Cytogenetics, Donor Type, and Use of Hypomethylating Agents in Myelodysplastic Syndrome with Allogeneic Stem Cell Transplantation

Abstract

We investigated the impact of patient and disease characteristics including cytogenetics, previous therapy and depth of response on the outcome of allogeneic hematopoietic stem cell transplantation (HSCT) on myelodysplastic syndrome (MDS). We analyzed 256 MDS patients transplanted from a matched related (n = 133) or matched unrelated (n=123) donor after 2001. Of 256, 78 (30.5%) did not receive cytoreductive therapy before HSCT; 40 (15.6%) received chemotherapy (chemo), 122 (47.7%) hypomethylating agents (HMA) and 16 (6.2%) both (chemo+HMA). Disease status at HSCT defined by International Working Criteria was complete remission (CR) in 46 (18%) patients. There were significant differences between therapy groups: There were more therapy-related MDS and the use of MRD in the untreated group. The chemo group had higher serum ferritin levels at HSCT. Patients were older and had more high-risk disease by revised international prognostic scoring (r-IPSS) in the HMA group. Despite those differences, transplant outcomes were similar in patients who were untreated and who received cytoreductive therapy prior to HSCT. Three-year EFS was 44.2%, 30.6%, 34.2% and 32.8% for untreated, chemo, HMA and chemo+HMA groups respectively (p=0.5). Multivariate analyses revealed that older age (HR=1.3, p=0.001); high-risk histologic subtypes including refractory anemia with excess blasts (HR=1.5, p=0.05) and chronic myelomonocytic leukemia (HR=2.1, p=0.03); high risk cytogenetics with MK (HR=4.0, p<0.0001) and high serum ferritin level at HSCT (HR=1.8, p=0.002) were poor prognostic factors for EFS. Bone marrow blast count 5% or higher at HSCT (HR=1.6, p=0.01) and MK (HR=4.2, p<0.0001) were the only prognostic factor for increased relapse incidence after HSCT. Patients with MK represented a poor prognostic group with 3-year LFS of 11.4% and RI of (RI) of 60.9%. In this analysis, various therapy approaches prior to HSCT did not lead to different transplant outcomes. Cytogenetics defined by MK was able to identify a very poor prognostic group that innovative transplant approaches to improve outcomes are urgently needed.

Comparison of Intensive Chemotherapy and Hypomethylating Agents before Allogeneic Stem Cell Transplantation for Advanced Myelodysplastic Syndromes: A Study of the Myelodysplastic Syndrome Subcommittee of the Chronic Malignancies Working Party of the European Society for Blood and Marrow Transplant Research

“…For example, in the Damaj study, 74% of patients were reported to have < 5% blasts before HSCT compared with only 55% of patients in our study considered to be in CR. Overall outcomes are similar to that reported by other groups of outcomes after HSCT for advanced MDS [7,10,11]. The recent publication of the cytogenetic scoring system used in IPSS-R [12] provided an improved method of predicting outcomes for patients with MDS in both general and transplantation settings [13,14].…”

“…Potential advantages include decreased toxicity and provision of time while an appropriate HLA-matched donor is identified. The impact of pre-HSCT AZA has been assessed in a limited number of studies [3][4][5][6][7], but these are retrospective and most include small numbers of patients. Overall, these appear to demonstrate similar overall survival (OS ), relapse-free sur-vival (RFS), relapse, and nonrelapse mortality (NRM) in pa-tients receiving AZA compared with those who received traditional induction chemotherapy.…”

Preparing Patients With Myelodysplastic Syndrome for Transplant When Is Pre-transplant Cytoreductive Therapy Appropriate?

“…In a retrospective analysis of 128 allo-transplanted MDS patients published by Damaj and colleagues [40], the 3-year OS and DFS were not significantly different between patients receiving a median of 4.5 cycles of azacitidine and those patients transplanted upfront. This observation has been confirmed recently by Oran et al [41], who found no differences in post-transplant outcome when comparing 162 patients receiving pre-transplant debulking approaches (40 intensive chemotherapy, 122 HMA) to 78 MDS transplanted without any pretransplant cytoreduction.…”

Monosomal Karyotype at the Time of Diagnosis or Transplantation Predicts Outcomes of Allogeneic Hematopoietic Cell Transplantation in Myelodysplastic Syndrome

“…[19] In fact, MK and marrow blast counts of >5% were the only prognostic factors for DFS in MDS patients receiving alloHCT. [44] Deeg et al reported that both MK and R-IPSS cytogenetic risk score were associated with relapse and survival after alloHCT in MDS patients. [15] In our study, MK was more predictive of alloHCT outcomes in MDS patients after alloHCT compared to other established scoring systems.…”