Eosinophils are a type of white blood cells involved in a variety of conditions, including allergic disorders (e.g. asthma, atopic dermatitis), drug hypersensitivity, parasitic infections, autoimmune disease, and, rarely, primary bone marrow neoplastic disorders.
Defined as an absolute eosinophil count between 0.5 × 109/L and 1.0 × 109/L, mild eosinophilia is a common finding in practice, occurring in 3% to 10% of individuals. However, severe eosinophilia, defined as an AEC >1.5 × 109/L is relatively rare, and when persistent, should raise the suspicion for a primary bone marrow neoplastic process (e.g. myeloproliferative neoplasm (MPN)).
Cases of severe eosinophilia presenting with clinical manifestations of organ damage have led to the first description of what is referred to as hypereosinophilic syndromes (HES) in 1968 ; a condition characterized by an elevated level of peripheral blood eosinophils and end-organ damage attributed to infiltration of eosinophils into tissues such as the heart, lungs, skin, or nerves. Since that first description, researchers and clinicians have gained a better understanding of HES such that, in many cases, the exact etiology of eosinophilia can now be attributed to specific disorders with effective therapies.
One of the most important advances in understanding the heterogeneous group of HES was the discovery of a tyrosine kinase created by a fusion of the platelet-derived growth factor receptor alpha (PDGFRA) with FIP1L1 in 2003 . This subset of patients with HES appeared to have dramatic responses to tyrosine kinase inhibitor therapy (e.g. imatinib), which led to the creation of a separate category of “Myeloid and lymphoid neoplasms associated with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1,” in the 2008 World Health Organization (WHO) classification . In multiple retrospective studies, approximately 20% of patients who presented with HES had features suggestive of a myeloid neoplasm, and up to 80% of those had a PDGFRA-associated MPN .
When a PDGFRA-associated MPN is suspected, bone marrow evaluation and detection of a FIP1L1-PDGFRA rearrangement by fluorescent in-situ hybridization (FISH) or reverse transcriptase-polymerase chain reaction (RT-PCR) is essential. Rarely, myeloid neoplasms can present with an extramedullary (outside the bone marrow) tumor associated with significant morbidity. Given the rarity of this presentation, two questions arise in clinical practice: first, can tyrosine kinase inhibitor therapy induce responses the same way they would in the absence of an extramedullary proliferation? Second, is testing for a FIP1L1-PDGFRA rearrangement from the extramedullary site feasible?
In an effort to compile all reported cases of extramedullary myeloid neoplasms with eosinophilia, this paper reviewed the differences in presentation and response to tyrosine kinase inhibitor therapy and reported the first case of a myeloid neoplasm with eosinophilia associated with an isolated extramedullary FIP1L1-PDGFRA rearrangement .
The paper presented a total of 6 cases published in the literature that show: first, tyrosine kinase therapy (specifically, imatinib) induced responses in all cases with a duration of responses lasting 10 months to 5 years. In four of these cases, induction conventional chemotherapy was not used, suggesting that even in the presence of an immature extramedullary tumor with myeloid blasts, imatinib alone is sufficient therapy. In two cases, traditional chemotherapy was utilized followed by imatinib therapy, but in both cases, allogeneic stem cell transplantation was not required.
The second point presented in the paper was that testing extramedullary tissue for FIP1L1-PFGDRA rearrangement was feasible, and in fact, led to the utilization of imatinib in the single case where bone marrow testing was negative. This case was the first of its kind in the literature wherein bone marrow testing did not yield the expected finding of a gene rearrangement found in extramedullary tissue. Of interest, in all 6 cases, the patients were male with the majority of extramedullary tumors located in the axial skeleton (e.g. paravertebral mass, chest wall).
As our understanding of the HES continues to advance, this work sheds some light on rare presentations of PDGFRA-associated MPNs that are important to recognize, given therapeutic implications and responsiveness to tyrosine kinase inhibitors. It also highlights the feasibility of testing extramedullary tissue when the diagnosis is suspected and bone marrow testing is non-diagnostic.
These findings are described in the article entitled Myeloid neoplasm with eosinophilia associated with isolated extramedullary FIP1L1/PDGFRA rearrangement, recently published in the journal Cancer Genetics. This work was conducted by Talal Hilal, Veena Fauble, Rhett P. Ketterling, and Katalin Kelemen from the Mayo Clinic.
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- Cools, J., et al., A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. N Engl J Med, 2003. 348(13): p. 1201-14.
- Vardiman, J.W., et al., The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood, 2009. 114(5): p. 937-51.
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- Hilal, T., et al., Myeloid neoplasm with eosinophilia associated with isolated extramedullary FIP1L1/PDGFRA rearrangement. Cancer Genet, 2018. 220: p. 13-18.
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