Lindsey Stevens

Rituximab versus a watch-and-wait approach in patients with advanced- stage, asymptomatic, non-bulky follicular lymphoma: an open-label randomised phase 3 trial

BACKGROUND Patients with advanced-stage, low-tumour-burden follicular lymphoma have conventionally undergone watchful waiting until disease progression. We assessed whether rituximab use could delay the need for chemotherapy or radiotherapy compared with watchful waiting and the effect of this strategy on quality of life (QoL). METHODS Asymptomatic patients (aged ≥18 years) with low-tumour-burden follicular lymphoma (grades 1, 2, and 3a) were randomly assigned centrally (1:1:1), by the minimisation approach stratified by institution, grade, stage, and age, to watchful waiting, rituximab 375 mg/m(2) weekly for 4 weeks (rituximab induction), or rituximab induction followed by a maintenance schedule of 12 further infusions given at 2-monthly intervals for 2 years (maintenance rituximab). On Sept 30, 2007, recruitment into the rituximab induction group was closed and the study was amended to a two-arm study. The primary endpoints were time to start of new treatment and QoL at month 7 (ie, 6 months after completion of rituximab induction). All randomly assigned patients were included in the analysis of time to start of new treatment on an intention-to-treat basis. The main study is now completed and is in long-term follow-up. The study is registered with ClinicalTrials.gov, NCT00112931. FINDINGS Between Oct 15, 2004, and March 25, 2009, 379 patients from 118 centres in the UK, Australia, New Zealand, Turkey, and Poland were randomly assigned to watchful waiting or maintenance rituximab. 84 patients were recruited to the rituximab induction group before it was closed early. There was a significant difference in the time to start of new treatment, with 46% (95% CI 39-53) of patients in the watchful waiting group not needing treatment at 3 years compared with 88% (83-92) in the maintenance rituximab group (hazard ratio [HR] 0·21, 95% CI 0·14-0·31; p<0·0001). 78% (95% CI 69-87) of patients in the rituximab induction group did not need treatment at 3 years, which was significantly more than in the watchful waiting group (HR 0·35, 95% CI 0·22-0·56; p<0·0001), but no different compared with the maintenance rituximab group (0·75, 0·41-1·34; p=0·33). Compared with the watchful waiting group, patients in the maintenance rituximab group had significant improvements in the Mental Adjustment to Cancer scale score (p=0·0004), and Illness Coping Style score (p=0·0012) between baseline and month 7. Patients in the rituximab induction group did not show improvements in their QoL compared with the watchful waiting group. There were 18 serious adverse events reported in the rituximab groups (four in the rituximab induction group and 14 in the maintenance rituximab group), 12 of which were grade 3 or 4 (five infections, three allergic reactions, and four cases of neutropenia), all of which fully resolved. INTERPRETATION Rituximab monotherapy should be considered as a treatment option for patients with asymptomatic, advanced-stage, low-tumour-burden follicular lymphoma. FUNDING Cancer Research UK, Lymphoma Research Trust, Lymphoma Association, and Roche.

Adapted treatment guided by interim PET-CT scan in advanced Hodgkin's lymphoma

BACKGROUND We tested interim positron-emission tomography-computed tomography (PET-CT) as a measure of early response to chemotherapy in order to guide treatment for patients with advanced Hodgkins lymphoma. METHODS Patients with newly diagnosed advanced classic Hodgkins lymphoma underwent a baseline PET-CT scan, received two cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) chemotherapy, and then underwent an interim PET-CT scan. Images were centrally reviewed with the use of a 5-point scale for PET findings. Patients with negative PET findings after two cycles were randomly assigned to continue ABVD (ABVD group) or omit bleomycin (AVD group) in cycles 3 through 6. Those with positive PET findings after two cycles received BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone). Radiotherapy was not recommended for patients with negative findings on interim scans. The primary outcome was the difference in the 3-year progression-free survival rate between randomized groups, a noninferiority comparison to exclude a difference of 5 or more percentage points. RESULTS A total of 1214 patients were registered; 937 of the 1119 patients (83.7%) who underwent an interim PET-CT scan according to protocol had negative findings. With a median follow-up of 41 months, the 3-year progression-free survival rate and overall survival rate in the ABVD group were 85.7% (95% confidence interval [CI], 82.1 to 88.6) and 97.2% (95% CI, 95.1 to 98.4), respectively; the corresponding rates in the AVD group were 84.4% (95% CI, 80.7 to 87.5) and 97.6% (95% CI, 95.6 to 98.7). The absolute difference in the 3-year progression-free survival rate (ABVD minus AVD) was 1.6 percentage points (95% CI, -3.2 to 5.3). Respiratory adverse events were more severe in the ABVD group than in the AVD group. BEACOPP was given to the 172 patients with positive findings on the interim scan, and 74.4% had negative findings on a third PET-CT scan; the 3-year progression-free survival rate was 67.5% and the overall survival rate 87.8%. A total of 62 patients died during the trial (24 from Hodgkins lymphoma), for a 3-year progression-free survival rate of 82.6% and an overall survival rate of 95.8%. CONCLUSIONS Although the results fall just short of the specified noninferiority margin, the omission of bleomycin from the ABVD regimen after negative findings on interim PET resulted in a lower incidence of pulmonary toxic effects than with continued ABVD but not significantly lower efficacy. (Funded by Cancer Research UK and Others; ClinicalTrials.gov number, NCT00678327.).

PET-CT for staging and early response: results from the Response-Adapted Therapy in Advanced Hodgkin Lymphoma study

International guidelines recommend that positron emission tomography-computed tomography (PET-CT) should replace CT in Hodgkin lymphoma (HL). The aims of this study were to compare PET-CT with CT for staging and measure agreement between expert and local readers, using a 5-point scale (Deauville criteria), to adapt treatment in a clinical trial: Response-Adapted Therapy in Advanced Hodgkin Lymphoma (RATHL). Patients were staged using clinical assessment, CT, and bone marrow biopsy (RATHL stage). PET-CT was performed at baseline (PET0) and after 2 chemotherapy cycles (PET2) in a response-adapted design. PET-CT was reported centrally by experts at 5 national core laboratories. Local readers optionally scored PET2 scans. The RATHL and PET-CT stages were compared. Agreement among experts and between expert and local readers was measured. RATHL and PET0 stage were concordant in 938 (80%) patients. PET-CT upstaged 159 (14%) and downstaged 74 (6%) patients. Upstaging by extranodal disease in bone marrow (92), lung (11), or multiple sites (12) on PET-CT accounted for most discrepancies. Follow-up of discrepant findings confirmed the PET characterization of lesions in the vast majority. Five patients were upstaged by marrow biopsy and 7 by contrast-enhanced CT in the bowel and/or liver or spleen. PET2 agreement among experts (140 scans) with a κ (95% confidence interval) of 0.84 (0.76-0.91) was very good and between experts and local readers (300 scans) at 0.77 (0.68-0.86) was good. These results confirm PET-CT as the modern standard for staging HL and that response assessment using Deauville criteria is robust, enabling translation of RATHL results into clinical practice.

Toxicity of fludarabine and cyclophosphamide with or without rituximab as initial therapy for patients with previously untreated mantle cell lymphoma: results of a randomised phase II study.

The National Cancer Research Network (NCRN) is currently coordinating a Phase III randomised study (LY05) comparing fludarabine and cyclophosphamide (FC) with or without rituximab (R) for previously untreated mantle cell lymphoma (MCL). The combination of FC is well-recognised as significantly immunosuppressive and there are concerns that adding rituximab may increase infection risk further. The impact of rituximab on other markers of toxicity is also unclear. We analysed the toxicity data on 139 patients treated within the NCRN LY05 trial. Non-hematological toxicity was similar between the two treatment arms. The only difference in hematological toxicity was a higher rate of lymphocytopenia with fludarabine cyclophosphamide and rituximab (FCR), which did not translate into increased febrile episodes or infections. In conclusion, the addition of rituximab to FC for previously untreated MCL has no significant impact on toxicity.

CAN BASELINE PET-CT FEATURES PREDICT OUTCOMES IN ADVANCED HODGKIN LYMPHOMA? A PROSPECTIVE EVALUATION OF UK PATIENTS IN THE RATHL TRIAL (CRUK/07/033)

therapy were eligible. Pts received 2 (cohort 1) or 3 (cohort 2) cycles of weekly BV (1.2 mg/kg days 1, 8, 15 of 28 day cycles); PET‐negative pts proceeded directly to autologous stem cell transplant (ASCT) while PET‐positive pts received augICE before ASCT. Serum cytokines and chemokines (TARC, IL‐6, IL‐10, TNF‐α, IFN‐γ) were measured at baseline and after BV. Metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were measured at baseline, after BV and after augICE. Results: 65 pts enrolled (45 cohort 1, 20 cohort 2), including 34 (52%) females, 29 (45%) with advanced stage disease, 34 (52%) with refractory disease (lack of CR after front‐line therapy), 10 (15%) with B symptoms, 24 (37%) with extranodal disease, and 16 (25%) with bulk (any mass > 5 cm). Overall, 18 of 65 (28%) pts achieved complete response (defined as Deauville ≤2) following BV. 19 pts (18 with Deauville 2 response and 1 with Deauville 3 response after BV) proceeded directly to ASCT. Among the other 46 pts, 1 was lost to follow‐up; 45 received augICE chemotherapy of which 31 (69%) achieved CR. Overall, 49 (75%) of 65 pts achieved complete response and 64 pts proceeded to ASCT. 3‐year overall survival and EFS were 95% and 82%. Factors predictive for EFS by univariate analysis included age over 45 years (p = 0.016), refractory disease (p = 0.033), B‐symptoms (p = 0.032), advanced stage at relapse (p = 0.011), as well as baseline MTV, TARC, and TLG (all p < 0.001). Factors that remained prognostic by multivariate analysis were MTV (p < 0.001, HR 54, 95% CI 9‐319) and refractory disease (p = 0.001, HR 82, 95% CI 6.1‐1107). The optimal cut‐off for baseline MTV, determined by a grid search of log‐rank test p values, was 109.5 cm. Using this cutoff, the 3‐year EFS for pts with low (n = 48) and high (n = 12) MTV was 92% and 27% respectively (p < 0.001) (Figure). Conclusion: In this phase II study of PET‐adapted ST with BV and augICE for rel/ref HL, baseline MTV and refractory disease were independent prognostic factors for EFS. Additional studies are needed to confirm the prognostic significance and optimal cutoff for MTV in rel/ref disease. Future studies should optimize efficacy and tolerability of ST by stratifying pts according to risk factors such as baseline MTV.

OUTCOMES OF TREATMENT FOR OBESE PATIENTS WITH ADVANCED HODGKIN LYMPHOMA IN THE RATHL TRIAL (CRUK/07/033)

HL, and the other had residual FDG‐uptake in a location not amenable to biopsy. Both patients received ISRT. The 25 patients who completed combined modality therapy (CMT) have achieved CRs. To date, the duration of remission ranges from 2 to 13 months, and no relapses have occurred. The efficacy is similar across cohorts 1 and 2 with interim PET negative rates of ≥90%, and all patients who completed CMT have achieved a CR (Figure 1). In cohort 1, 2 patients had biopsy‐proven primary refractory HL after 4 cycles of chemotherapy, and in cohort 2, there have been no treatment failures. Conclusion: BV + AVD x 4 cycles followed by 20 Gy ISRT has promising preliminary efficacy for the treatment of early stage, unfavorable risk HL, including a high proportion of patients with bulky disease. As with 4 cycles of escalated BEACOPP tested in the GHSG HD11 clinical trial, 20 Gy ISRT may be adequate consolidation after BV + AVD x 4 cycles. We recommend that BV + AVD x 4 + 20 Gy ISRT is studied in a larger, randomized prospective study for early stage, bulky HL. Updated response data for all patients will be presented at the meeting.