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Treatment of relapsing AML following hematopoietic stem cell transplantation

Despite considerable advances realized during the past four decades in the treatment of pediatric acute lymphoblastic leukemia, treating acute myelogenous leukemia (AML) in children remains a considerable challenge. Induction therapy for AML is extremely aggressive yet, partly as a result of considerable toxic mortality, results in remission rates of only 85–92% (1, 2). Pediatric patients with matched sibling donors, except those with more favorable prognosis Down syndrome or acute promyelocytic leukemia, are consolidated with allogeneic stem cell transplant in first complete remission (CR) while the remainder continue with aggressive chemotherapy. Nonetheless, continuous complete remission rates disappoint. The approach to salvage therapy generally involves sibling or unrelated donor transplant for the roughly 80% of patients either declining stem cell transplant (SCT) or without a matched related donor, not transplanted in CR1. Previously transplanted patients, whether in relapse or CR2, represent a greater challenge. Proposed curative options include chemotherapy alone, second stem cell transplant, immunotherapy and more recently, adoptive immunotherapy with donor lymphocyte infusions. Published results frequently conflict and rarely include only pediatric patients. The scant data on the use of chemotherapy alone in post-allogeneic stem cell transplant (SCT) relapse supports the intuitive conclusion that less aggressive cytotoxic therapy cannot salvage resistant disease. Although approximately one third of patients may achieve a second CR, <3% survive 1 yr (3). The results of second allogeneic stem cell transplant in AML are somewhat more encouraging. While most transplant results are reported as part of a larger series, the following data are available: the Seattle group reports a 10% (n 1⁄4 32) disease free survival (DFS) in patients in CR2 who all received total body irradiation (TBI) as conditioning for their first SCT (4); Shing et al. report lengthy second remissions in three of four patients who received TBI as part of the conditioning regimen for their second transplant (5); one of two patients who received busulfan/cyclophosphamide conditioning for a second transplant, described by Chiang et al., survives in CR at 55 months (6); and the Italian group reports 52% DFS for 21 AML patients including eight transplanted in relapse (7). Although it is likely that allogeneic stem cell transplant’s efficacy is at least partly the consequence of graft-provided adoptive immunotherapy, the correlation of clinical graft vs. host disease (GVHD) with DFS is inconsistent. In Seattle DFS was strongly associated with acute GVHD with a relative risk of 0.5 (p 1⁄4 0.0085) (4), yet in the Italian experience, while risk of relapse decreased from 39 to 27% in those with grade II–IV GVHD, event-free survival (EFS) decreased to 27% in the GVHD group compared with 43% in those without GVHD (7). While these data include diagnoses other than AML, the higher failure rate appears to be result from the very high incidence of severe veno-occlusive disease encountered by the Seattle group, supporting the contention of Shing et al. that conditioning including TBI for the first SCT is an adverse prognostic factor. Despite the questionable impact on survival, these data do support the presence of a graft vs. leukemia effect. Thus adoptive immunotherapy may remain the most promising therapy for patients relapsing postSCT (8), if toxicity can be ameliorated. In this issue of Pediatric Transplantation Vettenranta et al. (9) present their early data on the use of adoptive immunotherapy after reinduction chemotherapy for three pediatric patients with AML who relapsed post-allogeneic SCT. They chose the approach of stopping immune suppression (when applicable) and using cytotoxic chemotherapy to reinduce remission in three patients prior to initiating immunotherapy. Pediatr Transplantation 2003: 7: 419–421