4. Umbilical cord blood transplantation after a non-myeloablative therapy in high risk adults and adolescents

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Bone marrow transplantation (BMT) in adults is associated with a high risk of graft-versus-host disease (GVHD), opportunistic infection and regimen related toxicity. For these reason, umbilical cord blood (UCB) after a non myeloablative preparative regimen has been explored. The underlying hypothesis is that umbilical cord blood T cells will be sufficiently alloreactive to effect engraftment in the non myeloablative setting. Fifty-one adults with advanced hematologic malignancies [median age 49 years (range 19-60)], ineligible for myeloablative conditioning by virtue of advanced age (73%), extensive prior therapy (42%) or serious co-morbidities/poor fitness (31%) received UCB transplantation (UCBT) after cyclophosphamide 50 mg/kg, fludarabine 200 mg/m², and 200 cGy TBI. Immunosuppression was with cyclosporine-A to at least day 100 and mycophenolate mofetil to day 30. Patients with no combination chemotherapy in the 6 months prior to transplant also received ATG during conditioning. Approximately 1/4 received single and 3/4 received double UCB grafts. Units were predominantly 1-2 antigen HLA mismatched with the recipient. The incidence of sustained neutrophil engraftment of donor origin was 89% (95% CI, 81-97) at a median of 8 days (range 5-32). Stratified into those with and without chemotherapy in the prior 4 months, the cumulative incidence of sustained donor engraftment was 98% (95% CI: 94-100) and 64% (95% CI, 39-89) (p = 0.03). The incidence of platelet recovery (50,000/μL) was 68% (95% CI, 53-83). The incidences of grade II-IV and grade III-IV acute GVHD were 63% (95% CI: 49-73) and 25% (95% CI: 14-36) at day 100, and chronic GVHD was 28% (95% CI: 16-40) at 1 year. TRM was 19% (95% CI: 9-29) at day 180. Regression of relapsed or persistent disease has been seen in patients with myelodysplasia and intermediate and low grade lymphoid malignancies. The probability of overall survival at 1 year is 44% (95% CI: 30-58). Notably, only fitness and not age was associated with poor outcome. These data suggest that the regimen is well tolerated and sufficient for engraftment particularly in patients with chemotherapy in the preceding 4 months. This approach extends access to transplant to many adults who would otherwise be ineligible based on lack of donor and/or inability to tolerate high-dose conditioning.