The hope and the reality of reduced intensity transplants in children with malignant diseases

Abstract

Summary:Reduced intensity preparative regimens are increasingly used for conditioning prior to allogeneic stem cell transplantation. As opposed to classical methods of pretransplant conditioning, patients receive predominantly immunosuppressive therapies that facilitate early engraftment, while cells within the graft itself promote continuation of the engraftment process. Despite early hopes that this form of transplant would be devoid of grade III and IV acute toxicities, there is a substantial amount of shortterm morbidity associated with the technique. Although long-term follow-up is not yet available, it is hoped that these regimens will spare young patients many of the late effects (cataracts, growth retardation, endocrine and reproductive problems) that are often associated with classical pre-transplant conditioning regimens. Reliable engraftment and leukemic control have been demonstrated in a large number of both adult and pediatric transplant recipients of these regimens, many of whom were deemed at high risk for standard conditioning because of serious co-morbidities, previous autologous transplantation or multiply relapsed disease. A brief review of the state of the art of this technology as it applies to pediatric transplantation is presented. Preliminary results of a survey of pediatric transplant centers indicate that a variety of protocols are used for a variety of indications. The use of standardized criteria for implementation of reduced intensity preparative regimens, the use of a limited number of regimens, and more extensive data collection will permit the elaboration of prospective comparative studies of this new and exciting modality. Bone Marrow Transplantation (2005) 35, S39-S43.

Treosulfan-based preparative regimens for allo-HSCT in childhood hematological malignancies: a retrospective study on behalf of the EBMT pediatric diseases working party

“…Thus, the early organ toxicity of TREO-prep-reg observed in the studied high-risk population seems to be comparable with that of RIC. 4,[35][36][37] Prompt myeloid engraftment was achieved in 94% of patients, which is comparable with the engraftment rate observed after standard-prep-reg, and remains in accordance with results reported in adults. 7,24,25 In contrast to this, RIC consisting of BU 8 mg/kg plus fludarabine and ATG, used in children with malignant and nonmalignant disorders, resulted in an engraftment rate of only 80%.…”

“…43,46,49,50 The significant anti-leukemic effect of TREO-based conditioning regimens along with their low toxicity, makes them also an attractive alternative to RIC regimens, especially for patients with high-risk hematological malignancies, in whom relapse remains the most common obstacle to a successful outcome of RIC. 4,[35][36][37] However, as a prodrug nonenzymatically activated to alkylating mono-and diepoxides, TREO demonstrates gonadotoxicity and mutagenicity, and thus monitoring and evaluation of its long-term effects, including secondary MDS in children demonstrating mixed chimerism, will be of special importance in children conditioned for HSCT with high-dose TREO.…”

Pediatric acute myeloid leukemia: towards high-quality cure of all patients

“…This has major limitations in children because of its side-effects. 137 A similar immunologic approach can be tried in patients who show increasing mixed chimerism in the post-allo-SCT setting. These patients experience a poor outcome, but early immunologic intervention with donor lymphocyte infusions and rapid tapering of immunosuppresion was able to rescue some patients.…”

Assessing the risk of transplant-related complications and individually tailoring the HSCT procedure in children and adolescents—is it possible?

“…However, specific data on RICs in children with refractory leukaemia are not currently available. 74 The most common indications for RIC in children include Fanconi anaemia, severe aplastic anaemia and severe combined immunodeficiency. Del Toro et al 75 reported that grades 3 or 4 nonhaematologic toxicity and several severe infections were observed in 21 children who had been transplanted for malignant and nonmalignant disease.…”