Phase II Trial of Busulfan-Based Tandem High-Dose Chemotherapy with Autologous Stem Cell Transplantation Followed By Reduced Intensity Allogeneic Stem Cell Transplantation for Patients with High-Risk Lymphoma

Introduction: Many patients with high-risk lymphoma will experience relapse after autologous stem cell transplantation (AutoSCT).  There are no therapies given to patients in remission after AutoSCT which are of proven benefit.  At time of disease relapse after AutoSCT, patients are often considered for allogeneic stem cell transplantation (AlloSCT) if remission can be achieved by salvage strategies.

Methods: We conducted a phase II clinical trial of tandem AutoSCT followed by reduced intensity conditioning (RIC) AlloSCT for patients with high-risk lymphoma. High-dose chemotherapy was BuCyE: busulfan (11.2 mg/kg IV total), cyclophosphamide (120 mg/kg IV total), and etoposide (30 mg/kg IV total).  RIC AlloSCT was performed any time between 40 days and 6 months after AutoSCT if disease had not progressed.  RIC was busulfan (3.2 mg/kg IV total) with fludarabine (120 mg/kg IV total) with GVHD prophylaxis comprised of tacrolimus, sirolimus, and methotrexate. 

Results: A total of 42 patients were enrolled.  All patients had at least a partial remission to their last therapy.  Eligible patients in the up-front setting included T-cell lymphoma, mantle cell lymphoma, and B-cell lymphoma with concurrent c-MYC and BCL-2 overexpression or translocations.  Other histologies were required to be relapsed / refractory as defined by number of lines of therapy or remission duration < 12 months.  All patients underwent BuCyE AutoSCT.  RIC AlloSCT was performed in 29 patients, 16 from a matched related donor and 13 from a matched unrelated donor. RIC AlloSCT was not performed in 13 patients because of patient choice (n=4), lack of a suitably matched donor (n=2), disease progression (n=6), and therapy-related AML (n=1). There has been no transplant-related mortality from AutoSCT. Of the 29 patients who underwent both HSCT procedures, median time from AutoSCT to AlloSCT was 96 days (range 48-169).  All patients engrafted successfully with day 100 median donor chimerism being 95% (range 85-99).  The 6-month cumulative incidence of grades II-IV acute GVHD was 7% (95% CI, 0.3%, 20%).  Cumulative incidence of chronic GVHD at one year was 36% (17%, 56%).  Non-relapse mortality at one year was 4.6% (0.3%, 20%) with one death from sepsis.  Cumulative incidence of disease relapse was 20% (9%, 33%) for the entire group and 8% (1%, 23%) for patients after AlloSCT.  At a median follow-up after 15.9 months (range, 3.5-36.5) after AutoSCT for the entire group, 1-yr progression-free survival was 77% (60%, 87%) and 1-yr overall survival was 87% (72%, 95%).  For the 28 survivors after AlloSCT, median follow-up is 11.8 months (range, 0.2-33.6), 1-yr PFS is 87% (66%, 96%) and 1-yr OS is 95% (72%, 99%).  

Conclusion: Busulfan based tandem AutoSCT followed by RIC AlloSCT appears safe and effective in patients with high-risk lymphoma.  Prospective trials comparing such a strategy to either AutoSCT or RIC AlloSCT alone in specific lymphoma subtypes are warranted.