Advanced Stage Follicular Lymphoma Research Articles

Extended Follow-up of the International Randomized Phase 3 First-Line Indolent Trial (FIT) Shows Durable Benefit of 90 Y-Ibritumomab Tiuxetan (Zevalin®) Consolidation of First Remission in Advanced Stage Follicular Non-Hodgkin's Lymphoma.

Initial findings from the Phase 3 trial of Zevalin consolidation of first remission in patients with advanced follicular lymphoma showed a significant improvement in PFS following Zevalin consolidation as compared to no further treatment, ie, 37.5 vs. 13 months (Hagenbeek et al, ASH 2007). Patients had been randomised to either no further therapy or Zevalin consolidation (250 mg/m2 rituximab on day -7 and on day 0, followed on day 0 by Zevalin 0.4 mCi/kg; maximal dose 32 mCi). Herein we report on an additional 1-year follow-up of the FIT study, at a median of 42 months (range: 2 – 77), which includes 409 patients who achieved a complete or partial response (CR or PR), after induction therapy. Patient demographics remain similar in the Zevalin (n=202) and control groups (n= 207): males 48%/50%; median age 55/53 yrs; at diagnosis, stage III 35.2%/31%, stage IV 64%/66%. Response status prior to randomization was also similar between study arms: 107 patients in CR/CRu and 100 pts in PR in the Zevalin arm and 108 pts in CR and 88 pts in PR in the control arm. The 48-month PFS is 52% in the Zevalin arm compared with 31% in the control arm. As shown in the figure 1A, patients with a CR after induction therapy achieved a median PFS of >67 months for the Zevalin arm compared with 30.8 months for patients who received no further treatment (HR 0.61 [95% CI .41–.91]; P= 0.015). In figure 1B, among patients with a PR after induction, the median PFS was 29.6 months for those on the Zevalin arm vs 6.7 months for those on the control arm (HR 0.36 [95% CI .25–.51]; P<0.001). Subsequent therapy with various modalities including chemotherapy, radiotherapy, immunotherapy, Zevalin and stem cell transplantation (ASCT) was given to 63 patients in the Zevalin arm and 108 patients in the control arm, who achieved an overall response rate of 81% and 73%, respectively. A total of 11 deaths have occurred in the Zevalin arm and 8 in the control arm, with no difference in overall survival between the treatment arms (P=0.593). No additional toxicities, no congenital malformations, and no increase in the incidence of secondary malignancies have emerged during follow-up. Details on subsequent therapies and a breakdown of outcomes based on induction subgroups and FLIPI scores are anticipated for presentation.Conclusion: Extended follow-up of the FIT trial shows that Zevalin consolidation does not preclude the use of various effective second-line treatment options. Moreover, these data confirm that the significant improvement in PFS achieved with Zevalin consolidation is durable for both patients with a PR and patients with a CR/CRu after induction. [Display omitted]

Rituximab in Combination with CHOP in Patients with Follicular Lymphoma: Analysis of Treatment Outcome of 552 Patients Treated in a Randomized Trial of the German Low Grade Lymphoma Study Group (GLSG) after a Follow up of 58 Months

We have previously reported that compared to CHOP alone the addition of Rituximab (R) to CHOP significantly increases the response rate (RR), the time to treatment failure (TTF) and also the overall survival (OS) in patients with newly diagnosed advanced follicular lymphoma. However, in the previous report, the median observation time was short with 18 months and no data were reported on the outcome of different risk groups according to the FLIPI (Hiddemann et al., Blood 2005). We now report on the treatment outcome of 552 patients with advanced stage follicular lymphoma randomized between R-CHOP versus CHOP alone after a median follow up of 58 months. Responding patients < 60 yrs. of age underwent a second randomization in first remission for Interferon alpha maintenance (IFN) versus myeloablative radio-chemotherapy with subsequent stem cell transplantation (ASCT), whereas all older pts received IFN maintenance.R-CHOP induced a significantly higher RR (97% vs. 91%, p=0.005). Furthermore immunochemotherapy resulted in significantly longer TTF (median not reached vs. 35 months, 5-years TTF 65% vs. 32%, p<0.0001), response duration (RD, 5-years RD 66% vs. 35%, p<0.0001), and OS (5-years OS R-CHOP 90% vs. CHOP 84%, p = 0.0493). To analyse the impact of R-chemotherapy in different risk groups we performed subgroup analyses for patients with low (LR), intermediate (IR) or high risk (HR) according to the FLIPI: R-CHOP prolonged significantly TTF in all risk groups compared to CHOP alone (5-years TTF: 84% vs. 46% for LR (p=0.0021); 73% vs. 37% for IR (p<0.0001); 49% vs. 23% for HR (p<0.0001). The superiority of R-CHOP vs. CHOP could be documented in the patient group not treated with ASCT: the RD was significantly prolonged by the immunochemotherapy (5-years probability 62% vs. 26%, respectively; p<0.0001). This could not be seen in the group of younger patients consolidated with ASCT (5-years probability 78% vs. 66%, p=0.43). However, the number of events was too low to draw any final conclusion.These data with a mature follow-up demonstrate that first–line R-CHOP significantly improves response rate and TTF in patients with FL compared to the respective chemotherapy alone. However, they also demonstrate that R-chemotherapy might be not sufficient for a long-lasting improvement. This indicates the necessity to perform clinical trials that test whether adding consolidation and/or maintenance after initial cytoreduction further improves treatment outcome.

Tolerability and Efficacy of Bortezomib Added to CVP-R for Previously Untreated Advanced Stage Follicular Lymphoma: Interim Analysis of a Phase II Study by the NCIC Clinical Trials Group.

Background: Despite recent improvements in therapy, follicular lymphoma (FL) remains incurable with standard treatment, warranting investigation of new approaches. Bortezomib, the first-in-class proteasome inhibitor has demonstrated promising efficacy as a single agent in heavily pretreated patients (pts) with FL. This is the first study to evaluate the safety and efficacy of the addition of bortezomib to cyclophosphamide, vincristine, prednisone and rituximab (CVP-R).Methods: This is a phase II multi-center open-label trial adding bortezomib (1.3 mg/m2 day 1&8) to standard dose C(750 mg/m2) V(1.4 mg/m2, capped at 2 mg) P(40 mg/m2 × 5) –R(375 mg/m2) for up to 8 cycles in pts with newly diagnosed stage III/IV FL requiring therapy. Planned accrual is 90 patients. A two-stage design was employed with a planned interim analysis of the first 28 patients to ensure an acceptable level of neurotoxicity (defined as less than 5/28 patients with grade 3/4 neurotoxicity after the first 4 cycles) and meaningful response rate (more than 12/28 patients with a complete response following 8 cycles), prior to enrolling remaining patients.Results: Median age of the first 28 patients was 55 years (range, 30–73). Fifty percent were male and 79% had stage IV disease. FLIPI score at study entry: low 14%, intermediate 43%, high 43%. Overall, the combination of bortezomib and CVP-R was extremely well tolerated. To date, no pts have developed grade 4 neurotoxicity and only 1/28 (4%) has developed grade 3 neurotoxicity within the first 4 cycles (neuropathic pain which resolved without need for treatment modification). The incidence of grade 1 and 2 neurotoxicity was 54% and 25% respectively. Only 3 pts discontinued therapy prematurely (2 pt refusal, 1 progressive disease). Ninety-four percent of planned bortezomib treatments in the first four cycles and 93% of vincristine doses were administered without dose reduction. Hematologic toxicity was mild, with no pts experiencing grade 3/4 anemia or thrombocytopenia. Only 2 episodes of febrile neutropenia occurred and no grade 3/4 infections were noted. Although it is too early to report on efficacy in this ongoing trial, response objectives for stage I have been met, and enrollment to stage 2 is underway.Conclusions: The addition of bortezomib to standard dose CVP-R is very well tolerated, with an acceptable level of neurotoxicity, without compromising the delivery of bortezomib or vincristine. This ongoing study will provide toxicity and efficacy data to facilitate the development of a planned phase III trial.

Phase III Trial of Consolidation Therapy With Yttrium-90–Ibritumomab Tiuxetan Compared With No Additional Therapy After First Remission in Advanced Follicular Lymphoma

We conducted an international, randomized, phase III trial to evaluate the efficacy and safety of consolidation with yttrium-90 ((90)Y)-ibritumomab tiuxetan in patients with advanced-stage follicular lymphoma in first remission. Patients with CD20(+) stage III or IV follicular lymphoma, who achieved a complete response (CR)/unconfirmed CR (CRu) or partial response (PR) after first-line induction treatment, were randomly assigned to receive (90)Y-ibritumomab tiuxetan (rituximab 250 mg/m(2) on day -7 and day 0 followed on day 0 by (90)Y-ibritumomab tiuxetan 14.8 MBq/kg; maximum of 1,184 MBq) or no further treatment (control). The primary end point was progression-free survival (PFS), which was calculated from the time of random assignment. A total of 414 patients (consolidation, n = 208; control, n = 206) were enrolled at 77 centers. (90)Y-ibritumomab tiuxetan consolidation significantly prolonged median PFS (after a median observation time of 3.5 years) in all patients (36.5 v 13.3 months in control arm; hazard ratio [HR] = 0.465; P < .0001) and regardless of whether patients achieved PR (29.3 v 6.2 months in control arm; HR = 0.304; P < .0001) or CR/CRu (53.9 v 29.5 months in control arm; HR = 0.613; P = .0154) after induction treatment. Median PFS with consolidation was prolonged in all Follicular Lymphoma International Prognostic Index risk subgroups. After (90)Y-ibritumomab tiuxetan consolidation, 77% of patients in PR after induction converted to CR/CRu, resulting in a final CR rate of 87%. The most common toxicity with (90)Y-ibritumomab tiuxetan was hematologic, and grade 3 or 4 infections occurred in 8% of patients. Consolidation of first remission with (90)Y-ibritumomab tiuxetan in advanced-stage follicular lymphoma is highly effective with no unexpected toxicities, prolonging PFS by 2 years and resulting in high PR-to-CR conversion rates regardless of type of first-line induction treatment.

Follicular Lymphoma, Survival, and Rituximab: Is It Time to Declare Victory?

Follicular Lymphoma, Survival, and Rituximab: Is It Time to Declare Victory?

Treatment of Follicular Non-Hodgkin's Lymphoma: The Old and the New

Despite remaining an incurable disease, overall survival improvements have been noted in patients with advanced-stage follicular lymphoma. The Follicular Lymphoma International Prognostic Index (FLIPI) is a robust prognostic index in this disease, and continues to provide prognostic information in the rituximab era. Rituximab has significantly changed the management of follicular lymphoma, and the most dramatic impact of rituximab is observed in combination with cytotoxic chemotherapy. However, resistance to rituximab remains a problem, and standard therapy in the rituximab-refractory setting includes radioimmunotherapy, autologous stem cell transplantation, and allogeneic stem cell transplantation. In addition, several novel agents show encouraging activity in follicular lymphoma, including bendamustine, lenalidomide, bortezomib, and other proteasome inhibitors, and BCL2 inhibitors.

Radiolabeled and Native Antibodies and the Prospect of Cure of Follicular Lymphoma

Advanced-stage follicular lymphoma is incurable by conventional treatment. Rituximab has been introduced in various combinations with chemotherapy and has resulted in a significantly superior treatment outcome compared with chemotherapy alone. Multiple studies have also shown the efficacy of radioimmunotherapy (RIT) both as a single agent and in combination with chemotherapy. Rituximab and RIT have clearly distinct mechanisms of action, the first acting exclusively as a biological treatment, while the second acts by a combination of biologic mechanisms and radiation effects. Despite the therapeutic efficacy of both approaches, the potential exists to further improve both modalities. Repeat administrations of RIT using appropriate radioisotopes for treatment of residual disease or new targeting strategies might afford additional benefits. Unlabeled antibody treatment could potentially benefit from the combination of antibodies directed against different target antigens or combination therapy with cytokines capable of further mobilizing patients' cellular defenses. In this review, we hypothesize that the combination of an optimized biological treatment together with radiolabeled antibodies and chemotherapy early in the disease course of advanced-stage follicular lymphoma may represent the best approach to achieve prolonged disease-free survival and eventually cure.

Rapid and sustained clearance of circulating lymphoma cells after chemotherapy plus rituximab: clinical significance of quantitative t(14;18) PCR monitoring in advanced stage follicular lymphoma patients†

This study of first-line treatment in advanced-stage follicular lymphoma patients analysed the effects of MCP (mitoxantrone, chlorambucil and prednisolone) chemotherapy alone or in combination with rituximab (R-MCP) on circulating lymphoma cells (CLC) and assessed the prognostic value of a quantitative monitoring of CLC. CLC numbers were determined by quantitative polymerase chain reaction (PCR) for the t(14;18)-translocation or by allele-specific PCR for rearranged immunoglobulin heavy chain genes. We analysed blood samples from 43 patients treated in a randomized trial comparing eight cycles of MCP versus R-MCP. Clearance of CLC at the end of therapy was achieved in 21/25 patients (84%) treated with R-MCP compared with 0/18 after MCP alone (P < 0.0001). A > or = 2 log CLC reduction was associated with a favourable clinical response (P = 0.0004) and prolonged event-free survival (P = 0.02). In R-MCP patients, stable CLC numbers or consistently PCR-negative blood samples were associated with a continuing clinical remission whereas in two patients a relapse was preceded by a > or = 2 log CLC increase. This study demonstrated that R-MCP led to a rapid and sustained eradication of CLC and a > or = 2 log CLC reduction was associated with a superior quality and duration of the clinical response.

Outcome of BEAM‐autologous and BEAM‐alemtuzumab allogeneic transplantation in relapsed advanced stage follicular lymphoma

The role of haematopoietic stem cell transplantation (HSCT) in relapsed follicular lymphoma remains controversial. This study analysed 126 patients with relapsed, advanced stage follicular lymphoma who received BEAM (BCNU [carmustine], cytarabine, etoposide, melphalan)-alemtuzumab allogeneic HSCT (BEAM-allo) (n = 44) or BEAM-autologous HSCT (BEAM-auto) (n = 82). The BEAM-allo group had a younger median age (48 years vs. 56 years, P < 0.001) but received a higher median number of therapies pretransplant (P = 0.015) compared with the BEAM-auto group. There was a higher non-relapse mortality (NRM) in the BEAM-allo group compared with the BEAM-auto group at 1 year (20% vs. 2%, P = 0.001). Older age and heavily pretreated patients were associated with a higher NRM and poorer survival in the BEAM-allo group. There was, however, a significantly lower relapse rate (20% vs. 43%, P = 0.01) at 3 years with BEAM-alemtuzumab, with no relapses after 2 years, compared with a continued pattern of relapse in the autologous group. No difference in overall survival (OS) (P = 0.99) or disease-free survival (DFS) (P = 0.90) was identified at 3 years, whereas a plateau in OS and DFS with crossing of the survival curves in favour of BEAM-allo group was observed. Furthermore, the ability to re-induce remissions with donor leucocytes provides additional benefit in favour of allogeneic HSCT.

High clinical and molecular response rates with fludarabine, cyclophosphamide and mitoxantrone in previously untreated patients with advanced stage follicular lymphoma

Purine analogs have demonstrated significant activity in patients with follicular lymphoma. The aim of this study was to analyze the efficacy and toxicity of a fludarabine combination as first-line treatment in patients with advanced-stage disease. This is a phase II trial including 120 patients (< or =65 years) treated with 6 cycles of fludarabine, cyclophosphamide and mitoxantrone (FCM). Molecular response was assessed by q-PCR in peripheral blood. Of 119 patients with an assessable response, complete response was achieved in 99 (83%) partial response in 13 (11%) and 7 (6%) did not respond. After treatment, 37 out of 46 (81%) patients achieved molecular response. After a median follow-up of 3.9 years, 32 patients have relapsed. The 5-year progression-free survival was 58% (95% confidence interval: 47-69). Variables associated with a shorter progression-free survival were a poor performance status (ECOG> or =2), > or =2 extranodal sites and high beta2-microglobulin. Sixteen episodes of grade 3-4 infections were observed. Two patients died during therapy (of progressive multifocal leukoencephalopathy and bronchoaspiration respectively). No late toxicity has been observed. Twelve patients died during follow-up (9 after relapse, 2 during chemotherapy, 1 in complete remission after surgery for meningioma). The overall survival at 5 years was 89%. ECOG > or =2 and high beta2-microglobulin were associated with a shorter survival. FCM results in high complete and molecular response rates, with prolonged response duration in younger patients with advanced-stage follicular lymphoma. The combination of FCM with rituximab as front-line treatment warrants further investigation.

The Architecural Pattern of FOXP3+ T Cells Predicts Risk of Transformation in Patients with Follicular Lymphoma (FL).

Background: FL is an indolent heterogeneous lymphoid neoplasm with a variable clinical course. Transformation into an aggressive lymphoma (Tly) is a dominant clinical event frequently associated with inferior survival. No consistent biological markers have been identified that predict for Tly. Recent studies have highlighted the role of the microenvironment, including lymphoma-associated-macrophages (LAM) and Treg cells as important prognostic factors in FL. The nuclear expression of FOXP3 is considered a specific marker of regulatory T cells (Treg). However, most series have included pts variably treated with a wide spectrum of protocols. Using tissue microarrays (TMA) we recently demonstrated that both LAM content and follicular/perifollicular pattern of FOXP3+ T cells are independent adverse prognostic factors for both overall (OS) and progression-free (PFS) survival in advanced-stage FL patients treated uniformly with an aggressive regimen. However, the impact of either LAM or Tregs on Tly is largely unknown. Using the same cohort we assessed the role of these cell types for predicting Tly.Methods: Between 1987 and 1993, 126 pts were enrolled on a phase II study of BP-VACOP chemotherapy with involved region radiotherapy. All patients were treatment naïve, < 61y and had advanced-stage FL. Paraffin blocks were available in 105 patients. The TMAs consisted of duplicate 1.0mm cores of diagnostic biopsies and were immunostained with both CD68 and a FOXP3-specific antibody. Both CD68+ macrophage content and FOXP3+ T cell content and immuno-architectural patterns were determined and correlated with RT including univariate and multivariate analyses.Results: There were 102 evaluable cases. The median follow-up of the living pts was 14.3 years and the estimated 10-year OS and Tly rates were 63% and 18%, respectively. The IPI was predictive of OS (RR = 2.4, 95% CI =1.4–4.2, p = 0.002) but not Tly (RR = 2.2, 95% CI =.9–5.1, p = 0.07). Histologic grade included 76 grade 1, 20 grade 2 and 6 grade 3a FLs. Cases revealed 1 to 28 CD68+ cells per high power field (median 7 cells/hpf) and zero to 731 FOXP3+ cells per core (median of 242 cells/core). In 38 pts there was a predominantly intrafollicular or perifollicular localization of positive cells (“follicular Treg pattern”) and in 64 pts the pattern was diffuse. Neither LAM content nor number of FOXP3+ cells had any impact on Tly. However, the immuno-architectural pattern of FOXP3+ cells was predictive of Tly, with the “follicular” pattern showing increased risk of Tly in univariate analysis (p=0.005). A Cox multivariate model including IPI and LAM showed only the FOXP3+ Treg pattern as an independent predictor of Tly (RR = 3.9, 95% CI =.1.5–9.9, p = 0.004).Conclusions: Treg cell distribution within the tumor is an important predictor of Tly in advanced-stage FL patients treated uniformly with an aggressive treatment regimen. Our results reinforce the importance of a FOXP3 follicular pattern as a good surrogate for functionally active Treg cells within the tumor microenvironment and further highlight the important role of the tumor microenvironment in FL biology. [Display omitted]

Radioimmunotherapy with 90Y-Ibritumomab Tiuxetan (Zevalin®) as Consolidation of First Remission in Patients with Advanced Stage Follicular Lymphoma: A 'Real-Time' MBR RQ-PCR Analysis.

Introduction: The randomized phase 3 First-line Indolent Trial (FIT) was conducted in newly diagnosed patients (pts) with stage III or IV follicular lymphoma (FL) to investigate the use of 90Y-ibritumomab tiuxetan (Zevalin) given as consolidation of first complete (CR/CRu) or partial remission (PR). Bcl-2 status was evaluated using 'real-time' quantitative PCR (RQ-PCR) for the major breakpoint region (MBR) Bcl2-IgH rearrangement at the time of randomization and at follow up (after treatment with Zevalin or observation).Methods: Peripheral blood samples were available for RQ-PCR analysis from 77 centers for 414 pts with grade 1 or 2 FL, in CR/CRu (n=216) or PR (n=198) following initial therapy. Pts were randomized to receive either Zevalin (n=208) or no further treatment (control; n=206). Initial therapies included CVP, CHOP/CHOP-like regimen, fludarabine combinations, chlorambucil and rituximab + chemotherapy. Zevalin treatment comprised rituximab 250 mg/m2 on day -7 and day 0, followed on day 0 by Zevalin 0.4 mCi/kg (maximum dose: 32mCi). Peripheral blood samples were analyzed using standard methodology (Summers et al J Clin Oncol 2001; 19:420), a result of 1 in 105 being regarded as negative. Only pts for whom clinical data, a peripheral blood sample at the time of randomization, and at least 1 follow-up sample (post-treatment for Zevalin arm; post-randomization for control arm) were available have been included in this analysis. Because not all pts with FL have an MBR rearrangement, the analysis was limited to those showing RQ-PCR positivity at some point.Results: Overall, 127/291 pts (44%) who fulfilled the above criteria were RQ-PCR positive at the time of randomization, ie, 68/141 (46%) and 59/150 (39%) in the Zevalin and control arms, respectively. Progression-free survival (PFS) of the control arm served as an internal control and benchmark. In the control arm, the 59 pts who were RQ-PCR positive at time of randomization had a median PFS of 8.2 months, compared with 2.4 years for the 91 pts who were RQ-PCR negative. In the Zevalin arm, the 73 pts who were RQ-PCR negative at the time of randomization had a median PFS of 3.1 years compared with 3.2 years for the 68 pts who were RQ-PCR positive. At the time of the follow-up evaluation, 61/68 pts (90%) who received Zevalin consolidation and 21/59 pts (36%) in the control arm converted from RQ-PCR positive to negative status. The 61 Zevalin-treated pts who converted had a median PFS of 3.4 years compared with 2 years for the 21 pts who converted in the control arm (p<0.005). Clinical evidence of recurrent lymphoma was observed in 24/61 (39%) and 16/21 (76%) of pts who converted to RQ-PCR negative status in the Zevalin and control arms, respectively.Conclusion: Conversion to RQ-PCR negativity was observed in both arms but was more frequent in the Zevalin arm. Treatment with Zevalin consolidation resulted in 90% of pts converting from RQ-PCR positive to negative status; this was associated with significant prolongation of PFS compared with the control arm.

Health-Related Quality of Life in Patients with Advanced-Stage Follicular Lymphoma Receiving Consolidation with 90Y-Ibritumomab Tiuxetan (Zevalin®) of First Remission: Results from the Randomized Phase 3 First-Line Indolent Trial (FIT).

A previous phase 3 study showed that in patients with relapsed/refractory low-grade, follicular or transformed non-Hodgkin's lymphoma, radioimmunotherapy with 90Y-ibritumomab tiuxetan (Zevalin) significantly improved patient-reported quality of life (QoL) as measured by the validated Functional Assessment of Cancer Therapy-General (FACT-G) questionnaire (Wiseman et al Blood 2000; 96(11):734a, abstract 3173). The study showed significant improvements in FACT-G total score, as well as in subscores for emotional, physical, and functional well-being. In the recent international phase 3 First-line Indolent Trial (FIT), patients with stage III or IV follicular lymphoma in first remission after initial chemotherapy were randomized to receive consolidation with Zevalin (n=208) or no further treatment (control; n=206). The impact of Zevalin on health-related QoL was evaluated as one of the secondary end points of this study. Health-related QoL was assessed using EORTC QLQ-C30 (version 2) and EuroQoL-5D (EQ-5D) questionnaires. The EORTC QLQ-C30 was developed to specifically assess QoL in patients with cancer, and comprises 30 items grouped into the following dimensions: functional (physical, role, cognitive, social, emotional), symptomatic (nausea, pain, fatigue), global QoL, and other (dyspnea, difficulty sleeping, anorexia, constipation, diarrhea, perceived financial difficulties). The EQ-5D was developed as a generic instrument to assess health-related QoL and comprises 2 sections, an assessment based on 5 dimensions (mobility, self-care, usual activity, pain/discomfort, and anxiety/depression) and a visual analogue scale (VAS). These questionnaires were administered at the screening visit, week 14, every 6 months thereafter, and at the end of the follow-up period. Descriptive statistics were used to compare scores across treatment groups. The change in scores from baseline was also assessed by gender, age, and first-line treatment. Mixed effects model was used to assess factors associated with final scores of the VAS of EQ-5D. No notable treatment differences were observed in EORTC QLQ-C30 (all domains) scores across timepoints or changes from baseline. This result was true for all subgroups. The mean scores for EQ-5D at the screening and final visits were 0.83 and 0.84, respectively, for the Zevalin arm, and 0.84 and 0.83, respectively, for the control arm. The mean VAS scores at the screening and final visits were 77.52 and 77.64, respectively, for the Zevalin arm, and 76.57 and 78.60, respectively, for the control arm. An analysis of factors associated with final VAS scores showed that only baseline VAS scores affected final VAS scores (P<0.0001) considerably. No differences were observed in health-related QoL parameters between patients receiving consolidation therapy with Zevalin and patients in the control arm as measured by EORTC QLQ C-30 and EQ-5D questionnaires. Thus, in patients with advanced-stage follicular lymphoma responsive to first-line therapy, treatment with Zevalin consolidation does not impact the health-related QoL compared with no further treatment.

Dosimetric Analysis of 90Y-Ibritumomab Tiuxetan (Zevalin®) Given as Consolidation of First Remission in Patients with Advanced-Stage Follicular Lymphoma in the International Phase 3 First-Line Indolent Trial (FIT).

Yttrium-90 (90Y)-ibritumomab tiuxetan (Zevalin) is an anti-CD20 monoclonal antibody immunoconjugate linked to the pure beta-emitting 90Y radioisotope, which is known to allow targeted delivery limiting normal tissue exposure. As part of the international, phase 3 randomized First-line Indolent Trial (FIT) evaluating the efficacy of Zevalin consolidation compared with observation alone in patients (pts) with advanced stage follicular lymphoma achieving a response to first-line therapy, we investigated the radiation exposure of pts in the Zevalin arm for whom dosimetry data were available. Among the 414 pts enrolled in the trial (age ≥18 yrs, normal peripheral blood cell counts, <25% bone marrow involvement with lymphoma), 70 had a diagnostic scan with 111In-ibritumomab tiuxetan. Dosimetry was not completed in 1 pt. In addition to local dosimetry, central dosimetry was performed by a single experienced nuclear medicine physician in 57 of the 69 pts, including 21 pts in one participating hospital (I) and 36 evaluated in a central facility (II). All pts were injected with 185 MBq 111In-ibritumomab tiuxetan after infusion of rituximab (250 mg/m2) on day -7. At least 3 simultaneous anterior and posterior whole body (WB) scans were performed 15–45 min, 3–6 hrs, 1, 3–4 and 6 days after injection. Blood samples were drawn at corresponding intervals. Using the region of interest (ROI) technique, WB and organ (lungs, liver, spleen, kidneys) radioactivity was estimated from the geometric mean of anterior and posterior ROI counts. Whole blood aliquots were counted, normalized and decay corrected. WB, organ and red marrow (RM) radiation absorbed doses were calculated using the decay constant for 90Y and the projected activity (14.8 MBq/kg) with the MIRDOSE3 software. [Display omitted] Median dose in the 57 pts evaluated by central dosimetry was 102 cGy (range 28–327) to RM and 74 cGy (range 46–106) to WB. Radiation exposure was within the protocol-defined upper limits to normal organs (2000 cGy) in all pts and to RM (300 cGy) in all but 2 pts. In one pt, the RM dose was 85175 cGy by local dosimetry, but 94 cGy by central dosimetry; the pt was treated without complications. In the other pt, the RM dose was 327 cGy by central dosimetry, but 155 cGy by local. Average RM exposure was similar between pts with grade 3–4 neutropenia and/or thrombocytopenia and those with grade 0–2. A larger percentage (45%) of the 40 pts with grade 3 or 4 neutropenia had above-average RM radiation dose compared with 18% of the 17 pts with grade 0–2, whereas, the percentage of pts with above-average WB radiation dose was comparable in both groups (42% and 41%, respectively). Overall, neither WB nor RM radiation dose was correlated with hematologic toxicity (Spearman correlation). These findings are consistent with published data (Wiseman et al J Nucl Med 2003; 44:465–474), and suggest that Zevalin is safely administered in pts with low tumor burden. Our study confirms that radiation exposure with Zevalin treatment is within safe limits to normal organs and that hematologic toxicity does not correlate with RM radiation dose estimates.

Vascularization Predicts Overall Survival (OS) & Risk of Transformation (RT) in Uniformly Treated Patients with Follicular Lymphoma (FL).

Introduction: FL is an indolent disease with heterogeneous survival. Transformation is asscoiated with short survival. In solid tumors, tumor angiogenesis is required for tumor growth/metastasis and microvessel density (MVD) has, in some tumor types, shown correlation with poor OS. In FL, the impact of MVD on prognosis is controversial. Recent studies have highlighted the effect of the microenvironment on FL prognosis including ours which showed that high numbers of lymphoma-associated-macrophages (LAM) are associated with adverse outcome. Because LAM have been shown to promote angiogenesis and neoplastic growth, we used a quantitative tumor mapping approach to determine whether the degree of vascularization in FL correlated with adverse outcome.Method: Between 1987 and 1993, 126 pts were enrolled on a phase II study of BP-VACOP with involved region radiotherapy. All pts were treatment naïve, < 61y and had advanced-stage FL. Paraffin blocks of the diagnostic biopsies were available for 105 pts. Images of whole sections stained for CD34 were captured using a cooled CCD camera, a motorized stage, and customized NIH-Image software. The motorized stage allowed for tiling of adjacent microscope fields of view, thereby allowing reassembly of the entire tumor section at high-resolution. The distance from each point in the tissue to the nearest CD34+ pixel was measured and the tumor to vessel distance that encompassed 90% of the tumor (TVD90) calculated. A TMA was immunostained with S100A8/Calgranulin A-specific antibody, a M2-like macrophage marker, to determine a subset of LAM. Univariate & multivariate analyses were used to determine OS and RT.Results: There were 84 evaluable cases. The median follow-up of the living patients was 14.3 y and the estimated 10-y OS and RT were 65% and 20%, respectively. The IPI was predictive of OS (RR =3.4, 95% CI =1.8–6.3, p < 0.001) and RT (RR =3.3, 95% CI =1.3–7.9, p = 0.01). Histologic grade included 66 grade 1, 14 grade 2 and 4 grade 3a. Cases revealed TVD90 of 50.3 to 144 microns (median 78.4) and were divided into quartiles. A subset of 14 cases showed high density of S100A8+ cells (> 5 per high power field). In univariate analysis the quartile (21 cases) with low TVD90 (i.e. high MVD) showed inferior OS (p < 0.001) and high RT (p = 0.012). Cases with high density of S100A8+ LAM also had inferior OS (p = 0.04), but the high density did not predict RT (p = 0.4). A Cox multivariate model with IPI, S100A8+ score and TVD90 showed only IPI and TVD90 to be independent predictors of OS (RR = 2.9, 95% CI = 1.6–5.6, P = 0.001; RR = 2.4, 95% CI = 1.3–4.7, p = 0.009, respectively), but only TVD90 predicted RT (RR = 3.1, 95% CI = 1.2–7.6, p = 0.017). Interestingly, low TVD90 (i.e. high MVD) correlated with increased content of S100A8+ cells (χ2, p < 0.001).Conclusion: These results show that in FL, increased vascularization is independently associated with an adverse clinical outcome and, most importantly, predicts for increased RT. These findings may provide a rationale for trials of antiangiogenic therapy in “aggressive” FLs. [Display omitted]

90Y-Ibritumomab Tiuxetan (Zevalin®) Consolidation of First Remission in Advanced Stage Follicular Non-Hodgkin's Lymphoma: First Results of the International Randomized Phase 3 First-Line Indolent Trial (FIT) in 414 Patients.

Radioimmunotherapy is effective in patients with relapsed/refractory and newly diagnosed follicular non-Hodgkin's lymphoma (FL). This study investigated the efficacy and safety of Zevalin consolidation in patients with advanced stage FL responding to first-line chemotherapy. The concept tested was whether a single infusion of Zevalin would prolong progression free survival (PFS) in patients with (minimal) residual disease. Major inclusion criteria were: CD20-positive grade 1 or 2 FL; stage III or IV at diagnosis; normal peripheral blood cell counts; <25% bone marrow involvement; age ≥18 yrs, and CR/CRu or PR after first line chemotherapy determined by physical examination, CT scans and bone marrow biopsy. From 8/2001 to1/2005, 414 patients were enrolled at 77 study centers in 12 European countries and Canada. After completing induction therapy, patients were randomized to receive either Zevalin (250 mg/m2 rituximab on day -7 and on day 0 followed on day 0 by Zevalin 0.4 mCi/kg; maximal dose: 32 mCi;[n=208]) or no further treatment [n=206]). The primary end point was prolongation of PFS, calculated from randomization, which was approximately 2 wks before Zevalin administration. Secondary end points were change of response status, ie, PR to CR/CRu and BCL2-JH PCR status from positive to negative; safety/tolerability and quality of life. Patient demographics were similar in both groups (Zevalin/control): males 48%/50%; median age 55/53 yrs; at diagnosis, stage III 35%/31%, stage IV 64%/66%; B-symptoms 22%/20%; response status after induction, PR 49%/47%; CR: 51%/53%. Induction therapies included: CVP n=106, CHOP (-like) n=188, fludarabine combinations n=22, chlorambucil n=39 and rituximab-chemotherapy combinations n=59. With a median follow-up of 2.9 yrs, the median PFS increased from 13.5 (controls) to 37 mo (Zevalin; p<0.0001; HR 0.463). For patient subgroups in PR or CR after induction, median PFS was 6.3 vs 29.7 mo (p<0.0001; HR 0.304) and 29.9 vs 54.6 mo (p=0.01; HR 0.609), respectively. After Zevalin consolidation, 77% of patients in PR after induction therapy converted to CR; in total, 87% of patients were in CR(u), 76% in CR and 11% in CRu. Subgroup analyses based on induction treatment and outcome according to FLIPI will be presented. Toxicity was primarily hematologic. Median platelet count nadir was 45x109/L; range 8–404x109/L) at wk 7 (∼5 wks post Zevalin); median neutrophil nadir was 1.0x109/L (range 0.02–6.6x109/L) at wk 8(∼ 6 wks post Zevalin). Grade 3/4 infections occurred in 16 (8%) patients after Zevalin vs 5 (2%) in the control arm. So far, 11 patients have died, 5 in control arm (1 sepsis, 4 progressive disease); 6 in Zevalin arm (1 neutropenic sepsis after subsequent chemotherapy, 1 pancreas carcinoma, 1 AML, 3 progressive disease).Conclusion: Zevalin consolidation of first remission in advanced stage FL is highly effective, resulting in a total CR(u) rate of 87% and prolongation of PFS by 2 yrs, with a favorable toxicity profile.

Radio-immunothérapie du lymphome folliculaire : un pas vers la guérison ?

Advanced stage follicular lymphoma is incurable by conventional treatment. Important progress has been observed with the development of new therapies based on monoclonal antibodies and on the use of radioimmunotherapy (RIT) in the treatment of non-Hodgkin lymphomas (NHL). Rituximab in combination with chemotherapy in the upfront setting significantly improved treatment outcome as compared with chemotherapy alone. Different studies also indicate that RIT has an important role in the management of NHL and could be beneficial in combination with chemotherapy. These two new treatment options have clearly distinctive mechanisms of action, rituximab being an exclusively biological treatment and RIT adding targeted systemic radiation therapy. Both RIT and the unlabeled antibody treatments might be further improved by different strategies including repetition of RIT or combination of different antibodies. We present here our experience with RIT using 131I-tositumomab (Bexxar) and discuss different topics regarding RIT, like the use of different antibodies, the best choice of the radioisotope or the place of radio-imaging. From the therapeutic point of view, we argue that the debate should not be as to which one among antibody immunotherapy or RIT should be best added to chemotherapy, but that all three treatments might be optimally combined with the aim to get the highest chance of cure for advanced stage follicular lymphoma.

Tumor Sclerosis but Not Cell Proliferation or Malignancy Grade Is a Prognostic Marker in Advanced-Stage Follicular Lymphoma: The German Low Grade Lymphoma Study Group

Follicular lymphoma is an indolent lymphoma with a long median overall survival. However, a considerable number of patients die within the first 2 years after the onset of the disease. Because the treatment options vary with respect to antitumor effect and potential toxic adverse effects, the identification of high-risk patients would be helpful in directing therapeutic decisions in individual patients. Several histopathologic biomarkers for risk stratification have been suggested, but most markers have not been validated in patients treated in prospective trials. We report a comprehensive approach to evaluate histopathologic biomarkers, including WHO grade, histology, and proliferation and quantitation of immune bystander cells, in 158 patients with nodal advanced-stage follicular lymphoma treated first line within a randomized trial. Tumor sclerosis was a significant prognostic marker of poor overall survival that was independent of the Follicular Lymphoma International Prognostic Index (FLIPI). WHO grade, proliferation, and total T-cell or macrophage content were not associated with overall survival. The presence of sclerosis within the lymphoma is a marker of poor overall survival that is independent of the FLIPI. The quantification of macrophage or absolute T-cell content, grading, and proliferation are of no help in predicting the outcome of FL. Future studies need to identify surrogate markers for the prognostic immune signatures identified by gene expression profiling. Most importantly, new prognostic markers need to be confirmed in patients treated within prospective trials.

BiovaxID™ idiotype vaccination: active immunotherapy for follicular lymphoma

Although advanced-stage follicular lymphoma (FL) has been considered incurable with standard therapy, novel strategies that utilize immunotherapy provide opportunities for prolonging disease-free survival. While passive immunotherapy with antibodies targeting the CD20 antigen on B cells has been the most widely applied lymphoma immunotherapy, active immunization with vaccines derived from the immunoglobulin idiotype present on the surface of FL provides an opportunity to induce specific humoral and cellular immune responses to the tumor, and have been demonstrated to produce significant benefits in prolonging disease-free survival. Promoting the benefits of all forms of immunotherapy will likely depend upon improving complete remission rates with initial treatment. BiovaxID™, a patient-specific idiotype vaccine, has demonstrated durable remissions when administered to FL patients in first complete remission along with keyhole limpet hemocyanin and granulocyte–macrophage colony-stimulating factor, and is now undergoing evaluation in a pivotal Phase III clinical trial.

Introduction of rituximab in front‐line and salvage therapies has improved outcome of advanced‐stage follicular lymphoma patients

It is unclear whether new treatment modalities have improved the survival of follicular lymphoma patients. Some data show that there has been no improvement in survival in the last 3 decades of the 20th century, whereas the results of recent retrospective studies suggest that evolving therapy has improved the outcome for follicular lymphoma patients. To evaluate the impact of evolving therapies for follicular lymphoma, particularly the introduction of rituximab, the overall survival (OS), failure-free survival (FFS), and survival after recurrence (SAR) was analyzed in 438 advanced-stage follicular lymphoma patients enrolled in consecutive Gruppo Italiano Studio Linfomi (GISL) trials between 1988 and 2004. A stepwise improvement in FFS and a significant reduction in the hazard ratio was observed with succeeding studies. Cox regression analysis showed an improvement over time for OS, with a decline in the hazard ratio particularly evident in the group treated with rituximab. Furthermore, the SAR significantly improved in the group of patients treated with chemotherapy + rituximab. After adjusting for all parameters with an impact on FFS and OS, the results of multivariate analysis suggest that rituximab therapy has a favorable effect on the prognosis of follicular lymphoma. The data show that FFS and OS have significantly improved in advanced-stage follicular lymphoma patients treated on GISL protocols during the last 18 years. These improvements are related to evolving front-line and salvage therapies, particularly the introduction of rituximab in combination with chemotherapy.