The evolution of hematopoietic SCT in myelodysplastic syndrome

Abstract

Allogeneic hematopoietic SCT (allo-HCT) is the only curative therapy for myelodysplastic syndrome (MDS). Numerous myeloablative (MA), nonmyeloablative SCT (NST) and reduced conditioning transplant (RIC) studies have included MDS patients. Twenty-four MA HCT studies published from 2000 and 2008 reported OS and disease-free survival (DFS) ranging from 25 and 16% at 2 years to 52 and 50% at 4 years. In these publications, the incidence of grades II-IV acute GVHD was 18-100%, chronic GVHD 13-88%, relapse risk 24% at 1 year to 54.5% at 4 years and TRM 19% at day 100 to 61% at 5 years. From 2003 to 2008, 30 publications combining RIC and NST reported OS and DFS from 22 and 20% at 2 years to 79 and 79% at 4 years. Incidence of grades II-IV acute GVHD ranged from 9 to 63%, chronic GVHD 18 to 80%, relapse risk 6 to 61% and TRM 0% at day 100 to 34% at 5 years. The wide range in the published results leaves many unanswered questions. Although no ideal transplant conditioning has emerged, many of the MA and RIC studies used BU-based regimens and used a recipient age cutoff of 50-55 years for MA HCT. Similarly, there is no agreement on the use of induction or hypomethylating therapy before HCT, but azacitidine and decitabine are gaining increasing attention as a bridge to HCT. Until recently, the International Prognostic Scoring System (IPSS) dictated the use and timing of HCT. The WHO classification and WHO Prognostic Scoring System (WPSS) may be better suited in predicting the outcomes and should probably be incorporated in transplant algorithms. Most published MDS transplant series combine matched related donors (MRD) and matched unrelated donors (MUD). Umbilical cord blood (UCB) grafts will likely broaden the population of MDS patients eligible for allografting, but outcome data for MDS are scant. At this time, it is reasonable to consider the availability of an MRD or MUD as separate from an UCB graft in the decision of transplantation for MDS. The development of RIC, improvements in supportive therapy and alternative donor selection will provide better OS for MDS patients undergoing transplantation. Simultaneously, better understanding and medical therapy of MDS are leading us to re-examine patient selection and the timing of HCT. The results of HCT for MDS continue to improve together with the outlook of patients afflicted with myelodysplasia.

Feasibility of hypomethylating agents followed by allogeneic hematopoietic cell transplantation in patients with myelodysplastic syndrome

“…HMT can also increase the rates of GVHD and other complications such as infection, contributing to increased treatment-related mortality rate. 21 We observed a treatment-related mortality rate of 11%, similar to previously reported rates, 12 which was even lower than our previously reported one among patients who did not receive HMT before alloHCT. 24 Our findings thus indicate that pre-transplant HMT did not adversely affect post-alloHCT outcomes.…”

“…12 As induction therapy, HMT before alloHCT can increase the risk of death or prevent proceeding to alloHCT owing to associated toxicities. HMT can also increase the rates of GVHD and other complications such as infection, contributing to increased treatment-related mortality rate.…”

“…11 Because alloHCT remains the only curative therapy for MDS, new treatment modalities such as hypomethylating agents (HMA) may be used as a bridge to more definitive therapy to improve the outcome of alloHCT, although the appropriate HMA dose and schedule before alloHCT have not yet been determined. 12 Several hypotheses have been advanced as rationales for bridging therapy to alloHCT. AZA and DEC inhibition of DNA methyltransferase is thought to be responsible for the hypomethylation and reactivation of tumor suppressor genes, inducing the terminal differentiation and apoptosis of neoplastic cells, which may contribute to improvements in alloHCT outcome by a reduction in tumor burden.…”

Reduced DNAM-1 expression on bone marrow NK cells associated with impaired killing of CD34+ blasts in myelodysplastic syndrome

“…7 Recent evidence suggest that natural killer (NK) cells may contribute to the graft-versus-leukemia effect observed in AML patients following haploidentical stem-cell transplantation. 8 Moreover, adoptive transfer of haploidentical NK cells into patients with refractory AML can induce complete remission in a fraction of the patients.…”

Epigenetics in Cancer: The Myelodysplastic Syndrome as a Model to Study Epigenetic Alterations as Diagnostic and Prognostic Biomarkers

“…In more advanced MDS subtypes (RAEB, RAEB-t), in some cases, it has been used the chemotherapy. The allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative therapeutic option for patients with MDS, however, its use is limited to patients up to 55 years old and patients who have histocompatible donors (Giralt et al, 2005;Kindwall-Keller & Isola, 2009). For children with MDS, allogeneic HSCT is considered as the best treatment option (Niemeyer & Kratz, 2008).…”