What are the causes of hypocellular marrow?

Causes of Hypocellular Marrow

Hypocellular marrow is primarily caused by aplastic anemia, but critical differential diagnoses include hypocellular myelodysplastic syndromes (H-MDS), hypocellular acute myeloid leukemia (H-AML), and secondary causes including drugs, toxins, infections, and inherited bone marrow failure syndromes. 1, 2

Primary Hematologic Causes

Aplastic Anemia (Most Common)

• Idiopathic aplastic anemia accounts for the majority of hypocellular marrow cases, characterized by severely reduced cellularity (<20% in severe cases, age-corrected) with blast percentage below 1% 1, 3
• Bone marrow shows fatty replacement of normal hematopoietic tissue without dysplasia or abnormal blast clusters 4, 3
• Immune-mediated destruction of hematopoietic stem cells is the underlying mechanism in most cases 5

Hypocellular Myelodysplastic Syndromes (H-MDS)

• Represents 7-29% of MDS cases (age-corrected: approximately 7%) and presents with hypocellular marrow but with unequivocal dysplasia distinguishing it from aplastic anemia 6
• More common in Asian populations compared to Western populations 6
• Features moderate to severe erythroid dysplasia, abnormal sideroblasts, and blast percentage of 5% or higher (in absence of significant dysplasia) 3
• Critical distinction: Risk of progression to acute leukemia is much greater in H-MDS than aplastic anemia, making accurate diagnosis essential for treatment planning 6

Hypocellular Acute Myeloid Leukemia (H-AML)

• Defined by ≥20% blasts on aspirate in a hypocellular setting, though this can be challenging to identify in inadequate aspirates 6
• Presence of clusters of immature precursors (ALIP) in biopsy with absence of sufficient numbers of granulocytes establishes H-AML diagnosis 6, 3
• Represents 2.2% of AML cases when age-corrected 6

Secondary and Acquired Causes

Toxic and Drug-Induced

• Chemotherapy exposure, particularly alkylating agents and purine analogues, causes secondary hypocellular marrow 6
• Benzene and its derivatives from occupational exposure 6, 7
• Busulfan and chloramphenicol can induce bone marrow failure 7

Radiation and Environmental

• Ionizing radiation and radiotherapy exposure 6
• Occupational factors in agricultural and industrial workers 6

Infectious Causes

• Viral infections can trigger immune-mediated bone marrow destruction 2, 7

Other Acquired Causes

• Nutritional deficiencies (vitamin B12, folate) 2
• Rheumatologic diseases 2
• Paroxysmal nocturnal hemoglobinuria (PNH) - requires screening by sensitive flow cytometry 3

Inherited Bone Marrow Failure Syndromes

• Fanconi anemia - more common in pediatric cases but can present in adults 6
• Down syndrome and neurofibromatosis 6
• Germline predisposition should be assessed in young adults or families with MDS, AML, or aplastic anemia 6, 8
• Congenital cytopenias with late manifestation 5

Critical Diagnostic Pitfalls

Age correction is mandatory when assessing bone marrow cellularity - failure to correct for age dramatically overestimates hypocellular cases (from 13% to 2.2% in AML when corrected) 6, 1, 3

Blast count accuracy requires 500-cell differential - a 100-cell count has unacceptably wide confidence intervals (95% CI: 1.6-11.3% for a 5% blast count) versus 500-cell count (95% CI: 3.3-7.3%) 6

Misdiagnosis between aplastic anemia and H-MDS/H-AML leads to inappropriate treatment - aplastic anemia requires immunosuppression or transplant, while H-AML requires acute leukemia chemotherapy, and H-MDS has intermediate management 1, 3

Review by at least two observers is essential when diagnostic doubt exists, particularly for H-AML cases where concordance among experts is only 57% 6