Final Results of a Multicenter Prospective Phase II Trial of Allogeneic Transplantation for Relapsed/Refractory CD20+ B-Cell Lymphomas: Effect of Rituximab on Graft-Versus-Host Disease-Free/Relapse-Free Survival (GRFS)

Introduction: Patients with refractory and relapsed B-cell lymphomas have few curative options. Despite novel target therapies, only patients receiving allogeneic stem cell transplantation (alloSCT) can achieve a long-term disease control. A lot of effort has been done over the last years to produce strategies reducing non-relapse mortality (NRM) without damaging the graft-versus-lymphoma effect. We conducted a multicenter prospective phase II trial to evaluate the benefit of high-dose Rituximab (R) in the conditioning regimen before alloSCT. The primary end-point of the study was progression-free (PFS) survival. We evaluated also the long-term outcome with the novel composite end-point of graft-versus-host disease-free/relapse-free survival (GRFS). Methods:The study enrolled 121 adult patients who received alloSCT for relapsed/refractory B-cell lymphomas [n=35 (28%) follicular lymphomas; n=29 (24%) chronic-lymphocytic leukemia; n=35 (28%) diffuse large B-cell lymphomas; n= 22 (18%) mantle cell lymphomas]. The median age was 52 years (range, 23-65). Seventy-four pts (61%) failed a previous autograft. The conditioning regimen consisted of thiotepa (12 mg/kg), cyclophosphamide (60 mg/kg) and fludarabine (60 mg/m2) and high-dose of rituximab (500 mg/m2 on day-6),. Graft-versus-host disease (GVHD) prophylaxis was based on cyclosporine and mini-methotrexate; ATG (7 mg/kg) was given to the patients allografted from unrelated donors. Sixty-seven (55%) and fifty-four (45%) patients received grafts from related and unrelated donors, respectively. Results: At a median follow-up of 41 months (range 6-95 months), the estimated 3-years PFS and overall survival (OS) were 50% (95%CI, 41%-61%) and 61% (95%CI, 51%-71%), respectively. The 1 and 3-years GRFS were 40% (95%CI, 32%-50%) and 34% (95%CI, 26%-44%), respectively. The GRFS was significantly better in patients affected by indolent disease (43% versus 22%, long-rank test, p=0.02); in addition there was a tendency for better GRFS for those transplanted from unrelated donors (41% versus 27%, p=0.096). The 3-years GRFS were 41% and 30% in patients with complete remission (CR) and partial remission (PR) at the time of transplant, respectively (p=0.185). The multivariate analysis showed that patients affected by aggressive histotype and with bone marrow (BM) infiltration at time of transplant had a poor outcome in terms of PFS, OS and GRFS [hystotype: PFS, HR 3.30 (p=0.003); OS, HR 3.73 (p=0.007); GRFS, HR 2.02 (p=0.026); BM infiltration: PFS, HR 4.79 (p<0.001); OS, HR 6.00 (p<0.001); GRFS, HR 2.7 (p=0.004)]. The crude cumulative incidence (CCI) of NRM was 21% (95%CI, 14%-30%) at 3-years whereas the CCI of acute GVHD grade II-IV was 22% (95%CI,15%-30%). The CCI of acute GVHD was not statistically significant different in matched sibling donors and unrelated donors (21% versus 22%, respectively p=0.717). According to the modified Seattle criteria, the CCI of extensive GVHD was 17% (95%CI, 11%-27%) whereas the limited form was 27% (95%CI, 19%-39%). In the univariable Fine and Gray model, the only factor that was protective against the occurrence of chronic GVHD was the transplant from unrelated donors when R and ATG were combined together [HR 0.50 (95%CI, 0.25-0.99), p=0.05]. In fact, the CCI of chronic GVHD at 3-years from matched sibling donors was 54% (95%CI,42%-71%) as opposed to 31% from unrelated donors (95%CI, 19%-49%) (p=0.04). Conclusions: Our trial showed:1) R did not improve PFS as compared with our historical control; 2) the combination of R and ATG is synergistic and resulted protective against chronic GVHD; 3) GRFS analysis showed that 34% of the patients are alive without any complications at 3-years after allograft and this should be the standard to compare novel drug results. Future protocols should consider the use of GRFS as endpoint and inclusion of ATG also for those receiving sibling grafts.