Spotlight Review

Leukemia (2008) 22, 1999–2010; doi:10.1038/leu.2008.287; published online 9 October 2008

Five years since the discovery of FIP1L1–PDGFRA: what we have learned about the fusion and other molecularly defined eosinophilias

J Gotlib1 and J Cools2,3

  1. 1Department of Medicine/Division of Hematology, Stanford Cancer Center, Stanford, CA, USA
  2. 2VIB Department of Molecular and Developmental Genetics, VIB, Leuven, Belgium
  3. 3Center for Human Genetics, K.U. Leuven, Leuven, Belgium

Correspondence: Dr J Gotlib, Stanford Cancer Center, Department of Medicine/Hematology, Stanford University School of Medicine, 875 Blake Wilbur Drive, Room 2324, Stanford, CA 94305-5821, USA. E-mail:; Dr J Cools, Herestraat 49, Box 602, Leuven B-3000, Belgium. E-mail:

Received 16 September 2008; Accepted 16 September 2008; Published online 9 October 2008.



The year 2008 marks the fifth anniversary since the publication which identified the FIP1L1–PDGFRA fusion gene in patients with idiopathic hypereosinophilia. With the benefit of time, a more comprehensive picture has emerged regarding several characteristics of the fusion, including its incidence, biological features and the clinical profile of patients who carry the molecular rearrangement. A few prospective trials have now better defined the natural history of imatinib-treated FIP1L1–PDGFRA-positive patients, from which some basic conclusions can be drawn: the prognosis is outstanding, acquired resistance is exceedingly rare, but ongoing imatinib treatment is likely required to prevent relapse. The emergence of genetically assigned eosinophilias has led the World Health Organization in 2008 to adopt a semi-molecular classification scheme, with one subcategory named 'myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB or FGFR1.' Molecular rearrangements involving other partner genes, such as ETV6 and JAK2, have also been associated with eosinophilic disorders, and will likely be assimilated into such classifications over time. Despite the molecularly defined eosinophilias comprising a small proportion of cases compared to the aggregate of other subtypes of hypereosinophilia, their recognition is critical because of the availability of highly effective molecularly targeted therapy.


hypereosinophilic syndrome, chronic eosinophilic leukemia, FIP1L1–PDGFRA, PDGFRB, FGFR1, imatinib


Terminology and classification

In contradistinction to 'secondary' or 'reactive' hypereosinophilia, FIP1L1–PDGFRA-positive chronic eosinophilic leukemia (CEL) and other molecularly defined myeloproliferative neoplasms (MPNs) are broadly categorized as either 'primary' or 'clonal' eosinophilias, because they are acquired hematopoietic stem cell or progenitor cell marrow disorders for which a specific genetic abnormality has been identified.1 CEL has also been defined by an increase in peripheral blood (>2%) or bone marrow (>5%) blasts in the absence of a clonal marker by conventional cytogenetic assays, fluorescence in situ hybridization (FISH) or other types of molecular studies (for example, X-chromosome inactivation analysis).1 In addition, eosinophilia-associated acute or chronic myeloid neoplasms must be excluded (for example, chronic myeloid leukemia (CML), acute myeloid leukemia (AML) (for example, French-American-British subtype M4Eo, inversion 16), myelodysplastic syndrome, systemic mastocytosis and so on). Although not formally adopted in the nomenclature of the World Health Organization (WHO), the term 'myeloproliferative variant of hypereosinophilic syndrome (M-HES)' has been commonly used in the literature to refer to these marrow-derived eosinophilic MPNs because they share one or more clinical or laboratory features suggestive of CML or the classic MPDs: hepato/splenomegaly, bone marrow hypercellularity or fibrosis, myeloid immaturity and elevated serum B12 or serum tryptase levels.2 Lymphocyte-variant hypereosinophilia relates to the existence of clonal, pathogenetic T-cell subsets with an aberrant surface immunophenotype (for example, CD3-CD4+, CD4+CD7-, CD3+CD4-CD8-), which overproduce eosinophilopoietic cytokines such as interleukin-5 (IL-5) and other Th2 cytokines such as IL-4, IL-13 and granulocyte macrophage colony-stimulating factor.3, 4 In these cases, the eosinophilia is non-clonal. In rare instances, transformation of the clonal T cells to T-cell lymphoma has been reported, although lymphocyte-variant hypereosinophilia generally follows a benign course. The diagnosis of idiopathic hypereosinophilic syndrome (HES) should be reserved for patients in whom no clonal marker has been identified, no increased blood or marrow blasts are present and for which no definite or suggestive clinical or laboratory features of a myeloproliferative or lymphocyte variant of hypereosinophilia can be found.1 According to the classic definition of Chusid et al.,5 patients with idiopathic HES should also have an absolute eosinophil count of >1500/mm3 and signs or symptoms of organ involvement; however, the requirement that the eosinophilia persist for >6 months has generally fallen out of favor, in part because some patients may require more urgent treatment, and modern diagnostic evaluations can proceed in a more timely manner. Table 1A and B highlight the 2001 WHO classification of chronic eosinophilic leukemia and HES and the revised 2008 WHO classification of 'myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1' as well as 'chronic eosinophilic leukemia, not otherwise specified (NOS).'1, 6, 7


Incidence of eosinophilic neoplasms associated with rearrangements of PDGFRA, PDGFRB and FGFR1

The incidence rates for the molecularly defined eosinophilias are not known, nor are there data regarding the proportion of patients with hypereosinophilia represented by these genetically defined cases. With these caveats, eosinophilic MPNs with rearrangements of PDGFRA, PDGFRB and FGFR1 are considered to be very rare entities (for example, incidence <1/100 000 persons). When the original case series of Cools et al.8 described the FIP1L1–PDGFRA fusion in 9 of 16 patients (56%) who were initially diagnosed as idiopathic HES or CEL, it was initially felt that the majority of patients would have their idiopathic hypereosinophilia explained by this cryptic molecular defect. However, the study was biased due to its preselected study population: patients were generally advanced cases for which other causes of hypereosinophilia had been thoroughly scrutinized, and they were being evaluated at tertiary referral centers by expert hematologists who were familiar with the clinical presentation of the myeloproliferative variant of HES with which the fusion ultimately segregated.

The median frequency of the FIP1L1–PDGFRA fusion in hypereosinophilia patients across eight published series enrolling more than 10 patients was 23% (range 3–56%) (Table 2). In a prospective, multicenter Italian study of 169 patients with eosinophilia, 72 were diagnosed with either primary eosinophilia or HES. Twenty-seven of the 63 patients who provided consent for testing were found to carry the FIP1L1-PDGFRA rearrangement (43%).9 However, the incidence of the FIP1L1–PDGFRA fusion was only 16% of the 169 patients initially enrolled with a diagnosis of eosinophilia. Similarly, the fusion was found in only 40 of 376 individuals (11%) in a European trial of patients with persistent, unexplained hypereosinophilia.10 In a Mayo series, 11 of 89 patients (12%) with moderate-to-severe eosinophilia were FIP1L1–PDGFRA positive.11 In a follow-up series of 714 unselected patients with eosinophilia, only 3% were fusion positive.12 Additional studies are listed in Table 2.13, 14, 15 Despite these studies having their own selection biases, these data support a FIP1L1–PDGFRA fusion incidence of approximately 10–20% among patients presenting with idiopathic hypereosinophilia in developed countries.

In addition to the FIP1L1–PDGFRA fusion gene, variant PDGFRA fusion genes, as well as different PDGFRB and FGFR1 fusion genes have been described in MPNs with eosinophilia. In the case of PDGFRA fusions, both the BCR–PDGFRA16, 17 and FIP1L1–PDGFRA8, 18 fusions were identified in 2002–2003 as recurrent rearrangements, with the FIP1L1–PDGFRA fusion being the most common fusion. A few other variant PDGFRA fusion genes have now also been described (Table 3).19, 20, 21 In 1994, the group of Golub and Gilliland22 described the ETV6–PDGFRB fusion as the first of these fusion genes in patients with chronic myelomonocytic leukemia with eosinophilia and t(5;12). Since then, a large variety of fusion partners for PDGFRB have been described, most of which, however, are single case reports (Table 4).23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36 Despite the rare frequency (<1%) of PDGFRB rearrangements in cytogenetically defined cases of chronic myelomonocytic leukemia and other myeloid neoplasms (for example, atypical CML, juvenile myelomonocytic leukemia, chronic basophilic leukemia, myelodysplastic syndrome/MPN overlap), their recognition is essential given the exquisite sensitivity of such cases to imatinib.

Fusions involving the FGFR1 gene are similarly rare. The association of t(8;13)(p11;q11) with lymphoblastic lymphoma with eosinophilia and myeloid hyperplasia (for example, 8p11 myeloproliferative syndrome (EMS)) was initially described in 1995, followed by the discovery of the ZNF198–FGFR1 fusion gene in 1998 by four groups.37, 38, 39, 40 Additional fusion partners for FGFR1, including BCR, have since been described (Table 5).41, 42, 43, 44, 45, 46, 47 The FGFR1 rearrangement can be found in both myeloid and lymphoid cells, suggesting an origin in a multipotent hematopoietic progenitor, and thus the basis for the disease's alternate designation of 'stem cell leukemia/lymphoma syndrome.' EMS manifests an aggressive course and therefore early allogeneic transplantation is often recommended. Small molecule inhibition of the constitutively activated FGFR1 tyrosine kinase may also hold promise, as demonstrated in the case of a patient with a ZNF198–FGFR1 fusion who responded to PKC412.48

Within all these different fusion genes, the FIP1L1–PDGFRA fusion is quite unique as it is generated by a cryptic chromosomal deletion, rather than a translocation. All other PDGFRA, PDGFRB or FGFR1 fusions are generated by reciprocal translocations or by complex rearrangements, the latter usually being identified in single cases.

Finally, in addition to rearrangements of PDGFRA, PDGFRB and FGFR1, the PCM1–JAK2 fusion gene was recently discovered in various eosinophilia-associated leukemias. The acquired JAK2 V617F mutation is found in >95% of patients with polycythemia vera, approximately 50% of patients with essential thrombocythemia or primary myelofibrosis and in a small proportion of patients with atypical myeloproliferative disorders.49 The mutation results in constitutive activation of the tyrosine kinase, and transplantation of JAK2 V617F-transduced bone marrow to mice can recapitulate phenotypic aspects of human myeloproliferative disease including erythrocytosis, extramedullary hematopoiesis and bone marrow fibrosis.49 In 2005, the PCM1–JAK2 fusion was identified as a second recurrent molecular abnormality, which results in dysregulation of JAK2 tyrosine kinase activity due to oligomerization mediated by the coiled-coil domains of PCM1.50 The chimeric oncoprotein results from the t(8;9)(p22;p24) chromosomal translocation and may have pleiotropic clinical presentations, including atypical CML, AML, acute B- and T-cell lymphoblastic leukemias, often with peripheral eosinophilia.50, 51, 52, 53, 54 The clinical course of the PCM1–JAK2 cases reported to date appears to be more aggressive than the JAK2 V617F-associated chronic MPDs. JAK2 inhibitors currently in phase I testing exhibit potential for treating these neoplasms characterized by constitutive JAK2 activation.


Biology of the FIP1L1–PDGFRalpha fusion

Mechanism of activation of the FIP1L1–PDGFRalpha tyrosine kinase

The structure of the FIP1L1–PDGFRalpha fusion protein resembles the structure of the ETV6–PDGFRbeta, ZNF198–FGFR1 and BCR–ABL proteins, for which homotypic oligomerization mediated by domains within ETV6, ZNF198 or BCR has been documented.55, 56, 57 Oligomerization of the corresponding fusion proteins leads to activation of the tyrosine kinase domains, which in turn activate downstream signaling pathways regulating cell proliferation and survival. In contrast to this, we have been unable to demonstrate oligomerization of the FIP1L1–PDGFRalpha fusion protein. However, we have observed that interruption of the juxtamembrane of PDGFRalpha is indispensable for kinase activation in the context of FIP1L1–PDGFRalpha.58 Indeed, it was previously shown that mutations or duplications within the juxtamembrane region of the PDGFR family of tyrosine kinases can cause constitutive activation of their kinase activity.59, 60 Also in cancer, this mechanism is well known from the internal tandem duplications in FLT3 and KIT in AML or gastrointestinal stromal tumors, respectively.61, 62 Fusion of FIP1L1 to the PDGFRalpha protein yields a constitutive active tyrosine kinase only if the juxtamembrane domain of PDGFRalpha is partially or completely removed.58 This is what happens in patients with the FIP1L1–PDGFRalpha fusion: there are very different break points within FIP1L1, but the break points within the PDGFRA gene are tightly clustered, invariably resulting in the removal of part of the juxtamembrane domain and activation of the kinase domain. A similar mechanism has now also been described in cases of the PRKG2–PDGFRbeta fusion, in which the break points in the PDGFRB gene are also within the juxtamembrane region.63 In contrast, in other PDGFRbeta fusions, the juxtamembrane is completely intact, and in these fusions the activation of PDGFRbeta kinase activity is obtained through oligomerization mediated by the fusion partner (Figure 1).

Figure 1.
Figure 1 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact or the author

The structure and mechanism of activation of PDGFRalpha and PDGFRbeta fusions. N: N-terminal site; C: C-terminal site; TM: transmembrane domain; JM: juxtamembrane domain; kinase: kinase domain; DIM: dimerization domain; W: tryptophan of the WW motif.

Full figure and legend (43K)

Role of FIP1L1

On the basis of the results described above, the role of the FIP1L1 part in the FIP1L1–PDGFRalpha fusion is less important than the role of ETV6 in the ETV6–PDGFRbeta fusion. Nevertheless, it is still the case that the FIP1L1–PDGFRA fusion gene is under control of the FIP1L1 promoter and translation start, and the FIP1L1 part in the fusion may determine the stability and subcellular localization of the fusion protein. Also, while FIP1L1 seems dispensable for transformation of Ba/F3 cells, Buitenhuis et al.64 documented the differences in in vitro colony formation between FIP1L1–PDGFRA transduced CD34+ cells and cells transduced by a deletion variant lacking part of FIP1L1.

Insights in the mechanism of FIP1L1–PDGFRA-induced eosinophilia

FIP1L1–PDGFRalpha is required to stimulate proliferation and mediate survival of the eosinophils in CEL patients, through activation of several signaling pathways including phosphoinositol 3-kinase, ERK 1/2 and STAT5.8, 64 The exact mechanism, however, by which FIP1L1–PDGFRalpha preferentially affects eosinophils remains unclear. The essential role of FIP1L1–PDGFRA is clear from in vitro studies with the EOL-1 cell line, from mouse models of FIP1L1–PDGFRA induced disease, and from the remarkable responses of FIP1L1–PDFGRA-positive CEL patients to imatinib treatment.8, 18, 65, 66 The mouse model, however, has also suggested that expression of the FIP1L1–PDGFRA fusion is most likely not sufficient to cause eosinophilia, as mice expressing FIP1L1–PDGFRA in their bone marrow cells develop a general myeloproliferative disease without eosinophilia.65

Expression of FIP1L1–PDGFRA together with overexpression of IL-5, however, mimics the disease much better in the mouse, with typical features of HES such as tissue infiltration of eosinophils.67 Similarly, a study of polymorphic variation at the IL-5 receptor-alpha (IL5RA) gene revealed an association between a SNP in the 5' UTR of IL5RA and the eosinophil count/presence of tissue infiltration in FIP1L1–PDGFRA-positive HES patients.68 These data suggest that FIP1L1–PDGFRA alone is not sufficient to explain the development of HES/CEL, and that additional factors such as IL-5 signaling may also be implicated or at least may influence the severity of the disease.


Detection of the FIP1L1PDGFRA fusion and variant PDGFRA fusions

In many cases, patients expressing PDGFRA, PDGFRB, or FGFR1 fusion genes will have an abnormal karyotype indicating a rearrangement of 4q12 (PDGFRA), 5q31–33 (PDGFRB) or 8p11–12 (FGFR1). Therefore, an important message to hematologists is not to ignore karyotyping in cases with eosinophilia in order to rapidly identify patients with chromosomal rearrangements who may benefit from targeted therapy with specific kinase inhibitors. In addition to karyotyping, FISH analysis with probes flanking the PDGFRA, PDGFRB and FGFR1 genes remains valid in cases with obvious chromosomal rearrangements to confirm that the break points are indeed within these genes, as well as in cases without these specific rearrangements to check for possible cryptic rearrangements of these kinases. An important example of such cryptic rearrangement is the 4q12 deletion that causes the FIP1L1–PDGFRA fusion.

The generation of the fusion between the 5' part of the FIP1L1 gene and the 3' part of the PDGFRA gene occurs through an uncommon mechanism by which the 800 kb genomic region between the two genes is deleted (Figure 2).8 This deletion begins within the FIP1L1 gene, with variable break points in the different patients, and ends in exon 12 of PDGFRA. Owing to the fact that the deletion is only 800 kb in size, this genomic rearrangement remains undetectable by standard cytogenetics, but can be detected by FISH with specific probes. FISH probes that hybridize to the region between the FIP1L1 and PDGFRA genes are now commonly used to detect the presence of the deletion. As the CHIC2 gene is located in this region, this FISH test is sometimes referred to as 'FISH to detect the CHIC2 deletion.'69

Figure 2.
Figure 2 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact or the author

Schematic representation of the 4q12 locus and the consequences of the deletion causing the FIP1L1–PDGFRA fusion. (a) Shows the normal 4q12 region, indicating where the different genes are located and where the 800 kb deletion occurs in cases with the FIP1L1–PDGFRA fusion. The four green bars denote possible probes that can be used to detect the deletion by fluorescence in situ hybridization. (b) Shows the consequences of the deletion: FIP1L1 usually breaks within an intron, while PDGFRA always breaks within exon 12. The consequence of the deletion at the DNA level is that a part of an intron of FIP1L1 (various introns possible) is directly fused to a piece of exon 12 of PDGFRA. To obtain splicing between FIP1L1 and PDGFRA, cryptic splice sites need to be used, as the normal splice site at the beginning of exon 12 is removed by the deletion. Dependent on the break points within FIP1L1 and PDGFRA, this cryptic splice site is either located within exon 12 of PDGFRA (type I fusion) or within the intron of FIP1L1 (type 2 fusion). In all cases, this 'abnormal' splicing results in the generation of in-frame fusion transcripts encoding catalytically active fusion proteins.

Full figure and legend (123K)

A more sensitive way to detect the presence of the FIP1L1–PDGFRA fusion gene in the blood of eosinophilia patients is the use of (nested) reverse transcription (RT)-PCR. Despite the fact that the break points in the FIP1L1 gene can be very different from patient to patient, a single primer combination is sufficient to detect the fusion transcript from most patients. In some patients, however, the fusion remains difficult to detect, which may be due to low-level expression of the fusion gene, heterogeneity in the FIP1L1 break points and difficulties with FISH in eosinophilia cases. Therefore, a combination of RT-PCR and FISH provides the best chance of identifying FIP1L1–PDGFRA-positive cases, and several groups are working on additional tests that could further limit the chances of false negative results. Despite some minor problems associated with RT-PCR to detect the FIP1L1–PDGFRA transcript, nested RT-PCR or quantitative RT-PCR remains the method of choice to monitor the response of the disease to therapy (see below).

As a variety of PDGFRA and PDGFRB fusion genes involving partner genes other than FIP1L1 and ETV6 have also been detected in hypereosinophilia patients (Tables 3 and 4), detection of these rare variants remains important, as these patients also benefit from imatinib treatment. These cases can be identified using specific primer sets for these fusions, or alternatively, can be identified using quantitative RT-PCR to detect increased levels of PDGFRA expression.19


Disease phenotypes associated with FIP1L1–PDGFRA

FIP1L1–PDGFRA is a clonal marker associated with the myeloproliferative variant of hypereosinophilia.2, 8 These patients often present with organomegaly, hypercellular bone marrows with increased mast cells and/or myelofibrosis, increased serum tryptase levels, and historically carried a poor prognosis before the successful therapeutic application of imatinib.2, 8, 13 Shortly, after its initial discovery in HES/CEL patients, the Mayo group linked the FIP1L1–PDGFRA fusion to pathologically confirmed cases of systemic mastocytosis with eosinophilia (SM-eo).69 Histopathologically, the bone marrows of patients with FIP1L1PDGFRA-positive SM-Eo exhibit less dense clusters of mast cells by tryptase immunostaining than are typically seen in SM, particularly cases with the common D816V KIT mutation.11 However, in some cases of CEL with increased bone marrow mast cells, the mast cells may exhibit spindle-shaped morphology, form multifocal clusters and aberrant surface expression of CD25, major and minor criteria, which establish the basis for a WHO diagnosis of SM. Such cases may be considered a hybrid category of SM-CEL, wherein the CEL component is the associated hematologic non-mast cell lineage disease, pathogenetically driven by FIP1L1–PDGFRA. However, this may be an insufficient explanation as the FIP1L1–PDGFRA rearrangement has been found in a variety of myeloid cell types (neutrophils, monocytes, eosinophils), including mast cells, consistent with a mutational origin in a multipotent hematopoietic progenitor.70 When clinical and pathologic features of CEL and SM co-exist in the same patient, it is certainly possible, if not likely, that both diseases originate from the same clone. The relative 'penetrance' of eosinophil versus mast cell symptoms and organ involvement may be modified by host- or disease-related factors that have yet to be ascertained.

The FIP1L1–PDGFRA fusion and D816V KIT appear to be mutually exclusive oncogenic mutations, as they have not been simultaneously reported in the same patient. Investigators from the NIH and Ann Arbor could reliably partition D816V KIT-positive SM-Eo from FIP1L1–PDGFRA-positive CEL into clinically distinguishable entities based on several clinical and laboratory features.71 In the D816V KIT-positive SM-Eo cohort, gastrointestinal symptoms, urticaria pigmentosa, thrombocytosis, the median serum tryptase value and the presence of dense mast cell aggregates in the bone marrow were statistically significantly elevated or more frequently represented compared to patients with FIP1L1–PDGFRA-positive CEL. Conversely, male sex, cardiac and pulmonary symptoms, median peak absolute eosinophil count, the eosinophil to tryptase ratio and serum B12 levels were significantly elevated or more frequently represented in the FIP1L1–PDGFRA-positive CEL group. A scoring system incorporating these clinical findings and laboratory tests was generated that could reliably predict the molecular status (D816V KIT versus FIP1L1–PDGFRA) of patients with peripheral eosinophilia and increased marrow mast cell burden.71

More recently, the FIP1L1–PDGFRA fusion was also identified in five patients with AML (FAB subtypes M0, M2 and M4) and in two patients with lymphoblastic T-cell non-Hodgkin's lymphoma.72 A search for the FIP1L1–PDGFRA rearrangement was prompted by the presence of eosinophilia either preceding or contemporaneous with the diagnosis of AML or T-NHL, or because eosinophilia persisted despite a complete hematologic remission after intensive chemotherapy. In the T-NHL cases, lymphoid involvement by FIP1L1–PDGFRA was confirmed by the presence of the CHIC2 deletion by FISH in CD3+ T lymphocytes.

Clinical features

In the pre-fusion era, the cumulative frequencies of organ-specific manifestations of HES were previously described in three case series.73, 74, 75 In addition to universal involvement by the bone marrow, the most common organ systems involved included cardiac (58%), dermatologic (56%), neurologic (54%), pulmonary (49%), splenic (43%) and 20–30% involvement of the ocular and liver/gallbladder/GI systems.73, 74, 75, 76 Although FIP1L1–PDGFRA-positive patients exhibit the previously alluded to myeloproliferative features, inconsistent reporting of their clinical features presentations makes comparisons to both historically described HES and FIP1L1–PDGFRA-negative patients challenging. In one larger series, less frequent lung and skin involvement, and more frequent splenomegaly characterized FIP1L1–PDGFRA-positive compared to FIP1L1–PDGFRA-negative cases of hypereosinophilia.9 It is possible that a proportion of the fusion-negative patients may have represented lymphocyte-variant hypereosinophilia (not tested in the study), as such individuals have a high rate of cutaneous manifestations (pruritis, urticaria, angioedema, eczema, erythroderma).



Imatinib therapy of FIP1L1–PDGFRA-positive CEL

The first report of imatinib treatment of HES was by Schaller and Burkland77 in an online medical journal in 2001 (Table 6). Several case reports and small case series followed in 2001–2002, highlighting the dramatic hematological responses of patients with HES empirically treated with imatinib primarily in the dose range of 100–400 mg daily.78, 79, 80 Complete and rapid hematologic remissions, with normalization of eosinophilia, were observed in a high proportion of patients.

The presence of a normal karyotype in responding patients implicated a subtle mutation or cryptic rearrangement of a tyrosine kinase as the therapeutic target of imatinib, which was ultimately identified as FIP1L1–PDGFRalpha.8, 18 Of the 16 HES/CEL patients enrolled in the study of Cools et al.,8 11 were treated with imatinib. Hematologic responses were observed in 10 of 11 HES patients treated with imatinib doses of 100–400 mg daily. The median time to response was 4 weeks (range 1–12 weeks). Nine of 10 patients demonstrated a durable hematologic response (lasting greater than or equal to3 months), with a median duration of 7 months at the time of publication. Now, more than 5 years later, the overwhelmingly majority of these patients remain in hematologic remission.

Numerous studies have since confirmed the hematologic benefit of imatinib in FIP1L1–PDGFRA-positive CEL. Similar to CML, sensitive real-time quantitative PCR-based assays are also used to follow in-depth molecular responses. Molecular remissions were first reported by the NIH group in five of six FIP1L1–PDGFRA-positive patients after 1–12 months of imatinib therapy.81 Several additional reports have since described molecular remissions in imatinib-treated patients with FIP1L1–PDGFRA-positive disease or after bone marrow transplantation.

The natural history of imatinib-treated FIP1L1–PDGFRA-positive CEL was recently reported by an Italian study which prospectively followed 27 patients (all male) for a median follow-up period of 25 months (range 15–60 months).9 Patients were dose escalated from an initial dose of 100 mg daily to a final dose of 400 mg daily after the first month (median daily dose 339 mg). A complete hematologic remission was achieved in all patients within 1 month, and all patients became RT-PCR negative for the FIP1L1–PDGFRA fusion after 1–10 months of therapy (median 3 months). All 24 patients who continued imatinib therapy remained PCR negative during a follow-up period of 6–56+ months (median 19 months).

Using real-time quantitative PCR, a European study prospectively assessed the natural history of molecular responses to imatinib (dose range100–400 mg daily) in 40 of 376 (11%) HES patients who were positive for the FIP1L1–PDGFRA fusion.10 Fusion-positive patients exhibited higher absolute and % eosinophil counts compared to fusion-negative patients, but there was no correlation between the load of FIP1L1–PDGFRA expression and variables such as the white blood cell count, absolute or % eosinophil count, or % cells with the CHIC2 deletion by interphase FISH. A variability of up to 3 logs in the normalized FIP1L1–PDGFRA transcript load was found in patient samples before imatinib treatment. Among 11 patients with high pretreatment transcript levels, all achieved a 3-log reduction in transcript levels by 1 year of therapy, and 9 of 11 patients (82%) achieved a molecular remission.

It has now become clear that despite the in-depth and durable molecular responses with imatinib, discontinuation of the drug can lead to relapse. In the Italian study, three patients who discontinued imatinib after 12, 14 and 15 months of therapy experienced a rise in FIP1L1–PDGFRA transcript levels; upon restart of imatinib, fusion transcripts again became undetectable after 2–5 months of therapy.9 In the European trial, withdrawal of imatinib in two patients was followed by a rapid rise in FIP1L1–PDGFRA fusion transcripts, with one of these patients achieving a second molecular remission after reinstitution of imatinib.10 In a dose de-escalation trial of imatinib in five patients who had achieved a stable hematologic and molecular remission at 300–400 mg daily for at least 1 year, molecular relapse was observed in all patients: in one patient after 5 months of a reduced dose of 100 mg daily, and in four patients 2–5 months after discontinuation of drug.82 Molecular remissions could be re-established with reinduction of imatinib in all cases at a dose range of 100–400 mg daily. Hematologic relapse was noted only several weeks after stoppage of imatinib in four patients in the Mayo series.12 These data indicate that imatinib can suppress, but not eradicate the FIP1L1–PDGFRA clone, and that ongoing therapy is warranted. Although 100 mg daily may be sufficient to achieve a molecular remission in some patients, others may require higher maintenance doses in the range of 300–400 mg daily. However, in a recent series, maintenance dosing of 100–200 mg weekly was sufficient to sustain a molecular remission in five of six fusion-positive patients.83 The ability of imatinib to produce a molecular remission may reflect differences in drug metabolism/absorption between individuals, disease burden and susceptibility of the various FIP1L1–PDGFRA breakpoints to the drug; however, the potential contributions of these factors have not been systematically analyzed.

Finally, it must also be noted that FIP1L1–PDGFRA fusion negative HES patients may benefit from imatinib therapy. In this group, however, hematologic responses tend to be partial, short-lived, and may reflect nonspecific drug-related myelosuppression.8, 9 Alternatively, some of the cases with complete responses may be patients in which the PDGFRA or PDGFRB rearrangement remained undiscovered. It may thus be valid to try imatinib treatment in HES patients without detectable PDGFR rearrangements.

Safety issues of imatinib in FIP1L1–PDGFRA-positive disease

The safety profile of imatinib-treated patients with FIP1L1–PDGFRA-positive disease generally parallels that of CML. However, several cases of incipient cardiogenic shock have been reported in several FIP1L1–PDGFRA-positive patients after initiation of imatinib therapy.84, 85 Endomyocardial biopsy revealed myocyte injury, likely an acute inflammatory response to imatinib resulting in degranulation of infiltrating eosinophils exacerbated by imatinib. Early use of high-dose corticosteroids led to the improvement of left ventricular dysfunction and clinical recovery. Currently, prophylactic use of steroids during the first 7–10 days of imatinib treatment is recommended for patients with known cardiac disease and/or elevated serum troponin T levels.86

Resistance to imatinib in FIP1L1–PDGFRA-positive disease

With more than 5 years of experience in the imatinib treatment of FIP1L1–PDGFRA positive disease, only four cases of acquired resistance have been reported.8, 18, 86, 87 We identified the first case of imatinib resistance in a patient with advanced AML arising from CEL.8 He exhibited the FIP1L1–PDGFRA fusion in addition to a complex karyotype. Despite a complete hematologic remission, the patient relapsed after 5 months of therapy, coinciding with the identification of a T674I mutation within the ATP-binding domain of PDGFRalpha. In agreement with this, Ba/F3 cells transformed by the FIP1L1–PDGFRalpha T674I mutant were 1000-fold more resistant to imatinib, compared to cells transformed by the wild-type fusion.8 The observed acquired resistance in this CEL patient also confirmed that the FIP1L1–PDGFRalpha fusion protein was indeed the therapeutic target of imatinib. Additional cases of molecular resistance were similarly due to the PDGFRalpha T674I mutation, one in a patient with CEL evolving to myeloid blast crisis (also after 5 months after imatinib therapy), and one in a patient with Langerhans histiocytosis with eosinophilia treated with multiagent chemotherapy.86, 87 Recently, we observed the development of resistance to imatinib in a fifth patient (Lierman E et al., unpublished data). This patient presented with FIP1L1–PDGFRA-positive AML with eosinophilia, and developed imatinib resistance again due to the T674I mutation. Taken together, these data suggest that the T674I mutation is the most common, if not the only, mutation that may cause clinical resistance to imatinib in patients with FIP1L1–PDGFRA-positive acute leukemia. To date, resistance to imatinib has not been reported in cases with the chronic phase of eosinophilic leukemia. Acquired resistance to imatinib in FIP1L1–PDGFRA-mediated disease is considerably rare compared to CML. It is unknown whether this relates to the 100-fold sensitivity of the FIP1L1–PDGFRA fusion to imatinib compared to the BCR-ABL tyrosine kinase or other biological properties of the FIP1L1–PDGFRA containing clone.

Treatment of imatinib-resistant FIP1L1–PDGFRalpha T674I: insights from preclinical studies

The FIP1L1–PDGFRalpha T674I mutation is analogous to the T315I BCR-ABL mutation in CML, which confers broad-spectrum resistance to the tyrosine kinase inhibitors imatinib, dasatinib and nilotinib.88 We tested several known PDGFR inhibitors for their activity against the imatinib-resistant T674I mutant form of FIP1L1–PDGFRalpha using a cellular screen in Ba/F3 cells (Table 7). PKC412, a potent FLT3 inhibitor that is in clinical development for the treatment of AML, was the first inhibitor to be identified with activity against the FIP1L1–PDGFRalpha T674I mutant.65 Using both in vitro and in vivo mouse models, we demonstrated the ability of PKC412 to induce apoptosis in FIP1L1–PDGFRalpha T674I-transformed cells, and to significantly reduce leukocytosis and splenomegaly in a FIP1L1–PDGFRalpha T674I mouse model.65 In a second study, we identified sorafenib, a BRAF and VEGFR inhibitor approved for the treatment of renal cell carcinoma, as another potent inhibitor of both FIP1L1–PDGFRalpha and the T674I mutant form.89 In addition, nilotinib was also shown to have some activity towards both FIP1L1–PDGFRalpha and the T674I mutant.90, 91 These data show that several small molecule kinase inhibitors are already available to treat FIP1L1–PDGFRA-positive patients who develop resistance to imatinib.



Increasing recognition of eosinophilia-associated cytogenetic and molecular abnormalities, in conjunction with the advent of targeted small molecule inhibitors, has resulted in substantial benefit for patients affected by these MPNs. However, to reap the benefits of this success, it is critical that clinicians test for the occult FIP1L1–PDGFRA fusion in the context of undiagnosed hypereosinophilia and recognize hallmark translocations involving 5q31approxq33, 4q12, 8p13 and 9p24, as these may represent 'druggable' molecular rearrangements (for example, PDGFRB, PDGFRA, FGFR1 and JAK2, respectively). Ongoing work is aimed at identifying the molecular basis for patients with idiopathic hypereosinophilia and developing tyrosine kinase inhibitors with activity against MPNs with rearranged FGFR1 and JAK2. Fortunately, 5 years after the discovery of FIP1L1–PDGFRA, acquired resistance to imatinib has been a rare problem.



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