High Dose Therapy / ASCT with Rituximab for In-Vivo Purging and Post-ASCT Consolidation in Relapsed Follicular Lymphoma Achieves Prolonged Clinical and Molecular Remissions.
Authors: Woods Anthony C. , Buckstein Rena , Mangel Joy , Imrie Kevin , Spaner David , Crump Michael , Pennell Nancy , Boudreau Angela , Reis Marciano , Berinstein Neil 
Published: October 2019

High-dose therapy and autologous stem cell transplantation (HDT/ASCT) is associated with prolonged remissions in relapsed follicular lymphoma (FL). Molecular remission in the graft and post ASCT predicts durable remissions and is a desirable endpoint. Rituximab (R) as an in vivo purge prior to HDT/ASCT and as consolidation after ASCT may help achieve this. To study this question, patients with relapsed FL were enrolled in a prospective, non-comparative phase II study between January 1998 and April 2000.

Methods: 23 consecutive patients age <65 yrs with <3 relapses underwent HDT/ASCT with CBV (Cyclophosphamide, BCNU and VP-16) following salvage with CHOP or DHAP. Patients achieving ≥75% reduction in bulk and <15% marrow involvement underwent stem cell mobilization with chemotherapy plus G-CSF 10 μg/kg daily x 5. R 375 mg/m2 was given as a single-dose purge prior to collection, and repeated as 4 weekly courses at 2 and 6 months post-ASCT. Samples for PCR detection of minimal residual disease (MRD) were taken from stem cell grafts, as well as blood and marrow for all patients with detectable disease at baseline. Response assessments were clinical, laboratory and radiologic, and analysis was intention-to-treat.

Results: Median cohort age at assessment was 50 yrs (32–57). Median number of prior regimens was 3 (1–7) and total treatment cycles was 9 (3–28). Median response duration to the preceding regimen was 10 months (1–86). Transplants were a median 2.4 years after diagnosis. At median follow-up of 4.5 yrs (1.3–6.3), there have been 10 relapses at a median of 2.8 yrs. 3 patients have died, 2 with relapse and one of presumptive sudden cardiac death. Significant toxicities were seen: 11 episodes of pneumonia (1 fungal), 4 episodes of herpes zoster (1 grade 3), 4 early episodes of grade 3/4 interstitial pneumonitis, and 1 episode each of grade 4 TTP and grade 3 optic neuritis. One patient developed AML at 4.7 years post-ASCT. Immune recovery has been delayed; at 600 days post ASCT, 16/18 (89%) of evaluable patients had not recovered IgG levels to normal. At baseline, 12/23 patients had detectable markers by PCR analysis (sensitivity 0.01%) for t(14;18) or patient-specific VDJ rearrangements in marrow or blood. Of these, all achieved at least a brief molecular remission in blood and marrow, 11/12 doing so pre-R consolidation. 5/12 patients have since relapsed at a median 3 yrs (2–4.5) post ASCT. Molecular relapse preceded clinical in 3/5 cases. 6/12 have had prolonged (median 4.8 yrs, range 3–5) molecular and clinical remissions. Median event-free survival for all patients is 63 months, with median overall survival not reached.

Conclusions: HDT/ASCT with R for in vivo purging and post-ASCT consolidation for relapsed FL is feasible and associated with prolonged clinical and molecular remission. Delay in recovery of humoral immunity may play a role in the high incidence of infectious complications. A single infusion of Rituximab for in-vivo purging did not eradicate PCR detectable disease in the graft, although sustained molecular remissions of at least 24 months were achieved in 75% of evaluable patients post transplant, possibly due to post ASCT Rituximab consolidation. Whether this translates into survival benefit will require longer follow-up and further comparative studies.