1. Viewpoint: What is the role of allogeneic haematopoietic cell transplantation in the era of reduced-intensity conditioning--is there still an upper age limit? A focus on myeloid neoplasia. Finke J, Nagler A. Leukemia. 2007;21:1357-62.

Allogeneic haematopoietic cell transplantation (HCT) is the most effective curative therapy in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). The incidence of AML and MDS increases with age, peaking in the seventh decade. Despite improved Ara-C and anthracyclin-based chemotherapy regimens, the prognosis of AML in patients beyond 60 years of age is dismal. Reduced-intensity conditioning (RIC) prior to allogeneic stem-cell transplantation makes transplantation in advanced age possible and significantly reduces transplant-related organ toxicity and mortality. The success of RIC HCT relies on the alloreactivity of the donor immune system and the graft-versus-leukemia effect.

Nowadays patients older than 60 years of age are regularly transplanted from related and, increasingly, from unrelated donors. The current upper age of patients undergoing successful allo-HCT, especially with grafts from unrelated donors, is around 75 years of age. Standard high-dose conditioning regimens are applied up to the age of 50-55 years in most centers, with reduced intensity conditioning beyond that age range, and no upper limit for otherwise-fit patients. Owing to the dismal outcome associated with conventional chemotherapies, every patient older than 60 years of age with AML or MDS should be informed about the possibility of allogeneic HCT after reduced intensity conditioning, and donor searches should be initiated as early as possible, for example, at initial diagnosis.

The authors go on to discuss the optimal timing of allogeneic HCT. For example, they state that allogeneic HCT as soon as possible after initial diagnosis of high-risk patients results in a 2-year DFS of 60% when performed in aplasia after induction or first consolidation chemotherapy. A rapid donor search initiated immediately at primary diagnosis is of utmost importance with this approach. The combination of reducing the tumor cell burden by conventional chemotherapy, rapidly followed by additional cell reduction induced by reduced-intensity conditioning appears to be highly effective and should be further explored within current AML trials. The restriction of allogeneic HCT to matched-sibling donor HCT alone is no longer justified with novel, efficient GVHD prophylaxis and improved HLA typing.

Factors that need to be optimized are type of RIC, GVHD prophylaxis as well as pre- and post-transplant measures; strategies are likely to vary from disease to disease. Large scale trials with specific RIC and GVHD prophylaxis protocols for specific diseases and states of remission should be performed.

2. Immune reconstitution after allogeneic stem cell transplantation with reduced-intensity conditioning regimens. Jiménez M, Ercilla G, Martínez C. Leukemia. 2007;21:1628-37.

This article provides an excellent review of the factors that make difficult the comparison between reduced-intensity stem cell transplants (RIC-SCT) and myeloablative conditioning stem cell transplants (MAC-SCT) in regard to immune reconstitution. A theoretical advantage of RIC-SCT is that it might lend to better immune reconstitution after transplantation due to less damage of the thymus, allowing regeneration of naive T cells derived from prethymic donor stem cells, and due to the proliferation of immunologically competent host T cells that survive the conditioning regimen. However, published studies have shown contradictory findings. Several factors contribute to the difficulty of the comparison. So far, no randomized studies are available since RIC-SCT has generally been reserved for elderly patients, patients that have received a previous autologous SCT, or patients with organ dysfunction who are not candidates for MAC regimens. Further, the myelosuppressive and immunosuppressive capacities of diverse RIC regimens vary depending on the protocol and, therefore, their impact on immune reconstitution after transplantation may be different.

The authors first review T-cell reconstitution (methods of analysis of T-cell reconstitution after SCT, thymic-independent T-cell reconstitution, and thymopoiesis after RTIC-SCT), and then review B and NK cell reconstitution, and dendritic cell reconstitution. They then review factors affecting immune reconstitution after RIC-SCT including GVHD, patient's age and chimerism.

The authors conclude by stating that immune reconstitution after RIC-SCT remains a field for debate. The current spectrum of RIC protocols, which vary considerably in myeloablative and immunosuppressive potential, and the absence of randomized studies comparing RIC-SCT to MAC-SCT make it difficult to draw accurate conclusions. Published studies so far suggest that the use of RIC regimens in allogeneic SCT results in significant quantitative and/or qualitative differences in immune reconstitution in comprison with conventional MAC-SCT. Several authors have reported faster recovery of total lymphocytes, memory and naïve CD34+ lymphocytes, and TRECs levels at least during the first months after RIC-SCT. More rapid reconstitution of T-cell repertoire complexity has also been observed. A combination of thymus function preservation and peripheral expansion of donor and residual host mature lymphocytes could explain these results. Despite these differences, infectious complications and relapse remain major causes of morbidity and mortality after RIC-SCT.

3. Reduced-intensity allogeneic stem cell transplantation in adults and children with malignant and nonmalignant diseases: end of the beginning and future challenges. Satwani P, Harrison L, Morris E, Del Toro G, Cairo MS. Biol Blood Marrow Transplant. 2005;11:403-22.

This is a useful review of recent experience of reduced-intensity (RI) allogeneic hematopoietic cell transplantation in adults and children with both malignant and nonmalignant diseases. Although this article does not refer specifically to cord blood transplantation, cord blood transplants have been increasingly performed using RI conditioning regimens (See: Annotated Bibliography IV. Reduced-Intensity and non-myeloablative transplants, i. cord blood transplants.)

Reduced-intensity transplantation allegedly eradicates malignant cells through a graft-versus-leukemia/graft-versus-tumor effect provided by alloreactive donor T lymphocytes, natural killer cells, or both. Various studies have clearly demonstrated a graft-versus-leukemia/graft-versus-tumor effect in hematologic malignancies and solid tumors. Acute short-term toxicity, including infection and organ decompensation after myeloablative conditioning therapy, can result in a significant incidence of early transplant-related mortality. More importantly, long-term late effects-including growth retardation, infertility, and secondary malignancies-are major complications after myeloablative conditioning therapy, especially in vulnerable children, who are more susceptible to these complications.

Recent results comparing RI conditioning with myeloablative conditioning followed by HLA-matched sibling transplantation have demonstrated a significant reduction in use of blood products, risk of infections, transplant-related mortality, length of hospitalization, and feasibility of conditioning therapy in outpatient settings. Despite such success, large prospective randomized multicenter studies are necessary to define the appropriate patient population, optimal conditioning regimens and pretransplantation immunosuppression, role of donor lymphocyte infusions, duration of hospitalization, overall survival, cost-benefit ratio, and differences in long-term effects to evaluate the role of RI allogeneic hematopoietic cell transplantation more fully.