To the Editor:

Acute lymphoblastic leukaemia (ALL) presents significant challenges in older adults due to various risk factors and poor response to traditional chemotherapy [1]. Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) provides graft-versus-leukaemia effect, and has been proposed to be the curative therapy with most potential for ALL. Allo-HSCT is generally recommended to treat ALL at the CR1 stage [2, 3]. However, in older adults, the potential survival benefit of transplantation may be offset by an increased risk of transplantation-related mortality (TRM). Advancements in transplantation technology, the refinement of reduced-toxicity conditioning regimens, and enhanced supportive care have led to a remarkable improvement in transplantation therapy for older patients [4]. Consequently, the upper age limit that was applied in the past when considering transplantation therapy for patients is gradually becoming less relevant. The question of whether transplantation can improve survival in older adults with ALL who achieve CR1 remains controversial.

Thus, we performed a retrospective analysis to compare the outcomes of allo-HSCT and chemotherapy in older adults with ALL.

ALL patients aged between 55 and 70 years who attained CR1 after induction chemotherapy were enrolled in this study. Cases were excluded if they underwent less than two courses of consolidation chemotherapy. Following the first remission, the chemotherapy or allo-HSCT was chosen by each physician and patients, as detailed in the Supplementary Material and Methods. The conditioning regimen had been reported in previous studies [5, 6]. This study was conducted in accordance with the principles outlined in the Declaration of Helsinki. Written informed consent was provided by all patients.

From January 2015 to December 2022, 132 patients with ALL were enrolled at Peking University People’s Hospital. Twenty-seven patients were included in the chemotherapy group and 58 were included in the HSCT group. The median age of the patients in the chemotherapy group was higher (61 versus 58 years, p = 0.003). Other clinical characteristics were shown in Supplementary Table 1.

All 58 patients who underwent allo-HSCT achieved neutrophil engraftment with a median time of 13 days. Additionally, 55 patients achieved platelet engraftment at a median of 14 days. The 3-year OS, LFS, and GRFS rates were 71.7%, 65.9%, and 55.2%, respectively.

At the last follow-up, 24 patients (72.4%) in the HSCT group and 13 (48.1%) in the chemotherapy group were alive. The primary cause of death in the HSCT group was TRM (81.2%), while all deaths in the chemotherapy group were due to disease recurrence. The OS and LFS in the HSCT group were numerically higher than those observed in the chemotherapy group, but without statistically significance (OS: 71.7% versus 49.1% at 3 years, p = 0.085; LFS: 65.9% versus 42.5% at 3 years, p = 0.051; Fig. 1). The cumulative incidence of relapse (CIR) was significantly lower in the HSCT group (11.1% versus 57.5%; p < 0.001). The 3-year TRM was 23% in the HSCT group. In the chemotherapy group, all patients ultimately succumb to disease.

Fig. 1: Comparison of HSCT versus chemotherapy.
figure 1

a Overall survival (71.7% versus 49.1% at 36 months, p = 0.085); b Leukaemia-free survival (65.9% versus 42.5% at 36 months, p = 0.051); c Cumulative incidence of relapse (11.1% versus 57.5% at 36 months, p < 0.001); d Cumulative incidence of treatment-related mortality (23% in the HSCT group; all patients died from relapse in the chemotherapy group).

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Multivariate analysis showed that male sex was an independent prognostic factor for LFS and OS (Supplementary Table 2).

Subgroup analysis revealed that HSCT significantly reduced CIR in older adult patients with Ph+ or Ph− B-ALL. The OS and LFS in the HSCT group were numerically higher than those observed in the chemotherapy group, but without statistically significance (Supplementary Table 2).

Further analysis showed that in minimal residual disease (MRD) positive patients, allo-HSCT significantly improved the OS (79.7% versus 18.0% at 36 months, p = 0.008), LFS (69.8% versus 37.5% at 36 months, p = 0.033), and reduced CIR (15.1% versus 62.5% at 36 months, p = 0.003) compared with continued chemotherapy (21 cases from HSCT group and 10 cases from chemotherapy group). However, in MRD-negative patients, although transplantation still significantly reduced the CIR, it did not show any advantage in OS and LFS, which may be related to the small sample size (36 cases from HSCT group and 17 cases from chemotherapy group). The details were shown in Supplementary Figs. 1 and 2.

In this study, we demonstrated that allo-HSCT significantly reduced the rate of relapse compared to chemotherapy as post-remission treatment for older adults with ALL, although this did not translate into a significant difference in their OS or LFS. However, subgroup analysis showed that in MRD-positive patients, allo-HSCT significantly improved the OS, LFS, and reduced CIR compared with continued chemotherapy.

Previous studies have shown that the emergence of TKI therapy and immunotherapy, the prognosis of ALL has noticeably improved. However, the high cost of immunotherapy limits its availability and restricts its wide adoption in clinical settings. And most patients eventually experience relapse without allo-HSCT.

The study by Chalandon et al. [7] demonstrated that allo-HSCT is associated with improved OS in adult patients with Ph+ ALL that were initially treated with a combination of imatinib and reduced-dose chemotherapy. Another study reported the use of a second-generation TKI in patients aged >55 years, most patients relapsed within 5 years [8]. Further investigations [9] explored the use of a third-generation TKI in young patients. Although only nine patients underwent allo-HSCT, the 2-year event-free survival was 81%. So far, it remains to be determined whether third-generation TKI can effectively address the high relapse rate and provide long-term survival benefits.

In this study, patients with Ph+ALL who underwent allo-HSCT exhibited a lower CIR, although no significant difference were found in survival, potentially due to the small sample size.

Compared to Ph+ ALL, Ph− ALL has a poorer therapeutic outcome. Currently, allo-HSCT remains the standard treatment for high-risk ALL as a post-remission therapy for all suitable patients. However, allo-HSCT in older patients presents more challenges. In a retrospective study in Switzerland [10], that included 26 older patients with ALL aged ≥60 years, the median OS was 9.5 months for those who did not receive transplantation. Conversely, among the eight patients who underwent allo-HSCT, the 3-year OS was 87.5%, indicating a significant improvement in survival with transplantation. A multicentre study evaluated the efficacy of transplantation in older adult patients with B-ALL [11] and revealed a 3-year OS of 38%, with a higher percentage of survivors (45%) observed in patients who received transplantation after CR1 [11].

In our study, 58 patients underwent allo-HSCT in CR1. The 3-year OS, LFS, and CIR were 71.7%, 65.9%, and 11.1% respectively. Therefore, allo-HSCT can be used as a consolidation therapy for older adult patients with ALL in CR1.

The main issue preventing the adoption of transplantation in older patients is TRM. The RIC protocols were introduced to make allo-HSCT more widely available to older patients. In the study conducted by Sun et al. [12], the majority of older patients with AML were treated with an RIC regimen. The TRM was significantly lower compared to the MAC regimen (29.8% versus 40%) [6]. Furthermore, the study found that age has little impact on TRM. In our study, 56.9% of the patients received the RIC regimen, and the TRM was 23%, which is consistent with the findings from older patients with AML. Therefore, it is important to recognise that age should not be considered a barrier to transplantation.

In conclusion, our data showed that allo-HSCT may serve as an alternative consolidation chemotherapy for post-remission treatment in older (aged ≥55 years) adult patients with ALL, especially for those with persistent MRD-positive. However, additional studies with improved design and larger sample sizes are needed to confirm these results.