Myelodysplastic Syndrome (MDS)

Background:

Diagnosis is based on morphological evidence of dysplasia in BMBx
- Additional studies: karyotyping, flow cytometry, molecular genetics
Pearl: Regardless of blast percentage, if a characteristic AML cytogenetic abnormality is seen on BMBx, then should treat as AML.
Can be associated with previous drug exposures
- Example: alkylating chemotherapy or topoisomerase inhibitors
  - Associated with del 5, del 7, or complex chromosomal abnormalities

Risk Stratification:

Based on the IPSS-R or IPSS-M (newer scoring system includes gene mutations)
- Classified as Low, Intermediate, High Risk
Favorable risk:
- Cytogenetics:
  - t(8;21), t(15;17), and inv(16)
  - Confer a favorable prognosis regardless of blast percentage
- Gene mutations:
  - NPM1 (without FLT3-ITD), in-frame bZIP CEBPA
Poor risk
- Cytogenetics:
  - Monosomy 7, inv(3), del(3q), del(7q), complex (2-3 abnormalities)
- Gene mutations:
  - ASXL1, EZH2, SRSF2, U2AF1, ZRSR2, RUNX1, TP53, IDH2, STAG2, NRAS, ETV6, GATA2, BCOR, FLT3, WT1, NPM1
Very Poor
- Cytogenetics:
  - Complex (>3 abnormalities)

Treatment:

Low/Intermediate Risk MDS (IPSS-R 1-4)

Erythropoiesis-Stimulating Agents (ESA):
- Consider first line treatment for symptomatic anemia if serum EPO <500
- Goal: Hb 10-12
Hypomethylating Agents (HMA):
- Acacitidine
- Decitabine
- Oral decitabine/cedazuridine
Lenalidomide:
- Treatment of choice for Deletion 5q
Luspatercept:
- “Ringed Sideroblasts” or “MDS-SF3B1”
- There is now an expanded indication to include in first-line setting regardless of ringed sideroblast status
Imetelstat
- Newer telomerase inhibitor
Immunosuppressive Therapy (cyclosporine/ATG)
- For hypoplastic MDS
Ivosidenib/olutasidenib
- IDH1 mutated
Supportive Care
- Transfusion and Iron Chelation Therapy

High Risk MDS (IPSS 5 or more):

Hypomethylating Agents (HMA):
- Acacitidine
- Decitabine
- Oral decitabine/cedazuridine
AlloSCT:
- Potentially curative for appropriate population
Intensive chemotherapy

Chronic Myelomonocytic Leukemia (CMML)

MDS with increased blasts

MDS/MPN overlap

Idiopathic Cytopenia of Undetermined Significance (ICUS)

Persistent unexplained cytopenia(s) that remain unexplained despite an appropriate evaluation including BMBx.
Without evidence of clonality (no somatic mutations or clonal cytogenetic abnormalities) and no morphologic dysplasia.
ICUS is a heterogeneous entity; some cases resolve spontaneously, while others may progress to myeloid neoplasms, but the overall risk is lower than CCUS or CHIP.
Typically observed

Clonal Hematopoiesis of Indeterminate Potential (CHIP)

Presence of clonal mutations in leukemia-associated genes, but without cytopenia or morphologic dysplasia (does not yet meet criteria for diagnosis of a hematologic neoplasm).
Common in older adults and confers a low but definite risk of progression to hematologic malignancy (1% per year) and increased risk of cardiovascular disease and all-cause mortality.
Typically observed

Clonal Cytopenia of Undetermined Significance (CCUS)

Persistent cytopenia(s) with evidence of clonality but without morphologic dysplasia or diagnostic criteria for MDS.
Higher risk of progression to MDS or AML compared to ICUS or CHIP, especially with high-risk mutations (spliceosome genes, RUNX1, JAK2) or multiple mutations.
- CCUS is considered a direct precursor to myeloid neoplasms.
Typically observed/supportive care

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