The optimal RIC regimen for NMA-PBSCT remains unclear. We designed a phase I/II trial of 2-CDA, TT and rATG to combine the favorable immunosuppressive and myelosuppressive properties of these agents. The starting doses were 2-CDA 5mg/m2/day IV for 5 days, days -10 to -6, TT 200 mg/m2/day IV for 3 days, days -5 to -3, and rATG (Thymoglobulin) 3 mg/kg/day, day -5 only. Post-transplant immunosuppression was with cyclosporine alone. The trial was initially designed to give the rATG only if the absolute lymphocyte count on day -5 was >200/L, but was later amended to give one dose of rATG to all patients (pts). All pts received PBSC from an HLA matched family member. Two pts were initially treated at the dose levels above, but received 2-CDA and TT only without rATG. They both experienced severe dose limiting toxicities (DLT), so the dose of TT was de-escalated to 133 mg/m2/day for 3 days in the same schedule as above. The subsequent 10 pts were treated on this schedule and all received one dose of rATG on day -5. Only 2 of the first 6 pts at this dose level developed DLT, defined as grade 2 or 3 toxicity on the Bearman scale depending on the particular organ, leading us to accept this as the dose level for the phase II part of the study. The 10 pts treated at the phase II dose included 2 pts with mantle cell lymphoma, 5 pts with myeloma, 2 pts with high risk AML in first remission and one pt with recurrent low grade non-Hodgkins lymphoma. The median age of the phase II pts was 48 years (range, 35-63) with 5 males and 5 females. Four pts had had prior autologous PBSCT. All pts achieved the primary endpoint of >20% donor chimerism (dc) by day +30 with a median dc of 95% (range 30-100%). The median time to neutrophils >0.5x109/L was 17 days (range 10-36) and to platelets >50x109/L was 20 days (range 11-not achieved). One myeloma pt engrafted initially, but then rejected by day +48 and received a second NMA-PBSCT (same donor), but died of infection and GVHD on day +108 of the second BMT. A second pt with mantle cell lymphoma developed grade III acute GVHD of the skin and gut and CMV colitis and died on day +132 from pulmonary aspergillosis. A third pt died of relapsed myeloma, day +200. Three pts with myeloma have progressed and received donor lymphocyte infusions with one responder. The other 4 pts are alive, well and disease-free (2 with high risk AML in first remission, one with mantle cell lymphoma who was in fourth PR and had had a prior autologous PBSCT and one with recurrent low grade lymphoma) with a median follow-up of 10 months (range, 3-24). Only one of the 10 pts treated on the phase II portion of the study developed grade II-IV acute GVHD. Two survivors have evidence of chronic GVHD that is not requiring treatment. One pt developed non-infectious interstitial pneumonia 7 mos post-BMT and responded to Enbrel therapy. Overall median follow-up for the phase II pts is 10 months (range 3-24 months). Day + 100 treatment-related mortality (TRM) is 0% and one year TRM to date is 20%. We conclude that this reduced intensity conditioning regimen of 2-CDA, TT and rATG achieves good donor chimerism with acceptable toxicity.
Full conference title:
American Society of Hematology 45th Annual Meeting
- ASH 45th (2003)