Disease recurrence is a devastating event after allogeneic hematopoietic stem cell transplantation as treatment for acute myeloid leukemia (AML). Median time to relapse is approximately 4 months and the majority of relapses occur within 2 years after transplant. The prognosis is usually poor. Overall 5-year survival of all patients relapsing post-transplant for AML or myelodysplastic syndrome (MDS) is about 5%. However, selected patients can respond to further treatment, and a substantial minority can still achieve a durable remission, usually after a second allogeneic transplant or donor lymphocyte infusion.
Relapse Considerations
Relapse generally results from residual malignant cells that survive the preparative regimen and are not eliminated by the graft-vs-leukemia effect. In a minority of patients, relapse appears to occur in donor-derived cells. Relapse may occur by immune escape from graft-vs-leukemia effects. This may be due to loss of expression of leukemia related antigens; one case was reported associated with loss of expression of an HLA haplotype by deletion of chromosome 6. Another mechanism of immune escape is development of tolerance in donor-derived T cells post-transplant.
Duration of remission after hematopoietic stem cell transplantation is an important predictor of survival after recurrence; the best results occur in patients with remission duration greater than 6 months. Patients may respond to salvage chemotherapy, particularly if they had chemosensitive disease before the initial transplant. Reported adverse prognostic factors include receiving the initial transplant while in relapse, having poor cytogenetic and molecular markers, and receiving transplants from alternative donors.
Treatment of Recurrence
Chemotherapy alone generally produces only short-term responses in patients relapsing post-transplant, and the best results have been achieved when a donor lymphocyte infusion or a second allogeneic transplant is performed to consolidate a chemotherapy-induced response. Results are very dependent on patient selection. Second hematopoietic transplants can induce durable complete remission in a fraction of AML/MDS patients with relapse post-transplant. Best results have occurred for patients in morphologic complete remission (or minimal disease state) prior to the second transplant; 20% to 30% of patients can achieve long-term survival in this setting.
Since much of the benefit of allogeneic hematopoietic transplantation is related to the immune graft-vs-leukemia effect, there has been speculation that use of a different donor might improve the outcome of a second transplant. This concept was tested in the study by Christopeit et al on behalf of the German Registry for Stem Cell Transplantation, recently published in the Journal of Clinical Oncology. They examined the results of second transplants for patients with relapsed acute leukemia, comparing the results using the same or an alternative donor. They could not demonstrate an advantage for using a different donor for the second transplant. Second transplants from a related donor had a better outcome than those from an unrelated donor.
Conclusion
Relapse of AML following an allogeneic hematopoietic transplant is an ominous event with a generally poor prognosis. Selected patients may respond to additional salvage chemotherapy. Approximately 20% of patients who respond to further chemotherapy achieve long-term remissions with a second transplant or with intensive chemotherapy followed by a donor lymphocyte infusion, particularly those who had a prolonged disease-free interval after the first transplant. There is no apparent advantage in selecting a different donor for the second transplant. ■
Dr. Champlin is Chair and Professor of Medicine, Department of Stem Cell Transplantation and Cellular Therapy, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston.
Disclosure: Dr. Champlin reported no potential conflicts of interest.
