STEM CELL TRANSPLANTATION Current update on reduced intensity regimens for allogeneic stem cell transplantation

Beside chemotherapy, immunotherapy represents an approach based on the more or less specific recognition of tumoral cells. Allogeneic stem cell transplantation (ASCT) has been used now for more than 3 decades in the treatment of malignant hemopathies. Several lines of evidence could show that donorderived immuno-competent effectors can exert a potent long lasting graft-versus-tumor activity. Today, this approach represents the most efficient and the most widely form of immunotherapy used worldwide. However allogeneic transplantation suffers from major weakness: Despite a common HLA identity between matched donor and recipient, the allogeneic recognition of some normal tissues, expressing epithelial antigens, is associated with a high rate of morbidity and mortality. Usually, the indications of allogeneic transplantation are still limited to the youngest patients (age under 45 or 50). Because of its high toxicity, ASCT has also been limited for years to diseases for which a potent antitumoral effect had been documented in the early years. Interestingly, the world experience of this approach in malignant diseases relies mainly on patients with leukemia (chronic or acute) and younger than 50 years which represent only a part of the wide spectrum of cancer population. Given the strength and curative potential of allogeneic transplantation, new strategies aiming to widen the use of this approach to other cancers, were urgently needed. On these bases, we and others started by the end of the 90s to develop new approaches that would allow overcoming the above cited limitations: The first step has been the switch from bone marrow to peripheral blood stem cells (PBSC) as source of graft [1]. We established that PBSC transplantation is associated with a quicker hematological recovery, lower transplant-related cost and identical incidence acute GVHD in comparison to bone marrow, despite a higher number of immunocompetent cells infused [1]. However chronic GVHD appears to be more frequent and severe [1,2]. The second step considered the preparative or so-called conditioning regimen. While it has been postulated for many years that transplant conditioning has to be myeloablative to allow long-term engraftment of allogeneic cells, different investigators succeeded to perform allogeneic transplantation after a non-myeloablative (NMA) or reduced intensity regimens (RIC) (Storb, 1997 #545) [3,4]. Early after the first reports, we started to develop our own strategy using a combination of fludarabine, low dose busulfan and anti-thymocyte globulin (ATG), as initially described by Slavin et al. Our initial work was focused on the optimization aspects [5,6]. We have now in hands a well defined platform allowing rapid engraftment, lower supportive care [7], low transplant related-infections [8] and mortality while preserving a high anti-tumor effect [5]. Simultaneously, we investigated the applicability of this strategy to new populations of cancer patients. We could confirm the feasibility in older populations essentially between 50 and 55 years [5], and participated to the demonstration of its activity in non-leukemic malignancies such as multiple myeloma (MM) [9], ovarian carcinoma [10] and different other metastatic solid tumors [11]. These clinical achievements leaded us to some important biological observations related to post-graft anti-infectious activity [8], some aspects of the GVHD reaction [12] and to study post graft immune reconstitution [13 /15] Presently, with the dramatic reduction of transplant-related mortality, ASCT has probably entered the era of global immunotherapy applicable to the largest number of patients. Despite these tremendous