Current Opinion in Hematology:
MYELOID DISEASE: Edited by Martin S. Tallman
Eosinophilic myeloid neoplasms
Noel, Pierre; Mesa, Ruben A.
Division of Hematology Oncology, Mayo Clinic Arizona, Scottsdale, Arizona, USA
Correspondence to Pierre Noel, MD, Division of Hematology Oncology, Mayo Clinic Arizona, 13400 East Shea Boulevard, Scottsdale, AZ 85259, USA. Tel: +1 480 301 8000; e-mail: Noel.Pierre@Mayo.edu
Purpose of review: In 2012, idiopathic hypereosinophilic syndrome (HES) is still the prevalent diagnosis in patients with persistent eosinophilia, in which a primary or secondary cause of eosinophilia has not been identified. HES is considered a provisional diagnosis until a primary or secondary cause of hypereosinophilia is established. The discovery of imatinib-sensitive fusion proteins in a subset of patients with hypereosinophilia has changed the way we approach the diagnosis and treatment of eosinophilic myeloid neoplasms [eosinophilic myeloproliferative neoplasms (MPNs)]. Despite the recent diagnostic developments, diagnosis of hypereosinophilic MPN is only made in 10–20% of patients with persistent primary hypereosinophilia.
Recent findings: In 2008 the World Health Organization (WHO) established a semi-molecular classification of hypereosinophilic MPNs. The discovery of PDGFRA, PDGFRB, FGFR1, JAK-2, and FLT3 fusion proteins in patients with eosinophilic MPNs provide opportunities for targeted therapy. Patients with hypereosinophilic MPNs associated with PDGFRA and PDGFRB fusion genes are responsive to imatinib.
Summary: Ongoing research continues to expand our understanding of the pathophysiology of persistent primary hypereosinophilia and clarify the boundaries between some of these disorders. A key challenge is to identify new targets for therapy and limit the number of patients who are classified as having HES.
Organ dysfunction and irreversible organ damage secondary to tissue infiltration and the effects of eosinophil-derived mediators are complications associated with persistent eosinophilia. The reason for the variability of onset and severity of organ dysfunction remains unknown. Determining a primary or secondary cause for persistent eosinophilia focuses therapy, minimizes iatrogenic side-effects, and decreases the risk of developing irreversible organ damage. A diagnosis of idiopathic hypereosinophilic syndrome (HES) requires an absolute eosinophil count superior to 1500 per μl for at least 6 months and evidence of organ involvement and dysfunction . With the availability of effective therapy and the risks of end-organ damage, it is no longer appropriate to wait 6 months to make a diagnosis of HES.
HES is considered a provisional diagnosis until a primary or secondary cause of eosinophilia is established. The description of the FIP1L1–PDGFRA (F/P) fusion gene in a patient with imatinib-responsive HES and a t(1;4)(q44;q12) translocation  redefined the way we evaluate and treat patients with eosinophilia. F/P myeloproliferative neoplasms (MPNs) account for approximately 10–20% of patients with a provisional diagnosis of HES . Fluorescent in-situ hybridization (FISH) and RT-PCR are used to detect the cytogenetically occult 800-kb deletion on 4q12 associated with the F/P fusion. Other recurrent molecular abnormalities involving 4q12 (PDGFRA fusion partners in addition to FIP1L1), 5q31–33 (PDGFRB), 8p11–13 (FGFR1), 9p24 (JAK2), and 13q12 (FLT3) are detected by conventional cytogenetics, FISH, and RT-PCR [2,4–8]. This review focuses on three molecularly defined eosinophilic myeloproliferative neoplasms (hypereosinophilic MPNs) as well as chronic eosinophilic leukemia not otherwise specified (CEL-NOS). Idiopathic HES and idiopathic hypereosinophilia will not be discussed herein.
CLASSIFICATION OF EOSINOPHILIC MYELOID DISORDERS
The 2008 revision of the World Health Organization (WHO) Classification of Tumors of the Haematopoietic and Lymphoid Tissues [5,6] divides eosinophilic myeloid neoplasms (eosinophilic MPNs) into two subgroups: myeloid–lymphoid neoplasms with eosinophilia associated with rearrangements of PDGFRA, PDGFRB, or FGFR1; and CEL-NOS. CEL-NOS is a myeloproliferative neoplasm defined by eosinophils of 1500 per μl or higher; evidence of eosinophil clonality or increase in either peripheral blood or bone marrow blasts (<20%); and absence of rearrangements of BCR-ABL, PDGFRA, PDGFRB, and FGFR1 . Idiopathic HES can only be diagnosed when there is an eosinophil count of 1500 per μl persisting for over 6 months; reactive eosinophilia is excluded; acute myeloid leukemia, myelodysplastic syndrome (MDS), MPN, MPN/MDS, and systemic mastocytosis have been excluded; a cytokine-producing, immunophenotypically aberrant, T-cell population is excluded; and there is tissue damage as a result of hypereosinophilia. If the first four criteria are met but there is no tissue damage, the appropriate diagnosis is idiopathic hypereosinophilia. With the availability of effective therapy and the risks of end-organ damage, it is no longer appropriate to wait 6 months to make a diagnosis of HES. The WHO classification of eosinophilic myeloid disorders is as follows :
1. myeloid and lymphoid neoplasms with PDGFRA rearrangement;
2. myeloid neoplasms with PDGFRB rearrangement;
3. myeloid and lymphoid neoplasms with FGFR1 abnormalities;
5. idiopathic HES;
6. idiopathic hypereosinophilia.
The WHO classification does not include lymphocytic and familial categories and does not recognize the diagnostic confusion occurring in patients with systemic mastocytosis associated with increased eosinophils (SM-Eo). In addition, patients with MPNs and cytogenetic markers have the potential of being incorrectly classified as CEL-NOS if their absolute eosinophils exceed 1500 per μl.
MYELOID NEOPLASMS WITH EOSINOPHILIA AND ABNORMALITIES OF PDGFRA
The success achieved with imatinib in a small number of patients with HES [10,11] led to the identification of the F/P fusion protein as the imatinib target. It was first described in a patient with imatinib-responsive HES and a t(1;4)(q44;q12) translocation .
F/P oncoprotein is a constitutively activated tyrosine kinase that is inhibited by imatinib. The F/P oncoprotein is generated by a karyotypically occult 800-kb interstitial deletion of chromosome 4q12. The breakpoints in FIP1L1 are variable but are typically located in a 40-kb region spanning introns 7–10 of FIP1L1. The breakpoints in PDGFRA appear to be restricted to a region of exon 12 that contains the WW-like region of the juxtamembrane domain. The majority of patients with F/P have a normal karyotype, only rare patients with reciprocal translocations have been described. KIF5B , CDK5RAP2 , STRN , BCR, and ETV6  have been identified as PDGFRA fusion partners.
The F/P mutation can be detected by interphase–metaphase FISH [4,15] or RT-PCR . There does not appear to be a difference in sensitivity or specificity between the two methods, and the fusion can be detected equally well in peripheral blood and bone marrow aspirates. F/P transcripts can be difficult to detect by single-step RT-PCR and, in many instances, nested PCR is required for reliable identification of the fusion . Deletion of CHIC2 locus at 4q12 detected by FISH is a surrogate marker for the F/P fusion [4,15]. The F/P fusion protein can also be found in acute myeloid leukemia and T-cell lymphoblastic lymphoma . Imatinib-sensitive activating PDGFRA point mutations have been described in a minority of patients with clonal eosinophilia. Screening for point mutations can identify patients who may be candidates for treatment with imatinib or other tyrosine kinase inhibitors (TKIs) . The role of PDGFRA point mutations in human disease remains unproven. Quantitative PCR looking at the 3′ region of PDGFRA identifies a small percentage of F/P-negative patients who overexpress PDGFRA and may be candidates for TKI therapy .
The peak incidence of F/P MPN occurs during the fourth decade, the majority of patients being men. Prior to targeted therapy, prognosis was poor with 30–50% mortality at 5 years [20,21]. Splenomegaly is present in 63% , B12 and tryptase levels are increased in the majority of patients , and anemia and thrombocytopenia are common [20,22]. Eosinophilia is the hallmark of F/P MPN. In patients with F/P MPN, rs4054760, a single-nucleotide polymorphism in the 5′ UTR of the alpha subunit of the interleukin-5 receptor (IL5RA) is associated with the degree of peripheral blood eosinophilia and the presence of tissue infiltration . The bone marrow is hypercellular, with increased eosinophils; eosinophil maturation is typically normal. Scattered or loose noncohesive aggregates of CD25+-positive mast cells are frequently present. Aggregates of more than 15 cohesive mast cells are not typical. Increased reticulin staining is frequently present .
F/P MPN is a multisystem disorder. Dermatologic manifestations are the most common (69%), followed by pulmonary (44%) and gastrointestinal (38%). Eosinophil-mediated cardiac injury developed in 20% (6% at presentation) .
A serum troponin and cardiac echocardiogram should be obtained prior to initiating imatinib. An increased level of serum cardiac troponin correlates with the presence of cardiomyopathy in patients with HES [24,25]. Prophylactic use of steroids (prednisone 1 mg/kg/day) during the first 7–10 days of treatment is recommended in patients with evidence of eosinophil-mediated cardiomyopathy and in patients with other cardiac comorbidities .
Imatinib is a small molecule TKI that targets the inactive conformation of F/P fusion protein, occupying the ATP-binding site and interfering with downstream phosphorylation [2,26]. The majority of patients achieve clinical and hematologic improvement within 2–4 weeks and molecular remission within 3–6 months [27▪].
Endomyocardial fibrosis, with ensuing restrictive cardiomyopathy, is the most feared complication. Scarring of the mitral and tricuspid valves can lead to valvular regurgitation and formation of intracardiac thrombi [28,29]. The incidence of venous and arterial thrombosis is increased. Superficial venous thrombophlebitis, diffuse systemic thrombophlebitis, and thrombotic microangiopathy [30,31] have been reported.
The FDA-recommended starting dose of imatinib for patients with the F/P MPN is 100 mg daily. There is some controversy on the optimal starting dose (100–400 mg daily) of imatinib. F/P is 100 times more sensitive to inhibition from imatinib than is BCR-ABL [2,32]. The cell line results correlate with the clinical findings that the effective dose of imatinib is lower in patients with F/P MPN (100 mg) than in those with BCR-ABL-positive chronic myelocytic leukemia (400 mg/day). The optimal maintenance dose of imatinib to sustain a molecular remission has not been determined. The majority of clinicians use an indefinite maintenance dosage of 100 mg daily, others use doses in the range of 300–400 mg daily. A total of 100 and 200 mg weekly maintenance doses have been used successfully in some institutions [27▪,33▪,34]. Imatinib suppresses but does not eliminate the F/P clone; discontinuation of imatinib leads to relapse [35,36]. Molecular remissions could be restored in all patients with re-induction of imatinib at a dose range of 100–400 mg daily . The dose required to maintain a remission may be higher than the dose used during the first molecular remission. The emergence of imatinib-resistant subclones may be favored by temporary withholding of treatment. In a prospective Italian study , complete hematologic and molecular remissions were achieved in every patient. Molecular remissions were achieved at a median of 3 months (1–10 months). Remissions were maintained on continued imatinib for a median follow-up of 19 months (6–56+ months). In 36 patients who did not carry the FIP1L1–PDGFRA rearrangement, 5 patients (14%) achieved a complete hematologic remission, which was lost in all cases after 1–15 months. In patients who are intolerant to imatinib, there is only limited published experience with the use of either dasatinib  or nilotinib .
Primary resistance to imatinib is uncommon in F/P MPN. One patient was reported with two mutations in the PDGFRA sequence, resulting in two amino acid modifications within the kinase domain: S601P and L629P . Acquired mutations conferring imatinib resistance are infrequent. The PDGFR kinase domain contains a limited number of residues where exchanges critically interfere with binding of and inhibition by available PDGFR kinase inhibitors at achievable concentrations. In vitro, at clinically achievable drug concentrations, the T674I mutation occurs after exposure to imatinib, whereas with nilotinib and sorafenib, the D842V mutation and the compound mutation T674I–T874I are more prevalent . In a review of seven patients with secondary resistance to imatinib in F/P MPN, the median time to imatinib resistance was 5 months (2–9), and marrow blasts were increased in five of seven patients, suggesting accelerated/blast phase . The T674I mutation is analogous to the T315I mutation occurring in the ABL domain of imatinib-resistant chronic myeloid leukemia patients. In vitro, the T674I mutants appear to be sensitive to nilotinib, sorafenib, and midostaurin . Anecdotal clinical experience treating patients with the T6741 mutation with nilotinib, sorafenib, and midostaurin has been disappointing . The D842V mutation is not sensitive to nilotinib or dasatinib .
Allogeneic stem cell transplantation remains an option for patients with aggressive disease unresponsive to TKIs [44–46]. Interferon-alpha-induced complete remissions have been reported in F/P MPN [47,48]. Interferon-alpha may be used in patients who are unresponsive to TKIs or as a bridge prior to transplantation.
Eosinophilia is present in a subset of patients diagnosed with systemic mastocytosis. Peripheral blood eosinophilia greater than 1500 per μl is found in approximately 15% of patients with F/P-negative systemic mastocytosis [49,50] and up to 50% of patients with D816V KIT-positive mast cell leukemia . The D816V KIT mutation is identified in both eosinophils and CD34+ hematopoietic stem cells in 30% of patients with mutation-positive systemic mastocytosis, regardless of whether eosinophilia is present . SM-Eo is defined by persistent eosinophilia of at least 6 months duration and an absolute eosinophil count (>1500 per μl) in patients otherwise meeting the WHO diagnostic criteria  for systemic mastocytosis. In situations where molecular assays are not available, clinical and laboratory features can be helpful in distinguishing F/P MPN from SM-Eo. Endomyocardial fibrosis is found exclusively in F/P-positive patients, urticaria pigmentosa occurs exclusively in KIT D816V patients. An absolute eosinophil count/tryptase ratio greater than 100, the absence of dense mast cell aggregates on bone marrow biopsy and a peak absolute eosinophil count greater than 10 000 per μl strongly correlate with a diagnosis of F/P MPN. A nonmolecular scoring system was established to help distinguish F/P MPN from SM-Eo . It is important to distinguish SM-Eo from F/P MPN because of the lack of response to imatinib in patients with SM-Eo .
MYELOID NEOPLASMS WITH EOSINOPHILIA AND ABNORMALITIES OF PDGFB
PDGFRB fusion genes represent the uncommon causes of clonal eosinophilia. Twenty PDGFRB fusion partners have been reported . PDGFRB rearrangements are rarely encountered in chronic myelomonocytic leukemia. t(5;12)(p12;q31–22) is the most common translocation, and is associated with the expression of the ETV6–PDGFRB protein and responsiveness to imatinib [54,55]. The recommended imatinib dose is 400 mg daily . t(5;12)(p12;q31–32) not associated with the ETV6–PDGFRB fusion is unlikely to be imatinib responsive.
MYELOID AND LYMPHOID NEOPLASMS WITH EOSINOPHILIA AND ABNORMALITIES OF FGFR1
Eosinophilic MPNs associated with FGFR1 fusion are rare [57,58]. Prognosis is poor, aggressive chemotherapy followed by allogeneic stem cell transplantation is recommended. Midostaurin (PKC412) induced a hematologic and cytogenetic response in a patient described in case report . The most frequent translocation consists of t(8;13)(p11;q12), and involves ZNF198 at 13q12 and FGFR1 at 8p11. More than 10 fusion partners of FGFR1 have been described . The majority of translocations and insertions involving FGFR1 are cytogenetically identifiable at the 8p11 locus .
CHRONIC EOSINOPHILC LEUKEMIA-NOT OTHERWISE SPECIFIED
CEL-NOS is uncommon: the disease is aggressive and unresponsive to therapy. The most common cytogenetic abnormality involves chromosome 8 . In a series of 10 patients, the median survival was 22.2 months; 5 of the 10 patients developed acute transformation after a median of 20 months from diagnosis . The optimal therapeutic strategy for patients with CEL-NOS is undefined. Some patients have responded to alpha-interferon [62,63], responses to imatinib have been short lived and disappointing [2,37]. Early allogeneic stem cell transplantation should be considered.
Eosinophilic MPNs represent a heterogeneous group of disorders with very different clinic courses, therapeutic strategies, and outcomes. Imatinib-responsive eosinophilic MPNs represent a small fraction of the identifiable causes of persistent eosinophilia. Their identification influences both therapy and prognosis. Patients with mutations leading to FGFR1, JAK2, and FLT3 fusion proteins may be candidates for several new promising therapeutic strategies.
Conflicts of interest
Pierre Noel's spouse is an employee of Novartis Pharmaceuticals.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 183).
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eosinophilia; hypereosinophilic syndrome; myeloproliferative neoplasms; PDGFRA; PDGFRB
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