Aggressive Lymphoma Patients Research Articles

Salvage therapy with mitoxantrone, etoposide, bleomycin and dexamethasone for refractory or relapsed aggressive non-Hodgkin's lymphoma patients with a poor performance status or comorbidity.

The treatment of refractory or relapsed aggressive non-Hodgkin’s lymphoma (NHL) in patients in a state of poor health is difficult due to their ineligibility to receive intensive salvage chemotherapy. In the present study, 16 refractory or relapsed aggressive NHL patients with a poor performance status or comorbidities were treated with mitoxantrone, etoposide, bleomycin and dexamethasone (MEBD) therapy. The treatment consisted of 10 mg/m2 intravenous (IV) mitoxantrone on day 1, 75 mg/m2 IV etoposide on days 1–3, 20 mg IV dexamethasone on days 1–4 and 15 mg intramuscular bleomycin on days 1, 4, 8 and 12, every 21 days. The efficacy and toxicity of the regimen were evaluated. The overall response rate was 68.8%, with a complete response rate of 18.8% and a partial response rate of 50.0%. The efficacy of the treatment for B-cell lymphoma was greater than that for T-cell lymphoma. The median progression-free survival time for the patients was 16.7 months and the median overall survival time was 22.4 months. The one-year overall survival rate was 62.5% and the two-year overall survival rate was 43.8%. The most common toxicity symptom was myelosuppression. In conclusion, refractory or relapsed aggressive NHL patients with a poor performance status or comorbidity are eligible for chemotherapy. MEBD therapy is an effective and feasible salvage regimen for NHL patients in a state of poor health.

The CBM signalosome: Potential therapeutic target for aggressive lymphoma?

The CBM signalosome plays a pivotal role in mediating antigen-receptor induced NF-κB signaling to regulate lymphocyte functions. The CBM complex forms filamentous structure and recruits downstream signaling components to activate NF-κB. MALT1, the protease component in the CBM complex, cleaves key proteins in the feedback loop of the NF-κB signaling pathway and enhances NF-κB activation. The aberrant activity of the CBM complex has been linked to aggressive lymphoma. Recent years have witnessed dramatic progresses in understanding the assembly mechanism of the CBM complex, and advances in the development of targeted therapy for aggressive lymphoma. Here, we will highlight these progresses and give an outlook on the potential translation of this knowledge from bench to bedside for aggressive lymphoma patients.

Portraying the Expression Landscapes of B-CellLymphoma-Intuitive Detection of Outlier Samples and of Molecular Subtypes.

We present an analytic framework based on Self-Organizing Map (SOM) machine learning to study large scale patient data sets. The potency of the approach is demonstrated in a case study using gene expression data of more than 200 mature aggressive B-cell lymphoma patients. The method portrays each sample with individual resolution, characterizes the subtypes, disentangles the expression patterns into distinct modules, extracts their functional context using enrichment techniques and enables investigation of the similarity relations between the samples. The method also allows to detect and to correct outliers caused by contaminations. Based on our analysis, we propose a refined classification of B-cell Lymphoma into four molecular subtypes which are characterized by differential functional and clinical characteristics.

The risk of CNS involvement in aggressive lymphomas in the rituximab era

The risk of CNS dissemination and CNS prophylaxis strategies in aggressive non-Hodgkin lymphoma (NHL) is still debated. CNS dissemination is a rare but fatal event. A CNS prophylaxis is common for Burkitt and B-cell lymphoblastic lymphoma; however, in other NHLs, prophylactic treatments are not systematically warranted. Current risk models showed low sensitivity in predicting CNS involvement, implying overtreatment in roughly 70% of high-risk patients. Risk models in the rituximab era were modulated for the detection of occult CNS disease at diagnosis using flow cytometry. The optimal regimen for CNS prophylaxis in aggressive lymphoma patients has not been established thus far and should be modulated at different levels of ‘intensity’ such as standard intrathecal chemotherapy, ‘active’ intrathecal chemotherapy with liposomal cytarabine or more aggressive systemic treatment with high doses of drugs having good CNS bioavailability reserved for patients who are truly at high risk of CNS dissemination.

Long term results of a phase 2 study of vincristine sulfate liposome injection (Marqibo®) substituted for non‐liposomal vincristine in cyclophosphamide, doxorubicin, vincristine, prednisone with or without rituximab for patients with untreated aggressive non‐Hodgkin lymphomas

Vincristine sulfate liposome injection (VSLI; Marqibo(®) ; M) is active in relapsed and refractory lymphomas, and approved in the United States for relapsed and refractory adult acute lymphocytic leukaemia. We evaluated VSLI (2·0 mg/m(2) without dose cap) substituted for non-liposomal vincristine (VCR) in a cyclophosphamide, doxorubicin, vincristine, prednisone ± ritiximab (CHOP±R) regimen, creating CHMP±R in 72 untreated, aggressive non-Hodgkin lymphoma patients, including 60 with diffuse large B-cell lymphoma (DLBCL). The overall response rate was 96% (69/72) including complete response (CR) in 65 (90%) and unconfirmed CR in 2 (3%). Median progression-free survival (PFS) and overall survival (OS) were not reached at median follow-up of 8 and 10·2 years, respectively. The 5- and 10-year PFS and OS were 75%, 63%, 87%, and 77%, respectively. Despite VSLI exposure of up to 35 mg, the safety profile of CHMP±R was comparable to that reported for CHOP±R. Grade 3 peripheral neuropathy was reported in 2 (3%) patients; there was no reported Grade 3/4 constipation. CHMP±R was highly active, generally well tolerated, and compared favourably to historical trials with R-CHOP in DLBCL. This enhanced activity probably reflects VCR dose intensification, pharmacokinetic optimization, and enhanced delivery afforded by VSLI. A Phase 3 trial of R-CHMP versus R-CHOP in elderly patients with untreated DLBCL is ongoing.

XVI. CNS prophylaxis in aggressive lymphomas: for whom and how

Dissemination in the central nervous system (CNS) in patients with aggressive lymphoma is a relatively rare but a frequently deadly complication that occurs between 5 (diffuse large B-cell lymphoma, DLBCL) and 30% (Burk itt lymphoma, BL and B-cell lymphoblastic lymphoma, B-LL) [1] in different subtypes of non-Hodgkin lymphoma (NHL). However, although a CNS prophylaxis is normally included into treatment regimens for BL and B-LL, in other NHL a prophylactic treatment is not systematically warranted because it may increase the toxicity of systemic chemotherapy.

A phase 2 study of epothilone B analog BMS‐247550 (NSC 710428) in patients with relapsed aggressive non‐Hodgkin lymphomas

The management of relapsed aggressive lymphomas remains problematic. Ixabepilone (BMS-247550, epothilone B analog), a potent inhibitor of tubulin disassembly, has promising preclinical and early-phase clinical activity in drug-resistant malignancies. This multicenter phase 2 clinical trial tested the activity and safety of ixabepilone in relapsed/refractory aggressive lymphoma patients with either chemosensitive (at least a partial response [PR] to most recent chemotherapy) or chemoresistant (less than PR to most recent chemotherapy) disease at 20 mg/m(2) given intravenously weekly on days 1, 8, and 15 of a 28-day cycle. Fifty-one enrolled patients with a median age of 66 years received at least 1 dose of ixabepilone. Diffuse large B-cell lymphoma (n = 25; 49%), mantle cell lymphoma (n = 16; 31%), and transformed follicular lymphoma (n = 5; 10%) were the most frequent histologies. Patients were heavily pretreated, with more than one-quarter having received 4 or more prior therapies. The overall response rate was 27% (14 of 51 patients) with 12% (6 patients) experiencing complete responses and 16% (8 patients) with PRs. All responses were in patients with chemosensitive disease. The median time to response was 2 cycles with a median duration of response of 9.7 months. Ixabepilone was well-tolerated, with neutropenia, peripheral sensory neuropathy, fatigue, and nausea as the major toxicities. Ixabepilone has modest single-agent activity in patients with recurrent chemosensitive aggressive lymphomas.

Richter Transformation in the Brain from Chronic Lymphocytic Leukemia

Richter syndrome (RS) involves the development of an aggressive lymphoma in patients with chronic lymphocytic leukemia (CLL). Diffuse large B-cell lymphoma (DLBCL) is the most common type of RS. Extranodal RS occasionally occurs; however, isolated lesions in the central nervous system (CNS) of RS are rarely seen and the features have not been well described. We describe a Japanese patient who developed isolated involvements of the parenchyma of the CNS as a manifestation of RS two years after the initial diagnosis of CLL. DLBCL in the cerebrum was confirmed to be clonally related to the CLL cells by immunoglobulin heavy chain (IGH) gene analysis, utilizing the identical VH-D-J regions with additional mutations in the IGH variable region.

Allogeneic Stem Cell Transplantation Is Associated with Prolonged Disease Control in Chemosensitive Aggressive Histology Lymphoma Patients When Done Early

Abstract 4525 IntroductionAllogeneic stem cell transplantation (Allo-SCT) is a treatment option in aggressive histology lymphoma (AG-NHL) patients who have either failed or relapsed after autologous SCT (ASCT) or if the potential for long term disease control after ASCT is limited. There is limited data in literature regarding the long term outcome of allo-SCT in AG-NHL. MethodsWe did a retrospective analysis of all aggressive histology patients who underwent Allo-SCT between 1989 and 2009 at our centre. A total of 41 patients with AG-NHL [diffuse large B cell lymphoma (DLBCL) and variants, follicular lymphoma grade 3 (FL3), biopsy proven aggressive transformation of indolent lymphoma (TRIL)] underwent Allo-SCT. All patients were in a chemosensitive remission at time of transplantation. The conditioning regimen was BU-CY in the majority (36 or 88%) of patients and 3 patients had reduced intensity transplantation (RIC) with fludarabine-based regimens. GVHD prophylaxis was cyclosporine and methotrexate until 2009 and was cyclosporine and mycophenolate mofetil after that. Alemtuzumab was used in matched unrelated donor (MUD) transplants in 5 (12%) cases. ResultsThere were 22 (54%) males and 19 (46%) females. The median age at BMT was 48 years (range: 20–65). Fifteen (37%) had DLBCL, 19 (46%) had TRIL and 7 (17%) had FL3. Fifteen (37%) patients had received 2 or less lines of chemotherapy and 26 (63%) had received more than 2 lines of therapy at time of transplantation. The median number of chemo regimens was 3 (range: 1–7). The chemotherapy regimens included prior anthracyclines in 40 (98%), prior platinum in 26 (63%) and prior mini BEAM in 19 (46%). Six (15%) patients had received Rituximab and 9 (22%) had received prior RT. Seven (17%) patients had prior ASCT. Thirty-five (85%) of patients received matched related donor transplant whereas 5 (12%) received MUD transplant. The graft source was bone marrow in 33 (80%) and peripheral blood stem cells in 8 (20%). Grade 1–2 acute GVHD was seen in 53% and grade 3–4 in 9%. Chronic GVHD was seen in 51% patients. With a median follow up of 49 months and 96 months in those who are alive, five (12%) patients have relapsed, 20 (49%) patients are alive and in remission. Non relapse mortality (NRM) was 16/41 (39%) and predominantly related to infection. The overall survival (OS) and progression free survival (PFS) of the entire cohort at 60 months was 55% (Fig-1). Patients, who had achieved CR pre-allo-SCT (compared to PR) had a statistically significantly improved PFS and OS (100% survival for those who were in CR). In multivariate analysis, number of chemotherapy regimens (≤2) was associated with improved OS (p=0.015) and presence of chronic GVHD showed a trend towards significant OS (p=0.052) ConclusionsWith a median follow up of 96 months in survivors, myeloablative allo-SCT is associated with durable remission in patients with chemosensitive AG-NHL. Results are less favourable in patients who have received multiple prior regimens. NRM remains a significant concern with myeloablative regimens. We believe there is a role for myeloablative regimens and research should focus on ways to reduce NRM in this setting. Disclosures:Gupta:Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. [Display omitted]

Phase I Study of mTOR Inhibitor Everolimus Plus CHOP in Patients with Advanced, Aggressive T-Cell lymphomas

Abstract 1642 Background:Advanced stage T-cell lymphomas usually follow aggressive clinical course and their treatment outcomes are worse than B-cell non-Hodgkin lymphoma. Furthermore, the optimal treatment regimen is still not established for these disease entities. Thus, cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) or CHOP-like regimens are still used as a primary treatment even though their efficacy is not satisfactory. This unmet need of T-cell lymphomas has required the development of more effective regimen. Thus, we incorporated an oral mTOR inhibitor, everolimus (RAD001, Afinitor®) into CHOP regimen to improve its efficacy. The mTOR complex is one of emerging targets in the lymphoma treatment because mTOR signal pathway is used by malignant cells to promote growth and survival. Previous studies demonstrated a single agent activity of mTOR inhibitor against relapsed or refractory lymphomas. Furthermore, several animal study results suggested that the mTOR inhibitor might enhance the effects of vincristine and cyclophosphamide when it was tried in combination with these drugs. Thus, we performed the phase I study to evaluate the feasibility and safety of everolimus plus CHOP chemotherapy for advanced stage, aggressive T-cell lymphomas. Methods:We enrolled patients with newly diagnosed T cell lymphomas including peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL), ALK-negative anaplastic large cell lymphoma (ALCL) and cutaneous T-cell lymphoma (CTCL). Extranodal NK/T-cell lymphoma was excluded because it is resistant to anthracycline-based chemotherapy, and mycosis fungoides was also excluded due to its indolent nature. All patients were Ann Arbor stage III/IV and had adequate organ function. Patients received everolimus from day 1 to day 15 (once daily schedule of four dose levels, 2.5, 5, 7.5, and 10mg/dose) in addition to 750 mg/m2 cyclophosphamide, 50 mg/m2 doxorubicin, 1.4 mg/m2 vincristine on day 1 and 100 mg/day prednisolone on days 1 to 5. Six cycles of therapy administered every 21 days were planned. As a pharmacokinetic study, steady state trough concentrations of everolimus were measured at the end of cycle 1 and 2. All patients provided written informed consents and this trial was registered at www.ClinicalTrials.gov (NCT01198665). Results:Fifteen patients were enrolled between October 2010 and April 2011 including PTCL-NOS (n = 8), AITL (n = 4), ALCL (n = 1) and CTCL (n = 2). Ten patients presented as stage IV (66.7%) and the majority of patients showed serum LDH elevation (n = 13, 86.7%). Thus, the International Prognostic Index risk was dominantly high or high-intermediate (n = 9, 60.0%). There was no dose-limiting toxicity (DLT) at the level I (2.5mg/dose of everolimus) while one patient experienced hematologic DLT (grade IV thrombocytopenia) at the level II (5mg/dose). Thus, after patients were enrolled up to six at the level II, dose of everolimus was escalated to 7.5mg (level III). At the level III, two patients experienced DLT (grade IV thrombocytopenia and febrile neutropenia) among six patients enrolled. Therefore, the maximum tolerated dose for everolimus was determined as 5mg. In the evaluation of pharmacokinetic profile, there were no differences in the trough concentrations of everolimus between cycle 1 and 2 for all of these three dose groups. There was no dose-limiting non-hematologic toxicity in the all three dose levels. Although the main toxicity of everolimus was hematologic toxicity and it was overlapped with the toxicity of CHOP regimen, these hematologic toxicities were manageable. Among 15 patients, 14 patients responded to the treatment including 7 complete responses and 7 partial responses. However, five patients relapsed or progressed during follow-up. Conclusions:Everolimus can be safely combined with CHOP chemotherapy and constitutes an active regimen in advanced stage, aggressive T-cell lymphoma patients. The recommended dose for subsequent phase II study of everolimus plus CHOP is 5 mg/dose of everolimus once daily for 15 days as first-line treatment. Disclosures:No relevant conflicts of interest to declare.

Early Macrophage and Mast Cell Responses in Diffuse Large B-Cell Lymphoma After Immunochemotherapy

Abstract 5206 Background:The prognostic impact of tumor microenvironment on the survival of lymphoma patients has recently been reported. However, early molecular and cellular responses to immunochemotherapy are unknown. Here, we have compared the tumor-associated macrophage (TAM) and mast cell (MC) contents in the lymphoma tissue in vivo before and after the first immunochemotherapy course in a small cohort of aggressive B-cell lymphoma patients. Patients and methods:The population of this pilot study consisted of seven diffuse large B-cell lymphoma (DLBCL) and three grade IIIB follicular lymphoma (FL) patients treated with rituximab in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)-like regimen (immunochemotherapy). Paired tumor samples were collected before and a day after the first course of therapy, and evaluated immunohistochemically for CD68+, CD163+ macrophages and tryptase+ MCs. Freshly frozen lymphoma tissue containing enough material for paired mRNA analyses was available from 8 patients. Results:Comparing pre- and post-treatment tissue samples, an increase in the number of CD68+ TAMs was observed (p=0.023), whereas no variation in MC contents was found. If the patients were grouped according to response, i.e. remission (n=7) vs relapse (n=3), the most significant increase after therapy was observed in M2-type CD163+ TAM content (p=0.001). In the exon array analyses, the mRNA levels of both CD68 (p=0.052) and CD163 (p=0.023) genes increased after therapy. Conclusions:Our preliminary data suggest significant changes in macrophage content and their relative subsets in the lymphoma microenvironment after the first course of immunochemotherapy. Disclosures:No relevant conflicts of interest to declare.

An Index of SNPs in Immune Genes May Enhance the Prognostic Value of IPI in Patients with Aggressive Non-Hodgkin's Lymphoma

Abstract 2653 INTRODUCTION:Non-Hodgkin's lymphoma (NHL) is a heterogeneous disease. The current International Prognostic Index (IPI) is useful, but not perfectly predictive and there is a need for a more precise prognostic index. The host immune response to cancer has been shown to predict outcome in multi-variate analyses in many types of cancer. We hypothesized that its genetics may contribute to prognostication. We focused on an evaluation of inherited functional polymorphisms in key immune genes that have previously been shown by others to influence outcome in various cancers. The objective was to determine whether an index of SNPs that alter function of critical immune system genes would enhance the predictive value of the IPI in patients with aggressive NHL.PATIENTS AND METHODS: Our study cohort consisted of 192 patients with NHL enrolled at diagnosis between 1990 and 1996. Patients provided informed consent and demographic, clinical and outcome data as well as tumor and blood samples were collected and stored on all patients. Patients were treated as per the standard of care at the time. 124 were of the aggressive type while 68 were low grade. We focused on the aggressive cohort in this analysis. DNA was extracted from blood, bone marrow and biopsy tissue. We evaluated the following genes; IL1A rs1800587, CXCR2 rs1126580, IL4R rs2107356, TNF rs1800629, IL4R175V rs454078, IL8 rs4073, FCGR3A rs396991, P2RX7 rs3751143, IL12B rs3212227. Genotyping was performed using allele-specific PCR primers tagged with GC tails to enhance melting point discrimination. PCR reactions were set up with the aid of a robot and run on a real-time PCR instrument. Kaplan-Meyer curves were generated for the overall survival of each genotype. Univariate analysis was performed to compare genotypes with IPI score, IPI factors and disease bulk. RESULTS:We evaluated relationships to existing standard prognostic factors. We found a significant relationship between IL12B CC carriers and IPI score 0–1 (p=0.0012). Patients with IL12B CC had less extranodal disease, lower stage and bulk. We modeled the data to identify combinations of SNPs with the most predictive power. The most predictive genotype combination included the genes for IL8, IL12B, IL4R, CXCR2 and TNF. A SNP score, determined by the number of favourable genotypes, showed significance in survival, p=0.004 [fig.1]. The group of 68 patients with an IPI score of 2–3 was analyzed to determine whether the SNP score could distinguish outcome within this IPI group [fig 2]. Patients with 3 of these favourable alleles had significantly improved survival [HR= 2.791]. Scoring with an index made up of three genes-IL8, CXCR2 and TNF alone -was also significant, p=0.02 [not shown]. CONCLUSIONS:We evaluated 10 SNPs with functional consequences on the immune response in a population of previously untreated aggressive lymphoma patients undergoing standard management. We found that a combination of SNPs statistically predicted outcome of these 124 patients with aggressive lymphoma. Although Habermann et al [Blood 2008 112(7); 2694–2702] had created a SNP score based on IL1A, IL8RB (CXCR2), IL4R and TNF, we have found that outcome is best predicted in our cohort with IL8, IL12, CXCR2, IL4R and TNF. A useful model could also be obtained using 3 SNPS (IL8, CXCR2 and TNF). Our results are important in that we have shown that this combination of SNPs can further enhance prognostification beyond IPI. Specifically statistically significant overall survival differences in IPI 2,3 patients was found based upon the SNP score using IL8, IL12, CXCR2, IL4R and TNF and the three-SNP combination. Incorporating SNP scores into IPI may be a useful strategy to further identify patients with increased likelihood of improved or adverse outcomes. [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Significant Prognostic Impact of [18F]Fluorodeoxyglucose-PET Scan Performed During and At the End of Treatment with R-CHOP in High-Tumor Mass Follicular Lymphoma Patients: A GELA-GOELAMS Study

Abstract 877 Introduction:Patients with follicular lymphoma (FL) usually respond well to immuno-chemotherapy as initial treatment and can have long survival times. However, a small proportion of patients are refractory or have early relapses. Early identification of this subgroup of patients could lead to early therapeutic changes and, potentially, to a better prognosis. [18F]Fluorodeoxyglucose-Positron Emission Tomography (FDG-TEP) is widely used for the staging and restaging of aggressive lymphoma patients but little is known about the use of FDG-PET in patients with FL, except that FL is almost uniformly FDG-avid. FDG-PET is not recommended today as a routine procedure in FL patients (Cheson et al. J Clin Oncol 2007). In this first prospective, multicentric study, we evaluated the prognostic value of FDG-PET performed at mid-treatment and at the end of treatment in patients with high-tumor mass FL treated with immuno-chemotherapy in first line. Patients & methods:Patients with previously untreated FL (grades 1–3A) presenting with a high tumor burden as defined by the GELF criteria, were treated with 6 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) plus 2 cycles of rituximab, given every 21 days. Patients did not receive rituximab maintenance. A FDG-PET was performed before treatment, after 4 cycles of R-CHOP (interim FDG-PET: I-PET), and at the end of treatment (final PET: F-PET). FDG-PET scans were first interpreted in each centre, then centrally reviewed by 3 investigators blinded to clinical data. Positivity or negativity was rated according to the Deauville visual semi-quantitative criteria (Meignan M: Leuk Lymphoma 2009), positivity being defined as a fixation at level 4 (FDG uptake superior to that of the liver) or 5 (uptake clearly superior to liver and/or new sites of disease). Results:121 patients were included. The median age was 57 years and the male-to-female ratio was 1.12. Ninety-three percent had Ann Arbor stage III–IV. Ninety-seven percent had a good performance status (ECOG score 0–1). The repartition according to the FLIPI was: 0–1 factors: 15%; 2 factors: 43%; 3–5 factors: 42%. The Kappa coefficient indicated a good degree of concordance between the 3 PET reviewers. The initial FDG-TEP was positive in all except 1 case out of 118 centrally reviewed cases. After central review, I-PET (n=111) was negative in 76% of patients and F-PET (n=106) was negative in 78%. With a median follow-up of 23 months, 2-year-progression-free survival rates for I-PET negative versus positive and for F-PET negative versus positive were I-PET 86% versus 61% (p=0.0046); F-PET 87% versus 51% (p <0.0001), respectively. Two year OS at the end of treatment also significantly differed according to F-PET results: 100% vs 88% (p = 0.0128). Conclusion:In FL patients treated in first line, FDG-PET performed either after 4 cycles of R-CHOP or at the end of immunochemotherapy induction is strongly predictive of outcome. Therapeutic intervention based on TEP results during inductive treatment should be evaluated in the future. Disclosures:Salles:Roche and/or Genetech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genzyme: Membership on an entity's Board of Directors or advisory committees; Calistoga/Gilead: Membership on an entity's Board of Directors or advisory committees.

Aflibercept-mediated early angiogenic changes in aggressive B-cell lymphoma

Diffuse large B-cell lymphoma is the most common and one of the most aggressive lymphomas in adults. The standard, R-CHOP-based treatment needs improvement. There has been recent interest in anti-angiogenic therapy, but its cellular effects in lymphoma are little known. In five aggressive B-cell lymphoma patients, we analyzed the microvessel and lymphoma cell changes after Aflibercept, an angiogenic inhibitor. Under ultrasonography, we performed two biopsies, one before any treatment and one two hours after Aflibercept, before R-CHOP. Using ultrasonography, immuno-histochemistry, double immuno-fluorescent staining, and electron microscopy, we compared the early changes induced by Aflibercept to the early changes induced by R-CHOP in three control patients. We identified microvessel damage in the five patients treated with Aflibercept but not in the three patients treated with R-CHOP. Two hours after Aflibercept, microvessel damage was focal, with severely damaged microvessel sections close to normal ones in the same area; different stages of microvessel damage were concomitantly found, with an increase in relative necrosis area in three cases. There was no difference in necrosis or relative microvessel area after R-CHOP. For lymphoma cells, the two biotherapies induced similar changes, with increase in apoptosis but not in proliferation. We identified focal microvascular damage, necrosis, and apoptosis of lymphoma cells in aggressive B-cell lymphoma as soon as 2h after Aflibercept. This suggests that there is more than one mechanism associated with the early effect of anti-angiogenic therapy in lymphoma.

Whole-body diffusion-weighted imaging compared with FDG-PET/CT in staging of lymphoma patients

Diffusion-weighted imaging (DWI) has become increasingly valuable in lymph node imaging, yet the clinical utility of this technique in the staging of lymphoma has not been established. To compare whole-body DWI with FDG-PET/CT in the staging of lymphoma patients. Thirty-one patients, eight with Hodgkin lymphoma (HL) and 23 with non-Hodgkin's lymphoma (18 aggressive and five indolent) underwent both whole-body DWI, whole-body MRI (T1W and T2W-STIR) and FDG-PET/CT. Lesions on whole-body DWI were only considered positive if they correlated with lesions on T1W and T2W-STIR images. The staging given by each technique was compared, according to the Ann Arbor staging system. Differences in staging were solved using biopsy results, and clinical and CT follow-ups as standard of reference. The staging was the same for DWI and FDG-PET/CT in 28 (90.3%) patients and different in three (9.7%). Of the 28 patients with the same staging, 11 had stage IV in both techniques and 17 had stages 0-III. No HL or aggressive non-Hodgkin's lymphoma patients had different staging. Three indolent small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL) lymphoma had higher staging with DWI when compared with FDG-PET/CT. One small subcutaneous breast lymphoma was not seen but all other extranodal sites were detected by both techniques. Whole-body DWI is a promising technique for staging of both (aggressive and indolent) non-Hodgkin's lymphoma and HL.

Incorporation of ABVD Increases Cure Rates of Patients with Limited Stage Nodular Lymphocyte Predominant Hodgkin Lymphoma (NLPHL)

AbstractAbstract 3887 Background:The appropriate therapy for limited stage NLPHL is the subject of debate. With favorable outcomes frequently reported, attempts have been made to reduce acute toxicity. In contrast to classical Hodgkin lymphoma, chemotherapy (CT) is often omitted; however, whether this omission affects outcome is unknown. At the BC Cancer Agency (BCCA), treatment guidelines are centrally driven and practiced throughout the province, facilitating survival comparisons across different treatment eras. Herein, we evaluated the outcome of patients with limited stage NLPHL treated with incorporation of ABVD (CT era) compared to those treated in the radiotherapy (RT) era. Patients and methods:The BCCA Lymphoid Cancer Database was used to identify all patients with limited stage NLPHL (non-bulky (<10cm) stage IA, 1B, 2A). Initially 106 patients were identified, however, following pathology and chart review 17 were excluded due to: an alternate lymphoma diagnosis (n=3); (non Hodgkin lymphoma not otherwise specified n=1; diffuse large B-cell lymphoma n=1; composite lymphoma n=1); diffuse morphology and blocks were not available for immunohistochemistry (n=2); benign histology (n=2); concurrent epithelial cancer (n=1); diagnosis out of province (n=9). Of the remaining 89 patients, 78 (88%) had a confirmed diagnosis of NLPHL and in 11 cases (12%), the slides or paraffin blocks were unavailable for re-review. In general, patients were treated according to era-specific guidelines: Before 1993 (n=33) extended field radiotherapy (RT); 1993-present (n=56) ABVD-like CT for 2 cycles with extended field RT (1993-1995), involved field RT (1995-2001) or involved nodal RT (2001-present) with the exception of 11 patients who received ABVD alone. Results:The majority of patients were male (67%), with a median age of 36.5 y (15-77) and 55 had stage I disease (62%). With a median follow-up of 6.4 y for living patients (range 1.2–40.5 y), the 10 y time to progression (TTP), progression-free survival (PFS) and overall survival (OS) for all 89 patients were 86%, 78% and 88%, respectively. Most patients were treated using the above guidelines except for 2 patients who were treated with MOPP CT + RT (physician's discretion) in the RT era and 6 patients treated solely with RT in the CT era (initial therapy out of province (n=1); high neck presentation (n=3); CT refusal (n=1); cardiac disease (n=1). In addition, 2 patients had undergone surgical resection alone in the RT era because the diagnosis of NLPHL was made retrospectively. In an era to era comparison, the 10 y TTP (98% v 74% p=0.0043, see figure 1), PFS (91% v 63%, p=0.0015) and OS (93% v 82%, p=0.053) favored the CT treatment era (> 1993) compared to the RT treatment era. Interestingly, there have been 5 cases of transformation to aggressive lymphoma in patients treated in the RT era and none in the CT era.In an ‘as treated’ analysis, patients given CT (n=52) had a superior 10 y TTP (97% v 77.5, p=0.0108) and PFS (90% v 66.5%, p=0.0035) versus those treated exclusively with RT (n=35). The sole patient who relapsed after CT had received MOPP. No patients treated with ABVD (n=50) have relapsed or developed transformed lymphoma. In multivariate analysis including treatment era, age >40 y, stage II disease, mass size > 5 cm and male sex, treatment in the CT era was the only factor impacting TTP (p=0.022, HR .088 (CI .011, .702)) and PFS (p=0.001, HR .126 (CI .028, .464)) and there was a trend towards an improved OS (p=.089 HR .156 (CI .018, 1.324). Conclusion:Since the introduction of ABVD CT into the treatment of patients with limited stage NLPHL, outcomes have improved considerably and patients are more likely to be cured of their lymphoma. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Consolidation Anti-CD22 Fractionated Radioimmunotherapy with 90Y Epratuzumab Tetraxetan Following R-CHOP In Elderly DLBCL Patients

AbstractAbstract 2875 Background:Radioimmunotherapy (RIT) is under study as a consolidation treatment after chemotherapy induction in follicular lymphoma patients. This approach also appears interesting in diffuse large B-cell lymphoma (DLBCL) patients >60 years, who are not candidates for bone marrow transplantation. 90Y-epratuzumab tetraxetan (Immunomedics, Inc.) is a radiolabeled humanized anti-CD22 antibody that has been used for a fractionated RIT, showing high rates of durable complete responses with manageable hematologic toxicity in previously-treated indolent and aggressive non-Hodgkin lymphoma (NHL) patients (Morschhauser et al., J Clin Oncol. 2010;28(23);3709-16). A French phase II trial sponsored by the GOELAMS group is ongoing, assessing fractionated RIT using 90Y-epratuzumab tetraxetan as a consolidation therapy after first-line chemotherapy in disseminated DLBCL patients >60 years. The protocol has been designed to include 75 patients; 64 patients have been already enrolled. We report the initial results, in particular safety data, on the first 29 available patients. Design and Method:From October 2008 to November 2009, 29 untreated DLCBL patients >60 years were studied in several French institutions with an initial course of six cycles of R-CHOP14 followed 8 weeks later by two weekly infusions of 90Y-epratuzumab tetraxetan (15 mCi/m2 [555 MBq/m2]) 7 days apart. Hematologic and non-hematologic toxicities were evaluated using NCI-CTC v.3.0. Treatment responses were classified according to the 1999 International Workshop for Response Criteria for NHL. Results:Twenty-six patients underwent the entire course of R-CHOP and 23 received the 2 weekly RIT injections. Following R-CHOP, grade 3–4 neutropenia was observed in 20 patients (68.9%) and grade 3–4 thrombocytopenia in 4 (13.7%). During RIT infusions, 4 patients showed transient change of pulse or blood pressure, with 2 attributed to vasovagal reactions. RIT toxicity included grade 3–4 hematologic toxicity in 18 of 23 patients (78.3%); the most common grade > 3 toxicities were neutropenia (N=18, 78.3%) and thrombocytopenia (N=17, 73.9%). Serious febrile neutropenia was observed in 4 cases (13.8%) after R-CHOP and in 2 patients (8.7%) following RIT. Compared to R-CHOP, RIT non-hematologic toxicity was uncommon; moderate or severe gastrointestinal toxicity was observed in 10 patients (34.5%) after R-CHOP and in 2 (8.7%) following RIT; moderate or severe infection in 9 patients (31.0%) after R-CHOP and in 1 (4.3%) after RIT; and moderate or severe mucositis in 10 (34.4%) patients following R-CHOP, while no patient had mucositis after RIT. Following RIT, red cells and/or platelets transfusions were given to 12 patients (52,2%). Following R-CHOP, 10 of the 25 patients (40.0%) achieved a complete response (CR) or unconfirmed CR (CRu), 13 patients (52.0%) had a partial response (PR) and 2 patients (8.0%) had a stable disease. Six weeks after RIT, 13 patients (56.5%) achieved a CR or CRu, 9 patients (39.1%) had PRs, and 1 patient (4.3%) had progressive disease. Four of 13 patients (30.7%) who achieved less than a CR or CRu with R-CHOP improved their remission status 6 weeks after RIT. Conclusion:These preliminary results indicate the feasibility and safety of fractionated RIT with 90Y-epratuzumab as a consolidation therapy for elderly DLBCL patients. Additional data will be presented at the time of the communication. Disclosures:Off Label Use: monoclonal antibody epratuzumab labeled with yttrium 90 in phase II clinical trial. Wegener:Immunomedics, Inc.: Employment, shareholders. Goldenberg:Immunomedics, Inc.: Employment, shareholders.

Defining Outcomes in Hispanic Aggressive Non-Hodgkin Lymphoma Patients.

Abstract 4542 BackgroundMultiple studies evaluating outcomes for oncology patients have demonstrated inferior overall survival rates among African-Americans. Hispanics comprise the largest ethnic minority in the United States. Surprisingly outcomes for Hispanic aggressive non-Hodgkin lymphoma (NHL) patients have not been evaluated and are therefore largely unknown. We aim to identify differences in epidemiology, treatment modalities and outcomes of Hispanic patients treated for aggressive NHL at our institution between the years 2000-2004. MethodsWe reviewed the medical records of 82 patients with aggressive type NHL who were identified using the tumor registry. Exclusion criteria include indolent and highly aggressive lymphomas per WHO classification as well as lymphomas related to AIDS or organ transplantation. Standard statistical analyses, including Kaplan-Meier survival estimates and Chi-squared analysis for group comparisons were used. P value of <0.05 was considered statistically significant. ResultsOf the 82 patients, 46 were self-reported Hispanic in origin; 36 were non-Hispanic. There were no significant differences with respect to age at diagnosis, LDH level, stage, or complete remission rate. Kaplan-Meier estimate of median overall survival (OS) of the cohort was 3.8 years with no statistically significant differences observed between the Hispanic and non-Hispanic ethnic groups. (P = 0.816). ConclusionEthnic patterns of disease occurrences have been reported, but responses to treatment and outcome for Hispanic patients have not been established. Interestingly from our preliminary analysis, there appears to be no statistically significant difference in overall survival between Hispanic and non-Hispanic patients. Further evaluation is warranted. Disclosures:No relevant conflicts of interest to declare.

Serum Interleukin-18 Level Determines Clinical Outcome in Patients with Diffuse Large B-Cell Lymphoma in Rituximab Era.

Abstract 1926Poster Board I-949 Purpose:Diffuse large B cell lymphoma (DLBCL) is a heterogeneous entity, with patients exhibiting a wide range of outcomes. The introduction of rituximab to CHOP (R-CHOP) has significantly altered improvement in survival. This raises concern regarding the utility of previously identified prognostic factors. Before rituximub era, some investigators have suggested that serum levels of some cytokines and their soluble receptors might reflect tumor growth and host tumor responses. Interleukin-18 (IL-18), originally designated as an interferon (IFN)-gamma inducing factor, is a cytokein which stimulates cytotoxic NK cell activity and T cells to produce IFN-gamma, IL-2, and GM-CSF. Increased IL-18 serum levels have been found in patients with some hematopoietic neoplasms. IL-18 is also immunostimulatory cytokine with antitumor activity in preclinical models, and a phase I study of recombinant human IL-18 was done to patients with advanced cancer. We have previously reported that IL-18 was strong prognostic factor in aggressive lymphoma patients who received CHOP without rituximab (ASH 2004, abstract #4543). The aim of the present study is to re-assess the prognostic significance of serum IL-18 in DLBCL treated with rituximab, and we also assessed IL-18 with subtype of DLBCL, GCB type and non GCB type. Meterials and methods:Consecutive 154 previously untreated patients with DLBCL prospectively participated in this study between 2002 and 2008. The patients were treated with 6-8 cycles of R-CHOP or R-THP (pirarubicin) -COP regimens. There was no difference with CHOP and THP-COP in our recent prospective randomized study (Tsurumi H et. al. JCRCO 2004). Serum IL-18 was determined by ELISA, and we classified subgroups of DLBCL according to Hans et al. Results:In all patients with DLBCL, the mean ± SD of serum IL-18 level was 829.5±1280.8 pg/ml (range 56 - 8697.5) with a median of 415.8 pg/ml. Various poor prognostic features, such as poor PS, many extranodal sites, advanced disease (CS III/IV) increased LDH and elderly people were strongly associated with a high serum IL-18 levels. The median serum IL-18 levels of the different IPI risk groups were as follows: 201pg/ml for the L risk; 361pg/ml for the LI risk; 440pg/ml for the HI risk; 691pg/ml for the H risk, respectively (P<0.0001). A similar result was provided in rivised IPI (219pg/ml for the very good risk; 271 pg/ml for the good risk; 658 pg/ml for the poor risk, respectively P<0.0001). In addition, the serum IL-18 levels were higher in the non-GCB subgroup than in the GCB subgroup (P<0.005). Patients with high IL-18 (500 pg/ml and over) at onset had significantly lower progression free survival (PFS) rates (5-year: 52%), than those with low IL-18 (5-year: 79 %), respectively (P<0.0001). and In both GCB and non-GCB subgroups, patients with high IL-18 had significantly lower progression free survival rates (GCB and low IL-18:5-ys PFS 90%, GCB and high IL-18 %:5-ys PFS 58%, non-GCB and low IL-18:5-ys PFS 65%, non-GCB and high IL-18:5-ys PFS 42% ; P<0.001). Multivariate analysis employing IL-18 and some conventional prognostic factors demonstrated that age, PS and IL-18 for PFS were poor prognostic factors. Conclusion:These results suggest that, in even rituximab era, a high serum IL-18 level predicts a poor prognosis of DLBCL and may be a useful biomarker for selecting appropriate treatment. Upfront high dose chemotherapy might be well indicated for non-GCB type DLBCL patients with serum high IL-18. Disclosures:No relevant conflicts of interest to declare.

Cerebrospinal Fluid Flow Cytometry Analysis in Newly Diagnosed Aggressive Non-Hodgkin Lymphomas at High Risk for Leptomeningeal Disease: Result of a Multicentric Prospective Italian Study.

Abstract 2919Poster Board II-895 Background:Flow cytometry (FCM) assessment of cerebrospinal fluid (CSF) has recently been known to increase the rate of positivity of occult leptomeningeal disease (LD) in comparison to conventional cytologic examination (CC). However it's still unknown its prognostic value. Patients and methods: The aim of this study was to compare CC vs FCM in a large cohort of patients with newly diagnosed aggressive NHL at high risk for LD (diffuse large B-cell lymphoma (DLBCL) IPI 2-3 and elevated LDH with at least two extranodal sites or with bone marrow, testis, paranasal sinuses, orbit or paravertebral involvement; Burkitt lymphoma (BL); blastoid variant of mantle cell lymphoma (B-MCL); B-cell precursor lymphoblastic lymphoma (B-LL); HIV+ aggressive lymphoma patients). All patients were required to have no evidence or signs of neurological disease. All patients received intrathecal standard prophylactic therapy with 12 mg of methothrexate except for BL that were given prophylaxis with 50 mg of liposomial aracytin for a total of 4 doses. CFS samples were analysed both with CC and FCM. The incidence of positive test for occult LD with FCM and CC was compared using the McNemar test for paired data. Results:Between August 2004 and June 2008, a total of 159 consecutive patients were enrolled in 11 Italian centres and underwent evaluation of CSF. Out of these, 128 patients (80%) were considered at high risk of occult LD. Clinical characteristics were: median age 53 years (IQR:43-62); DLBCL 96 patients (75%); BL 21 pts (16%); B-MCL 6 pts (5%); B-LL 5 pts (4%); 26 pts (20%) were HIV positive. FCM was able to detect a clonal population in 17 out of 128 patients (13%) whereas CC detected abnormal cells only among 7 pts (5%)(p= 0.0002). Therefore, 10 patients (8%) were discordant: FCM+/CC-. Among the 128 patients, there was no association between the CFS total protein, glucose level and the presence of positive analysis of FCM, whereas the difference between the number of WBC cells in CSF was significantly higher in patients with positive versus negative FCM with a median value of 12 cells/ul (IQR: 3.5;40) versus 1.0 cells/ul (IQR: 0.0;3.0) (p=0.0120). Univariate and multivariate analyses, using logistic models, showed that abnormal LDH (OR 3.98, 95%CI: 1-15.92)(p=0.05) and number of WBC cells in CSF ≥5 (OR 4.57, 95%CI:1.37-15.33)(p=0.014) were the only predictive factors of a positive test performed by FCM. From date of diagnosis, overall median follow up of survivors was 14 months (IQR:8-22). We observed 39 (30%) systemic progressions, 6 (5%) CNS progressions (in 5 cases an isolated CNS progression whereas 1 pts experienced a CNS along with systemic progression). Thirty-two (25%) patients died and causes of deaths were as follows: 27 progressive disease, 1 infection, 1 treatment related toxicity, 1 hepatitis, 2 unknown. PFS at 1 year was 71% (95%CI:62-78) in the whole group of patients. The progression risk was significantly higher in patients both FCM+/CC+ compared with patients both FCM-/CC- (1-yr PFS 43% vs 74%) (HR 3.8 95%CI:1.6-9.0) (p=0.003). An higher but not significant risk of progression was found in pts discordant (FCM+/CC-) with respect to patients both FCM-/CC- (1-yr PFS 65% vs 74%) (HR 1.61, 95%CI:0.63-4.11) (p=0.315). In the univariate and multivariate analyses performed with Cox models, we found that the presence of ECOG PS≥2 (HR 2.14, 95%CI: 1.14-4)(p=0.018) and level of protein in CSF >40/ul (HR 1.83 95%CI: 1.01-3.29)(p=0.045) were prognostic factor of PFS. Conclusion:FCM assessment of CSF increase the rate of positivity of occult LD compare with CC but it's clinical relevance is still to be clearly defined. Our preliminary data suggest that patients both FCM+/CC+ have an higher risk of progression compared with those both negative, whereas discordant cases may have an intermediate prognosis. [Display omitted] Disclosures:No relevant conflicts of interest to declare.