 13%) versus 9% (95% CI, 5% to 13%), 47% (95% CI, 41% to 52%) versus 39% (95% CI, 33% to 46%), 44% (95% CI, 38% to 50%) versus 52% (95% CI, 45% to 59%), and 50% (95% CI, 44% to 56%) versus 67% (95% CI, 60% to 74%), respectively. On multivariate analysis, ERF was not associated with higher NRM (relative risk [RR], 1.31; P = .34). The ERF cohort had a higher risk of treatment failure (progression/relapse or death) (RR, 2.08; P < .001) and overall mortality (RR, 3.75; P < .001) within the first 9 months after autologous HCT. Beyond this period, PFS and OS were not significantly different between the ERF and LRF cohorts. Autologous HCT provides durable disease control to a sizeable subset of DLBCL despite ERF (3-year PFS, 44%) and remains the standard-of-care in chemosensitive DLBCL regardless of the timing of disease relapse.

Comparative outcomes of splenectomy and rituximab-based chemotherapy in elderly patients with splenic marginal zone lymphoma.

8549 Background: Despite advances in diagnosis and therapy, over 50% of patients with splenic marginal zone lymphoma (SMZL) undergo splenectomy. The objective of this retrospective study was to compare outcomes in SMZL patients undergoing surgery or rituximab-containing chemoimmunotherapy (RCIT) based on the Surveillance, Epidemiology, and End Results-Medicare linked database. Methods: Records of 521 SMZL patients diagnosed between 2000 and 2007 were extracted, excluding cases with incomplete Medicare coverage. Two treatment arms were defined by receipt of RCIT or splenectomy within 2 years of diagnosis. Factors confounding treatment selection or prognosis were balanced in both arms using a propensity score. The primary endpoint was lymphoma-related death, estimated using competing risk models, with overall survival (OS) and toxicities as secondary endpoints. Results: Of the 341 eligible patients (median age, 77 years), 67 (20%) were untreated, while 169 (50%) underwent splenectomy and 97 (28%) chemotherapy (64% single-agent rituximab) at median 1.4 months from diagnosis. Stage IE, treatment in a teaching hospital and good performance status were associated with a preference for splenectomy. There was no evidence of significantly different risk of lymphoma-related death after treatment with RCIT rather than surgery (hazard ratio, HR, 1.10, 95%CI 0.56-2.18, P=0.78). There was an excess of early mortality after splenectomy (7% within 90 days) but more later events with RCIT (OS at 3 years 69% vs. 67%, respectively). More patients required chemotherapy after surgery (38%) than vice versa (14%, P&lt;0.001). Nursing home admissions were more common after splenectomy (22%, P=0.03). There were more inpatient hospitalizations after multidrug RCIT (P=0.003), but not after rituximab alone (P=0.65). Conclusions: Although SMZL is considered indolent, most elderly patients required treatment soon after diagnosis in this population-based study. Survival outcomes were similar after either RCIT or splenectomy. Complications of surgery or combination chemotherapy are significant, suggesting rituximab alone as a more suitable option in elderly patients.

ARL-IPI - A New Prognostic Score for AIDS-Related Lymphomas in the Rituximab Era

Abstract 1564 INTRODUCTION:The International Prognostic Index (IPI) and the age-adjusted IPI (aaIPI) are commonly used to predict outcomes in immunocompetent patients with aggressive B-cell Non-Hodgkin Lymphomas (NHL). Although the IPI has also been validated for AIDS-related lymphomas (ARL), HIV-infection is an important competing risk that has not been adequately evaluated as a factor contributing to prognosis in the context of contemporary rituximab-containing chemoimmunotherapy. Here, we assessed whether HIV-specific factors in addition to the IPI provided more accurate prediction of clinical outcomes than IPI alone. METHODS:We obtained patient-level data for 487 patients from 8 prospective phase 2 or 3 clinical trials including patients with HIV-associated aggressive B-cell NHL receiving initial therapy with rituximab containing chemoimmunotherapy identified by systematic literature review, and randomly divided the population in a training (N=244) and validation set (N=243). We defined an HIV-score by combining individual HIV risk-factors: (1) baseline CD4 count (cells/ul): <50 =3, 50–199=2, 200–499=1, 500 or more =0; (2) HIV viral load (copies/ml): <400=0; 400-9, 999=1,10,000 or more =2; (3) prior history of AIDS=1, thereby yielding an HIV-score that could range from 0–6. We examined the association of HIV-score in addition to patient-, and lymphoma-specific factors with overall survival (OS) using a Cox-PH-model in the training and validation set independently by comparing 4 different multivariate models by a LR-chi2 test: model 1 (included age, sex, & histology), model 2 (model 1 + aaIPI), model 3 (model 2 + number of involved extranodal disease sites [ENS]) and model 4 (model 3 + HIV-score). Next, we defined a new score (ARL-IPI) by assigning appropriate weights to each significant predictor depending on the strength of association in the multivariate model in the training set: 2 for aaIPI score (0,1,2 or 3); 1 for ENS: no ENS=0, 1 ENS=1, 2 ENS=2, 3 or more ENS=3; and 1 for HIV-score. We examined the difference in OS for 3 risk groups: low (LR), intermediate (IR) and high risk (HR) based on the ARL-IPI in the validation set. We compared the discrimination power of the ARL-IPI with the aaIPI by comparing the difference in OS across the 3 groups defined by each score. RESULTS:487 patients were included in the analysis with a median follow-up of 2.3 years (0.1–12.1). There were no significant differences in patient characteristics between training and validation set. Considering the entire population, 77% were male, median age was 42 years (20–74), median CD4 count 174 cells/ul (0–2,457), and median HIV viral load 23,802 copies/ml (0–6×106). The histologies included DLBCL (69%), BL or BLL (29%), and other histologies (3%). All patients received rituximab plus either CHOP (49%), EPOCH (19%), CDE (15%), or other multi-agent intensive regimens (16%). In the training set, only aaIPI, ENS and HIV-score were significantly associated with OS, but not age, sex, extranodal sites as defined in the IPI (<2 or 2 or more), or histology. When tested in the validation set, the addition of the HIV-score (model 4; ARL-IPI) showed a significant improvement in predictive power for OS over all other models (p-value=0.009). When we compared the risk groups defined by the aaIPI (LR: <1, IR: 1–2, HR: 3) versus the ARL-IPI (aaIPI + ENS + HIV-score: LR: <7, IR: 7–10, HR: >10) in the validation set, the ARL-IPI was able to more clearly define prognosis based on the 3 risk groups in regards to OS (p=0.013; Table 1), which was confirmed by KM survival analysis (Figure 1). The ARL-IPI also compared favorably to a score defined by aaIPI and ENS (LR: <4, IR: 4–6, HR: >6), demonstrating the significant impact of the HIV-score on prediction power. In our dataset, the ARL-IPI could not significantly improve prediction power for CR rate or PFS compared with the two other scores. CONCLUSION:By combining HIV-associated factors with known prognostic patient- and lymphoma factors into a composite prognostic risk score (ARL-IPI) we were able to more accurately define prognosis for patients with ARL treated with chemoimmunotherapy. [Display omitted] Table 1.Median OS as per risk group adjusted for age, sex & histology in the validation set.Risk Group2-year OS % (95%CI)aaIPIaaIPI+ENSARL-IPILow0.83 (0.61–0.93)0.75 (0.58–0.85)0.87 (0.57–0.97)Intermediate0.64 (0.55–0.71)0.63 (0.51–0.74)0.60 (0.40–0.75)High0.60 (0.43–0.74)0.55 (0.37–0.70)0.50 (0.23–0.72) Disclosures:No relevant conflicts of interest to declare.

Considerations with Newer Regimens for Indolent Non–Hodgkin Lymphoma

Follicular lymphoma (FL) is considered incurable with current therapies and shows a pattern of multiple remissions and repeated relapses. After demonstrations of significant improvements in clinical outcomes with the addition of rituximab to chemotherapy regimens including alkylating agents and anthracyclines, rituximab-containing chemoimmunotherapy strategies have become central to the management of FL. More recently, novel cytotoxic agents such as bendamustine and pixantrone, that circumvent some of the limitations of conventional chemotherapeutic agents, have been developed and are being clinically investigated. These novel agents are showing promising clinical activity alone and in combination with rituximab in indolent lymphomas. In order to further improve the therapeutic index for patients with FL, rituximab is being combined with novel biologic agents such as immunomodulatory cytokines and monoclonal antibodies targeting CD80 and CD22. This article provides a review of newer chemoimmunotherapy strategies in the management of patients with FL.