Is allogeneic transplantation necessary in acute myeloid leukaemia of intermediate risk in the first complete remission?

INTRODUCTION

Acute myeloid leukaemia (AML) is a heterogeneous clonal disease caused by the accumulation of acquired somatic genetic alterations leading to uncontrolled proliferation of immature hematopoietic precursors. This genetic diversity becomes particularly relevant in patients with AML classified as intermediate risk according to the European LeukemiaNet (ELN) guidelines. The emergence of new markers (genetic, functional, post-remission, etc.) and targeted therapies (FLT3 inhibitors) has defined more precisely the prognosis, leading to the reclassification of these patients into favourable or adverse risk groups. Currently, post-remission treatment options for the intermediate-risk patient group are controversial due to the uncertainty regarding the benefits of allogeneic hematopoietic stem cell transplantation (allo-HSCT), recommended for patients in the adverse risk group.

Current indications and outcomes of allo-HSCT in AML

AML represents the most common indication for allo-HSCT, serving as a cornerstone in its therapeutic approach. In recent decades, there has been a sustained increase in the number of transplants performed in AML patients, attributed to advances in conditioning regimens (such as the implementation of non-myeloablative and reduced-intensity regimens) and the emergence of alternative sources of progenitors (expanding the availability of donors).

Typical indications for allo-HSCT include: (1) patients in first complete remission (CR1) if the risk of relapse exceeds 35-40%; (2) patients in second or subsequent complete remissions; and (3) patients refractory to the first-line treatment regardless of risk.¹

The decision to undergo allo-HSCT in CR1 is made by weighing the risk-benefit ratio, influenced by the reduction in relapse risk (CIR) and the increase in non-relapse mortality (NRM).² Although the evaluation should be personalized considering factors such as age, functional status, and comorbidities, it has been observed that patients who derive greater benefits are those with intermediate or unfavourable risk according to the ELN 2017 criteria, or favourable risk with measurable residual disease (MRD) persistence after consolidation/intensification treatment.

This indication is based on the findings of several studies comparing outcomes in patients with available versus unavailable donors, demonstrating better overall survival (OS) in high-risk patients defined by cytogenetic characteristics. In this regard, the HOVON-SAKK group study analysed AML patients in CR1 eligible for allogeneic transplantation based on the availability of an HLA-identical family donor (32%) or unavailable donor (58%). Although treatment-related mortality (TRM) was significantly higher in the donor group (21% vs. 4%), both CIR and disease-free survival (DFS) were lower in the donor-available group. Subgroup analysis revealed significantly better DFS and OS in patients with a donor belonging to the intermediate or adverse cytogenetic risk group. From this, it was concluded that AML patients with intermediate or adverse cytogenetic risk significantly benefited from allo-HSCT.³

Changes in the definition of intermediate risk: differences between ELN 2017 and 2022

The continuous progress in genetic knowledge, resulting from gene expression analyses and next-generation sequencing (NGS), has enhanced the identification of biomarkers related to acute leukaemia leading to enhanced diagnostic and prognostic precision. The genetic, cytogenetic, and molecular advancements justified the update of the previously unified fourth edition of the World Health Organization Hematolymphoid Tumor Classification⁴, resulting in the current fragmentation into two distinct classifications: the fifth edition of the World Health Organization Hematolymphoid Tumor Classification⁵ and the International Consensus Classification.⁶

These changes have brought about a reclassification of intermediate-risk patients, as highlighted by the study of Huber et al, emphasizing the following findings: (1) a reduction in entities defined by morphology, decreasing from 13% in the WHO 2016 Classification to 5% in the WHO 2022 Classification and ICC; (2) an increase in the incidence of MDS-related AML, rising from 22% in the WHO 2016 Classification to 28% in the WHO 2022 Classification and 26% in the ICC, after the inclusion of myelodysplasia-related gene mutations in this group and (3) the reclassification of AML-RUNX1; (4) the existence of different inclusion criteria for CEBPA mutant AML in each classification, as well as those related to myelodysplasia (the ICC excludes TP53-mutated AMLs from this group).⁷

Similarly, the European LeukemiaNet 2022 guidelines were updated following the criteria proposed by the ICC. The intermediate-risk group was mainly affected by two changes: (1) all patients with FLT3-ITD mutations were moved to the intermediate-risk group regardless of the coexistence of NPM1 mutations and FLT3-ITD allelic ratio; and (2) AMLs with molecular alterations not classified as adverse or favourable have decreased in account of the inclusion of AMLs with myelodysplasia-related gene mutations in the adverse-risk group.⁸

The consequences of this update have been analysed in other studies where ELN 2022 was not a better prognostic tool compared to ELN 2017 in the intermediate-risk group.^9,10

In order to validate ELN 2022, the PETHEMA group conducted an analysis of the effects of the classification change in a cohort of 546 patients eligible for intensive treatment. A decrease in the representation of favourable and intermediate-risk groups, accompanied by an increase in the adverse group was observed compared to the ELN 2017 classification. This phenomenon was attributed to a change in risk group in 14.5% of patients, mainly due to the lack of recognition of FLT3 allelic ratio prognosis and the inclusion of AML with myelodysplasia-related gene mutations in the adverse risk group. To improve the prognostic capacity of ELN 2022, subgroup analysis revealed that patients included in the adverse risk group but with a single mutation related to myelodysplasia-associated genes had higher survival than those with ≥2 mutations. These patients had a similar survival to the intermediate-risk group, suggesting the appropriateness of placing this subgroup of patients in the intermediate-risk category rather than the adverse-risk group.¹¹

Results of allo-HSCT vs auto-HSCT vs standard consolidation chemotherapy in intermediate-risk AML

Controversy surrounds the optimal post-induction treatment for intermediate-risk patients, as, unlike their adverse-risk counterparts, there is no clearly demonstrated benefit in employing allo-HSCT as a post-remission strategy.

Traditionally, post-remission intensification through allo-HSCT has been associated with increased OS and a reduced risk of relapse. However, TRM has led to the consideration of alternative therapeutic approaches, among which auto-HSCT stands out. Auto-HSCT results in fewer complications due to the absence of the graft-versus-leukaemia effect. To understand the effect of these therapeutic options, the PETHEMA group retrospectively analysed the outcomes of a cohort of intermediate-risk cytogenetic patients who underwent auto-HSCT or allo-HSCT in CR1 after intensive chemotherapy. The results indicated that allo-HSCT was significantly associated with better OS, leukaemia-free survival (LFS), CIR and NRM compared to auto-HSCT. This study suggests that within the intermediate cytogenetic risk group in CR1, auto-HSCT may be a valid option for patients with favourable molecular risk, while allo-HSCT should be the preferred post-remission strategy for patients with intermediate or adverse molecular risk.¹²

On the other hand, the ETAL-1 clinical trial allowed the comparison of outcomes between intermediate-risk cytogenetic AML patients randomly assigned to receive allo-HSCT or conventional consolidation chemotherapy with the option of rescue allo-HSCT in case of relapse. Despite premature closure due to slow patient enrolment, notable results included allo-HSCT being associated with significantly longer DFS but similar OS compared to the chemotherapy group. Although the classification scheme used was appropriate at the initiation of the trial in 2012, it does not reflect current guidelines for classifying AML patients. Therefore, a substantial portion of the patients included in this study would now be classified in the adverse or favourable-risk groups according to ELN 2017 and 2022 criteria.¹³

In another study, the outcomes of haploidentical transplantation were explored compared to intensive chemotherapy as post-induction therapy in intermediate-risk cytogenetic AML patients in CR1 without an HLA-identical family donor. The 3-year LFS and OS were significantly better in the group receiving haploidentical transplantation than in the chemotherapy group. In multivariate analysis, the type of post-remission treatment (haplo-HSCT vs chemotherapy) was an independent risk factor in both the overall cohort and when stratified by minimal residual disease after the second consolidation. The authors concluded that, in the absence of an HLA-identical family donor, haploidentical transplantation could be a superior post-remission therapy to chemotherapy as a first-line post-remission treatment for intermediate-risk cytogenetic AML.¹⁴

Importance of MRD and post-remission treatment in intermediate-risk AML

Measurable residual disease (MRD) is one of the most important markers for predicting the risk of post-remission relapse, as its positivity implies the presence of leukaemia cells not detectable below the sensitivity limit of optical microscopy. Supporting this assertion, Araki et al analysed the survival difference based on MRD in a cohort of 359 patients undergoing allo-HSCT in CR. MRD was assessed using 10-color multiparametric flow cytometry (MFC), and any level of positivity was considered MRD positive. The results concluded that patients with MRD-negative CR had significantly higher OS and PFS compared to MRD-positive or actively diseased patients, with similar outcomes between the last two groups.¹⁵

Due to its predictive capability, various studies have explored incorporating MRD (via MFC, PCR, or NGS) into algorithms that integrate it alongside the genetic risk of the patients, aiming to select the most suitable therapeutic strategy based on their post-remission relapse risk. This approach becomes relevant in the absence of data supporting the benefits of allo-HSCT in intermediate-risk patients.

The GIMEMA AML 310 clinical trial (#NCT01452646) was designed to determine the post-remission treatment strategy considering cytogenetic/genetic factors and post-consolidation MRD levels using flow cytometry in young patients with de novo AML. In this context, intermediate-risk AML patients with MRD-positive CR1 received allo-HSCT, while those with MRD-negative CR1 received auto-HSCT. The comparison between both cohorts revealed similar rates of OS and PFS. Thus, the antileukemic effect exerted by allogeneic transplantation in intermediate-risk patients with MRD positivity was demonstrated and implied that intermediate-risk patients achieving MRD negativity may not necessarily require allo-HSCT, contributing to reducing potential toxicity.¹⁶

MRD could also play a crucial role in determining the type of conditioning regimen used in allo-HSCT. This hypothesis is based on a retrospective analysis of MRD using NGS by Hourigan et al from the BMT CTN 0901 clinical trial (#NCT01339910), where AML patients in CR were randomly assigned to receive myeloablative conditioning (MAC) or reduced-intensity conditioning (RIC) allo-HSCT. The analysis revealed MRD negativity in 32% of patients treated with MAC and 37% treated with RIC, showing similar OS. However, OS and CIR at 3 years were significantly worse in MRD-positive patients receiving RIC conditioning compared to those receiving MAC conditioning. This finding suggests that, in AML patients with genomic MRD detected before allo-HSCT, MAC regimens might result in better survival compared to RIC regimens.¹⁷

In response to the growing evidence on the impact of MRD on prognosis and therapeutic decisions, Jentzsch et al refined ELN 2022 based on post-remission MRD to improve its prognostic capacity. In this way, the intermediate group of ELN 2022 was reclassified as favourable if they achieved MRD negativity and adverse if they presented MRD positivity. This change resulted in 50% of patients initially classified as intermediate risk in ELN 2022 now being categorized as favourable risk.¹⁸

Perhaps the only way to answer the question of the best post-remission treatment in intermediate-risk AML patients would be to conduct randomized clinical trials using a more up-to-date risk strategy, where MRD-negative AML patients are randomly assigned between allo-HSCT, auto-HSCT, and consolidation chemotherapy.¹⁹

Post-remission treatment in AML patients with FLT3-ITD mutation

One of the significant changes introduced in the ELN 2022 update is the inclusion of AML with FLT3-ITD mutation in the intermediate-risk group, regardless of allelic ratio or coexistence with NPM1 mutation. These factors previously determined favourable, intermediate, or adverse risk with different post-consolidation therapeutic approaches. The addition of FLT3 inhibitors along with standard intensive chemotherapy has improved OS and PFS, sparking a debate about the need for allo-HSCT in all FLT3-ITD mutated patients.

Döhner et al conducted a subanalysis of the RATIFY clinical trial to evaluate the prognostic impact of NPM1/FLT3-ITD genotypes according to ELN 2017 classification. They found that the addition of midostaurin provided significant benefits in all three risk groups in terms of overall survival and suggested that only NPM1^wt/FLT3-ITD^mut patients benefit from allo-HSCT.²⁰

A retrospective analysis of 27 Spanish centres with 175 AML patients with FLT3 mutations examined the "real-world" impact of adding midostaurin to intensive chemotherapy. When comparing ELN 2017 intermediate-risk group patients who received allo-HSCT with those who continued treatment with midostaurin, no significant differences in OS were observed (Figure 1). Consequently, it can be concluded that the role of allogeneic transplantation in AML patients with FLT3 mutations in the era of FLT3 inhibitors is not clearly defined.²¹

Figure 1. Effect of the allelic ratio of FLT3 and the ELN 2017 classification on overall survival in patients with AML with FLT3 mutation treated with midostaurin.



In figure 1a, FLT3 ratio ≥ 0.5 (green) and FLT3 ratio < 0.5 (blue). In figure 1b: Favorable risk (blue), intermediate risk (green), and adverse risk (yellow).

CONCLUSIONS

1. Post-first remission treatment in intermediate-risk AML patients remains controversial.
2. Due to changes in risk stratification, post-remission treatment options for intermediate-risk AML patients should be continuously updated.
3. Allogeneic transplantation remains the preferred option, especially if the risk of relapse is high.
4. However, it is unclear whether allogeneic transplantation is preferable in patients who achieve complete remission with negative measurable residual disease.
5. MAC regimens are clearly advantageous over RIC in patients undergoing Allo-HSCT with detectable MRD.
6. The role of allogeneic transplantation in FLT3-ITD mutated patients belonging to the ELN 2022 intermediate-risk group is controversial in the era of FLT3 inhibitors.

CONFLICT OF INTEREST

The authors declare no competing financial interests.

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Posted on 1 May 202425 June 2024