Abstract
A graft-versus-leukemia/lymphoma (GVL) effect after allografting has been documented for advanced or refractory indolent B cell Non-Hodgkin’s lymphoma (NHL), mantle cell lymphoma (MCL), and chronic lymphocytic leukemia (CLL). However, widespread application of allografting in these patients has been limited by lack of suitable donors as well as high transplant-related mortality (TRM) when conventional myeloablative conditioning is used. NMA conditioning is associated with reduced TRM and has been successful in patients with these B cell lymphoid malignancies transplanted with HLA-matched sibling donors. Therefore, to extend access to transplant, we evaluated the effectiveness of NMA conditioning followed by unrelated donor UCB transplantation (UCBT) in patients with these diseases. Patients received 50 mg/kg cyclophosphamide, 200 mg/m2 fludarabine and 200 cGy TBI with cyclosporine and mycophenolate mofetil immunosuppression. Sixteen patients with advanced or refractory follicular NHL (n=7), MCL (n=3), or CLL (n=6) were transplanted between 10/3/2001 and 11/30/2004. Median patient age was 51 years (range, 37–67) and weight was 81 kg (range, 60–102). Patients received single (n=4) or double unit (n=12) 4–6/6 HLA-matched (intermediate resolution DNA typing at HLA-A and B; high resolution HLA-DRB1) UCB grafts with a median infused cell dose of 3.5 x 107 NC/kg (range, 2.6–4.6) and 5.0 x 107 CD34+ cells/kg (range, 2.6–14.3). Cumulative incidence of sustained donor engraftment was 81% (95%CI: 62–100) with a median day of neutrophil recovery of 8 days (range, 5–30). Two of the 3 patients with failure of donor engraftment had received only a single cycle of CVP chemotherapy immediately prior to UCBT. Twelve patients had grade 2–4 acute graft-versus-host disease (GVHD) (9 grade 2, 2 grade 3, and 1 grade 4) for a cumulative incidence of 75% (95%CI: 49–100) by day 100, while 6 patients had extensive chronic GVHD for a cumulative incidence of 39% (95%CI: 14–64) by 1 year. The cumulative incidence of TRM at 6 months was 6% (95%CI: 0–17). At a median follow-up of 22 months (range 7–42), 4 patients (3 follicular NHL, 1 CLL) have died (3 with progressive disease and 1 with infection) whereas 12 are alive in complete remission with a probability of progression-free survival of 63% (95%CI: 49–87) at 1 year. Two follicular NHL patients, both refractory to rituximab pre-transplant, required the addition of rituximab post-transplant to achieve sustained remission. Also, 2 of 3 patients (both with CLL) who had transient donor engraftment but subsequent autologous recovery are in remission at 14 and 15 months after UCBT, respectively. In conclusion, these preliminary results suggest that UCBT after NMA conditioning is an effective treatment for B cell lymphoid malignancies in adults with a low rate of TRM. Based on these data, and data in other patients undergoing NMA transplantation, therapy immediately prior to UCBT is likely an important factor in donor engraftment. A GVL effect is suggested and may be augmented by the addition of rituximab. This strategy extends treatment options for patients with advanced or refractory follicular NHL, mantle cell NHL, and CLL who are otherwise fit and warrants further investigation. Finally, given the low TRM, patient referral prior to the development of refractory disease should be strongly considered and may further improve outcomes.
The biology behind B-cell lymphoma 2 as a target in chronic lymphocytic leukemia
