In a patient with a JAK2 exon 12 mutation, can hemoglobin remain within the normal range for more than seven years without treatment?

Can Hemoglobin Remain Normal for 7+ Years in JAK2 Exon 12-Mutated Polycythemia Vera Without Treatment?

No, hemoglobin typically cannot remain normal for 7+ years in untreated JAK2 exon 12-mutated polycythemia vera, as this mutation drives clonal erythrocytosis that characteristically presents with elevated hemoglobin levels at diagnosis. 1

Disease Biology and Natural History

JAK2 exon 12 mutations are found in approximately 2–4% of polycythemia vera patients who lack the JAK2V617F mutation 2. These mutations are functionally similar to JAK2V617F and drive constitutive activation of the JAK-STAT signaling pathway, leading to autonomous erythroid proliferation 2.

The defining characteristic of JAK2 exon 12-mutated PV is elevated hemoglobin at presentation, with patients typically showing:

• Higher hemoglobin levels at diagnosis compared to JAK2V617F-positive PV (mean hemoglobin significantly elevated) 1, 3
• Isolated erythrocytosis in approximately two-thirds of cases, without accompanying leukocytosis or thrombocytosis 1
• Hemoglobin levels meeting WHO diagnostic thresholds (≥18.5 g/dL in men, ≥16.5 g/dL in women) in the majority of cases at diagnosis 2

Clinical Presentation Patterns

Research demonstrates that JAK2 exon 12-mutated PV presents in two distinct patterns 1:

• Isolated erythrocytosis subset (64% of cases): Normal white blood cell and platelet counts with markedly elevated hemoglobin
• Polycythemic subset (36% of cases): Elevated hemoglobin plus leukocytosis and/or thrombocytosis

Both subsets demonstrate elevated hemoglobin at diagnosis, indicating that the mutation drives erythrocytosis from disease onset 1.

Why Normal Hemoglobin for 7+ Years is Unlikely

Several factors make sustained normal hemoglobin implausible in untreated exon 12-mutated PV:

1. Mutation-driven erythropoiesis is constitutive and progressive 2

• JAK2 exon 12 mutations cause autonomous red cell production independent of erythropoietin regulation
• Without treatment, erythrocytosis progresses rather than remaining stable

2. Diagnostic criteria require elevated hemoglobin 2

• The WHO major criterion for PV diagnosis includes hemoglobin ≥18.5 g/dL (men) or ≥16.5 g/dL (women)
• Patients with exon 12 mutations who maintain normal hemoglobin would not meet diagnostic criteria for PV

3. Clinical studies show elevated hemoglobin at presentation 1, 3

• A European collaborative study of 106 exon 12-mutated PV patients found significantly elevated hemoglobin at diagnosis in all cases
• Taiwanese cohort data confirmed higher hemoglobin and hematocrit levels at diagnosis compared to JAK2V617F patients

Important Caveats and Alternative Scenarios

Iron deficiency can mask elevated hemoglobin 2:

• Concurrent iron deficiency may lower hemoglobin below diagnostic thresholds
• However, this represents masked disease rather than truly normal hemoglobin
• Red blood cell count remains elevated with low mean corpuscular volume (56-60 fL) 4

Some patients present with atypical features 4:

• A minority of exon 12-mutated cases may have hemoglobin/hematocrit below PV diagnostic thresholds at initial detection
• These cases often show increased red blood cell count with microcytosis, suggesting occult disease
• Such patients typically progress to overt PV if untreated

MPN-unclassified designation may apply 4:

• Patients with exon 12 mutations who don't meet full PV criteria may be classified as MPN-unclassified
• This represents early or atypical disease, not sustained normal hemoglobin over years

Clinical Implications

If a patient has a confirmed JAK2 exon 12 mutation with normal hemoglobin for 7+ years without treatment, consider 2, 4:

• Re-evaluation of the mutation testing: Ensure the mutation was detected in granulocytes (preferred) rather than whole blood, as mutation burden may be low 2
• Assessment for iron deficiency: Check ferritin and iron studies, as deficiency masks erythrocytosis 2
• Review of complete blood count trends: Look for elevated red blood cell count with microcytosis 4
• Bone marrow examination: Evaluate for isolated erythroid hyperplasia characteristic of exon 12-mutated PV 5
• Alternative diagnosis: Consider whether the patient truly has PV or represents a different condition

The natural history of untreated PV involves progressive erythrocytosis with attendant thrombotic risk 6, 1, making sustained normal hemoglobin over 7 years biologically inconsistent with active disease.