Prospective, multicenter randomized GITMO/IIL trial comparing intensive (R-HDS) versus conventional (CHOP-R) chemoimmunotherapy in high-risk follicular lymphoma at diagnosis: the superior disease control of R-HDS does not translate into an overall survival advantage

Abstract

In this randomized multicenter study of 136 patients, 6 courses of CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone) followed by rituximab (CHOP-R) were compared with rituximabsupplemented high-dose sequential chemotherapy with autografting (R-HDS) to assess the value of intensified chemotherapy as a first-line treatment for highrisk follicular lymphoma (FL) after the introduction of monoclonal antibodies. The analysis was intention to treat with event-free survival (EFS) as the primary endpoint. Complete remission (CR) was 62% with CHOP-R and 85% with R-HDS (P < .001). At a median follow-up (MFU) of 51 months, the 4-year EFS was 28% and 61%, respectively (P < .001), with no difference in overall survival (OS). Molecular remission (MR) was achieved in 44% of CHOP-R and 80% of R-HDS patients (P < .001), and was the strongest independent outcome predictor. Patients relapsing after CHOP-R underwent salvage R-HDS in 71% of cases. Salvage R-HDS had an 85% CR rate and a 68% 3-year EFS (MFU, 30 months). We conclude that (1) achieving MR is critical for effective disease control, regardless of which treatment is used; IntroductionIn the last 15 years, our approach to treatment of follicular lymphoma (FL) has evolved considerably, chiefly due to 3 major achievements. First, new agents, particularly rituximab, have improved overall outcome in patients with FL. 1,2 Second, a subset of patients with a rapid and progressive course has been recognized. [3][4][5] The International Prognostic Index (IPI), the age-adjusted IPI (aaIPI), and more recent FL-specific scores such as the Intergruppo Italiano Linfomi (IIL) score and Follicular Lymphoma International Prognostic Index (FLIPI) now allow simple and effective identification of these high-risk patients, whose management is currently far from satisfactory. 4,5 Finally, many phase 2 studies have demonstrated that the achievement of molecular remission (MR) as determined by polymerase chain reaction (PCR) is associated with a better outcome in the context of a wide array of different treatments. [6][7][8][9][10][11] In this rapidly evolving field, the place for intensified regimens with autologous stem cell transplantation (ASCT) is poorly defined. Most data arise from pre-rituximab studies. [12][13][14][15][16] ASCT improves overall survival (OS) in relapsed patients, 7,12 while data at diagnosis are less clear. The 3 phase 3 studies published so far The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734. For personal use only. on May 7, 2018. by guest www.bloodjournal.org From have been based on total body irradiation (TBI)-containing regimens, did not select patients according to validated prognostic scores, and did not include molecular analysis. [13][14][15] Two of these trials showed that intensive therapy ensures better progression-free survi...

Prognostic Factors in Follicular Lymphoma in the Rituximab Era: How to Identify a High-Risk Patient?

“…the absence of the bcl-2/IgH transcript in bone marrow or peripheral blood examination, has a significant predictive value. The impact of molecular remission detected by RT-PCR has been confirmed both in patients treated with conventional CHOP therapy [35][36][37] and in those receiving high-dose chemotherapy with autologous stem cell transplantation 16,38 . Patients who achieve complete remission according to the conventional criteria but remain bcl-2/IgH-positive in bone marrow are at a higher risk of lymphoma relapse, regardless whether they were or were not given maintenance therapy 39,40 .…”

“…So far, no prospective randomized study comparing a larger number of induction chemotherapy schemes has been carried out. Further, there are very few prospective randomized studies to assess the impact of therapy intensification [16][17][18] . The published data suggest that the benefit of adding rituximab to induction therapy is not comparable for all risk subgroups.…”

Autologous stem cell transplantation with in vivo purged progenitor cells shows long‐term efficacy in relapsed/refractory follicular lymphoma

“…In a randomized multicenter study comparing R-CHOP with rituximab-supplemented high-dose sequential chemotherapy with autotransplant (R-HDS) [14], EFS but not OS was in favor of R-HDS. Patients relapsing after CHOP-R underwent R-HDS in 71% of cases.…”

Autologus Stem Cell Transplantation for Cancers: India: 2017

“…The routine use of upfront ASCT consolidation in follicular lymphoma is not recommended in the rituximab era because though ASCT may offer better event free of progression free survival, it does not associated with better overall survival rather it is associated with increased TRM and greater percentage of secondary malignancies [16].…”

“…CBV and BEAM are standard conditioning regimens for ASCT in lymphoma. Radioimmunotherapy based conditioning regimens are not favoured in various studies [16][17][18][19][20][21][22][23].…”