A single-center retrospective cohort study compared the clinical outcomes between a group with WT1 monitoring and pre-emptive therapy and a group with hematological relapse after HCT. Log-rank tests showed that the group with increased WT1 expression was associated with favorable OS and EFS compared to the group with hematological relapse. Although multivariate analysis was not performed due to the small size of the cohort, these findings suggest that pre-emptive therapy based on WT1 monitoring may improve outcomes compared to therapy after hematological relapse. Although several studies have suggested the significance of MRD monitoring and pre-emptive therapies, this is the first real-world study to demonstrate the significance of WT1-guided pre-emptive therapy compared to therapy after hematological relapse in allografted patients with AML. [9, 10]
Subgroup analysis showed no difference in OS and EFS between the two groups in patients with CR at HCT, but in patients with NR at HCT, the group with increased WT1 had significantly better OS and EFS than the group with hematological relapse, suggesting the usefulness of pre-emptive therapy. According to the risk of karyotype, the group with increased WT1 showed significantly better OS and EFS than the group with hematological relapse in the favorable and intermediate risk, whereas there was no difference between the two groups in the adverse risk, suggesting the limitations of pre-emptive therapy.
There were no differences in patient demographics between the two groups in terms of age, karyotype risk, or disease status at HCT. The median value of WT1 was significantly higher and the performance status was worse in the group with hematological relapse than in the group with increased WT1. These findings suggest that poor performance status is associated with disease progression or transplant-related complications and is also a barrier to receiving appropriate chemotherapy. By contrast, in the group with increased WT1 expression, a good performance status was maintained without disease progression, and less intensive chemotherapy was well tolerated. Previous studies have documented the relationship between WT1 relapse and hematological relapse and showed that hematological relapse occurred at a median of 38–43 days after WT1 relapse. [14, 16] In this study, the median duration from HCT to an event was longer in the group with WT1 increase. Although the difference was not statistically significant, the group with an increase in WT1 expression might have a more favorable chance of survival than the group with hematological relapse.
WT1 monitoring as a marker of MRD in clinical practice can be easily performed and is useful even if it is a nonspecific AML marker. [14–17] However, the clinical evidence in post-HCT settings is limited. Several studies have shown an association between WT1 increase and adverse outcomes, and suggest a high specificity for disease relapse or positive MRD. [19–21] However, there are several limitations for WT1 expression in post-HCT; thresholds or non-specific reaction of WT1 has not been fully investigated. Post-HCT, various complications can occur including GVHD. From these clinical issues, in this study, WT1 increase was defined from the consecutive increase of WT1 > 50 copies/µgRNA, and therapeutic intervention was performed from the confirmation of WT1 increase. There are still many unknown factors regarding the threshold for WT1. Pozzi et al. reported that the relapse rate was higher in patients with WT1 expression in the bone marrow at any time post-HSCT, exceeding 100 copies /104 ABL.[22] Cho BS, et al. reported that 250 copies/104 ABL of WT1 in bone marrow samples predicted post-transplant relapse.[11] Polak J, et al. reported that WT1 expression levels in the peripheral blood exceeding 50 copies/104 ABL were considered signs of impending hematological relapse, in accordance with morphological, flow cytometry, and chimerism data, as well as with the expression of specific fusion genes.[21] Thus, methods for measuring WT1 and thresholds for WT1 have not been standardized by the studies, and determining its thresholds is impossible. However, there is a consensus that at least post-transplant WT1 elevation is associated with the risk of AML recurrence.
Maintenance and pre-emptive therapies should be strictly distinguished from MRD monitoring: intervention at negative MRD and the detection of positive MRD. [4, 23] It is highly important to evaluate the clinical significance of these two types of post-transplant interventions because a pre-emptive therapy has the advantage of identifying treatment-free follow-up patients who will not relapse in the long term. This is extremely meaningful in terms of the patient burden and medical economics. Regarding post-HCT maintenance therapy, prospective clinical studies have suggested the usefulness of sorafenib, an FLT3 inhibitor, in allograft patients with FLT3 mutation-positive AML.[24, 25] Other maintenance therapies with hypomethylating agents and/or venetoclax have also been reported and two prospective randomized clinical trials are ongoing (NCT04161885, NCT04128501).[26, 27] In particular, prospective clinical trials are designed to start maintenance therapy as soon as possible and not to evaluate the difference between these interventions based on the MRD monitoring. Therefore, the clinical significance of differences between maintenance and pre-emptive therapies should be validated in further prospective studies.
Comparing the primary therapies after events, in the group with hematological relapse, 8 patients (40%) received intensive chemotherapy or best supportive care, whereas, in the group with WT1 increase, all 10 patients received low-intensity chemotherapy. These treatment biases may be due to background factors, such as disease progression, performance status, comorbidities, and venetoclax approval. The group with increased WT1 expression showed better OS and EFS rates than the group with hematological relapse. Four patients showed WT1 re-increase and experienced hematological relapse despite pre-emptive therapy. All patients died of disease progression or transplant-related complications. Nevertheless, the relapse rate was relatively low (40%), demonstrating the significance of pre-emptive therapy. These findings imply that pre-emptive therapy in patients with low disease burden is likely to prevent disease relapse. Based on the details of pre-emptive therapy shown in the swimmer’s plot, all patients received low-intensity chemotherapy, including AZA/AraC or venetoclax. In the safety profile of pre-emptive therapy, four patients (40%) had grade 3 or higher hematological toxicity; however, no patients received transfusions or other complications requiring a longer hospitalization. Low-intensity chemotherapy reduces complications and can be continued for a long time. These factors may also prevent hematological relapses. In the group with hematological relapse, only three patients who received a second HCT had longer disease-free, and no other patients who failed hematological remission or repeated hematological relapse had longer survival.
This study had several limitations. Given the single-center retrospective nature of the analysis, clinical practice depends on the discretion of the attending physician. First, WT1 monitoring may have affected patients’ backgrounds and treatment decisions. Second, the type of chemotherapy, dose reduction, and treatment modifications, including the number of days and cycle intervals of the therapeutic agents, were not standardized. A prospective study with a larger cohort is required to address these issues.
In conclusion, this single-center retrospective study showed that the group with WT1 increase based on WT1 monitoring was associated with better OS and EFS compared to the group with hematological relapse. These findings suggest that pre-emptive therapy based on WT1 monitoring is valuable in terms of patient burden and medical economics.