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

As the majority of patients with acute myeloid leukaemia (AML) under the age of 60 years enter complete remission (CR) (Zittoun et al, 1995; Hann et al, 1997; Buchner et al, 1999), a top priority is to convert this initial response into cure. In this respect allogeneic transplantation from a matched sibling donor has been a standard approach for the last 20 years. This was followed by a similar enthusiasm for autologous transplantation after pioneering work demonstrated that cryopreserved marrow collected in remission could restore haemopoiesis after total body irradiation (TBI)based myeloablation (Dicke et al, 1979). Several phase 2 and much registry data perpetuated the standing of transplantation as the desired approach to prevent relapse (Burnett et al, 1984; Stewart et al, 1985; Goldstone et al, 1986; Gorin et al, 1990; Lowenberg et al, 1990; Gale et al, 1996). Early comparative studies were rare, but did support the survival benefit of allogeneic bone marrow transplantation (BMT) when compared with contemporarily available chemotherapy (Appelbaum et al, 1988). 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). This tended to be supported by the clinical experience of T-cell depletion, which was highly effective in eliminating GVHD but was associated with an increased relapse risk. In none of these circumstances was the GVL effect as evident in AML as, for example, in chronic myeloid leukaemia (Marmont et al, 1989; Ringden et al, 1996). Further supportive information came from the limited data in identical twin transplants which demonstrated a high relapse rate and was taken to mean that the subclinical GVL effect – unrelated to GVHD – was making a contribution to allogeneic transplant cure. All these observations conditioned the development of autologous transplantation in which it was assumed that, due to the lack of a GVL mechanism, if it was to work then it was most likely to do so as a treatment of minimal disease, i.e. after consolidation had been optimized, rather than to achieve minimal residual disease. This was also partly influenced by the observation from registry data that autografts done early in CR were less effective than if done after 4–6 months, which presumably corresponded with the addition of consolidation chemotherapy (Gorin et al, 1991). As enthusiasm developed for treating all patients with either allogeneic or autologous BMT, there was also the realization that the patients who received the transplant were, because of the time delay, at a reduced risk of relapse. This time-censoring effect called in to question whether there was indeed such a major advantage for transplantation (Gray & Wheatley, 1991; Gale et al, 1999). It was also not appreciated how small a proportion of newly diagnosed patients actually survive to transplantation (Berman et al, 1992). For all these reasons prospective trials were initiated principally to evaluate the role of autologous BMT in first remission against, or in addition to, chemotherapy. Patients were recruited at diagnosis so that the proportion of patients reaching transplant could be defined. This also enabled patients who had a matched sibling donor available to be tracked. They could be compared within the trial by genetic randomization which compared those who had a donor with those who did not, as a surrogate for an intentto-treat analysis.