Rapid Review

Hypereosinophilia: Current Classification and Treatment Approaches

By William B. Ershler, MD

With the development of an increased understanding of cellular biology, in general, and the regulation of eosinophils, in particular, the heterogeneous diagnosis of hypereosinophilic Syndrome (HES) has now been better defined and a classification system has been developed with clear clinical implications.1 Most commonly, eosinophilia is secondary and the result of parasitic infections, vasculitis, allergy, or drugs. Accordingly, the diagnosis and management are often undertaken by infectious-disease specialists or allergists. However, when a cause for secondary eosinophilia is not readily apparent, it is reasonable to undertake a focused diagnostic approach to classify the condition and provide appropriate management. By definition, patients with hypereosinophilia have eosinophil counts > 1,500/uL persisting for at least six consecutive months, and are considered to have HES if there is end organ impairment or dysfunction related to the hypereosinophilia.2

Hypereosinophilia

Our understanding of the pathogenesis of primary eosiniophilic disorders has evolved dramatically over the past decade, and there are currently three major subsets considered, two of which are demonstrably clonal. These three categories are: 1) patients with chronic eosinophilic leukemia; 2) patients with IL-5/Th2 lymphocyte-mediated clonal hypereosinophilia (sometimes referred to as "lymphoproliferative" HES); and, idiopathic eosinophilia without evidence for clonal proliferation.1,3 Thus, patients with "idiopathic" hypereosinophilia include both those who have associated organ impairment (HES) and those for whom the finding is not associated with organ involvement. However, excluded from the "idiopathic" category are those with either secondary eosinophilia or those with clonal eosinophilia.

There are now well-described specific mutations associated with each of the two clonal hypereosinophilias, and these include mutations and rearrangements of PDGFRA, PDGFRB, and FGFR1 genes. Efforts at correct classification are warranted, as there is now sufficient information that such will help guide appropriate treatment choices (Table 1).

Table 1: Approach to Eosinophilia

History

Travel, infections, allergies, other medical conditions, drugs

Rule out secondary eosinophilia

Treat the primary cause

Physical examination

Signs of infection, hepatosplenomegaly, lymphadenopathy, cardiac murmur

Routine Laboratories/Imaging studies

Routine chemistries, stool for ova/parasites, serological tests for suspected pathogens, troponin, chest X-ray, CT scan

Peripheral blood

Screen for FIP1L1-PDGFRA using FISH or RT-PCR

Mutation present, diagnosis of FIP1L1-PDGFRA clonal eosinophilia established, proceed to treatment

Imatinib

Flow cytometry for lymphocyte phenotype

If abnormal or clonal lymphocytes present, 'lymphocytic' variant eosinophilia

Chemotherapy, MAb (anti-IL5, anti CD52)

T cell Receptor gene re-arrangement studies

Bone marrow

Histopathology

Dysplastic features, increased blasts (chronic eosinophilic leukemia-NOS, or other myeloid neoplasm)

Treat underlying myeloid malignancy

Cytogenetics

5q33 translocation (PDGFRB rearranged clonal eosinophilia)

8p11 translocation (FGR1-rearranged clonal eosinophilia)

Imatinib

Aggressive lymphoma management

All of the above negative

Idiopathic eosinophilia (including HES)

Treatment aimed at avoiding organ damage (Steroids, Interferon, cytotoxic drugs, others)

For a more comprehensive discussion of treatment options, see references 1 and 10.Source: Adapted from Teferri, et al.1

Thus, HES was once used to describe primary eosinophilia, but currently the term HES is now reserved for those with idiopathic eosinophilia and end organ damage resulting from the high eosinophil number.

Management

Once secondary eosinophilia is ruled out, as best possible, treatment considerations are directed by category. For patients in whom clonal eosinophilia is associated with the fusion gene FIP1L1-PDGFRA, treatment should be initiated with the tyrosine-kinase inhibitor imatinib mesylate, as this has proven highly effective, even at very low doses (e.g., 100 mg/day, or even less).4-6 Imatinib therapy also is effective for clonal eosinophilia associated with PDGFRB mutations, although higher doses might be required.7 In contrast, FGFR1-rearranged clonal eosinophilia presents as an aggressive myeloproliferative disease and is associated with T-cell lymphoblastic lymphoma and/or progression to AML. Patients with this disorder need to be treated aggressively, but even so, durable responses are uncommon.

Novel therapies have been studied for patients with each type of eosinophilia, and these include alternative kinase inhibitors (e.g., nilotinb, surafenib), and monoclonal antibodies to IL-5 (mepolizumab) and CD52 (alemtuzumab). For patients refractory to these approaches, they have been treated with some success with chemotherapy. For patients with idiopathic eosinophilia and tissue injury mediated by eosinophils (i.e., HES), the goal of therapy is to reduce eosinophil number, and corticosteroid therapy has been most commonly employed. Chemotherapy, such as with cladarabine, has been of some benefit, as has treatment with mepolizumab or alemtuzumab. Imatinib, unfortunately, has little role in this setting,8 although occasional reports have been positive.9

Summary

As the molecular pathogenesis of eosinophilia is increasingly understood, it is apparent that accurate diagnosis is of critical importance for optimal management. Specifically, the discovery of FIP1L1-PDGFRA has transformed both the understanding and management of at least one form of eosinophilia previously considered HES, and has led to a much greater understanding of the management of other forms.

References

1. Tefferi A, Gotlib J, Pardanani A. Hypereosinophilic syndrome and clonal eosinophilia: Point-of-care diagnostic algorithm and treatment update. Mayo Clin Proc. 2010;85:158-164.

2. Chusid MJ, et al. The hypereosinophilic syndrome: analysis of fourteen cases with review of the literature. Medicine (Baltimore). 1975;54:1-27.

3. Gotlib J. Chronic eosinophilic leukemia/hypereosinophilic syndrome. Cancer Treat Res. 2008;142:69-106.

4. Jovanovic JV, et al. Low-dose imatinib mesylate leads to rapid induction of major molecular responses and achievement of complete molecular remission in FIP1L1-PDGFRA-positive chronic eosinophilic leukemia. Blood. 2007;109:4635-4640.

5. Metzgeroth G, et al. Safety and efficacy of imatinib in chronic eosinophilic leukaemia and hypereosinophilic syndrome: A phase-II study. Br J Haematol. 2008;143:707-715.

6. Pardanani A, et al. FIP1L1-PDGFRA fusion: Prevalence and clinicopathologic correlates in 89 consecutive patients with moderate to severe eosinophilia. Blood. 2004;104:3038-3045.

7. David M, et al. Durable responses to imatinib in patients with PDGFRB fusion gene-positive and BCR-ABL-negative chronic myeloproliferative disorders. Blood. 2007;109:61-64.

8. Jain N, et al. Imatinib has limited therapeutic activity for hypereosinophilic syndrome patients with unknown or negative PDGFRalpha mutation status. Leuk Res. 2009;33:837-839.

9. Butterfield JH. Success of short-term, higher-dose imatinib mesylate to induce clinical response in FIP1L1-PDGFR alpha-negative hypereosinophilic syndrome. Leuk Res. 2009;33:1127-1129.

10. Antoniu SA. Novel therapies for hypereosinophilic syndromes. Neth J Med. 2010;68:304-310.