MYELODYSPLASTIC SYNDROMES (MDS)

These are clonal abnormalities of marrow cells characterized by varying degrees of cytopenias affecting one or more cell lines. The World Health Organization (WHO) classification of MDS is shown in Table 66-3. Other terms that have been used to describe one or more of the entities include preleukemia and oligoblastic leukemia.

TABLE 66-3: World Health Organization (WHO) Classification of Myelodysplastic Syndromes (MDS)/Neoplasms
NAME	RING SIDEROBLASTS	MYELOBLASTS	KARYOTYPE
MDS with single lineage dysplasia (MDS-SLD)	<15% (<5%)^a	BM <5%, PB <1%, no Auer rods	Any, unless fulfills all criteria for MDS with isolated del(5q)
MDS with multilineage dysplasia (MDS-MLD)	<15% (<5%)^a	BM <5%, PB <1%, no Auer rods	Any, unless fulfills all criteria for MDS with isolated del(5q)
MDS with ring sideroblasts (MDS-RS)
MDS-RS with single lineage dysplasia (MDS-RS-SLD)	≥15% / ≥5%^a	BM <5%, PB <1%, no Auer rods	Any, unless fulfills all criteria for MDS with isolated del(5q)
MDS-RS with multilineage dysplasia (MDS-RS-MLD)	≥15% / ≥5%^a	BM <5%, PB <1%, no Auer rods	Any, unless fulfills all criteria for MDS with isolated del(5q)
MDS with isolated del(5q)	None or any	BM <5%, PB <1%, no Auer rods	del(5q) alone or with 1 additional abnormality except −7 or del (7q)
MDS with excess blasts (MDS-EB)
MDS-EB-1	None or any	BM 5–9% or PB 2–4%, no Auer rods	Any
MDS-EB-2	None or any	BM 10–19% or PB 5–19% or Auer rods	Any
MDS, unclassifiable (MDS-U) • with 1% blood blasts • with single lineage dysplasia and pancytopenia • based on defining cytogenetic abnormality	None or any None or any 15%	BM <5%, PB=1%, no Auer rods BM <5%, PB=1%, no Auer rods BM <5%, PB=1%, no Auer rods	Any Any MDS-defining abnormality
MDS, unclassifiable (MDS-U) • with 1% blood blasts • with single lineage dysplasia and pancytopenia • based on defining cytogenetic abnormality	None or any None or any 15%	BM <5%, PB=1%, no Auer rods BM <5%, PB=1%, no Auer rods BM <5%, PB=1%, no Auer rods	Any Any MDS-defining abnormality
Refractory cytopenia of childhood	None	BM <5%, PB <2%	Any

^aIf SF3B1 mutation is present.

Abbreviations: BM, bone marrow; PB, peripheral blood.

Incidence and Etiology

About 3000 cases occur each year, mainly in persons >50 years old (median age, 68). As in AML, exposure to benzene, radiation, and chemotherapeutic agents may lead to MDS. Chromosome abnormalities occur in up to 80% of cases, including deletion of part or all of chromosomes 5, 7, and 9 (20 or 21 less commonly) and addition of part or all of chromosome 8. Mutations in genes involved in RNA splicing such as SF3B1 have a more favorable outcome; mutations in genes often involve in AML such as RUNX and ASXL1 have poorer prognosis.

Clinical and Laboratory Features

Symptoms depend on the affected lineages, 85% of pts are anemic, 50% have neutropenia, and about one-third have thrombocytopenia. The pathologic features of MDS are a cellular marrow with varying degrees of cytologic atypia including delayed nuclear maturation, abnormal cytoplasmic maturation, accumulation of ringed sideroblasts (iron-laden mitochondria surrounding the nucleus), uni- or bilobed megakaryocytes, micromegakaryocytes, and increased myeloblasts. Table 66-3 lists features used to identify distinct entities. Prognosis is defined by marrow blast %, karyotype, and lineages affected. The Revised International Prognostic Scoring System is shown in Table 66-4.

TABLE 66-4: Revised International Prognostic Scoring System (IPSS)
PROGNOSTIC VARIABLE	SCORE
PROGNOSTIC VARIABLE	0	0.5	1.0	1.5	2.0	3.0	4.0
Cytogenetics^a	Very good		Good		Intermediate	Poor	Very poor
Bone marrow blast (percent)	≤2		>2 to <5		5 to 10	>10
Hemoglobin (g/dL)	≥10		8 to <10	<8
Platelets (cells/µL)	≥100	50 to 100	<50
Absolute neutrophil count (cells/µL)	≥0.8	<0.8
Risk Group	IPSS-R Score	Median Overall survival (Years)		Median Time to 25 Percent AML Evolution (Years)
Very low	≤1.5	8.8		>14.5
Low	>1.5 to 3.0	5.3		10.8
Intermediate	>3 to 4.5	3.0		3.2
High	>4.5 to 6	1.6		1.4
Very high	>6	0.8		0.7
The prognostic value of the IPSS-R was validated in an external cohort of 200 pts with MDS.

^aCytogenetic definitions: Very good: –Y, del(11q). Good: Normal, del(5q), del(12p), del(20q), double including del(5q). Intermediate: del(7q), +8, +19, i(17q), any other single, double not including del(5q) or –7/del(7q), or independent clones. Poor: –7, inv(3)/t(3q)/del(3q), double including –7/del(7q), complex: 3 abnormalities. Very poor: Complex: >3 abnormalities.

Abbreviations: AML, acute myeloid leukemia; MDS, myelodysplastic syndromes.

Treatment: Myelodysplastic Syndromes

Allogeneic bone marrow transplantation is the only curative therapy and may cure 60% of those so treated. However, the majority of pts with MDS are too old to receive transplantation. 5-Azacytidine (75 mg/m² daily × 7, q 4 weeks) can delay transformation to AML by 8–10 months. Decitabine (15 mg/m² by continuous IV infusion, q8h daily × 3, q 6 weeks) may induce responses lasting a median of 1 year in 20% of pts. Lenalidomide (10 mg/d), a thalidomide analogue with fewer central nervous system effects, causes a substantial fraction of pts with the 5q– syndrome to become transfusion-independent. Pts with low erythropoietin levels may respond to erythropoietin, and a minority of pts with neutropenia respond to granulocyte colony-stimulating factor. Supportive care is the cornerstone of treatment.

Outline

Myeloid Leukemias, Myelodysplasia, and Myeloproliferative Syndromes
- ACUTE MYELOID LEUKEMIA (AML)
- CHRONIC MYELOID LEUKEMIA
- MYELODYSPLASTIC SYNDROMES (MDS)
- MYELOPROLIFERATIVE SYNDROMES