The combined effect of total body irradiation (TBI) and cyclosporin A (CyA) on the risk of relapse in patients with acute myeloid leukaemia undergoing allogeneic bone marrow transplantation

Abstract

One hundred and fifty acute myeloid leukaemia (AML) patients in first remission received an allogeneic bone marrow transplant (BMT), after conditioning with cyclophosphamide 120 mg/kg and total body irradiation (TBI) 3.3 Gy x 3 (total nominal dose 9.9). The received dose, as recorded by thermoluminescent dosimeters, ranged between 7. 83 and 12.25 Gy. Patients who received TBI < 9.9 Gy (n = 34) had a significantly higher relapse rate when compared with patients receiving >/= 9.9 Gy (n = 116) (43% vs. 19%; P = 0.002). Graft versus host disease (GvHD) prophylaxis consisted of cyclosporin A (CyA) with or without methotrexate (MTX). The dose of CyA was either 1 or 5 mg/kg/day i.v. from day -1 to + 20, then 10 mg/kg/day orally until day + 365. Patients receiving 5 mg/kg CyA (n = 40) had a higher risk of relapse (49% vs. 15%; P = 0.0001). Thus, low-dose TBI (< 9.9 Gy) and high-dose CyA (5 mg/kg) were significant predictors of leukaemia relapse. Patients were then divided into three groups: those who had both negative predictors (< 9.9 Gy TBI and 5 mg/kg CyA; n = 26); those who had only one (either < 9.9 Gy TBI or 5 mg/kg CyA; n = 22); and those who had neither (>/= 9.9 Gy TBI and 1 mg/kg CyA; n = 102). The three groups were comparable for FAB subtype, interval diagnosis transplant and age. The 5-year actuarial relapse rate for these three groups of patients was 49%, 41% and 15%, with no difference between the first two and a significant difference when compared with the latter (P < 0.01). These data indicate that acute myeloid leukaemia can be cured with allogeneic bone marrow transplantation given an intensive conditioning regimen and low-dose immunosuppression post-graft. Either alone is insufficient to produce long-term disease-free survival. These results may be relevant for programmes of reduced intensity conditioning designed for patients with acute leukaemia.

Fludarabine and melphalan-based conditioning for patients with advanced hematological malignancies relapsing after a previous hematopoietic stem cell transplant

“…[6][7][8]31 This low intensity conditioning regimen by itself, while having some antileukemic activity, is unlikely to sustain a remission in patients with advanced AML, as has been suggested previously by de Lima et al 31 Others have also suggested that employing a less intensive pretransplant conditioning may increase the risk of relapse in patients with AML. 32 Four of the five patients who suffered relapse never developed acute or chronic GVHD prior to the onset of relapse. In contrast, three of the four patients who maintained remission for at least 5 months following transplant developed chronic GVHD.…”

Full-intensity and reduced-intensity allogeneic stem cell transplantation in AML

“…29 Remarkably reducing the cyclosporin A (CsA) dose administered in the first 20 days post transplant is sufficient to reduce the relapse rate by more than 30%. 30,31 However, exploitation of a GVL effect-an approach which can bypass the intracellular mechanisms of drug resistance which characterize adult AML-has been hampered by the risk of attendant severe GVHD.…”

HLA-identical haematopoietic stem cell transplantation for acute leukaemia in children: less relapse with higher biologically effective dose of TBI

“…A similar TBI dose-related effect on relapse was seen for adults with AML in first CR (CR1) 15,16 and with ALL. 17 Another possibly important variable with respect to the occurrence of relapse is the so-called 'GVL effect'.…”