In decades, recent advances of the remission induction treatment strategies for the specific subtype of AML, have significantly improved the rates of CR and OS. However, almost all AML patients will relapse during their first CR peroid without appropriate post-remission therapy, even favorable and intermediate risk according to ELN 2017 risk stratification for AML. ELN recommended 2–4 cycles of intermediate-dose cytarabine for favorable-risk genetics younger AML patients (18–60/65 years) eligible for intensive chemotherapy, and allogenic hematopoietic stem cell transplantation (allo-HSCT) from matched-related or unrelated donor, 2–4 cycles of intermediate-dose cytarabine (IDAC), high-dose therapy and ASCT for the intermediate-risk genetics patients. For older patients (༞60/65 years) eligible for intensive chemotherapy, 2–3 cycles of intermediate-dose cytarabine (HiDAC), allo-HSCT in patients with low HCT-Comorbidity Index, or investigational therapy could be chose. Inaddition to, previous studies have also showed that MST as a post-remission therapy may improve outcomes and avoid GVHD in CR1 AML patients. Owing to the heterogeneity of AML and a paucity of randomized controlled trial data with large samples, Nevertheless, the optimal post-remission treatemt for an individual favorable and intermediate risk genetics AML patient has not yet been established. The retrospective study was to compare the difference in efficacy and safety of MST and ASCT or CSA as post-remission treatment in favorable and intermediate risk AML patients.
Many studies have explored the optimal post-remission strategy for favorable and intermediate risk AML patients. The majority of favorable risk AML patients recevied IDAC or HiDAC for consilidation therapy in CR1 according to ELN 2017. However, the preferred dose of cytarabine and the optimal number of cycles necessary to acquire the best outcomes are unknown. It was recently reported that the 3-year risk of relapse was significantly higher in IDAC compared to HiDAC, HiDAC is the preferred dose for single agent cytarabine consilidation in younger, favourable-risk AML. A meta-analysis also compared the efficacy of HiDAC to IDAC or low-dose cytarabine as post-remission for AML patients including 9 studies. HiDAC was benefit from RFS in the favorable risk group, but it did not translate into an OS benefit. Moreover, CPX-351, hypomethylating agents, targeted agents (i.e. gemtuzumab ozogamicin) were also used as post-remission treatment for AML patients, there was no material OS benefit from these regimens[14–17]. ASCT is feasible when matched sibling donor is not available for patients with favorable and intermediate risk AML in CR1, but the MRD status before HSCT is a key factor to determine whether a patient is suitable for ASCT and to predict the outcome after transplantation[18–20]. Clinical studies have showed that MST could improve remission rates and OS with rapid hematopoietic recovery and without GVHD in AML patients, particularly in elderly patients, although the precise mechanism of MST is still unclear[5, 21, 22]. The majority of MST patients were received HLA-mismatched peripheral blood stem cells from donors, but for AML patients without available donors, CBMST was also an optimal option, the two regimens both implied low risk procedure with chemotherapy and with no risk of GVHD, the HLA were both mismathcded[5, 8]. In the study, 7 patients were treatment with CBMST and 15 patients were treatment with PBMST, the median for RFS and OS time were 19 months and 40 months in CBMST group, and RFS and OS time were both undefined in PBMST group.
In this study, sixty-three patients were enrolled between 2014 and 2021 with a median follow-up time of 23.5 months, 21 months, and 11.5 months in MST, ASCT, and CSA treatment groups, respectively. There were no significant differences in baseline characteristic among the three groups, except for age, the median age in MST group was 64 years (range 20–80), which showed that MST could improve the outcomes of older AML patients with low or intermediate risk without increasing treatment-related toxicity, it was consistent with previous report. Compared to CSA, neutrophil recovery time was shorter in the MST group ( median time to neutrophil recovery, 11(9–15) days vs 13(11–18) days, P = 0.003), rapid neutrophil recovery can significantly reduce the incidence of infections in the granulocytosis phase. There was no significant difference in three groups of the most common complication including infection and bleeding, and there was no grade of GVHD in MST group.
The 2-year cumulative incidences of relapse were 27.27% and 29.41% in the MST and ASCT groups (P = 0.581), and the 2-year cumulative incidence of relapse in CSA group was 41.67% higher than that of MST and ASCT groups. During the period of follow-up, there were 21 patients (33.3%) died to relapse. The estimated OS and RFS at 2 years were 62.2% vs 50.0% ( P = 0.101) and 57.1% vs 50.0% ( P = 0.136) in MST and CSA group ( P = 0.101) for patients over 60 years. The estimated OS at 2 years was 100.0%, 66.2%, and 69.1% in MST, ASCT and CSA group ( MST vs CSA, P = 0.044), the estimated RFS at 2 years was 100.0%, 65.4%, and 59.8% ( MST vs CSA, P = 0.050) in patients ≤ 60 years. These results suggested that MST could improve the outcomes of favorable and intermediate AML patients over 60 years and prolong the OS and RFS for patients ≤ 60 years.
Our results analyzed that MST, ASCT and CSA were all acceptable options for favorable and intermediate risk AML patients as post-remission treatment. However, what option is the optimal for different individuals as post-remission regimen? Guo et al first reported that MST increased the 2-year OS rate from 11–39% in older patients with AML, then a long term follow-up study showed that LFS and OS rates were 84.4% and 89.5% in low risk AML patients treated with MST as post-remission consolidation. Particularly in older AML patients, MST achieved a high CR rate and 1-year OS. Moreover, in recent years, MST for refractory secondary AML and the immunomodulatory agent lenlidomide combined with MST for AML have been reported[25, 26]. Compare to HLA-matched sibling donor (MSD) transplantetion, OS and LFS of MST were inferior to MSD transplantation for favorable and intermediate risk AML patients in CR1. Our results indicated that MST as post-remission treatment may be suitable for elderly patients and younger patients without an available donor for allo-HSCT suffered favorable and intermediate risk AML in CR1. The potential mechanisms of MST were direct cytotoxicity mediated by transferred alloreactine or tumor-speicific donor cells, rejection of donor cells and concomitant cytokine release, and donor CD4 + cells enhanced host cytotoxic T cells responses[5, 21, 28–31]. Nevertheless, the precise mechnism of MST remains unclear so far. Prospective randomized controlled design with large samples and basic experiments for mechanism of MST need to be further investigated. Reseachs in recent years have showed that ASCT is the acceptable option for post-remission treatment with favorable and intermediate risk AML in CR1, especially for favorable risk patients. Compared to ASCT, allo-HSCT should be the preferred post-remission strategy for intermediate risk AML patients[20, 32–34]. Furthermore, it was reported that the regimen of repeated courses of HiDAC and idarubicin with limited autologous CD34 positive peripheral blood stem cell support was proved feasible and effective in non-high risk AML patients. Therefore, ASCT should be used as post-remission treatment for younger AML patients in CR1 with favorable risk and intermediate risk in the absence of an available donor, whose MRD were negative. However, the limitations of our study were the small samples size and not the prospective randomized controlled study.
In conclusion, MST could not only improve the prognosis of the elderly but also prolong the OS and RFS of favorable or intermediate risk patients ≤ 60 years. MST, ASCT and CSA were all acceptable options for favorable and intermediate risk AML patients as post-remission treatment. MST is more suitable for elderly patients and younger patients without an available donor suffered favorable and intermediate risk AML in CR1, and ASCT is the preferred stragegy for younger favorable risk AML patients in CR1 with MRD negative. Further investigations need to be comfirmed the conclusion.