Myelodysplastic Syndromes Medical Services in China

Myelodysplastic Syndromes (MDS) are a heterogeneous group of clonal hematopoietic stem cell disorders characterized by ineffective blood cell production, peripheral cytopenias, and an increased risk of progression to acute myeloid leukemia (AML). Pathogenically, MDS arises from acquired somatic mutations in hematopoietic stem or progenitor cells—commonly affecting genes involved in RNA splicing (e.g., SF3B1, SRSF2), DNA methylation (TET2, DNMT3A), chromatin modification (ASXL1), transcription regulation (RUNX1), and signal transduction (RAS pathway). These mutations disrupt normal differentiation and promote apoptosis in the bone marrow, leading to dysplastic morphology across one or more myeloid lineages (erythroid, granulocytic, megakaryocytic). The bone marrow is typically hypercellular, though hypocellular variants exist. Disease progression correlates with accumulating genetic lesions and worsening cytogenetic abnormalities—particularly complex karyotypes or monosomy 7. Epidemiologically, MDS predominantly affects older adults, with a median age at diagnosis of 70–75 years. Incidence rises sharply after age 60, estimated at 3–5 per 100,000 persons annually in Western populations; however, recent epidemiologic studies in China suggest incidence may be underreported but is likely comparable—approximately 2–4 per 100,000 among those aged ≥65. Risk factors include prior exposure to chemotherapy (especially alkylating agents and topoisomerase II inhibitors), radiation therapy, benzene and other organic solvent exposures, smoking, and inherited bone marrow failure syndromes (e.g., Fanconi anemia, telomere biology disorders). Age remains the strongest non-modifiable risk factor. Quality of life in MDS is significantly impaired—not only due to fatigue, shortness of breath, recurrent infections, and bleeding tendencies stemming from anemia, neutropenia, and thrombocytopenia—but also from psychological burden, treatment-related side effects (e.g., transfusion iron overload, immunosuppression), and uncertainty around disease evolution. Patients frequently report reduced physical functioning, social withdrawal, anxiety about AML transformation, and diminished capacity for daily activities and employment. Supportive care—including red blood cell and platelet transfusions, growth factor use (e.g., erythropoietin analogs), and iron chelation—is foundational, yet does not alter disease biology. Higher-risk MDS requires disease-modifying therapies such as hypomethylating agents (azacitidine, decitabine), lenalidomide (particularly in del(5q) cases), or allogeneic hematopoietic stem cell transplantation—the only potentially curative option, albeit limited by age, comorbidities, and donor availability. Comprehensive management demands multidisciplinary coordination between hematologists, transfusion medicine specialists, psychologists, and palliative care teams to optimize both survival and patient-centered outcomes.

Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis, peripheral blood cytopenias, dysplasia in one or more myeloid lineages, and an increased risk of progression to acute myeloid leukemia (AML). The pathogenesis of MDS involves acquired somatic mutations in hematopoietic stem and progenitor cells, leading to disrupted differentiation, increased apoptosis in the bone marrow, and eventual clonal dominance. While the precise initiating event remains incompletely defined in most cases, MDS arises from cumulative genetic and epigenetic alterations that impair normal myeloid maturation and confer selective survival advantages to abnormal clones.

Common causes include prior exposure to cytotoxic chemotherapy and ionizing radiation—termed therapy-related MDS (t-MDS). Alkylating agents (e.g., cyclophosphamide, melphalan, busulfan) and topoisomerase II inhibitors (e.g., etoposide, doxorubicin) are strongly associated with t-MDS, typically manifesting 5–10 years and 1–3 years post-exposure, respectively. Radiation exposure—whether therapeutic (e.g., total body irradiation for transplant conditioning) or accidental—induces DNA double-strand breaks and chromosomal instability, predisposing to high-risk MDS subtypes often with complex karyotypes.

Genetic factors play a central role. Recurrent somatic mutations affect genes involved in RNA splicing (SF3B1, SRSF2, U2AF1, ZRSR2), DNA methylation (TET2, DNMT3A, IDH1/IDH2), chromatin modification (ASXL1, EZH2), transcription regulation (RUNX1), signal transduction (NRAS, KRAS, CBL), and cohesin complex function (STAG2, RAD21). SF3B1 mutations correlate strongly with ring sideroblasts and favorable prognosis, whereas TP53 mutations—particularly multi-hit (biallelic) lesions—are linked to complex karyotypes, resistance to hypomethylating agents, rapid progression to AML, and poor overall survival. Germline predisposition syndromes also contribute: GATA2 deficiency (associated with monocytopenia, NK-cell lymphopenia, and high risk of MDS/AML), RUNX1 familial platelet disorder, ETV6-related thrombocytopenia, DDX41-associated familial MDS/AML, and telomere biology disorders (e.g., dyskeratosis congenita) significantly increase lifetime risk, especially when diagnosed before age 50.

Environmental exposures constitute important modifiable risk factors. Chronic benzene exposure—common in petroleum refining, rubber manufacturing, and shoemaking—is dose-dependently associated with MDS and AML via oxidative stress, inhibition of topoisomerase II, and induction of chromosomal aberrations. Smoking tobacco introduces benzene, polycyclic aromatic hydrocarbons, and reactive oxygen species, conferring a 1.5- to 2-fold increased risk, particularly for higher-risk MDS subtypes. Pesticide exposure (e.g., organophosphates, chlorinated compounds) and heavy metals (e.g., lead, mercury) have shown epidemiologic associations, though evidence is less robust than for benzene or smoking. Additionally, chronic immune dysregulation—including autoimmune conditions (e.g., rheumatoid arthritis, systemic lupus erythematosus) and prolonged immunosuppressive therapy (e.g., azathioprine, cyclosporine)—may promote clonal selection through chronic inflammatory cytokine signaling (e.g., TNF-α, IFN-γ) and T-cell–mediated marrow suppression.

Demographic and clinical risk factors include advanced age (median diagnosis at 70–75 years), male sex (slight predominance), and preexisting hematologic conditions such as aplastic anemia, paroxysmal nocturnal hemoglobinuria (PNH), or clonal hematopoiesis of indeterminate potential (CHIP). CHIP—defined by the presence of somatic driver mutations (e.g., DNMT3A, TET2, ASXL1) in peripheral blood at variant allele frequency ≥2% without cytopenias or dysplasia—confers a 0.5–1% annual risk of progression to MDS or AML. Comorbidities including chronic kidney disease, diabetes mellitus, and cardiovascular disease may exacerbate marrow stress and influence treatment tolerance but are not direct etiologic factors. Importantly, the majority of MDS cases are idiopathic (de novo), with no identifiable external trigger; these likely result from stochastic accumulation of age-related mutations compounded by intrinsic genomic instability and declining DNA repair fidelity in aging hematopoietic stem cells. Understanding this multifactorial etiology is essential for risk stratification, surveillance in high-risk cohorts, and development of targeted preventive and therapeutic strategies.

Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis, peripheral blood cytopenias, dysplasia in one or more myeloid lineages (erythroid, granulocytic, megakaryocytic), and an increased risk of progression to acute myeloid leukemia (AML). As a disorder primarily managed within the Department of Hematology, MDS often presents insidiously, with symptoms reflecting underlying bone marrow failure rather than overt malignancy. Early symptoms are frequently nonspecific and may be attributed to aging, chronic fatigue, or other common conditions—leading to diagnostic delays averaging 6–12 months from symptom onset.

Early symptoms typically arise from progressive cytopenias and include persistent fatigue, diminished exercise tolerance, and unexplained pallor—most commonly due to anemia (hemoglobin <10 g/dL). Patients may report mild exertional dyspnea, lightheadedness upon standing (orthostatic intolerance), or palpitations, especially in those with preexisting cardiovascular disease. Mild, recurrent infections—such as upper respiratory tract infections, sinusitis, or skin abscesses—may occur early in the course, particularly when absolute neutrophil count (ANC) falls below 1.5 × 10⁹/L; however, severe or life-threatening infections are uncommon at initial presentation unless profound neutropenia (<0.5 × 10⁹/L) is present. Easy bruising, petechiae, or prolonged bleeding after minor trauma may signal thrombocytopenia (platelet count <100 × 10⁹/L), though spontaneous mucocutaneous hemorrhage is rare unless platelets drop below 30 × 10⁹/L.

Typical symptoms reflect established multilineage cytopenias and morphologic dysplasia. Anemia remains the most prevalent manifestation: macrocytic or normocytic anemia (mean corpuscular volume often >100 fL) with associated reticulocytopenia, anisopoikilocytosis, and basophilic stippling on peripheral smear. Neutropenia manifests as recurrent bacterial infections (e.g., cellulitis, pneumonia, urinary tract infections), fever of unknown origin (FUO), or delayed wound healing. Dysgranulopoiesis may be evident as hypogranular or pseudo-Pelger–Huet neutrophils. Thrombocytopenia-related signs include mucosal oozing (e.g., gingival bleeding, menorrhagia), purpura, and prolonged bleeding time; megakaryocytic dysplasia often correlates with abnormal platelet morphology (e.g., hypolobated or monolobated megakaryocytes) and functional platelet defects despite near-normal counts.

Accompanying symptoms may include constitutional features such as low-grade fevers (<38.3°C), night sweats, and unintentional weight loss (>5% body weight over 6 months)—though these are less common in lower-risk MDS and should raise suspicion for higher-risk disease or transformation to AML. Some patients report neuropathic symptoms (e.g., paresthesias, distal sensory loss) secondary to vitamin B12 or folate deficiency—often exacerbated by ineffective erythropoiesis and increased cellular turnover—or iron overload from repeated red blood cell transfusions. Splenomegaly is uncommon in de novo MDS but may occur in advanced or therapy-related cases; hepatomegaly is rare. Fatigue severity often exceeds what would be expected from hemoglobin levels alone, suggesting contributions from chronic inflammation (elevated IL-6, TNF-α), mitochondrial dysfunction in hematopoietic progenitors, and cytokine-mediated neurologic effects.

Complications of MDS are directly linked to cytopenias, clonal evolution, and therapeutic interventions. The most serious complication is leukemic transformation: approximately 30% of patients with higher-risk MDS (per IPSS-R) progress to AML within 2 years, marked by rapid cytopenia worsening, circulating blasts (>20%), organ infiltration, and poor response to induction chemotherapy. Infection-related mortality remains the leading cause of death in lower-risk MDS, particularly among elderly patients with comorbidities. Iron overload—due to chronic transfusion dependence (typically >20 units RBCs)—can lead to end-organ damage including cardiomyopathy, hepatic fibrosis, and endocrine dysfunction (e.g., diabetes mellitus, hypogonadism). Thrombohemorrhagic complications occur paradoxically: while thrombocytopenia predisposes to bleeding, certain MDS subtypes (e.g., MDS with isolated del(5q)) and JAK2-mutated clones confer increased thrombotic risk—including deep vein thrombosis, pulmonary embolism, and arterial events. Therapy-related complications include cytopenia exacerbation following hypomethylating agents (azacitidine/decitabine), immune-mediated cytopenias post-transplant, and secondary malignancies following intensive chemotherapy or allogeneic hematopoietic cell transplantation (allo-HCT).

Diagnosis requires integration of clinical, morphologic, cytogenetic, and molecular data per WHO 2022 and ICC 2022 criteria. Initial evaluation includes complete blood count with differential, peripheral blood smear review (assessing dysplasia, blast percentage, and abnormal cell morphology), and reticulocyte count. Bone marrow aspiration and biopsy are mandatory: aspirate morphology evaluates dysplasia across lineages (≥10% dysplastic cells in ≥1 lineage required for diagnosis); trephine biopsy assesses cellularity, fibrosis, and architecture. Cytogenetic analysis (karyotyping) detects clonal abnormalities in ~50% of cases—common findings include del(5q), −7/del(7q), +8, del(20q), and complex karyotype (≥3 abnormalities). Fluorescence in situ hybridization (FISH) augments detection of specific lesions (e.g., del[5q], TP53 deletions). Next-generation sequencing (NGS) panels targeting ≥30 genes (e.g., SF3B1, TET2, ASXL1, SRSF2, U2AF1, RUNX1, TP53, EZH2) are now standard: SF3B1 mutation strongly predicts ring sideroblasts and favorable prognosis; TP53 multi-hit status (mutation + deletion) defines a distinct, very high-risk entity. Serum ferritin, lactate dehydrogenase (LDH), vitamin B12, folate, and iron studies help exclude nutritional or reactive causes. Flow cytometry assists in detecting aberrant immunophenotypes and excluding acute leukemia or lymphoproliferative disorders.

Differential diagnosis is broad and necessitates exclusion of mimics. Reactive causes of cytopenias and dysplasia include nutritional deficiencies (B12, folate, copper), chronic inflammatory states (e.g., rheumatoid arthritis, IBD), viral infections (EBV, HIV, parvovirus B19), autoimmune disorders (e.g., Evans syndrome), and drug-induced myelosuppression (e.g., chemotherapy, azathioprine, valproic acid). Clonal mimics include chronic myelomonocytic leukemia (CMML), which features persistent monocytosis (>1 × 10⁹/L) and overlapping dysplasia; juvenile myelomonocytic leukemia (JMML) in children; and AML with minimal differentiation (blasts ≥20%). Other considerations include aplastic anemia (pancytopenia with hypocellular marrow but no dysplasia or clonality), large granular lymphocyte leukemia (associated with neutropenia and CD3+CD8+ T-cell expansion), and inherited bone marrow failure syndromes (e.g., Fanconi anemia, telomere biology disorders), particularly in younger patients. Paroxysmal nocturnal hemoglobinuria (PNH) clones may coexist with MDS and contribute to cytopenias; flow cytometry for GPI-anchored proteins is indicated in select cases. Accurate distinction relies on comprehensive phenotyping, cytogenetics, and molecular profiling—underscoring the necessity of multidisciplinary hematologic evaluation.

Myelodysplastic Syndromes (MDS) are a heterogeneous group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis, peripheral blood cytopenias, dysplasia in one or more myeloid lineages, and an increased risk of progression to acute myeloid leukemia (AML). Management is highly individualized, guided by prognostic scoring systems—including the Revised International Prognostic Scoring System (IPSS-R)—which integrate cytogenetics, blast percentage, and severity of cytopenias. Treatment strategies span supportive care, disease-modifying pharmacotherapy, and potentially curative interventions, with goals ranging from symptom control and transfusion independence to long-term remission or cure.

Conservative (supportive) treatment remains foundational for all MDS patients, particularly those with lower-risk disease (IPSS-R Very Low, Low, or Intermediate). It focuses on mitigating complications of cytopenias without directly targeting the underlying clone. Red blood cell (RBC) transfusions alleviate anemia-related fatigue, dyspnea, and cardiac strain; however, iron overload—especially after >20 units—is monitored via serum ferritin and MRI-based liver iron concentration, with iron chelation (e.g., deferasirox) initiated when indicated. Platelet transfusions are reserved for active bleeding or procedural support in thrombocytopenic patients (platelets <10 × 10⁹/L), avoiding routine prophylaxis due to alloimmunization risk. Granulocyte colony-stimulating factor (G-CSF), often combined with erythropoiesis-stimulating agents (ESAs) like epoetin alfa or darbepoetin, may improve hemoglobin levels in select low-risk patients with low endogenous erythropoietin (<500 U/L) and minimal transfusion dependence. Antibiotic prophylaxis is not routinely recommended, but prompt evaluation and broad-spectrum empiric therapy are critical for febrile neutropenia. Vaccination against influenza, pneumococcus, and hepatitis B is strongly advised.

Pharmacologic therapy targets disease biology and modifies natural history. Hypomethylating agents (HMAs)—azacitidine and decitabine—are standard first-line therapy for higher-risk MDS (IPSS-R High or Very High) and selected intermediate-risk patients. Azacitidine improves overall survival, reduces AML transformation, and achieves hematologic improvement in ~40–50% of patients; decitabine shows comparable efficacy with alternative dosing schedules. Lenalidomide is uniquely effective in del(5q) MDS, inducing transfusion independence in ~67% of patients and cytogenetic responses in ~50%, with durable responses often lasting >2 years. Immunosuppressive therapy (IST), including antithymocyte globulin (ATG) and cyclosporine, may benefit a subset of younger, HLA-DR15-positive, hypocellular MDS patients with features overlapping aplastic anemia. Emerging agents include luspatercept—a transforming growth factor-beta (TGF-β) superfamily trap approved for ring sideroblast-positive (RS+) MDS with anemia refractory to ESAs—demonstrating robust transfusion reduction and hemoglobin increases. Venetoclax combinations are under active investigation in higher-risk MDS, particularly with TP53 mutations, though data remain preliminary. All pharmacotherapies require vigilant monitoring for myelosuppression, infection, and secondary malignancies.

Surgical treatment is limited to allogeneic hematopoietic stem cell transplantation (allo-HSCT), the only potentially curative modality. Indicated primarily for fit patients with higher-risk MDS and suitable donors, allo-HSCT offers 5-year overall survival rates of 30–50%, heavily influenced by age, comorbidity burden (HCT-CI score), donor type (matched sibling vs. matched unrelated vs. haploidentical), and disease status at transplant. Reduced-intensity conditioning (RIC) regimens have expanded eligibility to older adults (up to age 70–75 in select centers), improving tolerability while preserving graft-versus-leukemia effects. Post-transplant management includes immunosuppression tapering, surveillance for relapse (via chimerism analysis and flow cytometry), and aggressive intervention for graft-versus-host disease (GVHD). Despite its curative potential, allo-HSCT carries significant risks—including treatment-related mortality (15–25%), chronic GVHD (30–50%), and late effects such as endocrine dysfunction and secondary cancers—necessitating comprehensive pre-transplant assessment and lifelong follow-up.

China offers distinct advantages in MDS management, anchored in rapidly advancing infrastructure and innovation. Over 200 accredited bone marrow transplant centers—including Peking University People’s Hospital, the First Affiliated Hospital of Sun Yat-sen University, and Ruijin Hospital—perform >10,000 allo-HSCTs annually, representing the world’s largest national transplant program. China pioneered widespread adoption of haploidentical HSCT using post-transplant cyclophosphamide, enabling near-universal donor availability and achieving outcomes comparable to matched donors. Domestic development of biosimilar HMAs (e.g., azacitidine generics) and novel agents—including the oral HMA ASTX727 (cedazuridine/decitabine) and the anti-CD47 antibody magrolimab in clinical trials—enhances accessibility and affordability. Integrated multidisciplinary teams (hematologists, transplant physicians, molecular pathologists, genetic counselors, and supportive care specialists) operate within tiered hospital networks, ensuring standardized diagnostics—including next-generation sequencing panels covering SF3B1, TET2, ASXL1, TP53, and splicing factors—and rapid turnaround for cytogenetics and molecular profiling. Moreover, China’s National Medical Products Administration (NMPA) has accelerated approval pathways for breakthrough therapies, shortening time-to-access for global innovations.

Recovery and long-term management emphasize proactive, patient-centered strategies. Patients should maintain rigorous infection prevention: hand hygiene, avoidance of crowded settings during neutropenia, and immediate reporting of fever (>38.0°C). Nutritional optimization—including iron- and folate-rich foods for non-transfused anemia, and protein supplementation during recovery from cytopenias or transplant—is essential. Physical activity tailored to energy levels (e.g., daily walking) combats fatigue and preserves functional capacity. Psychosocial support—including counseling, peer-led support groups, and cognitive-behavioral interventions—is integral, given high rates of anxiety and depression. Regular surveillance includes complete blood counts every 1–3 months (depending on risk and stability), annual bone marrow examinations for higher-risk patients or those with new cytopenias, and periodic assessment of iron stores, renal/hepatic function, and endocrine parameters post-transplant. Smoking cessation and alcohol moderation are strongly encouraged. Finally, shared decision-making—grounded in updated prognostic models, patient values, and realistic expectations—is paramount: for example, clarifying that HMAs aim for disease control rather than cure, while allo-HSCT entails substantial trade-offs between longevity and quality-of-life impact. With evolving therapeutic paradigms and growing expertise across Chinese hematology centers, outcomes for MDS continue to improve, underscoring the importance of timely referral to specialized hematologic care.