Hypereosinophilic syndrome: two case reports of contrasting variants.

Abstract: Two cases of hypereosinophilic syndrome that illustrate different variants are reported. Recognition of the specific variant is important because the treatments differ. Patients with hypereosinophilic syndrome should be monitored for evidence of a myeloproliferative process because treatment with tyrosine kinase inhibitors in these patients is effective and may prevent significant morbidity.

Key Words: FIPIL1-PDGFR-[alpha], hypereosinophilic syndrome, imatinib mesylate, myeloproliferative variant, tyrosine kinase inhibitor

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It is now important to separate idiopathic hypereosinophilic syndrome from the chronic myeloproliferative disorders, which may present as hypereosinophilic syndrome but involve a persistent stem cell disorder of the bone marrow. The advent of tyrosine kinase inhibitors is playing an increasingly important role in the treatment and potential cure of chronic myeloid leukemia and chronic myeloproliferative disorders presenting with marked elevations of leukocytes and hypereosinophilia. In this report, we will contrast a patient with idiopathic hypereosinophilia with a patient presenting with hypereosinophilia involving a chronic myeloproliferative disorder. Peripheral blood and bone marrow findings will be presented with a summary of recent literature.

Case Reports

Case 1

A 24-year-old man with a history of asthma presented with atypical chest pain. Computed tomography of the chest showed diffuse cylindrical bronchiectasis and mild subcarinal mediastinal lymphadenopathy. Cardiac enzymes were elevated at presentation, and an echocardiogram showed global nonischemic cardiomyopathy confirmed by coronary angiography. He had persistent peripheral eosinophilia, with a white blood cell count of approximately 20,000 and 50% eosinophils. Serum immunoglobulin-E was markedly elevated. Bone marrow biopsy showed marked eosinophilia with myeloid hyperplasia. He was started on corticosteroids and responded well to this regimen with a resolution of symptoms and eosinophilia.

Case 2

The second patient is a 46-year-old man with a 2-year history of eosinophilia who presented with chronic nonproductive cough, marked pruritus, and splenomegaly. During workup, he had a white blood cell count up to 179,000 with up to 46% eosinophils and a marked left shift. Bone marrow studies showed virtually 100% cellular marrow with extensive, severe myeloid hyperplasia and eosinophilic maturation. His leukocyte alkaline phosphate level was low, but the Philadelphia chromosome was absent in the face of this chronic myelogenous leukemia-like syndrome. The patient had endocardial fibrosis with mitral regurgitation and did not respond to steroids, but his symptoms and blood count normalized after treatment with [alpha]-interferon and cyclosporine. He later responded well to imatinib mesylate, a tyrosine kinase inhibitor.

Discussion

By definition, hypereosinophilic syndrome (HES) is a diagnosis of exclusion and requires at least 6 consecutive months of persistent absolute eosinophilia greater than 1,500/[micro]L. Other reactive causes of eosinophilia such as parasitic infections, allergic diseases, and drug reactions must be ruled out clinically. Additional diagnostic findings include bone marrow eosinophilia and hypercellularity, as well as tissue damage (usually cardiac) due to eosinophil granule contents. (1)

At least two variants of the hypereosinophilic syndrome have been identified. (2) The myeloproliferative variant is characterized by increased serum [B.sub.12], abnormal leukocyte alkaline phosphate, anemia and/or thrombocytopenia, hepatomegaly, splenomegaly, and circulating leukocyte precursors. This variant of HES also requires the absence of chromosomal evidence of clonality, in which case the diagnosis of chronic eosinophilic leukemia is more appropriate. The lymphocytic variant is associated with increased immunoglobulin-E levels, cutaneous manifestations, and an aberrant interleukin-5--producing T-cell population.

The first patient's hypereosinophilia appears to be truly idiopathic. It is unlikely to be the result of the lymphocytic variant of HES because he lacks the cutaneous symptoms that are the hallmark of this process. Further study of his T cell, including phenotype and interleukin-5 production, would be necessary to rule out this diagnosis. Another possibility in the differential diagnosis is Churg-Strauss. In any case, this patient does not have the myeloproliferative variant of HES, whereas the second patient clearly fits the criteria for the myeloproliferative variant of HES.

The treatment regimen for HES has evolved rapidly in the last few years. Patients with eosinophilia but no end-organ damage may not require any treatment. Both of the patients in this study showed cardiac involvement and had other symptoms, so they were initially treated with corticosteroids, which suppresses eosinophil production and reduces the effects of the granules. Alpha-interferon, which affects the stem cells, has been effective in steroid-resistant patients and in those with clonal eosinophilia. The second patient in this report responded to [alpha]-interferon but had significant morbidity as the result of side effects. Cyclosporine inhibits T-cell-driven eosinophilia and would be expected to be useful in the lymphocytic variant.

The tyrosine kinase inhibitor imatinib mesylate has been shown to be useful in the myeloproliferative form of HES. The molecular basis for this response in most patients is inhibition of a fusion tyrosine kinase, FIP1L1-PDGFR-[alpha], in which platelet-derived growth factor receptor-[alpha] is fused to the newly described gene FIP-like-1. (3) Although recent studies show clinical improvement of eosinophilia and bone marrow pathology with this treatment, reversal of cardiac dysfunction has not been reported. (4)

Conclusion

Because of the diversity of available treatments, it is important to differentiate between the myeloproliferative variant of HES and the other variants. In the case of the second patient, the Philadelphia chromosome was absent, although there were other features of a clonal myeloproliferative process, such as CD-117 positivity, peripheral immature eosinophil precursors, and 100% bone marrow hypercellularity. This patient benefited from treatment with tyrosine kinase inhibitors, whereas he had no response to the conventional treatments for HES.

Follow-up and treatment of patients with HES should include monitoring for cytogenetic and molecular evidence of clonality, which would indicate a myeloproliferative disease rather than HES. (5) Serial assessment should be made because patients with HES may develop clonal cytogenetic abnormalities, primarily involving translocations of 5q33 or 8p11, or transcription of FIP1L1-PDGFR-[alpha]. Delay in starting patients on the proper treatment regimen may result in permanent organ damage, especially cardiac. Identification of the specific variant of HES would help to guide treatment regimens.

Accepted August 10, 2004.

References

1. George TI, Arber DA. Pathology of the myeloproliferative diseases. Hematol Oncol Clin North Am 2003;17:1101-1127.

2. Roufosse F, Cogan E, Goldman M. The hypereosinophilic syndrome revisited. Ann Rev Med 2003;54:169-184.

3. Gotlib J, Cools J, Malone J, et al. The FIP1l1-PDGFR[alpha] fusion tyrosine kinase in hypereosinophilic syndrome and chronic eosinophilic leukemia: implications for diagnosis, classification, and management. Blood 2004;103:2879-2891.

4. Klion AD, Robyn J, Akin C, et al. Molecular remission and reversal of myelofibrosis in response to imatinib mesylate treatment in patients with the myeloproliferative variant of hypereosinophilic syndrome. Blood. 2004;103:473-478.

5. Brito-Babapulle, F. The eosinophilias, including the idiopathic hypereosinophilic syndrome. Br J Haematol 2003;121:203.

RELATED ARTICLE: Key Points

* There are at least two variants of hypereosinophilic syndrome, illustrated by the case reports presented herein.

* It is important to determine which variant a patient has because of differing treatments.

* Tyrosine kinase inhibitors are effective in the myeloproliferative variant, and act by inhibiting a newly described gene fusion product called FIP1L1-PDGFR-[alpha].

Jared Szymanski, DO, and Edward Rappaport, MD

From the Department of Pathology, Texas A & M Health Science Center College of Medicine, Scott and White Hospital, Scott, Sherwood, and Brindley Foundation, Temple, TX.

Reprint requests to Jared Szymanski, D.O., Department of Pathology, Scott and White Hospital, 2401 South 31st Street, Temple, TX 76508. Email: [e-mail]