Rituximab-based Therapy Research Articles

Chimeric Antigen Receptor Modified T Cells Directed Against CD19 (CTL019) in Patients with Poor Prognosis, Relapsed or Refractory CD19+ Follicular Lymphoma: Prolonged Remissions Relative to Antecedent Therapy

BACKGROUND: Patients (pts) with follicular lymphoma (FL) who have progression of disease within 2 years of immunochemotherapy have poor outcomes and represent a distinct group for whom development of new therapies is warranted (Casulo et al. J Clin Oncol 2015). Autologous T cells genetically modified to express a chimeric antigen receptor consisting of an external anti-CD19 single chain murine antibody domain with CD3ζ and 4-1BB signaling domains (CTL019 cells) can mediate potent anti-tumor effects in pts with relapsed or refractory chronic lymphocytic leukemia, acute lymphoblastic leukemia, and B cell lymphomas. We evaluated the safety and efficacy of CTL019 cells in pts with relapsed or refractory FL as part of an ongoing phase IIa clinical trial (NCT02030834). METHODS: Eligible pts have CD19+ FL with progression of lymphoma RESULTS: To date, 14 pts with FL are enrolled (9 pts with FL grade 1-2 and 5 pts with FL grade 3a). The median age is 59 years (range: 43-72), male: female ratio is 7:7, median number of prior therapies is 5 (range: 2-10), and number of pts with prior transplant is 3 (21%; 2 auto, 1 allo transplant). Ann Arbor stages at enrollment are: Stage IV 9 pts (64%), Stage III 3 pts (21%), and Stage II 2 pts (14%); 4 pts (29%) have bone marrow involvement. LDH is increased in 9 pts (64%). ECOG PS is 0 in 10 pts (71%) and 1 in 4 pts (28%).FLIPI score at enrollment is high risk in 10 (71%) pts, intermediate risk in 2 (14%), and low risk in 2 (14%). All pts had previously received rituximab, either alone or in combination, with failure to respond or progression of disease after rituximab-based combination therapy. As of July 24, 2016, 14 patients received the protocol-specified dose of CTL019 cells.Lymphodepleting chemotherapy regimens are bendamustine (6 pts), cyclophosphamide (2 pts), cyclophosphamide-fludarabine (1 pt), radiation-cyclophosphamide (3 pts), EPOCH (1 pt), and carboplatin-gemcitabine (1 pt). Median CTL019 cell dose/kg is 6.08E+06 (range: 3.08-8.87E+06). Median peak CTL019 cell expansion in blood occurred 7 days after infusion (range: 7-14 days); there is no difference in peak expansion between responders and non-responders.Fourteen pts are evaluable for response, and 13 pts are evaluable for response duration. Overall response rate (ORR) at 3 mo is 79% (11/14 pts) with complete response (CR) rate 50% (7/14 pts). At 6 mo response assessment, 2 of 3 pts with partial response (PR) converted to CR. Best response is CR in 9 of 14 pts (64%). One pt with PR at 3 mo, who remained in PR at 6 and 9 mo, ultimately had progression of disease at 13 mo. At the median follow-up 11.4 mo from CTL019 infusion, the proportion of pts progression-free is 77% (95%CI: 45-92%) and the median TTNT not yet reached compared to median TTNT 7.2 mo (95%CI: 4.4 to 13.8 mo) for antecedent therapy (p CONCLUSIONS: These results suggest that a single treatment with CTL019 cells with no subsequent therapy has efficacy in FL and can improve time to next treatment compared with prior therapy in patients with poor prognosis, relapsed or refractory FL. Disclosures Svoboda:Celgene: Research Funding; Seattle Genetics: Research Funding; Pharmacyclics: Research Funding. Nasta:Millennium Pharmaceuticals: Research Funding. Porter:Immunovative Therapies: Other: Travel, Accommodations, Expenses; University of Pennsylvania: Patents & Royalties; Novartis: Research Funding; Novartis: Consultancy; Incyte: Honoraria; Genentech/Roche: Equity Ownership; Genentech/Roche: Employment. Mato:Pharmacyclics: Consultancy; TG Therapeutics: Consultancy; Abbvie: Research Funding; Acerta Pharma: Research Funding; Gilead Sciences: Research Funding; ProNAi: Research Funding; TG Therapeutics: Research Funding; Theradex: Research Funding; Gilead Sciences: Consultancy; Abbvie: Consultancy. Lacey:Novartis: Research Funding. Melenhorst:Novartis: Research Funding. Chew:Novartis: Research Funding. Hasskarl:Novartis: Employment. Marcucci:Novartis: Research Funding. Levine:Novartis: Patents & Royalties, Research Funding; GE Healthcare Bio-Sciences: Consultancy. June:Novartis: Honoraria, Patents & Royalties, Research Funding; Novartis: Honoraria, Patents & Royalties, Research Funding; Celldex: Consultancy, Equity Ownership; Tmunity Therapeutics: Equity Ownership; Johnson & Johnson: Honoraria; Pfizer: Honoraria; Immune Design: Consultancy, Equity Ownership. Schuster:Gilead: Research Funding; Nordic Nanovector: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Research Funding; Hoffman-LaRoche: Research Funding; Janssen Research & Development: Research Funding; Genentech: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Research Funding; Merck: Research Funding.

Survival Trends in Young Patients with Waldenstrom Macroglobulinemia: Over 5 Decades of Experience

BackgroundWaldenstrom macroglobulinemia (WM) is an IgM-associated lymphoplasmacytic lymphoma, first described over seven decades ago. Although WM is typically a disease of the elderly, with a median age at diagnosis of ~ 67 years, approximately 10% of patients are ≤50 years (y) of age at diagnosis. Data for young patients are sparse and the few available studies demonstrate inconsistent findings, with potential overestimation of survival owing to inclusion of patients with smoldering WM. In this case-control study, we evaluate outcomes, prognostic features and impact of changing therapies in a large cohort of young symptomatic WM patients compared to matched older patients seen over the course of the past five decades.MethodsThe medical records of all WM patients seen consecutively at Mayo Clinic from 01/1960 to 10/2013 were reviewed. Of 1181 patients, 140 (11.8%) were ≤ 50 y of age at diagnosis. A cohort of patients 65 y or older at diagnosis, matched 1:1 by the time of diagnosis, served as the control population. The patients were divided into 3 groups based on the timing of initiation of therapy: Group 1 (1960-1977), Group 2 (1978-1995) and Group 3 (1996-2013). The baseline characteristics were compared. Initiation of frontline therapy was used for all time-to-event analysis using the Kaplan Meier method.ResultsYounger patients were more likely to present with adenopathy and splenomegaly, have higher IgM levels and hyperviscosity symptoms (Table 1). The median follow-up from the frontline therapy was similar (10.7 y vs. 10 y for the control population). At the time of analysis, 91% of the deaths for the younger cases were WM-related compared to 58% in the control arm (p=0.0001). Younger patients had a better OS with a median disease-specific survival (DSS) of 15.6 y (95% CI: 13-21; 10-y OS of 77%) vs. 11 y (95% CI: 7.8-12; 10-y OS of 51%) for the older patient (p=0.0003).Among the young patients, there was no difference in the median DSS across the 3 groups (p=0.42). However, the median DSS for the control group incrementally improved (p=0.02) over the 3 time periods (Table 1).In the younger patients, no improvement in DSS was noted with the use of either frontline rituximab-based therapy compared to non-rituximab based regimens [median NR (95% CI: 7.6-NR) vs. 15.8 y (95% CI: 13-22) with other regimens, p=0.30], or frontline chlorambucil-based compared to non-chlorambucil based regimens [median 16 y (95% CI: 12-22) vs 15.6 y (95% CI: 12-NR) with other regimens, p=0.73]. In the control group, however, there was significant difference in DSS among patients who received frontline rituximab-based compared to non-rituximab based regimens [median NR (95% CI: 8.3-NR) vs 9.1 y (95% CI: 5.6-12) with other regimens, p=0.04], or frontline chlorambucil-based vs non-chlorambucil based regimens [8 y (95% CI: 5-12) vs 12.3 y (95% CI: 11-NR) in other regimens; p=0.001].ConclusionStriking differences in presentation are evident in young WM patients compared to their older counterparts. The incorporation of rituximab to the previously existing anti-WM regimens and the transition to non-chlorambucil based regimens has resulted in substantial survival gains in the older WM population over the past five decades. However, such improvement in outcome has not yet been observed in the young patients. The majority of younger patients, despite a protracted disease course, succumb to their disease. [Display omitted] DisclosuresAnsell:BMS, Seattle Genetics, Merck, Celldex and Affimed: Research Funding. Ailawadhi:Pharmacyclics: Consultancy; Novartis: Consultancy; Amgen Inc: Consultancy; Takeda Oncology: Consultancy. Reeder:Novartis: Research Funding; Celgene: Research Funding; BMS: Research Funding; Millennium: Research Funding. Kumar:Kesios: Consultancy; Janssen: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; AbbVie: Research Funding; BMS: Consultancy; Onyx: Consultancy, Research Funding; Glycomimetics: Consultancy; Millennium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees. Dispenzieri:Alnylam: Research Funding; Celgene: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; pfizer: Research Funding; Jannsen: Research Funding. Kapoor:Celgene: Research Funding; Takeda: Research Funding; Amgen: Research Funding.

De Novo Anti-HLA DSA Characteristics and Subclinical Antibody-Mediated Kidney Allograft Injury.

It is unclear whether all donor-specific antibodies (DSA) can cause chronic antibody-mediated rejection (AMR). Subclinical stage before manifestation of renal dysfunction may be a critical period for reversing AMR. The aim of our study was to identify factors related to the development of subclinical AMR and to clarify the characteristics of de novo DSA. Eight hundred ninety-nine renal transplants were screened for HLA antibody. De novo DSA were detected in 95 patients. Forty-three patients without renal dysfunction who underwent renal biopsies were enrolled in this study. Eighteen patients (41.9%) were diagnosed with biopsy-proven subclinical AMR and treated with plasmapheresis and rituximab-based therapy, whereas 25 showed no findings of AMR. Significant subclinical AMR-related factors were younger recipients, history of acute T cell-mediated rejection and DSA class II, especially DR-associated DSA. Mean fluorescence intensity (MFI) values of DR-DSA were significantly higher, whereas DQ-DSA was not different between subclinical AMR and no AMR. The ΔMFI (>50%), DSA-MFI values greater than 3000, and C1q binding DSA were also significant subclinical AMR-related factors (P < 0.05). Among 18 patients treated for subclinical AMR, 8 patients (44.4%) obtained over 50% reduction of DSA-MFI and/or improvement or no deterioration of pathological findings. In contrast, 25 patients without subclinical AMR did not show renal dysfunction clinically. Moreover, all of the 8 patients with rebiopsy after 2 years continued to demonstrate no AMR. About 40% of patients with de novo DSA demonstrated biopsy-proven subclinical AMR, leading to progressive graft injury. To validate the intervention and treatment for de novo DSA-positive patients without renal dysfunction, further study is necessary.

The FCGR3A polymorphism predicts the response to rituximab-based therapy in patients with non-Hodgkin lymphoma: a meta-analysis.

Epidemiological studies have assessed the association between Fc gamma receptor IIIA (FCGR3A) 158 V/F and the response to rituximab-based therapy in patients with non-Hodgkin lymphoma (NHL), but the findings have been inconsistent. We performed this meta-analysis to obtain a better assessment of this relationship. Electronic database searches were conducted for relevant studies. A pooled odds ratio (OR) with a 95% confidence interval (95% CI) was used to assess the strength of the association. Analyses of the subgroup and publication bias were conducted. A total of 10 studies involving 1050 patients were analyzed. In all the genetic models, no clear relationship was found between the FCGR3A 158 V/F polymorphism and the response to rituximab-based therapy in NHL patients. When categorized by ethnicity, Asian individuals with the FCGR3A 158 V/V allele (OR = 4.37; 95% CI = 1.07-17.73; P = 0.039) or the non-F/(FV + VV) (OR = 2.50; 95% CI = 1.04-5.98; P = 0.040) allele have a significantly higher complete response rate (CR) compared to FF individuals. No obvious heterogeneities were observed. In addition, no statistical evidence for a publication bias was found. Our study suggested that the FCGR3A 158 V/F polymorphism can predict the treatment response to rituximab-based chemotherapy in NHL patients, especially for Asian individuals.

Obinutuzumab plus bendamustine versus bendamustine monotherapy in patients with rituximab-refractory indolent non-Hodgkin lymphoma (GADOLIN): a randomised, controlled, open-label, multicentre, phase 3 trial

Patients with indolent non-Hodgkin lymphoma who fail to achieve adequate disease control with rituximab-based treatment have few treatment options and a poor prognosis. We aimed to assess a combination of obinutuzumab (GA101), a novel glyco-engineered type II anti-CD20 monoclonal antibody, and bendamustine in this patient population. In this open-label, randomised, phase 3 study (GADOLIN), patients aged 18 years or older with histologically documented, CD20-positive indolent non-Hodgkin lymphoma refractory to rituximab were enrolled at 83 hospital and community sites in 14 countries in Europe, Asia, and North and Central America. Patients were randomly assigned (1:1) using a hierarchical dynamic randomisation scheme stratified by indolent non-Hodgkin lymphoma subtype, rituximab-refractory type, number of previous therapies, and geographical region, to receive induction treatment (six 28-day cycles) with obinutuzumab plus bendamustine or bendamustine monotherapy, both given intravenously. Obinutuzumab plus bendamustine dosing was obinutuzumab 1000 mg (days 1, 8, and 15, cycle 1; day 1, cycles 2-6) plus bendamustine 90 mg/m(2) per day (days 1 and 2, cycles 1-6), and bendamustine monotherapy dosing was 120 mg/m(2) per day (days 1 and 2, all cycles). Non-progressing patients in the obinutuzumab plus bendamustine group received obinutuzumab maintenance (1000 mg every 2 months) for up to 2 years. The primary endpoint was progression-free survival in all randomised patients, as assessed by an independent review committee. Safety was assessed in all patients who received any amount of obinutuzumab or bendamustine. This study is registered with ClinicalTrials.gov, number NCT01059630, and has stopped recruiting patients. Between April 15, 2010, and Sept 1, 2014, when the study was stopped after a pre-planned interim analysis, 396 patients were randomly assigned (194 to obinutuzumab plus bendamustine and 202 to bendamustine monotherapy). After a median follow-up time of 21·9 months (IQR 12·1-31·0) in the obinutuzumab plus bendamustine group and 20·3 months (9·5-29·7) in the bendamustine monotherapy group, progression-free survival was significantly longer with obinutuzumab plus bendamustine (median not reached [95% CI 22·5 months-not estimable]) than with bendamustine monotherapy (14·9 months [12·8-16·6]; hazard ratio 0·55 [95% CI 0·40-0·74]; p=0·0001). Grade 3-5 adverse events occurred in 132 (68%) of 194 patients in the obinutuzumab plus bendamustine group and in 123 (62%) of 198 patients in the bendamustine monotherapy group. The most frequent grade 3 or worse adverse events were neutropenia (64 [33%] in the obinutuzumab plus bendamustine group vs 52 [26%] in the bendamustine monotherapy group), thrombocytopenia (21 [11%] vs 32 [16%]), anaemia (15 [8%] vs 20 [10%]) and infusion-related reactions (21 [11%] vs 11 [6%]). Serious adverse events occurred in 74 patients (38%) in the obinutuzumab plus bendamustine group and in 65 patients (33%) in the bendamustine monotherapy group, and deaths due to adverse events occurred in 12 patients (6%) and 12 patients (6%), respectively. Three (25%) of 12 adverse event-related deaths in the obinutuzumab plus bendamustine group and five (42%) of 12 in the bendamustine monotherapy group were treatment related. Obinutuzumab plus bendamustine followed by obinutuzumab maintenance has improved efficacy over bendamustine monotherapy in rituximab-refractory patients with indolent non-Hodgkin lymphoma, with manageable toxicity, and is a new treatment option for patients who have relapsed after or are no longer responding to rituximab-based therapy. F Hoffmann-La Roche Ltd.

Mantle Cell Lymphoma: A North Indian Tertiary Care Centre Experience

Background:Mantle cell lymphoma (MCL) is an aggressive non-Hodgkin’s lymphoma, with a pathognomonic chromosomal translocation t (11;14). Prognosis is uniformly dismal but there is a paucity of information on MCL from India.Materials and methods:We retrospectively analysed clinicopathological information on all treated patients with MCL at our centre. STATA 14.0 was used for analysis. Survival was assessed by Kaplan-Meier analysis and the Cox’s proportional hazards method. Statistical significance was defined as a P value of < 0.05.Results:Fifty-one patients with MCL were reviewed. The median age at presentation was 57.0 years. Extranodal involvement was seen in 39.0 (74.0%) while bone marrow positivity at presentation was found in 27.0 (54.0%). Initial treatment was chemotherapy with or without rituximab. Patients receiving rituximab-based therapy (n = 24) had 5-year progression-free survival (PFS) of 21.0 (88.0%), compared with 14.0 (61.0%) for those not receiving rituximab (n = 23, P = 0.036). Twenty-three patients were alive with a median follow-up of 20.7 months (range 2.5-89.2). PFS at 1 and 2 years was 51.0% and 27.0%, and overall survival (OS) 78.0% and 72.0%, respectively. Use of more than 2.0 lines of therapy, use of bendamustine-rituximab, and high TLC (>10,000.0/cu.mm) significantly affected PFS.Conclusions:In our experience, MCL patients from north India have an early age at presentation. When treated with regimens including rituximab results in an improved response rate and PFS. This study provided comprehensive insights into the treatment of MCL in a developing country.

Consolidation Radiotherapy Improved Survival in Limited Stage Diffuse Large B-Cell Lymphoma (DLBCL): A Nationwide Multi-Institutional Registry of 816 Cases in Thailand

IntroductionThe additional benefit of consolidation radiotherapy (RT) following chemotherapy in limited stage DLBCL remains controversial. Previous 5 randomized trials, 4 trials before rituximab era (SWOG 8736, ECOG 1484, GELA 93-1 and 93-4 studies) and 1 trial with R-CHOP combination (Lysa/Goelams 02-03), could not demonstrate a remarkable benefit of RT. The purpose of this study is to explore the benefit of combined modality treatment including the combination of RT and rituximab (R)-based chemotherapy in limited stage DLBCL.MethodsFrom the 4,371 patients in a multi-institutional registry of newly diagnosed lymphoma in Thailand between 2007-2014, there were a total of 2,399 patients with DLBCL. We included patients with limited stage DLBCL receiving CHOP/CHOP-liked chemotherapy +/- R and +/- RT. The baseline patient characteristics and clinical outcomes were analyzed according to treatment modalities.ResultsA total of 816 patients with a median age of 56 years (range, 15-91) were included in the study. Male:female was 1:1.1. Majority of patients had primary extranodal diseases (58%), stage II (68%), good performance status (89%), normal LDH (55%) and no B-symptoms (59%). The IPI scores were 0 (30.6%), 1(45%), 2 (20%) and 3 (3.9%), respectively. The modalities of treatment were CHOP alone (48.5%), R-CHOP (26.5%), CHOP+RT (17.9%) and R-CHOP+RT (7.1%). Patients in R-CHOP group were older than in other groups (P =0.001) (Table 1).There was a higher proportion of patients in stage II disease in R-CHOP (74.1%) and R-CHOP+RT (74.1%) groups than in CHOP (66.9%) and CHOP+RT (57.5%) groups (P =0.007), whereas the patients were relatively equally distributed between the IPI scores. Complete response (CR) rate was higher in R-CHOP+RT group (82.8%) than in R-CHOP (75%), CHOP+RT (70%) and CHOP groups (58%) (P<0.001). CR was independently associated with consolidation RT (OR 0.65, 95%CI: 0.45-0.97), rituximab-based therapy (OR 0.66; 95%CI: 0.55-0.79) and IPI score (OR 1.90; 95%CI: 1.41-2.57). With a median follow up of 52 months, 4-year progression free survival (PFS) were 76.4%, 69.4%, 61.4% and 49.9% in R-CHOP+RT, R-CHOP, CHOP+RT and CHOP alone, respectively, (P<0.001) (Figure. 1). The corresponding figures of 4-year OS for each group were 78.6%, 76.3%, 64.3% and 59.6%, respectively (P<0.001) (Figure. 2). Multivariate analysis showed that factors associated with survivals were consolidation RT (HR for PFS 0.63, 95%CI: 0.48-0.82; HR for OS 0.70, 95%CI: 0.53-0.94), rituximab-based therapy (HR for PFS 0.72, 95%CI: 0.64-0.83; HR for OS 0.69, 95%CI: 0.60-0.81) and IPI scores (HR for PFS 1.87, 95%CI: 1.54-2.26; HR for OS 1.96, 95%CI: 1.60-2.41)ConclusionIn limited stage DLBCL, consolidation RT plus R-CHOP yielded a superior outcome compared to R-CHOP, CHOP + RT and CHOP alone. Thus, RT continues to have an important role and should not be omitted in management of limited stage DLBCL in rituximab era.Table 1Comparison of characteristics of patients according to treatment modalitiesClinical characteristicsCHOP alone(n= 396)CHOP + RT(n = 146)R-CHOP alone (n = 216)R-CHOP + RT (n = 58)p-valueMale211 (53%)75(51.4%)125 (57.9%)24 (41.4%)0.14Median age (years)56 (15-90)52 (15-86)60 (17-91)55 (15-81)0.001Age ≥ 60155 (39.1%)51 (34.9%)109 (50.5%)20 (34.5%)0.008Primary extranodal disease226 (57.1%79 (54.1%)136 (63.0%34 (58.6%)0.35Stage Stage I Stage II131 (33.1%) 269 (66.9%)62 (42.5%) 84 (57.5%)56 (25.9%) 160 (74.1)15 (25.9%) 43 (74.1%)0.007B-symptom116 (32.6%)47 (36.2%)58 (31.4%)13 (28.9%)0.76HIV seropositivity15 (4.6%)9 (7.0%)--0.004High serum LDH173 (43.7%)74 (50.7%)95 (44.0%)26 (44.8%)0.51ECOG ≥ 231 (7.8%)22 (15.1%)25 (11.6%)7 (12.1%)0.08IPI Low (IPI =0-1) Low-intermediate (IPI =2) High-intermediate (IPI = 3)312 (78.8%) 75 (18.9%) 9 (2.3%)107(73.3%) 32 (29.1%) 7 (4.8%)157 (72.7%) 48 (22.2%) 11 (5.1%)46 (79.3%) 9 (15.5%) 3 (5.2%)0.35Response Overall response Complete response258 (65.2%) 230 (58.1%)116(79.4%) 103(70.5%)179 (82.9%) 162 (75%)51 (88%) 48 (82.8%)<.0001 [Display omitted] [Display omitted] DisclosuresKhuhapinant:Roche: Honoraria.

Palbociclib (PD-0332991), a Potent Selective CDK4/6 Inhibitor, Overcomes Therapy-Resistant and Sensitizes Diffuse Large B-Cell Lymphoma Pre-Clinical Models to Chemo-Reagents

Background: Results from the Collaborative trial in relapsed aggressive lymphoma (CORAL) study highlighted the poor clinical outcome of relapsed/refractory diffuse large B-cell lymphoma (DLBCL) patients previously treated with rituximab-based therapy. To better understand the molecular mechanisms underlining the acquired resistance to rituximab, we generated and characterized several rituximab-resistant DLBCL cell lines (RRCLs). We found that RRCL exhibited a unique cell cycle distribution (accumulation in S-phase) and an increase in cyclin D Kinase-4 (CDk4) mRNA/protein levels. In our current work, we evaluated Palbociclib, a novel orally bioavailable CDK4/6 inhibitor recently approved by the Food and Drug Administration for the treatment of breast cancer in rituximab-sensitive and -resistant lymphoma pre-clinical models.Methods: A panel of rituximab-sensitive cell lines (RSCL) or RRCL were exposed to escalating dosages of PD0332991 (0-80µM) for 24-72 hrs. Changes in cell viability and cell cycle distribution were evaluated using the Presto Blue assay and flow cytometry respectively. IC50 values were calculated using the GraphPad Prism6 software. Subsequently RSCL or RRCL were exposed to PD0332991 or vehicle control and doxorubicin (0.5, 1, 2µM), dexamethasone (1µM), ibrutinib (1µM), bortezomib (10-20nM) or carfilzomib (10nM) for 48 hours. Changes in cell viability were determined by the Presto Blue assay. Coefficient of synergy was calculated using the CalcuSyn software.Results: Palbociclib induced dose- and time-dependent decrease in cell viability in both RSCL and RRCL. Of interest, palbociclib was more potent in RRCL than RSCL. The IC50 values were lower in RRCL Raji-4RH and RL-4RH (12.12µM and 13.43µM) than in RSCL Raji and RL cells (14.7µM and 19.99µM). In vitro exposure of lymphoma cells to palbociclib resulted in G1 cell cycle arrested and it was more evident in RRCL than in RSCL. Synergistic activity was observed by combining palbociclib with doxorubicin, dexamethasone and proteasome inhibitors (bortezomib and carfilzomib) in vitro. Our data suggests that, palbociclib is active against in rituximab-sensitive or resistant pre-clinical models. In addition, CDK4/6 inhibition resulted in synergistic effects with several chemotherapeutic agents. A better understanding in the molecular events triggered by palbociclib is necessary to better develop optimal combination strategies using this novel agent in future clinical trials. (Research, in part, supported by a NIH grant R01 CA136907-01A1 awarded to Roswell Park Cancer Institute and The Eugene and Connie Corasanti Lymphoma Research Fund). DisclosuresCzuczman:Celgene: Employment; MorphoSys: Consultancy; Immunogen: Other: Advisory board; Boehringer-Ingelheim: Other: Advisory Board.

Interfollicular CD10 Expression and Follicular PD1 Tumor-Infiltrating Lymphocytes As Biologic Risk Factors in Patients with Previously Untreated Follicular Lymphoma Receiving Rituximab-Based Biologic Therapy: An Alliance Correlative Science Study (CALGB 50901, 50402, 50701, 50803, 50401)

Interfollicular CD10 Expression and Follicular PD1 Tumor-Infiltrating Lymphocytes As Biologic Risk Factors in Patients with Previously Untreated Follicular Lymphoma Receiving Rituximab-Based Biologic Therapy: An Alliance Correlative Science Study (CALGB 50901, 50402, 50701, 50803, 50401)

Cell-of-Origin (COO) Classification, BCL2 and MYC Expression Associated-Outcome in Younger Patients Treated By RCHOP Front-Line Therapy Versus Intensive Regimen Followed By Autologous Transplant for De Novo Advanced Diffuse Large B Cell Lymphoma (DLBCL) : Results of the French Prospective Multicenter Randomized Trial Goelams -075

Background: The prognostic value of COO classification by immunohistochemistry (IHC) for de novo untreated advanced DLBCL remains controversial after Rituximab-based frontline therapy. Other biomarkers such as BCL2 or MYC protein expression have been proposed to predict survival. IHC characteristics were investigated in a large multicenter randomized study.Methods: Three hundred twenty-three patients (pts) younger than 60 years with de novo untreated advanced DLBCL were randomized in the french prospective multicenter trial GOELAMS-075 to receive either 8 courses of RCHOP14 (n=161) or 2 courses of RCEEP (Rituximab, Cyclophosphamide, Eldisine, Epirubicine, Prednisone) and 1 course of Rituximab-Methotrexate-Cytarabine (RMC) followed by intensive BEAM conditionning with autologous transplant (ASCT) (n=162) upon negative interim PET-CT (visual analysis). In case of positivity, salvage regimen followed by ASCT was applied. Three years Event-free-survival (3y-EFS) was the primary endpoint. Event was defined by interim PET-CT positivity, progression or relapse, or death from any cause. Central pathology review confirmed de novo DLBCL diagnosis for 300 pts (93%). COO determination using Hans algorithm, BCL2 protein expression (clone 124, Dako) and MYC protein expression (clone Y69, Abcam) were recorded. Cut-off values were 70% for BCL2, and 40% for MYC.Results: COO analysis could be performed for 125/161 pts in RCHOP arm and 134/162 pts in intensive regimen arm including 36 and 34 Primary-Mediastinal-B-Cell subtype (PMBL) respectively. Repartition of non-PMBL was: 33/89 (37%) Germinal-Center subtype (GC), 56/89 (63%) Non-Germinal-Center subtype (NGC) in R-CHOP arm; 48/100 (48%) GC, 52/100 (52%) NGC in intensive regimen arm. Of 70 PMBL there were 50 NGC, 4 GC and 16 NE equally distributed in both arms. Clinical characteristics were similar in both GC and NGC subtypes, whereas PMBL presented with more frequent bulky disease and predominantly female gender. BCL2 ≥70% and MYC ≥40% were found in 147/285 (55%) and 85/185 (46%) of available samples, without difference between two arms. No correlation was found between BCL2 or MYC protein expression and GC or NGC subtype, however there were seen in a significantly lower proportion of PMBL (34% and 17% respectively). Coexpression of BCL2≥70% and MYC≥40% (MYC+/BCL2+) occurred in 52/184 (28%) cases, without difference between two arms or COO subtypes. By contrast, PMBL subtype displayed an extremely low rate of MYC+/BCL2+ cases (1/49, 2%).3y-EFS rates were 52% ± 6% for GC, 58% ± 5% for NGC and 49% ± 6% for PMBL (p= 0,42) with no significant difference according to treatment arm. Of note, in PMBL, the majority of events was positive interim PET-CT. Worse EFS was seen in BCL2≥70% cases (3y-EFS: 47% ± 4% vs 60% ± 4%, p= 0,05) but this difference was erased in RCHOP arm (3y-EFS: 52% ± 6% vs 58% ± 6%).3y-Progression Free Survival (PFS) rates were 73% ± 6% for GC, 76% ± 6% for NGC and 94% ± 4% for PMBL (p=0,03) with no difference between the two arms (Fig 1). There was no PFS difference in BCL2≥70% vs <70% cases (3y-PFS: 71% ± 4% vs 82% ± 4%, p= 0,11). EFS and PFS rates were similar between MYC≥40% and <40% cases (3y-EFS: 56% vs 59%; 3y-PFS: 78% vs 84%) without further advantage of one arm compared to another. Same results were obtained for MYC+/BCL2+ vs non MYC+/BCL2+ cases (3y-EFS: 53% vs 58%; 3y-PFS: 78% vs 81%).After a median follow-up of 71 months, PMBL was associated with significant better overall survival (OS) whereas no difference was observed between GC and NGC subtypes (5y-OS : 96% vs 75% and 78% respectively, p= 0,002) (Fig 2). OS rates were similar for BCL2 positive and BCL2 negative cases after exclusion of PMBL (5y-OS: 75% vs 78%, p=0,65). There was no significant impact of IHC MYC positivity (5y-OS : 80% vs 86% for MYC negative cases, p=0,29) or MYC+/BCL2+ coexpression (5y-OS : 80% vs 85% for negative cases, p=0,50) on outcome. There was no significant impact of treatment on OS of MYC and/or BCL2 positive cases.Conclusion: In younger patients, outcome of IHC defined GC and NGC subtype of non-PMBL DLBCL was not different following R-CHOP14 or intensive treatment including ASCT. Similarly, regardless of treatment arm, BCL2 or MYC or both overexpression did not impair significantly the prognosis. IHC defined COO or BCL2/MYC overexpression could not identify DLBCL in need of intensive therapy with ASCT. Finally the good prognosis of PMBL subtype with excellent PFS and OS was confirmed. [Display omitted] [Display omitted] DisclosuresCartron:Sanofi: Honoraria; Celgene: Honoraria; Gilead: Honoraria; Roche: Consultancy, Honoraria; GSK: Honoraria.

Epstein-Barr Virus-Related Post-Transplantation Lymphoproliferative Disorder after Unmanipulated Human Leukocyte Antigen Haploidentical Hematopoietic Stem Cell Transplantation: Incidence, Risk Factors, Treatment, and Clinical Outcomes.

We examined the incidence, risk factors, treatments, and clinical outcomes of post-transplantation lymphoproliferative disorder (PTLD) after unmanipulated haploidentical (haplo) hematopoietic stem cell transplantation (HSCT) in 1184 patients between 2006 and 2012. Age-, transplantation time-, and transplantation duration-matched controls were randomly selected from the same cohort. Forty-five patients experienced PTLD. The median time from HSCT to PTLD occurrence was 61 (range, 33 to 360) days and the 1-year cumulative incidence of total PTLD after haplo-HSCT was 3.0%. In multivariate analysis, a lower absolute count of CD8(+) T lymphocytes at day 30, a lower absolute count of immunoglobulin M at day 30, and cytomegalovirus DNAemia after HSCT were significantly associated with higher risk of PTLD. The 2-year probability of overall survival (OS) after HSCT was 42.8%, which was comparable between the probable PTLD and the proven PTLD patients. Patients who received rituximab-based therapy had significantly better 2-year OS (48.2% versus 13.2%, P = .02). Thus, we were able to identify individuals at a high risk of developing PTLD after unmanipulated haplo-HSCT. Rituximab-based therapy can help to improve the outcomes of PTLD patients.

Abstract CT221: CHRONOS-3: A phase III, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of phosphatidylinositol-3 kinase (PI3K) alpha/delta inhibitor copanlisib in combination with rituximab in patients with relapsed indolent B-c

Abstract Background: Copanlisib is a novel pan-Class I PI3K inhibitor with potent preclinical inhibitory activity against both PI3K-δ and PI3K-α isoforms. In a phase II study of copanlisib monotherapy in patients with relapsed/refractory indolent or aggressive lymphoma, an overall response rate of 53% was seen in patients with iNHL (Dreyling et al., ENA 2014). Rituximab in combination with chemotherapy is standard first-line therapy for indolent iNHL and is a therapeutic option for relapsed patients who cannot tolerate chemotherapy or who had a long response following the last rituximab-based therapy. The objective of this study is to evaluate the efficacy and safety of copanlisib in combination with rituximab versus placebo plus rituximab in patients with iNHL who relapsed after one or more lines of therapy, including rituximab and alkylating agents, and who are either unfit for chemotherapy or had a treatment-free interval of at least 12 months following last rituximab-based therapy. Methods: Patients must meet the following criteria: histologically confirmed diagnosis of iNHL, with follicular lymphoma (FL) grade 1-2-3a, marginal zone lymphoma (splenic, nodal, or extra-nodal), small lymphocytic lymphoma, or lymphoplasmacytoid lymphoma/Waldenström macroglobulinemia, and who have previously received at least one line of therapy including rituximab and alkylating agents. Patients must be not refractory to rituximab during any prior line of therapy (response &amp;lt;6 months). Approximately 567 patients (435 FL patients and 132 other iNHL patients) will be randomized 2:1 and stratified according to the four factors: NHL histology (FL vs. other iNHL), treatment-free interval after rituximab treatment vs. contraindication for chemotherapy, bulky disease (yes vs. no), and previous treatment with PI3K inhibitors (yes vs. no). Patients will receive 60 mg of copanlisib or placebo administered intravenously on days 1, 8 and 15 of a 28-day cycle in combination with 375 mg/m2 of rituximab administered on days 1, 8, 15 and 22. Radiologic tumor assessment will be performed every 8, 12, or 24 weeks for years 1, 2, and 3, respectively. The primary endpoint will be progression-free survival (PFS) as assessed by central review. Secondary objectives include objective tumor response rate, duration of response, complete response rate, time to progression, overall survival, time to improvement and the time to deterioration in disease-related symptoms - physical (DRS-P) of at least 3 points as measured by the FLymSI-18 questionnaire. The study is planned to detect a 50% increase in median PFS in copanlisib plus rituximab arm versus the placebo plus rituximab arm (hazard ratio of 0.6667) within the FL patients, using a stratified log-rank test. Citation Format: Pier Luigi Zinzani, John F. Gerecitano, Marius Giurescu, Rodrigo Ito, Katharina Mueller, Barrett H. Childs. CHRONOS-3: A phase III, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of phosphatidylinositol-3 kinase (PI3K) alpha/delta inhibitor copanlisib in combination with rituximab in patients with relapsed indolent B-c [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT221. doi:10.1158/1538-7445.AM2015-CT221

Abstract LB-242: PTEN regulates the CD20 antigen expression and affects rituximab-based therapy of lymphoma malignancies

Abstract The therapeutic strategies currently used in B cell malignancies include the treatment with monoclonal antibodies (rituximab and ofatumumab) directed against CD20 antigen. These antibodies specifically eliminate B cells by triggering indirect effector mechanisms of the immune system, like complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), or immunophagocytosis. In many patients, the reduced level of CD20 antigen on the surface of tumor B cells leads to the resistance to anti-CD20 therapy. The aim of this study was to explore the molecular mechanisms governing the regulation of CD20 expression in lymphoma cells as a potential explanation of the resistance to rituximab/ofatumumab therapy. We previously observed that CD20 mRNA expression is significantly affected by the SRC family inhibitors. Here, we report that also PTEN tumor suppressor is a negative regulator of CD20 expression. To uncover the transcriptional mechanisms governing the CD20 expression we employed the construct encoding the promoter region of CD20 cloned upstream of the firefly luciferase gene. Overexpression of wild-type PTEN (but not the phosphatase-deficient mutant) strongly affected the promoter activity and the expression of CD20, leading to decreased binding of rituximab and ofatumumab and increased resistance of tumor cells to complement-dependent cytotoxicity. Using the truncated versions of the CD20 promoter we identified a particular region (-313/-198) as the major region sensitive to PTEN overexpression. We found that the negative regulation of CD20 promoter activity by PTEN was mediated by inhibition of AKT signaling. We observed that the overexpression of constitutively active AKT1 (CA-AKT1) overcame the negative effect of PTEN and sensitized cells to rituximab/ofatumumab treatment. The results of our studies indicate that PTEN status in tumor cells should therefore be considered when analyzing the mechanisms of resistance of B cell malignancies to anti-CD20 therapies. Citation Format: Beata Pyrzynska, Kamil Bojarczuk, Marta Siernicka, Michal Dwojak, Malgorzata Bobrowicz, Nina Miazek, Piotr Zapala, Agnieszka Zagozdzon, Jakub Golab, Magdalena Winiarska. PTEN regulates the CD20 antigen expression and affects rituximab-based therapy of lymphoma malignancies. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-242. doi:10.1158/1538-7445.AM2015-LB-242

Can Rituximab Improve the Outcome of Patients with Nodular Lymphocyte-Predominant Hodgkin's Lymphoma?

Background: Nodular lymphocyte-predominant Hodgkin's lymphoma (NLPHL) is a rare subtype of Hodgkin's lymphoma showing strong CD20 expression. The role of rituximab in treating NLPHL still needs clarification. Methods: We retrospectively reviewed the outcome of 23 patients with NLPHL treated with rituximab alone or in combination with chemotherapy and/or radiotherapy as part of their first- or second-line treatment. Results: The median follow-up of the whole group was 67 months, and all patients remained alive. Twenty-two patients achieved complete remission after rituximab-based therapy, and one of them relapsed 32 months after treatment. One patient treated with rituximab alone achieved partial remission and progressed 22 months after treatment. Conclusion: The prognosis of NLPHL is excellent. Rituximab combined with chemotherapy and/or radiotherapy appears to prevent disease progression/relapse.

Waldenström macroglobulinemia: 2015 update on diagnosis, risk stratification, and management.

Waldenström macroglobulinemia (WM) is a lymphoplasmacytic lymphoma with immunoglobulin M (IgM) monoclonal protein. Clinical features include anemia, thrombocytopenia, hepatosplenomegaly, lymphadenopathy, and rarely hyperviscosity. Presence of IgM monoclonal protein associated with ≥10% clonal lymphoplasmacytic cells in bone marrow confirms the diagnosis. The L265P mutation in MYD88 is detectable in more than 90% of patients. Age, hemoglobin level, platelet count, β2 microglobulin, and monoclonal IgM concentrations are characteristics required for prognosis. Not all patients who fulfill WM criteria require therapy; these patients can be observed until symptoms develop. Rituximab-based therapy is used in virtually all US patients with WM and can be combined with alkylating agent or purine nucleoside analog (or both). The preferred Mayo Clinic nonstudy therapeutic induction is rituximab, cyclophosphamide, and dexamethasone. Future stem cell transplantation should be considered in induction therapy selection. Management of Refractory Disease: Bortezomib, thalidomide, everolimus, ibrutinib, carfilzomib, lenalidomide, and bendamustine have all been shown to have activity in WM. Given WM's natural history, reduction of complications will be a priority for future treatment trials.

English

De novo CD5-positive (CD5+) diffuse large B-cell lymphoma (DLBCL) is a highly aggressive subtype of DLBCL with a high incidence of misdiagnosis when spinal cord compression is the initial symptom. We report a case of a 45-year old man with de novo CD5+ DLBCL primarily presenting as spinal cord compression. Unfortunately, this patient was resistant to rituximab-based therapy, which indicated a poor prognosis.

Tumor-associated and immunochemotherapy-dependent long-term alterations of the peripheral blood NK cell compartment in DLBCL patients

Natural Killer (NK) cells are a key component of tumor immunosurveillance and thus play an important role in rituximab-dependent killing of lymphoma cells via an antibody-dependent cellular cytotoxicity (ADCC) mechanism. We evaluated the phenotypic and functional assets of peripheral blood NK cell subsets in 32 newly-diagnosed diffuse large B-cell lymphoma (DLBCL) patients and in 27 healthy controls. We further monitored long-term modifications of patient NK cells for up to 12 months after rituximab-based immunochemotherapy. At diagnosis, patients showed a higher percentage of CD56dim and CD16+ NK cells, and a higher frequency of GrzB+ cells in CD56dim, CD56bright, and CD16+ NK cell subsets than healthy controls. Conversely, DLBCL NK cell killing and interferon γ (IFNγ) production capability were comparable to those derived from healthy subjects. Notably, NK cells from refractory/relapsed patients exhibited a lower “natural” cytotoxicity. A marked and prolonged therapy-induced reduction of both “natural” and CD16-dependent NK cytotoxic activities was accompanied by the down-modulation of CD16 and NKG2D activating receptors, particularly in the CD56dim subset. However, reduced NK cell killing was not associated with defective lytic granule content or IFNγ production capability. This study firstly describes tumor-associated and therapy-induced alterations of the systemic NK cell compartment in DLBCL patients. As these alterations may negatively impact rituximab-based therapy efficacy, our work may provide useful information for improving immunochemotherapeutic strategies.

Treatment patterns and outcomes among patients with high-intermediate/high-risk diffuse large B-cell lymphoma in the USA

ObjectiveClinical trials have demonstrated improved outcomes for patients with diffuse large B-cell lymphoma (DLBCL) treated with regimens containing rituximab, but variations in real-world treatment patterns and outcomes have not been studied. The objective of this study was to characterize real-world treatment patterns and outcomes in higher risk DLBCL patients.MethodsPatients with an International Prognostic Index score (IPI) ≥3 who received initial rituximab-based therapy from 2005 to 2012 were identified via electronic medical record data from the International Oncology Network. Initial therapy, rates of complete response (CR), post-CR treatments, and outcomes were evaluated.ResultsAmong 257 eligible patients, 75% achieved a CR: 77% (158/206) of patients receiving R-CHOP compared to 71% (36/51) of patients receiving initial therapies other than R-CHOP. Post-CR, 78% of the 158 patients receiving R-CHOP underwent active surveillance; 13% received maintenance rituximab-based treatment; and 6% received radiation therapy. Relapse rates among patients receiving maintenance rituximab, active surveillance, and radiation therapy were 28% (6/21), 19% (24/124), and 0%, (0/10), respectively (P = 0.08).DiscussionThis study found that active surveillance continues to be the most commonly utilized treatment regimen among DLBCL patients with an IPI score ≥3 achieving a CR on first-line R-CHOP. Other approaches aimed at increasing the time to relapse are being utilized as well, but the clinical benefit of these modalities is unclear.ConclusionResults of this study are consistent with the results from clinical trials and suggest the need for further evaluation of maintenance therapy options for patients at higher risk of relapse.

Impact of Rituximab-Based Immunochemotherapy Induction and Maintenance on the Immunisation Rate Against Tetanus Toxin in Follicular Lymphoma Treated Patients : A Subanalysis of the PRIMA Study

BackgroundCD20 is a cell surface antigen commonly expressed on B-cell lineage, but is absent on hematopoïetic stem cells and plasma cells. Therefore, it has been postulated that its targeting should not significantly affect immunoglobulin serum concentrations. However, due to rapid and prolonged B-cell depletion, rituximab-based therapy has been shown to impair humoral response. In addition, protective serologic response to influenza vaccination in lymphoma patients in the 6 months following rituximab-containing regimen has been found to be particularly low1. Because the vast majority of adults individuals have been previously vaccinated against tetanus, we decided to analyse the impact of prolonged rituximab-based therapy on the immune protection rate against tetanus toxin in patients, and conducted in this aim a sub-analysis in follicular lymphoma (FL) patients treated into the PRIMA study.MethodsThe PRIMA study is a multicentre, phase III, randomized study in patients with advanced FL evaluating the benefit of maintenance therapy with rituximab after induction of response with chemotherapy plus rituximab in comparison with no maintenance therapy, whose results have been previously published2. In a subset of patients, serum samples were prospectively collected and antitetanus toxin antibodies were measured at baseline, end of immunochemotherapy induction and end of maintenance period. Protective titer was defined as > 0.1 UI/mL according to standards. Statistical analysis aimed to determine if serum antitetanus antibodies titers significantly changed over time according to different phases of treatment, and if rituximab maintenance arm had a significant impact as compared to observation arm.ResultsOverall, 104 patients were evaluable for this subanalysis. Fifty-five percent were male. Median age was 57 (range, 27-80), 88.5% had Ann-Arbor stage III-IV disease. All patients had received R-CHOP induction. Among those patients, 56 were randomised into rituximab arm, 48 into observation arm. At baseline, median serum antitetanus antibodies titers in the overall population was 0.8 UI/mL (range, 0–8) and 89.4% of patients had protective titers. At the end of induction, among the 70 evaluable subjects, 90% had still a protective titer with a median of 0.7 UI/mL (range, 0-4), and at the end of maintenance period, among the 62 evaluable patients, 93% had still protective titer with a median of 0.8 (range, 0-3). When comparing the two arms, at the end of maintenance period, median serum antitetanus antibodies titer was 0.8 UI/mL in the rituximab arm, not significantly different from that in the observation arm (0.6 UI/mL) (p=0.17). At the end of the maintenance period, 100% of subjects had still protective titer in the rituximab arm versus 84.6% in the observation arm.ConclusionIn this subanalysis of 104 FL treated patients issued from the PRIMA study, rituximab-based induction and maintenance therapy did not significantly affect the immunisation rate against tetanus toxin in previously immunized patients. These results are in contrast with the poor serologic response rate obtained following rituximab-based therapy, emphasizing that common serum vaccinal titers should be controlled, and vaccination updated, when possible, before treatment initiation and the first rituximab administration.References1-Yri O, Torfoss D, Hungnes O, et al. Rituximab blocks protective serologic response to influenza A (H1N1) 2009 vaccination in lymphoma patients during or within 6 months after treatment. Blood 2011, 118 (6769 – 6771).2-Salles G, Seymour J, Offner F, et al. Rituximab maintenance for 2 years in patient with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet 2011, 377 (42-51). DisclosuresKarlin:Sandoz: Consultancy; celgene: Consultancy, Honoraria; Janssen: Honoraria. Delmer:Roche: Honoraria. Brice:Seattle Genetics, Inc.: Research Funding; Takeda Pharmaceuticals International Co.: Honoraria, Research Funding; Roche: Honoraria.

Corticosteroid-Free Primary Treatment of Chronic Graft-Versus-Host Disease with Rituximab Results in Excellent Responses and Rapid Time to Immunosuppression Discontinuation

Chronic graft-versus-host disease (cGVHD) is the most important cause of late morbidity and mortality after allogeneic transplant, occurring in 60% to 70% of long-term survivors. Patients with extensive involvement typically receive long courses of corticosteroids in conjunction with a calcineurin inhibitor, with a median duration of therapy of about 2 years with 15% of patients still requiring immunosuppression at 7yrs post-transplant. Furthermore, steroid-related complications like myopathy, avascular necrosis, diabetes, osteoporosis, and neuropsychiatric issues may be more problematic at times than cGVHD itself. Rituximab is an attractive agent for the upfront treatment of cGVHD due to its favorable toxicity profile, proven efficacy in steroid-refractory cGVHD, and ability to serve as a steroid sparing agent in other autoimmune diseases. We hypothesized that a steroid-free regimen based on the early use of Rituximab would improve outcomes in cGVHD. Twenty-five patients (median age 56 years [range 29–77]) with extensive cGVHD were enrolled on a prospective phase II trial. Enrollment was limited to patients with first onset extensive cGVHD requiring systemic immunosuppression and without residual or concurrent acute GVHD. Chronic GVHD was classified as de novo, interrupted, and progressive in 12, 11, and 2 patients respectively. NIH cGVHD severity was mild, moderate, and severe in 3, 14, and 8 patients respectively. Median NIH symptom score at study onset was 5 (range 4-9). All patients received Rituximab 375mg/m2 x 4 weekly doses, then one dose q3months x 4 doses, in addition to mycophenolate mofetil and tacrolimus (sirolimus could be substituted for tacrolimus). No other systemic immunosuppression was permitted, and only a short-course of steroids (≤4 weeks) was allowed at physician discretion; otherwise patients would be deemed a treatment failure and were treated off study. Twenty-two of 25 patients (88%) responded to treatment, while 2 patients were deemed treatment failures and 1 patient died early of GVHD-related mortality and was thus non-evaluable. Of the 22 responding patients, median time to maximum response was 161 days (range 35–300 days) with maximum response being complete in 21/22 patients and partial in 1 patient defined by improvement in severity grade. Excluding the two patients taken off study for treatment failure, corticosteroids were used sparingly with only 8 patients receiving any steroids for a median of 5 days (range 3-18 days), and only two patients receiving more than one week of steroids. Immunosuppression was ultimately discontinued in 17 of 22 evaluable patients (77%) with median time to discontinuation of 300 days (range 138–488 days). Following immunosuppression discontinuation, cGVHD did recur in 6 patients after a median of 166 days (range 21-393 days), requiring reinstitution of systemic therapy. With a median f/u of 20 months, estimated 2-year overall survival is 82%. Of the surviving patients at 2 years, 74% are predicted to be free of active GVHD while 60% have discontinued systemic immunosuppression. Rituximab-based therapy was overall well tolerated and there were no unexpected severe adverse events. Rituximab has significant activity in chronic GVHD when utilized early in the course of the process. It permits early discontinuation of immunosuppression while obviating the need for long courses of systemic corticosteroids, which may translate into reduced treatment-related morbidity and mortality associated with cGVHD. Prevention of GVHD recurrence remains an issue, and future studies will evaluate the effects of extending the course of Rituximab past 12 months. DisclosuresOff Label Use: Rituxan for treatment of graft versus host disease.