To the Editor: Acute myeloid leukemia (AML) with antecedent hematological disorder or arising from exposure to cytotoxic therapy is known to have an inferior prognosis. Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) may be the only curative option for secondary acute myeloid leukemia (sAML) patients who have no access to matched donors. However, there are controversies regarding the outcome comparison of de novo AML and sAML patients in the setting of haplo-HSCT, and inconsistent prognostic factors have been observed. To address these issues, we conducted this retrospective study to compare the clinical outcomes of patients with de novo AML and sAML who underwent ‘Beijing Protocol’ haplo-HSCT, which has been described previously.1 Detailed information concerning the eligibility criteria, patient cohorts, transplantation protocol, and statistical analysis is provided in the Supplementary File, https://links.lww.com/CM9/C899. This study was approved by the Ethics Committee of Peking University People’s Hospital (2019PHD005-01). Informed consent was obtained from patients or guardians in accordance with Declaration of Helsinki. In all, 47 sAML patients and 248 de novo AML patients who underwent haplo-HSCT from 2019 to 2022 met the inclusion criteria. Among sAML group, nine had therapy-related AML following the treatment of tumors, and the remaining 38 had preceding hematological diseases with the majority being myelodysplastic syndromes. High-frequency genetic aberrations were observed in patients with sAML; moreover, compared with patients with de novo AML, those with sAML are more likely to be classified into a higher risk stratification Supplementary Figure 1 and Supplementary Table 1, https://links.lww.com/CM9/C899. Considering the confounding factors, propensity score matching was conducted, and 88 de novo AML patients and 47 sAML patients were included in the subsequent analysis. There was no significant difference in the incidence of recovery or graft-versus-host disease (GVHD) between the de novo AML group and the sAML group Supplementary Table 2, https://links.lww.com/CM9/C899. All patients achieved neutrophil recovery. A total of 89.8% (79/88) of the patients in the de novo AML group and 85.1% (40/47) of the patients in the sAML group achieved platelet recovery (P = 0.426). The median time of neutrophil recovery was 12 and 13 days (P = 0.110), and the median time of platelet recovery was 14 and 15 days (P = 0.693) for the de novo AML group and sAML group, respectively. Upon univariate analysis, the incidence of grade II–IV acute graft-versus-host disease (aGVHD) at day +100 for the de novo AML group and the sAML group was 34.1% (95% confidence interval 95% CI: 24.1–44.1%) and 23.4% (95% CI: 11.2–35.7%; P = 0.091) and the incidence of moderate to severe chronic graft-versus-host disease (cGVHD) at 2-year was 13.2% (95% CI: 5.5–20.9%) and 22.6% (95% CI: 10.1–35.1%; P = 0.260) for the de novo AML group and the sAML group, respectively Supplementary Table 3, https://links.lww.com/CM9/C899. As illustrated in Figure 1, the 2-year cumulative incidence of relapse (CIR) was 23.7% and 10.9% (P = 0.116), the 2-year non-relapse mortality (NRM) was 6.1% and 8.7% (P = 0.519), the 2-year leukemia-free survival (LFS) was 70.2% and 80.4% (P = 0.295), and the 2-year overall survival (OS) was 90.7% and 88.9% (P = 0.769) for the de novo AML group and the sAML group, respectively. We failed to obtain any significant difference in the CIR (HR = 0.49, 95% CI: 0.21–1.15, P = 0.100), NRM (HR = 1.50, 95% CI: 0.39–5.62, P = 0.550), LFS (HR = 0.74, 95% CI: 0.62–1.51, P = 0.404), OS (HR = 0.99, 95% CI: 0.34–2.93, P = 0.991), aGVHD (HR = 0.58, 95% CI: 0.29–1.15, P = 0.120), cGVHD (HR = 1.61, 95% CI: 0.75–3.44, P = 0.220) or GVHD-free/relapse-free survival (GRFS, HR = 0.88, 95% CI: 0.54–1.44, P = 0.624) between two disease categories in the multivariate analysis Supplementary Table 4, https://links.lww.com/CM9/C899. Nevertheless, pretransplantation measurable residual disease (preMRD) was determined to be an adverse factor for CIR, LFS and moderate to severe cGVHD Supplementary Table 4, https://links.lww.com/CM9/C899. When it was restricted to the sAML group, preMRD had no significant effect on 2-year OS (negative vs. positive, 93% vs. 81.6%, P = 0.269) or 2-year CIR (negative vs. positive, 6.9% vs. 17.6%, P = 0.349) Supplementary Figure 2, https://links.lww.com/CM9/C899, whereas the relatively higher CIR in sAML patients with positive preMRD suggests that preMRD remains essential for the assessment of sAML patients in advance of haplo-HSCT.Figure 1: Outcomes for patients with secondary acute myeloid leukemia or de novo acute myeloid leukemia after haplo-HSCT. (A) Cumulative incidence of relapse. (B) Cumulative incidence of non-relapse mortality. (C) The 2-year leukemia-free survival. (D) The 2-year overall survival. NRM: Non-relapse mortality; haplo-HSCT: Haploidentical hematopoietic stem cell transplantation; sAML: Secondary acute myeloid leukemia (AML).The results of the present study support several major conclusions. First, the post-haplo-HSCT outcomes of sAML patients were comparable to those of de novo AML patients. Consistent with previous studies, sAML patients were older and had a high prevalence of genetic abnormalities; these factors are associated with poor prognosis.2 However, the OS of sAML patients was strikingly favorable when compared with that in previous investigations.3 This phenomenon might be explained by the inclusion of pediatric patients and the predominance of patients who were negative for preMRD. Notably, although the outcomes between sAML and de novo AML patients were not statistically significant, NRM tended to be higher for sAML patients. Apart from the competing risk effect, these results may be due to the pronounced comorbidities and chemotherapy-related toxicity burden in sAML patients.4 Next, our multivariate model identified preMRD as a risk factor for CIR, LFS, and cGVHD. Most studies have reported a correlation between preMRD and poor transplantation outcomes in de novo AML patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT).5 However, Maffini et al6 focused on 219 patients with sAML and reported no significant differences in post-HSCT outcomes between preMRD-positive and preMRD-negative patients. A larger cohort, specifically sAML, is needed to verify these findings. Several clinical observations may relate to our findings. Recent studies have emphasized the prognostic significance of high-risk mutations for sAML.7 Since sAML patients tend to harbor adverse genetic abnormalities, they are generally categorized into adverse-risk groups according to European Leukemia Net risk stratification. A prospective and multicenter study by Liu et al8 verified the superiority of haplo-HSCT in graft-versus-leukemia, especially in those with high-risk AML. We hypothesized that immune reconstruction after haplo-HSCT might overcome the barrier driven by genetic aberrations, resulting in a comparatively low CIR for sAML patients, although no significance was observed in the present study. Addressing preMRD, Guo et al9 reported that haploidentical allografts had a stronger effect on alleviating preMRD and its side effects on relapse. To some degree, we can assume that haplo-HSCT might achieve a higher disease-free rate among patients with sAML through eradicating preMRD positivity. Several limitations of this study should be acknowledged. First, due to its retrospective nature, selection bias may have been introduced. Second, the dataset is relatively small. Additionally, we were unable to obtain long-term follow-up data for all patients. Taken together, our study demonstrated a comparable prognosis for patients with sAML and de novo AML in the scenario of haplo-HSCT, suggesting that haplo-HSCT can be considered as a viable option for sAML patients. Additionally, care must be taken to achieve MRD negativity prior to receiving haplo-HSCT. Funding This work was partly supported by the National Key Research and Development Program of China (No. 2023YFC2508905), the Noncommunicable Chronic Diseases-National Science and Technology Major Project (No. 2026ZD0553900), the National Natural Science Foundation of China (Nos. 82470214 and 82270227), Beijing Research Ward Excellence Program (No. BRWEP2024W134080102), Major Program of the National Natural Science Foundation of China (Nos. 82293630 and 82530009), Beijing Municipal Science & Technology Commission (No. Z211100002921071), Beijing Municipal Science & Technology Commission, Administrative Commission of Zhongguancun Science Park (No. Z241100009024043). Conflicts of interest None.
Zhang et al. (Mon,) studied this question.