Chemotherapy For Follicular Lymphoma Research Articles

A Phase II Study of Lenalidomide Plus Rituximab in Patients with Newly Diagnosed Follicular Lymphoma: An Interim Analysis

A Phase II Study of Lenalidomide Plus Rituximab in Patients with Newly Diagnosed Follicular Lymphoma: An Interim Analysis Zhong Zheng1, Li Wang1,2, Shu Cheng1, Peng-Peng Xu1, Wei-Li Zhao1,2 1State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Shanghai Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China 2Pôle de Recherches Sino-Français en Science du Vivant et Génomique, Laboratory of Molecular Pathology, Shanghai, China Abstract Background: Follicular lymphoma (FL) is the most common subtype of indolent non-Hodgkin lymphoma (iNHL). Rituximab plus chemotherapy for FL significantly improves the outcome of the patients, nevertheless, most patients ultimately relapse. Therefore, novel agents along with Rituximab have been applied to increase treatment efficacy in this subset of iNHL patients. Tumor immune eascape plays a crucial role in lymphoma progression. Through modulating tumor microenvironment, lenalidomide, are emerging as effective therapeutic approaches to affect tumor immunity and inhibit lymphoma cells proliferation. However, its anti-tumor activity activity has not yet been assessed in de-novo chinese FL patients. This prospective phase II study is to evaluate the efficacy and safety of lenalidomide in combination with Rituximab (R2) in newly diagnosed FL patients (NCT 03715309). Methods: Patients with newly diagnosed FL (grade 1 to 3a), aged 16 to 75 years, Eastern Cooperative Oncology Group performance status of 0 to 2 are enrolled. The doses and administration schedule are as follows: rituximab 375 mg/m2 on day 0, lenalidomide 25mg from day 1 to day 10 every 3 weeks for 6 cycles. The primary endpoint is complete response (CR) rate assessed by PET-CT, and secondary endpoints include progression-free survival (PFS), overall survival (OS), overall response rate (ORR) and main adverse events (AEs). Results: To date, eighty-six patients have been enrolled, with median age of 48 years (range, 22-73). At diagnosis, Seventy-seven patients (89.5%) presented advanced Ann Arbor stage and 19 cases (22.0%) showed elevated serum LDH level. Twenty-nine patients (33.7%) had multiple extra-nodal sites involving bone marrow, bone, gastrointestinal, and spleen. Twenty-one patients (24.4%) had IPI scores ≥ 3. For Sixty-four patients available for response evaluation, the CR rate was 81.2% (52/64) and the ORR was 90.1% (58/64). Grade 3-4 neutropenia was found in 18 cases (20.9%). No grade 3-4 thrombocytopenia and grade 3-4 anemia were observed. For non-hematological AEs, cutaneous reactions and tumor flare reaction were observed in 12 cases (13.9%) and in 1 case (1.16%), respectively, while no grade 4 non-hematological AEs were presented. Conclusion: Lenalidomide Plus Rituximab as first-line therapy for de novo patients with FL showed encouraging response and good tolerability. Disclosures No relevant conflicts of interest to declare.

Exposure to Ibritumomab Tiuxetan and Incidence of Treatment-Related Myeloid Neoplasms Among Older Patients with B-Cell Lymphoma: A Population-Based Study

Background: Ibritumomab tiuxetan (IbT) is a radioimmunoconjugate linking rituximab with 90Y isotope. IbT is approved for treatment of relapsed/refractory indolent B-cell lymphomas, or for consolidation after chemotherapy in follicular lymphoma (FL), yet its use has been limited by concern about treatment-related myeloid neoplasms (tMDS/AML: acute myeloid leukemia and myelodysplastic syndrome). The risk of tMDS/AML may differ among older patients who experience significant competing mortality. Our objective was to use population-based data to examine real-life patterns of use of IbT, and associated incidence of tMDS/AML among older patients with B-cell lymphomas. Methods: From the SEER-Medicare registry, which covers about 28% of the United States population, we selected fee-for-service Medicare beneficiaries >60 years [y] old, with B-cell lymphomas diagnosed between 2001-2015, who received systemic therapy. We identified the use of IbT, purine analogues, alkylating agents, and rituximab. We defined tMDS/AML as myeloid neoplasms diagnosed >2 months from the start of first-line therapy for lymphoma, or use of tMDS/AML-directed chemotherapy. We estimated incidence rate and incidence rate ratio (IRR) for tMDS/AML after IbT exposure using a time-split survival model. By matching IbT recipients with non-recipients according to age, sex, lymphoma histology, and observation time from the start of lymphoma therapy, we compared the cumulative incidence function of tMDS/AML using competing risk models stratified by matched groups. We fitted the univariate model, and model adjusting for prior exposure to purine analogues or alkylators. Results: Among 43,945 Medicare beneficiaries (median age of 76 y) treated for diffuse large B-cell (DLBCL, 48%), FL (22%), mantle cell (7%), marginal zone (10%), or unspecified B-cell lymphoma (14%), 428 (1%) received IbT, at median 18 months from first-line chemotherapy (interquartile range [IQR], 8-34). IbT was used most frequently in FL (50%) and DLBCL (23%), and was applied as first-line treatment in 30 patients (7%). With median follow-up of 8.5 y, 618 cases of tMDS/AML were recorded (15 among IbT recipients, and 603 among non-recipients). Median latency from the start of first-line lymphoma therapy to tMDS/AML was 38 months (IQR, 18-65). The cumulative incidence rate of tMDS/AML after IbT exposure was 2.8% at 5y (95%CI, 1.2-4.4) and 3.9% at 10y (95%CI, 1.8-6.0). No tMDS/AML was observed among patients who received IbT as first-line treatment, before chemotherapy exposure. In the time-split survival analysis, the incidence of tMDS/AML was 0.39 per 100 person-years (95%CI, 0.18-0.60) without IbT exposure, and 1.02 (95%CI, 0.56-1.71) after IbT exposure, with an IRR of 3.22 (95%CI, 1.80-5.26). There was no significant heterogeneity in the IRR by lymphoma histology (Mantel-Haenszel test of homogeneity, P=.47). In the matched analysis (Fig A), the cumulative incidence of tMDS/AML was significantly higher among patients receiving IbT (subhazard ratio [SHR], 2.16; 95%CI, 1.32-3.55). However, the association became non-significant after adjusting for prior exposure to myelotoxic chemotherapy (SHR, 1.58; 95%CI, 0.93-2.68). Prior exposures to a purine analogue (SHR 3.83; 95%CI, 2.96-4.95) or an alkylator (SHR, 1.39; 95%CI, 1.11-1.75) remained significantly associated with increased risk of tMDS/AML. Median overall survival after tMDS/AML diagnosis was 0.6y (95%CI, 0.5-0.7), and it did not differ according to IbT exposure status (P=.62; Fig B). Conclusions: The cumulative incidence of secondary tMDS/AML in this large population-based cohort is similar to reports from clinical trials (Czuczman et al. J Clin Oncol. 2007), and lower than in some prior observational series (Epperla N, et al., Br J Haematol 2017). Our results support the use of IbT for older patients with indolent lymphomas. Exposure to IbT was associated with an increased incidence of tMDS/AML, but it was no longer significant after adjustment for prior exposure to myelotoxic chemotherapy. This result suggests that the increased incidence of tMDS/AML is a cumulative effect of IbT with other myelotoxic agents. Caution should thus be exercised when using IbT after exposure to chemotherapy. The fact that no tMDS/AML were observed in patients receiving IbT as first line therapy suggests that earlier use of IbT may be preferable from the point of view of the tMDS/AML risk. Disclosures Olszewski: Genentech: Research Funding; TG Therapeutics: Research Funding; Spectrum Pharmaceuticals: Research Funding; Adaptive Biotechnologies: Research Funding. OffLabel Disclosure: Ibritumumab tiuxetan - for treatment of any B-cell lymphoma in any setting

Volumetric and texture analysis on FDG PET in evaluating and predicting treatment response and recurrence after chemotherapy in follicular lymphoma.

The purpose of this study was to determine if quantitative SUV-related, volumetric FDG PET parameters, and texture features (SPs, VPs, and TFs, respectively) were useful to evaluate and predict response and recurrence after chemotherapy in follicular lymphoma (FL). Pre- and posttreatment FDG PET examinations in 45 FL patients were analyzed retrospectively. In addition to SPs in the representative lesion, metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were calculated as VPs for the representative and whole-body lesions. Six TFs were calculated in the pretreatment representative lesion. Response results with reduction of SPs or VPs after treatment (Δ) were compared to the Lugano classification based on visual assessment. SPs, VPs, and Δ of them as well as TFs were also evaluated if they allow prediction of response and recurrence after chemotherapy. Quantitative assessment with SPs and VPs provided 89% and 93-96% concordant results, respectively, with Lugano classification. Among pretreatment PET parameters, low gray-level zone emphasis (LGZE) in TFs solely showed statistical significance to predict complete response. All of posttreatment and Δ of SPs and VPs were considered as the predictors of progression free survival in the univariate Cox regression analysis, but none of them was the predictor in the multivariate analysis. This study demonstrated that quantitative PET parameters were applicable to evaluate treatment response in FL. Texture analysis showed promise in predicting treatment response. Although posttreatment and Δ of PET parameters were the candidates, all of them proved to have limited value in predicting recurrence after chemotherapy.

914P - Impact of the addition of rituximab in overall survival in first line chemotherapy in follicular lymphoma: a population-based study from the Spanish Lymphoma Oncology Group (GOTEL)

914P - Impact of the addition of rituximab in overall survival in first line chemotherapy in follicular lymphoma: a population-based study from the Spanish Lymphoma Oncology Group (GOTEL)

Predicting Time to Treatment in Follicular Lymphoma Using Population-Based Data

IntroductionPatients diagnosed with Follicular Lymphoma (FL) either require immediate immuno-chemotherapy or, may simply be observed until the development of symptoms suggests that treatment should be initiated. Although there is no evidence to indicate that early intervention in asymptomatic, stage II - IV disease improves outcomes, both doctors and patients find "watch and wait" (W+W) strategies difficult to accept as it leaves considerable uncertainty as to the future. The ability to predict the likely time to treatment (TTT) being required would be helpful, both to give reassurance in cases where the likelihood of therapy in the near future is low and to identify higher risk cases where close observation or early intervention might be justified. Prognostic indices are usually derived using data from clinical trials or institutional datasets where patients who do not require treatment tend to be underrepresented; accordingly we constructed an improved prognostic index for TTT for those patients initially on a W+W strategy in an unselected, population-based cohort.MethodsThis study was based on an established population-based cohort, which since 2004 has tracked all patients newly diagnosed with a haematological malignancy in a representative UK population of nearly 4 million people (www.hmrn.org). All diagnoses, including disease progressions and transformations, are made by a single specialist haematopathology laboratory (www.hmds.info), and clinical teams work to UK guidelines (www.bcshguidlines.com). Clinical and treatment information is systematically collected for all patients and survival data is acquired through links with national data sources.All 296 out of 741 patients newly diagnosed with FL from 2004-2011 initially managed by a W+W approach were included in the analyses and these patients were followed up to February 2015. Prognostic indices for TTT were constructed using the components of the Follicular Lymphoma International Prognostic Index (FLIPI) and other routinely measured clinical variables. Modern machine learning techniques were used, in particular the LASSO applied to semiparametric survival regression, using bootstrapped model selection to confirm Lasso variable selection. The appropriate functional forms for individual variables were chosen on the basis of the Akaike Information Criterion. Predictive performance was measured using area under the ROC curve (AUC) and the concordance index (C).ResultsWith a median age of 65.4 years (range 21-95), 42% of patients were male, 16% had B-symptoms and 37% had stage IV disease at presentation. Median follow-up was 6.4 years; 83 patients were subsequently treated for FL, a further 34 patients transformed to diffuse large B-cell lymphoma and 9 others died from disease progression prior to receiving chemotherapy for FL; median time to these events was 1.4 years. Whilst the FLIPI score for patients initially managed on W+W was predictive for TTT (Figure 1) - achieving an AUC=0.64 and C=0.61, as a result of the model building process a proposed new index for TTT achieved AUC=0.75 and C=0.70 retaining blood albumin, haemoglobin, presence/absence of bulky disease (1/0 respectively) and a score based on the number of nodal sites in the prognostic model (Risk_Score = Albumin (g/dL) x 0.0412 + 0.719 * bulky_disease - 0.102 x Hb (g/dL) + 0.159 x nodal_score). The relation between index value and expected time-to-event for TTT is shown in Figure 2.ConclusionOur population-based data demonstrates that the FLIPI can be used to predict TTT in patients diagnosed with FL and put onto a W+W strategy. By utilising all of the information contained in the components of the FLIPI and by adding additional routine clinical factors we show that the accuracy of prediction of TTT can be improved leading to the production of an accurate and simple TTT curve that can be used in routine clinical practice. [Display omitted] [Display omitted] DisclosuresPatmore:Gilead: Honoraria; Janssen: Honoraria.

Follicular lymphoma: first-line treatment without chemotherapy for follicular lymphoma.

Opinion statement: The optimal initial treatment of follicular lymphoma (FL) is not known, and initial management of patients varies considerably between providers and institutions. The assertion that patients with low tumor burden can be observed for a period of time is being challenged owing to the safety and tolerability of novel therapeutics and the movement of the field away from traditional chemotherapy agents. Single agent rituximab has become increasingly popular as initial management of patients with low tumor burden disease, and there is evidence that prolonged treatment with rituximab can improve progression-free survival (PFS) when compared to induction with rituximab or observation. Radioimmunotherapy (RIT) has similarly shown efficacy in low tumor burden disease. Novel agents such as lenalidomide, idelalisib, and ibrutinib are being studied in the first-line setting. Importantly, none of these strategies have demonstrated an improved overall survival in a randomized study versus observation. It is the opinion of the authors that endpoints such as PFS alone, while important, should not drive changes in management with limited resources. Composite endpoints including quality of life are more informative on the true impact of treatments on patients with follicular lymphoma. Providers should encourage all patients to be treated in the context of an appropriate clinical trial when possible. If a patient is not a clinical trial candidate, we typically treat patients with advanced stage and high tumor burden with chemoimmunotherapy. The decision to give maintenance rituximab is individualized to the patient, as there is no overall survival benefit. In patients with early stage disease, we favor consideration of radiation therapy if the patient is a candidate. Our initial recommendation to patients with advanced stage, low tumor burden disease, is close observation or "watch and wait." We have observed that most patients become comfortable over time with an observation approach. If a patient is not comfortable with this recommendation, we will use single agent rituximab. If the patient responds to therapy, we do not recommend maintenance rituximab in low tumor burden disease but rather prefer a retreatment strategy or an extended schedule of four additional doses of rituximab.

Is Stem Cell Transplantation for Transformed Follicular Lymphoma Required in the Rituximab Era?: The Royal Marsden Experience 2003-2013

Abstract Background: High-grade transformation (HT) of follicular lymphoma (FL) to diffuse large B-cell lymphoma (DLBCL) occurs at a rate of 3% per year and has been associated with a very poor prognosis, with a median overall survival (OS) of 1 year reported by Montoto et al in the pre-rituximab era. Treatment often includes upfront autologous or allogeneic stem cell transplantation (SCT) due to the poor prognosis, but rarely maintenance rituximab despite evidence in FL. These patients are excluded from the majority of clinical trials and hence the role of SCT in the rituximab era and maintenance rituximab are not well evaluated. Methods: We performed a retrospective analysis of all patients aged ≥18 years with histologically proven transformed follicular lymphoma (TFL) diagnosed and treated (≥1 cycle of chemotherapy) at our institute in the 10-year period 2003-2013. Histopathology databases were searched to identify patients diagnosed with DLBCL and FL (grade 1-3a). Clinical data were collated from electronic patient records. Patients with grade 3b FL were excluded. A minimum interval of 6 months between the diagnosis of FL and development of HT was required for inclusion to outrule a discordant lymphoma. All histological specimens were reviewed by an expert haematopathologist. The study was approved by our institutional review board. Results: Between March 2003 and May 2013, a total of 56 patients were diagnosed with TFL (to DLBCL) and received first-line induction treatment +/- autologous/allogeneic SCT. The median follow-up was 5.6 years. The median time from diagnosis of FL to HT was 5.3 (range 0.6-29.3) years with a median age at diagnosis of TFL of 61 years (range 34-85). 59% (n=33) had received prior chemotherapy for FL. At diagnosis of TFL 89% (n=50/56) of patients received chemotherapy +/- radiotherapy (IFRT) without subsequent SCT. Upfront autologous or allogeneic SCT post induction was performed for 4 (7%) and 2 (3.5%) patients respectively. 91% of patients (n=51/56) received rituximab containing (R) chemotherapy and 68% (n=38/56) were treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP). 16.1% (9/56) received IFRT post induction. 14.3% (8/56) patients received R-maintenance following first-line treatment for TFL. For patients treated with R-chemotherapy alone (n=46) the 2 and 5-year OS and PFS (for TFL) were 84.5% and 70.9% and 58.7% and 49.3% respectively. In patients aged >65 years (n=17) 5-year OS was similarly 71.6%. Patients treated with R-CHOP had 2 and 5-year OS of 89% and 76% and PFS (TFL) rates of 59.5% and 51.7% respectively. Patients who received R-chemotherapy induction followed by R-maintenance (n=8) had both 2-year OS and PFS (TFL) of 100%. 82% of all patients (46/56) underwent FDG-PET on completion of induction treatment +/- SCT. A negative PET (n=30) was associated with 2 and 5-year OS rates of 90% and 74.1% and PFS (TFL) of 60% and 49.2%. Conclusion: The outcome for TFL has significantly improved with the advent of rituximab. In our analysis the 2 and 5-year OS rates of 84.5% and 70.9% with R-chemotherapy alone are superior to reported OS for patients undergoing upfront autologous/allogeneic SCT, while PFS rates are comparable to those quoted for upfront autologous SCT. Although the numbers are small (n=8) and follow-up shorter, the outcomes for patients treated with R-chemotherapy followed by R-maintenance (2-yr OS and PFS of 100% and 100%) are particularly encouraging while offering minimal additional toxicity. In conclusion our data indicate that upfront SCT may no longer be required for TFL in the rituximab era. Rituximab maintenance should be considered in the management of these patients. Disclosures Hawkes: Roche: Travel grant Other. Peckitt:Sanofi: Membership on an entity's Board of Directors or advisory committees. Dearden:Roche: Membership on an entity's Board of Directors or advisory committees. Cunningham:Astra Zeneca: Research Funding; Novartis: Research Funding; Merck Serono: Research Funding; Sanofi: Research Funding; Celgene: Research Funding; Amgen: Research Funding; Roche: Research Funding.

Therapy-related myeloid neoplasm with bone marrow involvement, myelosarcoma, and a t(8;16)(p11.2;p13.3)—a case report

Therapy-related leukemia is a well-documented complication of conventional therapy for cancer. Therapy-related acute myeloid leukemia (t-AML) is grouped along with therapy-related myelodysplastic syndrome (t-MDS) and therapy-related myelodysplastic syndrome/myeloproliferative neoplasms (t-MDS/MPNs) as therapy-related myeloid neoplasms (t-MNs) by the 2008 World Health Organization classification system. Therapy-related myeloid neoplasms differ clinically from their de novo counterparts in terms of response to therapy, aggressiveness of disease, and associated poor prognosis. The occurrence of extramedullary myeloid sarcomas with bone marrow involvement has been shown to be a poor prognostic indicator for patients with t-MN. The karyotype of leukemic blasts has also been reported to have a significant impact in t-MN and may predict survival and outcomes in patients. The t(8;16)(p11.2;p13.3) is a rare, balanced translocation that is frequently associated with the M4/M5 subtype of de novo acute myeloid leukemia. It has also been reported in patients with t-MN, typically in those with poor outcomes. Here we report a case of t-MN with myeloid sarcoma and bone marrow involvement in an adult patient with a karyotype of 47,XY,t(8;16)(p11.2;p13.3),+21 after rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy for follicular lymphoma.

Highlights of This Issue

Photodynamic therapy (PDT) has shown promise in the treatment of a range of solid cancerous tumors. The study by Rigual and colleagues is the first to use 3-(1′-hexyloxyethyl) pyropheophorbide-a (HPPH) PDT for the treatment of squamous cell carcinoma of the oral cavity. PDT-induced signal transducer and activator of transcription 3 (STAT3) cross-linking was measured as a molecular marker for the evaluation of PDT mediated photoreaction. The HPPH-PDT was found safe, while sparing healthy vital and functional structures. The level of STAT3 cross-linking is a significant reporter for evaluating the PDT mediated photoreaction, and has the potential of serving as a prognostic biomarker for evaluating tumor response.Current chemoradiotherapy is effective only for proliferating cancer cells, while having little effect on quiescent cancer stem-like (CS-like) cells. Using a fluorescent ubiquitination cell-cycle indicator (FUCCI), Yano and colleagues demonstrated that oncolytic adenovirus OBP-301 decoys chemoresistant quiescent CS-like cells to cycle and lethally traps them in S-phase. Viability loss of the CS-like cells in the S/G2/M-phase trap was enhanced by chemotherapy, which was initiated at the time of fluorescence indication of entry into S/G2/M-phase. Oncolytic virus treatment and fluorescence indication for the time of chemotherapy initiation are thus a powerful approach to target chemoresistant quiescent CS-like cells.Recently, several studies have reported that FDG-PET-based response assessment may be more predictive than conventional CT-based response assessment after chemotherapy for follicular lymphoma. However, the question has remained whether these individual studies provide enough evidence to incorporate FDG-PET into routine practice. To generate a more evidence-based systematic summary for this issue, Pyo and colleagues conducted a meta-analysis of eight studies, which revealed consistent evidence that FDG-PET is more predictive of progression-free survival after chemotherapy and more efficient in distinguishing complete remission from residual disease than CT. These results favor adopting FDG-PET in the response evaluation of follicular lymphoma.Despite radical surgery and various regimens of chemoradiotherapy (CRT), survival rates remain lower than 50% for head and neck squamous cell cancer (HNSCC). The patients initially responsive to therapy develop recurrent disease, second primaries, or metastases. Mechanisms responsible for HNSCC patients' resistance to CRT remain unclear but may be in part related to CRT effects on the host immune system. Schuler and colleagues show that CRT increases the frequency of highly suppressive regulatory T cells (Treg) in the patients' circulation. The expanded Treg are resistant to activation-induced cell death, increase expression of prosurvival proteins BcL-2/BcL-xL, and are not affected by cisplatin. The persistence of Treg in the patients' circulation could be responsible for post-therapeutic immunosuppression leading to cancer recurrence in HNSCC patients.

Therapy-related acute myeloid leukemia with chromosomal abnormalities involving t(9;22)(q34;q11) and t(3;21)(q26;q22) during chemotherapy for follicular lymphoma

Therapy-related acute myeloid leukemia with chromosomal abnormalities involving t(9;22)(q34;q11) and t(3;21)(q26;q22) during chemotherapy for follicular lymphoma

Addition of Rituximab to Front-Line-Treatment Highly Improved the Outcome of Elderly Patients with Follicular Lymphoma: a Population Based-Study From the Modena Cancer Registry

AbstractAbstract 5077 Background:The benefit of adding Rituximab to combination chemotherapy in Follicular Lymphoma (FL) has been established in several randomized clinical trials (RCT). All of them have shown improvements in response rates, time to progression or overall survival (OS). The aim of the study was to assess the impact of the introduction of Rituximab in the treatment of FL in the general population of elderly patients, usually not included in RCT. Methods:All FL patients diagnosed in the province of Modena, Italy that had been diagnosed between 1997 and 2010 were identified from the archives of the Modena Cancer Registry that covers a population of approximately 600. 000 people. In the studied region Rituximab was available for first line treatment of FL since 2004. Therefore, for study purposes patients were grouped according to the year of diagnosis in 2 study periods (1997–2003, and 2004–2010). Elderly patients were defined using a cut off for age at 60 years. Clinical and treatment characteristics and also OS were compared according to the period of diagnosis and also, regarding the use or not of Rituximab as part of first line treatment. Moreover, a Cox regression analysis was performed to identify clinical factors and treatment characteristics associated with OS. Results:A total of 340 FL patients were identified of whom 177 (52%) were older than 60 years. No difference was found regarding clinical characteristics at diagnosis (age, gender, stage, bulky disease and LDH level) among study periods. Regarding treatment, no difference was found for the first general approach (watch and wait, chemotherapy or radiotherapy) across time. Among 229 patients initially treated with chemotherapy, antracyclines (ADM) or fludarabine (F)-based-regimens were the most frequently used. However, the use of ADM and/or F-based-regimens decreased from 82% (85/104) in the first period to 66% (83/125) in the last period (p=0. 03). Elderly patients (67%; 83/124) received less frequently ADM or F-based-regimens in comparison with younger patients (81%; 85/105) (P<0. 001). In contrast, the use of Rituximab alone or as part of front line treatment remarkably increased from 15% (16/104) in the first period to 94% (118/125) after 2003 (p<0. 001). This increase was also observed among elderly patients (8% (4/49) in the first period and 92% (69/75) in the last period, p<0. 001). After a median follow up of 68 months (range 8 to 176) for living patients, median OS was not reached. In univariate analysis factors associated with inferior OS were older age (>60), period of diagnosis before 2004, no use of Rituximab and abnormal LDH levels. The 5-years OS increased from 73% to 85% moving from first to second study periods (p=0. 008). In the Cox-Regression analysis, age > 60 (HR 11. 27 95%CI 5–25) and abnormal LDH level (HR 2. 7 95%CI 1. 56–4. 8) at diagnosis were identified as independent adverse risk factors. In contrast, the use of Rituximab yielded a protective effect (HR 0. 4 95%CI 0. 23–0. 79). In multivariate analysis period of diagnosis and use of Rituximab were mutually exclusive. Comparing young with elderly patients, only the latter group had a significant improvement in OS across the study periods: among the young, the 5-years OS in the first and second period was 89% and 98%, respectively, p= 0. 07; and among the elderly the 5-years OS in the first and second period was 58% and 72%, respectively p=0. 02. Conclusion:The present population based study showed a remarkable improvement in OS of FL patients after 2003, as a consequence of introduction of Rituximab as part of first line treatment. This improvement was mostly pronounced in the elderly population. Disclosures:No relevant conflicts of interest to declare.

The evaluation and optimal use of rituximab in lymphoid malignancies

The evaluation and optimal use of rituximab in lymphoid malignancies Tadeusz Robak1, Pawel Robak2, Piotr Smolewski21Department of Hematology, 2Experimental Hematology, Medical University of Ł&oacute;dź, Ł&oacute;dź, PolandAbstract: Rituximab is an IgG1, chimeric monoclonal antibody (mAb) containing murine light- and heavy-chain variable-region sequences and human constant-region sequences. Rituximab targets the CD20 molecule expressed on normal and malignant B-lymphocytes. At present, rituximab is the most important mAb of clinical value in patients with B-cell lymphoid malignancies. Since approval in 1997, rituximab has become widely used in chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), mantle cell lymphoma (MCL), and diffused large B-cell lymphoma (DLBCL) when combined with chemotherapy. Currently, rituximab is commonly combined with first-line chemotherapy for FL and should be offered as maintenance therapy to all appropriate patients with this disease. Randomized Phase III trials demonstrated the superiority of rituximab added to CHOP chemotherapy against CHOP chemotherapy alone in patients with DLBCL. Rituximab alone has limited activity in MCL but can be used in MCL in combination with chemotherapy, despite the benefits not being as impressive as when used against other lymphoma entities. In addition, for the less frequent B-cell lymphomas, small series show considerable activity for most of these entities. Fludarabine and rituximab combination therapies in CLL yielded promising results in several studies. Two large Phase III randomized trials demonstrated the superiority of chemoimmunotherapy with rituximab compared with chemotherapy alone in previously untreated and refractory/relapsed patients with CLL. Therefore, it can be concluded that rituximab, with only few exceptions, can generally be accepted as a standard component of anti B-cell non-Hodgkin&#39;s lymphoma therapies. In this review, the pharmacology, mode of action, pharmacokinetics, and current place in the therapy of B-cell lymphoid malignancies of rituximab are presented. In addition, an overview of studies conducted to date and optimal use of this drug, including timing and doses, is presented.Keywords: chronic lymphocytic leukemia, combined therapy, rituximab, DLBCL, follicular lymphoma, NHL, side effects, pharmacokinetics

Impact on Medical Cost, Cumulative Survival, and Cost-Effectiveness of Adding Rituximab to First-Line Chemotherapy for Follicular Lymphoma in Elderly Patients: An Observational Cohort Study Based on SEER-Medicare

Rituximab improves survival in follicular lymphoma (FL), but is considerably more expensive than conventional chemotherapy. We estimated the total direct medical costs, cumulative survival, and cost-effectiveness of adding rituximab to first-line chemotherapy for FL, based on a single source of data representing routine practice in the elderly. Using surveillance, epidemiology, and end results (SEER) registry data plus Medicare claims, we identified 1,117 FL patients who received first-line CHOP (cyclophosphamide (C), doxorubicin, vincristine (V), and prednisone (P)) or CVP +/− rituximab. Multivariate regression was used to estimate adjusted cumulative cost and survival differences between the two groups over four years after beginning treatment. The median age was 73 years (minimum 66 years), 56% had stage III-IV disease, and 67% received rituximab. Adding rituximab to first-line chemotherapy was associated with higher adjusted incremental total cost ($18,695; 95% Confidence Interval (CI) $9,302–$28,643) and longer adjusted cumulative survival (0.18 years; 95% CI 0.10–0.27) over four years of followup. The expected cost-effectiveness was $102,142 (95% CI $34,531–296,337) per life-year gained. In routine clinical practice, adding rituximab to first-line chemotherapy for elderly patients with FL results in higher direct medical costs to Medicare and longer cumulative survival after four years.

R-CHOP with Iodine-131 Tositumomab Consolidation for Advanced Stage Diffuse Large B-Cell Lymphoma (DLBCL): Southwest Oncology Group Protocol S0433

AbstractAbstract 590 Background:Although the majority of patients (pts) with DLBCL have durable remissions following R-CHOP chemotherapy, a substantial proportion of pts with advanced stage disease and other clinical risk factors are not cured. Low toxicity options are required for the majority of pts who are over age 60, or have medical comorbidities. Radioimmunotherapy, a low-toxicity option, is active in relapsed DLBCL (Blood 110:54), and improves PFS when used as consolidation after chemotherapy in follicular lymphoma (JCO 26:5156). We therefore evaluated consolidative radioimmunotherapy with iodine-131 tositumomab in pts with previously untreated DLBCL. Methods:Eligible pts had bulky stage II, or advanced stage DLBCL with measurable disease and adequate organ function. Treatment was 6 cycles of R-CHOP-21, followed by 2 cycles of CHOP-21 (no rituximab), followed by iodine-131 tositumomab (65 cGy if platelet count between 100 and 150/mm3 or 75 cGy if normal platelet count) 4–12 weeks after last dose of CHOP. Results:Eighty six pts (84 eligible; 45 females) were enrolled. Median age was 64 years; International Prognostic Index risks were low (n=20, 24%), low intermediate (n=27; 32%), high intermediate (n=27, 32%) and high (n=10, 12%). Five pts died of toxicities possibly related to therapy including one case each of febrile neutropenia, acute myeloid leukemia, and renal failure; there were two deaths from cardiac ischemia including one following a GI bleed in setting of thrombocytopenia after iodine-131 tositumomab. With a median follow-up of 12 months, 26 pts have progressed or died, with a 1-year progression-free survival (PFS) estimate of 75% (95%CI: 64%-85%), and 1-year overall survival (OS) estimate of 83% (95% CI:74%-93%). Based on prior studies, the estimated historical 1-year PFS rate with R-CHOP alone in this population is 74%. Complete data on iodine-131 tositumomab treatment is available for 73 of 84 eligible patients: 23 pts (32%) did not receive iodine-131 tositumomab due to early progression (n=3), other adverse event (n=6), refusal (n=6), death (n=3), or other reasons (n=5). Conclusions:A consolidation strategy utilizing iodine-131 tositumomab after 8 cycles of CHOP chemotherapy (6 with rituximab) for DLBCL does not appear to be promising in regard to 1 year PFS or OS. Unlike follicular lymphoma, in this population of DLBCL, early progressions, deaths, and declining performance status during CHOP chemotherapy limits the number of pts who ultimately can benefit from a planned consolidation approach. These current results suggest that the incorporation of novel agents earlier in therapy may ultimately have greater impact in DLBCL than consolidation or maintenance approaches. (Supported by 5U10CA32102-31, 5U10CA38926-25, and GlaxoSmithKline). Disclosures:Friedberg:Genentech: Honoraria. Off Label Use: Iodine-131 tositumomab for large cell lymphoma. Gopal:GlaxoSmithKline: Research Funding. Press:Trubion Pharmaceuticals: Consultancy, Equity Ownership; PhaseRx: Equity Ownership; Algeta: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Genentech: Honoraria; Spectrum: Honoraria.

Effect of prior rituximab on high-dose therapy and autologous stem cell transplantation in follicular lymphoma

Autologous stem-cell transplantation (ASCT) has been used in follicular lymphoma (FL) to achieve durable responses in first remission or in the relapsed or refractory settings. Addition of rituximab to chemotherapy for FL has been shown to improve survival. The impact of prior therapy with rituximab upon the effectiveness of high-dose therapy (HDT) and ASCT in patients with FL is unknown. We retrospectively reviewed consecutive patients with FL who underwent HDT and ASCT. Patients were categorized according to prior therapy with rituximab. Outcomes were compared between groups in all patients and in a well-matched subset. In all 35 patients received prior rituximab and 71 rituximab-naive patients were analyzed. The rituximab-naive group had a median overall survival (OS) that was not reached during follow-up, with a median relapse-free (RFS) survival of 49.9 months. The prior rituximab group also did not reach median OS and had a median RFS of 24.6 months. Survivals were not significantly different in this group or in the well-matched subset. In conclusion, these results suggest that the use of rituximab-based regimens for the treatment of FL does not compromise the effectiveness of HDT and ASCT as a salvage strategy in patients with FL.

Efficacy of rituximab plus chemotherapy in follicular lymphoma depends on Ki-67 expression.

Rituximab is widely used for the treatment of B-cell non-Hodgkin's lymphoma (NHL), and encouraging results have been obtained. However, some CD20-positive NHL show minimal response to rituximab, indicating that the treatment effect depends on the presence or absence of an unidentified factor. We analyzed the relationship between the effect of rituximab plus chemotherapy and expression of Ki-67, p53 and bcl-2 and several clinical variables in cases of B-NHL, particularly follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). Forty-four patients were included in the present study, and the overall treatment response rate was 68%. Twelve of 30 patients (40%) achieved a complete response, five (16%) reached an unconfirmed complete response and 13 (43%) achieved a partial response. A high serum lactate dehydrogenase level and International Prognostic Index of high or high intermediate risk were associated with a decreased response in the case of FL. Immunohistochemical assays were performed in 18 FL patients (55%) and 15 DLBCL patients (45%). Significant correlation was found between an inferior response to treatment and high Ki-67 expression in the cases of FL (P = 0.006). p53 and bcl-2 expression did not correlate significantly with the response rate. The cell cycle appears to be an important factor in the efficacy of rituximab treatment. Ki-67 expression might be a predictor of efficacy of rituximab plus chemotherapy.

Splenic angiosarcoma following chemotherapy for follicular lymphoma

A case of splenic angiosarcoma in a patient who had been treated for a follicular lymphoma with chemotherapy over a period of about nine years is reported. The etiologic agents for angiosarcomas at various sites, and their associations with other tumors, are reviewed. The most important of these associations are radiotherapy and lymphedema with tumors of the skin and soft tissues; and vinyl chloride, arsenic, and thorium dioxide with hepatic tumors. For splenic angiosarcomas, only isolated associations with breast carcinoma and thorium dioxide exposure have been reported. In the present case long-term combination chemotherapy seems to be the most likely etiologic association.