Pocket Oncology (Pocket Notebook Series), 1st Ed.

MYELODYSPLASTIC SYNDROMES

Justin M. Watts and Virginia M. Klimek

Epidemiology

• ∼10000 cases diagnosed annually in the United States

• Incidence >20/100000 in adults >70 y → actual incidence probably higher, as some older adults w/MDS may go undiagnosed due to comorbid illnesses, etc.

• Median age of onset ≥65 y; uncommon under age 50; male predominance (∼2:1)

• RF: Cytotoxic chemotherapy (esp. alkylators & anthracyclines/etoposide), RT/exposure, benzene

Disease Biology/Pathogenesis (NEJM 2009;361:1872)

• MDS consists of a group of acquired, clonal disorders of hematopoietic stem cells

• Ineffective hematopoiesis → cytopenias & dysplastic changes in BM precursors & circulating blood cells

• Several cytogenetic abnormalities are characteristic of MDS → +8, loss or deletions of chromosomes 5 or 7, del (20q)

• Recurrent Mt in genes involved in RNA splicing machinery recently identified & implicated in subset of MDS cases (eg, SF3B1 Mt a/w RS)

• Leukemic transformation: Evolution to AML varies greatly across subtypes → RAEB-2 (>50%), RARS (<5%)

Clinical Presentation

• Non-specific sx such as fatigue, infxn, & bleeding d/t anemia (85%), neutropenia (50%), thrombocytopenia (25%)

• Infxn common, resulting from neutropenia as well as impaired granulocyte function

• Occasionally a/w autoimmune phenomenon (eg, vasculitis, ITP)

• Progressive cytopenias (though time course can vary greatly depending on subtype)

• Risk of transformation to AML

Diagnosis

• DDx: AML, MPN (can be overlap), aplastic anemia, PNH, viral infxn (HIV, hepatitis, parvovirus), nutritional deficiencies (B12, copper), EtOH, meds, lead or arsenic poisoning

• Most pts anemic, often w/macrocytosis (1/3 pts), & have ≥1 other cytopenia

• Peripheral smear: Oval macrocytes, hyposegmented neutrophils (pseudo-Pelger–Huët cells), hypogranulated neutrophils & plt

• BM: Typically hypercellular; ≥10% dysplasia in ≥1 myeloid lineage (neutrophils, RBC precursors, or megakaryocytes); impaired myeloid maturation; small &/or hypolobated megakaryocytes

• BM exam also used to quantify the blast percentage & detect presence of RS (esp relevant if RA only)

• Cytogenetic testing (karyotyping) mandatory; FISH optional → the value of routine FISH testing for common cytogenetic abnormalities is unclear in MDS

WHO Classification (2008)

FAB classification no longer used

Unique Subtypes of MDS

5q-syndrome

• Characterized by progressive anemia, preserved/elevated plt count, & del(5q) as sole cytogenetic abnormality

• Female predominance; classically benign course w/low-risk of transformation to AML

• In addition to dyserythropoiesis, micromegakaryocytes present in most cases (80%)

• Excellent RR to lenalidomide, w/most pts achieving red cell transfusion-independence & some w/complete cytogenetic response (Blood 2011;118:3765)

Hypoplastic MDS

• Rare, can be difficult to distinguish from aplastic anemia (cytogenetics helpful) although tx is similar

MDS/MPN overlap syndrome (also see MPN section)

• Now classified separately from MDS

• Pts have coexisting features of dysplasia & proliferation; blast count <20%; absence of specific genetic abnormalities such as BCR–ABL, JAK-2PDGFRα/β

• CMML: Characterized by peripheral monocytosis (>1000/μL), anemia & thrombocytopenia, dysplastic neutrophils, often massive splenomegaly

• RARS-T (RARS & thrombocytosis) → RARS + Plt count >450 k/μL; frequently JAK-2 Mt positive

Prognosis

• IPSS score most commonly used & best validated prognostic scoring system

• Correlates w/OS & evolution to AML(Blood 1997;89:2079)

• Revised IPSS (IPSS-R) score: Assigns greater prognostic significance to cytogenetics & utilizes 5 rather than 3 prognostic subgroups; uses modified cytopenia thresholds; subdivides original <5% blast count to ≤2% or 3–4% blasts (Blood 2012;120:2454)

• Older age, poor PS, ↑ serum ferritin, & ↑ LDH also correlate w/↓survival but not transformation to AML

Treatment

• Must consider age, PS, & IPSS score/risk status, & transplant candidacy

• IPSS Low/Int-1 risk: Supportive care including ESAs (epoetin alfa or darbepoetin; esp if Epo level <500); consider ESA + G-CSF for RARS; lenalidomide (esp for 5q-syndrome); if progression → hypomethylating agents (azacitidine or decitabine)

• IPSS Int-2/High risk: Hypomethylating agents → survival benefit compared to best supportive care (BSC) & some pts achieve CR (9–17%) (Lancet Oncol 2009;10:223; Cancer 2006;106:1794); consider induction chemo (AML regimen such as “7 + 3”)

• Allogeneic transplant is only curative strategy, usu w/a matched related or unrelated donor

• Hypoplastic MDS → can be treated like aplastic anemia w/antithymocyte globulin (ATG) & cyclosporine

• Supportive care (regardless of risk & Rx strategy): ESAs, G-CSF, RBC & Plt transfusions, iron chelation Rx if needed (esp if transplant candidate), abx for neutropenic Ppx including antifungal agents (azoles)