Allogeneic marrow transplantation in patients with acute myeloid leukemia in first remission: a randomized trial of two irradiation regimens [see comments]

Abstract

A randomized trial of 12.0 Gy versus 15.75 Gy of total body irradiation (TBI) was performed in patients with acute myeloid leukemia undergoing allogeneic marrow transplantation while in first complete remission. All patients received 120 mg/kg cyclophosphamide followed by TBI and marrow from HLA-identical siblings. Cyclosporine and methotrexate were used for prophylaxis against acute graft-versus-host disease (GVHD). Thirty-four patients received 2.0-Gy fractions of irradiation daily for 6 days and 37 received 2.25-Gy fractions daily for 7 days. The 3-year actuarial probabilities for relapse-free survival were 0.58 for the patients who received 12.0 Gy and 0.59 for those who received 15.75 Gy. The 3-year probabilities of relapse were 0.35 for the 12.0 Gy group and 0.12 for the 15.75 Gy group (P = .06). The 3-year probabilities of transplant-related mortality were 0.12 and 0.32, respectively (P = .04). The probability of moderate to severe acute GVHD was 0.21 for the 12.0 Gy group and 0.48 for the 15.75 Gy group (P = .02). Patients exposed to the higher irradiation dose received less immunoprophylaxis against, and had a higher incidence of, acute GVHD. The increased dose of TBI significantly reduced the probability of relapse but did not improve survival because of increased mortality from causes other than relapse.

Bone marrow transplantation for chronic myeloid leukaemia: the effects of differing criteria for defining chronic phase on probabilities of survival and relapse

“…The association of advanced leukaemia and the occurrence of severe GVHD has also been reported by Nash et al (1992). Cumulative effects of prior chemotherapy and reduced tolerance of the intensive conditioning regimens used at BMT (Biggs et al, 1992;Bortin et al, 1981;Clift et al, 1987Clift et al, , 1990Clift et al, , 1991Deeg et al, 1991;Nash et al, 1992) may account in part for the severe GVHD seen in patients transplanted for advanced leukaemia.…”

Extreme heterogeneity of myeloablative total body irradiation techniques in clinical practice: A survey of the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation

“…17 Clift et al conducted 2 trials among patients with acute myeloid leukemia and chronic myeloid leukemia, comparing a dose of 12 Gy of TBI with dose-escalated 15.75 Gy TBI. 3,4 In both cases, higher doses were found to be associated with a reduced risk of disease recurrence, although this finding was counterbalanced by a higher incidence of severe or fatal toxicities involving mainly the liver, lungs, and mucosa. Therefore, no effect on the overall survival could be demonstrated.…”

“…1,2 The antineoplastic effect of TBI was documented as dose-dependent with fewer instances of leukemia recurrence after escalated dose treatment. 3,4 In the 1980s, a radiation-free regimen (ie oral busulfan combined with cyclophosphamide) was developed for patients with leukemia. 5,6 However, prospective and retrospective comparisons suggested TBI was a preferable option in this setting.…”

“…[9][10][11] The incidence of nonrecurrence mortality increases with increased doses of TBI. 3,4 Although the delivery of chemotherapy is relatively easy and uniform, applying TBI has many technical and procedural requirements which in turn may be the cause of the significant diversity of the treatment options. Potential heterogeneity may affect the doses used for myeloablative TBI, the method of fractionation, the modes of delivering the dose, the type of immobilization, the methods of dosimetry, and organ shielding.…”

Current Controversies: Which Patients With Acute Myeloid Leukaemia Should Receive A Bone Marrow Transplantation? – An Adult Treater's View

“…The pioneers of transplant technology will have recognized that an important component of the curative mechanism was a graft-versus-leukaemia effect (GVL), and perhaps had little to do with the myeloablative treatment. The fact that the TBI dose has been shown to have an impact on relapse risk, if not on survival, suggests that both play a role (Clift et al, 1990). Early data demonstrating the relationship between relapse risk and the occurrence and severity of acute and ⁄ or chronic graft-versus-host disease (GVHD) supported the concept that the GVL effect played a role (Weiden et al, 1981).…”