In a 72‑year‑old man with macrocytic anemia, absolute monocytosis, elevated C‑reactive protein and erythrocyte sedimentation rate, and subclinical hypothyroidism, what is the most likely diagnosis and recommended treatment?

Diagnosis: Chronic Myelomonocytic Leukemia (CMML)

This 72-year-old man most likely has chronic myelomonocytic leukemia (CMML), and the recommended treatment is bone marrow evaluation followed by hypomethylating agents (azacitidine or decitabine) if blast count is elevated, or supportive care with cytoreductive therapy (hydroxyurea) if this represents myeloproliferative CMML with low blast count. 1

Diagnostic Reasoning

The constellation of findings strongly suggests CMML:

• Absolute monocytosis (1.2 × 10⁹/L) is the hallmark diagnostic criterion for CMML, which requires sustained monocytosis ≥1.0 × 10⁹/L for >3 months with monocytes comprising ≥10% of white blood cells 2, 3, 4
• Macrocytic anemia (MCV 100 fL) is consistent with CMML, as macrocytosis commonly occurs in myelodysplastic/myeloproliferative disorders 5
• Markedly elevated ESR (50 mm/hr) and CRP (0.93 mg/dL) reflect the chronic inflammatory state characteristic of CMML, where up to 20% of patients have concurrent inflammatory or autoimmune conditions 4
• Subclinical hypothyroidism (TSH 4.550) is an incidental finding that does not explain the hematologic abnormalities 1

The elevated inflammatory markers distinguish this from simple macrocytic anemia due to B12/folate deficiency or hypothyroidism alone 1.

Essential Diagnostic Workup

Immediate bone marrow evaluation is mandatory and must include 1:

• Bone marrow aspiration and biopsy to assess blast percentage (critical for treatment decisions)
• Cytogenetic analysis (abnormalities present in ~30% of CMML cases) 2, 3
• Molecular testing for common mutations: TET2 (60%), SRSF2 (50%), ASXL1 (40%), and RAS pathway (30%) 2, 3
• Serum erythropoietin level if hemoglobin ≤10 g/dL 1

Risk stratification using the Mayo Molecular Model (MMM) should be performed, which incorporates 3:

• Truncating ASXL1 mutations
• Absolute monocyte count >10 × 10⁹/L
• Hemoglobin <10 g/dL
• Platelet count <100 × 10⁹/L
• Circulating immature myeloid cells

Treatment Algorithm

If Myelodysplastic CMML with High Blast Count (≥10% in bone marrow or ≥5% in blood):

Hypomethylating agents are first-line therapy 1:

• Azacitidine or decitabine with overall response rates of 40-50% and complete remission rates of 7-17% 2, 3
• Minimum of 6 cycles should be administered before assessing response 1, 6
• Consider allogeneic stem cell transplantation in selected patients (though age 72 makes this less feasible) 1

If Myeloproliferative CMML with Low Blast Count (<10%):

Hydroxyurea is the drug of choice to control proliferative myelomonocytic cells 1:

• Standard dose: 2 g/day for at least 3 months 1
• Monitor for hydroxyurea-related toxicities including leg ulcers, mucocutaneous manifestations, and cytopenias 1, 5

If Myelodysplastic CMML with Low Blast Count (<10%):

Supportive therapy aimed at correcting cytopenias 1:

• Erythropoietic stimulating agents if hemoglobin ≤10 g/dL and serum erythropoietin ≤500 mU/dL 1
• Prophylactic folic acid is recommended as hydroxyurea causes macrocytosis that can mask B12/folate deficiency 5

Critical Management Considerations

Common pitfalls to avoid:

• Do not delay bone marrow evaluation—blast percentage determines treatment strategy and prognosis 1
• Do not attribute macrocytosis solely to hypothyroidism or B12/folate deficiency without excluding CMML 1
• Monitor for secondary malignancies, as hydroxyurea is a human carcinogen with increased risk of secondary leukemia and skin cancer 5
• Watch for vasculitic toxicities (ulcerations, gangrene) if hydroxyurea is used 5

Prognosis: Median survival varies dramatically by risk stratification from 16 months (high-risk) to 97 months (low-risk), with ~15-20% risk of acute leukemic transformation over 3-5 years 2, 3, 4.

The subclinical hypothyroidism (TSH 4.550) can be monitored but does not require immediate treatment as it does not explain the primary hematologic disorder and is not contributing significantly to the anemia in this inflammatory context 1.