In the Era of Chemoimmunotherapy, Relapse Post Autologous Stem Cell Transplantation for Follicular Lymphoma Is Associated with Prolonged Overall Survival. an Analysis By the Lymphoma Working Party of the European Society for Blood and Marrow Transplantation (EBMT)

Introduction. Autologous stem cell transplantation (ASCT) for patients (pts) with follicular lymphoma (FL) is generally reserved as a consolidation strategy in the relapse setting. However, recurrence of the FL is a significant problem and by 10 years after an ASCT between 50 and 70% of pts will have relapsed. To date the outcome of pts relapsing after an ASCT has been poorly characterised and there is no published data describing the outcome in pts that have received chemoimmunotherapy (CIT) prior to the ASCT. We therefore conducted a retrospective analysis of pts with FL who received CIT for FL, undergone an ASCT for relapsed disease and subsequently relapsed again.

Methods. The EBMT registry was searched for adult pts who had undergone an ASCT for relapsed FL between the years 2005 and 2013 inclusive. All pts had received CIT prior to ASCT and relapsed after the ASCT. Exclusion criteria were an ASCT performed in first remission, high grade (HG) transformation prior to the ASCT and planned multiple graft programs. EBMT centres were invited to submit additional data required for the study. The primary endpoint of the study was overall survival (OS) from the time of relapse post ASCT. Of 540 pts on whom additional data were received there was minimal essential data available on 374 pts who constitute the current study population.

Results. The median age at diagnosis was 50 years (range 24-71) and 61% of pts were male. 25% of pts were diagnosed before 2003, 40% between 2003 and2006 and 35% between 2007 and 2012. 69% of pts received first line CIT and 31% received CIT in 2nd or later lines prior to ASCT. The number of treatment lines before ASCT were 2 in 57% of pts, 3 in 26%, and 4 in 16%, and the median time from diagnosis to ASCT was 38 months (range 2.5-365). The median age at ASCT was 55 years (range 27-74). At ASCT 42% of pts were in CR, 35% in PR and 23% of pts had either refractory, stable, progressive or untreated relapse. The conditioning regimen employed was BEAM in 79%, BEAC in 2%, LACE in 4% and other regimens in 15%. 13% of pts received purging of the graft and 15% received maintenance Rituximab post ASCT.

The median time from ASCT to relapse was 15 months (range 0.4-84). 41% of pts relapsed < 12 months post ASCT and 72% < 24 months. 16% of pts experienced HG transformation at either first relapse post ASCT or at a later time point. The pts were managed with a variety of strategies for relapse including anti-CD20 antibodies only (n=32), bendamustine based therapy (n=87), CHOP like therapy (n=16), fludarabine based regimens (n=27), HG salvage therapy (n=48), radioimmunotherapy (n=13) other anti-lymphoma therapy (n=58) and 93 pts had no further anti-lymphoma therapy reported. 50 pts received radiotherapy after relapse. The median time from relapse tobstart of therapy was 36 days (range 0-37 months). Responses to first line therapy post ASCT were CR in 42%, PR 28%, stable disease 12%, progression 12%, unknown/not evaluated 6%. 109 pts received a second stem cell transplant (SCT) procedure (103 allogeneic SCT) at a median of 10 months after relapse (range 23 days-73 months). With a median follow up post relapse of 49 months (range 2 days -129 months) in surviving pts the overall survival (OS) was 53% (95% CI 47-58%) at 4 years. Causes of death were FL: 116, SCT related: 28, second malignancy: 12, other causes: 16 and unknown: 4. In multivariate analysis time from diagnosis to ASCT >24 months (hazard ratio 0.67 CI 0.46-0.97, p=0.034) and purging of the ASCT (HR 0.47, CI 0.25-0.87, p= 0.016) were associated with an improved OS from relapse. Time to relapse post ASCT had no significant impact on subsequent survival.

For the group of 103 pts that underwent a subsequent alloSCT the 4 year OS from alloSCT was 56%. Causes of death in this group included: SCT related n=28, lymphoma n=12, second malignancy n=2, other/unknown n=2. For the 58 pts that experienced HG transformation the OS at 4 years was 43% with 26 deaths attributable to disease, 3 due to SCT and 5 other/unknown.

Conclusions

OS in pts who relapse after ASCT for FL is 53% at 4 years. Only a short duration of first response prior to ASCT and lack of stem cell purging were associated with a worse OS. In contrast, early relapse after the ASCT was not associated with a worse survival. A variety of different treatment strategies including allogeneic SCT can be employed in this setting with high response rates.