Anti-lymphoma Treatment Research Articles

Clinical and prognostic analysis of 78 patients with human immuno-deficiency virus associated non-Hodgkin\u2019s lymphoma in Chinese population

BackgroundHuman Immuno-deficiency Virus (HIV) associated non-Hodgkin’s lymphoma (NHL) was a special group of disease, which manifests distinct clinical features and prognosis as compared with NHLs in patients without HIV. We performed this study to describe the clinical features of the disease and investigated the potential prognostic factors.MethodsHIV-infected patients who were newly diagnosed with NHL were enrolled in this study. The selection of anti-lymphoma treatment regimen was mainly dependent on the pathological subtypes of NHLs. Tumor response was reviewed and classified according to the International Workshop Criteria.ResultsA total of 78 patients were enrolled, among whom, 42 (53.8%) were with Diffuse large B cell Lymphoma (DLBCL), and 29 (37.2%) were with Burkitt lymphoma (BL). BL patients presented with higher risk features as compared with DLBCL in terms of numbers of extranodal diseases (P = 0.004) and poor Eastern cooperative oncology group (ECOG) score (P = 0.038). The estimated 2-year overall survival (OS) and progression free survival (PFS) rate was 74.3 ± 8.1%, 28.9 ± 11.0%, and 54.2 ± 8.1%, 19.2 ± 7.5% for DLBCL and BL, respectively. In multivariate analysis, international prognostic index (IPI) score was an independent prognostic factor for predicting both OS (OR = 2.172, 95% CI 1.579–2.987, P < 0.001) and PFS (OR = 1.838, 95% CI 1.406–2.402, P < 0.001).ConclusionsHIV associated NHLs represents a group of heterogeneous aggressive diseases with poor prognosis. IPI parameters were still effective in predicting the prognosis of HIV associated NHLs.

Obinutuzumab plus Bendamustine Followed by Obinutuzumab Maintenance Prolongs Overall Survival Compared with Bendamustine Alone in Patients with Rituximab-Refractory Indolent Non-Hodgkin Lymphoma: Updated Results of the GADOLIN Study

Obinutuzumab plus Bendamustine Followed by Obinutuzumab Maintenance Prolongs Overall Survival Compared with Bendamustine Alone in Patients with Rituximab-Refractory Indolent Non-Hodgkin Lymphoma: Updated Results of the GADOLIN Study

Longer Term Efficacy and Safety of Subcutaneous Compared with Intravenous Rituximab: Updated Results of the Phase 3 SABRINA Study

Longer Term Efficacy and Safety of Subcutaneous Compared with Intravenous Rituximab: Updated Results of the Phase 3 SABRINA Study

Rituximab Plus Lenalidomide Versus Rituximab Monotherapy in Untreated Follicular Lymphoma Patients in Need of Therapy. First Analysis of Survival Endpoints of the Randomized Phase-2 Trial SAKK 35/10

Background: The randomized phase-2 trial SAKK 35/10 was conducted by the Swiss Group for Clinical Cancer Research (SAKK) and the Nordic Lymphoma Group (NLG) to compare the activity of single-agent rituximab versus rituximab plus lenalidomide in the first-line treatment of symptomatic follicular lymphoma (FL). The results of primary endpoint (complete remission [CR/CRu] at week 23) assessment were previously reported, showing that addition of lenalidomide to rituximab results in a significantly higher CR/CRu rate at the expected cost of increased but manageable toxicity (Kimby et al. Blood 2014.124 (21):799; Zucca et al. Hematol Oncol 2015. 33(s1): 105). Here we report the first analysis of secondary endpoints, progression-free survival (PFS), time to next anti-lymphoma treatment (TTNT), CR duration, as well as CR/CRu rate at 30 months (CR30).Methods: 154 patients (pts) with grade 1 to 3a FL, untreated and in need of systemic therapy, were randomized to receive either rituximab (375mg/m2 at week 1, 2, 3, 4, 12, 13, 14 and 15) or rituximab (same schedule) plus lenalidomide (15 mg daily, from 14 days before the first until 14 days after the last rituximab administration). The sample size was calculated to allow the detection of a 20% increase of the CR/Cru rate with 90% power and type I error 0.10; a one-sided Z-test for proportions was used to compare the two arms. Treatment was discontinued in pts who did not achieve at least a 25% reduction in the sum of products of tumor diameters at week 10. Primary and secondary endpoints were defined according to the NCI international standardized criteria (Cheson et al 1999).Results: 77 pts (median age 63 years, 52% with stage IV and 47% with poor-risk FLIPI score) were allocated in the single-agent rituximab arm and 77 (median age 61 years, 48% with stage IV and 47% with poor-risk FLIPI score) in the combination arm. A higher CR/CRu rate in the combination arm was documented both by the investigator assessment (36% vs 25%) and by the independent response reviewers of CT scans (61% vs. 36%). Adverse events of grade ≥3 were more common (56% vs 22% of pts) in the combination arm, including neutropenia (23% vs 7%). At a median follow up of 3.1 years, a longer CR duration was seen for the pts in the combination arm (median not reached vs 2.3 years) as well as a longer PFS (median not reached vs. 2.3 years), these differences were not statistically significant. The CR30, recently identified as a reliable surrogate of PFS (Sargent et al. Hematol Oncol 2015. 33(s1): 166), was significantly improved by the addition of lenalidomide to rituximab (42% vs 19%, p=0.001). Moreover, TTNT was significantly longer with the combination (median not reached vs 2.1 years, p=0.02) [Figure1]. Overall survival rates at 3 years were 93% and 92%, respectively.Conclusions: The SAKK 35/10 randomized trial confirmed that lenalidomide plus rituximab is an active and feasible initial treatment for FL pts in need of therapy. Addition of lenalidomide significantly increased the CR/CRu rate at week 23 (primary endpoint) and was maintained throughout 30 months. Although the trial was not powered to detect survival differences (secondary endpoints), a significantly better TTNT and a trend towards prolonged PFS and CR duration was seen in the combination arm. The excellent overall survival in both arms suggests that chemotherapy-free strategies should be further explored. [Display omitted] DisclosuresKimby:Jansen: Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lecture at educational session; Celgene: Other: Honoraria for lecture. educational meeting; Pfizer: Other: Research grant; Roche: Other: Honoraria for lecture in educational meetings; Gilead: Honoraria, Other: honoraria for educational lecture in meeting sponsored by Gilead. Mey:roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Research Funding. Wahlin:Roche: Consultancy. Hernberg:Roche: Consultancy, Honoraria. de Nully Brown:Roche: Research Funding. Ferreri:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Zander:Bristol Myers, Celgene, Amgen, Mundipharma, Janssen-Cilag, Takeda Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees.

PC3 - 128 Clinical Profile and Treatment Outcomes of Patients with Primary CNS Lymphoma in a Tertiary Hospital in the Philippines: An Eight-Year Retrospective Review

Primary CNS Lymphoma (PCNSL) is an unusual extranodal form of Non-Hodgkin’s lymphoma with a locally aggressive course but a rare tendency to disseminate systemically. It has been documented in that the clinical characteristics and response to treatment among Asians is comparable to the Western population yet no studies done locally are available. Objectives: This study aims to determine the clinico-pathologic profile of patients diagnosed with PCNSL seen at Philippine General Hospital (PGH) from January 2006 to September, 2014 and to evaluate the patients’ response to the following treatment modalities: 1) Combination chemotherapy 2) Chemo-RT 3) Single agent chemotherapy and 4) no specific anti-lymphoma treatment. Methodology: This is a descriptive and retrospective study that included all cases of histologically-proven PCNSL seen at the PGH from January 2006 to September, 2014. The clinical profile, imaging studies and biopsy findings were obtained from the patient records. The survival rates at the end of one and two years of diagnosis were computed. Results and Conclusion. Among patients diagnosed with PCNSL at PGH, there is a higher incidence of PCNSL among males with a male to female ratio of 1.4:1 and have a younger onset with a median age of 50.2 years. Most patients presented with signs of increase ICP and majority had solitary cortical lesions with histopathologic diagnosis of diffuse large B cell lymphoma. Patients who did not undergo any form of treatment had a mean survival of 10 months. Immunocompromised patients had a shorter life-span with a mean survival of 7.5 months. Treatment of combination chemotherapy with HD-MTX and Rituximab had the most favorable outcome followed by HD-MTX only with a 2 year survival rate of 100% and 66% respectively while patients who underwent chemo-RT had a 2 year survival rate of 33% with a high incidence of neurocognitive delay.

Proportion of false-positive lesions at interim and end-of-treatment FDG-PET in lymphoma as determined by histology: Systematic review and meta-analysis

PurposeTo systematically review and meta-analyze the proportion of false-positive lesions at interim and end-of-treatment 18F-fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) in lymphoma using biopsy as reference standard. Materials and methodsMedline was searched for original studies. Methodological quality of included studies was evaluated, and results were meta-analytically summarized using random effects (in case of interstudy heterogeneity [I2≤50%]) or fixed effects (in case of no interstudy heterogeneity [I2>50%]). ResultsEleven studies, comprising 139 patients who underwent biopsy of an FDG-avid lesion during or after completion of antilymphoma treatment, were included. Overall methodological quality was moderate. The proportion of false-positive results among all biopsied FDG-avid lesions at PET performed during of after completion of treatment ranged between 7.7% and 90.5% (the vast majority was due to inflammatory changes), with a weighted summary proportion (random effects, I2=75.7%) of 55.7% (95% confidence interval [CI]: 32.6–76.6%). There were no available studies on interim FDG-PET in Hodgkin lymphoma. The pooled summary false-positive proportions were 83.0% (95% CI: 72.0%–90.2%) for interim FDG-PET in non-Hodgkin lymphoma (fixed effects, I2=27.7%), 23.1% (95% CI: 4.7%–64.5%) for end-of-treatment FDG-PET in Hodgkin lymphoma (random effects; I2=67.1%), and 31.5% (95% CI: 3.9%–83.9%) for end-of-treatment FDG-PET in non-Hodgkin lymphoma (random effects, I2=68.3%). ConclusionBoth interim and end-of-treatment FDG-PET scans in patients with lymphoma suffer from a very high number of false-positive FDG-avid lesions. This finding, in combination with the previously reported high number of false-negative FGD-PET scans for residual disease detection, suggests that the role of interim and end-of-treatment FDG-PET should be reconsidered.

Influence of Different Components of the Tumor Microenvironment on Human Patient-Derived Lymphoma Cell Engraftment in Immmunodeficient Mice

Patient-derived xenografts (PDX) have become reliable tools for preclinical research for many types of cancer. We recently reported the establishment of 4 human diffuse-large B-cell lymphoma (DLBCL) PDX in mice arising from patient prostate carcinoma tissue (Wetterauer,C. et al. 2015). All PDX were EBV associated and of ABC subtype as determined by the new algorithm of Choi et al. 2009. In contrast, none of the donor patients showed clinical or histological evidence of lymphoma disease. To address the question why lymphoma engraftment takes place in immunodeficient mice whereas patients do not show clinical evidence of disease, we compared growth behavior of the DLBCL PDX in 4 different mouse strains harboring different immunological deficiencies. Furthermore using 3 different implantation routes the dissemination behavior of these models into different immunological niches was evaluated. Results were compared to a similar study carried out with an EBV negative DLBCL PDX of a secondary, cerebral lymphoma (ABC-subtype).None of 4 EBV+ DLBCL PDX showed tumor growth after implantation in NMRI nu/nu (B- cells+, T cells-, NK cells+, n=5 mice/PDX) or 1147-F mice (B cells-, T cells+, NK cells+ n=5 mice/PDX). Subcutaneous implantation into NOD/SCID mice (B cells-, T cells-, NK cells+ n=5 mice/PDX) revealed tumor growth for 2 of 4 lymphomas displaying take rates of 80% (4 out of 5 mice) and 100% (5 out of 5 mice) within one model. Infiltration of murine NK cells in tumor tissue was determined by IHC (analyses ongoing). All 4 EBV+ lymphoma models showed stable growth in NOG mice (B cells-, T cells-, NK cells- n= 10 - 12 mice/PDX) with a take rate of 100% and an average passaging time of 20 days, ranging from 14 to 26 depending on the specific model. Taken together these results indicate that tumor growth of EBV+ lymphomas in mice depends on the NK cell activity as well as the B- and T cells status of the recipient mouse. These cell populations control tumor engraftment in mice, which might explain the absence of lymphoma disease in donor patients. In contrast the PDX of a clinically apparent EBV- DLBCL patient was able to circumvent NK cell block in NMRI nu/nu mice and showed similar take rates (100%, 5 out of 5 engrafted mice) but prolonged passaging times (35 days) as compared to NOG (26 days).Comparison of tumor cell engraftment after subcutaneous (s.c.), intravenous (i.v.) and intratibial (i.t.) injection of tumor cells in NOG mice revealed disseminated tumor growth for the EBV- DLBCL PDX exclusively when injected i.v. or i.t.. After subcutaneous implantation of lymphoma material, no tumor cells could be detected by flow cytometry or IHC in lymph nodes, blood, spleen, brain, liver, lung or bone marrow of recipient mice. However, lymphoma cells could be detected in liver and bone marrow of all (n= 8) i.v. and i.t. injected mice. Currently we are analyzing the dissemination behavior of the EBV+ lymphomas after injection into the different immunological niches as described above.In summary these data highlight the importance of the tumor microenvironment in lymphoma engraftment and dissemination in vivo. Accordingly we could show for our EBV associated lymphoma models that NK-, T- and B cell population control engraftment in vivo and are possibly involved in controlling EBV+ transformed lymphatic cells in patients. Furthermore, we showed that injection into the biologically relevant niche enables lymphoma cells to form multiple tumor nodules in distinct organs in vivo. These models contribute to a better understanding of the interplay between lymphoma cells and their microenvironment. They will thereby facilitate the discovery of new targets for innovative anti-lymphoma treatment strategies. DisclosuresTschuch:Oncotest GmbH: Employment. Klingner:Oncotest GmbH: Employment. Lenhard:Oncotest GmbH: Employment. Haapaniemi:Biositehisto Oy: Employment. Schueler:Oncotest GmbH: Employment.

To maintain or not, that is the question

To maintain or not, that is the question

Longitudinal risk of herpes zoster in patients with non-Hodgkin lymphoma receiving chemotherapy: A nationwide population-based study

This study investigated the incidence of and risk factors for herpes zoster in patients with non-Hodgkin lymphoma (NHL) who were receiving anti-lymphoma treatment. The overall incidence density of herpes zoster was 12.21% (472/3865); 11.79% (258/2188) of the patients received conventional chemotherapy and 12.76% (214/1677) of the patients received rituximab-containing chemotherapy. For the patients who received conventional chemotherapy, the risk factors included female gender, multiple courses of chemotherapy and autologous hematopoietic stem cell transplantation. For the patients who received rituximab-containing chemotherapy, the risk factors included female gender, diabetes mellitus, multiple courses of chemotherapy, autologous hematopoietic stem cell transplantation and higher accumulated rituximab dose. The majority of the herpes zoster episodes occurred within the first two years after the diagnosis of NHL. After adjusting for the propensity score matching, rituximab-containing chemotherapy was not associated with a higher overall incidence density of herpes zoster (P = 0.155). However, the addition of rituximab to conventional chemotherapy increased the short-term risk of herpes zoster with adjusted odd ratios of 1.38 (95% confidence intervals (CI) = 1.05–1.81, P = 0.021) and 1.37 (95% CI = 1.08–1.73, P = 0.010) during the 1-year and 2-year follow-up periods, respectively.

Autoimmune haemolytic anaemia in mantle cell lymphoma : an insidious complication associated with leukemic disease

Autoimmune haemolytic anaemia in mantle cell lymphoma : an insidious complication associated with leukemic disease

Influence of the Watch and Wait Strategy on the Clinical Outcome in Patients with Follicular Lymphoma in the Rituximab Era

IntroductionThe watch and wait (WW) strategy has been regarded as one of the standard approaches in patients with asymptomatic follicular lymphoma (FL) regardless of their tumor burden. However, the impacts of initial WW on treatment efficacy, outcomes and histologic transformation in FL patients in the rituximab era remain elusive.Patients and methodsWe retrospectively analyzed 348 consecutive patients who were initially diagnosed as having FL of grade 1 to 3a at our institution between 2000 and 2012. We analyzed time to treatment failure (TTF), and compared patients who underwent treatment following WW with those who immediately received treatment without WW. Both overall survival (OS) and time to transformation in the WW cohort and the immediate treatment cohort were also analyzed. In this particular study, TTF was defined as the time from diagnosis until progression after the initiation of first treatment.ResultsIn all 348 patients with a median age of 57 years (range: 19-85), 101 patients were initially managed with WW and 247 were immediately treated at the physician’s discretion. The proportions of patients with low tumor burden according to the GELF criteria were 80% (81 patients) in the WW cohort and 47% (117 patients) in the immediate treatment cohort. The median follow-up duration of all 348 patients was 75 months (range: 7-169). In the WW cohort, 45 patients (45%) received anti-lymphoma treatment, mainly because of FL progression, after a median WW duration of 16 months (range: 3-122). The majority of patients (84% in the treatment following WW group, 77% in the immediate treatment group) received a rituximab-containing regimen. The estimated median TTF in the treatment following WW cohort and the immediate treatment cohort were 92 months (95%CI, 60.1-NA) and 85 months (95%CI, 66.3-113), respectively, which were not significantly different (P=0.336) (Figure 1). In multivariate analysis, clinical stage was the predictive factor of TTF (HR 1.18, 95% CI, 1.02-1.38, P <0.05). Neither OS rate nor cumulative risk of transformation between the WW cohort and the immediate treatment cohort was statistically significant (P=0.294 and P=0.64, respectively) (Figures 2A and 2B). As risk factors of death, clinical stage (HR2.05, 95% CI, 1.12-3.75, P <0.05), age >60years (HR 3.87, 95% CI, 1.52-9.85, P <0.05) and transformation (as a time-dependent covariate) (HR 6.15, 95%CI, 1.64-23.02, P <0.05) were detected. None of the variables was significant regarding the risk of transformation. Tumor burden based on the GELF criteria was also not detected as a risk factor for treatment failure, death or transformation.ConclusionThe results of our analysis suggested that the WW strategy does not have negative impacts on TTF, OS and histologic transformation in selected patients with FL regardless of tumor burden, indicating that this strategy can still be regarded as an acceptable approach to FL patients in the rituximab era. Further investigations, especially a prospective cohort study including evaluation of the optimal timing for starting anti-lymphoma treatment following WW, are needed to confirm our results. [Display omitted] [Display omitted] DisclosuresMaruyama:Eisai Co., Ltd: Honoraria. Kobayashi:Behringer Ingelheim GmbH: Research Funding; Ohtsuka Pharmaceutical Co., Ltd: Research Funding; ARIAD Pharmaceutical Co., Ltd: Research Funding. Tobinai:Chugai Pharmaceutical: Research Funding; Zenyaku Kogyo: Research Funding.

Quantification of DAPK1 Promoter Methylation in Bone Marrow and Peripheral Blood as a Follicular Lymphoma Biomarker

Hypermethylation of DAPK1 promoter gene was found to be a frequent epigenetic alteration in follicular lymphoma (FL). We evaluated whether the quantification of DAPK1 methylation in the bone marrow (BM) and peripheral blood of FL patients at diagnosis and during follow-up provides important prognostic information. DAPK1 methylation was quantitated by real-time MethyLight PCR in 107 patients at diagnosis, at end of therapy, and during follow-up. Information on BCL2-IGH rearrangement and clinical characteristics were available for all patients. Aberrant DAPK1 methylation was found in 22 of 26 (85%) lymph node biopsy samples, 62 of 107 (58%) BM specimens, and 25 of 63 (40%) peripheral blood samples at diagnosis. DAPK1 methylation was greater in patients with BM infiltration and a higher Follicular Lymphoma International Prognostic Index score. The presence of aberrant DAPK1 methylation in BM significantly reduced progression-free survival following immunochemotherapy, independent of Follicular Lymphoma International Prognostic Index score. Residual or increased methylation after treatment was associated with an increased risk for relapse. With watchful waiting, greater DAPK1 methylation at diagnosis was associated with a shorter time to antilymphoma treatment. Our study indicates that quantification of DAPK1 methylation represents a prognostically relevant FL biomarker, with promising implications for risk assessment.

Obinutuzumab (GA101) Plus CHOP Or FC In Relapsed/Refractory Follicular Lymphoma: Final Data From The Maintenance Phase Of The Phase 1b GAUDI Study (BO21000)

Rituximab-based chemoimmunotherapy is standard treatment for non-Hodgkin's lymphoma (NHL), but some patients relapse or do not respond to treatment. GA101, the first glycoengineered, humanized, anti-CD20 monoclonal antibody, was developed to induce increased direct cell death and antibody-dependent cellular cytotoxicity relative to rituximab. Phase 1 and 2 studies of patients with NHL have shown that GA101 monotherapy has promising activity. The phase 1b GAUDI study (NCT00825149, BO21000) evaluated the safety and efficacy of induction treatment with GA101 plus chemotherapy in patients with relapsed/refractory follicular lymphoma (FL). GA101 was partnered with cyclophosphamide, doxorubicin, vincristine, and prednisone (G-CHOP) or with fludarabine and cyclophosphamide (G-FC). The end-of-induction overall response rate was 96% for G-CHOP and 93% for G-FC (Radford et al. Blood. 2013). Here we report results from the cohort of patients who received GA101 maintenance monotherapy after responding to induction treatment.During induction, patients with relapsed/refractory FL received G-CHOP (every 3 weeks, 6–8 cycles) or G-FC (every 4 weeks, 4–6 cycles). Chemotherapy backbone was selected by the investigator on the basis of patient characteristics and treatment history. Patients were randomized to either high-dose GA101 (1600 mg on days 1 and 8 of cycle 1, 800 mg on day 1 of subsequent cycles) or to low-dose GA101 (400 mg on days 1 and 8 of cycle 1 and day 1 of subsequent cycles). Patients with complete response (CR) or partial response after induction were eligible to receive GA101 monotherapy (at the same dose used for induction) as maintenance treatment every 3 months for 2 years or until disease progression. Patients who completed maintenance therapy were followed for 2 years after the last GA101 dose or until progression/initiation of a new antilymphoma treatment. The primary end point was safety. Progression-free survival (PFS) was a secondary end point.Median observation time from study start in the G-CHOP and G-FC cohorts was 31.8 and 37.5 months, respectively. In the G-CHOP cohort, 82% (23/28) and 65% (15/23) of patients started and completed maintenance therapy, respectively. There were 7 discontinuations due to stable disease (SD) or progressive disease (PD) and 1 due to an adverse event (AE; hepatosplenic T-cell lymphoma). In the G-FC cohort, 61% (17/28) and 53% (9/17) of patients started and completed maintenance therapy, respectively. There were 4 discontinuations due to AEs (pancytopenia/septicemia, n=1; diarrhea/weight loss, n=1; neutropenia, n=2), 2 due to SD or PD, 1 due to administrative/other (patient moved away), and 1 due to death (chronic obstructive pulmonary disease, which was considered unrelated to GA101). During the maintenance period, 3 and 6 patients in the G-CHOP and G-FC cohorts, respectively, experienced a serious AE. No grade ≥3 AEs occurred in >1 patient in the G-CHOP cohort; in the G-FC cohort, the most common grade ≥3 AE was neutropenia (n=3). The proportion of patients with CR as a best overall response increased between the end of induction and the end of maintenance in the G-CHOP (39% [9/23] to 52% [12/23]) and G-FC cohorts (59% [10/17] to 82% [14/17]). Median PFS was not reached for G-CHOP; median PFS in the G-FC cohort was 46.0 months (95% CI: 24.4–46.0 months). Pharmacokinetic data will be presented.In this phase 1b study, maintenance treatment with GA101 monotherapy was well tolerated and CR rates increased compared with the end of the induction phase. This suggests that GA101 could be used to sustain and extend the clinical response achieved after induction with GA101 plus chemotherapy in patients with relapsed/refractory FL. The majority of responders completed maintenance treatment. No new safety signals emerged during maintenance treatment with GA101 monotherapy. In summary, data from the GAUDI study show that GA101 maintenance monotherapy is well tolerated and confers clinical benefit after induction with GA101 plus chemotherapy. Disclosures:Davies:Roche: Consultancy, Honoraria, Research Funding. Off Label Use: GA101 is a novel, glycoengineered, type II anti-CD20 monoclonal antibody that is designed to enhance direct cell death and antibody-dependent cellular cytotoxicity. It is being investigated in chronic lymphocytic leukemia, Non-Hodgkin's Lymphoma and other hematologic indications. Cartron:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Morschhauser:Roche, Celgene, Mundipharma, Spectrum: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Salles:Roche: Consultancy, Honoraria, Research Funding. Marcus:Roche: Consultancy, Honoraria. Wenger:Genentech: Employment. Lei:Roche: Employment. Wassner-Fritsch:Roche: Employment. Vitolo:Roche, Celgene, Takeda: Membership on an entity's Board of Directors or advisory committees.

The Prognostic Value Of Dynamic Monitoring C-Reactive Protein (CRP) Serum Levels In NK/T-Cell Lymphoma

The prognostic value of dynamic monitoring C-reactive protein (CRP) serum levels in NK/T-cell lymphoma Background and ObjectiveC-reactive protein (CRP) is a kind of acute phase protein against inflammatory reaction. CRP has been proved to be associated with prognosis in various malignancies. Yet, the prognostic value of CRP in natural killer/T-cell lymphoma (NK/TCL) remains to be discussed. In this study, we aimed to observe the dynamic change of CRP serum levels during anti-lymphoma treatment, and to evaluate the prognostic value of CRP as a simple and economical biomarker during the early stage of treatment in patients with NK/T-cell lymphoma. Patients and MethodsBetween January 2003 and December 2011, 161 patients with newly diagnosed NK/TCL at the Sun Yat-sen University Cancer Center (SYSUCC) were reviewed retrospectively. Clinical and laboratory information was collected and analyzed. The following CRP serum levels were evaluated: pretreatment CRP (CRP0), early-treatment CRP (CRP1, after one cycle of chemotherapy, or two or three weeks since beginning of radiation), and post-treatment CRP (CRP2, after first-line treatment, or failure of first-line treatment). ResultsOverall, 161 patients were reviewed and analyzed. The median age was 44 years (range, 11¨C74). The majority had localized disease (stage I/ II; 75.5%). The CRP serum levels (mean ± standard deviation) were as follows: CRP0, 17.2±23.1 mg/L; CRP1, 14.0±30.0 mg/L; CRP2, 14.1±27.0 mg/L. The pretreatment CRP serum levels correlated with others unfavorable factors, including serum lactate dehydrogenase (LDH) (P = 0.005), presence of bulky disease (P = 0.002), presence of B symptoms (P = 0.017), the International Prognostic Index (IPI) score (P = 0.001) and the Korean Prognostic Index (KPI) score (P = 0.001). By the time of the final follow up assessment (May 2013), the median follow-up time was 23.0 months (range, 1.0-106.0 months). The median overall survival (OS) and progression-free survival (PFS) were 45.0 months (range, 1.0-106.0 months) and 32.0 months (range, 1.0-74.0 months), respectively. The independent unfavorable prognostic factors for OS (P < 0.05) in multivariate analysis included: elevated CRP1 (P < 0.001), presence of bulky disease (P = 0.007), and elevated β2-microglobulin (β2-mg) serum levels (P = 0.004). The receiver operating characteristic analysis revealed a similar cut-off value of CRP (8.16 mg/L) to the default value of the biochemical analyzer (8.2 mg/L). In addition, the result suggested a satisfying capacity of CRP1 in predicting response to initial treatment (sensitivity 94%, specificity 74%) and 5-year OS (sensitivity 75%, specificity 90%), among different serum biomarkers, including EBV-DNA, LDH, β2-mg, CRP0, CRP1, and CRP2. In all groups of patients classified according to dynamic CRP values, the patients with CRP0 (+) /CRP1(-) presented the most favorable prognosis (5-year estimated OS: 72.5%). ConclusionsOur study suggests that elevated early-treatment CRP is an independent unfavorable prognostic factor for patients with NK/TCL. Compared with the baseline CRP, the dynamic change of CRP levels may provide more important information for prognosis during treatment. [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Updated 6 Year Follow-Up Of The PRIMA Study Confirms The Benefit Of 2-Year Rituximab Maintenance In Follicular Lymphoma Patients Responding To Frontline Immunochemotherapy

Updated 6 Year Follow-Up Of The PRIMA Study Confirms The Benefit Of 2-Year Rituximab Maintenance In Follicular Lymphoma Patients Responding To Frontline Immunochemotherapy

Lymphoma Occurring Over the Age of 90: Clinical Presentation and Outcome

AbstractAbstract 1582▪▪This icon denotes a clinically relevant abstract BackgroundLymphoma occurring in very elderly patients (i.e. >90 years of age) is not uncommon and its incidence is expected to increase due to prolongation of life expectancy. Its management raises therapeutic as well as ethical considerations. However, no reports are currently available in this population of patients rendering their management particularly challenging. The purpose of our study is to describe the clinical presentation, management and outcome of patients diagnosed with lymphoma at the age of 90 or over. MethodsIn a retrospective, multicenter study, we analyzed 234 patients with Non-Hodgkin (NHL, n=227) and Hodgkin (HL, n=7) lymphoma diagnosed at the age of 90 or over, between 1990 and 2012. ResultsHistologic incidence of lymphoma subtypes was evaluated using 3 epidemiologic cancer registries, accounting for 128 patients. In this cohort, 55% of the patients presented with aggressive NHL, 42% with indolent NHL and 3% with HL. The most frequent histologies were diffuse large B cell lymphoma (46%), follicular lymphoma (9.5%), lymphoplasmacytic lymphoma (8%) and marginal zone lymphoma (5.5%).Clinical characteristics, management and outcome were collected for 169 patients among several institutions. At diagnosis, median age was 92 [range 90–100]. Most patients were female (66%) and still living at home (73%). Charlson index was low (i.e. ≤2) in 68% of the patients. Forty-five percent of the patients had a low (i.e. ≤1) performance status (PS).The majority of the patients (63.5%) received a treatment (Fig. 1).Median overall survival (OS) for the entire cohort was 6.9 months. OS was significantly shorter in patients with aggressive lymphoma (OS = 5.2 vs 19.2 months, p<0.001, Fig. 2), poor (i.e. ≥2) PS (OS = 4.1 vs 16.6 months, p=0.001), advanced (i.e. III-IV) Ann Arbor stage (OS = 2.3 vs 7.1 months, p=0.04), low (i.e. ≤36g/L) albumin level (OS = 4.6 vs 13.8 months, p=0.002) and in the absence of treatment (OS = 4.5 vs 9 months, p=0.05).Causes of death were: lymphoma in 58% of cases, anti-lymphoma treatment in 8.5% of cases and other causes in 33.5% of cases. ConclusionsLymphoma occurring over the age of 90 is more frequently aggressive than indolent. Most of the patients die of lymphoma rather than from toxicities of the treatment. This suggests that a subset of patients may benefit from adapted therapies in spite of their very advanced age. Management of these patients may be guided by prognostic factors such as histologic subtype, PS, Ann Arbor stage and albumin level. [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Maintenance therapy in follicular lymphoma

This article reviews the potential benefit of maintenance therapy for patients with follicular lymphoma. Follicular lymphoma, despite substantial improvements in survival, is usually incurable. Several randomized studies have shown that the combination of anti-CD20 and chemotherapy can improve overall survival for these patients. Recently, the old concept of maintenance treatment developed for acute leukemias was reintroduced in the treatment of indolent lymphomas. On the basis of its favorable toxicity profile, single agent rituximab remains a valuable option when given in a prolonged schedule to obtain durable remissions. A first remission is easily obtained but relapses appear unavoidable. Patients achieving a partial response have poorer outcomes compared with those achieving complete remission. Furthermore, it has been demonstrated that among patients with follicular lymphoma who reach complete remission, those obtaining negative minimal residual disease, as assessed by molecular biology, have a better outcome compared with those remaining with residual disease. There is, therefore, a rationale to give additional treatment in an attempt to eradicate or to control the lymphoma cells responsible for relapse. An ideal maintenance regimen would have limited toxicity and should be easy to administer. Results of the International Primary Rituximab and Maintenance study show that 2 years of rituximab maintenance prolongs progression free survival, delays the time to next antilymphoma treatment and improves the quality of response in patients with previously untreated follicular lymphoma. Rituximab maintenance was well tolerated with a limited number of adverse events.

Rituximab

Rituximab is a recombinant chimeric murine/human monoclonal IgG(1-κ) antibody. It binds specifically to the CD20 antigen on normal and malignant B lymphocytes and produces complement-dependent and antibody-dependent cytotoxicity and induces apoptosis in these cells. Prolonged treatment with rituximab in patients with follicular lymphoma results in a sustained reduction in circulating B lymphocytes. Two years of single-agent maintenance therapy with rituximab significantly prolonged progression-free survival (primary endpoint) compared with observation in patients with follicular lymphoma who were responsive to first-line induction therapy with rituximab plus chemotherapy. Furthermore, maintenance therapy with rituximab significantly delayed the time to the next antilymphoma treatment and the next chemotherapy compared with observation in these patients. Rituximab had an acceptable tolerability profile as single-agent maintenance therapy in patients with follicular lymphoma with no new or unexpected adverse events compared with induction therapy.

Updated Results of the PRIMA Study Confirms the Benefit of 2-Years Rituximab Maintenance In Follicular Lymphoma Patients Responding to Immunochemotherapy.

AbstractAbstract 1788The GELA-sponsored intergroup PRIMA Phase III study was designed to investigate the potential benefit of 2-years of rituximab maintenance in high tumour burden follicular lymphoma patients responding to one of three non-randomised first line immunochemotherapy treatments. The results of the pre-planned interim analysis with 24 months median follow-up were positive and demonstrated a significant reduction in the risk of progression for patients randomized to rituximab maintenance (Salles et al., ASCO 2010). We present here the updated efficacy and safety results after an additional year of follow-up, when all randomized patients had completed the observation/maintenance period.From December 2004 until April 2007, 1217 patients were enrolled from 223 centres. Complete data are available for 1193 patients who had the following pre-induction treatment characteristics: median age 56 years [range 22–87]; 52% male; 90% Ann Arbor stage III-IV; 33% B symptoms; 55% bone marrow involvement; 4% ECOG performance status >1; 34% elevated LDH; 32% β2-microglobulin≥3mg/L; FLIPI score 0–1 (21%), FLIPI 2 (36%), FLIPI 3–5 (43%). Most patients (74%) received R-CHOP induction (22% R-CVP, 4% R-FCM).Patients responding to induction therapy were stratified based on their immunochemotherapy regimen and response [CR/CRu versus PR], and randomized to observation or rituximab maintenance, 1 infusion (375 mg/m2) every 8 weeks for 2 years. A total of 1018 randomised patients were analyzed according to the ITT principle (513 observation/505 rituximab maintenance). All initial pre-treatment characteristics were well balanced between arms and the response status at time of randomization was CR=39%; CRu=31% and PR=29% (others 1%).After a median follow-up of 36 months, 3-year progression free survival was 60.3% (95% confidence interval [CI] 55.8 – 64.5%) in the observation arm and 78.6% (95% CI 74.7 – 82%) in the rituximab maintenance arm, respectively (stratified Log-Rank, P<.0001; hazard ratio [HR]=0.55, 95% CI 0.44 – 0.68). In pre-planned analyses of patient subgroups categorized by age, sex, FLIPI score, induction chemotherapy and response to induction, the effect of rituximab maintenance was found to be consistent with the overall study results. In a Cox regression multivariate analysis, older age (P=.0013), male sex (P=.013), higher FLIPI group (P<.0001), R-CVP induction treatment (P=.003) and rituximab maintenance (P<.0001) were all significant variables associated with inferior progression free survival. A significant reduction in the number of patients starting a new anti-lymphoma treatment (HR=0.60, 95% CI 0.47 – 0.76) or starting a new chemotherapy (HR=0.62, 95% CI 0.47 – 0.81) was also observed for rituximab maintenance. Regarding response to treatment, 52% of the patients that were in PR at the time of randomization converted to CR or CRu at the end of 2-year maintenance in the rituximab maintenance arm compared to 30% of patients in the observation arm (P=.0001). As a result, 361 out of 482 patients evaluated (75%) in the rituximab maintenance arm were in CR or CRu as compared to 268 out of 491 patients evaluated (55%) in the observation arm (P< .0001). At the time of the data cut-off, 30 patients (6%) had died in the observation arm compared to 26 patients (5%) in the rituximab maintenance arm (HR=0.87, 95% CI 0.51 – 1.47).The most common adverse events reported were infections, which occurred in 24% and 39% of the patients in the observation and rituximab maintenance arms respectively. Grade 3–4 adverse events were reported in 17% of patients in the observation arm and 24% in the rituximab maintenance arm (neutropenia 1% vs 4%; infections 1% vs 4%, respectively) but these lead to treatment discontinuation in only 8 and 19 patients, respectively.In conclusion, after an additional year of follow-up, these data demonstrate a sustained benefit of 2 years of rituximab maintenance therapy after immunochemotherapy, resulting in improved progression free survival and complete response rates. No additional or unexpected toxicities were observed. All randomized patients have an excellent survival to date and longer follow-up will explore factors affecting overall survival in these patients. The PRIMA results indicate that rituximab maintenance should be considered in all follicular lymphoma patients who have responded to first line immunochemotherapy. Disclosures:Salles:Roche: Consultancy, Honoraria. Off Label Use: The use of rituximab maintenance in follicular lymphoma patients. Catalano:Celgene: Research Funding; Roche: Honoraria, Research Funding, Travel Grants. Feugier:roche: Consultancy, Honoraria. Belada:Roche: Consultancy, Honoraria. Tilly:Amgen: Honoraria. Leppa:Roche: Honoraria. Soubeyran:Roche: Honoraria, Research Funding. Hagenbeek:roche: Consultancy. Lister:Allos: Consultancy; Bioconnections: Consultancy; Astra Zeneca: Consultancy; Tenet: Consultancy; GSK: Chairman of Safety Monitoring Committee. Lopez-Guillermo:Roche: Consultancy, Honoraria. Seymour:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau, Travel support; Bayer-Schering: Honoraria, Travel Support.

A Phase 3 Trial Comparing Bortezomib Plus Rituximab with Rituximab Alone In Patients with Relapsed, Rituximab-Naive or -Sensitive, Follicular Lymphoma

A Phase 3 Trial Comparing Bortezomib Plus Rituximab with Rituximab Alone In Patients with Relapsed, Rituximab-Naive or -Sensitive, Follicular Lymphoma