Myelodysplastic Syndromes: 2026 Update on Diagnosis, Risk-Stratification and Management.

Disease Overview

MDS comprises a heterogeneous group of myeloid malignancies with very distinct natural histories [ 1 ]. MDS occurs in 3 to 4 individuals per 10 5 in the US population [ 2 ]. Prevalence increases with age. In individuals age 60 and above, prevalence is 7–35 per 10 5 [ 2 ]. Other series have reported higher rates [ 3 ]. MDS affects males more frequently than females [ 2 ]. Exposure to prior chemo or radiation therapy is a risk for the development of MDS. MDS arises from distorted hematopoietic stem cell function [ 4 ], inflammatory and innate immune deregulation [ 5 ], deregulated apoptosis [ 6 ] and multiple genomic events [ 7 ]. This combination of molecular alterations results in anemia, increased risk of infections, bleeding, and transformation to AML [ 8 ]. Most patients with MDS will die from complications of MDS without transforming to AML and therefore the need for unique treatment strategies for patients with MDS [ 8 ]. Further adding importance to this concept is the discovery of the relation between comorbidities and clonal hematopoiesis [ 9 ] and MDS [ 10 ] suggesting an interplay between MDS and the development of other conditions such as cardiovascular disease [ 11 ].

MDS is usually suspected by the presence of cytopenia on a routine analysis of peripheral blood. This prompts evaluation of bone marrow cell morphology (aspirate) and cellularity (biopsy). A manual count of bone marrow blasts is fundamental for risk assessment. Cytogenetic and genomic data help in predicting risk and in selecting therapy. Once this information is collected, MDS risk can be calculated. Patients with MDS can be stratified according to several internationally accepted scoring systems. The original IPSS [ 12 ] is still in use but has been replaced by the IPSS‐R [ 13 ]. These two systems are important because they still serve as part of the eligibility criteria for ongoing clinical trials [ 14 ]. Patients with MDS are generally divided in two different broad subgroups: lower and higher risk disease. Patients with lower risk disease by IPSS are those with low and intermediate‐1 disease and less than 3.5 points by IPSS‐R. Patients with higher risk disease are those with intermediate‐2 and high risk by IPSS or more than 3.5 points by IPSS‐R [ 15 ]. Using IPSS‐M, patients with lower risk disease are those with very low, low or moderate low risk whereas those with higher risk disease are those with moderate high, high and very high risk. It should be noted that in close to 10% of patients, IPSS‐R and IPSS‐M are discordant [ 16 ]. An increased number of mutations is associated with increased risk [ 17 ].

Several other important data points are needed when making treatment decisions in patients with MDS. These include age of the patient, type and severity of comorbidity [ 18 ], significance and number of cytopenias, transfusion needs, presence of specific genomic alterations (for instance presence of p53 mutations [ 19 ]), now computed by the IPSS‐M [ 20 ], percentage of blasts, cytogenetic profile, potential for alloSCT and prior treatment with an HMA [ 21 , 22 ].

Diagnosis

The diagnosis of MDS is suspected based on the presence of cytopenia. Diagnosis is confirmed by performing a bone marrow aspiration and biopsy. Both procedures provide different information. The bone marrow aspirate allows for detailed evaluation of cellular morphology and evaluation of percent of blasts. The bone marrow biopsy allows for determination of bone marrow cellularity and architecture. Diagnosis is established by the presence of dysplasia. Several morphological classifications are in place. In 2022, the WHO classification was reported (Table 1 ) [ 23 ]. Under this classification, MDS is now myelodysplastic neoplasm, acronym MDS. A parallel effort was proposed by the ICC [ 24 ]. We expect a new classification system unifying WHO and ICC in 2026.

Several additional tests are needed to complete the laboratory evaluation of a patient with MDS. Cytogenetics are of importance to calculate prognosis of patients and in some subsets of patients to select the most effective form of therapy. The MDS cytogenetic risk classification includes 5 different subgroups including 20 different alterations (Figure 1 ) [ 25 ]. Cytogenetic patterns are not stable in MDS, and a significant fraction of patients can acquire additional cytogenetic changes with disease evolution. This phenomenon is associated with increased risk of transformation to AML and worse survival [ 26 ]. New techniques to assess large structural chromosomal changes, such as optical genome mapping or whole genome sequencing, have been reported to be able to perform cytogenetic analysis without the need to culture marrow cells or band interpretation. This results in a lower percentage of failed assays [ 27 ].

A number of other assays can be used to help in the diagnosis of MDS. These include flow cytometry, fluorescent in situ hybridization (FISH) and genomic sequencing techniques. Flow cytometry can help in the identification of abnormal phenotypic patterns and can be of help in cases of minimal dysplasia. There is no evidence that a panel of FISH probes could replace routine 20 metaphase cytogenetic analysis. FISH and flow cytometry should not be considered part of the standard workup evaluation procedure of the patient with MDS and should be used in specific situations. Thanks to the discovery of multiple genetic mutations in MDS, we now have access to clinical tools for molecular annotation of patients with MDS. These can be of use to not only calculate prognosis, IPSS‐M, but also to complement other diagnostic tools. A majority of MDS patients will carry at least 1 or more somatic mutations in genes involved in DNA methylation, chromatin regulation, RNA splicing, transcription regulation, DNA repair, cohesin function or signal transduction [ 7 , 28 ].

Because diagnosis of MDS is based on morphological assessment, it can be subjective particularly in patients with early low‐risk disease and minimal dysplasia. It is calculated that diagnostic discrepancy can occur at the time of initial presentation in close to 20% of patients [ 29 ]. This has obvious implications for therapeutic decision making and patient counseling. Diagnosis is obvious in patients with excess blasts. The problem is in patients without excess blasts where diagnosis is based on dysplasia. Clinical assessment is needed in patients with minimal or not diagnostic evidence of dysplasia. In these cases, it is recommended that other causes of cytopenia be excluded. Routine tests include the analysis of anemia and thrombocytopenia, and exclusion of the cause of blood loss or inflammatory processes. When suspected, evaluation of the GI tract needs to be considered. Once other potential causes of cytopenia are excluded, additional diagnostic tools described above should be used.

ICUS , CHIP and CCUS

Before the incorporation of genomic sequencing in MDS, patients with cytopenia but no dysplasia were considered to have idiopathic cytopenia of undetermined significance (ICUS). Now we know that a fraction of these patients may have cytogenetic abnormalities or somatic mutations in genes recurrently mutated in myeloid malignancies [ 30 , 31 ]. The presence of a somatic mutation in the context of cytopenias with no diagnostic criteria for MDS is now considered a clonal cytopenia of undetermined significance (CCUS) [ 32 ]. This distinction is supported by data which suggests that, although close to 25% of patients with ICUS may ultimately develop MDS or AML, this risk significantly increases in the presence of a clonal mutation from 9% to 82% at 5 years, particularly in the presence of highly predictive mutation patterns [ 30 , 33 ]. A detailed evaluation and careful differential diagnosis between ICUS, CCUS and MDS is therefore essential (Table 2 ). The presence of clonal somatic mutations has also been reported in hematopoietic cells from older individuals without evidence of hematological disorder or cytopenia [ 35 , 36 ]. This is considered as age‐related clonal hematopoiesis of indetermined potential (CHIP) [ 32 ]. Clonal hematopoiesis has also been identified as a risk factor for therapy‐related MDS and AML [ 37 ]. The most frequent mutation in CHIP/CCUS is DNMT3A . This is associated with a relative low frequency of progression to MN [ 38 ]. There is significant interest in the evaluation and potential treatment of patients with CHIP or CCUS. This stands from the relationship between other systemic disorders, for instance cardiovascular disease, and CHIP/CCUS and the hypothesis that by treating CHIP/CCUS we could prevent progression to myeloid neoplasm (MN). It is also becoming evident that there are two main distinct groups of patients with clonal hematopoiesis: those with age‐related factors versus those in the context of other malignancies and prior chemoradiation therapy. The natural history of these two subsets of patients is very different [ 39 ]. A number of centers have developed “CHIP clinics” and clinical trials. Potential targets include IL‐1, splicing alterations and IDH mutations among others. Several prognostic systems have been developed including the CHRS [ 40 , 41 ]. These scoring systems may allow proper selection of individuals with CHIP/CCUS for therapy or more intensive interventions.

Overlap Synsdromes

A subset of patients of importance is those with MDS/MPN features. These are patients with evidence of a myeloproliferative component (with or without fibrosis). At the present time, except for chronic myelomonocytic leukemia (CMML), we do not fully understand the natural history of patients with MDS/MPN [ 42 ]. In our center, they are currently treated as MDS, but studies are ongoing to clarify this issue. Of note, specific MDS/MPN subtypes have mutational profiles and may benefit from specific therapeutic approaches. An example includes patients with MDS/MPN with ring sideroblasts and thrombocytosis who typically have mutations in SF3B1 and JAK2 [ 43 , 44 ] and may have a good response to therapy with luspatercept or lenalidomide [ 45 ].

Risk Stratification

The prognosis of patients with MDS is heterogeneous and therefore the need to develop prognostic systems that allow risk stratification and help in the timing and choice of therapy. Apart from the intrinsic prognostic value of morphological classifications [ 46 ], several prognostic scores are currently in use in MDS. The IPSS [ 12 ] has been in place since 1997. This score has been discussed in prior versions of this manuscript [ 47 ]. It has been replaced by the IPSS‐R [ 13 ]. The IPSS‐R includes different cut‐off points of cytopenias when compared to IPSS and incorporates a more comprehensive cytogenetic score [ 13 ]. IPSS‐R is still the standard tool to assess risk. The IPSS‐M has now been validated by several centers [ 20 , 48 ]. This model includes detailed information regarding p53 (mono versus biallelic mutations) and incorporates the mutational status of 16 genes.

The natural history of patients with lower risk disease is also heterogeneous [ 49 ]. We evaluated outcomes in a large series of patients with low or int‐1 disease by IPSS. We found that prognosis varied significantly in patients with lower risk MDS and were able to develop a lower risk MDS specific prognostic score [ 49 ]. This has significant implications for the development of specific interventions for patients with lower risk disease. This model has been validated on several occasions, and it is being used to identify patients with poor prognosis lower risk disease that could be candidates for early intervention. Bejar et al. published data indicating that patients with poorer prognosis and lower risk disease accumulate a higher number of mutational events than the better risk counterpart [ 50 ]. This data provides a potential molecular basis for the identification of this group of patients and poorer prognosis. The IPSS‐M also identifies these patients with lower risk features such as diploid cytogenetics and low percentage of blasts but significant mutational burden.

MDS occurs in older patients that suffer from comorbidities. None of the systems discussed above include the impact of comorbidity in the calculation of the prognosis of MDS. We used the ACE‐27, a comprehensive comorbidity score, in a cohort of 500 patients with MDS [ 18 ]. Presence of comorbidity had a significant independent impact on survival. A prognostic score was developed that included age, IPSS, and ACE‐27 score. Similar results were obtained using IPSS‐R [ 51 ]. This data indicates the need to add comorbidity scores in MDS [ 52 ].

Additional prognostic scoring systems include systems for hypocellular MDS [ 53 ] and for therapy related MDS [ 54 ]. It should be noted that prognosis in t‐MDS is strongly associated with the presence of cytogenetic alterations and p53 mutations [ 54 , 55 ].

Cytogenetic and Molecular Alterations

Bejar et al. first published an analysis of 18 genes using different techniques on 439 patients [ 56 ]. Subsequently, two major studies described the mutational landscape of MDS in larger series analyzing more genes [ 7 , 28 ]. A European consortium reported an analysis of mutations in 111 genes using next generation sequencing technology in a cohort of 738 patients [ 7 ]. Frequency of common mutations is shown in Table 3 . Since then, multiple other studies describing the mutational landscape of MDS and its potential prognostic and therapeutic implications have been published. Mutations in genes such as RUNX1 [ 7 , 28 , 60 ], TP53 [ 7 , 28 , 60 , 61 , 62 ] or EZH2 [ 28 , 60 ] have consistently been associated with adverse prognosis while mutations in the splicing factor SF3B1 are associated with favorable outcomes and prolonged survival [ 7 , 60 , 63 ].

Risk Adapted Therapy

Current Conceptual Framework for the Therapy of MDS in 2026

We divide patients into six different categories. First is the subset of patients with CHIP or CCUS [ 34 ]. Next, we divide patients with MDS into lower or higher risk but further subdivide them based on whether they have been exposed to an HMA: lower risk MDS, lower risk HMA failure, higher risk, and higher risk HMA failure [ 21 ]. Finally, a group of patients with extremely poor prognosis is that of patients with AML evolving from MDS, particularly after HMA‐based therapy. We are not going to discuss this last subset of patients in this review. In addition, clinical‐grade genomic is aiding in treatment decisions for all these subsets of patients. We discuss these five subsets of patients below. Figure 2 summarizes current treatment strategies for patients with MDS.

Treatment of ICUS / CHIP / CCUS

The field of ICUS/CHIP/CCUS was transformed by pioneer work led by Ebert and colleagues. Better understanding of these entities has transformed our understanding of MDS and our approach to this group of patients [ 36 ]. Several important manuscripts have defined and contextualized ICUS/CHIP/CCUS a topic beyond this review [ 34 ]. Today there is no data to support treatment of patients with ICUS/CHIP/CCUS. Individuals with ICUS have very low risk of progressing to MN. These individuals could be followed in the community. For patients, risk should be assessed by either CHRS [ 40 ] or CCRS [ 41 ]. A number of institutions have developed “CHIP clinics” to follow such patients and develop guidelines of care. In our group, these patients are followed with peripheral blood analysis every 6–12 months based on degree of cytopenia and type of mutation. Another important finding associated with CHIP/CCUS is not only the increased risk of transformation to MN but also the collateral risk of associated comorbidities [ 11 ]. Therapies directed toward comorbidities, that is, cardiovascular disease, are warranted and should be monitored in clinical trials.

One very important subset of patients with CHIP/CCUS is the group of patients that have received prior therapy for another malignancy. Work by Wong et al. showed that in patients with therapy‐related neoplasms (T‐MN) with a p53 mutation, the mutation could be detected in bone marrow specimens obtained prior to the patient ever receiving any therapy for their primary malignancy [ 64 ]. This finding is important as it suggests that chemotherapy or radiation therapy used to treat primary malignancy may not cause DNA damage per se but expansion of clonally mutated hematopoietic cells that expand with time. Based on this concept, Takahashi and Padron et al. in two independent but parallel studies demonstrated that CHIP/CCUS in patients treated for another malignancy are at a very high risk of progression to T‐MN [ 37 , 65 ]. Of interest, the data from these two investigators indicated that this phenomenon was not restricted to p53 but can be observed with any other gene mutated in CHIP/CCUS. Also of importance is the observation from a study at MD Anderson that patients with lymphoproliferative process or multiple myeloma treated with an autologous stem cell transplant are at particular risk of developing therapy related neoplasm [ 54 ].

Recommendation: In 2026, patients with ICUS/CHIP/CCUS should not be treated but followed preferentially in a dedicated “CHIP” clinic. Attention should be paid to the care of comorbidities. Clinical trials could be considered if available. There are no changes since the last version of this manuscript .

Options for Patients With Lower Risk MDS

Therapy in this subset of patients is based on transfusion needs. In general, patients that are transfusion independent are observed until they become transfusion dependent. This concept is currently being challenged (see below). Table 4 shows a summary of agents currently available for patients with lower‐risk MDS.

Erythroid Growth Factor Support

The use of erythroid stimulating agents (ESA) is common practice [ 66 ]. Several ESAs are available. Response rates range from 30% to 60% depending on study [ 67 ]. Data from the Swedish group indicated that the addition of G‐CSF to erythropoietin increased response rates. In a retrospective observational study, early introduction of this combination in patients with low‐risk disease and minimally transfusion‐dependent patients had an impact on survival [ 68 ]. The Swedish group also developed an algorithm to predict response to ESA [ 69 ]. The French group also evaluated the impact of ESA on survival in a retrospective study of 284 patients and compared it to a group of patients that formed the IPSS cohort [ 70 ]. In this study, patients treated with ESA had a better survival (HR for death was 0.43, 95% CI 0.25–0.72) [ 70 ]. Results from a recently published randomized placebo‐controlled phase 3 study of darbepoetin alfa for 147 patients with lower‐risk MDS showed significantly higher erythroid responses (14.7% vs. 0%, p = 0.016) and reduction in transfusion incidence in weeks 5–24 of therapy (36% vs. 59.2%, p = 0.008) with darbepoetin compared to placebo, with no significant differences between groups in the incidence of thromboembolic events, solid malignancies, or transformation to AML [ 71 ]. However, questions on the potential tumorigenic effect of these drugs have resulted in increased scrutiny of their use. G‐CSF is not approved by the FDA for patients with anemia of MDS in the US.

Recommendation: A course of ESA with or without G‐CSF is not contraindicated in most patients with low risk MDS with significant anemia without other cytopenia. Data indicate that early incorporation of these agents is more effective. We maintain therapy for at least 3 months to judge efficacy. In responding patients, we continue therapy until transfusion effect is lost. These recommendations are being challenged by the results of the COMMANDS trial (see below) [ 72 ].

Luspatercept

Luspatercept is a TGF‐β inhibitor [ 73 ]. This agent was initially tested in preclinical mouse models and in phase 1 and 2 trials with luspatercept and the related compound sotarcept [ 74 ]. The Medalist trial [ 75 ] was a multicenter randomized trial of luspatercept for patients with red cell transfusion dependent RARS that were not benefiting from ESAs or were unlikely to benefit [ 75 ]. x 229 were randomized on the trial. 153 to luspatercept and 76 to placebo. The primary end point of the study was red blood cell (RBC) transfusion independency (TI) for more than 8 weeks following IWG06 criteria [ 76 ]. Luspatercept resulted in an increase rate of TI in this subset of patients resistant to ESA. TI was achieved in 37.9% of patients with luspatercept versus 13.2% in the control ( p < 0.001). At more than 12 weeks, TI was documented in 33.3% of patients on luspatercept versus 11.8% in control. Median duration of RBC TI was 30.6 weeks versus 13.6. Other endpoints such as hematological response‐erythroid were also in favor of luspatercept. Toxicity of this compound, that is injected subcutaneously every 3 weeks, was acceptable without drug related mortality or increased risk of transformation to AML. Based on this data, the US FDA approved luspatercept in 2020 for RS+ disease [ 75 ]. Following the results of the Medalist trial, the COMMANDS trial ( NCT03682536 ) was designed to compare luspatercept versus an ESA in previously untreated transfusion dependent patients with lower risk MDS [ 72 ]. This study randomized 181 patients to epoetin‐alpha and 182 to luspatercept. Response criteria included both 12‐week transfusion independence and concomitant increase in hemoglobin of at least 1.5 g/dL. Using these criteria, response was achieved in 34.8% of patients with epoetin alpha and 60.4% with luspatercept [ 72 ]. With a median duration of follow up of 30 months, cumulative duration of response was 95 weeks with epoetin alpha and 150 with luspatercept ( p = 0011, HR 0.523). In addition, a preplanned secondary analysis presented at ASCO 2025 (Garcia‐Manero) indicated that survival was 46 months for patients treated with epoetin alpha and was not reached with luspatercept (HR = 0.805, p = 0.02). The potential impact of luspatercept on the natural history of MDS is of great interest as this agent for no antileukemia effect. Despite the positive results of COMMANDS trial, there is some controversy regarding its role in front line patients particularly in the subset of ring sideroblast negative patients where response rates are similar. Despite similarity on response rates, duration of response is longer in luspatercept RS‐ treated patients than in those treated with epoetin‐alpha [ 77 ]. These factor and together with the emerging survival results make in my opinion luspatercept the drug of choice in front line transfusion dependent patients. A trial known as ELEMENTS‐MDS ( NCT05949684 ) is studying the role of luspatercet in anemic transfusion independent patients.

Recommendation: In previously untreated transfusion dependent patients, luspatercept is the drug of choice in RS+ disease. At MD Anderson, this agent is also favored in RS‐ patients but clinicians have the choice to continue an ESA. In ESA failure RS+ patients, luspatercept is still the drug of choice but imetelstat (below) is emerging as an alternative for RS‐ negative patients and those with a high erythropoietin level [ 75 ]. This recommendation has changed since the last version of the paper .

Imetelstat

Imetelstat is a telomerase inhibitor that has been studied in myelofibrosis and MDS [ 78 ]. The registration trial of imetelstat in MDS was termed IMerge [ 79 ]. Patients with ESA‐relapsed, ESA‐refractory, or ESA‐ineligible lower‐risk disease were randomized in a 2:1 ratio to receive imetelstat 7.5 mg/kg or placebo every 4 weeks. The primary endpoint was red blood cell transfusion independence (RBC‐TI) for at least 8 weeks. A total of 178 patients were enrolled. Median follow‐up was 19.5 months in the imetelstat group and 17.5 months in the placebo group. An 8‐week or longer RBC‐TI was achieved in 47 patients (40%; 95% CI, 30.9–49.3) receiving imetelstat compared with nine patients (15%; 95% CI, 7.1–26.6) receiving placebo, corresponding to a rate difference of 25% (95% CI, 9.9–36.9; p = 0.0008). Grade 3–4 treatment‐emergent adverse events occurred in 107 of 118 patients (91%) in the imetelstat group and 28 of 59 patients (47%) in the placebo group. The most common adverse events with imetelstat were neutropenia and thrombocytopenia (62% vs. 8%). Importantly, no treatment‐related deaths were reported. Although this study was open to both RS+ and RS− negative patients, a majority of patients were RS+. Therefore, these results could be compared to those of the MEDALIST trial REF. An important characteristic of the study was that in contrast to COMMANDS, there was no limit on erythropoietin level. Therefore, it is possible that untreated patients with high epo levels could benefit from imetelstat. In addition, pooled data presented at ASH 2024 (Platzbecker et al.) suggested that response rates were also observed in patients that had received other than ESA therapy including HMAs, lenalidomide or luspatercept.

Recommendation

Imetelstat should be considered as a second line agent in transfusion dependent patients after either ESA or luspatercept. It may have a role in earlier patients with higher epo levels.

Lenalidomide

Lenalidomide is approved for patients with lower risk MDS, anemia and alteration of chromosome 5 [ 80 ]. Phase I results [ 81 ] were confirmed in a subsequent phase II study of lenalidomide in patients with anemia and alteration of chromosome 5 [ 81 ]. In that study 148 patients received 10 mg of lenalidomide for 21 days every 4 weeks or daily. Of those, 112 had decreased need for transfusions (76%; 95% CI 68–82) and 99 patients (67%; 95% CI, 59–74) became transfusion independent. Response was fast: median time 4.6 weeks. The median rise of hemoglobin was 5.4 g/dL. Of interest, cytogenetic responses were observed in close to 50% informative patients. Predictors of response included presence of a platelet count of 100 × 10 9 /L and less than 4 prior units of red cells transfused. It should be noted that in this study patients with a platelet count of less than 50 × 10 9 /L were excluded. Subsequently, these results were confirmed in a phase III known as AZA‐004 comparing two different doses of lenalidomide (5 and 10 mg orally daily) versus placebo. This study was also designed to clarify the issue of transformation to AML. 10 mg daily was the superior arm and that there was no increased incidence of transformation to AML in patients treated with lenalidomide [ 82 ]. Of importance, a report from the initial MDS‐003 trial of lenalidomide indicated a longer survival for patients responding to therapy [ 83 ].

Results from a subset analysis from the multicenter RevMDS study including 381 patients treated with 10 mg daily of lenalidomide suggested that early intervention in transfusion independent patients with Hgb < 10 g/dL was associated with erythroid responses. In this study, among 12 TI patients with Hgb < 10 g/dL therapy with lenalidomide was associated with universal erythroid responses and improved QoL scores compared to pretreatment values (+12.5; p = 0.02) [ 84 ]. Following this lead, one of the most recent interesting contributions to field of MDS was published by Diez‐Campelo et al.: the Sintra‐Rev trial [ 85 ]. In this study, European investigators randomized 60 transfusion independent patients with del5q‐ MDS to 5 mg lenalidomide or placebo and measured the transfusion free survival (TFS) in each arm. TFS was not reached in patients on the low dose lenalidomide arm versus less than 1 year for those on the placebo (p 0.003, HR 0.3, p.0.005). Furthermore, cytogenetic responses were documented in 94% of the lenalidomide patients versus 0% in the placebo. Uncensored data analysis did not show improvement of median survival (8.4 vs. 7.4 years), but it is possible that with more time these curves could separate. Of importance, there was no evidence of increased risk of transformation in patients with p53 mutated disease. I believe this data is of importance as is one of the first examples of successful early intervention in MDS. These results could be replicated by the ELEMENTS trial in non‐del5q patients.

Lenalidomide has been investigated in patients without chromosome 5 alterations [ 86 ]. In an initial study, 214 patients received lenalidomide 10 mg orally daily or 10 mg on days 1–21 of a 28‐day cycle. Fifty‐six (26%) patients achieved transfusion independence after a median of 4.8 weeks of therapy. Median response duration was 41 weeks. An international phase III, randomized, placebo‐controlled study including 239 transfusion‐dependent lower‐risk non‐del5q MDS patients confirmed the efficacy of lenalidomide in this setting [ 87 ]. Patients receiving lenalidomide 10 mg daily for 21 days were significantly more likely to achieve RBC transfusion independence for ≥ 8 weeks compared to placebo (26.9% vs. 2.5%, p < 0.001). Median duration of TI was 30.9 weeks, and TI was associated with significant improvement in HRQoL scores. In addition, higher response rates were observed in patients with baseline endogenous EPO ≤ 500 mU/mL. Of note, a recent study not only reported the negative impact of TP53 mutations in response outcomes to lenalidomide in del5q MDS, but also suggested U2AF1 mutations may be likewise associated with a lower likelihood of response both in del5q and non‐del5q MDS and that mutations in DEAD box RNA helicase genes ( DDX41, DDX54 and DHX29 ) may be enriched among responders in non‐del5q MDS [ 88 ]. However, these findings need to be confirmed in larger studies.

Recommendation: The degree of response with lenalidomide in patients with lower‐risk MDS, anemia, good platelets , and del5q makes it the standard of care for this subset of patients. This is further reinforced by the data on survival in responding patients [ 83 ]. We do not consider this agent in patients with thrombocytopenia. Based on the results of the phase III randomized study, lenalidomide can be considered an option for selected red cell‐transfusion‐dependent patients with non‐del5q MDS. Evaluation of TP53 mutation status could be advisable in patients with del5q MDS prior to starting therapy with lenalidomide. Although current evidence does not support withholding therapy with lenalidomide in patients with TP53 mutations, these patients should be monitored closely for signs of inadequate response, loss of response , or progression. The final report of the Sintra‐Rev trial supports the use of low‐dose lenalidomide in del5q‐ MDS transfusion‐independent patients .

Azanucleosides

Three azanucleosides are approved for MDS: 5‐azacitidine [ 89 ], 5‐aza‐2′‐deoxycitidine (decitabine) [ 90 ] and oral decitabine/cedazuridine (oral dac/ced, ASTX727) [ 91 ]. 5‐azacitidine is approved for all subsets of MDS. Decitabine is for those with INT‐1 disease and above. Oral dac/ced has the same indication as decitabine. Although these agents are not approved in the European Union for patients with lower risk MDS, they are commonly used in the US. Currently, the main use is for patients with multilinear cytopenia or as second line therapy. The main question in the US is the dose and schedule of this class of compound in lower risk MDS. Work from the original studies with oral azacytidine (CC‐486) indicated that lower exposures, as determined by its pharmacokinetic profiling, resulted in significant clinical activity [ 92 , 93 ]. Based on this information, we designed a series of clinical trials investigating attenuated doses and schedules of both azacytidine and decitabine. The first one was a randomized trial of decitabine on a daily schedule × 3 days every 28 days compared to a weekly × 3 also every 28 days [ 94 ]. Although no differences were observed between both arms, the ORR was 23% and drug related mortality was 0%. Median overall survival was not reached. 70% of patients were alive at 500 days. This study was followed by a randomized study comparing the 3‐day decitabine schedule at a dose of 20 mg/m 2 versus azacytidine at a dose of 75 mg/m 2 also for 3 days [ 95 ]. From this data, it appeared that the attenuated schedule of decitabine was more effective than that of azacytidine. This study was criticized because it was not comparing equivalent doses of the two HMAs. A third study was designed by the US MDS consortium comparing 2 schedules of azacytidine (3 and 5 days) and one of decitabine (3 days) in both transfusion dependent and independent patients. This study randomized 247 patients and was presented at ASH 2025 (Bouligny et al.). Results indicated that the 5‐day azacitidine arm was superior to either 3‐day decitabine or 3‐day azacitidine in terms of event free survival and overall survival. In a community study, a 5‐day schedule was compared to a 7‐day 5–2‐2 schedule (weekend off) or a 5–2‐5 schedule of 10 days [ 96 ]. Fifty patients were assigned to each arm (except 5–2‐2 was 51 patients). Most patients had lower risk disease. Hematologic improvement was achieved by 44%–56% of patients in each arm. Transfusion independency was documented in 50%–64% of patients. There was a trend for better response rates and less toxicity with the 5‐day schedule of 5‐azacitidine. These results need to be placed in the context of current results with luspatercept. It is reasonable to use a shorter (5‐day schedule) of 5‐azacitidine in lower risk MDS.

The use of HMAs in lower risk MDS could be facilitated if oral versions of these agents were available. Oral dac/ced is an oral agent that combines decitabine with the cytidine deaminase inhibitor cedazuridine [ 91 ]. CC‐486 is an oral form of azacytidine [ 97 ]. CC‐486 is not approved for MDS. Oral dac/ced has been studied in several phase 1 and 2 studies [ 98 ]. In the registration phase 3 trial, patients were randomized to two different sequences of either intravenous decitabine or oral dac/ced. This allowed for intrapatient PK comparison. Oral dac/ced demonstrated an identical pharmacokinetic profile between both IV decitabine and the oral version [ 99 ]. Further supporting these results are equivalence on induction of global DNA hypomethylation and early reports on clinical activity REF. An attenuated schedule of oral dac/ced is being studied in patients with lower risk MDS. A combination of oral azacytidine and cedazuridine (ASTX‐030) is also being investigated.

Recommendation

Both 5‐azacitidine and decitabine are used in the US in patients with lower risk disease that are transfusion dependent. Most patients treated with these agents have failed or were not candidates for growth factor support or lenalidomide. Although further results from randomized studies will be needed to determine whether these agents can modify the natural history of lower‐risk disease and be considered standard of care in the frontline setting or after growth factor support, recent data support the use of these agents at lower doses particularly in patients with more adverse features. In the future oral HMAs may have a role in lower risk MDS [ 93 , 97 ]. The sequential use of HMAs in lower risk MDS needs to be understood in the context of luspatercept and imetelstat .

Immune Therapy

This is an area of controversy. It is accepted that a subset of patients with MDS are characterized by deregulation of both cellular and innate immunity [ 5 , 100 , 101 ]. Agents studied include anti‐thymocyte globulin (ATG), cyclosporine, and steroids. These therapies have been modeled after the treatment of aplastic anemia [ 100 ]. The NIH group also developed an algorithm to predict response to this class of agents [ 102 ]. This model included younger age, HLA‐DR15 positivity, and shorter duration of transfusion dependency. Using this algorithm, the NIH group reported that alemtuzumab, an antibody against CD52, has significant activity in patients with MDS predicted to respond to immune suppressive therapy [ 103 ]. The group at Moffitt Cancer Center has suggested that a CD4/CD8 ratio could also be used to predict response [ 104 ]. Our group has not been capable of reproducing some of the data discussed above. Response rates with ATG observed at MDACC are significantly lower than those of the NIH [ 105 ]. The most important predictor for response for us has been the presence of marrow hypocellularity [ 106 ]. This is consistent with the results of Mufti et al. in London [ 107 ].

Also, recently the impact of ATG based therapy on survival has been questioned. Data from a Swiss study comparing ATG versus supportive care indicated a higher response rate but no survival benefit [ 108 ]. In this study, patients were randomized to a combination of horse ATG with cyclosporine versus best supportive care (BSC). Forty‐five patients received ATG+CSA and 43 patients received BSC. By month 6, 13 of 45 patients on ATG+CSA had a hematologic response compared with four of 43 patients on BSC ( p = 0.0156). Despite higher response rates, no significant effect on survival or transformation was observed.

The NIH group has also reported on the clinical activity of eltrombopag in patients with aplastic anemia as salvage therapy [ 109 ] and in addition to standard immunosuppressive therapy [ 110 ]. This data was of importance since responses were multilineage and not just restricted to platelets and significantly higher than those reported in historical cohorts with immunosuppressive therapy alone. Several studies are investigating this agent in MDS.

Recommendation: This is a particularly difficult group of patients. A majority of older patients cannot tolerate ATG , and most patients are treated with some form of supportive care that could include cyclosporine, growth factors , and steroids. The impact of it is not known either. In younger patients with severe hypoplastic MDS, allogeneic stem cell transplantation (alloSCT) should be considered as soon as possible. For those that are not candidates, a combination with horse ATG is recommended .

Allogeneic Stem Cell Transplantation

AlloSCT is usually not recommended in patients with lower risk disease even if they are young. This is based on data from Cutler et al. [ 111 ]. The anticipated early mortality with alloSCT cannot be overcome by the potential beneficial survival effect of alloSCT. This concept was confirmed by Koreth et al. at [ 112 ]. Using another Markov model, the investigators analyzed the impact of reduced intensity transplant in older patients with MDS. Patients with lower risk disease did not benefit from these less toxic transplant approaches [ 112 ]. In a study describing the outcomes of 438 patients with lower‐risk MDS after failure to hypomethylating agents, the overall survival of patients who underwent alloSCT was significantly longer than that observed in patients not receiving further therapy, those receiving conventional chemotherapy or investigational agents (median survival of 39 months versus 10 months, 28 months, and 17 months, respectively) [ 22 ].

Recommendation: We generally do not recommend alloSCT in patients with lower risk disease at initial presentation. That said , because of time required for donor identification, we refer all potential candidate patients for a transplant consult in anticipation of future needs. Patients who are candidates for alloSCT and who have been exposed to multiple therapies (growth factors, lenalidomide, azanucleosides, etc .) should be considered for transplantation. These patients are also candidates for clinical trials. Patients with hypoplastic MDS who are young should be considered for alloSCT up front .

Supportive Care Measures in MDS

A number of interventions can be used in patients with MDS. These include the use of prophylactic antibiotics and iron chelation. No randomized data exist to make formal recommendation for any of these interventions. In our experience, patients with isolated neutropenia and MDS not receiving therapy are not at significantly increased risk of infection to support recommendation of prophylactic antibiotics. Prophylactic antibiotics are commonly used in the context of active therapy for these patients. The role of iron chelation in MDS has been clarified by the results of the TELESTO trial [ 113 ] discussed below. Data from thalassemia indicate that iron chelation has an important role in this setting. Iron accumulation is frequent in MDS. The consequences of this are not fully understood in MDS. A study evaluating the impact of iron chelation therapy on overall survival of transfusion‐dependent lower‐risk MDS patients reported longer median overall survival from the time of transfusion‐dependence in patients receiving chelation (5.2 years vs. 2.1 years, p < 0.001) [ 114 ]. This survival advantage remained after matched pair analysis adjusting for age, frailty, comorbidity, and R‐IPSS. There is controversial data about the serum ferritin threshold which should trigger chelation [ 115 ]. The NCCN guidelines recommend the use of chelation therapy in patients with ferritin levels above 2500 ng/mL [ 116 ]. Iron accumulation could have a role in transformation to AML [ 117 ] and in the increased risk of infectious complications known to occur in these patients.

Recommendations

We do not routinely recommend antibiotics in patients with isolated neutropenia and MDS that are not receiving some form of cytotoxic or immunosuppressive therapy. We use prophylactic antibiotics in patients receiving active therapy. We use iron chelation in patients with ferritin levels more than 2500 ng/mL, but we consider all these patients for a clinical trial of iron chelation .

Thrombomimetic Agents

The use of thrombopoietin agonists for patients with lower‐risk MDS and thrombocytopenia has been explored in several studies. Initial results of a study with romiplostin [ 118 ] questioned its use in patients with lower‐risk MDS, particularly due to complications related to disease transformation and marrow fibrosis. Results from an extension study evaluating the use of romiplostin monotherapy in 60 patients with Low or Int‐1 IPSS and thrombocytopenia (defined as platelet count of ≤ 50 × 10 9 /L) reported 57% platelet responses with a median response duration of 33 weeks and only 2 patients with progression to AML [ 119 ]. Several studies evaluated eltrombopag in MDS, another TPO agonist. Results from a phase 1 single‐arm, randomized portion of the phase 2 superiority EQoL‐MDS study [ 120 ] evaluating the efficacy and safety of eltrombopag in patients with lower‐risk MDS reported significantly higher platelet responses (47% vs. 3%, p = 0.0017) and fewer bleeding events (14% vs. 42%, p = 0.0025) in the eltrombopag arm compared to placebo. No differences in leukemic transformation were observed (12% vs. 16%, p = 0.81). Although promising, the use of TPO agonists should be restricted to clinical trials until additional data are available.

Recommendation: Thrombomimetics agents should be used with caution and likely only in refractory patients with no other options .

Options for Patients With Relapsed or Refractory Lower Risk MDS and Investigational New Agents in Lower Risk MDS

Treatment options for patients with lower‐risk MDS have improved significantly since the previous version of this paper. The approval of luspatercept and imetelstat constitutes significant progress for this group of patients. The treatment of these patients remains sequential. A common practice at my center is to start luspatercept followed by imetelstat. HMAs are becoming a third‐line option, but the results from Bouligny et al. need to be understood in proper context.

A number of agents are being studied for lower risk MDS. These include the TGF‐β inhibitor elritercept [ 121 ], momelotinib [ 122 ] and the IRAK1/4 inhibitor R289. The first two agents are being studied in large, randomized studies. Data with R289 was presented at ASH 2025 (Garcia‐Manero) suggesting an excellent safety profile and evidence of clinical activity in heavily pretreated patients.

Options for Newly Diagnosed Patients With Higher Risk MDS

Options for patients with higher risk MDS have not evolved significantly since the last version of this paper. The azanucleosides remain the standard of care for a majority of patients [ 123 ].

Azanucleosides

Decitabine was studied in an initial randomized study comparing it to BSC [ 90 ]. In this study the dose of decitabine was 15 mg/m 2 IV infused over 3 h every 8 h for 3 days (at a dose of 135 mg/m 2 per course) and repeated every 6 weeks. Although there was no clear benefit in terms of survival in this study, the use of decitabine was associated with a complete response rate of 9% and overall response rate of 17%. These results led to the approval of decitabine in the US. Based on the results of a phase I trial of decitabine performed at MDACC, a Bayesian randomized phase II trial of three different doses and schedules of decitabine was conducted [ 124 ]. In this study a 5‐day schedule of decitabine administered daily at a dose of 20 mg/m 2 was shown to be superior to a 10‐day or subcutaneous schedule. A multicenter phase II trial of decitabine (ADOPT) using the 5‐day schedule confirmed the safety of this schedule although response rates were lower than those reported by the MDACC [ 125 ]. In the ADOPT study the median number of courses administered was 5, the CR rate was 17% and the median survival was 19.4 months. No randomized survival study of a 5‐day schedule of decitabine has been conducted in MDS. In parallel with this work, European investigators developed a randomized study of decitabine using the initial 3‐day schedule. The major objective of the study was survival. Unfortunately, the use of decitabine at this dose and schedule was not associated with improved survival in patients with higher risk MDS [ 126 ].

Oral decitabine/cedazuridine [ 98 , 127 ] was approved based on the results of the Ascertain trial ( NCT03306264 ) for the same indications of IV decitabine REF. This study confirmed the results of the initial phase 2 trial [ 98 ] where oral dac/ven was shown to have almost identical PK and PD characteristics to IV decitabine. The dose of oral dac/dec is 35 mg/100 mg daily for 5 days every 4 weeks. The CR in the phase 3 trial was 22% [ 99 ]. A recent report has indicated that this oral agent has significant clinical activity in p53 mutated disease [ 128 ] and may prolong survival in patients with CMML (ASH 2025, Wiseman et al.).

5‐azacitidine has been studied in higher‐risk MDS in two major randomized multicenter trials: CALGB 9221 [ 129 ] and AZA‐001 [ 89 ]. In the CALGB 9221 [ 129 ] study, 191 patients with MDS were randomized between 5‐azacitidine (75 mg/m 2 /day for 7 consecutive days every 28 days) and best supportive care (BSC). Median age was 68 years. Sixty percent of the patients in the 5‐azacitidine group, compared with 5% of control arm patients, responded to treatment ( p < 0.0001). The median time to leukemic transformation or death was 21 months in patients treated with 5‐azacitidine versus 12 months in the BSC arm ( p = 0.007). No significant difference in survival was observed. A landmark analysis suggested a survival advantage for patients initially on 5‐azacitidine or who had crossed‐over to 5‐azacitidine within 6 months of inclusion on study ( p = 0.03). A significant improvement in quality of life was documented in patients treated with 5‐azacitidine compared to BSC [ 130 ]. AZA‐001 was a randomized study designed to test the concept that treatment with 5‐azacitidine resulted in improved survival compared to a menu of standard of care options [ 89 ]. These included BSC, low dose cytarabine (ara‐C) or AML‐like therapy. In AZA‐001, 358 patients with higher‐risk MDS were randomized to either 5‐azacitidine (as per CALGB9221 schedule) or to standard of care. Median age of patients was 69 years. Median survival was significantly better in patients treated with 5‐azacitidine versus standard of care options: 24.5 months versus 15 months ( p = 0.0001). Progression to AML was significantly delayed, and RBC transfusion requirements and rate of infections were also significantly improved with 5‐azacitidine. The survival advantage with 5‐azacitidine was irrespective of age (including patients older than 75 years), percent of marrow blasts (including patients with 20%–30% blasts, now classified as AML using WHO criteria) or karyotype. This effect was significant when compared to BSC and low dose ara‐C. The number of patients treated with AML‐like therapy was too small to allow comparison with 5‐azacitidine. No consistent biomarkers of response to azanucleosides have been developed. A newer form of oral azacitidine is currently under development (ASTX030, azacitidine/cedazuridine NCT04256317 ).

Recommendation

The azanucleosides are the standard of care for most patients with higher risk disease. No study has compared 5‐azacitidine vs decitabine. Although response rates appear to be similar, only 5‐azacitidine has been associated with improvement of survival in a randomized trial. Based on this, we consider 5‐azacitidine standard therapy for front‐line treatment in higher risk MDS .

AML ‐Like Chemotherapy

AML‐like protocols in higher risk MDS have generally used classical anthracycline‐araC combinations like those used in de novo AML [ 131 , 132 ]. When used in MDS or AML post‐MDS, AML‐like therapy results in lower CR rates (40%–60%), shorter CR duration (median duration of 10–12 months), and tend to be associated with more prolonged periods of aplasia than observed in AML. In addition, the feasibility of AML‐like therapy is also reduced by the advanced median age of patients with MDS. The most important prognostic factor of response to AML‐like therapy is karyotype and presence of TP53 mutations: patients with unfavorable karyotype (−7/del 7q or complex karyotype) or TP53 mutations have a low CR rate and short duration of response [ 133 ]. This is of importance as, at least in the AZA‐001 study [ 89 ], patients with alterations of chromosome 7 had a significant benefit with 5‐azacitidine versus other therapies. Similarly, other prospective and retrospective studies report either similar or higher responses to azacitidine or decitabine in patients with MDS or AML with TP53 mutations compared to those with wild type TP53 , suggesting this should be considered the standard over chemotherapy for patients with these genomic abnormalities [ 61 , 134 , 135 , 136 ]. Currently, AML‐like therapy is only recommended for relatively younger patients with favorable karyotype that are candidates for alloSCT.

Recommendation: The randomized AZA‐001 study was not powered to demonstrate the superiority of 5‐azacitidine versus AML‐like therapy. The reason for this being that most investigators did not consider their patients candidates for such therapy. Therefore, the question is who may be a candidate for AML therapy. In our practice this is restricted to younger patients with a high likelihood of response to the therapy, such as diploid patients or candidates for alloSCT. We rarely use AML therapy in older patients or in those with poor risk cytogenetics or TP53 mutation .

AlloSCT

AlloSCT is the only curative treatment of higher‐risk MDS. Results from selected studies report prolonged DFS in about 30%–50% of the patients [ 137 ]. However, its use is mainly restricted to younger patients with an appropriate donor. Different transplant modalities of different intensities and donor sources are now in use. Most of them remain investigational, with available studies including small numbers of patients with MDS and highly heterogeneous populations [ 138 , 139 ], and therefore in our opinion all patients should be transplanted in the setting of a clinical trial. Current advances in transplant technology are allowing the consideration of older patients and alternative donors. Studies have suggested reduced intensity conditioning may be able to achieve similar relapse‐free and overall survival in patients with MDS [ 140 ], and that comorbidity and disease risk indexes may be more relevant in outcomes than chronological age itself [ 141 ]. This should result in a greater number of older patients benefitting from this potentially curative treatment modality. A recent report studying biological assignment in patients with higher risk MDS ages 50–75 years suggested that survival on an intent to treat analysis was superior (48% at 3 years) on the donor arm versus 26% for the non‐donor arm [ 142 ]. US guidelines for alloSCT in MDS have been proposed [ 143 ].

There are several relevant practical questions regarding alloSCT in MDS. These include timing of transplant and what to do with patients that achieved a complete response to hypomethylating agent prior to alloSCT. A study from the IBMTR indicated that early transplantation in higher‐risk MDS was associated with longer life expectancy [ 111 , 112 ]. Although data suggest longer survival with SCT in patients with higher risk disease, it should be noted that curves cross close to 3 years after initiation of therapy when compared with hypomethylating agents. It will be important to identify who are long‐term survivors that benefit the most from transplant. A prospective study is comparing azanucleosides use versus transplant in MDS. In terms of what to do in responding patients, no recommendation can be given at this time. For patients who experience failure to HMAs, transplant has been considered an option, but a recent retrospective study seemed to indicate these patients are at high risk of post‐transplant relapse compared to responding patients [ 144 ]. Prospective studies will be required to clarify this. Other questions include whether alloSCT should be preceded by a cytoreductive regimen (with chemotherapy or perhaps hypomethylating agents). Many authors consider that when marrow blasts > 10% at the time of transplant, because of the very high relapse risk post‐transplant, pretransplant therapy is required. A report from the EBMTR has indicated that long‐term survival of patients with monosomy 7 is very poor with alloSCT [ 145 ]. Similarly, as we previously detailed, two major studies [ 146 , 147 ] concluded that mutations in TP53, RUNX1, ASXL1, JAK2 and RAS pathway genes are associated with significantly shorter overall survival or relapse‐free survival [ 148 ] after alloSCT with TP53 mutations being particularly adverse. These results have significant implications for the use of alloSCT in MDS, as this suggests that the current practice of reserving transplant for poor prognostic features may not be indicated. In patients at higher risk for relapsed post alloSCT, data from a single arm trial indicated that post‐transplant hypomethylating use can improve outcome [ 149 ].

Recommendations

All patients potential candidates for alloSCT should be counseled regarding the possibilities of undergoing alloSCT. Optimally patients will be enrolled in an MDS specific clinical trial of alloSCT. Although alloSCT should be considered for patients with higher‐risk MDS this may not be the case in patients with high risk mutations such as TP53, in whom, in our opinion, transplant may have to be considered only if an optimal donor is available, optimal pre‐transplant response has been obtained and if lower doses of post‐transplant 5‐azacitidine or decitabine are considered. Lower doses of 5‐azacitidine can also be considered in patients at high risk for relapse post transplantation. I endorse recently proposed US guidelines [ 143 ].

Investigational Approaches for Patients With Higher MDS

The results of the AZA‐001 trial still represent the best standard of care for patients with higher risk disease [ 89 ]. Several combinations have been evaluated to improve on the results of single agent HMA. The status of some of these combination phase III studies has been reviewed in detail [ 150 ]. The VERONA trial was recently presented REF. This was a placebo randomized study of azacitidine with or without venetoclax for patients with higher risk MDS REF. This study followed the success of the VIALE trial in AML [ 151 ]. Even though ORR was significantly higher in patients treated with the combination (76% vs. 57%, p = 0.0001), survival was not different between both arms (22.2 months for the venetoclax combination vs. 21.7 for azacitidine and placebo). We are expecting a full manuscript of this study to be able to interpret these results. A follow up phase 3 study with a second generation BCL2 inhibitor, lisaftoclax (GLORA‐4 NCT06641414 ) is ongoing. A combination study of oral dac/ced with venetoclax is ongoing. This example of total oral therapy has demonstrated encouraging results with an ORR of 94% and a median survival of 30 months [ 152 ]. Based on results from these combinations studies with azacitidine, several groups are evaluating the role of non HMA approaches such as CPX‐351 [ 153 ], and cladribine‐ara‐C‐venetoclax.

Recommendation: All patients with MDS should be considered for an investigational clinical trial when possible .

Hypomethylating Agent Failure Still a Major Unmet Need in MDS

The prognosis of patients with HMA failure is very poor. Natural history differs between patients still in a lower risk category where the survival is 15–17 months versus those with higher risk failure that have a survival of 4–6 months. A study with the multikinase inhibitor rigosertib in higher risk HMA failure identified two subsets of patients in the higher risk category: those with primary failure (never responded to HMA therapy) and those with secondary failure (relapsed) [ 154 ]. At the present time, there is no therapy that has been shown to have significant activity for this group of patients. For patients with higher risk HMA failure options that have been investigated included rigosertib [ 154 ], venetoclax [ 155 , 156 ], and guadecitabine among several.

Cytogenetic and molecular NGS data have value when deciding therapy, particularly AML‐like approaches, in patients with HMA failure MDS. Data from a phase II trial of clofarabine and low dose ara‐C in patients with relapsed refractory MDS indicated that lower doses of this combination in patients with diploid cytogenetics were associated with significant response rates and that response in this trial was associated with a median survival of 22 months [ 157 ]. Therefore, selecting patients for this type of therapy (i.e., diploid cytogenetics) could be associated with improved outcomes in this group of patients. This observation is being followed with studies using lower doses of cladribine and low dose ara‐C and in a phase 1 trial of CPX‐351.

Recommendations

All patients with higher risk disease that have relapsed or refractory disease should be considered for an investigational clinical trial and potentially alloSCT .

Incorporating Precision Medicine in MDS

One of the major advances in research in MDS has been the incorporation of NGS assays, first in the laboratory, and now in the clinic. This data is not only allowing better understanding and prognostication of the disease but also design of targeted approaches for patients with MDS. Genes of interest include SF3B1, IDH2, IDH1, Flt‐3, p53, and the small subset of patients with NPM1 mutated disease. SF3B1 is involved in gene splicing and is the most commonly mutated gene in MDS [ 57 ]. Luspatercept is indicated for a patient population enriched for SF3B1. Agents that target IRAK4 also seem to be dependent on splicing patterns [ 158 ]. IDH1 and 2 are mutated in MDS in 5%–15% of patients, respectively [ 159 ]. Initial data in AML studies that included a small group of patients with MDS suggested significant activity of IDH inhibitors also in MDS [ 160 , 161 ]. A follow‐up study with enasidenib has demonstrated significant activity of this compound in MDS [ 162 ]. The IDH1 inhibitor ivosidenib was approved in 2023 for MDS. Despite that, Flt‐3 mutations are very rare in patients with MDS [ 163 ], they have been shown to occur in 15%–30% of patients with HMA failure [ 164 ]. Those patients tend to have laboratory evidence of leukocytosis. Data from an add‐back design with sorafenib by Ravandi et al. indicated significant activity of the addition of the Flt‐3 inhibitor to azacitidine in patients with HMA failure [ 165 ]. This is being followed by several small studies using second and third generation Flt‐3 inhibitors in MDS. Mutation on the p53 gene has been reported in close to 10% of patients with MDS [ 166 ]. Most of them are therapy related and have complex cytogenetics and therefore have a very poor prognosis. These patients tend to be resistant to conventional chemotherapy and, although they seem to be sensitive to HMA‐based therapy, responses are short and prognosis still dismal [ 55 ]. Of importance, the presence of p53 mutations is associated with a very high rate of relapse post transplantation [ 146 ]. Treatment of p53 mutated disease is still a major need. Finally, around 1% of patients with MDS carry a mutation on the NPM1 gene [ 167 ]. Although it can be argued that these patients constitute a rare subset of patients with AML, as those the presence of core binding factor abnormalities, the reality is that morphologically these patients are undistinguishable from other patients with higher risk MDS. A report from a small series of patients from MD Anderson indicates a very high rate of response and potentially cure with a cytarabine type of approach followed by alloSCT [ 167 ].

Recommendation: We advocate the use of an NGS panel at baseline and each time a therapeutic decision is going to be made in patients with MDS .

The Case for Total Therapy Incorporating alloSCT in MDS

Therapy for MDS has been dichotomized between patient candidates for alloSCT and those not candidates. Indeed, even today there is a debate of whether we need bridge therapy prior to SCT [ 168 ]. This is probably related to the fact that single agent HMA may not be very effective in achieving deep responses in MDS and not due to the fact that complete cytogenetic or molecular responses would not be associated with better outcomes in the transplant setting. This is further complicated by the fact that we observe very high relapse rates post‐transplant in specific subsets of patients such as those with p53 mutations or complex cytogenetics [ 146 ]. But the outcomes of patients that receive powerful new combinations (i.e., oral decitabine/venetoclax) followed by alloSCT are approximating long term survival rates in close to 60% of patients; REF still argue for a concept total therapy.

Conclusions

The treatment landscape for patients with MDS has changed since 2023. The approval of luspatercept and imetelstat has transformed the care of patients with lower‐risk MDS. The development of oral decitabine/cedazuridine represents an improvement for patients with higher‐risk MDS and CMML. Data with alloSCT continues to improve. Despite this progress, we need alternatives that improve survival in higher‐risk MDS. Areas of special need are the group of p53‐mutated disease and patients with HMA failure disease.

Funding

This work was supported by the University of Texas MD Anderson Cancer Center, CA016672.

Conflicts of Interest

The author declares no conflicts of interest.

Acknowledgments

This work was supported in part by the University of Texas MD Anderson Cancer Center Support Grant CA016672 and by generous philanthropic contributions to the MD Anderson's MDS/AML Moon Shot Program.

Data Availability Statement

This is a review manuscript. Data reported here is publicly available.

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