Age-adjusted International Prognostic Index Score Research Articles

R-CHOEP14 in younger high-risk patients with large B cell lymphoma: an effective front-line regimen with cardiac toxicity: a real-life, single-center experience.

Currently, there is no consensus regarding optimal front-line treatment for younger high-risk patients with large B cell lymphoma. American recommendations list only R-CHOP as standard, while European also include R-ACVBP and R-CHOEP14. We have been routinely using the latter regimen at our institution since 2011 and performed this retrospective real-life single-center study to analyze outcomes. Between September 2011 and April 2019, 66 newly diagnosed patients aged 18 to 60 years with B-large cell lymphoma and high-risk age-adjusted International Prognostic Index score were scheduled to receive 6 or 8 cycles of bi-weekly chemoimmunotherapy with cyclophosphamide, doxorubicin, vincristine, etoposide, steroids, and rituximab (R-CHOEP14). After a median follow-up of 4.7 years, the estimated 3-year progression-free survival was 87% (95% CI 80-96%) and 3-year overall survival 90% (95% CI 83-98%). Grade ≥ 3 hematological side effects occurred in 83% and infectious in 41% of patients; one patient died of toxicity. Grade ≥ 2 cardiac toxicity occurred in 21% of patients, more frequently than previously reported. The cumulative 5-year risk of congestive heart failure with all-cause mortality as the competing risk was 17%. R-CHOEP14 is a very effective and manageable regimen for younger high-risk patients with B-large cell lymphoma, but the risk of cardiotoxicity warrants further investigations.

Real-World Gaps in Chart Documentation and Patient-Centered Care Inform Team-Based Action Plans for Relapsed/Refractory DLBCL: Results from a Quality Improvement Study

Background Using shared decision-making (SDM) to define therapeutic goals and shape individualized treatment plans for relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) can profoundly improve patient-reported outcomes. However, unique barriers within oncology systems can impede patient-centered care coordination and delivery. In this quality improvement (QI) initiative, we assessed barriers to patient-centered R/R DLBCL care in 2 community oncology systems and conducted team-based audit-feedback (AF) sessions within each system to facilitate improved care coordination. Methods Between 12/2019 and 1/2020, 33 hematology/oncology healthcare professionals (HCPs) completed team-based surveys designed to assess barriers to quality R/R DLBCL care in 2 community oncology systems (Table 1). In addition, we retrospectively audited electronic medical records (EMRs) of 75 patients with R/R DLBCL to compare documented practice patterns with self-reported survey results. To address identified gaps, 31 HCPs practicing within the 2 systems participated in AF sessions; together, clinical teams developed action plans guided by survey insights and EMR findings. Additional surveys completed before and after the AF sessions measured changes in participants' beliefs and confidence in care delivery. A planned prospective follow-up EMR audit of 75 patients will assess changes in documentation and practice behavior. Results Team Surveys and EMR Audit: Using a 5-point Likert scale (0 = extremely unlikely; 5 = extremely likely), HCPs indicated a high likelihood of using prognostic scores (mean score, 3.8) and cell of origin (mean score, 3.9) to inform DLBCL treatment decisions. However, despite documentation of individual prognostic factors, only 30% of EMRs included the calculated International Prognostic Index (IPI) risk score and only 8% included cell of origin. No EMRs included an age-adjusted IPI, stage-modified IPI, or NCCN-IPI score (Figure 1). Despite only 6% of HCPs identifying engaging patients in SDM as a major practice challenge, SDM resources were consistently underutilized (Figure 2). Only 30% of HCPs estimated using SDM in more than half of their patients; 23% of HCPs reported using SDM with none of their patients with R/R DLBCL. Moreover, while 63% of HCPs reported routinely asking the patient what role he/she wishes to play (active, passive, collaborative), fewer HCPs integrated other SDM tools: using visual aids to communicate treatment benefits/risks (59%), referring patients to online education resources (53%), including the patient's spouse/family members in decisions (47%), and discussing financial toxicity (38%). Small-Group AF Sessions: When asked to identify a single aspect of R/R DLBCL care in greatest need for improvement in their systems, HCPs most commonly selected care coordination (34%) and adverse event recognition/management (20%), followed by individualizing treatment (16%) and prognostic scoring (14%). As part of their action plans, HCPs prioritized 3 practice behaviors to address with their clinical teams: individualizing treatment decisions based on patient- and disease-related factors (40%), improving communication during care transitions (40%), and providing adequate patient education about treatment options and potential side effects (20%). As a result of participating in the AF sessions, HCPs reported a meaningful shift in beliefs about collaborative care: 84% of HCPs agreed or strongly agreed that collaboration across the extended oncology care team is essential for achieving DLBCL treatment goals, an increase from 64% prior to the AF sessions. Further, HCPs reported increased confidence in their ability to perform each of 6 aspects of evidence-based, collaborative, patient-centered care (Figure 3). Conclusions Key system-based barriers to providing individualized R/R DLBCL care include adequate documentation of prognostic factors, care coordination, and effective SDM. After participating in this QI initiative, HCPs demonstrated improved commitment to team-based collaboration and increased confidence in delivering patient-centered care. Remaining practice gaps and challenges can inform future QI programs. Study Sponsor Statement The study reported in this abstract was funded by an independent educational grant from Genentech. The grantor had no role in the study design, execution, analysis, or reporting. Disclosures No relevant conflicts of interest to declare.

Response-Adapted Therapy with Infusional EPOCH Chemotherapy Plus Rituximab in HIV-Associated, B-Cell Non-Hodgkin's Lymphoma

Introduction: Six cycles of rituximab plus infusional EPOCH is considered a preferred regimen for first-line treatment of HIV-associated diffuse large B-cell lymphoma (DLBCL), HHV8-positive DLBCL, and primary effusion lymphoma, and is among the preferred regimens for HIV-associated Burkitt's lymphoma in the 2019 NCCN guidelines. A phase III trial demonstrated non-inferiority of 4 cycles of R-CHOP (followed by 2 additional doses of rituximab) compared with 6 cycles of R-CHOP in immunocompetent patients with low-risk DLBCL (stage I-II, age 18-60 years, and an age-adjusted International Prognostic Index score of 0), indicating that de-escalation of treatment duration may be safely achieved without compromising curability in an appropriately selected patient population. Here we report the outcomes for patients with HIV-associated DLBCL and high-grade non-Hodgkin lymphoma (NHL) treated with 4-6 cycles of EPOCH plus rituximab based a response-adapted treatment strategy under a completed prospective clinical trial (AMC-034). Methods: One hundred-six patients with HIV-associated DLBCL or high-grade CD20-positive NHL enrolled at multiple centers across the U.S. were randomized to receive rituximab (375 mg/m2) given either concurrently prior to each infusional EPOCH cycle, or sequentially (weekly for 6 weeks) following completion of dose-adjusted EPOCH regimen tailored for HIV+ patients. EPOCH consisted of a 96-hour IV infusion of etoposide, doxorubicin, and vincristine plus oral prednisone followed by IV bolus cyclophosphamide every 21 days for 4 to 6 cycles. Patients received 2 additional cycles of therapy after documentation of a complete response (CR) by computerized tomography after cycles 2 and 4. Results: Sixty-four of 106 patients (60%, 95% CI 50%, 70%) had a CR in both treatment arms; characteristics of entire population and CR proportions stratified by number of EPOCH treatment cycles were similar (Table 1).The 2-year event-free survival (EFS) rates were similar in the 24 patients with CR who received 4 or fewer EPOCH cycles (78%, 95% confidence intervals [55%, 90%]) due to achieving a CR after 2 cycles, compared with those who received 5-6 cycles of EPOCH (85%, 95% CI 70%, 93%) due to failure to achieve a CR after 2 cycles (Table 2 and Figure 1). Time to disease progression and overall survival wer also similar for those treated with 4 or fewer cycles compared with 5-6 cycles (91% vs. 87%, and 78% vs. 90%, respectively) (Table 2 and Figure 1). Conclusion: A response-adapted strategy may permit a shorter treatment duration without compromising therapeutic efficacy in an appropriately selected population of patients with HIV-associated NHL, which merits further evaluation in additional prospective trials. Disclosures Noy: Janssen: Consultancy; Medscape: Honoraria; Prime Oncology: Honoraria; NIH: Research Funding; Pharamcyclics: Research Funding; Raphael Pharma: Research Funding.

Refractory diffuse large B-cell lymphoma after first-line immuno-CT: Treatment options and outcomes.

In the rituximab era, one-third of diffuse large B-cell lymphoma patients experience relapse/refractory disease after first-line anthracycline-based immunochemotherapy. Optimal management remains an unmet medical need. The aim of this study was to report the outcomes of a cohort of refractory patients according to their patterns of refractoriness and the type of salvage option. We performed a retrospective analysis, which included 104 diffuse large B-cell lymphoma patients treated at Lyon Sud University Hospital (2002-2017) who presented with refractory disease. Refractoriness was defined as progressive/stable disease during first-line treatment (primary refractory, N=47), a partial response after the end of first-line treatment that required subsequent treatment (residual disease, N=19), or relapse within 1year of diagnosis after an initial complete response (CR) (early relapse, N=38). The 2-year overall survival (OS) rates for primary refractory, early relapse, and residual disease patients were 27%, 25%, and 52%, respectively, while the event-free survival rates for those groups were 13%, 13%, and 42%, respectively. In a univariate analysis, lactate dehydrogenase level, Ann Arbor stage, poor performance status, high age-adjusted International Prognostic Index score, and age>65years were associated with shorter OS. The use of rituximab and platinum-based chemo during the first salvage treatment was associated with prolonged OS. In a multivariate analysis, age (HR:2.06) and rituximab use (HR:0.54) were associated with OS. Among patients <65years who achieved a CR, autologous stem-cell transplant was associated with higher 2-year OS (90% vs 74%, P=0.10). Patients who were treated with a targeted therapy in the context of a clinical trial after second-line treatment had a higher 2-year OS (34% vs 19%, P=0.06). In conclusion, patients with primary refractory disease or early relapse have very poor outcomes but may benefit from rituximab retreatment during the first salvage treatment.

Results of an Ongoing Phase 2 Study of Brentuximab Vedotin with Rchp As Frontline Therapy in Patients with High-Intermediate/High-Risk Diffuse Large B Cell Lymphoma (DLBCL)

Results of an Ongoing Phase 2 Study of Brentuximab Vedotin with Rchp As Frontline Therapy in Patients with High-Intermediate/High-Risk Diffuse Large B Cell Lymphoma (DLBCL)

Anemia is an important prognostic factor for very elderly patients with diffuse large B-cell lymphoma treated with rituximab and attenuated chemotherapy.

e20518 Background: The combination of rituximab and attenuated chemotherapy is increasingly used to treat very elderly (age ≥ 80 years) diffuse large B-cell lymphoma (DLBCL) patients. However, prognostic factors in this patient population have not been thoroughly studied. Methods: Data were collected from 109 very elderly DLBCL patients, including clinical characteristics, treatments, toxicities, responses, and outcomes. Prognostic factors associated with overall survival (OS) and event free survival (EFS) were also analyzed. Results: The median age was 83 years, and 29% of patients were aged > 85 years. At diagnosis, 71% of patients had an age-adjusted International Prognostic Index score ≥ 2, and 60% had anemia (hemogloblin < 12 g/dL). The median doses of anthracycline and cyclophosphamide in the first cycle were reduced to 50% and 80% of reference doses, respectively. 63% of patients experienced grade 3–4 hematological toxicities and infection complications. Median OS was 10.8 months, with a 2-year OS ...

Improved outcome of adult Burkitt lymphoma/leukemia with rituximab and chemotherapy: report of a large prospective multicenter trial

AbstractThis largest prospective multicenter trial for adult patients with Burkitt lymphoma/leukemia aimed to prove the efficacy and feasibility of short-intensive chemotherapy combined with the anti-CD20 antibody rituximab. From 2002 to 2011, 363 patients 16 to 85 years old were recruited in 98 centers. Treatment consisted of 6 5-day chemotherapy cycles with high-dose methotrexate, high-dose cytosine arabinoside, cyclophosphamide, etoposide, ifosphamide, corticosteroids, and triple intrathecal therapy. Patients >55 years old received a reduced regimen. Rituximab was given before each cycle and twice as maintenance, for a total of 8 doses. The rate of complete remission was 88% (319/363); overall survival (OS) at 5 years, 80%; and progression-free survival, 71%; with significant difference between adolescents, adults, and elderly patients (OS rate of 90%, 84%, and 62%, respectively). Full treatment could be applied in 86% of the patients. The most important prognostic factors were International Prognostic Index (IPI) score (0-2 vs 3-5; P = .0005), age-adjusted IPI score (0-1 vs 2-3; P = .0001), and gender (male vs female; P = .004). The high cure rate in this prospective trial with a substantial number of participating hospitals demonstrates the efficacy and feasibility of chemoimmunotherapy, even in elderly patients. This trial was registered at www.clinicaltrials.gov as #NCT00199082.

Blood Soluble PD-L1 Protein In Aggressive Diffuse Large B-Cell Lymphoma Impacts patient's Overall Survival

PurposeProgrammed death 1 (PD-1) protein is a key immune-checkpoint receptor expressed by activated T cells and it mediates immunosuppression. It has been recently shown that the blockade of PD-1 or its ligand, PD-L1, by monoclonal antibodies may lead to significant antitumor effects. In diffuse large B-cell lymphoma PD-L1 has been reported expressed by tumor cells and PD-1 by tumor-associated T cells. The dosage of soluble programmed death ligand 1 (sPD-L1) protein in the blood of adults with cancer has never been performed during a clinical trial. We evaluated the clinical impact of PD-L1 level measured at the time of diagnosis for newly diagnosed aggressive diffuse large B-cell lymphomas. MethodsTranslating a previous study (NEJMed2004; 350: 1287) in the rituximab era, the Groupe Ouest-Est des Leucemies et des Autres Maladies du Sang (GOELAMS) 075 study is a multicenter randomized trial in which adults 18 to 60 years old with untreated histologically proved CD20 positive diffuse large B-cell lymphoma were randomly assigned to receive 8 courses of R-CHOP or, high-dose chemotherapy associated to rituximab followed by autologous stem cell support (clinicaltrials.gov: NCT00561379). Patients were required to have an Ann Arbor stage of I or II with bulk greater or equal to 7 cm or, III or IV with 0 to 3 adverse prognostic factors as defined by the age-adjusted International Prognostic Index. The population of interest consisted of 288 of the 340 consecutively enrolled patients with available plasma collected at the time of diagnosis before any treatment. Soluble PD-L1 was measured using an ELISA assay. The median follow-up was 41.4 months. ResultssPD-L1 levels were found significantly increased in the plasma collected at diagnosis for patients compared to healthy -gender and age matched- subjects' levels (P<0.0001). The optimal cut-off point for PD-L1 measured at diagnosis was found to be equal to 1.52 ng/mL. Eighty-nine (30.9%) patients had a PD-L1 level greater than the cut-off point as compared to two (3%) controls. The high-level sPD-L1 group was significantly associated with bone marrow involvement, more than one extranodal localization and, 2-4 performance ECOG status. None of the other patients' characteristics, including the assigned arms of randomization and, the positive vs. negative FDG-PET scan response at the intermediate evaluation, was associated with high PD-L1 level. The PD-L1 immunohistochemical analysis showed that 55 out of the 73 interpretable tissue microarrays presented at least 5% of PD-L1-positive tumor cells. No association was found between sPD-L1 and tumor PD-L1 expressions (p=0.5). The 73 patients were representative of our 288 patients' cohort, with significantly decreased overall survival for patients with a high level of sPD-L1 compared to those with low sPD-L1 levels (64.6 vs. 86.7%, P=0.007). Cell-of-origin analysis using Hans's criteria on the tissue microarrays did not shown any correlation between elevated sPD-L1 and GC or non-GC origin.Patients with elevated PD-L1 experienced a poor prognosis with a three-year overall survival of 76 vs. 89 percent (P<0.001).There was no difference of overall survival rates between the two arms of treatment. Univariate analysis identified age greater than 50 years old, high-intermediate and, high age-adjusted International Prognostic Index score, bone marrow involvement, more than one extranodal localization, Ann Arbor stage after FDG-PET scan of III or IV, abnormal lymphocyte-monocyte score and, high level of sPD-L1 as factors associated with poor survival. High level of sPD-L1, bone marrow involvement and, abnormal lymphocyte-monocyte score were found after multivariate analysis to be the only factors remaining significant after adjustment with a P-value <0.05. Soluble PD-L1 was detectable in the plasma and not in the serum, found elevated in lymphoma patients at diagnosis compared to healthy subjects and its level dropped back to normal value for patients in complete remission. The intention-to-treat analysis showed that elevated PD-L1 was associated with a poorer prognosis for patients randomized within the R-CHOP arm (P<0.001). [Display omitted] ConclusionSoluble PD-L1 protein expression in peripheral blood at the time of diagnosis is a potent predicting biomarker in diffuse large B-cell lymphoma and may indicate usefulness of alternative therapeutic strategies using PD1 axis inhibitors. Disclosures:Fest:Roche SA France: Research Funding.

Autologous haematopoietic cell transplantation for non-Hodgkin lymphoma with secondary CNS involvement.

Pre-existing central nervous system (CNS) involvement may influence referral for autologous haematopoietic cell transplantation (AHCT) for patients with non-Hodgkin lymphoma (NHL). The outcomes of 151 adult patients with NHL with prior secondary CNS involvement (CNS(+) ) receiving an AHCT were compared to 4688 patients without prior CNS lymphoma (CNS(-) ). There were significant baseline differences between the cohorts. CNS(+) patients were more likely to be younger, have lower performance scores, higher age-adjusted international prognostic index scores, more advanced disease stage at diagnosis, more aggressive histology, more sites of extranodal disease, and a shorter interval between diagnosis and AHCT. However, no statistically significant differences were identified between the two groups by analysis of progression-free survival (PFS) and overall survival (OS) at 5 years. A matched pair comparison of the CNS(+) group with a subset of CNS(-) patients matched on propensity score also showed no differences in outcomes. Patients with active CNS lymphoma at the time of AHCT (n = 55) had a higher relapse rate and diminished PFS and OS compared with patients whose CNS lymphoma was in remission (n = 96) at the time of AHCT. CNS(+) patients can achieve excellent long-term outcomes with AHCT. Active CNS lymphoma at transplant confers a worse prognosis.

Management of HIV-Associated Hodgkin Lymphoma: How Far We Have Come

Although Hodgkin lymphoma (HL) is not considered an AIDSdefining malignancy, population-based studies have demonstrated an increased incidence of this disease in the setting of HIV infection. In a prospective cohort study of 11,112 individuals who were positive for HIV, with 71,687 patient-years of follow-up, the incidence of HL was 14 times higher than in the general population. In contrast to other HIV-associated malignancies that occur more commonly with severe immunocompromise, HL is associated with moderate immunologic impairment and the incidence actually seems to decline at CD4 lymphocyte counts of less than 200/ L. Although incidence rates for the AIDS-defining malignancies (Kaposi’s sarcoma, aggressive B-cell non-Hodgkin lymphoma [NHL]) have fallen, the incidence of HL may actually be increasing since the advent of combination antiretroviral therapy (cART), perhaps as a consequence of improvement in the level of immune function. However, the increased relative risk of HL is substantially lower than that observed for aggressive B-cell lymphoma. As a result of the small number of cases, studies investigating approaches to management of HIV-associated HL have been largely retrospective in design. For the more common AIDS-defining lymphomas, diffuse large B-cell lymphoma and Burkitt lymphoma, outcomes have improved dramatically in the 16 years since the introduction of active antiretroviral therapies, which have transformed HIV disease into a survivable chronic illness. Prospective studies in the pre-cART era demonstrated 2-year overall survival (OS) in the 10% to 20% range with complete remission (CR) rates of 35% to 50%, far inferior to those observed in non-HIV–associated lymphomas. Prognosis at that time was largely dependent on the severity of immunosuppression rather than on features of the lymphoma. This experience changed with the advent of cART such that now treatment outcomes using standard regimens such as rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone or dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab approach those observed in the non-HIV–infected population, with CR rates of 65% to 77% and 2-year OS rates of more than 60%. The International Prognostic Index (IPI) score seems to be a significant prognostic factor in patients treated with chemotherapy and concurrent cART. On the basis of the age-adjusted IPI score, the survival of patients in one trial using rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone was similar to that achieved by patients with aggressive lymphomas who were not infected with HIV. HL in the HIV-seropositive population is more likely to have mixed cellularity or lymphocyte-depleted histology and is almost always Epstein-Barr virus–associated. The majority of patients present with advanced-stage disease. Before the introduction of cART, treatment outcomes for HIV-HL were poor. In an Italian retrospective study of 114 patients with HIV-associated HL who received various standard chemotherapeutic regimens, the median OS was 15 months. Sixty percent died, 35% of those from opportunistic infection, 33% from HL, and 12% from both. As has been the case for aggressive B-cell lymphomas in patients with HIV infection, small retrospective and prospective studies have suggested improvement in outcome with the advent of cART. A retrospective study of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) with cART in 62 patients with advanced-stage HIVassociated HL demonstrated a CR rate of 87% and 5-year OS of 76%. A prospective trial reported a CR rate of 81% and 2-year OS of 51% in 59 patients treated with the Stanford V regimen (doxorubicin, vinblastine, mechlorethamine, vincristine, bleomycin, etoposide, and prednisone) administered with antiretroviral therapy. The fact that only 10% of these patients received radiotherapy suggests that the regimen was either not delivered as designed or that the inclusion of patients with early-stage and low-bulk disease (factors associated with inferior outcome with this regimen) resulted in relatively disappointing outcomes. In the article that accompanies this editorial, the German HIV-Related Lymphoma Study Group presents data from the largest prospective trial ever conducted in patients with HIV-associated HL. In this study, 112 patients were allocated to treatment on the basis of stage and risk category. Those with early-stage favorable disease (IA/B or IIA/B) received two to four cycles of ABVD plus 30 Gy of involved-field radiotherapy. Patients with early-stage unfavorable disease received four cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) at baseline or four cycles of ABVD followed by 30 Gy of involved-field radiotherapy if disease was 5 cm or residual disease was 2 cm. Those with advanced disease received eight cycles of BEACOPP with or without radiotherapy to sites 2.5 cm. Patients with advanced HIV disease, including Eastern Cooperative Oncology Group performance score 2, received ABVD. There were five toxic deaths: 4% with early favorable, 0% with early unfavorable, and 7% with advanced disease. CR rates were 96%, 100%, and 86% for these three groups, respectively, and 2-year PFS JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 30 NUMBER 33 NOVEMBER 2

Prognostic Role of Host Immune Gene Polymorphisms for Patients with Diffuse Large B-Cell Lymphoma Treated with Rituximab and Chemotherapy. A Study Based on 554 Patients Included in the GELA (Groupe d'Etude des Lymphomes de l'Adulte) Prospective Multicentric Program LNH2003,

Abstract 3676 Background:Diffuse Large B-cell Lymphoma (DLBCL) is a heterogeneous disease based on biological analyses of tumor cells, with for instance the determination of two molecular subgroups, one with a profile close to germinal center B-cells and the second to activated B-cells. Data from the biology of tumor microenvironment could also be helpful to define different prognostic subgroups of DLBCL. The role of the biology of the patient with DLBCL, i.e. the host-related factors is little explored. Epidemiological studies showed that some inherited genetic variation in immune genes could increase the risk of lymphoma development and some retrospective studies indicated that patient’s outcome could be predicted by some germ line polymorphisms (SNPs) in cytokine genes. The aim of this study is to determine the prognostic impact of 13 SNPs in 7 immune genes, IL10 (4 SNPs), Tumor Necrosis factor α (TNFA), lymphotoxin α (LTA), BAFF (3 SNPs), IL1A, IL8RB, IL4R (2 SNPs) in a cohort of newly diagnosed DLBCL patients included in the GELA LNH2003 prospective trials all treated by rituximab combined with chemotherapy.Patients and Methods: 1564 patients from France, Switzerland and Belgium were included in the 5 prospective multicentric trials of the LNH2003 program of the GELA designed for DLBCL patients who were stratified in different subgroups based on age and International Prognostic Index (IPI) score. A sample of peripheral blood lymphocytes was collected before treatment from 760 patients who signed a specific consent form for this genetic study. After pathologic review and exclusion of patients not receiving rituximab (48 patients), 554 DLBCL patients were available for this study. SNPs were genotyped using a TaqMan® based assay. Results:The median age of the 554 patients was 61 years (range, 18–93 years), 57% of them were male and 50% of patients presented at diagnosis a 2–3 age-adjusted IPI score. Chemotherapy regimen consisted in a combination of rituximab with CHOP-21 (110 patients, 20%), CHOP-14 (181 patients, 33%), low dose CHOP for patients older than 80 years (60 patients, 11%), or ACVBP regimen (203 patients, 36%). At the end of treatment, complete response (CR) or unconfirmed CR was observed in 75% of patients. After a median follow-up of 38 months, the 3-year progression free survival (PFS) and overall survival (OS) was 70.2% and 75.7%, respectively. All the polymorphism distributions of the SNPs analyzed were consistent with Hardy-Weinberg equilibrium. The main initial clinical characteristics of patients were not different according to the 13 studied SNPs, except for IL4R (rs2107356), CC carriers presented less frequently B symptoms than CT and TT carriers (28% vs. 41% and 61%, P = .01). No correlation was observed between the quality of the response at the end of the treatment and each genotype of the 13 studied SNPs. The 3-year PFS and OS were overall not influenced by the genotyping of the 13 SNPs. However, a trend for a better 3-year PFS for LTA +252GG carriers compared to LTA +252AG and AA carriers was observed (79.7% vs. 64.6% and 72.7%, P = .04). Conclusions:To our knowledge, this is the largest prospective multicentric study that investigates the role of immune SNPs on treatment response and outcome in a large cohort of newly diagnosed patients with DLBCL receiving rituximab. No correlation between SNPs and treatment response was observed. Analyses of the impact on outcome of each individual SNP showed only a trend for a prognostic role on PFS of LTA A252G SNP, which is already described as a functional SNP. The results will be further precise by the correlation of IL10, BAFF and TNFA /LTA full haplotypes with response and outcome. Disclosures:No relevant conflicts of interest to declare.

FCGR3A and FCGR2A Polymorphisms Do Not Affect Response and Outcome of Patients with Diffuse Large B-Cell Lymphoma Treated with Rituximab and Chemotherapy. A Study Based on 554 Patients Included in GELA (Groupe d'Etude des Lymphomes de l'Adulte) Prospective Multicentric Study LNH2003

Abstract 90 Background:rituximab had dramatically improved the prognosis of patients with Diffuse Large B-cell Lymphoma (DLBCL) in combination with chemotherapy. Many biological and clinical studies suggested considerable inter-individual variability in term of anti-CD20 monoclonal antibody (mAb) activity with tumor and host-related influencing factors. Among host-related factors, the presence of functional polymorphisms in FcG receptors genes as FCGR3A-158V/F influences the affinity for IgG1 and consequently the antibody dependant cellular cytotoxicity (ADCC) with therapeutic mAbs such as rituximab. The clinical consequence reported to date consists in a better response rate to rituximab monotherapy for FCGR3A-158V homozygous patients treated for follicular lymphoma compared FCGR3A-158F carriers. In DLBCL and in the context of combination with chemotherapy, the role of FCGR3A and FCGR2A SNPs on treatment response and patient's outcome is not clear with few prospective studies. The aim of this study is to determine the impact of FCGR3A and FCGR2A SNPs on response and outcome of newly diagnosed DLBCL patients included in the prospective trials of the GELA (LNH2003 program). Patients and Methods:1564 patients from France, Switzerland and Belgium were included in the 5 prospective multicentric trials of the LNH2003 program of the GELA designed for DLBCL patients who were stratified in different subgroups based on age and International Prognostic Index (IPI) score. A sample of peripheral blood lymphocytes was collected before treatment from 760 patients who signed a specific consent form for this genetic study. After pathologic review and exclusion of patients not receiving rituximab (48 patients), 554 DLBCL patients were available for this study. SNPs were genotyped using a TaqMan® based assay. Results:The median age of the 554 patients was 61 years (range, 18–93 years), 57% of them were male and 50% of patients presented at diagnosis a 2–3 age-adjusted IPI score. Chemotherapy regimen consisted in a combination of rituximab with CHOP-21 (110 patients, 20%), CHOP-14 (181 patients, 33%), low dose CHOP for patients older than 80 years (60 patients, 11%), or ACVBP regimen (203 patients, 36%). At the end of treatment, complete response (CR) or unconfirmed CR was observed in 75% of patients. After a median follow-up of 38 months, the 3-year progression free survival (PFS) and overall survival (OS) was 70.2% and 75.7%, respectively. The distribution of the VV, VF and FF FCGR3A alleles was 14.8%, 46.4%, 38.8%, and 27.8%, 48.6%, 23.6% for HH, HR and RR FCGR2A alleles, respectively, and were therefore consistent with Hardy-Weinberg equilibrium. Initial clinical characteristics of patients (age, sex, Performance Status, stage, B-symptoms, number of extra-nodal sites, LDH level, IPI) were not different according to the two FCGR SNPs. CR/CRu after induction therapy was observed in 61%, 66%, 61% for VV, VF and FF carriers (P = .46) and 60%, 64%, 64% for HH, HR and RR carriers (P =.70), respectively. No difference of response after consolidation treatment was observed between each genotype of FCGR3A and FCGR2A SNPs. The 3-year PFS was 65.3%, 71.4%, 70.5% for FCGR3A VV, VF and FF carriers (P = .43) and 69.2%, 67.6%, 76.6% for FCGR2A HH, HR, RR carriers (P =.09), respectively. The 3-year OS was also not different between the three genotypes of each FCGR SNPs. Conclusions:To our knowledge, this is the largest prospective multicentric study that investigates the role of FCGR2A and FCGR3A SNPs on treatment response and outcome in a large series representing the whole spectrum of DLBCL patients. Based on these results, modification of rituximab schedule according to the FCGR3A and FCGR2A genotypes does not appear worth investigating. Others host-related factors influencing the efficiency of immunotherapy need to be investigate. Disclosures:No relevant conflicts of interest to declare.

The Significance of Bone Marrow Involvement in Aggressive Lymphomas: A Retrospective Comparison of Clinical Outcomes between Peripheral T Cell Lymphoma and Diffuse Large B Cell Lymphoma in China

Background: Peripheral T cell lymphomas (PTCL) have been demonstrated to have a poorer prognosis than diffuse large B cell lymphoma (DLBCL) due to a high frequency of bone marrow involvement (BMI). However, the clinical characteristics of PTCL with BMI have not been fully described, and the clinical outcomes of PTCL with BMI and DLBCL with BMI have not been well compared. Methods: The clinical characteristics and survival of 25 nodal PTCL cases with BMI and 42 DLBCL cases with BMI were compared. Results: Most of the PTCL patients with BMI had lymphadenopathy (88%), B symptoms (76%), an elevated LDH level (68%), anemia (64%), splenomegaly (60%), and a poor performance status (52%). Except for the differences of lymphadenopathy and thrombocytopenia between PTCL with BMI and DLBCL with BMI, similarities in gender, age, hepatomegaly, splenomegaly, a bulky mass, B symptoms, elevated LDH, ≧2 extranodal sites, ECOG scores ≧2, anemia, and international prognostic index (IPI) and age-adjusted IPI scores were observed between the 2 groups. The 2 groups also had similar 3-year overall survival (25.8 vs. 30.0%, p = 0.846) and progressive-free survival (21.3 vs. 25.2%, p = 0.815) rates. Conclusions: PTCL with BMI have a similar aggressive course and poor survival compared to DLBCL with BMI. Thus, the immunophenotype of either T or B lineage may not be a crucial prognostic indicator of survival for these 2 aggressive lymphomas.

R-CHOEP-14 × 6 Followed by Systemic CNS Prophylaxis for Diffuse Large B-Cell Lymphoma/Follicular Lymphoma Grade 3 with Age Adjusted IPI Score 2–3: Final Results of a Nordic Lymphoma Group Phase 2 Study Including 156 Patients Aged 18–65 Years.

AbstractAbstract 2805CHOP – based chemotherapy for aggressive lymphomas in patients with age-adjusted International Prognostic Index (IPI) score of 2–3 resulted in a historical 3-year progression free survival of approximately 30% in a previous Nordic phase III study. The aim of the present study is to determine whether an intensified regimen with chemoimmunotherapy and CNS prophylaxis improves outcome. Methods:From October 2004 to June 2008 patients were included in a phase II study. Inclusion criteria: 1) Age 18–65 years. 2) Newly diagnosed de novo diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL) grade III. 3) No clinical sign of CNS disease and negative CSF cytology/flow cytometry by lumbar puncture. 4) No HIV infection. 5) WHO performance score 0–3. 6) Adequate organ functions. Schedule: Six courses of R-CHOEP14. Pegfilgrastim 6 mg sc. day four of each cycle. One course of high dose cytarabine 12 g/m2 (6 g/m2 for patients 60–65 years). One course of high dose methtrexate 3 g/m2 (1 g/m2 for patients 60–65 years). Biopsy and/or 18FDG PET/CT imaging of residual masses after fulfilled therapy was recommended, but not mandatory. Radiotherapy was given to residual masses of uncertain significance. Results.Demographic data:.156 eligible patients were included (97 males). Median age: 54 years (range 20–64). Histology: DLBCL: 145, FL grade 3: 12 (three patients no data). Age adjusted IPI score: 2: 117; 3: 39. Stage III-IV: 150 patients. LDH elevated: 151 patients. Performance status 2–3: 51 patients. B-symptoms were registered in 97 patients, more than one extranodal site in 42 and bulky lesions (≥ 10 cm) in 68. Median observation time for patients alive at last follow up was 36 months. Toxicity: Three toxic deaths are registered, one large bowel perforation, one fulminant hepatic necrosis and one septic shock. Hematological toxicity grade 4 was seen in 78% of the patients, infection grade 4 in 8%. Radiotherapy was given to 16% of the patients. Response: Response rates at end of therapy: CR/CRu: 69%, PR: 22%, SD: 1%, PD: 4.5%. Seventeen patients (7%) were not treated according to protocol, either due to lack of response (6 patients) or due to toxicity (eleven patients). The majority of the PR patients were considered to have residual masses and not viable tumour tissue. Survival: Three year overall survival was 80% (95% CI +/− 6.5%) and three year treatment failure free time 67% (95% CI +/−8.0%). CNS events: Seven patients had a CNS relapse, all but one were isolated (4 intracerebral, 3 meningeal). All CNS relapses occurred within 6 months after inclusion. Conclusions:The results are promising with a low three year treatment failure rate, a low toxic death rate and fewer CNS events than expected. The CNS events might be further reduced by earlier CNS prophylaxis.The study was supported by an unrestricted grant from Amgen Disclosures:Holte:Roche: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. LeppÃ: Roche: Honoraria. Bjorkholm:Roche: Research Funding. Jyrkkiö:Roche: Honoraria. Kolstad:Roche: Honoraria; Amgen: Honoraria. Fosså:Roche: Honoraria. φstenstad:Roche: Honoraria; Amgen: Honoraria. Eriksson:Amgen: Research Funding.

Second-line age-adjusted International Prognostic Index in patients with advanced non-Hodgkin lymphoma after T-cell depleted allogeneic hematopoietic SCT

T-cell depleted allogeneic hematopoietic SCT (TCD-HSCT) have shown durable disease-free survival with a low risk of GVHD in patients with AML. We investigated this approach in 61 patients with primary refractory or relapsed non-Hodgkin lymphoma (NHL), who underwent TCD-HSCT from January 1992 through September 2004. Patients received myeloablative cytoreduction consisting of hyperfractionated total body irradiation, followed by either thiotepa and cyclophosphamide (45 patients) or thiotepa and fludarabine (16 patients). We determined the second-line age-adjusted International Prognostic Index score (sAAIPI) before transplant transplant. Median follow-up of surviving patients is 6 years. The 10-year OS and EFS were 50% and 43%, respectively. The relapse rate at 10 years was 21% in patients with chemosensitive disease and 52% in those with resistant disease at time of HSCT. Nine of the 18 patients who relapsed entered a subsequent CR. OS (P=0.01) correlated with the sAAIPI. The incidence of grades II-IV acute GVHD was 18%. We conclude that allogeneic TCD-HSCT can induce high rates of OS and EFS in advanced NHL with a low incidence of GVHD. Furthermore, the sAAIPI can predict outcomes and may be used to select the most appropriate patients for this type of transplant.

Long-term follow-up of patients with diffuse large B-cell non-Hodgkin's lymphoma receiving purged autografts after induction failure

Patients with diffuse large B-cell lymphoma (DLBCL) who do not achieve a complete response to front-line combination chemotherapy are often offered high-dose therapy and autologous hematopoietic cell transplantation (AHCT). However, the efficacy of this therapy in this patient population has been addressed in only a few published reports. We retrospectively analyzed the outcomes of patients with a diagnosis of de novo DLBCL who underwent AHCT at our center between 1988 and 2002, and identified 43 consecutive patients who had not achieved a CR before AHCT, although most showed at least a partial response (PR) to either induction or subsequent salvage chemotherapy. A total of 15 patients received a conditioning regimen that included high-dose chemotherapy with fractionated TBI (FTBI), whereas 28 patients received high-dose chemotherapy only. All autografts were treated ex vivo with MoAbs and complement in an effort to remove any residual malignant B cells. A total of 33 (77%) patients achieved a CR after AHCT. With a median follow-up of 7.3 years, the 5-year OS was 69% and EFS was 59%. Four patients died from non-relapse mortality. By univariate analyses, the following characteristics did not significantly impact OS: disease stage at diagnosis, age-adjusted IPI (International Prognostic Index) score, age > or =40 years, earlier radiotherapy and the use of FTBI in the conditioning regimen. These results confirm the long-term efficacy of AHCT for patients with DLBCL after induction failure.

R-CHOEP-14 X 6 Followed by Systemic CNS Prophylaxis for Diffuse Large B-Cell Lymphoma (DLBCL)/Follicular Lymphoma (FL) Grade 3 with Age Adjusted IPI Score 2–3: Preliminary Results of a Nordic Lymphoma Group (NLG) Phase 2 Study Including 160 Patients Aged 18- 64 Years

CHOP – based chemotherapy for aggressive lymphomas in patients with age-adjusted International Prognostic Index (IPI) score of 2–3 resulted in a historical 3-year progression free survival of approximately 30% in a previous Nordic phase III study. The aim of the present study is to determine whether an intensified regimen with chemoimmunotherapy and CNS prophylaxis improves outcome.Methods. From October 2004-June 2008 patients in Norway, Finland, Sweden and Denmark were included in a phase II study.Inclusion criteria: Age 18–64 years, newly diagnosed de novo DLBCL or FL grade III, no clinical sign of CNS disease and negative CSF cytology/flow cytometry by lumbar puncture, HIV negative, WHO performance status grade 0–3, adequate organ functions.Schedule: Six courses of rituximab and CHOP with the addition of etoposide 100 mg/m2 day 1–3 by i.v. route given every 14 day. Pegfilgrastim 6 mg sc. day 4 of each cycle. One course of cytarabine 12 g/m2 (6 g/m2 for patients 60–64 years). One course of methotrexate 3 g/m2 (1.5 g/m2 for patients 60–64 years). Biopsy and/or 18FDG PET/CT exam. of residual masses after fulfilled therapy was recommended, but not mandatory. Radiotherapy was given to residual masses of uncertain significance.Results. Demographic data: 160 patients were included (99 males). Median age: 54 years (range 20–64). Histology: DLBCL: 148, FL grade 3: 12. Age adjusted IPI score: 2: 120; 3: 40. Stage 3–4: 154 patients. LDH elevated: 154 patients. Performance status 2–3: 53 patients. B-symptoms were registered in 40% of the patients, more than one extranodal site in 23%, and bulky lesions (≥ 10 cm) in 43%. Data on toxicity and response rates were registered for 127 patients by Aug. 1st 2008 after the end of therapy and will be available for all patients by Dec 1st.Toxicity: Two toxic deaths were registered, one after large bowel perforation and one after an acute toxic necrosis of the liver. Hematological toxicity grade 4 was seen in 78% of the patients, infection grade 4 in 8%. Seven patients (5.5%) had major protocol deviations due to toxicity.Response: Two of the patients were non-responders at evaluation after 3 courses and were taken off therapy. Radiotherapy was given to 25 patients (20%). Response rates at end of therapy: CR: 54 (43%), CRu: 38 (30%), PR: 27 (21%), SD: 1 (1%), PD: 7 (5%). The majority (23/27) of the PR patients were considered to have residual masses and not viable tumor tissue and were observed without further treatment.Conclusions: Preliminary data indicate a low rate of toxic deaths despite intensive therapy. Remission rates are highly satisfactory for this subgroup of patients. Data are too premature for survival analysis at this time point.

Central nervous system occurrence in elderly patients with aggressive lymphoma and a long-term follow-up

Secondary central nervous system (CNS) involvement by aggressive lymphoma is a well-known and dreadful clinical complication. The incidence and risk factors for CNS manifestation were studied in a large cohort of elderly (>60 years) patients with aggressive lymphoma. In all, 444 previously untreated patients were randomized to receive 3-weekly combination chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone or cyclophosphamide, mitoxantrone, vincristine and prednisone (CNOP) (doxorubicin substituted by mitoxantrone) chemotherapy with or without filgrastim. Prophylactic intrathecal methotrexate was given to patients with lymphoma involvement of bone marrow, testis and CNS near sites. In all 29 of 444 (6.5%) developed CNS disease after a median observation time of 115 months. CNS was the only site of progression/relapse in 13 patients while part of a systemic disease manifestation in 16 patients. In univariate risk factor analysis, CNS occurrence was associated with extranodal involvement of testis (P = 0.002), advanced clinical stage (P = 0.005) and increased age-adjusted International Prognostic Index score (aaIPI; P = 0.035). In multivariate analysis, initial involvement of testis remained significant and clinical stage was of borderline significance. The median survival time was 2 months after presentation of CNS disease. A significant proportion of elderly patients with advanced aggressive lymphoma will develop CNS disease. CNS occurrence is related to testis involvement, advanced clinical stage and high aaIPI and the prognosis is dismal.

High Dose Therapy and Autologous Hematopoietic Cell Transplantation for Primary Refractory Diffuse Large Cell Non-Hodgkin's Lymphoma.

The efficacy of high dose therapy (HDT) and autologous hematopoietic cell transplantation (AHCT) for patients with diffuse large cell non-Hodgkin's lymphoma (NHL) who never achieve a first complete remission (CR) with conventional chemotherapy have been addressed by few published studies. We retrospectively analyzed outcomes for 43 consecutive patients with chemotherapy-sensitive primary refractory diffuse large cell NHL treated with HDT and AHCT at our center between November 1988 and January 2002. The median age at transplant was 43 years (range: 18 – 64). At diagnosis 26 patients (60%) had stage IV disease, 28 patients (65%) had extranodal involvement, and bulky disease was present in 17 patients (40%). The age-adjusted NHL international prognostic index (IPI) score was low in 4 patients (9%), low-intermediate in 18 patients (42%), high or high-intermediate in 12 patients (28%), and not available in 9 patients (21%). All patients failed to achieve a first CR following CHOP (n = 31, 72%), R-CHOP (n = 6, 14%), and other anthracycline-containing regimens (n = 6, 14%). Fourteen patients (33%) did not receive additional conventional chemotherapy before proceeding to HDT and AHCT. The remaining 29 patients (67%) received in addition between 1 – 6 cycles of salvage chemotherapy. None of the 43 patients had achieved a CR at any time point before HDT and AHCT and all patients had measurable disease at the start of the HDT regimen. The median interval from diagnosis to HDT was 8.9 months (range: 2.4 – 15.5). The HDT regimen consisted of total body irradiation, etoposide, and cyclophosphamide in 15 patients (35%); BCNU, etoposide, and cyclophosphamide in 26 patients (60%); and CCNU, etoposide, and cyclophosphamide in 2 patients (5%). All but three patients (7%) were rescued with peripheral blood stem cells mobilized with cyclophosphamide 4 gm/m2 plus G-CSF and purged with monoclonal antibodies and complement. With a median follow-up of 5.8 years (range: 0.2 – 15.8) among surviving patients, the 5-year Kaplan-Meier estimates for overall survival was 67.4% (95% CI: 52.4 – 82.4), freedom from progression was 60.1% (95% CI: 43.7 – 76.6), and event-free survival was 55.8% (95% CI: 39.2 – 72.4). Two patients with relapse post-AHCT proceeded to non-myeloablative allogeneic HCT and were censored at the time of second transplant. By univariate analyses the following characteristics were not prognostically significant for overall survival: disease stage at diagnosis (I–II versus III–IV), prior radiotherapy, age-adjusted IPI score (low versus high) in evaluable patients, and the HDT regimen (TBI versus non-TBI). These results demonstrate that HDT and AHCT is effective treatment for chemotherapy-sensitive primary refractory diffuse large cell NHL. [Display omitted]

Secondary Central Nervous System Lymphoma

This review summarizes current knowledge of secondary central nervous system lymphoma (SCNSL) in adults. We define SCNSL as CNS involvement not obvious at the initiation of treatment for systemic lymphoma. Recently, polymerase chain reaction and flow cytometry assays of cerebrospinal fluid have become available for the correct diagnosis of SCNSL. We reviewed reports of patients treated without CNS prophylaxis to evaluate the incidence of SCNSL. Elevated serum lactate dehydrogenase levels, the involvement of more than one extranodal site, an advanced stage, a high age-adjusted International Prognostic Index score at presentation, and special anatomic sites of involvement such as the testis are important risk factors for SCNSL. Histologic evidence of aggressiveness is generally an indicator of risk for SCNSL. In addition to conventional treatment, stem cell transplantation, intrathecal administration of rituximab, and liposomal cytarabine have come into clinical use for the treatment of established SCNSL. Prevention of isolated CNS recurrence is thought to be the main target of CNS prophylaxis. The value of CNS prophylaxis according to histologic subtype, status of systemic lymphoma, and other risk factors is summarized. Although prophylaxis is fundamental for treating highly aggressive non-Hodgkin's lymphoma (NHL), it is beginning to be appreciated for the treatment of aggressive NHL. CNS involvement is almost always fatal; however, a CNS-active strategy could complement other approaches that have led to recent improvements in the prognosis for lymphoma.