GLSG.

Methods	Randomised controlled trial with two arms: chemotherapy arm and HDT + ASCT arm. Conducted by the German Low‐Grade Lymphoma Study Group (GLGSG), 332 FL patients from 130 centres in Germany were enrolled. Recruitment period from July 1996 to September 2000. 332 were enrolled, 25 patients were not randomised (13 refused IFN α, 8 refused HDT + ASCT, 4 aged over 60); 307 Patients were randomised 1:1; 154 to IFN arm and 153 to HDT + ASCT arm 240 Patients were evaluated; 126 patients in the IFN‐arm and 114 patients in the HDT + ASCT arm. 67 Patients were excluded from analysis; 28 patients were not analysed in IFN arm: 20 did not receive assigned therapy, 1 patient had an Ann Arbor stage I or II, 3 abort of induction in remission; 1 radiation in remission. 39 patients were not analysed in HDT + ASCT arm: 35 did not receive assigned therapy; 4 abort of induction in remission. Baseline patient characteristics described. Staging: clinical examination, complete blood count, serum biochemistry profile, chest radiography, abdominal ultrasound, computed tomography of the neck, chest, and abdomen, and bone marrow biopsy. Staging was performed before therapy, after every second cycle of induction therapy, and before and after ASCT. Median follow‐up time: 50 months ITT analysis
Participants	Inclusion criteria: Untreated patients between 18 to 59 years of age with advanced Ann Arbor stage III and IV follicular lymphoma, mantle cell lymphoma, or lymphoplasmacytic lymphoma according to the current WHO classification. For this meta‐analysis patients with FL were evaluated. Patients had to be in need of therapy as defined by one of the following: B symptoms, hematopoetic insufficiency progressive disease as defined by 50% progression in the past 6 months, or bulky disease Exclusion criteria: Patients with the potential for curative radiation therapy and those with poor performance status (ECOG performance status greater than 2). Patients with seriously impaired cardiac, pulmonary, hepatic or renal function (creatinine > 2 mg/dL). Stage IV: IFN‐arm 93 (73.8%), HDT + ASCT arm 85 (74.6%) FLIPI‐Score: IFN‐arm: low risk 74 (62.2%), low‐intermediate risk 34 (28.6%), high‐intermediate risk 11 (9.2%); HDT + ASCT arm: low risk 53 (54.1%), low‐intermediate risk 38 (38.8), high‐intermediate risk 7 (7.1%) Mean age (range): IFN: 49.1 (26 to 59) years; HDT + ASCT arm: 49.1 (29 to 59). Gender: chemotherapy: 56 males (44.4%), 70 females; HDT + ASCT arm: 62 males (54.4%), 52 females. Similar baseline patients' characteristics in comparison arms.
Interventions	Initially, patients were randomly assigned for cytoreductive therapy with CHOP (cyclophosphamide 750 mg/m2 i.v., day 1; doxorubicin 50 mg/m2 i.v., day 1; vincristine 1.4 mg/m2 [maximum, 2 mg] i.v., day 1; and prednisone 100 mg/m2 orally, days 1 to 5) or with MCP (mitoxantrone 8 mg/m2 i.v., days 1 to 2; chlorambucil 3 x 3 mg/m2 orally , days1 to 5; and prednisone 25 mg/m2 orally, days 1 to 5). Beginning in July 1998, all patients received CHOP because a randomised comparison of CHOP with MCP showed that MCP was associated with a significant impairment of hematopoietic stem cell mobilization. After 2 cycles of therapy, patients were randomly assigned to myeloablative radiochemotherapy followed by ASCT or to IFN‐maintenance after the completion of induction therapy. Patients achieving CR after 4 cycles of initial cytoreductive chemotherapy immediately proceeded to consolidation therapy. All other patients received 6 cycles of induction therapy. Patients who had progressive disease during induction therapy or who did not achieve at least partial remission after the completion of induction therapy were removed from the study. Intervention after randomisation: IFN‐arm: 2 additional courses of conventional chemotherapy to balance the mobilization scheme (Dexa‐BEAM). Subsequently, alpha‐interferon was applied at a dose of 5 x 106 units s.c. 3 times weekly until progression. HDT + ASCT arm: Dexa‐BEAM (dexamethasone 3 x 8 mg orally , days 1 to 10;cBCNU 60 mg/m2 i.v., day 2; melphalan 20 mg/m2 i.v., day 3; etoposide 75 mg/m2 i.v., days 4‐7; cytarabine 2 100 mg/m2 i.v., days 4‐7; and G‐CSF initiated on day 11). Peripheral stem cells were harvested and subsequently cryopreserved without any purging procedure. At least 2.0 106/kg body weight CD34 cells (and 2.0 106/kg body weight CD34 cells as back‐up) were required for ASCT. Myeloablative therapy was performed within 2 months of mobilization and consisted of a combined TBI (12 Gy; TBI was fractionated into 6 applications of 2 Gy on days 6 to 4; pulmonary dosage was limited to 8Gy) and cyclophosphamide (60 mg/kg body weight i.v., days 3 and 2) regimen. Previously harvested peripheral blood stem cells were re infused on day 0. G‐CSF was initiated on day
Outcomes	Primary trial endpoint was defined as PFS after the completion of induction therapy. Secondary outcomes: Response to therapy, OS, toxicity
Notes	Treatment information: Beginning in July 1998, all patients received CHOP instead of MCP or CHOP because a randomised comparison of CHOP with MCP showed that MCP was associated with a significant impairment of hematopoietic stem cell mobilization.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Prospective randomised trial
Allocation concealment (selection bias)	Low risk	"Randomization was carried out centrally."
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 analysis (patients excluded from analysis who did not receive assigned therapy : 55 of 307 patients)
Selective reporting (reporting bias)	Unclear risk	No protocol is available.
Other bias	Unclear risk	"Beginning in July 1998, all patients received CHOP because a randomised comparison of CHOP with MCP showed that MCP was associated with a significant impairment of hematopoietic stem cell mobilization."