Busulfan/Fludarabine/Thymoglobulin as a Reduced Intensity Conditioning Regimen for Lymphoid Malignancies.

Over the last decade there has been an increase in the use of reduced intensity conditioning (RIC) regimens to mitigate transplant related toxicity while maintaining graft viability and maximizing the graft versus disease effect. There is an abundance of data on busulfan (Bu) based RIC for myeloid malignancies; however, there is a paucity of data on Bu based RIC regimen for allografting in lymphoid malignancies. We conducted a retrospective analysis of a large cohort of patients treated at a single institution who were transplanted using a uniform RIC regimen of Bu/Fludarabine (Flu)/Thymoglobulin (Thymo) for a variety of lymphoid neoplasms.

We identified 40 patients (pts) who were transplanted for lymphoid malignancies between 2004 and 2008 using the RIC regimen of Bu 0.8 mg/kg q6 hrs x 8 doses on d-4 and d-3, Flu 30 mg/m2 IV daily on days -7 to -3, and Thymo 2 mg/kg x 4 doses on d-4 to d-1. Graft versus host disease (GVHD) prophylaxis consisted of tacrolimus (0.03 mg/kg starting d-2)/methotrexate (5mg/m2 on d+1, 3, 6, 11)/mycophenolate (15mg/kg bid starting d-2) in 34 pts (85%), tacrolimus/methotrexate in 5 patients (12.5%), cyclosporine/mycophenolate/methotrexate in 1 pt (2.5%). Chimerism analysis was done on days +30, 90, 180, and 365.

Median age was 54 (range 35-65) years; males 26 (65%) and females 14 (35%); CLL/SLL 22 (55%), non-Hodgkins lymphoma 15 (37.5%) and transformed lymphomas 3 (7.5%). Median number of lines of therapy prior to transplant was 4 (range 0-12). 12 pts (30%) were refractory to initial therapy (less than a PR). 15 pts (37.5%) had received prior radiation therapy (XRT). 12 pts (30%) had undergone a prior autologous stem cell transplant (ASCT). 22 pts (55%) had chemo-sensitive disease at the time of transplant, and 18 (45%) had disease refractory to their pre-transplant regimen. The donor was related (RD) in 10 pts (25%) and unrelated (URD) in 30 pts (75%). The graft source was peripheral blood for 36 pts (90%) and bone marrow in 4 pts (10%). Median number of CD34+ cells infused was 7.9×10 6 (range, 1.1-17.9) /kg recipient body wt.

Median time to absolute neutrophil count recovery was 12 (0-21) days. Median time to platelet recovery was 18 days (9-57 days). Median time to 100% donor chimerism was 39 (24-321) days. After a median follow-up of 25.8 (0.87-48.9) months, Kaplan-Meier estimates of median overall survival (OS) and progression-free survival (PFS) were 11.3 months and 9.9 months, respectively. The 2-yr OS and PFS were both 44%. We performed an analysis of the effects of histology, number of lines of prior therapy, prior XRT, prior ASCT, disease status at time of transplant, and graft source (URD vs RD) on OS and PFS (Table 1). Non-relapse mortality (NRM) at 100 days, 1 year, and 2 years was 8% (95% CI, 3-22%), 33% (95% CI, 20-52%), and 41% (95% CI, 26-60%), respectively. Acute GVHD was seen in 19 pts (48%) with Grade III/ IV acute GVHD in 9 pts (23%). Chronic GVHD was seen in 17 pts (43%), limited in 5 pts (13%), extensive in 12 pts (30%). Acute GVHD was more common among pts receiving URD vs RD transplants (35% vs. 13%, p=0.016), but incidence of chronic GVHD did not differ between these two cohorts.

This analysis represents the largest single institution experience using the RIC regimen of Bu/Flu/Thymo in lymphoid malignancies. Our results demonstrate that this Bu based RIC regimen can successfully be used to allograft heavily pre-treated patients with lymphoid malignancies, with prompt and durable engraftment and relatively low early NRM. In this patient population, OS and PFS were not significantly associated with lymphoma histology, prior therapy, or chemosensitivity.

DiPersio:Genzyme Corp.: Honoraria. Vij:Otsuka Pharmaceuticals: Research Funding.