Non‐myeloablative stem cell transplants

Background Despite 30 years of steady progress in allogeneic stem cell transplantation (SCT), the complications following the procedure still largely limit its application to recipients less than 60 years of age with an HLA-identical donor. These hazards restrict allogeneic SCT to situations where the alternative to the transplant is death from progression of the malignancy or (in the case of non-malignant diseases) an unacceptable quality of life. Transplant-related mortality (TRM) is due in part to the side-effects of the myeloablative preparative regimen and in part to the consequence of transplanting a donor immune system, namely graft-versushost disease (GVHD), and delayed recovery of cell-mediated immunity. Despite its limitations, allogeneic SCT remains a valuable treatment because it can exert a unique and potentially curative graft-versus-leukaemia (GVL) effect (reviewed in Barrett & Malkovska, 1996). In the last decade, there has been a growing realization that the GVL effect, mediated through an alloresponse of donor lymphocytes, makes a major contribution to the cure of haematological malignancies (Horowitz et al, 1990). Indeed, donor lymphocyte infusions (DLI) alone can induce permanent remissions in patients with leukaemia relapsing after allogeneic bone marrow transplants (BMT) (Kolb et al, 1995). To exploit the GVL potential of allogeneic SCT, while improving the safety of the procedure, three strategies have been developed: (i) use of reduced intensity preparative regimens, (ii) induction of tolerance between the host and the donor immune systems by creating a mixed chimaeric state after transplant and (iii) optimizing the GVL effect by increasing the speed and completeness of donor immune recovery. These approaches are collectively grouped under the term `non-myeloablative stem cell transplants' (NSTs), or more colloquially `minitransplants'. In the last few years, the number of transplants prepared with low-intensity regimens has grown rapidly. Although the concept is relatively new, it is clear that NST have already revolutionized transplant thinking and promise to reshape the indications for allogeneic SCT (allo-SCT) by greatly extending the range of conditions that can be safely treated. Here, we discuss the rationale for NST, the engraftment kinetics, clinical results, current indications and future developments in this exciting new field. Development of NST Clinical approaches to NST are shaped by two concepts. First, low-intensity preparative regimens can be expected to have low regimen-related mortality making allo-SCT safer and extending its use to older or debilitated individuals. Second, these preparative regimens coupled with post-transplant immune manipulation can be used to optimize immune recovery and create a controlled mixed chimaeric state, thereby inducing tolerance to prevent graft rejection and GVHD. The principles on which NST are based are summarized in Table I. Decreasing the intensity of the preparative regimen. NSTs represent a change of emphasis, arising from the perception that the GVL effect may alone be sufficient to cure some haematological malignancies and that a reduction in preparative regimen intensity could improve the outcome in patients at high risk of dying from transplant-related causes (reviewed by Champlin et al, 1999). At the MD Anderson Cancer Center, Giralt et al (1997) exploited the immunosuppressive and chemotherapeutic properties of purine analogues [2-chlordeoxyadenine (2-CDA) or fludarabine] in conjunction with cytosine arabinoside or idarubicin as low-intensity preparative regimens for older or debilitated patients with advanced or refractory acute myeloid leukaemia (AML) or myelodysplastic syndrome (MDS). Subsequently, the same group reported the use of low doses of fludarabine and cyclophosphamide in a preparative regimen for older and debilitated patients with chronic lymphocytic leukaemia (CLL) and non-Hodgkin's lymphoma (Khouri et al, 1998). These regimens were considered non-myeloablative because they were of equal intensity to standard chemotherapy treatment not requiring stem cell rescue. Slavin et al (1998a) in Jerusalem pioneered low-dose busulphan (8 mg/kg), fludarabine and antithymocyte globulin (ATG) in somewhat younger individuals with malignant or non-malignant haematological diseases. Their intention was to create a transplant technique that would ensure engraftment, confer an anti-malignancy effect through GVL and have low overall toxicity. To boost engraftment, they gave DLI to patients who had persisting low levels of donor chimaerism after transplant. Although the use of busulphan renders the regimen more intensive, the protocol can be considered non-myeloablative because thalassaemia transplant recipients who have received similar doses of busulphan have had high rates of autologous recovery (Barrett et al, 1989). Optimizing donor immune recovery. We designed a NST regimen to (i) establish full donor T-cell engraftment, (ii) optimize the graft-versus-malignancy effect by using shortterm immunosuppression after transplant, (iii) use the graft-versus-marrow effect to achieve full donor marrow British Journal of Haematology, 2000, 111, 6±17