Prolonged Clinical and Molecular Remissions Following High-Dose Therapy/Autologous Stem Cell Transplantation (HDT/ASCT) and Rituximab and Interferon-alpha Maintenance for Relapsed High-Risk Follicular Lymphoma.

Abstract

High-dose therapy and autologous stem cell transplantation (HDT/ASCT) are associated with prolonged remissions in relapsed follicular lymphoma (FL). Maintenance rituximab (R) has an accepted role in extending remissions and preclinical evidence suggests that its effects may be enhanced by the immunomodulatory capacity of interferon alpha (IFN-α). We designed a phase II study to incorporate in-vivo purging (with R) and post-transplant maintenance immunotherapy (with combined R and IFN-α) to prolong the remissions attained by HDT/ASCT. We present a planned analysis of 30 patients age ≤65 with 1–2 relapses of FL. Individuals received salvage CHOP or DHAP and proceeded with stem cell mobilization and HDT/ASCT with cyclophosphamide/carmustine/etoposide if they achieved ≥75% reduction in bulk and <15% marrow involvement. R 375 mg/m2 was given as 3 weekly doses prior to collection and as 6 weekly maintenance doses starting 12 weeks post-ASCT. IFN-α was initiated at week 10 post-ASCT with titration to a dose of 3 million units/m2 tiw for 2 years. Samples for PCR (sensitivity 0.01%) of t(14;18) or VDJ rearrangements were taken from blood/marrow to assess for molecular remission (MR).Results: Twenty-nine patients are assessable with a median follow-up for survivors of 3.1 years. Median age was 46 years (30–65) and median number of prior regimens was 2. Median response duration to prior therapy was 0.6 years and patients were enrolled 2.3 years (median) following diagnosis. The overall response rate to salvage was 93% (95% CI 83.7% to 100%) and n=23 proceeded to HDT/ASCT. Six patients did not undergo ASCT due to inadequate response (n=2), failed mobilization (n=2), cardiomyopathy (n=1), and patient withdrawal (n=1). Significant non-hematologic ASCT toxicities (grade 3/4) included: 5 episodes of interstitial pneumonitis, retinal vein occlusion (n=1), and thrombotic thrombocytopenic purpura (n=1). One patient was diagnosed with ALL 30 months following ASCT. Twenty-one individuals initiated IFN-α with 14 able to complete 2-years of maintenance (median dose of 3 × 106 units/m2 tiw). The most common reason for discontinuation was depression. At baseline, 19 patients had detectable markers by PCR. Despite in-vivo purging with R, 8 of 17 stem cell grafts had molecular disease, although graft contamination did not affect subsequent MR (p=NS). Of 16 assessable patients post-transplantation, 11/16 achieved MR prior to immunotherapy and 16/16 achieved MR during maintenance. Three patients have had a molecular relapse at 12, 18, and 36 months post-ASCT, with molecular preceding clinical relapse in 2/3 patients. Median progression-free survival for all patients is 50 months and median overall survival has not been reached.Conclusions: HDT/ASCT was feasible and well-tolerated in this high-risk population of relapsed FL. Molecular detection of lymphoma in the auto-graft did not preclude extended MR and clinical remissions post-transplant. This may be due to the enhanced clearance of minimal residual disease achieved by combination maintenance immunotherapy (R and interferon-α) post-ASCT. This is our third study in a sequential program of HDT/ASCT trials incorporating immunotherapy pre- and post-transplantation; we will present comparative evidence across the series to determine the added benefit of IFN-α in this latest approach.