The annual risk of transformation of FL is 3% continuing without plateau beyond 15 years. Advanced stage at diagnosis is predictive of future transformation. Clinically diagnosed transformation has an equal impact on outcome as biopsy proven transformation.

Previous studies of follicular lymphoma (FL) patients treated heterogeneously have suggested that decreased numbers of regulatory T cells correlates with improved survival. We studied advancedstage FL patients from a single institution phase 2 trial. All patients were treated uniformly with multiagent chemotherapy and radiation. Tissue microarrays were constructed using diagnostic biopsies available in 105 patients and stained with CD4, CD8, CD25, and forkhead/winged helix transcription factor 3 (FOXP3) antibodies. Both cell content and cell distribution were evaluated. For all antibodies, there were cases with a predominant intrafollicular or perifollicular localization of cells (follicular pattern) while others displayed a diffuse pattern. The median follow-up of living patients was 17.1 years. The International Prognostic Index score predicted overall survival (OS; P ‫؍‬ .004) but not risk of transformation (RT). Cell content did not impact survival, while immunoarchitectural patterns of CD4/ CD8 were significant for progression-free survival (PFS; P ‫؍‬ .056), CD25 for both PFS and OS (P ‫؍‬ .002 and P ‫؍‬ .024, respectively), and FOXP3 ؉ predicted PFS, OS, and RT (P ‫؍‬ .001, P < .001 and p ‫؍‬ .002, respectively). A Cox multivariate model showed both International Prognostic Index score and FOXP3 ؉ pattern were independent predictors of OS (P ‫؍‬ .008 and P < .001, respectively), while only FOXP3 ؉ pattern predicted RT (P ‫؍‬ .004). We conclude that FOXP3 ؉ cell distribution significantly predicts survival and RT in FL. (Blood. 2010;115: 289-295)

The secondary genetic events associated with follicular lymphoma (FL) progression are not well defined. We applied genome-wide BAC array comparative genomic hybridization to 106 diagnostic biopsies of FL to characterize regional genomic imbalances. Using

Patients undergoing autoSCT had better outcomes than those treated with rituximab-containing chemotherapy alone. AlloSCT did not improve outcome compared with rituximab-containing chemotherapy and was associated with clinically significant toxicity.

Outcome is poor with conventional therapy for relapsed transformed non-Hodgkin's lymphoma (NHL). Autologous SCT has been successfully employed; however the impact of allogeneic SCT has not been well defined. We therefore studied 40 consecutive patients who received allogeneic SCT for relapsed composite and transformed NHL (25 transformed, 8 composite (same site) and 7 discordant (different sites)) with related (n ¼ 25) and unrelated donors (n ¼ 15) to evaluate long-term outcome. Conditioning was myeloablative in the majority (39 of 40). Of 40 patients, 11 survive with median follow-up of 25 months. Death occurred in similar proportions due to relapsed NHL (n ¼ 14) or treatment-related complications (transplant-related mortality, TRM; n ¼ 15). The cumulative incidence of TRM was 36% at 3 years and disease relapse was 42% at 5 years. Probability of 2-and 5-year event-free survival is 36 and 23% with overall survival 39 and 23%. Performance of SCT within 1 year of NHL diagnosis predicted improved outcome. Relapse and TRM remain significant problems in this setting, indicating the need for strategies whereby patients at high risk of transformation should be selected for early SCT, ideally before their actual transformation.

There are limited effective therapies for most patients with relapsed diffuse large B-cell lymphoma (DLBCL). We conducted a phase II trial of the multi-targeted vascular endothelial growth factor receptor (VEGFR) kinase inhibitor, sunitinib, 37.5 mg given orally once daily in adult patients with relapsed or refractory DLBCL. Of 19 enrolled patients, 17 eligible patients were evaluable for toxicity and 15 for response. No objective responses were seen and nine patients achieved stable disease (median duration 3.4 months). As a result, the study was closed at the end of the first stage. Grades 3—4 neutropenia and thrombocytopenia were observed in 29% and 35%, respectively. There was no relationship between change in circulating endothelial cell numbers (CECs) and bidimensional tumor burden over time. Despite some activity in solid tumors, sunitinib showed no evidence of response in relapsed/refractory DLBCL and had greater than expected hematologic toxicity.

Background: Transformation of indolent lymphoma into diffuse large B-cell lymphoma (DLBCL) has been associated with poor survival and the optimal therapy is unknown. The addition of rituximab to CHOP chemotherapy (CHOP-R) has been shown to significantly improve the survival of patients (pts) with de novo DLBCL. However, the impact of rituximab on the survival of patients with transformed DLBCL remains unknown. Methods: As part of a large retrospective analysis examining the long term natural history of pts initially diagnosed with indolent lymphoma in British Columbia (B.C.) (n=690; follicular 600, small lymphocytic 49, lymphoplasmacytic 41), we have identified those pts who developed transformed lymphoma. The definition of transformation was based on either histological confirmation or clinical features, defined as one or more of the following: rapid discordant nodal or extranodal growth; sudden rise in LDH to > 2 x previous baseline; involvement of unusual extranodal sites; or hypercalcemia. Pts were excluded from this analysis if they received high-dose chemotherapy and stem cell transplant as part of the treatment for their transformed lymphoma (n= 9). Pts who were too frail to be treated with multi-agent chemotherapy were also excluded. The extent of disease at transformation was considered limited in pts with single nodal region involvement, no B symptoms, non-bulky disease (<10 cm) and with limited extranodal involvement. Pts with more extensive disease were considered to have advanced transformation. Results: 108 pts with transformed lymphoma were identified in the B.C. lymphoid database, the majority of whom had a prior history of follicular lymphoma (n=103, 95%). Median age at transformation was 60 y (22–71). Transformation was histologically confirmed in 74 (69%) pts. The outcome of 23 pts who were treated with CHOP-R was compared to 85 pts who were treated with CHOP-like chemotherapy. None of the 108 pts had received rituximab as part the management of their indolent lymphoma. The median follow-up for all living pts in the CHOP-like cohort was 7 y (3–14) and 3 y (0.5–5) in the CHOP-R cohort. The post-transformation 5 y overall survival following CHOP-like chemotherapy was 33% vs 61% after CHOP-R (P= 0.01). This difference in survival remained significant when pts with clinically diagnosed transformation were excluded from the analysis (P= 0.02). For the 78 pts with advanced disease extent (59, CHOP-like; 19, CHOP-R) there was a significant difference in PT-5yOS (21% vs 57%, respectively; P= 0.005). For pts with limited disease extent (CHOP-like, 26; CHOP-R, 4) no significant difference in PT-5yOS was observed (P= 0.2). Conclusions: In rituximab-naive patients with indolent lymphoma, the addition of rituximab to CHOP chemotherapy significantly improves overall survival after transformation.

Introduction: While the majority of patients (pts) with advanced stage DLBCL will be cured with R-CHOP, pts who fail front-line therapy continue to have a dismal outcome. Optimization of initial therapy remains an important goal. Interim PET scanning has been demonstrated to be prognostic in DLBCL and may be a promising tool to select pts in whom alternate non-cross-resistant therapies should be considered prior to the emergence of further drug resistance. With this rationale, a phase 2 trial was initiated to assess the feasibility and efficacy of PET-tailored therapy for DLBCL within the province of BC. Methods: This phase II trial was conducted at multiple sites within the BC Cancer Agency. Patients >17 years of age with biopsy proven de novo advanced stage DLBCL, including PMBCL (stages 3 and 4, or stages 1 and 2 with B-symptoms or bulky mass > or = 10cm), with an ECOG PS <3 and no significant co-morbidities that would preclude administration of curative-intent R-CHOP were potentially eligible. Pts were treated with standard dose 3-weekly R-CHOP and could be enrolled at any time prior to cycle 4, provided they met all eligibility criteria and had routine staging investigations performed prior to treament. Staging PET scans were not required. Interim PET scans were performed at a centralized site following cycle 4 (between days 21-28 to minimize the risk of a falsely positive scan). PET scans were interpreted by a small core group of functional imaging radiologists according to International Harmonization Project criteria. Pts with a negative PET scan (PET-neg) received 2 additional cycles of R-CHOP, while pts with a positive PET scan (PET-pos) were switched to receive 4 cycles of R-ICE and underwent a final PET scan post-completion. As per policy in BC, pts with a positive PET post-treatment received consolidative radiation therapy (XRT) if feasible, and this was not considered to be an event with respect to progression-free survival (PFS). Pts with an indeterminate PET (PET-ind) were recommended to complete treatment with R-CHOP. Pts with disease progression during cycles 1-4 of R-CHOP were taken off study. Results: 155 patients were enrolled between Oct 2006 and May 2014. Patient characteristics: median age 53 y (range 19-79); 54% male; 105 (68%) stages 3 or 4; 52 (34%) age >60 y; 55 (35%) ECOG PS >1; 90 (60%) elevated LDH; 44 (28%) extranodal sites >1; 81 (52%) bulky mass ³10cm; and 65 (42%) IPI score 3-5. 2 patients were non-evaluable: no interim PET due to toxicity (n=1), withdrawal (n=1). 3 pts were taken off study due to progression on R-CHOP. Of the 150 evaluable pts with interim PET, 88 (59%) were PET-neg, 50 (33%) were PET-pos and 12 (8%) were PET-ind. PET-pos pts were more likely to have elevated LDH and bulky disease at diagnosis. All PET-neg pts completed treatment with R-CHOP as intended and none received XRT. Of the 50 PET-pos pts, 2 refused to switch to R-ICE and completed treatment with R-CHOP (both received XRT). 48/50 PET-pos pts proceeded to R-ICE: 9 pts failed to complete all 4 cycles R-ICE due to toxicity and 6/9 switched back to R-CHOP; 3 progressed during R-ICE and did not have a final PET scan. The remaining 36/50 PET-pos pts completed 4 cycles R-ICE and underwent a final PET: 11/36 had a negative PET post R-ICE (2 received XRT, regardless); 25/36 had a positive PET post R-ICE (12 received XRT). Of the 12 PET-ind pts, 10 completed treatment with R-CHOP (1 with XRT), while 2 were switched to R-ICE (no XRT). With a median follow-up time of 45 mos, 4-y PFS and overall survival (OS) for the evaluable cohort were 79% and 87%, respectively. PET-neg pts had a very favorable outcome (4-y PFS 91%, 4-y OS 96%), whereas PET-pos pts had a less favorable outcome (4-y PFS 59%, 4-y OS 73%). PET-ind pts had an intermediate outcome with 4-y PFS 83% and 4-y OS 82%. Conclusions: While PET-tailored therapy in pts with advanced stage DLBCL was feasible in BC, approximately 20% of patients were unable to tolerate the planned 4 cycles of R-ICE due to various toxicities, mainly myelosuppression. Pts who were PET-neg following 4 cycles of R-CHOP had an excellent outcome, without need for XRT. PET-pos pts had a poorer outcome, but did better than expected compared to historical reports. However, relatively few PET-pos pts converted to a negative PET scan following R-ICE, suggesting that simply switching to this alternate non-cross resistant chemotherapy regimen is insufficient to overcome the inherent resistance in this poor risk population. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Sehn: Roche/Genentech: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria. Off Label Use: Use of R-ICE chemotherapy in front-line therapy of DLBCL.. Hardy:Roche Canada: Research Funding. Gill:Roche Canada: Research Funding. Al-Tourah:Roche Canada: Research Funding. Shustik:Roche Canada: Research Funding. Macpherson:Roche Canada: Research Funding. Yee:Roche Canada: Research Funding. Lam:Roche Canada: Research Funding. Savage:Roche Canada: Research Funding. Klasa:Roche Canada: Research Funding. Villa:Roche Canada: Research Funding. Gerrie:Roche Canada: Research Funding. Shenkier:Roche Canada: Research Funding. Slack:Roche Canada: Research Funding. Gascoyne:Roche Canada: Research Funding. Benard:Roche Canada: Research Funding. Wilson:Roche Canada: Research Funding. Tonseth:Roche Canada: Research Funding. Connors:Roche Canada: Research Funding.