The relevance of a low JAK2V617F allele burden in clinical practice: a monocentric study

Abstract

Since low JAK2V617F allele burden (AB) has been detected also in healthy subjects, its clinical interpretation may be challenging in patients with chronic myeloproliferative neoplasms (MPNs). We tested 1087 subjects for JAK2V617F mutation on suspicion of hematological malignancy. Only 497 (45.7%) patients were positive. Here we present clinical and laboratory parameters of a cohort of 35/497 patients with an AB ≤ 3%.Overall, 22/35 (62.9%) received a WHO-defined diagnosis of MPN and in 14/35 cases (40%) diagnosis was supported by bone marrow (BM) histology (''Histology-based'' diagnosis). In patients that were unable or refused to perform BM evaluation, diagnosis relied on prospective clinical observation (12 cases, 34.3%) and molecular monitoring (6 cases, 17.1%) (''Clinical-based'' or ''Molecular-based'' diagnosis, respectively). In 11/35 (31.4%) patients, a low JAK2V617F AB was not conclusive of MPN. The probability to have a final hematological diagnosis (ET/PV/MF) was higher in patients with thrombocytosis than in patients with polyglobulia (73.7% vs 57.1%, respectively). The detection of AB ≥ 0.8% always corresponded to an overt MPN phenotype. The repetition of JAK2V617F evaluation over time timely detected the spontaneous expansion (11 cases) or reduction (4 cases) of JAK2V617F-positive clones and significantly oriented the diagnostic process.Our study confirms that histology is relevant to discriminate small foci of clonal hematopoiesis with uncertain clinical significance from a full blown disease. Remarkably, our data suggest that a cut-off of AB ≥ 0.8% is very indicative for the presence of a MPN. Monitoring of the AB over time emerged as a convenient and non-invasive method to assess clonal hematopoiesis expansion.

Keywords: JAK2; MPN; V617F mutation; allele burden; myeloproliferative neoplasms.

Figure 1. Schematic representation of the study population and the study plan

ET: Essential Thrombocythemia; PV: Polycythemia Vera; MF: primary Myelofibrosis; MPN NOS: Myeloproliferative Neoplasm Not Otherwise Specified; MPDs: Myeloproliferative Diseases.

Figure 2. Diagnostic workflow of patients with suspected MPN and low JAK2^V617F allele burden

*Main hematological abnormality motivating the JAK2^V617F evaluation. ‘’Histology-based’’ diagnosis was made when BM histology was available. In patients that were unable or refused to perform BM evaluation, prospective clinical observation and prospective molecular monitoring were crucial to direct diagnostic uncertainty, allowing to define a ‘’Clinical based’’ or ‘’Molecular based’’ diagnosis, respectively.

Figure 3. JAK2^V617F allele burden over time in patients with suspected essential thrombocytemia and polycythemia vera

Fifteen patients received the second evaluation of JAK2^V617F allele burden after a period of 12 months from the first mutational test. Dark red line: final diagnosis of PV. Light red line: final diagnosis of secondary polyglobulia. Dark blue line: final diagnosis of ET. Light blue line: final diagnosis of secondary thrombocytosis.