High Levels of Early Donor Chimerism and Treatment-Responsive Disease Predict Improved Progression-Free Survival Following Non-Myeloablative Transplantation for Advanced CLL.

Abstract CLL remains an incurable disease with standard chemotherapy. Although recent data suggest that CLL can respond to graft vs leukemia effects, myeloablative allogeneic stem cell transplantation is associated with a high transplant-related mortality in this population of older, heavily pretreated patients. We report the outcomes of 50 patients with advanced CLL who underwent NST between January 2001 and August 2004. All patients received fludarabine 30 mg/m2 x 4 days and intravenous busulfan 0.8 mg/kg/d x 4 days. 94% received G-CSF mobilized peripheral blood stem cells while 6% received bone marrow. Graft vs host disease (GVHD) prophylaxis included tacrolimus plus low dose methotrexate (56%) or cyclosporine plus prednisone (30%) based regimens. Most patients had a HLA-matched unrelated donor (62%), 30% a HLA-matched related donor, and 8% a HLA-mismatched donor. The median age of the patients was 53 years (range 35–67), with a median time from diagnosis to NST of 6.4 years (range 0.2–14.7). The patients were heavily pretreated, with a median of 5 prior therapies; 98% of patients had received fludarabine, 96% alkylating agents, 80% rituximab, and 32% alemtuzumab. 22% of patients had relapsed after prior autologous stem cell transplant. Most patients had active disease at time of NST, with only 16% in complete remission and 26% in partial remission. 52% of patients were in active relapse and 6% had failed to respond to any attempted therapy (induction failures). 50% of patients developed grade 4 neutropenia and their median time to neutrophil engraftment was 11.5 days. The incidence of grade 2–4 acute GVHD was 36%, and of chronic extensive GVHD 33%. Eleven of 25 patients (44%) in active relapse or induction failure at time of NST achieved an objective response. The median follow-up of surviving patients is 12.4 months (range 5.6 mos-4.0 yrs), with one-and two-year PFS 38% (95% CI 24–52%) and 28% (13–42%). The one- and two-year OS in this highly refractory population is 59% (95% CI 44–75%) and 48% (31–65%). Patients achieving >75% donor-derived hematopoiesis 1–2 months post-NST had a 30% risk of relapse or death from disease, as compared to 72% for those with lower donor chimerism (p= 0.007). Relapse was the principal cause of treatment failure, resulting in 10 deaths; other deaths were due to infection (n = 5), GVHD (n = 3) and respiratory failure (n = 1). In Cox proportional hazards regression analysis considering pre-transplant parameters such as age, sex mismatch, disease status (CR/PR vs relapse/induction failure), donor type, aGVHD prophylactic regimen and Rai stage, only disease status was an independent risk factor for poor OS (HR 4.7, p= 0.02). Both older age and disease status (HR 2.7, p= 0.02) were associated with poor PFS. Although treatment-responsive disease was the primary predictor of outcome, nonetheless 44% of patients with refractory disease still achieved objective responses after NST. High levels of donor chimerism 1–2 months post-NST were associated with a reduced risk of relapse or death from disease. These results suggest that NST is a reasonable treatment option for patients with advanced CLL, and that strategies to augment donor chimerism early after NST may result in improved long-term outcomes.