Long-Term Follow-Up of Autologous Bone Marrow Transplantation for Follicular Lymphoma in First Remission: Bone Marrow Involvement at Harvest and PCR Detectable Disease after Ex Vivo Purging Predict Relapse.
Authors: Brown Jennifer R. , Gribben John G. , Feng Yang , Neuberg Donna , Mauch Peter , Nadler Lee M. , Freedman Arnold S. 
Published: October 2019

Abstract
ASCT improves progression-free and likely overall survival in patients with relapsed follicular lymphoma. Randomized trials of ASCT as upfront therapy have generally also found an improvement in progression-free survival, but this benefit has been counterbalanced by an increase in second malignancies. We report the long-term outcome of two sequential prospective clinical trials of autologous bone marrow transplantation for advanced stage follicular lymphoma patients under 60 in first remission. In the 1st study 83 previously untreated patients received 6–8 cycles of CHOP induction and in the 2nd study 20 patients received 4 cycles of high-dose CHOP induction (cyclophosphamide 1.5 g/m2 d1–2 with g-csf support). The median age of the patients was 42 (range 19–57). 17% had high FLIPI scores, 58% intermediate and 25% low; all patients were under 60 and 21% had missing data required in the FLIPI. 96% had stage III or IV disease. 77 of 83 patients on the 1st study, and 19 of 20 on the 2nd study (N=96 total), achieved a protocol-defined minimal disease state after CHOP induction (< 2 cm masses, <20% bone marrow involvement). 35% of patients achieved CR after induction. Nine patients required IFRT to achieve protocol eligibility. Marrow was purged in vitro with anti-B1 (CD20), B5 and J5 (CD10) monoclonal antibodies and complement. Subjects were conditioned with cyclophosphamide and total body irradiation prior to re-infusion of purged bone marrow. Two early treatment-related deaths were observed. The 12 year relapse-free survival is 42.7% (95% CI 32.3–52.7%) and overall survival 60.7% (95% CI 49.5–70.1%). 44 patients (45.8%) have relapsed with follicular lymphoma of whom 24 have died of disease and 15 are alive. The median survival following relapse is 6.1 years (95% CI 4.1–9.0). 27 patients (28%) have developed a second malignancy, at a median 8.7 years following ABMT, including 10 cases of MDS/AML, 2 non-MDS hematologic malignancies, 8 solid tumors and 10 non-melanoma skin cancers. 9 patients (9.4%) have died of a secondary malignancy. Age, stage, FLIPI, hemoglobin, LDH, number of nodal sites, IFRT, and induction therapy were not predictive of PFS or OS. Histologic evidence of residual bone marrow disease at harvest was associated with a 12 year PFS 33.9% (95% CI 20.5–47.9%), compared to 50% (95% CI 34.8–63.5%) for those without marrow involvement (p= 0.02, log-rank test). 70 patients with known detectable bcl-2/IgH translocations prior to therapy had post-purging bone marrow samples analyzed by PCR; 30 of these 70 were negative. The 12 year RFS for PCR negative patients is 66.7% (95% CI 47–81%), compared to 26.3% (95% CI 14–41%) for those with PCR detectable disease (p= 0.001, log-rank test). In Cox proportional hazards regression analysis evaluating the impact of pre-transplant factors on PFS, only histologic bone marrow involvement at harvest (HR 2.27, 95% CI 1.31–3.93, p<0.004) and PCR positivity after ex vivo purging (HR 4.18, 95% CI 1.99–8.80, p= 0.0002) were independent predictors of outcome. These results, showing that 42.7% of patients are in ongoing complete remission and 60.7% are alive at twelve years following ABMT, suggest that a subset of follicular lymphoma patients can experience prolonged survival with ABMT in first remission.