GITMO/IIL.

Methods	Randomised controlled trial with two arms: chemotherapy arm and HDT + ASCT arm. Conducted by the Gruppo Italiano Trapianto di Midollo Osseo (GITMO), Intergruppo Italiano Linfomi (IIL), 136 patients from 30 centres in Italy were enrolled. Recruitment period from March 2000 to May 2005. 136 Patients were randomised 1:1; 68 to control arm and 68 to HDT‐arm. 134 Patients were evaluated; 66 patients in the CHOP‐arm and 68 patients in the HDT‐arm. Two CHOP‐Patients were not included in the analysis; One patient withdrew consent before treatment start and one patient lacked a documented aaIPI score of 2 or greater. Baseline patient characteristics described. Median follow‐up time: 51 months. ITT analysis
Participants	Inclusion criteria: Patients aged 18 to 60 were eligible if they had Ann Arbor stage III or IV FL, according to REAL/WHO lymphoma classification (grades 1, 2, and 3, patients with grade 3b were not excluded). Eligible patients had no history of cancer and were chemotherapy‐or extended field radiotherapy‐ free. Absence of concurrent heart, kidney, lung, or liver disease was required plus HIV and hepatitis C negativity. HBV positive patients without active viral replication were eligible under lamivudine prophylaxis. Exclusion criteria: not reported aaIPI 2 or more, No. (%): CHOP‐arm: 61 (92); HDT + ASCT‐arm: 59 (87) FLIPI 3 or more, No. (%): CHOP‐arm: 34 (51); HDT + ASCT‐arm: 44 (65) Mean age (range): CHOP‐arm: 51 (22 to 59) years; HDT + ASCT‐arm: 51 (25 to 59). Gender: CHOP‐arm: 40 males (61%), 26 females; HDT + ASCT‐arm: 38 males (56%), 30 females. Similar baseline patients' characteristics in comparison arms.
Interventions	Conventional chemotherapy arm: 6 courses of CHOP (cyclophosphamide/ doxorubicin/ vincristine, prednisone) supplemented by an identical number of rituximab courses (4 x 375 mg/m2) HDT+ ASCT arm: Phase 1 (intensive debulking): 2 complete, full‐dose APO (doxorubicin, vincristine, prednisone) courses, totaling four 75 mg/m2 doxorubicin administrations. Patients not achieving CR received 2 additional DHAP (Ara‐C, cisplatin, dexamethasone) courses. Phase 2 (High‐dose chemotherapy): HD phase consisted of 2g/m2 etoposide (VP16) followed by a chemotherapy‐free interval of 40 days for optimal PBSC mobilization. During this phase, patients received 2 rituximab courses (375mg/m2). Then, 7g/m2 cyclophosphamide (Cy) was delivered. In vivo purging was performed by delivering 2 rituximab doses (375mg/m2) on the day after Cy, and on the first day the pat had a white blood cell count greater than 1000/µL. HD courses were supported with G‐CSF (5µg/kg/day). A minimum of 5 x 106 CD34+ cells/kg was required for autologous transplantation with PBSCs only (plus at least 3 x 106 CD34+ cells/kg or a bone marrow harvest as backup). Patients failing to meet this minimum did not undergo autografting. Phase 3 (autografting): The autografting conditioning regimen consisted of mitoxantrone (60 mg/m2) on day ‐5 and melphalan (180 mg/m2) on day ‐2. Duration of treatment (days, cycles): A single APO‐course consisted of doxorubicin (75 mg/m2) on days 1 and 22, vincristine (1.2mg/m2) on days 1 and 15, and prednisolone (50 mg/m2) on days 1 and 22. The DHAP course consisted of cisplatin (100 mg/m2) on day 1, Ara‐C (4 g/m2) on day 2, and dexamethasone (40 mg) on days 1 to 4. Radiotherapy: Radiotherapy (30 to 36 Gy) was planned in both treatment arms on bulky sites or on residual masses approximately 2 months after the end of treatment. Important treatment information: CHOP‐arm in case of CHOP‐R failure, most centres (90%) agreed to treat patients with R‐HDS (cross‐over). Only patients with the following characteristics were not considered eligible for cross‐over: (1) localized, limited relapse, (2) relapses requiring a specific treatment such as CNS or testis, (3) the presence of severe co‐morbidities, (4) age older than 60 years at the time of starting R‐HDS and (5) patient refusal. Patients with histologic shifts at relapse were not excluded from cross‐over and were included in analysis. When delivered at relapse, the R‐HDS schedule was identical with the exception that no APO courses were delivered in order to avoid excessive cardiac toxicity in patients already treated with CHOP. Thus, these patients started their R‐HDS schedule from 2 DHAP courses. HDT‐arm: in case of R‐HDS failure, the salvage treatment was free. Supportive treatment: In both treatment arms, patients in PR or who remained PCR received 2 final rituximab courses at the end of the program.
Outcomes	Primary endpoint: EFS Secondary endpoints: OS, RR, PFS, DFS, molecular outcome
Notes	Supported in part by Roche
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Prospective multi‐centre randomised trial
Allocation concealment (selection bias)	Low risk	"A centralized computer generated a simple randomisation sequence."
Blinding (performance bias and detection bias) patients	High risk	Usually trials evaluating stem cell transplantation are not blinded
Blinding (performance bias and detection bias) physicians	High risk	Usually trials evaluating stem cell transplantation are not blinded
Blinding (performance bias and detection bias) assessors	Unclear risk	No information about blinding of the assessors.
Incomplete outcome data (attrition bias) All outcomes	Low risk	ITT basis
Selective reporting (reporting bias)	Low risk	Protocol available at www.controlled‐trials.com/mrct/trial/printfriendly/399237
Other bias	Unclear risk	Trial stopped early "A sample size of 246 patients (123 per arm) over 5 years was required to detect a 20% absolute increase (from 35% to 55%) in 3‐year EFS with an error of .05 and a error of .20, with a median follow‐up of 3 years. A single interim analysis was planned, including the 120 patients who completed the treatment before March 24, 2005. R‐HDS showed a significant EFS improvement (29% absolute increase) compared to CHOP‐R. This result led the steering committee to stop enrolment on May 30."