Prof. Pierre Fenaux, Head of the Department of Hematology and Immunology at Assistance Publique-Hôpitaux de Paris Nord (Hôpitaux Saint-Louis, R Debré, Avicenne) is a leading expert in haematology with extensive experience in the treatment and management of myelodysplastic syndromes (MDS). In this interview, he discusses key considerations for first-line therapies in lower-risk MDS, the latest advances in treatment and the role of organizations like the European School of Hematology (ESH) in supporting haematologists.
Q1: What are the key considerations for using first-line therapies in clinical practice for lower-risk MDS?
The traditional first-line treatment has been erythropoietic-stimulating agents (ESAs), such as erythropoietin (EPO) or derivatives like darbepoietin. These therapies remain widely used but have recently been challenged, at least in sideroblastic forms of MDS, by the emergence of luspatercept. Luspatercept has shown better efficacy in sideroblastic forms of MDS1 and could potentially replace ESAs in these patients in the future.
Luspatercept’s role in non-sideroblastic MDS is less clear, at least to replace ESAs in first line treatment of anaemia, as the benefits over ESAs are not well established. Cost is also a major factor since luspatercept is significantly more expensive. Additionally, luspatercept wasn’t initially approved for first-line treatment, raising questions about the optimal sequence—whether to use luspatercept after EPO failure or the reverse. Both treatments generally have transient effects, the aim to prolong the period before patients become transfusion-dependent. Combinations of ESAs and luspatercept are also being tested, given their different mechanisms of action on erythropoiesis
For now, ESAs remain the preferred first-line treatment in Europe in non-sideroblastic forms due to their availability, lower cost and tolerability.
Q2: What novel therapies are emerging to tackle the unmet needs in lower-risk MDS treatment?
In addition to luspatercept, imetelstat, a telomerase inhibitor, is emerging as a potential treatment. It shows efficacy in about 40% of patients but can cause myelosuppression and cytopenias, which are concerns in low-risk MDS.2
Other notable therapies in patients without del(5q) include lenalidomide in combination with EPO, even in EPO-resistant cases. Hypomethylating agents are also used in some cases. However, progress has been slow, and there are relatively few new drugs with proven efficacy in this space.
Q3: What are the latest updates from clinical trials on emerging treatments for high-risk MDS, and how might these new therapies fit into the current treatment algorithm?
Many combinations with hypomethylating agents have been tested, but results have so far been negative, except when the IDH inhibitors targeted drugs were used. Currently, there are promising phase I–II results using the combination of hypomethylating agents, such as azacitidine, with venetoclax or other BCL-2 inhibitors. Results of a phase III study comparing azacitidine alone with azacitidine-venetoclax combination are eagerly awaited. These trials may confirm whether the benefits seen in AML extend to MDS. I suspect this will be true for a significant part of the patients, though resistance to the combination—similar to resistance observed with single agents—may occur.
One significant advantage of the azacitidine-venetoclax combination is its ability to produce quicker responses. While this comes with an increased risk of myelosuppression, the faster responses may shorten the overall duration of this side effect. This pattern has already been observed in AML.
The ability of the combination to rapidly reduce blast counts, is already making it a useful strategy to bridge patients to transplantation—still the only curative option for high-risk MDS. In this context, the combination is clearly more effective than hypomethylating agents alone.
In some cases, intensive chemotherapy (including with encapsulated drugs like in CPX 351) can also serve as a bridge to transplantation, or transplantation might even be considered a first-line treatment if the blast count is not excessively high or rapidly evolving.
As for other approaches, there are limited new options. IDH inhibitors are an exception and show potential in specific scenarios. FLT3 inhibitors, while relevant in AML, are rarely applicable in MDS due to the infrequency of FLT3 ITD mutations.
Another important consideration in clinical trials is the selection of appropriate primary endpoints. Survival is often a challenging endpoint to assess, especially when patients undergo transplantation or receive second-line treatments. In such cases, endpoints like event-free survival may be more meaningful, as they account for not only response but also relapse. For example, relapse or failure to respond constitutes an event, even if a patient is later salvaged by transplantation and achieves a survival outcome comparable to those who never relapsed. Using survival as the sole endpoint may, therefore, underestimate the differences between treatments.
It’s also worth noting that small details can significantly impact survival analysis. For instance, a few patients receiving transplant or salvage therapy can alter the results, potentially masking the true effect of a treatment. Adjusting trial designs to consider these nuances is crucial for better evaluation.
Additionally, recent updates to response criteria in MDS have aimed to improve the accuracy of treatment assessment. For instance, the “marrow complete response” category, which required blast clearance in the marrow but not cytopenia improvement, has been removed. This change addresses the issue of false responses, where transient blast disappearance did not translate into meaningful clinical benefit. These adjustments should help refine how responses are evaluated in future trials.
Q4: How does mutational burden impact prognosis and risk stratification in high-risk MDS?
I am sometimes sceptical about the current emphasis on mutations in MDS. The most concerning mutation is TP53, particularly the biallelic TP53 mutation. However, this mutation can generally be predicted by the karyotype. Most patients with biallelic TP53 mutations have a complex karyotype, often described as monosomal (less than 46 chromosomes). Typically, this involves the loss of one TP53 allele through a 17p deletion, with the remaining allele being mutated, leaving no functional TP53 protein. These patients often also have del(17p), del(5q), and other complex karyotypic abnormalities, making the mutation already predictable.
A small TP53 clone, on the other hand, is unlikely to have a significant impact. For other mutations, prognosis worsens with an increasing number of mutations, as most are associated with poor outcomes—except for isolated SF3B1 mutations in low-risk MDS. SF3B1 in lower risk MDS is the other important mutation, because when isolated or associated with a mutation like TET2, it generally indicates a stable disease course with very low risk of progression to AML. In such cases, especially for older patients, the risks of transplantation outweigh the benefits due to the high transplant-related mortality rate, which can still reach 15% for patients in their 60s.
In my practice, I generally do not base transplant decisions solely on the presence of mutations. Instead, I consider factors like blast count and karyotype. Mutations alone, especially if isolated, in my view generally do not justify a transplant. Some patients with mutations but no cytopenias can live normal lives, and transplanting such patients would not be advisable, especailly above a certain age. We perform next-generation sequencing (NGS) on all patients and repeat it during follow-up, but we must remain cautious about overinterpreting these findings.
The exceptions are targeted mutations like IDH1 and IDH2, which can sometimes be present at diagnosis or develop during follow-up. These mutations are actionable and can be effectively targeted with specific inhibitors. Unfortunately, FLT3 mutations, such as FLT3-ITD, are rare in MDS and thus not commonly relevant.
In summary, while some mutations, like biallelic TP53 actionable IDH mutations, SF3B1 mutations are critical, the practical impact of other mutations alone in guiding decisions like transplantation is often overemphasized. Decisions should be based on a combination of clinical and genetic factors, with mutations considered as part of a broader context.
Q5: How does ESH support haematologists?
The European School of Hematology (ESH) provides a unique platform for education and collaboration. As a board member and treasurer, I value its focus on creating an intimate learning environment with more time for discussion. Because of its different format compared to larger meetings like American Society of Hematology (ASH) or the European Haematology Association (EHA), which must generally stick to the «10 minute presentation + 5 min discussion» format, ESH meetings dedicate significant time for Q&A sessions and foster interaction among faculty and attendees, including during informal settings like meals.
Each meeting focuses on a specific theme, bringing together international experts and allowing for in-depth exploration of key topics. This format distinguishes ESH from ASH and EHA meetings, making it an invaluable resource for advancing the field of haematology.
To learn more about ESH, visit their official website.
Disclosures: Prof. Fenaux has nothing to disclose in relation to this article. No fees or funding were associated with this short article.
References:
- Della Porta MG, Garcia-Manero G, Santini V, et al.Luspatercept versus epoetin alfa in erythropoiesis-stimulating agent-naive, transfusion-dependent, lower-risk myelodysplastic syndromes (COMMANDS): primary analysis of a phase 3, open-label, randomised, controlled trial. Lancet Haematol, 2024;11:e646 – e658
- Imetelstat in patients with lower-risk myelodysplastic syndromes who have relapsed or are refractory to erythropoiesis-stimulating agents (IMerge): a multinational, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2024;403:249-260.
