How do Chronic Myeloid Leukemia (CML), Chronic Myelomonocytic Leukemia (CMML), Acute Myeloid Leukemia (AML), Myelodysplastic Syndromes (MDS), and leukemoid reaction appear on bone marrow aspiration?

Bone Marrow Aspiration Findings in Myeloid Disorders

Chronic Myeloid Leukemia (CML)

CML bone marrow shows marked hypercellularity with granulocytic hyperplasia and a left shift in myeloid maturation, with blasts typically <10% in chronic phase. 1

• Hypercellular marrow with myeloid:erythroid ratio increased to 10:1 or higher (normal is 3:1), reflecting massive expansion of granulocytic lineage 1, 2
• Granulocytic hyperplasia with full spectrum of myeloid maturation present—myeloblasts, promyelocytes, myelocytes, metamyelocytes, bands, and segmented neutrophils all visible 2
• Blast count <10% in chronic phase; 10-19% defines accelerated phase; ≥20% defines blast phase 1, 3
• Basophilia and eosinophilia commonly present, with basophils often increased 1
• Megakaryocytes are increased in number and may show hypolobulated (dwarf) forms 2
• BCR::ABL1 fusion is the defining molecular feature—detected by cytogenetics showing t(9;22) Philadelphia chromosome in 85-90% of cases, or by FISH/RT-PCR in cryptic cases 1
• Minimal dysplasia is characteristic—unlike MDS, maturation is orderly despite being left-shifted 1, 2

Chronic Myelomonocytic Leukemia (CMML)

CMML bone marrow demonstrates dysplastic changes across multiple lineages with blasts <20%, combined with persistent peripheral blood monocytosis ≥1×10⁹/L. 4, 5

• Bone marrow blasts <20% by definition; CMML-0 has <5% blasts, CMML-1 has 5-9% blasts, CMML-2 has 10-19% blasts 4, 5
• Multilineage dysplasia is prominent—dysplastic granulocytes, erythroid precursors, and megakaryocytes are characteristic 1, 4
• Monocytic proliferation in marrow with promonocytes often increased 5, 6
• Hypercellular marrow in most cases, though cellularity can be variable 4
• Peripheral blood monocytosis ≥1×10⁹/L sustained for >3 months with monocytes comprising ≥10% of white blood cells is mandatory for diagnosis 1, 4, 5
• Cytogenetic abnormalities in ~30% of cases, most commonly +8, -7/del(7q), and complex karyotypes 4, 6
• Molecular mutations in >90% of cases—TET2 (60%), SRSF2 (50%), ASXL1 (40%), and RAS pathway (30%) are most frequent 5, 6

Acute Myeloid Leukemia (AML)

AML bone marrow is characterized by ≥20% myeloblasts with replacement of normal hematopoietic elements. 1, 7

• Blast count ≥20% in bone marrow or peripheral blood defines AML by WHO criteria 1, 7
• Blasts show high nuclear:cytoplasmic ratio, visible nucleoli, fine nuclear chromatin, variable cytoplasmic basophilia, with or without Auer rods 1, 7
• Hypercellular marrow with replacement of normal trilineage hematopoiesis by blast population 1
• Minimal residual normal hematopoiesis—erythroid precursors, mature granulocytes, and megakaryocytes are markedly reduced 1
• Auer rods when present are pathognomonic for myeloid lineage and indicate AML even if blast count is <20% 1, 7
• Cytogenetic abnormalities such as t(8;21), t(15;17), inv(16) are diagnostic of AML regardless of blast percentage 1
• Immunophenotyping shows blasts expressing CD34, CD117, HLA-DR, and myeloid markers (CD13, CD33, MPO) 1

Myelodysplastic Syndromes (MDS)

MDS bone marrow shows dysplastic changes in ≥10% of cells in one or more lineages with blasts <20%, often with hypercellular marrow paradoxically producing peripheral cytopenias. 1

• Dysplasia in ≥10% of cells in at least one myeloid lineage is required for diagnosis—megaloblastoid erythropoiesis, nuclear-cytoplasmic asynchrony, hypolobulated megakaryocytes 1
• Blast percentage determines subtype: <5% in lower-risk MDS (RCUD, RARS, RCMD); 5-9% in RAEB-1; 10-19% in RAEB-2 1, 8
• Hypercellular marrow in 70-80% of cases despite peripheral cytopenias (ineffective hematopoiesis); hypocellular MDS occurs in 10-15% 1
• Ring sideroblasts ≥15% define RARS subtype—erythroid precursors with iron-laden mitochondria encircling nucleus on iron stain 1, 8
• Abnormally localized immature precursors (ALIP) are CD34+ blast clusters away from paratrabecular areas, indicating aggressive disease 9
• Cytogenetic abnormalities in 50-60% of cases—del(5q), -7/del(7q), +8, del(20q) are most common; certain abnormalities (Table 4) provide presumptive evidence of MDS even without definitive dysplasia 1
• Megakaryocyte dysplasia includes hypolobulated nuclei (pseudo-Pelger-Huët), multiple separated nuclei, or micromegakaryocytes 1
• Minimum cell count of 500 cells in bone marrow aspirate (including 100 erythroblasts and 30 megakaryocytes) is recommended for accurate assessment 1

Leukemoid Reaction

Leukemoid reaction bone marrow shows granulocytic hyperplasia with orderly maturation, normal blast percentage (<5%), and absence of dysplasia or clonal markers. 7

• Normal blast percentage <5% with no increase in immature forms beyond what is appropriate for the degree of left shift 7
• Orderly myeloid maturation without dysplastic features—maturation proceeds normally through all stages 7
• Hypercellular marrow with granulocytic hyperplasia, but myeloid:erythroid ratio typically <10:1 (unlike CML) 2
• Normal megakaryocyte morphology and number—no dwarf forms or dysplasia 2
• Absence of basophilia and eosinophilia that characterizes CML 1
• Normal cytogenetics—no Philadelphia chromosome, no clonal abnormalities 1
• Negative BCR::ABL1 by FISH or RT-PCR is essential to exclude CML 1
• Clinical context reveals underlying cause—infection, inflammation, malignancy, medications, or hemolysis 7
• Toxic granulation, Döhle bodies, and cytoplasmic vacuoles in neutrophils suggest reactive process rather than clonal disorder 7

Critical Diagnostic Pitfalls

• Blast enumeration requires 500-cell differential on bone marrow aspirate to ensure accuracy; 100-cell counts have unacceptably wide confidence intervals 1, 7, 9
• CD34 immunohistochemistry is invaluable when marrow is hypocellular, fibrotic, or yields a dry tap—allows blast quantification when morphology is inadequate 7, 9
• Exclude secondary causes of dysplasia before diagnosing MDS—copper deficiency, HIV, medications, alcohol, recent chemotherapy can all mimic MDS morphologically 1, 7
• Cytogenetic analysis of 20-25 metaphases is mandatory in all suspected myeloid neoplasms to detect clonal abnormalities and establish diagnosis 1
• Persistent monocytosis >3 months is required for CMML diagnosis to exclude transient reactive monocytosis 4, 5
• Morphologic blast count takes precedence over flow cytometry for prognostic stratification in MDS and AML 7