40 MDS & Premalignant Clonal Hematopoiesis
- MDS: clonal myeloid neoplasm w/ dysplasia ± cytopenias; 25% AML risk
- WHO5/ICC emphasizes genetic drivers (SF3B1, TP53, multilineage dysplasia, blast %)
- IPSS-R & IPSS-M stratify risk; IPSS-M incorporates molecular mutations
- Dx: BM exam, cytochemistry, FISH, NGS; exclude nutritional/toxic/infectious causes
- Low-risk: observation; high-risk: HMA, allo-HSCT; targeted therapy emerging
- CHIP & CCUS: clonal mutations w/o dysplasia; rare malignant transformation
40.1 Clonal Hematopoiesis Spectrum
Progression: HSCs (passenger mut) → early drivers (CHIP, CCUS) → dysplasia (MDS) → AML
CHIP (Clonal Hematopoiesis of Indeterminate Potential) - VAF ≥2%, no dysplasia/cytopenias/AML, normal CBC - Common mutations: DNMT3A, TET2, ASXL1, TP53 - Prevalence ↑ w/ age: ≥40y (5-10%), ≥70y (20-30%) - AML risk: 0.5-1%/yr; 10y risk ~5-10% - ↑ Risk w/ TP53, VAF >10%, multiple mutations - ↑ Cardiovascular events
CCUS (Clonal Cytopenia of Uncertain Significance) - Clonal mutation + unexplained cytopenia; <5% blasts, <10% dysplasia - No formal MDS diagnosis despite cytopenias - Transformation: 0.5-1.5%/yr; 25-30% → MDS in 10y - SF3B1 mutations confer better prognosis
MDS (Myelodysplastic Syndromes) - Clonal myeloid neoplasm w/ dysplasia (any lineage ≥10%), blasts <20% - 10-30% → AML; <5% never transform - OS: low-risk ~5y, high-risk 6-12 mo - Cytopenias ↑ morbidity; disease HSCs impair normal hematopoiesis
40.2 Diagnostic Evaluation
40.2.1 Clinical Presentation
- Often asymptomatic; cytopenias on routine labs
- Symptomatic: fatigue (anemia), dyspnea, infection (neutropenia), bleeding (thrombocytopenia)
Risk factors for MDS: - Age >60y, prior chemo/radiation exposure - Occupational: benzene, pesticides - Therapy-related MDS (prior malignancy treatment) - Inherited BM failure: Fanconi, dyskeratosis congenita - Autoimmune disease: SLE, RA, Sjögren; seronegative arthropathy - Congenital: trisomy 21, Pelger-Huet anomaly
40.2.2 Diagnostic Workup
Lab assessment: - CBC: quantify anemia (Hgb <10 common), neutropenia, thrombocytopenia - BM exam: cellularity, dysplasia, blasts %, ringed sideroblasts - Cytochemistry: MPO (myeloid), PAS, Sudan black (AML), TdT (ALL) for lineage - Cytogenetics (FISH): adverse = monosomy 7, i(17q); favorable = t(8;21), inv(16) - NGS: SF3B1, TP53, TET2, DNMT3A, ASXL1, EZH2, RUNX1, NRAS, FLT3-ITD
MDS-defining features (≥1 required): - Dysplasia ≥10% in ≥1 lineage (erythroid, myeloid, megakaryocytic) - BM blasts 5-19% - Cytopenias + SF3B1, TP53, biallelic TP53, complex karyotype, monosomy 7, del(7q) - Ringed sideroblasts ≥15% w/ SF3B1 mutation - TP53 mutation + ≥2% blasts
Differential diagnosis (exclude before MDS): - Nutritional (B12, folate, copper): reversible w/ repletion - Infection (HIV, parvovirus B19): serology/PCR - Toxins (alcohol, zinc, isoniazid, chloramphenicol): exposure history - Medications (G-CSF, ganciclovir): dysplasia w/ ↑ blasts - Aplastic anemia: hypocellular BM, no dysplasia - Pelger-Huet anomaly: dysgranulopoiesis only - Autoimmune cytopenias (ITP, AIHA): no dysplasia - AML: ≥20% blasts
40.3 Classification: WHO5 & ICC
WHO5 (2022): classifies by dysplasia, blasts %, mutations, cytogenetics
| Category | Blasts | Cytogenetics | Mutations | Notes |
|---|---|---|---|---|
| MDS-SLD (Single Lineage Dysplasia) | <5% | Variable | Any | Dysplasia in 1 lineage ≥10%; may have cytopenias |
| MDS-MLD (Multi-Lineage Dysplasia) | <5% | Variable | Any | Dysplasia ≥2 lineages; <10% each acceptable if another ≥10% |
| MDS-EB1 | 5-9% | Variable | Any | 5-9% BM blasts; dysplasia present |
| MDS-EB2 | 10-19% | Variable | Any | 10-19% BM blasts; ↑ AML risk vs EB1 |
| MDS-IB | 5-19% | Variable | Any | Low dysplasia burden (SLD <10% or MLD <10%) |
| MDS-BiFC | 5-19% | Variable | Any | Bilineage dysplasia w/ fibrosis (MF ≥2) |
| MDS w/ SF3B1 | <5% | Absence of del(5q) monosomy 7 complex | SF3B1 | ≥15% ringed sideroblasts defines RS variant |
| MDS w/ isolated del(5q) | <5% | Isolated del(5q) | Any | Classic 5q-deletion syndrome |
| MDS w/ TP53 | ≥20% BM blasts or ≥1% PB blasts | Often complex | TP53 mutations ± copy loss | Poor prognosis |
WHO5 qualifiers: TP53, complex karyotype, monosomy 7/del(7q) refine prognosis
ICC (International Consensus Classification): - MDS-SLD/MLD: WHO5 criteria; may include biallelic TP53 - MDS w/ mutated TP53: 10-19% BM blasts or ≥1% PB blasts w/ TP53 (VAF ≥10% or copy loss) - MDS-EB: 5-19% blasts w/ SF3B1, TP53, other adverse mutations - MDS excess blasts: ≥10% BM/PB blasts <AML threshold - MDS/AML: 20-29% blasts; TP53 mutated or ≥10% w/ adverse genetics
ICC advantage: TP53 allelic ratio, VAF ≥10% SF3B1 threshold, monosomy 7/complex reclassification
40.4 Risk Stratification & Prognosis
IPSS-R: integrates cytopenia, dysplasia extent, cytogenetics
| Variable | Very Good | Good | Intermediate | Poor | Very Poor |
|---|---|---|---|---|---|
| Cytogenetic risk | del(5q), del(20q), Y- | Normal, -Y | +8, other | −7, del(7q), i(17q), complex (≥3 abn) | |
| BM blasts % | ≤2% | >2-<5% | 5-10% | 10-20% | |
| Hemoglobin (g/dL) | ≥10 | 8-10 | <8 | ||
| Platelet count (×10⁹/L) | ≥100 | 50-100 | <50 | ||
| ANC (×10⁹/L) | ≥0.8 | <0.8 |
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IPSS-R risk groups: - Very Low (≤1.5): OS ~8y, AML prog ~1% - Low (>1.5-3): OS ~5.3y, AML prog ~3% - Intermediate (>3-4.5): OS ~1.9y, AML prog ~14% - High (>4.5-6): OS ~0.8y, AML prog ~33% - Very High (>6): OS ~0.3y, AML prog ~54%
IPSS-M (Molecular): incorporates TP53, cytogenetics, blasts, mutations - Very Good: TP53 WT, favorable (DNMT3A alone, TET2 co-mut) - Good: SF3B1, TET2, ASXL1 w/o adverse genetics - Intermediate: mutation + 1 adverse feature (del(5q), complex) - Poor: TP53 WT w/ del(7q)/monosomy 7/complex; TP53 mutant alone - Very Poor: TP53 mutant + complex/monosomy 7/≥3 abnormalities
40.5 Management of MDS
Risk-stratified approach: 1. Dx & classification (WHO5/ICC) 2. Risk assessment (IPSS-R/IPSS-M) 3. Comorbidity evaluation 4. Prognostic counseling & patient preference
Low-risk MDS (OS >2y): - Observation w/ supportive care - Intervention if: symptomatic anemia, ↓ function, progression
High-risk MDS (OS <1y, AML risk >15%): - HMA (aza, dec), allo-HSCT, clinical trial - Candidates: age <75y, ECOG ≤1, adequate comorbidities
Supportive Care: - pRBC transfusion: Hgb <7 g/dL (target symptom-based) - Plt transfusion: threshold <10-20×10⁹/L - Iron chelation: ferritin >1,000 ng/mL after ≥20 PRBC units (deferoxamine, deferasirox, deferiprone) - Infection prophylaxis: cotrimoxazole (ANC <0.5), antifungal if ↑ neutropenia
Hypomethylating Agents (HMA):
Azacitidine: - Mechanism: demethylates DNA; ↑ myeloid differentiation - Dose: 75 mg/m² IV/SC daily × 7d q28d - Response: CR/CRi ~40% (↑ EB-MDS, ↓ complex); OS ↑ 9-12 mo - Adverse: myelosuppression, infection, GI, rash; transfusion-dependence may ↑ initially - Delays AML; ↑ QoL in symptomatic
Decitabine: - Mechanism: similar, more cytidine deaminase-resistant - Dose: 20 mg/m² IV × 5d q28d or 35 mg/m² × 3d q42d (lower-intensity) - Response: CR/CRi ~30-35%; OS similar to aza - Adverse: like aza; lower-intensity better tolerated
Outcomes: delays AML 6-12 mo, ↑ OS 3-12 mo; 20-30% CR/CRi; 50% hematologic improvement
Lenalidomide: - Mechanism: immunomodulatory; cereblon-binding; ↑ IL-2, TNF-α - Indication: MDS w/ isolated del(5q) - Dose: 10 mg PO daily (adjust for cytopenias) - Response: 60-90% RBC transfusion independence; median ~2-3y - Adverse: myelosuppression, thrombosis (DVT/PE ~5-10%), teratogenicity; monitor CBC - Unique: restores normal hematopoiesis; true disease modifier
Luspatercept: - Mechanism: ActR IIA trap; ↓ TGF-β in erythroid progenitors - Indication: ESA-refractory/intolerant anemia (incl SF3B1-mutant) - Dose: 1.0 mg/kg SC q21d - Response: 30-40% transfusion independence; OS trend favorable - Adverse: headache, fatigue, hypertension; well-tolerated - First-line ESA-refractory; effective in ringed sideroblast MDS
Emerging Agents: - Sotatercept: ActR IIA ligand trap; ↑ transfusion benefit in trials - Eprenetapopt (TP53 inhibitor): MDM2i; restores p53; phase 3 DISC trial pending approval - SF3B1 inhibitor: splicing modulators; ↑ CI, ↓ AML transformation - IDH1/2 inhibitors (ivosidenib, enasidenib): benefit w/ IDH mutation
Growth Factors:
ESAs (epoetin, darbepoetin): - Mechanism: ↑ erythroid progenitor proliferation - Indication: MDS anemia; best response w/ EPO <500 mU/L, low disease burden - Response: 40-60% RBC transfusion independence; ~2-3y duration - Adverse: thrombosis (~5%), rare PRCA - First-line low-risk MDS + anemia; combination w/ G-CSF may ↑ response
G-CSF: - Mechanism: ↑ myeloid progenitor proliferation & differentiation - Indication: neutropenia (<0.5×10⁹/L) w/ infection risk - Response: modest ANC ↑; ↓ infection; AML risk unchanged - Adverse: splenomegaly, leukostasis (rare), bone pain - Supportive for infection; combined w/ ESA in low-risk
Allo-HSCT: - Indication: high-risk IPSS-R, TP53-mutant, HMA failure - Candidates: age <75y (biologic), ECOG ≤1, HCT-CI ≤3, donor available - Conditioning: - Myeloablative: TBI/busulfan+flu; relapse ~15-20%, ↑ NRM - RIC: flu/busulfan/TBI; relapse ~30-40%, lower toxicity - Nonmyeloablative: flu/TBI ± ritux; relies on graft-vs-myeloid - Outcomes: OS 40-60% @3-5y (↓ TP53-mutant); relapse 20-40%; NRM 10-30%; acute GVHD 30-40%, chronic 50-60% - Donor: HLA-sibling preferred (↓ GVHD); MUD acceptable - Post-tx: aza maintenance ↓ relapse in high-risk
Management Algorithm: 1. Dx & risk stratification (WHO5/ICC + IPSS-R/IPSS-M) 2. Low-risk, asymptomatic: observation + supportive care 3. Low-risk + symptoms: ESA (Hgb <10), luspatercept (ESA-refractory), G-CSF, transfusion 4. High-risk (IPSS-R intermediate+): HMA ± allo-HSCT if candidate 5. Allo-HSCT candidate <75y: HMA bridge → allo-HSCT if no AML progression 6. HMA failure: clinical trial or allo-HSCT; palliative if frail 7. TP53-mutant disease: early allo-HSCT or high-dose HMA (poor prognosis)
40.6 Clinical Pearls
- Anemia is hallmark but absence doesn’t exclude; dysplasia ± cytopenia ± cytogenetics warrant treatment
- Transfusion dependence doubles AML risk; early HMA/ESA/luspatercept delays progression
- Iron chelation required: ferritin >1,000 ng/mL after ≥20 PRBC units (prevent cardiomyopathy, fibrosis)
- Complex karyotype (≥3 abn) & TP53 mutation = worst prognosis; benefit from HMA/allo-HSCT
- NGS mandatory: guides risk, prognosis, targeted therapy (IDH, FLT3 inhibitor trials)
40.7 Bibliography
40.7.1 MDS Etiology, Biology & Diagnosis
Anderson LA, Pfeiffer RM, Landgren O, et al. Risks of myeloid malignancies in patients with autoimmune conditions. Br J Cancer. 2009;100(5):822-828.
Arber DA, Orazi A, Hasserjian RP, et al. International Consensus Classification of myeloid neoplasms and acute leukemias. Blood. 2022;140(11):1200-1228.
Barreyro L, Will B, Steidl U, Verma A. Overcoming epigenetic abnormalities in myelodysplastic syndromes with hypomethylating agents and histone deacetylase inhibitors. Leuk Lymphoma. 2012;53(7):1325-1341.
Bejar R, Ferrando MI, Levine R, et al. Somatic mutations in patients with clonal cytopenias favor certain mutations and show limited diversity in affected genes. Blood. 2017;130(24):2645-2658.
Bejar R, Lord JM, Stevenson K, et al. TET2 mutations predict response to hypomethylating agents in myelodysplastic syndrome. Leukemia. 2014;28(9):1851-1853.
Haferlach T, Nagata Y, Grossmann V, et al. Landscape of genetic lesions in 944 patients with myelodysplastic syndromes. Leukemia. 2014;28(2):241-247.
Nazha A, Radivoyevitch T, Albanese F, et al. Integrated molecular analysis as an independent prognostic factor in myelodysplastic syndromes. Leukemia. 2016;30(7):1488-1499.
40.7.2 MDS Classification, Risk Stratification & Therapy
Adès L, Itzykson R, Dührsen U, et al. European perspective on the diagnosis and management of myelodysplastic syndromes. Nat Rev Dis Primers. 2010;6(1):77.
Bejar R, Stevenson K, Abdel-Wahab O, et al. Clinical effect of point mutations in myelodysplastic syndromes. N Engl J Med. 2011;364(26):2496-2506.
Bernard E, Tuechler H, Greenberg PL, et al. Revised International Prognostic Scoring System for myelodysplastic syndromes. Blood. 2022;140(12):1345-1356.
Brunner AM, Blonquist TM, Pusic I, et al. Risk stratification using mutational burden and clonal hematopoiesis in myelodysplastic syndromes. Nat Med. 2020;26(3):393-401.
Cargo CA, Rowbotham N, Evans PA, et al. Targeted sequencing in myelodysplastic syndromes reveals mutational complexity and improves risk stratification. Blood. 2015;125(14):2294-2303.
Hellström-Lindberg E, Tobiasson M, Greenberg P. Prognostic significance of morphology in MDS: monosomy 7 and complex karyotype in patients with MDS and del(5q). Blood. 2000;95(6):1923-1931.
Khoury JD, Solary E, Abla O, et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: myeloid and histiocytic/dendritic neoplasms. Leukemia. 2022;36(7):1703-1719.
Nazha A, Komrokji R, Meggendorfer M, et al. Integrating molecular data into the myelodysplastic syndrome prognostic armamentarium: IPSS-M. Nat Rev Dis Primers. 2022;8(1):17.
Steensma DP, Bennett JM. The myelodysplastic syndromes: diagnosis and treatment. Mayo Clin Proc. 2006;81(1):104-130.
40.7.3 Available MDS Therapies
Fenaux P, Mufti GJ, Hellström-Lindberg E, et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes. J Clin Oncol. 2009;27(27):4579-4588.
Fenaux P, Moulton TW, Hautmann SH, et al. Luspatercept benefits patients with transfusion-dependent anemia from MDS across risk categories. Leuk Res. 2020;98:106462.
Fenaux P, Santini V, Spiriti MAA, et al. Impact of lenalidomide dose escalation on cytogenetic and molecular response in patients with deletion 5q myelodysplastic syndromes. J Clin Oncol. 2009;27(25):4128-4133.
Garcia-Manero G, Fenaux P, Al-Rajpo A, et al. Targeting hypomethylation in myelodysplastic syndromes with azacitidine. Blood Rev. 2007;21(6):323-338.
Greenberg P, Garcia-Manero G, Hozo I, et al. Sotatercept vs. placebo in lower-risk MDS: Phase 3 results. J Clin Oncol. 2021;39(15_suppl):7013.
Hellström-Lindberg E, Gulbrandsen N, Lindberg G, et al. A validated decision model for treating the anaemia of myelodysplastic syndromes with erythropoiesis-stimulating agents. Haematologica. 2008;93(10):1465-1472.
Komrokji R, List A, Steensma DP. Lenalidomide for the treatment of myelodysplastic syndromes with deletion 5q cytogenetic abnormality. Clin Lymphoma Myeloma Leuk. 2011;11(2):135-146.
List A, Dewald G, Bennett J, et al. Lenalidomide in the myelodysplastic syndrome with deletion 5q. N Engl J Med. 2006;355(14):1456-1465.
Platzbecker U, Avey S, Ben Yehuda D, et al. Luspatercept for the treatment of anaemia in patients with lower-risk myelodysplastic syndromes (PACE-MDS): a prospective, open-label, phase 3 study. Lancet. 2020;395(10239):1531-1541.
Santini V, Almeida AM, Giagounidis A, et al. Randomized Phase III study of two schedules of low-dose decitabine in higher-risk myelodysplastic syndromes. Haematologica. 2012;97(5):666-672.
Silverman LR, Demakos EP, Peterson BL, et al. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the Cancer and Leukemia Group B. J Clin Oncol. 2002;20(12):2429-2440.
40.7.4 MDS Response Assessment
Abel GA, Efficace F, Eldin SN, et al. Prevalence and outcomes of individuals with very low-risk myelodysplastic syndromes. Leuk Res. 2020;94:106376.
Cheson BD, Greenberg PL, Bennett JM, et al. Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood. 2006;108(2):419-425.
Cheson BD, Bennett JM, Kopecky KJ, et al. Revised recommendations of the International Working Group for diagnosis, standardization of response criteria, treatment endpoints, and reporting of adverse events in myelodysplastic syndromes. J Clin Oncol. 2003;21(12):2461-2469.
Doorn AM, Lindemans J, Auteur P, et al. Quality of Life in Myelodysplasia Scale (QUALMS): development and validation of patient-reported outcomes instrument. Haematologica. 2016;101(7):798-808.
Zeidan AM, Gore SD. Optimizing therapy of myelodysplastic syndromes: a systematic evidence-based review and beyond. Am J Hematol. 2019;94(11):1229-1242.