Hematopoietic Stem Cells: Eosinophilia and Hypereosinophilic Syndrome, Mastocytosis, and Myelodysplastic Syndromes

Added 6 August 2026

Eosinophilia and Hypereosinophilic Syndrome

Eosinophilia is defined as an absolute eosinophil count above 500/µL (0.5 × 109/L). In most patients the elevation is mild, transient, and secondary to another process, so the first task is to look for a reactive explanation rather than a primary hematologic disease. Parasitic infection should be considered in anyone who lives in or has traveled to an endemic area, including the southeastern United States, where strongyloidiasis is encountered.

CHINA — a mnemonic for the causes of eosinophilia: Collagen vascular disease (classically eosinophilic granulomatosis with polyangiitis); Helminthic (parasitic worm) infection such as Strongyloides; Idiopathic hypereosinophilic syndrome (a diagnosis of exclusion after extensive evaluation); Neoplasia — myeloproliferative neoplasms, acute myeloid leukemia, lymphomas (the most common neoplastic association), and some solid tumors; Allergy, atopy, asthma, and drug reactions (e.g., carbamazepine, sulfonamides).

Hypereosinophilic Syndrome: Definition and Subtypes

Hypereosinophilic syndrome (HES) is defined by a persistently elevated eosinophil count >1500/µL (1.5 × 109/L) together with organ damage directly mediated by eosinophils. Dermatologic, pulmonary, and gastrointestinal complications are the most commonly seen, but virtually any organ can be affected — described manifestations include gastroenteritis, sinusitis, pneumonitis, neuritis, vasculitis, thromboembolic events, and hepatosplenomegaly. Although infrequent, eosinophilic myocarditis is a major cause of morbidity and mortality; an echocardiogram and serum troponin belong in the initial evaluation, because troponin elevation correlates with cardiomyopathy and characteristic echo findings include apical ventricular thrombus, endocardial thickening, mitral or tricuspid valve abnormalities, a dilated left ventricle, and pericardial effusion.

Key point: Hypereosinophilic syndrome is defined by persistent eosinophil counts greater than 1500/µL (1.5 × 109/L) with end-organ damage.

HES is subclassified by mechanism. Primary HES is a rare clonal myeloproliferative neoplasm, often driven by abnormal tyrosine kinase activation through platelet-derived growth factor receptor-α or -β (PDGFRA or PDGFRB) gene fusions — the prototype being the karyotypically occult FIP1L1::PDGFRA deletion on chromosome 4q12. Secondary HES is reactive, caused by infections, solid tumors, drugs, or allergic/vasculitic disease, and is managed by treating the underlying condition. Cases that are neither clonal nor reactive are labeled idiopathic; some of these harbor a clonal or phenotypically abnormal T-cell population (lymphocytic-variant hypereosinophilia), detected by T-cell immunophenotyping and T-cell receptor gene rearrangement studies. An elevated serum tryptase in a patient with eosinophilia suggests mast cell involvement and should prompt molecular testing for FIP1L1::PDGFRA.

Treatment of HES

Patients with primary HES carrying a PDGFRA or PDGFRB rearrangement respond remarkably well to low-dose imatinib — in large series essentially all treated patients achieved complete hematologic responses, and treatment-free remissions are possible in some after discontinuation. In secondary HES the priority is addressing the underlying cause. For idiopathic disease, glucocorticoids are the cornerstone: prednisone is typically started at 1 mg/kg/day for one to two weeks, then tapered slowly over two to three months; hydroxyurea or interferon-α serves as a steroid-sparing agent if symptoms recur above 10 mg/day of prednisone. Mepolizumab, an anti–IL-5 monoclonal antibody, was FDA approved for HES in September 2020 and significantly reduces disease flares; alemtuzumab is an option in refractory cases.

Before giving glucocorticoids for HES, rule out active Strongyloides infection. Steroids can trigger hyperinfection and dissemination of strongyloidiasis, which can be fatal.

Mepolizumab remains the only approved biologic for HES so far, but the phase 3 NATRON trial recently reported that benralizumab — an eosinophil-depleting anti–IL-5 receptor-α antibody — significantly delayed time to first flare or worsening in FIP1L1::PDGFRA-negative disease, with a regulatory decision pending as of early 2026 [8].

Mastocytosis

Mastocytosis shares many features with the myeloproliferative neoplasms: excess clonal mast cell proliferation and accumulation in one or more organ systems. Cutaneous mastocytosis is limited to the skin — reddish-brown macules and papules that urticate when rubbed (Darier sign), solitary mastocytomas, or diffuse cutaneous infiltration. Systemic mastocytosis (SM) involves extracutaneous sites, most often the bone marrow but also the liver, spleen, and gastrointestinal tract, with or without skin disease. More than 95% of patients with SM carry an activating KIT mutation, classically KIT D816V. Most adult disease is indolent SM (>70% of cases) with normal life expectancy; the spectrum continues through smoldering SM (high mast cell burden without organ dysfunction), aggressive SM (organ damage from mast cell infiltration), SM with an associated hematologic neoplasm (for example MDS or CMML), and the rare, rapidly fatal mast cell leukemia. Progression from indolent to advanced forms is uncommon (∼5% lifetime risk), but patients should be monitored for emerging hematologic disease and end-organ damage.

Key point: Systemic mastocytosis involves clonal mast cell proliferation and infiltration into organ systems; more than 95% of cases carry an activating KIT mutation (usually D816V), and most are indolent with normal life expectancy.

Day-to-day symptoms are driven by mast cell mediator release — histamine, leukotrienes, and prostaglandins — causing vasodilation, flushing, pruritus and urticaria, nausea, vomiting, crampy abdominal pain, diarrhea, and gastric acid hypersecretion with peptic ulceration. Patients are at increased risk of anaphylaxis, most commonly induced by Hymenoptera stings and NSAIDs, and episodes can present with rapid, life-threatening vascular collapse.

Diagnosis requires tissue confirmation, usually from bone marrow. The major criterion is multifocal dense aggregates of 15 or more mast cells; minor criteria include atypical (spindle-shaped) morphology in more than 25% of mast cells, aberrant expression of CD25, CD2, or CD30, detection of KIT D816V or another activating KIT mutation, and a basal serum tryptase >20 ng/mL. One major plus one minor criterion, or three minor criteria, establishes the diagnosis; a basal serum tryptase is a useful noninvasive screen before biopsy. The differential includes carcinoid tumor (24-hour urine 5-hydroxyindoleacetic acid), pheochromocytoma (metanephrines), and hereditary α-tryptasemia.

Treatment is stepwise and symptom-directed: H1 antihistamines for flushing and pruritus, H2 antihistamines or proton pump inhibitors for gastric acid hypersecretion, oral cromolyn sodium for diarrhea and abdominal pain, and antileukotriene drugs. Because of the anaphylaxis risk, patients should carry self-injectable epinephrine, and those with systemic Hymenoptera venom reactions should receive lifelong venom immunotherapy if venom-specific IgE is present. Cytoreductive therapy is reserved for more aggressive forms and includes midostaurin, cladribine, interferon-α, and KIT-directed tyrosine kinase inhibitors; allogeneic stem cell transplantation may benefit selected patients with advanced variants.

The imatinib trap: imatinib is highly effective in PDGFR-rearranged eosinophilic neoplasms but is ineffective in most systemic mastocytosis, because the KIT D816V mutation mediates resistance. Do not extrapolate the imatinib responsiveness of one clonal mast cell/eosinophil disorder to another.
Post-publication update — avapritinib for indolent SM: In May 2023 avapritinib (25 mg daily) became the first FDA-approved therapy for indolent systemic mastocytosis, based on the placebo-controlled PIONEER trial: significant improvements in total symptom score, mast cell burden and tryptase, and quality of life, deepening through 48 weeks and well tolerated. ISM management is shifting from purely supportive care to disease-modifying, KIT D816V–directed therapy. [7]

Myelodysplastic Syndromes

Definition, Epidemiology, and Causes

The myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell disorders in which ineffective hematopoiesis produces a dysplastic, usually hypercellular bone marrow alongside peripheral blood cytopenias. Every case carries some risk of transformation to AML, and that risk — which correlates with prognosis — separates “low-risk” disease dominated by marrow failure from “high-risk” disease dominated by leukemic progression. Most patients die from complications of pancytopenia rather than from leukemic transformation, and a substantial proportion die of unrelated comorbid disease.

MDS is predominantly a disease of aging: the mean age at onset exceeds 70 years, with a slight male predominance and an incidence of 35 to more than 100 per million in the general population — rising to 120–500 per million in older adults. Most cases are idiopathic, but secondary MDS follows prior chemotherapy or radiation (therapy-related disease), benzene exposure, or smoking. Therapy-related MDS linked to alkylating agents typically appears after a 5–7 year latency, whereas topoisomerase II inhibitor–related disease has a latency of about 2 years; in patients younger than 40, constitutional marrow failure syndromes and germline predisposition (for example GATA2, RUNX1, or telomere biology disorders) should be considered.

Rule out reversible causes of dysplasia before diagnosing MDS: vitamin B12, folate, or copper deficiency; alcohol consumption; medications; and infections such as HIV. Dysplastic marrow changes are not specific to MDS and can be seen with deficiencies, drug effects, and acute viral illness.

Classification

The 2016 WHO classification organized MDS by the number of dysplastic lineages, the blast percentage, and defining cytogenetic abnormalities: MDS with single lineage dysplasia; MDS with ring sideroblasts (strongly associated with SF3B1 mutations); MDS with multilineage dysplasia; MDS with excess blasts-1 (5%–9% marrow blasts) and excess blasts-2 (10%–19% blasts or Auer rods); MDS with isolated del(5q); and unclassifiable cases. Historically, the boundary separating MDS from AML has been set at 20% blasts in the marrow.

Post-publication update — the 2022 classifications: Both the 5th edition WHO classification and the International Consensus Classification (ICC, 2022) reorganize MDS around molecular lesions: MDS with low blasts and isolated 5q deletion, MDS with SF3B1 mutation, and the new entity MDS with biallelic (multi-hit) TP53 inactivation, alongside morphologically defined categories such as MDS with low blasts, hypoplastic MDS, and MDS with increased blasts-1/-2. The ICC additionally introduces an MDS/AML category (10%–19% blasts), emphasizing the continuum between high-blast MDS and AML. [4]

Presentation and Diagnosis

Macrocytic anemia is the most common cytopenia; patients report the gradual onset of fatigue, weakness, dyspnea, and pallor, but at least half are asymptomatic and discovered incidentally on routine blood counts. The dysplastic cells that do reach the circulation work poorly — hypogranular neutrophils and dysfunctional platelets raise the risk of infection and bleeding out of proportion to the absolute counts. Fever and weight loss favor a myeloproliferative rather than a myelodysplastic process, and about 20% of patients have splenomegaly.

MDS is suspected in any patient with otherwise unexplained cytopenias, especially when the peripheral smear shows dysplastic features: hypogranular and hyposegmented neutrophils, large granule-poor platelets, macrocytosis, or circulating blasts. Bone marrow biopsy is required for diagnosis and risk stratification — the marrow is typically normal or hypercellular with dyserythropoietic changes, ring sideroblasts, hypogranulated granulocytic precursors, and dysplastic megakaryocytes, although about 20% of cases are hypocellular and can be confused with aplastic anemia. The blast percentage should be enumerated carefully, and cytogenetic and molecular studies are now routine: clonal cytogenetic abnormalities occur in roughly half of patients (losses of 5, 7, and 20 and trisomy 8 are nonrandom) and strongly predict survival and leukemic transformation.

Key point: MDS is suspected in patients with unexplained cytopenias — particularly macrocytic anemia — and dysplastic findings on the peripheral blood smear; bone marrow biopsy is required for diagnosis and risk stratification.

Prognosis and Risk Stratification

Prognosis in MDS depends on the depth of the cytopenias (transfusion dependence), the bone marrow blast percentage, and cytogenetics. Patients with low-risk disease may have a median survival approaching 9 years, whereas those with more than 10% blasts, severe pancytopenias (hemoglobin <8 g/dL, platelets <50,000/µL, absolute neutrophil count <800/µL), and adverse cytogenetics survive less than 1 year. The Revised International Prognostic Scoring System (IPSS-R) formalizes this using marrow blast categories, refined cytogenetic risk groups, and clinically relevant cut points for cytopenias. Therapy-related MDS, regardless of subtype, carries an extremely poor prognosis, with most patients progressing to refractory AML within months; high-risk patients overall face roughly a 25% risk of conversion to AML in the first year.

Post-publication update — molecular risk stratification (IPSS-M): The IPSS-Molecular score adds somatic mutations in 31 genes (including SF3B1, multi-hit TP53, RUNX1, and ASXL1) to the IPSS-R clinical and cytogenetic variables, defining six risk categories and reclassifying nearly half of patients relative to IPSS-R — mostly by upstaging. IPSS-M with a next-generation sequencing panel at diagnosis has become the preferred prognostic tool in current practice. [3]
Clonal hematopoiesis of indeterminate potential (CHIP) is not MDS: somatic clonal mutations in genes recurrently mutated in hematologic malignancies (DNMT3A, TET2, ASXL1) without cytopenias or a known hematologic malignancy are common with aging. The risk of CHIP progressing to MDS is very low — but CHIP carriers are at increased risk of atherosclerotic cardiovascular disease.

Treatment

The primary goals are treating symptomatic cytopenias and reducing the risk of progression to AML. Asymptomatic low-risk patients can be monitored without therapy. Symptomatic anemia is treated with transfusions — accompanied by iron chelation to prevent secondary iron overload — and erythropoiesis-stimulating agents, which work best in patients with low serum EPO levels and modest transfusion needs. Immunosuppression (ATG with or without cyclosporine) can produce sustained transfusion independence in selected younger, lower-risk patients, particularly those with hypocellular marrow.

Key point: Allogeneic hematopoietic stem cell transplantation is the only cure for MDS, but it is too toxic for most older adult patients; hypomethylating agents decrease transfusion dependence and leukemic transformation.

For higher-risk patients who are not transplant candidates, the hypomethylating agents azacitidine and decitabine (plus the oral formulation decitabine-cedazuridine) are the workhorses: they improve blood counts, decrease transfusion dependence, and lower the risk of conversion to AML, and azacitidine improves survival compared with supportive care alone. Responses require at least four cycles to assess and depend on continued drug administration — most patients eventually become refractory. Notably, although venetoclax plus azacitidine is approved for AML, the combination is not approved in MDS. Patients with low-risk MDS and the isolated del(5q) abnormality who are transfusion dependent respond strikingly to lenalidomide: a high proportion become transfusion independent, often with cytogenetic normalization, though myelosuppression and thromboembolic risk require monitoring.

Post-publication update — luspatercept moves first-line (COMMANDS): In ESA-naive, transfusion-dependent lower-risk MDS, luspatercept was superior to epoetin alfa for achieving red-cell transfusion independence of 12 weeks or longer (≈58% vs ≈31%), in both SF3B1-mutated and non-mutated subgroups, with durable independence beyond 18 months on long-term follow-up. Luspatercept is now a preferred first-line option for transfusion-dependent anemia in lower-risk MDS. [5]
Post-publication update — imetelstat approved (June 2024): Imetelstat, a first-in-class telomerase inhibitor, is FDA approved for low- and intermediate-1-risk MDS with transfusion-dependent anemia after ESA failure or intolerance. In the phase 3 IMerge trial, red-cell transfusion independence of 8 weeks or longer was achieved by about 40% versus 15% on placebo, with a median response duration of roughly one year; the key toxicity is myelosuppression. [6]

Allogeneic hematopoietic stem cell transplantation remains the only potentially curative option. Three-year survival approaches 50% in selected patients and is improving, with matched unrelated donors performing similarly to siblings; reduced-intensity conditioning has extended transplantation to older patients, albeit at higher relapse risk. Because treatment-related mortality rises with age and comorbidity, only a small proportion of MDS patients actually undergo transplantation — typically those whose risk profile predicts a poor outcome without it.

A Note on Chronic Myelomonocytic Leukemia

Chronic myelomonocytic leukemia (CMML) was traditionally considered a subset of MDS but is now classified as a separate MDS/MPN overlap entity, blending features of both worlds: persistent monocytosis for at least 3 months, often with splenomegaly and other cytopenias, and a dysplastic marrow with fewer than 20% blasts. Reactive causes of monocytosis (tuberculosis, endocarditis, connective tissue disease, recovery from marrow suppression) and BCR::ABL1-positive CML must be excluded first. Prognosis and treatment parallel higher-risk MDS, with allogeneic transplantation the only curative option for fit, higher-risk patients.

References

  1. MKSAP 19 — Hematology American College of Physicians (2022). "Hematopoietic Stem Cells and Their Disorders," pp. 7–9.
  2. Harrison's Principles of Internal Medicine, 22e McGraw-Hill (2024). Ch. 107 "Bone Marrow Failure Syndromes Including Aplastic Anemia and Myelodysplasia" (Young, Groarke) + Ch. 115 "Less Common Lymphoid and Myeloid Malignancies" + Ch. 366 "Mastocytosis".
  3. IPSS-M: Molecular International Prognostic Scoring System for myelodysplastic syndromes Bernard E, Tuechler H, Greenberg PL, et al. NEJM Evid 2022;1(7):EVIDoa2200008.
  4. WHO 2022 / ICC 2022 MDS classifications: external validation in ICC-2022-defined MDS Blood Cancer J 2023;13:120.
  5. COMMANDS trial: luspatercept versus epoetin alfa as first-line therapy in lower-risk MDS Platzbecker U, Della Porta MG, Santini V, et al. Lancet 2023.
  6. FDA approves imetelstat for low/intermediate-1-risk MDS with transfusion-dependent anemia (June 6, 2024) Platzbecker U, Santini V, Fenaux P, et al. Lancet 2024;403:249–260.
  7. Avapritinib for indolent systemic mastocytosis: FDA approval and PIONEER trial (May 22, 2023) Gotlib J, et al. NEJM Evid 2023;2(6):EVIDoa2200339.
  8. NATRON: benralizumab phase 3 trial in FIP1L1::PDGFRA-negative hypereosinophilic syndrome Ogbogu P, Roufosse F, Akuthota P, et al. Blood 2025;146(Suppl 1):abstract 79.
Hematopoietic Stem Cells: Eosinophilia and Hypereosinophilic Syndrome, Mastocytosis, and Myelodysplastic Syndromes
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Added 6 August 2026