Learning objectives and key messages
- WHO 2022 renamed the disease "myelodysplastic neoplasm" and divided its subtypes into those "with defining genetic abnormalities" (MDS-5q, MDS-SF3B1, MDS-biTP53) and those "defined morphologically"; ICC 2022 introduced the MDS/AML category (10 to 19% blasts) and MDS with mutated TP53 [1, 2].
- The definition of cytopenia is the same in both systems: haemoglobin below 13 (men) or 12 g/dL (women), neutrophils below 1.8 and platelets below 150×109/L [1, 2]; in WHO 2022 the dysplasia threshold in each lineage is 10% [1].
- IPSS-M, by adding mutations in 31 genes to the IPSS-R variables, moved 46% of patients into a different risk group and improved prediction of outcome for every endpoint [3, 4].
- The aims of treatment in lower-risk MDS are to reduce transfusion need and the risk of progression to higher-risk disease or AML and to improve survival; in higher-risk MDS, to prolong survival [5].
- In transfusion-dependent, ESA-naive lower-risk MDS, more patients reached transfusion independence with a rise in haemoglobin on luspatercept than on epoetin alfa in COMMANDS (60% vs 35%) [6].
- In higher-risk MDS, azacitidine increased median survival from 15.0 to 24.5 months, and in patients aged 50 to 75, having a donor and a reduced-intensity transplant increased 3-year survival from 26.6% to 47.9%; new HMA combinations have failed in phase 3 [7, 8, 9].
Diagnosis and the WHO 2022 and ICC 2022 classifications
- From CCUS to MDS: CCUS means mutations associated with myeloid malignancy at a VAF of at least 2% with persistent, unexplained cytopenia, without the criteria for a myeloid neoplasm [1]; in the ICC the cytopenia must persist for at least 4 months, and CCUS is separated from MDS by the absence of dysplasia and of increased blasts [2].
- MDS-defining lesions even without dysplasia (ICC): del(5q), monosomy 7 or del(7q), complex karyotype and multi-hit TP53; SF3B1 with a VAF ≥10% is also enough for MDS-SF3B1 without dysplasia or ring sideroblasts. Other cytogenetic abnormalities that used to be "MDS-defining" are now regarded as CCUS without dysplasia [2].
- Hypoplastic MDS: a separate subtype in WHO 2022 (cellularity ≤25% adjusted for age), and many patients have a durable response to antithymocyte globulin (ATG); exclude a germline background of GATA2, DDX41, Fanconi anaemia or telomerase genes, because it does not respond to immunosuppression [1].
- TP53: about two thirds of patients with a TP53 mutation have multi-hit (biallelic) disease, and the poor outcome applies only to this group; patients with a monoallelic mutation had outcomes similar to wild type [10]. WHO says MDS-biTP53 may be regarded as equivalent to AML for treatment purposes [1].
| Topic | WHO 2022 | ICC 2022 |
|---|---|---|
| del(5q) | MDS-5q: blasts below 5% in the marrow and 2% in the blood; del(5q) alone or with one other abnormality other than monosomy 7 or del(7q); an SF3B1 mutation or a single (not multi-hit) TP53 mutation does not change the diagnosis [1] | MDS-del(5q): the same cytogenetic criterion; any mutation except multi-hit TP53 [2] |
| SF3B1 | MDS-SF3B1 with low blasts; no del(5q), monosomy 7 or complex karyotype; ring sideroblasts of 15% or more can substitute for the SF3B1 mutation [1] | MDS-SF3B1: VAF at least 10% without multi-hit TP53 or RUNX1; MDS with ring sideroblasts without SF3B1 falls under MDS, NOS [2] |
| TP53 | MDS-biTP53 (blasts below 20%): two or more mutations, or one mutation with evidence of copy loss or cnLOH; takes precedence over MDS-5q and MDS-SF3B1 [1] | MDS with mutated TP53 (blasts 0 to 9%): a multi-hit mutation or one mutation with a VAF above 10% and a complex karyotype; MDS/AML with mutated TP53 (10 to 19%): any mutation with a VAF above 10% [2] |
| Low blasts without defining genetics | MDS with low blasts (MDS-LB); separating single-lineage and multilineage forms is optional; hypoplastic MDS is a separate subtype [1] | MDS, NOS: without dysplasia (with monosomy 7/del(7q) or complex karyotype), with single-lineage or multilineage dysplasia [2] |
| Increased blasts | MDS-IB1: marrow 5 to 9% or blood 2 to 4%; MDS-IB2: marrow 10 to 19%, blood 5 to 19% or Auer rods; MDS with fibrosis (marrow 5 to 19%, blood 2 to 19%) [1] | MDS-EB: marrow 5 to 9% or blood 2 to 9%; 1% blood blasts on two occasions is also MDS-EB [2] |
| The MDS–AML boundary | The 20% blast boundary was kept; MDS-IB2 may be regarded as equivalent to AML for treatment purposes [1] | MDS/AML for 10 to 19% blasts in adults; these patients are eligible for both MDS and AML trials [2] |
| MDS, unclassifiable (MDS-U) | Removed [1] | Removed [2] |
| Therapy-related and germline | In the secondary myeloid neoplasms category: "post cytotoxic therapy" (now including PARP inhibitors) and "associated with germline predisposition" [1] | As a qualifier after the main diagnosis (for example "therapy-related") [2] |
The criteria proposed by the IWG-PM for MDS with mutated SF3B1 are cytopenia, a somatic SF3B1 mutation, dysplasia (with or without ring sideroblasts) and blasts below 5% in the bone marrow and 1% in the blood; this subtype has a relatively good prognosis and responds to luspatercept [11].
Risk stratification: IPSS-R versus IPSS-M
| Variable | 0 points | 0.5 | 1 | 1.5 | 2 | 3 | 4 |
|---|---|---|---|---|---|---|---|
| Cytogenetics | Very good | — | Good | — | Intermediate | Poor | Very poor |
| Bone marrow blasts (%) | ≤2 | — | More than 2 to less than 5 | — | 5 to 10 | More than 10 | — |
| Haemoglobin (g/dL) | ≥10 | — | 8 to less than 10 | Less than 8 | — | — | — |
| Platelets (×1000/µL) | ≥100 | 50 to less than 100 | Less than 50 | — | — | — | — |
| Neutrophils (/µL) | ≥800 | Less than 800 | — | — | — | — | — |
Cytogenetic groups: very good: −Y, del(11q); good: normal karyotype, del(5q), del(12p), del(20q), double abnormality including del(5q); intermediate: del(7q), trisomy 8, trisomy 19, i(17q) and any other single or double clone; poor: monosomy 7, inv(3)/t(3q)/del(3q), double abnormality including −7/del(7q), complex karyotype with 3 abnormalities; very poor: complex karyotype with more than 3 abnormalities [12].
| Risk group | Score | Percentage of patients | Median survival (years) | Time to AML transformation in 25% of patients (years) |
|---|---|---|---|---|
| Very low | ≤1.5 | 19 | 8.8 | Not reached |
| Low | More than 1.5 to 3 | 38 | 5.3 | 10.8 |
| Intermediate | More than 3 to 4.5 | 20 | 3.0 | 3.2 |
| High | More than 4.5 to 6 | 13 | 1.6 | 1.4 |
| Very high | More than 6 | 10 | 0.8 | 0.73 |
IPSS-R was built on 7012 patients; age, performance status, ferritin and LDH added to survival prediction but not to AML transformation [12].
IPSS-M was built from profiling of 152 genes in 2957 patients and validated in 754 Japanese patients; 94% of patients had at least one oncogenic lesion. Multi-hit TP53, FLT3 mutation and MLL-PTD were the strongest adverse genetic factors, and SF3B1 (depending on co-mutations) was a favourable factor. The final model, with haematological variables, cytogenetics and mutations in 31 genes, produces an individual score and 6 risk groups (very low, low, moderate-low, moderate-high, high and very high), reclassified 46% of patients and applies to primary and secondary or therapy-related MDS; its online calculator also handles missing data [3].
In a real-world validation (2876 patients), the concordance index of IPSS-M versus IPSS-R for overall survival was 0.81 versus 0.74; IPSS-M better predicted relapse and survival after transplant (5-year survival after transplant from 61% in the low group to 27% in the very high group) but did not predict response to hypomethylating agents. For acceptable accuracy, the status of at least 15 genes is needed: ASXL1, CBL, DNMT3A, ETV6, EZH2, FLT3, IDH2, MLL-PTD, NPM1, NRAS, RUNX1, SF3B1, SRSF2, multi-hit TP53 and U2AF1 [4].
Lower-risk MDS: treating anaemia
Algorithm for treating anaemia in lower-risk MDS
- 1
del(5q): lenalidomide
In MDS-003 (10 mg), 67% of patients became transfusion independent and the response was rapid (median 4.6 weeks) [13]. In the phase 3 MDS-004 trial, transfusion independence for at least 26 weeks was 56.1% with 10 mg, 42.6% with 5 mg and 5.9% with placebo [14]. Neutropenia and thrombocytopenia were the commonest reasons for interruption or dose modification [13].
- 2
Without del(5q), low serum EPO and low transfusion need: ESA
Serum EPO ≤500 U/L and a need of fewer than 2 units a month predict a high chance of response (61% with erythropoietin + G-CSF) [15]. Epoetin alfa 450 U/kg a week improved the erythroid response compared with placebo (31.8% vs 4.4% by IWG 2006 criteria and 45.9% after review) [16]; darbepoetin alfa also reduced transfusion need (36.1% vs 59.2%) [17].
- 3
Transfusion-dependent and ESA-naive: luspatercept or ESA
In COMMANDS (serum EPO below 500, need of 2 to 6 units in 8 weeks), transfusion independence for at least 12 weeks with a haemoglobin rise of at least 1.5 g/dL was 60% with luspatercept and 35% with epoetin alfa [6, 18]. Luspatercept is approved for anaemia in very low- to intermediate-risk, ESA-naive MDS [19].
- 4
- 5
ESA failure or unsuitability with high transfusion need: imetelstat
In IMerge (IPSS low or intermediate-1, need of 4 units or more in 8 weeks, no del(5q) and no previous lenalidomide or HMA), 8-week transfusion independence was 40% versus 15%; grade 3 to 4 neutropenia (68%) and thrombocytopenia (62%) were common [21, 22].
- 6
Transfusion and iron chelation
In the TELESTO trial (225 patients with lower-risk MDS, ferritin above 2247 pmol/L and 15 to 75 previous transfusion units), deferasirox prolonged event-free survival by about a year (3.9 vs 3.0 years; HR 0.64); creatinine rises were more common, and the study design was changed midway from phase 3 to phase 2 [24].
According to the label, chelation is started only with evidence of chronic iron overload: transfusion of at least 100 mL/kg of red cells (about 20 units in a person of 40 kg or more) and a persistent ferritin above 1000 µg/L. Deferasirox is contraindicated in higher-risk MDS, platelets below 50×109/L, eGFR below 40, poor performance status and advanced malignancy, and carries a boxed warning for renal and hepatic failure and gastrointestinal bleeding [25].
Higher-risk MDS: hypomethylating agents
In AZA-001 (higher-risk MDS), azacitidine 75 mg/m² for 7 days every 28 days, compared with conventional care (supportive care, low-dose cytarabine or intensive chemotherapy), increased median survival from 15.0 to 24.5 months (HR 0.58), and 2-year survival was 50.8% versus 26.2% [7]. Before judging failure, at least 4 to 6 cycles of azacitidine [26] or 4 cycles of decitabine [27] are needed. Oral decitabine-cedazuridine is approved for MDS (IPSS intermediate-1, intermediate-2 and high risk) and CMML [28].
Apart from allogeneic transplant, the standard in higher-risk MDS is still HMA monotherapy; combinations of azacitidine with eprenetapopt (APR-246), magrolimab, pevonedistat, sabatolimab, tamibarotene and venetoclax failed to improve complete response or survival in phase 3 trials. MDS with TP53 inactivation is best treated in dedicated trials, and the IWG 2023 response criteria should replace IWG 2006 [9].
Allogeneic transplant: who and when?
Deciding on transplant in MDS
- 1
Timing by risk
In a Markov decision analysis, delayed transplant (before leukaemic transformation) in IPSS low and intermediate-1, and transplant at diagnosis in intermediate-2 and high risk, gave the greatest life expectancy [29].
- 2
Candidates
- 3
Older age is not an absolute barrier
In BMT CTN 1102 (age 50 to 75, IPSS intermediate-2 or high, allocation by finding a donor within 90 days), 3-year survival in the donor group was 47.9% versus 26.6%, and leukaemia-free survival 35.8% versus 20.6% [8].
- 4
Conditioning and reducing disease burden
- 5
After transplant
In patients at high risk of relapse, pre-emptive donor lymphocyte infusion (DLI) strategies are recommended, and for relapse later than 6 months after transplant, DLI or a second transplant is an option [30].
Regimens and doses
Treatment regimens and doses: index10 regimens
- Lenalidomide: teratogenic; two negative pregnancy tests before starting and two contraceptive methods until 4 weeks after stopping are required. In MDS with del(5q), 80% of patients needed a dose delay or reduction; blood counts weekly for the first 8 weeks and then at least monthly. Risk of venous and arterial thrombosis (boxed warning) [32].
- ESA: boxed warning for increased risk of death, myocardial infarction, stroke, venous thromboembolism and tumour progression; use the lowest dose that reduces transfusion need [33]. In EPOANE the dose was reduced or stopped at a haemoglobin above 12 g/dL [16].
- Luspatercept: blood pressure before each dose; grade 3 to 4 hypertension in 2 to 9.6%; monitor for thromboembolism; contraception until at least 3 months after the last dose [19].
- Imetelstat: grade 3 to 4 thrombocytopenia (65%) and neutropenia (72%); weekly blood counts in the first 2 cycles; premedication for infusion reactions [22].
- Hypomethylating agents: cytopenias and infection; the dose is adjusted by count nadirs and kidney function [26, 27].
Anaemia treatment and iron chelation in lower-risk MDS
Epoetin alfa
Lower-risk MDS with haemoglobin ≤10 g/dL and low or moderate transfusion need; response more likely with serum EPO ≤500 U/LCycle length: Weekly
Lower-risk MDS with haemoglobin ≤10 g/dL and low or moderate transfusion need; response more likely with serum EPO ≤500 U/L
| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Epoetin alfa | 450 U/kg once a week (in COMMANDS escalated up to 1050 U/kg; maximum total 80,000 U) | Subcutaneous | Weekly |
In EPOANE the dose was increased or reduced according to the weekly haemoglobin and was reduced or stopped at a haemoglobin above 12 g/dL [16]; the dose and the escalation ceiling are from COMMANDS [6]. ESA boxed warning: the lowest effective dose [33]. The response prediction model was built with erythropoietin combined with G-CSF [15].
Evidence: COMMANDS (2024)
Lenalidomide (MDS with del(5q))
Transfusion-dependent anaemia in IPSS low or intermediate-1 MDS with del(5q), with or without other cytogenetic abnormalitiesCycle length: Continuous
Transfusion-dependent anaemia in IPSS low or intermediate-1 MDS with del(5q), with or without other cytogenetic abnormalities
| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Lenalidomide | 10 mg once a day | Oral | Daily |
Thrombocytopenia in the first 4 weeks (baseline ≥100,000/µL): stop at platelets below 50,000 and resume at 5 mg once 50,000 is reached; after 4 weeks: stop at platelets below 30,000 (or below 50,000 with platelet transfusion) and resume at 5 mg (if on 5 mg: resume at 2.5 mg). Neutropenia in the first 4 weeks (baseline ≥1000): stop below 750 and resume at 5 mg once ≥1000; after 4 weeks: neutrophils below 500 for 7 days or with fever ≥38.5 °C: stop and resume at 5 mg once ≥500 (and if it happens on 5 mg, at 2.5 mg). Kidney: CrCl 30 to 60: 5 mg daily; below 30 not on dialysis: 2.5 mg; on dialysis: 2.5 mg after dialysis [32].
Luspatercept
Anaemia in very low- to intermediate-risk (IPSS-R), ESA-naive MDS that may need regular transfusions; or ESA failure with a need of ≥2 units in 8 weeks in MDS with ring sideroblastsCycle length: Every 3 weeks
Anaemia in very low- to intermediate-risk (IPSS-R), ESA-naive MDS that may need regular transfusions; or ESA failure with a need of ≥2 units in 8 weeks in MDS with ring sideroblasts
| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Luspatercept | Start at 1 mg/kg; increase to 1.33 and then 1.75 mg/kg | Subcutaneous | Every 3 weeks |
Increase the dose after at least 2 consecutive doses (6 weeks) at each level if the patient still needs transfusions or (in an ESA-naive patient) has a haemoglobin below 10 g/dL with a rise of less than 1 g/dL from the previous dose; do not increase more often than every 6 weeks. Pre-dose haemoglobin ≥12 (ESA-naive) or ≥11.5 g/dL (after ESA failure) without transfusion: hold and resume at the same dose at ≤11; a rise of more than 2 g/dL in 3 weeks: reduce by one level (1.75 to 1.33, 1.33 to 1, 1 to 0.8, 0.8 to 0.6, and stop at 0.6). The haemoglobin target in an ESA-naive patient is 10 to 12 g/dL [19].
Darbepoetin alfa
Lower-risk MDS with haemoglobin ≤10 g/dL, low transfusion need and serum EPO ≤500 U/LCycle length: Every 3 weeks
Lower-risk MDS with haemoglobin ≤10 g/dL, low transfusion need and serum EPO ≤500 U/L
| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Darbepoetin alfa | 500 µg | Subcutaneous | Every 3 weeks |
Imetelstat (IMerge)
IPSS low or intermediate-1 MDS with transfusion-dependent anaemia of ≥4 units in 8 weeks, not responding to, having lost response to, or unsuitable for ESACycle length: Every 4 weeks
IPSS low or intermediate-1 MDS with transfusion-dependent anaemia of ≥4 units in 8 weeks, not responding to, having lost response to, or unsuitable for ESA
| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Imetelstat | 7.1 mg/kg | IV, 2-hour infusion | Every 4 weeks |
Premedication at least 30 minutes before: diphenhydramine 25 to 50 mg and hydrocortisone 100 to 200 mg; monitor for at least an hour after the infusion. Blood count before each dose, weekly in the first 2 cycles; delay the cycle if neutrophils are below 1×109/L or platelets below 50×109/L. Dose reduction for grade 3 to 4 toxicity: 5.6 and then 4.4 mg/kg; intolerance at 4.4: stop permanently. Contraception until 1 week after the last dose. The label gives the IMerge dose as 7.1 mg/kg (as imetelstat); each 47 mg of imetelstat equals 50 mg of imetelstat sodium [22], and the paper reported the dose as 7.5 mg/kg [21].
Deferasirox (iron chelation)
Chronic transfusional iron overload (≥100 mL/kg red cells and persistent ferritin above 1000 µg/L) in lower-risk MDSCycle length: Continuous
Chronic transfusional iron overload (≥100 mL/kg red cells and persistent ferritin above 1000 µg/L) in lower-risk MDS
| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Dispersible tablet (Exjade) | |||
| Deferasirox | 20 mg/kg once a day (adjust by 5 to 10 mg/kg; maximum 40) | Oral | Daily |
| Film-coated tablet (Jadenu) | |||
| Deferasirox | 14 mg/kg once a day (adjust by 3.5 to 7 mg/kg; maximum 28) | Oral | Daily |
Monthly ferritin and dose adjustment every 3 to 6 months; creatinine (twice before starting) and kidney function at least monthly, transaminases every 2 weeks in the first month and then monthly. eGFR 40 to 60: reduce the starting dose by 50%; below 40: contraindicated. Moderate hepatic impairment: reduce by 50%; severe: avoid. Contraindicated in higher-risk MDS and with platelets below 50×109/L [25, 34].
Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.
Higher-risk and relapsed MDS
Azacitidine (AZA-001)
Higher-risk MDS; also as a bridge to transplantCycle length: Every 4 weeks
Higher-risk MDS; also as a bridge to transplant
| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Azacitidine | 75 mg/m² a day (if no response after 2 cycles and no toxicity other than nausea: 100 mg/m²) | Subcutaneous or IV (10 to 40 minute infusion) | Days 1 to 7 |
Antiemetic premedication; blood count, liver tests and creatinine before the first dose. In a patient with normal baseline counts, the next cycle's dose by nadir: neutrophils below 0.5 or platelets below 25×109/L: 50%; neutrophils 0.5 to 1.5 or platelets 25 to 50: 67%. Unexplained serum bicarbonate below 20 mEq/L: reduce by 50%; unexplained rise in BUN or creatinine: delay until recovery and reduce by 50% [26]. AZA-001 used the same 7-day schedule every 28 days [7].
IV decitabine
MDS (including higher risk)
MDS (including higher risk)
| Drug | Dose | Route | Schedule |
|---|---|---|---|
| 5-day regimen | |||
| Decitabine | 20 mg/m² | IV, 1-hour infusion | Days 1 to 5; every 4 weeks |
| 3-day regimen | |||
| Decitabine | 15 mg/m² every 8 hours | IV, 3-hour infusion | Days 1 to 3; every 6 weeks |
The next cycle after recovery (neutrophils ≥1000 and platelets ≥50,000/µL). If recovery takes more than 6 and less than 8 weeks: delay up to 2 weeks and temporarily reduce to 11 mg/m² every 8 hours (3-day regimen); 8 to 10 weeks: assess the bone marrow for progression. With creatinine ≥2 mg/dL, ALT or bilirubin ≥2 times the upper limit or active infection, delay until resolved [27].
Oral decitabine-cedazuridine
MDS (IPSS intermediate-1, intermediate-2 or high risk), treated or untreated, and CMMLCycle length: Every 28 days
MDS (IPSS intermediate-1, intermediate-2 or high risk), treated or untreated, and CMML
| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Decitabine 35 mg + cedazuridine 100 mg | One tablet once a day | Oral, fasting (2 hours before or after food) | Days 1 to 5 |
Do not substitute for IV decitabine in the middle of a cycle; consider an antiemetic before each dose. In the ASTX727-01-B crossover study (80 patients), the tablet was compared in cycle 1 or 2 with IV decitabine 20 mg/m² on days 1 to 5 [28].
Ivosidenib (IDH1-mutated MDS)
Relapsed or refractory MDS with an IDH1 mutation in adultsCycle length: 28-day cycles
Relapsed or refractory MDS with an IDH1 mutation in adults
| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Ivosidenib | 500 mg once a day | Oral, without a high-fat meal | Continuous |
Boxed warning for differentiation syndrome; ECG before starting, weekly for the first 3 weeks and then monthly; with a strong CYP3A4 inhibitor, 250 mg. In the AG120-C-001 study, 7 of 18 patients (38.9%) reached complete response [23].
Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.
Key trials and guidelines
Key MDS evidence
6 itemsThe 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms
Molecular International Prognostic Scoring System for Myelodysplastic Syndromes
Lenalidomide in the Myelodysplastic Syndrome with Chromosome 5q Deletion
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
Luspatercept in Patients with Lower-Risk Myelodysplastic Syndromes
Efficacy and safety of luspatercept versus epoetin alfa in erythropoiesis-stimulating agent-naive, transfusion-dependent, lower-risk myelodysplastic syndromes (COMMANDS): interim analysis of a phase 3, open-label, randomised controlled trial
- In WHO, ring sideroblasts ≥15% can substitute for an SF3B1 mutation; in the ICC they cannot, and SF3B1 must have a VAF ≥10% [1, 2].
- MDS-biTP53 takes precedence over MDS-5q and MDS-SF3B1; a single monoallelic TP53 mutation does not change a diagnosis of MDS-5q [1].
- Monoallelic TP53 in MDS has outcomes like wild type; the poor outcome is specific to multi-hit TP53 [10].
- In IPSS-R, haemoglobin below 8 g/dL scores 1.5 and platelets below 50×109/L score 1 [12].
- IPSS-M predicts outcome after transplant, not response to HMA [4].
- Predictors of ESA response: serum EPO ≤500 and a need of fewer than 2 units a month [15].
- Luspatercept was better than epoetin alfa in ESA-naive patients (COMMANDS) [6].
- Deferasirox is contraindicated in higher-risk MDS and with platelets below 50×109/L [25].
- Before declaring HMA failure, at least 4 to 6 cycles of azacitidine are needed [26].
- Lower-risk MDS: delayed transplant; higher-risk MDS: transplant at diagnosis [29].
- Venetoclax, magrolimab and sabatolimab with azacitidine failed in phase 3 trials in higher-risk MDS [9].
Self-assessment questions
A 72-year-old man with haemoglobin 8.5 g/dL, platelets 120,000 and neutrophils 1500/µL, 3% bone marrow blasts, normal karyotype and an SF3B1 mutation with a VAF of 35%. What is the diagnosis and IPSS-R score?
In WHO: MDS with low blasts and SF3B1 mutation; in the ICC: MDS-SF3B1 (if there is no multi-hit TP53 or RUNX1) [1, 2]. IPSS-R score: good cytogenetics 1 + blasts more than 2 to less than 5% 1 + haemoglobin 8 to less than 10 1 + platelets 0 + neutrophils 0 = 3, that is the "low" group [12]. If transfusion-dependent and ESA-naive, luspatercept or an ESA is an option, and luspatercept was superior in COMMANDS [6].
A 70-year-old woman with MDS, isolated del(5q) and transfusion dependence. What is the treatment of choice and the monitoring needed?
Lenalidomide 10 mg daily; in MDS-003, 67% of patients became transfusion independent [13]. Blood counts weekly for the first 8 weeks and then monthly, dose modification for cytopenias and kidney function, contraception and attention to thrombosis risk [32]. Multi-hit TP53 would change the diagnosis to MDS-biTP53 [1].
A fit 66-year-old man with MDS, 12% bone marrow blasts and a complex karyotype who has a matched sibling donor. What is the right approach?
This is higher-risk disease, and allogeneic transplant at diagnosis gives the greatest life expectancy [29]; age up to 75 is not a barrier [8]. With blasts of 10% or more, cytoreductive treatment (for example an HMA) before transplant is recommended [30]. If multi-hit TP53 is also present, a dedicated trial is preferred [9].
Why is deferasirox not suitable for a patient with higher-risk MDS and platelets of 40,000/µL?
According to the label, deferasirox is contraindicated in higher-risk MDS and with platelets below 50×109/L, and there is a risk of fatal gastrointestinal bleeding, especially in older people with advanced haematological malignancy and low platelets [25].
How does MDS-biTP53 in WHO differ from "MDS with mutated TP53" in the ICC?
WHO: blasts below 20% with two TP53 mutations or one mutation with copy loss or cnLOH [1]. ICC: blasts 0 to 9% with a multi-hit mutation or one mutation with a VAF above 10% and a complex karyotype; with blasts of 10 to 19%, any TP53 mutation with a VAF above 10% is enough for MDS/AML with mutated TP53 [2].
Which patient with MDS is a candidate for imetelstat?
IPSS low or intermediate-1 MDS with transfusion-dependent anaemia of ≥4 units in 8 weeks that has not responded to, has lost response to, or is unsuitable for an ESA [22]. IMerge excluded patients with del(5q) or previous lenalidomide or HMA, and required neutrophils ≥1.5 and platelets ≥75×109/L [22].
Related cancer types
Treatment regimens (physicians)
Physician tools and lessons
References
34 referencesShow all references, 6 with a study cardClose the reference list
Numbers in the text, such as [1], refer to these sources. Sources with a “Study card” button are summarised in the site’s evidence library.
- 1
- 2
- 3Molecular International Prognostic Scoring System for Myelodysplastic Syndromes
- 4
- 5Myelodysplastic syndromes: 2023 update on diagnosis, risk-stratification, and management
- 6
- 7
- 8
- 9
- 10
- 11SF3B1-mutant MDS as a distinct disease subtype: a proposal from the International Working Group for the Prognosis of MDS
- 12
- 13
- 14A randomized phase 3 study of lenalidomide versus placebo in RBC transfusion-dependent patients with Low-/Intermediate-1-risk myelodysplastic syndromes with del5q
- 15
- 16
- 17
- 18Efficacy and safety of luspatercept versus epoetin alfa in erythropoiesis-stimulating agent-naive, transfusion-dependent, lower-risk myelodysplastic syndromes (COMMANDS): interim analysis of a phase 3, open-label, randomised controlled trial
- 19
- 20Luspatercept in Patients with Lower-Risk Myelodysplastic Syndromes
- 21
- 22
- 23
- 24Iron Chelation in Transfusion-Dependent Patients With Low- to Intermediate-1-Risk Myelodysplastic Syndromes: A Randomized Trial
- 25
- 26
- 27
- 28
- 29
- 30
- 31Myeloablative Versus Reduced-Intensity Hematopoietic Cell Transplantation for Acute Myeloid Leukemia and Myelodysplastic Syndromes
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- 34JADENU (deferasirox) tablets and granules — Prescribing Information
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