Unexplained cytopenias management

 April 2025 Blood journal

Cytopenia of any lineage: SPEP, CRP, RA, ANA, anti ds DNA, C3, C4, HIV, CMV, EBV, Hep B, C, anti parvovirus B19, SARS-CoV-2

Isolated anemia: haptoglobin, erythropoietin, uric acid, Hb electrophoresis,  DAT and indirect Coomb's

Isolated neutropenia: Flow cytometry, ANCA

Isolated thrombocytopenia: APLA testing, H pylori, plt in sodium citrate

Severe pancytopenia differential:

• malignancy like AML 
• MDS, 
• rheumatologic
• drug toxicity 
• infectious/viral
• nutritional

• immune dysregulation
•  inherited bone marrow failure
•  aplastic anemia

1. Chronic idopathic neutropenia: isolated neutropenia,  middle aged women. BMBx needed. Uncomplicated. Low risk of transformation.

2.  ICUS: at least one lineage affected ie. Hb < 11 or ANC < 1500 or plt < 100K. Bmbx needed. No proof of clonality needed. Variable course and risk of transformation.  Repeat work up and continued surveillance needed.

3. CCUS: bmbx needed, persistent unexplained cytopenia, non MDS somatic mutation,  higher risk of progression to malignancy than ICUS or CIN.

4. CCMUS: (persistent monocytosis plus CCUS > 0.5), 1 myeloid mutation of at least VAF 2%,  no dysplasia, not meeting criteria for CMML

5. CHIP: no unexplained cytopenia, but myeloid driver mutation, no MDS defining cytogenetic abnormality. Can be seen in inflammatory disorders. Increased risk of cardiovascular abnormalities.

6. CH in aplastic anemia: bm cellularity less than 25%. Somatic mutation in non MDS myeloid driver or non MDS defining cytogenetic aberration.

7. VEXAS syndrome: autoimmune manifestations, UBA1 somatic mutation, no MDS defining genetic abnormality

Clonal hematopoiesis risk score

Multivariable analysis 

 single DNMT3A mutations,

 high-risk mutations, 

two or more mutations,

 a VAF of 0.2 or more, 

65 years of age or older, 

having CCUS versus CHIP, 

and red blood cell indices, influenced MN risk in a variable direction. CHRS was used to define low-risk (n=10,018 [88.4%]), intermediate-risk (n=1196 [10.5%]), and high-risk (n=123 [1.1%]) groups. In clinical cohorts, most MN events occurred in high-risk patients with CHIP/CCUS.

DNMT3A, TET2, and ASXL1 mutations were the most commonly mutated genes in CHIP/CCUS 

Mutations in splicing factor: SRSF2, SF3B1, ZRSR2 and AML like genes- IDH1/IDH2, FLT3 , RUNX1 and TP53 are high risk.

Increased RDW and high MCV are risk factors too

General approach: rule out infection, vit def, autoimmune condition or non clonal bone marrow issue like aplastic anemia. Clonal process can be MDS, AML, PNH Then get a bmbx to see if clonality identified. If clonality identified close monitoring to see if they progress. If no clonality, evaluate alternate causes.

In patients with ICUS, look for inherited mutations. DDX41 is the most common associated with late malignant potential.