Sequential Myeloablative Autologous Stem Cell Transplantation and Reduced Intensity Allogeneic Stem Cell Transplantation in Children, Adolescents and Young Adults with Poor Risk Refractory or Recurrent Hodgkin (HL) and Non-Hodgkin Lymphoma (NHL)

The outcome of newly diagnosed children, adolescents and young adults (CAYA) with lymphoma has improved significantly over the past 30 years. However, for patients with poor-risk recurrent/refractory lymphoma, outcomes are still dismal (<30%) despite intensive salvage therapy with myeloablative conditioning and autologous stem cell transplantation (MAC AutoSCT) [Bradley/ Cairo, et al. BMT, 2008]. To address this problem, we designed a stem cell transplantation approach to maximize an allogeneic graft versus lymphoma effect in the setting of low disease burden (Cairo et al. BBMT, 2013). We conducted a multi-center prospective study of MAC-AutoSCT, followed by a reduced intensity conditioning and allogeneic hematopoietic stem cell transplant (RIC-AlloHSCT) in selected poor-risk CAYA, with refractory or recurrent HL and NHL. Eligible patients with HD had primary induction failure, early relapse (<12 months off therapy, excluding patients with no prior therapy or radiation only), or late relapse (>12 months off therapy, limited to patients with stage III/IV disease and/or B symptoms at relapse). Eligible patients with NHL had primary induction failure or were in first, second, or third relapse. Conditioning for MAC-AutoSCT consisted of carmustine/etoposide/cyclophosphamide (Harris/Cairo et al. BBMT, 2011). The RIC regimen prior to AlloHSCT consisted of busulfan/fludarabine (Satwani/Cairo et al. BBMT, 2013). Thirty patients (16 HL and 14 NHL), median age of 16yrs and median follow-up of 5yrs, were entered on study.  Twenty three patients completed both MAC-AutoSCT and RIC-AlloHSCT. Allogeneic sources included unrelated cord blood (n=9), unrelated donor (n=8) and matched sibling donor (n=6). Following RIC-AlloHSCT (n=23), the incidence of grade II-IV aGvHD was 21.74% and the probability of cGvHD was 13%. The incidence of transplant related mortality following RIC-AlloHSCT was 12%. The 10 year event free survival (EFS) following sequential MAC-AutoSCT and RIC-AlloHSCT (n=23) was 64.0% (95% CI: 46.7%-87.7%); EFS for patients with HL and NHL was 59.8% (95% CI: 37.8%-94.7%) and 70% (95%CI: 46.7%-100%) (p=0.613), respectively. Comparing primary refractory and relapsed lymphoma patients undergoing tandem transplant, the 10 year EFS for patients with refractory disease vs. relapse with stage III-IV disease vs. relapse with stage II disease was 71% vs. 60% vs. 66%, respectively. In summary, this novel approach of MAC-AutoSCT followed by RIC-AlloHSCT in CAYA patients with poor risk lymphoma is feasible and safe. The long-term EFS with this approach is encouraging considering the poor-risk patient characteristics and the use of unrelated donors for RIC-AlloHSCT in the majority of cases.