MDS & Acute Leukemias
Learning objectives
- LO 1Define myelodysplastic syndrome and explain what its classification is based on.
- LO 2Link the symptoms of each cytopenia to the lab tests that show it.
- LO 3Describe the cytogenetic changes and complications of MDS.
- LO 4Compare MDS with the myeloproliferative neoplasms.
- LO 5Separate leukemia from lymphoma, and acute from chronic.
- LO 6Compare the clinical and pathologic features of AML and ALL.
- LO 7Contrast how acute leukemia presents with how chronic leukemia presents.
- LO 8Explain how AML is classified and how the classification reflects its biology.
- LO 9Contrast de novo AML with AML arising from MDS.
- LO 10Match AML translocations to their subtypes and prognosis.
- LO 11Know the features used to classify ALL.
- LO 12Describe the typical patient with ALL.
- LO 13List ALL markers and cytogenetics and how they predict outcome.
MAPThree myeloid neoplasms on one axis: the blast count
LO 1What is myelodysplastic syndrome?
Q1. How is MDS defined?
- Heterogeneous clonal stem cell disorders with maturation defects → disorderly and ineffective hematopoiesis
- Quantitative and qualitative defects in one, two or all three lines (RBC, neutrophils, platelets)
- Doesn't meet criteria for acute leukemia, but causes similar problems (marrow suppression) and carries a risk of transformation to AML
- Primary: idiopathic, slow onset, older (>50). Therapy-related (t-MDS): 2–8 years after genotoxic therapy; progresses to AML more often and faster
Analogy — the sloppy factory
MPN = accelerator stuck, too many good products. MDS = sloppy assembly line: busy factory (hypercellular marrow) but most products are defective and get scrapped before shipping (cytopenias). AML = the line stops; half-built parts pile up.
Q2. What is clonal hematopoiesis, and why does it matter?
- A clone with ≥1 acquired pathogenic mutation in a cancer gene, in a person with normal blood counts
- ≈10% of people by age 70; genes TET2, DNMT3A (tumor suppressors regulating DNA methylation)
- Consequences: 1%/year risk of a hematopoietic neoplasm; pro-inflammatory (worse atherosclerosis, NAFLD, COPD); ↑ RDW (independent mortality predictor)
Q3. What is the MDS classification based on?
Like the leukemias, it combines clinical features, blood and marrow findings, and cytogenetics. You don't need to memorize the WHO 2022 list:
Defined by genetics
- Low blasts + isolated 5q deletion
- Low blasts + SF3B1 mutation
- Biallelic TP53 inactivation
Defined by morphology
- Low blasts
- Hypoplastic
- Increased blasts
- Any of the above with fibrosis
Step 1
5q− syndrome: older woman, macrocytic anemia, normal or ↑ platelets; responds to lenalidomide. SF3B1 → ringed sideroblasts.
LO 2Cytopenias: symptoms and labs
Q1. How does each cytopenia show up?
| Low line | Symptom | Lab |
|---|---|---|
| Neutrophils | Infection | ↓ ANC; hypogranular, hypolobated neutrophils |
| Red cells | Fatigue, weakness | ↓ Hb, often macrocytic; most common presenting abnormality |
| Platelets | Bleeding | ↓ platelet count |
- MDS: mean age ≈70 (range 60–75), men > women; often found on a routine CBC
- Smear: cells too big, hypogranular, irregular nuclei. Marrow: hypercellular but dysplastic
- Think MDS in an older patient with unexplained anemia or abnormal counts
MDS smear
- Hypolobated (pseudo-Pelger-Huët), hypogranular neutrophils
Dysplastic precursors
- Abnormal nuclei and maturation
MDS aspirate
- Busy marrow, ugly cells
In-house exam
74-year-old, fatigue, macrocytic pancytopenia, normal B12, hypogranular neutrophils, ringed sideroblasts, blasts <20% → MDS.
Trap
Macrocytic anemia + odd cells mimics B12/folate deficiency ("megaloblastoid" change). Check B12, folate and copper before calling MDS.
Memory tool
Cytopenia triad: "I F B": Infection (WBC), Fatigue (RBC), Bleeding (platelets).
LO 3MDS genetics and complications
Q1. What drives MDS genetically?
- An initial event damages DNA; secondary "hits" drive progression
- Driver mutations partly overlap with AML: epigenetic regulators, RNA-splicing factors (SF3B1), transcription factors, TP53
- Often complex cytogenetic profiles: −7, del(5q), TP53 (−7, complex, TP53 = bad; isolated del(5q) = better)
Q2. How does MDS end?
- Gradual, progressive; survival from weeks to years
- Transformation to AML: 30% (slides) / 10–40% (handout)
- Death from complications of cytopenias: infection, bleeding
- Treatment: supportive in the elderly; marrow transplant in children and young adults
High yield
Therapy-related MDS (2–8 years after alkylators/radiation; ringed sideroblasts, 5q deletions) progresses faster and more often to AML than primary MDS.
LO 4MDS vs myeloproliferative neoplasms
Q1. How do MPN and MDS differ?
| MPN | MDS | AML | |
|---|---|---|---|
| Marrow cellularity | Increased | Increased (usually) | Increased |
| Marrow blasts | Normal | ↑ but <20% | >20% |
| Hematopoiesis | Effective | Ineffective | Arrested |
| Blood counts | Increased | Decreased (cytopenias) | ↓ normal cells ± ↑ blasts |
| Organomegaly | Common | Uncommon | Variable |
In-house exam
Same busy marrow, opposite blood: MPN marrow ships product (↑ counts); MDS marrow scraps it (↓ counts).
LO 5Leukemia vs lymphoma; acute vs chronic
Q1. What separates leukemia from lymphoma?
Leukemia
- Mainly involves bone marrow with circulating tumor cells
- Myeloid or lymphoid; acute or chronic
Lymphoma
- Lymphocyte clone forming tissue masses in lymph nodes or extranodal sites
- CML is a myeloproliferative disorder; CLL is a peripheral B-cell neoplasm, the same disease as small lymphocytic lymphoma (nodes + marrow + blood)
The 2 × 2
- AML, CML, ALL, CLL
In-house exam
Acute leukemia diagnosis: >20% blasts in the bone marrow.
LO 6AML vs ALL
Q1. How do AML and ALL compare?
| AML | ALL | |
|---|---|---|
| Who | Adults, peak >60 (also infants) | Children 2–10 (B); adolescents (T) |
| Risk syndromes | Trisomy 21, Bloom, Fanconi anemia, neurofibromatosis; radiation, chemo, benzene, smoking | Down syndrome, ataxia-telangiectasia |
| Distinct features | DIC (APL), gingival hyperplasia (monocytic) | Bone/joint pain; CNS, testes, thymus spread |
| Markers | CD13, CD33 (myeloid); MPO, Auer rods | TdT; B: CD10, CD19, CD20 · T: CD2, CD3, CD5, CD7 (± CD4/CD8) |
| Good cytogenetics | t(8;21), inv(16), t(15;17) | Hyperdiploidy >50, t(12;21) |
| Bad cytogenetics | −5/−7, del(7q), t(11q23), TP53, complex | Hypodiploidy, t(9;22), t(1;19), 14q11 (T) |
Age tells the lineage
- Kids → ALL; adults → AML
Trap
Myeloblasts and lymphoblasts can look alike; flow cytometry markers decide. Auer rods and MPO = myeloid; TdT = lymphoblast.
LO 7Acute vs chronic presentation
Q1. Why does acute leukemia present so differently from chronic?
| Acute | Chronic | |
|---|---|---|
| Cells | Immature blasts | Mature and maturing cells |
| Mechanism | Maturation arrest | Increased proliferation |
| Clinical | Early marrow failure: bleeding, infection, fatigue | Non-specific; organ infiltration; marked leukocytosis; late marrow failure |
| Treatment | Urgent | Non-urgent |
Bleeding
- Petechiae, purpura (↓ platelets, DIC)
Gingival hyperplasia
- Monocytic AML infiltrating gums
Memory tool
Acute = Arrest (blasts pile up, marrow fails now). Chronic = Crowd (mature cells overproduced, fails later).
LO 8AML classification and biology
Q1. What goes wrong in AML?
- Acquired oncogenic mutations → abnormal myeloid or undifferentiated clone replaces normal marrow → marrow failure
- Mechanisms: maturation arrest, block in terminal differentiation, ↓ apoptosis
| Mutation class | Examples | Effect |
|---|---|---|
| Transcription factors | t(8;21), inv(16) → RUNX1/CBFB fusion; t(15;17) PML-RARα | Block myeloid maturation |
| Signaling proteins | Tyrosine kinases | Always-on growth/survival |
| Epigenome | DNA-methylation and chromatin regulators | Abnormal gene expression |
| TP53 | TP53 or its regulators | Complex karyotype, poor prognosis |
WHO classification groups AML by defining genetic abnormalities first (each with its own biology and prognosis), then by differentiation (minimally differentiated, with/without maturation, myelomonocytic, monocytic, erythroid, megakaryocytic).
AML with genetic aberrations
- Prognosis follows the genetics
Analogy — two hits
AML usually needs a brake failure (transcription factor fusion that blocks maturation) plus a stuck accelerator (signaling mutation that drives growth).
Step 1
M7 (acute megakaryoblastic) is the AML of Down syndrome under age 5. Monocytic AML infiltrates gums and skin.
Q2. How is AML diagnosed?
- Presentation: peak >60; fatigue, fever, infection, petechial bleeding; pronounced bleeding (DIC) in APL; gingival hyperplasia in monocytic AML
- Blood: high WBC with circulating blasts, neutropenia, thrombocytopenia, anemia
- Marrow: hypercellular, >20% blasts, normal elements reduced
- Immunophenotype: CD13, CD33
Myeloblast
- Fine chromatin, nucleoli, irregular contour
AML smear
- Sheets of blasts
AML marrow
- Packed; normal elements gone
Normal marrow
- Fat + mixed lineages
In-house exam
Vignette labs: WBC 52k, platelets 10k, Hb 7, blasts on smear, marrow 60% blasts, CD13/CD33, inv(16). Prognosis depends on age, counts, molecular findings, speed to remission.
LO 9De novo AML vs AML from MDS
Q1. Why does it matter where AML came from?
| De novo AML | MDS-related / therapy-related AML | |
|---|---|---|
| Patient | Younger | Older, or post-chemotherapy |
| History | Abrupt | Months–years of cytopenias |
| Genetics | Balanced translocations (t(8;21), inv(16), t(15;17)) | Deletions (−5, −7, del(7q)), TP53, complex karyotypes |
| Prognosis | Better | Worse |
Memory tool
"Balanced swap in a young patient = good; lost chromosomes in an old marrow = bad."
LO 10AML translocations and prognosis
Q1. Which AML genetics are favorable and which are not?
| Abnormality | Fusion | Subtype | Prognosis |
|---|---|---|---|
| t(8;21) | RUNX1-RUNX1T1 | AML with maturation (M2); Auer rods | Favorable |
| inv(16) | CBFB-MYH11 | Myelomonocytic with abnormal eosinophils | Favorable |
| t(15;17) | PML-RARα | Acute promyelocytic leukemia (M3) | Very favorable (ATRA) |
| t(11q23) | KMT2A rearranged | Monocytic features | Poor |
| −5 / −7, del(7q) | — | MDS-related | Poor |
| TP53, complex | — | Older, therapy-related | Poor |
In-house exam
Favorable: inv(16), t(8;21), t(15;17). Unfavorable: −7 or −5, del(7q), t(11q23).
Q2. Why is acute promyelocytic leukemia special?
- t(15;17): PML (15q22) + retinoic acid receptor-α (17) → abnormal RAR blocks myeloid differentiation at the promyelocyte
- Distinct morphology (promyelocytes stuffed with granules and Auer rods, "faggot cells"), DIC, unique prognosis
- Treatment: all-trans retinoic acid (ATRA), a vitamin A derivative, makes the blasts differentiate
APL promyelocyte
- Bilobed nucleus, heavy granules
Faggot cells
- Bundles of Auer rods
Memory tool
"15;17 breaks the retinoic acid receptor → vitamin A (ATRA) fixes it."
Step 1
APL: ATRA + arsenic trioxide; watch for differentiation syndrome. Starting chemo in any acute leukemia → tumor lysis syndrome (↑ K⁺, ↑ phosphate, ↑ uric acid, ↓ Ca²⁺) → hydrate + allopurinol/rasburicase.
LO 11How ALL is classified
Q1. What is ALL, and what classifies it?
- Clonal proliferation of lymphoblasts, immature precursors of B or T cells, from marrow or thymus progenitors
- Classification: lineage (B vs T by immunophenotype) + recurrent genetic abnormalities (WHO/ICC lists B-ALL by translocation, ploidy, BCR-ABL1-like, etc.)
- Genetics: transcription factors for B/T development (NOTCH1 for T; PAX5, E2A for B) + growth/survival genes
- ≈90% have numerical or structural chromosome changes; most common is hyperdiploidy (>50)
B and T maturation
- TdT in early precursors; markers define lineage
LO 12The patient with ALL
Q1. What does a child with ALL look like?
- Children 2–10 (B-ALL most common)
- Marrow failure (lethargy, bleeding, infection) + bone or joint pain
- Extramedullary spread: CNS (meninges), testes, thymus (T)
- Blood: high WBC with lymphoblasts, thrombocytopenia, anemia. Marrow: hypercellular blasts, no normal hematopoiesis
- Relapse: CNS and testes most common; morphology and immunophenotype usually preserved; cytogenetics evolve
ALL blood and marrow
- Lymphoblasts replace normal cells
Lymphoblasts
- Scant cytoplasm, fine chromatin
ALL marrow
- Hypercellular, blasts only
In-house exam
Vignette: WBC 22k, platelets 14k, Hb 8.2, blasts on smear, marrow 80% blasts, CD19, TdT, hyperdiploidy → B-ALL (favorable).
Q2. How does T-ALL differ?
- Adolescents (often male) with a mediastinal (thymic) mass → difficulty breathing, stridor, hoarseness
- T-cell markers; higher white counts
Mediastinal mass
- Stridor, dyspnea, SVC syndrome
T-lymphoblasts
- Diffuse sheets of blasts
Memory tool
T-ALL = Thymus + Teen + Tight airway; NOTCH1.
LO 13ALL markers, cytogenetics and prognosis
Q1. Which markers and genetics predict outcome in ALL?
| Markers | |
|---|---|
| All lymphoblasts | TdT |
| B-ALL | CD10, CD19, CD20 |
| T-ALL | CD2, CD3, CD4, CD5, CD7 or CD8 |
| Abnormality | Lineage | Prognosis |
|---|---|---|
| Hyperdiploidy (>50 chromosomes) | B; most common in kids | Favorable |
| t(12;21) ETV6-RUNX1 | B; children | Favorable |
| Hypodiploidy | B | Unfavorable |
| t(1;19) | B | Unfavorable |
| t(9;22) Ph | B; 25% of adult ALL | Unfavorable (children and adults) |
| 14q11 (TCR gene) | T; 45% of T-ALL | Unfavorable |
Hyperdiploidy
- >50 chromosomes → good prognosis
Memory tool
"12;21 is good for kids" (12 + 21 = a good age range). "More chromosomes, more cure": hyperdiploid good, hypodiploid bad.
Step 1
Children with ALL: ≈90% cure. Other bad signs: age <1 or >10, WBC >50–100k, T-cell phenotype, CNS disease at diagnosis; t(4;11) KMT2A in infants. Ph+ ALL gets a TKI. LP in every patient.
IDImage ID
Image 1 — smear
Image 2 — mouth
Image 3 — smear
Image 4 — cell
Image 5 — chest
Image 6 — karyotype
Image 7 — marrow
Image 8 — foot
MCQExam-style questions
1A 74-year-old man has fatigue and macrocytic pancytopenia. B12 and folate are normal. Smear: hypogranular, bilobed neutrophils. Marrow: hypercellular, dysplastic, 8% blasts. Diagnosis?
2Seven years after chemotherapy for breast cancer, a woman develops cytopenias, dysplasia and a del(5q). Compared with primary MDS, her disease will most likely:
3Which feature best separates an MPN from MDS?
4What marrow blast percentage defines acute leukemia in this course?
5A 65-year-old has fatigue, fever, petechiae and swollen gums. WBC 52k with blasts that are CD13+ and CD33+. Diagnosis?
6A 38-year-old has DIC and purpura. Marrow is packed with promyelocytes containing bundles of Auer rods. Which therapy targets the molecular defect?
7Which AML cytogenetic finding carries a poor prognosis?
8Compared with de novo AML, AML arising from MDS typically has:
9A 4-year-old has fever, petechiae and bone pain. Marrow: 80% blasts that are TdT+, CD10+, CD19+. Most likely diagnosis?
10A 16-year-old boy has stridor and a mediastinal mass; WBC is very high with TdT+ CD3+ CD7+ blasts. Which gene is classically involved?
11Which B-ALL finding predicts the best outcome?
12A boy treated for ALL relapses 2 years later. Besides the marrow, which site is most common?
13Which syndrome raises the risk of both AML and ALL?
!Numbers that differ between in-house and Step 1
| Item | In-house | Step 1 / board review |
|---|---|---|
| MDS → AML | Slides 30%; handout 10–40% | ≈30% |
| MDS age | Slides 60–75; handout mean 70 | >60 |
| Acute leukemia cutoff | >20% blasts | ≥20%; WHO 2022 drops the cutoff for AML with defining genetic abnormalities |
| AML markers | CD13, CD33 | Also MPO+, CD34, CD117; Auer rods |
| ALL hypodiploidy | "Loss of Ch 20" | <44 chromosomes (no single chromosome) |
| inv(16) | Slide written "Inv(16)(13;q22)" | inv(16)(p13.1q22), CBFB-MYH11 |