We report the outcomes of 30 patients with chemo-sensitive, relapsed FL who underwent either high-dose therapy with autologous HCT or RIC allogeneic HCT with assignment to treatment arm based on the availability of an HLA-matched sibling donor. This represents the first and only trial to date that attempted to prospectively compare the efficacy of autologous HCT vs RIC allogeneic HCT for patients with relapsed FL. Unfortunately, this trial closed prematurely due to slow patient accrual. Analysis of the reasons for poor accrual indicated lack of equipoise for the two treatments being tested. There was also a general concern about the potential for treatment-related morbidity and mortality following allogeneic HCT in this older patient population. Consequently, some clinicians favored use of allogeneic HCT for patients they perceived at very high risk of recurrence and autologous HCT for others, making them reluctant to enroll patients in a trial that could assign to either therapy.
With approximately 3 years of median follow-up, one patient in the allogeneic HCT arm vs 3 patients in the autologous HCT arm have relapsed. This observation adds to a growing literature supporting the existence of a robust graft vs lymphoma effect against FL. Additionally, there were no cases of TRM in the allogeneic HCT arm and no observed grade 2–4 acute GVHD. Three patients in the autologous HCT arm died from TRM, 1 from pneumonitis and 2 patients from infection. All allogeneic HCT recipients remain alive at a median of 36 months (range, 33 – 49) post-HCT. However, definitive conclusions comparing the efficacy of one treatment arm over the other cannot be drawn due to the limited sample size.
There are many treatment options available to patients with FL but allogeneic HCT remains the only known cure. Two large retrospective registry analyses demonstrated lower relapse rates among FL patients after allogeneic versus autologous HCT but prohibitive TRM after myeloablative allogeneic HCT has impeded long term survival8
. Another separate registry analysis from the CIBMTR compared the outcome of FL patients after HCT using a myeloablative regimen versus an RIC regimen11
. Interestingly, there were no significant differences in OS, PFS or TRM between the two types of conditioning regimens but there was a significantly increased risk of disease progression in the RIC patients. Compromised performance status and chemo-resistant disease adversely affected survival and increased the risk of TRM. A report from the Princess Margaret Hospital of 37 FL patients who received allogeneic HCT with a myeloablative regimen reported 5 year TRM of only 15% with OS and PFS of 79% and 76%, respectively10
. This is an exceptionally low TRM considering that an ablative regimen was employed and could be explained in part by the fact that all patients were chemo-sensitive and the median age was only 45 years old.
RIC allogeneic regimens are increasingly offered to FL patients with the goal of utilizing the graft vs lymphoma effect while ameliorating the prohibitive TRM associated with myeloablative allogeneic HCT. Four prospective studies have reported favorable and encouraging results with some studies also including patients who had failed a prior autologous HCT12–15
. All four studies incorporated fludarabine-based preparative regimens. The most favorable data so far originated from the M.D. Anderson Cancer Center in which 47 patients with relapsed FL with chemo-sensitive disease received the FCR conditioning regimen as utilized in our study (fludarabine, cyclophosphamide, rituximab)14
. With a median follow up of 60 months, the OS and EFS were 85% and 83%, respectively. The TRM was 15% with infection being the leading cause of death. Only 2 patients relapsed and no patients died of progressive disease. In a recently published report, the GEL-TAMO group detailed the outcomes of 37 patients with FL who received allogeneic HCT after fludarabine and melphalan as the conditioning regimen13
. Remission status at the time of HCT significantly impacted both OS and TRM. The 4 yr OS for patients in CR, PR and progressive disease was 71%, 48% and 29% with an TRM of 26%, 33% and 71%, respectively. The relapse incidence was only 8% for all patients. Several retrospective studies of RIC allogeneic HCT for FL patients have reported PFS ranging from 38% to 77% with follow-up intervals of ~1–3 years16, 26–29
. TRM, however, has been considerably higher than in the above mentioned prospective studies. Such disparities can be explained in part by patient selection as some studies included a higher proportion of refractory patients while other studies allowed only chemo-sensitive patients.
The 3 yr OS and PFS rates after autologous HCT in this study were 73% and 63%, respectively, which compares favorably to other published autologous reports with relapsed FL patients. The use of rituximab represents a distinctive feature of our trial. We incorporated rituximab during mobilization as in vivo
purging of the graft and as maintenance therapy after autologous HCT as a means of eradicating minimal residual disease30–31
. Three patients have relapsed to date with all 3 relapses occurring within 2 years of autologous HCT.
Previous reports have consistently shown improved DFS with autologous HCT compared to conventional salvage therapy but only one study so far has shown a benefit in OS5
. The `CUP' trial from Europe was the first randomized trial that prospectively addressed the role of autologous HCT vs conventional salvage chemotherapy. One hundred and forty patients with relapsed, chemo-sensitive follicular NHL were randomized to chemotherapy alone, autologous HCT with a purged graft or autologous HCT with an unpurged graft. The OS at 4 years for the 3 groups were 46%, 71% and 77%, respectively. There was a significant reduction in hazard rates for both PFS and OS when comparing the chemotherapy patients and the combined groups of autologous HCT. There were too few patients in the 2 HCT arms to assess the effect of ex vivo
purging. In contrast to our study, the patients in the CUP trial were rituximab-naïve and did not receive rituximab during the peri-transplant period as this trial was initiated prior to routine rituximab use. In summary, our results show promising outcomes with both autologous HCT and RIC allogeneic HCT for FL patients with relapsed disease. Unfortunately, this trial suffered early closure due to slow accrual as did the `CUP' trial, the only other published randomized trial for relapsed FL patients. The numerous other choices of non-transplant therapies for patients with advanced FL most likely explain the poor accrual. Based on our results, we cannot definitively conclude which arm is more efficacious but the low relapse rate and TRM seen in the allogeneic HCT arm and previously published RIC allogeneic studies lends compelling support to further study of this modality. The BMT CTN therefore, has embarked on a phase II multicenter trial for relapsed FL patients with the goal to validate the highly promising results using the FCR regimen in the allogeneic HCT setting. This ongoing trial (BMT CTN #0701, Clinicaltrials.gov
NCT00912223) is being conducted with the upfront participation of three National Cancer Institute cancer cooperative groups (Cancer and Leukemia Group B, Southwest Oncology Group and Eastern Cooperative Oncology Group).