Overview
Eosinophilic disorders and related syndromes represent a heterogeneous group of neoplastic and nonneoplastic conditions, characterized by more eosinophils in the peripheral blood, and may involve eosinophil-induced organ damage.1–3
Hypereosinophilia (HE) is defined as persistent elevated eosinophil count >1.5 x109/L in blood and/or tissue and is divided into 4 variant types per an international consensus proposal: hereditary (familial), HEFA; primary (clonal/neoplastic), HEN; secondary (reactive), HER; and HE of undetermined significance, HEUS.4 Hypereosinophilic syndrome (HES) is the term applied for any of these HE variants with evidence of eosinophil-induced tissue/organ damage and the term idiopathic HES should be applied when HE with associated organ damage is detected with no apparent underlying disease or syndrome.4 The international consensus criteria, definition, and classification of HE, HES, and other conditions accompanied by HE are outlined in Table 1 and Table 2.
Primary (clonal/neoplastic) HE (HEN) is characterized by neoplastic proliferation of eosinophils and can be associated with any of the WHO-defined myeloid and/or lymphoid neoplasms.4 A number of dysregulated tyrosine kinase (TK) fusion genes have been implicated in the pathogenesis of myeloid/lymphoid neoplasms with eosinophilia (MLN-Eo).5–7
In 2008, the WHO classification of eosinophilic disorders was revised to include clonal/neoplastic eosinophilia resulting from TK fusion gene rearrangements as a new category termed, Myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB or FGFR1.8 In the 2017 WHO classification, myeloid/lymphoid neoplasms with PCM1-JAK2 rearrangement was added as a provisional entity.9–11 In addition to these aforementioned TK fusion genes, rearrangements involving FLT3 and ABL1 genes have also been described in MLN-Eo, but have not yet been formally added to the WHO classification.6 Myeloproliferative neoplasms (MPNs) with peripheral blood eosinophilia (eosinophil count >1.5 x109/L) that lack all of the aforementioned TK fusion genes as well as BCR-ABL1, and exhibit increased blasts (5% to <20%) and/or nonspecific cytogenetic and/or molecular abnormalities, are classified as chronic eosinophilic leukemia, not otherwise specified (CEL, NOS) in the absence of another WHO-defined myeloid neoplasm.11
The identification of specific TK fusion genes and the emergence of TK inhibitors (TKIs) has significantly improved the diagnosis and treatment of some patients with MLN-Eo.12 The management of patients with MLN-Eo requires a multidisciplinary team approach, preferably in specialized medical centers.
The NCCN Guidelines for Myeloid/Lymphoid Neoplasms with Eosinophilia and TK Fusion Genes include recommendations for the diagnosis, staging, and treatment of any of the MLN-Eo associated with a TK fusion gene included in the 2017 WHO Classification, as well as MLN-Eo with a FLT3 or ABL1 rearrangement.
Diagnostic Criteria
The diagnosis requires the presence of a TK fusion gene rearrangement confirmed by cytogenetic and/or molecular testing (See “Cytogenetic and Molecular Testing,” page 1259).8,11
Eosinophilia is frequently observed, but it is not a prerequisite for the diagnosis of these neoplasms. Although prominent eosinophilia is present in most patients with FIP1L1-PDGFRA, it is not invariably present in patients with a PDGFRB, FGFR1, JAK2, FLT3, or ABL1 rearrangement.5 Patients also present with other blood count abnormalities, and organ damage may develop irrespective of the underlying TK fusion gene (“Clinical Presentation,” page 1252).
The clinical phenotype of MLN-Eo is driven by the TK (eg, PDGFRA, PDGFRB, FGFR1, JAK2, FLT3, ABL1) as well as the partner gene. A large number of variant fusion partner genes (>70) have been characterized to date.5–7 See “TK Fusion Genes in Myeloid/Lymphoid Neoplasms with Eosinophilia” in Table 1 in the algorithm (page 1261).
Myeloid/Lymphoid Neoplasms With Eosinophilia and FIP1L1-PDGFRA Rearrangement
The diagnosis requires the presence of FIP1L1-PDGFRA fusion gene (resulting from an interstitial deletion of CHIC2 gene on chromosome 4q12) or a PDGFRA rearrangement with a variant fusion gene or an activating PDGFRA mutation.11,13–15 If appropriate molecular analysis is not available, this diagnosis should be suspected in the presence of a Ph-negative MPN with the hematologic features of CEL associated with splenomegaly, a marked elevation of serum vitamin B12, elevation of serum tryptase, and more mast cells and/or fibrosis in the bone marrow.5,7,16 MLN-Eo with FIP1L1-PDGFRA rearrangement has a very strong male predominance.
The bone marrow is hypercellular with increased eosinophil precursors (generally without dysplasia) and proliferation of loosely distributed, interstitial CD25+ spindle-shaped mast cells may be seen, whereas KIT D816V mutation and dense clusters of mast cells typically seen in systemic mastocytosis (SM) are absent.16
CEL is the most common clinical presentation. Blast phase MPN, acute myeloid leukemia (AML), and rarely T-cell acute lymphoblastic lymphoma (T-ALL) or myeloid sarcoma have also been described.5,17,18 Pediatric cases have also been reported.19–22
Myeloid/Lymphoid Neoplasms With Eosinophilia and PDGFRB Rearrangement
The diagnosis requires the presence of t(5;12)q31∼q33;p13) or a variant translocation resulting in ETV6-PDGFRB fusion gene or a PDGFRB rearrangement with a variant fusion gene.11,23 Cases with fusion genes typically associated only with BCR-ABL1-like B-cell lymphoblastic leukemia are specifically excluded.
Chronic myelomonocytic leukemia, atypical chronic myeloid leukemia (CML), MPN, myelodysplastic syndromes (MDS)/MPN, juvenile myelomonocytic leukemia, and blast-phase disease involving the bone marrow and/or extramedullary disease (EMD) involving myeloid, lymphoid, or mixed lineages are the clinical presentations associated with MLN-Eo and PDGFRB rearrangement.5,24 This entity also has a strong male predominance.
Myeloid/Lymphoid Neoplasms With Eosinophilia and FGFR1 Rearrangement
The diagnosis requires the presence of t(8;13)(p11;q12) or a variant translocation leading to FGFR1 rearrangement demonstrated in myeloid cells, lymphoblasts, or both.11,25,26
MLN-Eo with FGFR1 rearrangement has a moderate male preponderance, and it is generally associated with an aggressive clinical course with rapid progression of chronic phase disease to blast phase/secondary acute leukemia.5,27
MPN or MDS/MPN with eosinophilia are the most common myeloid neoplasms associated with FGFR1-rearranged eosinophilia. FGFR1-ZMYM2 fusion gene and t(8;13) are associated with high incidence of T-ALL.6 De novo AML, B-cell lymphoblastic leukemia/lymphoma or mixed phenotype acute leukemia (usually associated with peripheral blood or bone marrow eosinophilia), and/or EMD of myeloid, lymphoid, or mixed lineage have also been described in some cases.5,28
Myeloid/Lymphoid Neoplasms With Eosinophilia and PCM1-JAK2 Rearrangement
This is included as a provisional entity in the 2017 WHO classification, and the diagnosis requires the presence of t(8;9)(p22;p24.1) or a variant translocation leading to JAK2 rearrangement.9–11
MLN-Eo with PCM1-JAK2 rearrangement has a strong male preponderance and is generally associated with an aggressive clinical course with rapid progression of chronic phase disease to blast phase/secondary acute leukemia.9,10
MPN or MDS/MPN with eosinophilia is the characteristic clinical presentation and de novo AML or ALL has been described in some patients.9,10 The differential diagnosis of JAK2 and ABL1 fusions with a phenotype of ALL includes Ph like ALL..
Myeloid/Lymphoid Neoplasms With Eosinophilia and FLT3 or ABL1 Rearrangement
This category has not been formally added to the WHO classification. The diagnosis requires the presence of t(12;13)(p13;q12) leading to FLT3 rearrangement (ETV6 is the most common partner gene in both cases) or t(9;12)(q34;p13) leading to ABL1 rearrangement.29
MLN-Eo with FLT3 or ABL1 rearrangement is generally associated with an aggressive clinical course, disease progression, or relapse. CEL-NOS is the characteristic clinical presentation in MLN-Eo with FLT3 rearrangement. Peripheral T-cell lymphoma or T-ALL have also been described.6 De novo ALL is the most common clinical presentation associated with ABL1 rearrangement in children; AML and chronic myeloid/lymphoid phenotypes have been described in adults.30 The differential diagnosis of JAK2 and ABL1 fusions with a phenotype of ALL includes Ph like ALL.29
Clinical Presentation
Chronic phase disease may present in the bone marrow or peripheral blood, with or without eosinophilia. Bone marrow may exhibit an atypical mast cell proliferation, often in an interstitial pattern but not the typical aggregates found in SM.16
There is no current definition for accelerated phase disease; however, the presence of 10% to 19% blasts in the bone marrow or peripheral blood has been used to define accelerated phase similar to myeloid neoplasms such as CML. Blast phase (≥20% blasts in the bone marrow and/or peripheral blood) may present as AML or ALL, or acute leukemias with mixed-lineage disease and/or extramedullary myeloid sarcoma, T-ALL, or B-cell acute lymphoblastic lymphoma (B-ALL). Blast phase may also present as an EMD with MPN-like features in bone marrow or peripheral blood. TK fusion genes have been identified in a number of cases where eosinophilia is concurrently diagnosed with T-cell lymphomas or blast phase acute leukemias of myeloid, lymphoid, or mixed lineage (de novo or secondary).6
EMD may present as extramedullary myeloid sarcoma, T-ALL or B-ALL, or myeloid/T- or B-cell lymphoid mixed-lineage blast phase disease. EMD may present alone or with chronic or blast phase disease involving the bone marrow or peripheral blood, and lineage may be different from the lineage involving the bone marrow/peripheral blood.
MLN-Eo with TK fusion gene rearrangements are associated with a variety of symptoms related to the overproduction of cytokines, growth factors, and eosinophil-derived mediators.2 The most common presenting signs and symptoms include weakness and fatigue, cough, dyspnea, myalgias or angioedema, rash or fever, and rhinitis.7 In addition, patients also present with various blood count abnormalities depending on the underlying neoplasm (eg, neutrophilia, basophilia, thrombocytosis, monocytosis, myeloid immaturity, and both mature and immature eosinophils with varying degrees of dysplasia and anemia and/or thrombocytopenia with or without increased blast cells or dysplasia).2,7
Organ damage may occur in HES irrespective of the underlying subtype of HE due to the increased production and/or persistent accumulation of eosinophils in tissue.2 The skin, lungs, gastrointestinal tract, heart, and nervous system are the most commonly involved organ systems, although all organ systems may be susceptible to eosinophilia.2,7 Endomyocardial thrombosis and fibrosis are often documented in primary (neoplastic) HES variants (HESN), particularly in association with the FIP1L1-PDGFRA fusion gene.2,7 Imaging studies and organ-directed biopsy are useful for the documentation of target organ involvement.2 See “Evaluation of Target Organ Involvement,” page 1258.
Diagnosis
Accurate diagnosis of the underlying cause of HE, taking into account the histopathologic, clinical, laboratory, cytogenetic, and molecular criteria, is essential to establish the appropriate treatment plan. It is important to rule out secondary (reactive) HE (HER) caused by the reactive expansion of eosinophils that can be associated with a wide range of nonneoplastic (ie, allergies, infections, autoimmune or inflammatory disorders) or neoplastic (hematologic or solid malignancies) conditions.1,3 Differential diagnoses of the nonneoplastic conditions, immunodeficiency syndromes, solid tumors, and hematologic malignancies should be considered in patients presenting with HE (see “Causes of Secondary (Reactive) Eosinophilia” in the algorithm on page 1258).
Allergic disorders (eg, allergic asthma, food allergy, atopic dermatitis, drug reactions) are the most common cause of secondary (reactive) HE (HER) occurring in about 80% of cases, and parasitic infections represent the second most common cause.1,3 Strongyloidiasis due to Strongyloides stercoralis exposure is generally the most common parasitic infection, although infections due to several other organisms have also been reported. If exposure to an infectious agent is suspected, initiation of appropriate treatment is necessary to prevent superinfection and consultation with an infectious agent specialist is recommended.
HE may also be present in individuals with certain immunodeficiency syndromes associated with abnormal immunoglobulin levels (eg, hyperimmunoglobulin E syndrome [formerly known as Job syndrome], Omenn syndrome, Wiskott Aldrich syndrome) and pulmonary eosinophilic diseases (eg, allergic bronchopulmonary aspergillosis [ABPA], eosinophilic granulomatosis with polyangiitis [also known as Churg-Strauss syndrome]).1,3 HES may also be associated with a wide spectrum of dermatologic conditions (eg, atopic dermatitis, urticaria, eczema).3,
Secondary (reactive) HE (HER) is frequently observed in patients with solid tumors and lymphoid malignancies (eg, Hodgkin lymphoma, B-cell and T-cell lymphomas) due to the increased production of growth factors and eosinophilopoietic cytokines.3 In solid tumors, the incidence of HE is generally limited to advanced stage disease, and among the lymphoid malignancies, the incidence of HE is more frequent in T-cell lymphomas.3 In myeloid malignancies (eg, CML, AML, advanced SM), HE may similarly develop. In some cases, the eosinophilia may be part of the abnormal clone; however, in some circumstances, it may be secondary, related to the elaboration of eosinophilopoietic cytokines from neoplastic cells. The term “myeloproliferative variant of HE” has been used to describe cases with MPN features such as splenomegaly or an increased serum tryptase or vitamin B12 level. Although many of these cases are FIP1L1-PDGFRA–positive, the term has not been formally recognized by the WHO classification.7
Lymphocyte-variant HES (L-HES) is characterized by clonal T-cells with an aberrant immunophenotype and is associated with increased number of eosinophils, elevated serum thymus and activation-related chemokine (TARC), and IgE levels (although these findings are neither sensitive nor specific).3,7,16 It is considered a mixture of a clonal disease with immunophenotypically aberrant T-cells (eg, double-negative immature T-cells [CD3+, CD4-, CD8-] or absence of CD3 [CD3-, CD4+] or CD3+, CD4+, CD7-) and secondary (reactive) HE due to the elaboration of T helper 2 cytokines, such as IL-4, IL-5, and IL-13 from the abnormal T-cell population. Approximately 10% to 20% of cases can evolve to various types of T-cell lymphoma or Sézary syndrome. Flow cytometry with T-cell immunophenotyping and molecular analysis to confirm T-cell clonality may provide additional support to confirm the diagnosis of L-HES.16 While there are no consensus diagnostic criteria for L-HES, it is felt that a clonal T-cell receptor (TCR) gene rearrangement alone is not sufficient to make the diagnosis of L-HES, as this finding can be nonspecific and can also be identified in patients with HES of undetermined significance or even in patients with a PDGFRA rearrangement.31,32
A diagnosis of a primary (clonal/neoplastic) HE (HEN) should be suspected in patients with elevated serum tryptase level, abnormal T-cell population, increased blasts, cytogenetic or molecular abnormality, and/or bone marrow fibrosis, splenomegaly, and/or lymphadenopathy, after ruling out all possible causes of secondary (reactive) HE (HER). Screening for TK fusion gene rearrangements (PDGFRA, PDGFRB, FGFR1, JAK2, ABL1, or FLT3) or other cytogenetic abnormality is recommended for patients with a suspected primary (clonal/neoplastic) HE (HEN).
The diagnosis of CEL, NOS should be considered in the absence of the aforementioned TK fusion gene rearrangements, when there are other cytogenetic or molecular abnormalities or increased blasts (≥5% to <20%) and/or morphologic evidence of an eosinophilic myeloid neoplasm. CEL, NOS may be distinguished from idiopathic HES by the presence of a nonspecific cytogenetic abnormality (trisomy 8 or isochromosome 17) or increased blast cells (>2% in the peripheral blood or >5% in the bone marrow, but <20% blasts in both compartments).11 Bone marrow morphology might by helpful to distinguish CEL, NOS from idiopathic HES.33
Next-generation sequencing (NGS) studies have revealed that somatic mutations associated with a hematologic malignancy can be detected in people with normal blood counts in the absence of diagnostic criteria for a hematologic malignancy, and the term clonal hematopoiesis of indeterminate potential has been proposed to describe such situations.34 In patients with eosinophilia in whom causes for secondary (reactive) HE (HER) have been excluded, additional cytogenetic or molecular testing and morphologic evaluation of the bone marrow and peripheral blood may be useful to confirm the differential diagnosis of clonal hematopoiesis of indeterminate potential versus CEL-NOS, since the composite picture of morphology and cytogenetic/molecular testing may allow for a more definitive determination of the presence of an eosinophilia-associated hematolymphoid neoplasm.
A diagnosis of idiopathic HE (organ damage absent) is equivalent to the respective term, HE of undetermined significance (HEUS) per international consensus criteria and HES (organ damage present) with no apparent underlying disease or syndrome is referred to as idiopathic HES.4 These are diagnoses of exclusion that are assigned after ruling out primary (clonal/neoplastic) HE (HEN) and all possible causes of secondary (reactive) HE (HER). NGS via myeloid mutation panels may also be useful to establish the clonality in selected circumstances where no TK fusion gene rearrangements are detected. Mutations detected by NGS may also provide a means to identify primary (clonal/neoplastic) HE (HEN) from secondary (reactive) HE (HER) (see “Role of NGS,” page 1261).
Workup
Initial evaluation should include a history (especially assessment of travel, new medications, recurrent history of infections, and/or family history of eosinophilia) and physical exam, including skin evaluation, palpation of the liver and spleen, and signs/symptoms of an immunodeficiency syndrome.
Diagnostic Studies
An elevated IgE level is a nonspecific finding in many of the underlying conditions (allergies, infections, and L-HES) related to secondary or reactive eosinophilia.5,16 As previously noted, an elevated serum tryptase and/or vitamin B12 level is commonly observed in myeloproliferative variants of HE, particularly in myeloid neoplasms with a PDGFRA fusion gene.5,7,16 Serum tryptase is elevated in the vast majority of patients with all subtypes of SM, and eosinophilia is more prevalent in patients with advanced SM.35–37 Aspergillus-specific immunoglobulins and increased serum IgE are characteristic findings of ABPA.3
Laboratory testing should include CBC with differential, comprehensive metabolic panel with uric acid, lactate dehydrogenase, and liver function tests, serum tryptase levels, and vitamin B12 levels. Peripheral blood smear should be reviewed for the evidence of other blood count abnormalities (eg, eosinophilia, dysplasia, monocytosis, circulating blasts).16
Additional laboratory testing may be considered based on the patient's history, symptoms, and findings on physical examination.7 This includes serology testing for Strongyloides and other parasitic infections; testing for antineutrophil cytoplasmic antibodies and antinuclear antibodies; stool ova and parasites test and gastrointestinal polymerase chain reaction (PCR); quantitative serum immunoglobulin levels (including IgE), erythrocyte sedimentation rate, and/or C-reactive protein; and Aspergillus IgE to evaluate for ABPA.
Bone marrow aspirate and biopsy with immunohistochemistry (IHC) for CD117, CD25, tryptase, and reticulin/collagen stains for fibrosis; conventional cytogenetics; fluorescence in situ hybridization (FISH) and/or nested reverse transcription PCR (RT-PCR) to detect the TK fusion gene rearrangement; and confirmatory FISH testing to identify breakpoints associated with TK fusion gene rearrangements is recommended for all patients to confirm the diagnosis of myeloid/lymphoid neoplasms.11,16
The diagnostic testing algorithms for TK fusion gene rearrangements are outlined in the algorithm (see MLNE-3, page 1251). See also the section on “Cytogenetic and Molecular Testing” (page 1259). Evaluation of bone marrow and peripheral blood including immunophenotyping, will help determine lineage and disease phase (chronic phase vs accelerated or blast phase). Diagnosis and staging considerations to determine the disease extent, disease phase, and lineage are outlined in the algorithm (see MLNE-4, page 1252).
Flow cytometry (preferred) and/or IHC to identify an immunophenotypically aberrant T-cell population and molecular analysis to confirm T-cell clonality may be useful in selected circumstances if a diagnosis of L-HES is suspected. The typical immunophenotype of L-HES is CD3-, CD4+, CD7-, and CD5++. Other abnormal immunophenotypes include CD3+, CD4+, and CD7- or CD3+, CD4-, and CD8-.16 When flow cytometry results are equivocal, molecular analysis to detect clonal TCR gene rearrangements may be additionally helpful to support the diagnosis of L-HES.16 STAT3 mutation has also been recently identified in the CD3-, CD4+T-cells in a patient with L-HES.38
Evaluation of Target Organ Involvement
Electrocardiogram, cardiac troponin, and/or NT-proBNP measurement and echocardiogram and/or cardiac MRI (in the presence of elevated cardiac troponin or clinical features of cardiac injury) are helpful to distinguish eosinophilic cardiac disease from other etiologies.2
Pulmonary function tests, chest X-ray, and bronchoscopy with bronchoalveolar lavage are useful to confirm lung involvement in patients with respiratory symptoms.2 Electromyography and nerve biopsy are needed to confirm eosinophil-induced peripheral neuropathy. Evaluation for sinusitis, nasal polyposis, and sensorineural hearing loss is recommended for patients presenting with ear, nose, and throat symptoms.2
Organ-directed biopsy (skin, lung, or liver biopsy) with appropriate IHC is needed to confirm tissue eosinophilia and eosinophil-induced organ damage.2 Endoscopy with relevant mucosal biopsy with IHC (CD25, CD117, and tryptase) is recommended for patients with gastrointestinal involvement. Deep skin biopsy that includes fascia and MRI are useful to confirm cutaneous involvement with eosinophilic fasciitis.
Cytogenetic and Molecular Testing
MLN-Eo With PDGFRA Rearrangement
FIP1L1-PDGFRA is the most common fusion gene in MLN-Eo and results from an interstitial deletion of CHIC2 gene on chromosome 4q12.13–15 CHIC2 deletion on chromosome 4q12 is undetectable by standard cytogenetics and can only be detected by FISH with specific probes (FISH for the CHIC2 deletion) used for the identification of the FIP1L1-PDGFRA rearrangement.14,39 Nested RT-PCR and quantitative RT-PCR (RT-qPCR) are more sensitive for the detection of FIP1L1-PDGFRA fusion gene in peripheral blood.5,15,39–41
PDGFRA fusions with other partner genes (BCR, ETV6, KIF5B, CDK5RAP2, STRN, TNKS2, and FOXP1) that are detectable by standard cytogenetics have been described. These fusions can be best detected by FISH with break-apart probes or RT-PCR for specific TK fusion gene rearrangements.5,6,15 In addition to these rearrangements, several novel imatinib-sensitive point mutations in PDGFRA have also been identified in patients with FIP1L1-PDGFRA–negative HES.42 These alternate PDGFRA rearrangements, like FIP1L1-PDGFRA, are associated with an excellent prognosis when treated with imatinib.
Peripheral blood or bone marrow FISH have similar sensitivities and the diagnosis can be made from either source. However, peripheral blood FISH may not robustly detect the deletion due to low clone size, and false-negative results have also been reported with bone marrow FISH.43 Decalcified bone marrow should not be used as this results in a yellow autofluorescence in cells that precludes FISH interpretation. Nested RT-PCR or RT-qPCR are the methods of choice to monitor response to treatment during follow-up. However, RT-qPCR is not appropriate for screening at diagnosis and the use of RT-PCR is complicated due to the considerable diversity of break points within the FIP1L1 gene.44 Therefore, a combination of RT-PCR and FISH is the most sensitive method for the detection of FIP1L1-PDGFRA rearrangement.
Chromosome genomic array testing (comparative genomic hybridization or single-nucleotide polymorphism arrays) can readily detect submicroscopic deletions at diagnosis when a clone size is at least 20%; however, these are not widely available.5
MLN-Eo With PDGFRB Rearrangement
ETV6-PDGFRB resulting from t(5;12)(q31-33;p13) is the most common fusion gene.23 However, not all cases with t(5;12)(q31-33;p13) have a PDGFRB rearrangement, and fusion gene rearrangements involving non-TK genes in the 5q31∼q33 region (eg, IL-3 or ACSL6) have also been reported in cases with t(5;12)(q31-33;p13).45 Identification of the fusion genes involved in t(5;12) is crucial to direct an effective treatment plan.
PDGFRB fusions with more than 30 different partner genes, in addition to ETV6, have been described and subtle or cryptic translocations have also been increasingly recognized.5,46–48 While the presence of PDGFRB fusion gene rearrangements can be detected using FISH with break-apart probes, this approach will not identify the specific translocation partner gene or the cryptic translocations. A dual color break-apart probe can be used to confirm the partner gene if a specific one is suspected.
Conventional cytogenetic analysis for t(5;12) followed by confirmatory FISH testing with break-apart probes to assess the involvement of PDGFRB is the most effective approach to identify the fusion gene.49 Confirmation of PDGFRB rearrangement by FISH is indicated in all patients with a 5q31∼33 breakpoint.
RT-PCR and RT-qPCR are more sensitive for the detection of complex and/or cryptic cases not evident by conventional cytogenetics and are well suited to monitor response to treatment.41,50 However, the use of RT-PCR is limited by the large number of partner fusion genes. RNA sequencing may also be considered in cases with complex/cryptic fusions.51
MLN-Eo With FGFR1 Rearrangement
FGFR1-ZMYM2 resulting from t(8;13)(p11;q12) is the most common fusion gene occurring in approximately 50% of cases.6,25,26 Several other partner genes have been described. FGFR1-CNTRL [t(8;9)(p11;q33)], FGFR1-FGFR1OP [t(6;8)(q27;p11)], and FGFR1-BCR [t(8;22)(p11.2; q11.2)] are the other common fusion gene rearrangements occurring in about 10% to 29% of cases.5,6,26,52,53 RUNX1 mutations have also been reported in patients with acute leukemia and an FGFR1 rearrangement confirmed by FISH.26
Conventional cytogenetic analysis for t(8;13) followed by confirmatory FISH testing using dual-color break-apart probes for FGFR1 is the effective diagnostic approach for the detection of FGFR1-ZMYM2 fusion gene and can be applied to other FGFR1 rearrangements.5,26
MLN-Eo With JAK2 Rearrangement
PCM1-JAK2 resulting from t(8;9)(p22;p24) is the most common fusion gene.6,10,54–56 ETV6-JAK2 [t(9;12)(p24;p13)] and BCR-JAK2 [t(9;22)(p24;q11)] are the other fusion genes reported only in few patients.6,10,57–59
As with other fusion gene rearrangements resulting from a translocation, conventional cytogenetics to identify t(8;9) followed by confirmatory FISH with JAK2 break-apart probes is recommended to confirm the diagnosis.6,10
MLN-Eo With FLT3 or ABL1 Rearrangement
ETV6-FLT3 resulting from t(12;13)(p13;q12) and ETV6-ABL1 resulting from t(9;12)(q34;p13) are the common fusion genes involved in the majority of cases.6,29,30,60 FLT3 fusion with other partner genes (SPTBN1, GOLGB1, TRIP11, and ZMYM2) and complex rearrangements resulting from fusion of ABL1 with partner genes (other than ETV6) have also been reported.6,46,61–63
Conventional cytogenetics for t(12;13) followed by confirmatory FISH with break-apart probes or nested RT-PCR (to identify reciprocal ETV6-FLT3 and FLT3-ETV6 transcripts) can be used to confirm the presence of ETV6-FLT3 gene fusion.29 However, conventional cytogenetics is inconclusive for the detection of ETV6-ABL1, mainly because the creation of the ETV6-ABL1 fusion gene requires at least 3 chromosomal breaks and the fusion gene rearrangement is not uniform across cases and typically involves cryptic insertions that can be missed with routine cytogenetics.30 FISH with a combination of ETV6 and ABL1 probes, RT-PCR, or RNA sequencing are more reliable tests for the identification of an ETV6-ABL1 fusion.6,30
Role of NGS
NGS studies have also identified driver mutations involving a broad spectrum of genes most frequently involved in DNA methylation/chromatin modifications in patients with idiopathic HES, although the number of genes screened and the rate of mutation detection in these studies have been variable.64–67 In one study, myeloid neoplasm-related somatic mutations involving a single gene or ≥2 genes have been identified in 28% of patients (14 of 51) with idiopathic HES, with ASXL1 (43%), TET2 (36%), EZH2 (29%), SETBP1 (22%), CBL (14%), and NOTCH1 (14%) being the most frequently mutated genes.65 In another study, 53% of patients (16 of 30) had at least one candidate mutation with NOTCH1 (27%), SCRIB and STAG2 (17%), and SH2B3 (13%) being the most frequently mutated genes; clonal TCR rearrangement was present in 13% of patients.66 Somatic STAT5B N642H mutations were reported in 1.6% (27/1,715) of patients with eosinophilia.67 The presence of STAT5B N642H mutation as a sole abnormality was associated with a shorter overall survival compared with published series in patients with HES, suggesting that these cases should be reclassified as CEL, NOS.67 Thus, targeted NGS studies will be helpful to establish clonality in a subset of patients with idiopathic HES leading to reclassification of some cases as CEL, NOS.
NGS studies are also useful for the detection of additional molecular abnormalities in patients with MLN-Eo and rearrangement of PDGFRA, PDGFRB, FGFR1, or PCM1-JAK2.68–70 In an analysis of 61 patients with MLN-Eo and rearrangement of PDGFRA, PDGFRB, FGFR1, or PCM1-JAK2, at least one additional mutation in several other genes (ASXL1, BCOR, DNMT3A, TET2, RUNX1, ETV6, NRAS, STAT5B, and ZRSR2) was detected in 14 patients (23%).68 Patients with FGFR1 rearrangement had a significantly higher frequency of additional mutations (83%; 5 out of 6 patients; all had RUNX1 mutation) in comparison with those with PDGFRA (14%; 5 of 35 patients), PDGFRB (23%; 3 of 13 patients), or PCM1-JAK2 (14%;1 of 7 patients) rearrangements. NGS-based fusion gene detection techniques have identified genetic variants of CSF3R and KIT mutations (CSF3R M696T and KIT P155S) in patients with myeloid neoplasms with eosinophilia and FIP1L1-PDGFRA rearrangement.69
NGS studies are not broadly available and currently the prognostic impact and pathogenicity of additional mutations detected by NGS have not been established. Further studies are needed to determine the impact of these novel mutations on disease course.
Treatment Considerations
All patients should be evaluated and managed by a multidisciplinary team (including engagement of other subspecialists based on clinical presentation and organ involvement) in specialized centers. Assessment for clinical situations that may require urgent intervention is recommended for all patients. Immediate institution of oral or high-dose intravenous corticosteroids may be necessary as clinically indicated, especially in patients in whom eosinophil-mediated cardiac damage/heart failure is present or suspected.
As noted earlier, consultation with an infectious disease specialist is recommended as clinically indicated for the management of infectious disease-related complications.
Myeloid/Lymphoid Neoplasms With Eosinophilia and PDGFRA or PDGFRB Rearrangement
Imatinib has resulted in high rates of durable hematologic and molecular responses in the vast majority of patients with MLN-Eo and PDGFRA or PDGFRB rearrangement.18,24,32,71–83 Concurrent administration of corticosteroids for 7 to 10 days and consultation with a cardiologist is recommended for patients with symptoms/signs of cardiac involvement including troponinemia, elevated NT-proBNP, and/or abnormal echocardiogram findings.74
Imatinib 100 mg daily is the recommended dose for induction therapy for chronic phase disease in patients with FIP1L1-PDGFRA rearrangement. Imatinib 100 mg to 400 mg daily is the recommended dose for chronic phase in patients with PDGFRB rearrangement, although 400 mg daily is generally used as the induction dose. Reduction to 100 mg daily can be considered after achievement of complete hematologic response and complete cytogenetic response (CCyR).
Blast phase disease may present either as de novo or as disease progression from chronic phase due to cytogenetic/molecular clonal evolution, including PDGFRA mutations associated with development of resistance to imatinib including T674I or D842V.72
Imatinib monotherapy (100–400 mg daily) is recommended for blast phase disease (400 mg daily is generally used as the induction dose in patients with PDGFRB rearrangement). Durable remissions are only rarely achieved with induction chemotherapy or allogeneic hematopoietic cell transplant (HCT). In instances when FIP1L1-PDGFRA or a PDGFRB rearrangement is identified only after the initiation of induction chemotherapy, imatinib should be added to induction chemotherapy (ALL-type chemotherapy for lymphoid blast phase and AML-type chemotherapy for myeloid blast phase), or a return to imatinib monotherapy may also be considered.24,77
Monitoring Response and Additional Treatment
Complete hematologic response (defined as the normalization of peripheral blood counts and eosinophilia) by 1 month and CCyR by 3 months is achieved in a vast majority of patients.84
Monitoring blood counts (CBC and eosinophilia), imaging to document target organ response (as clinically indicated), and peripheral blood or bone marrow evaluation (FISH for FIP1L1-PDGFRA because standard karyotyping cannot detect the fusion; standard cytogenetics and/or FISH for PDGFRB) are recommended at 3 months after initiation of imatinib. RT-PCR (if available) can be considered to document molecular response.
Continuation of imatinib at the initial dose is recommended for patients achieving a complete response (complete hematologic response, CCyR, or complete molecular response). Although low doses of 100 to 200 mg daily have been sufficient to maintain molecular remission in most patients with FIP1L1-PDGFRA rearrangement, and in some cases this dose range has been used only once weekly,73 higher doses (maximum of 400 mg daily) may be required for some patients.74,75
Monitoring hematologic response, cytogenetic response (FISH), and molecular response (if RT-qPCR is available) every 3 and 6 months is recommended for patients experiencing a durable complete response to initial treatment. Clinical trial and/or early referral to allogeneic HCT should be considered for patients with loss of response. Evaluation of patient compliance or drug interactions is recommended before initiation of additional treatment of patients with loss of response.
Acquired resistance to imatinib mediated by PDGFRA T674I and D842V mutations has been reported in few patients with blast phase disease.72,85 Nilotinib, ponatinib, and sorafenib have shown limited activity in patients with PDGFRA T674I and D842V mutations.85–88 PDGFRB T681I has been shown to confer resistance to imatinib in vitro, but has not yet been identified in patients treated with imatinib; acquired resistance to imatinib mediated by other PDGFRB mutations has been described only in 2 case reports.89–91 Evaluation for cytogenetic/molecular clonal evolution can identify PDGFRA (T674I and D842V) or PDGFRB mutations conferring resistance to imatinib in patients with loss of response. Referral to clinical is recommended, if resistance mutation found.
Avapritinib is approved for unresectable or metastatic gastrointestinal stromal tumors harboring a PDGFRA exon 18 mutation, including D842V mutations.92,93 This suggests a possible role for avapritinib in patients with MLN-Eo and PDGFRA rearrangement harboring PDGFRA D842V mutation resistant to imatinib. If this mutation is identified, a clinical trial of avapritinib is preferred (if available), rather than off-label use.
The feasibility of discontinuation of imatinib in patients with MLN-Eo and PDGFRA rearrangement who have experienced complete molecular response has been shown mostly in retrospective studies in a limited number of patients.32,71,94,95 Substantial variability has been seen in the relapse-free survival rates (57%–91% at 12 months; 42%–65% at 24 months), although molecular remissions have been re-established after restarting imatinib in most patients experiencing relapse after discontinuation of imatinib. The feasibility of discontinuation of imatinib in patients with MLN-Eo and a PDGFRB rearrangement has not been evaluated. At the present time, there are no definite criteria to identify patients suitable for discontinuation of imatinib and it is therefore not recommended outside the context of clinical trials.
Myeloid/Lymphoid Neoplasms With Eosinophilia and FGFR1 or JAK2 or FLT3 or ABL1 Rearrangement
MLN-Eo with the previously mentioned TK fusion gene rearrangements are generally associated with an aggressive clinical course, relapse, or disease progression to blast phase and allogeneic HCT is the only potentially curative option.9,10,27,30,96
Clinical trial is the preferred treatment option for patients with chronic phase disease. In the absence of a clinical trial, patients with chronic phase disease can be treated with TKI monotherapy. However, early referral to allogeneic HCT should be considered for eligible patients, since TKI therapy alone does not result in durable remissions.
Clinical trial and early consideration of allogeneic HCT for eligible patients is the preferred treatment approach for patients with blast phase disease. In the absence of a suitable clinical trial, TKI ± induction chemotherapy followed by allogeneic HCT is the appropriate treatment approach. The selection of chemotherapy for blast phase disease should be based on the cell lineage (ALL-type chemotherapy for lymphoid blast phase and AML-type chemotherapy for myeloid blast phase; either of these induction chemotherapy regimens can be considered for mixed-lineage blast phase disease).
TKIs with activity against FGFR1, JAK2, ABL1, or FLT3 are listed Table 3. Given the rare nature of this disease, available evidence is mainly from case reports and/or their potential clinical activity is extrapolated from other diseases with the same target. Although TKI ± induction chemotherapy does not result in long-term disease control, it may be of potential benefit when used as a bridge to allogeneic HCT for disease cytoreduction prior to transplantation.26,96–99
TKIs With Activity Against FGFR1, JAK2, FLT3, and ABL1
Clinically relevant imaging studies to document response in the EMD component and evaluation of peripheral blood or bone marrow (FISH or cytogenetics) and RT-PCR (if available) for specific TK fusion gene rearrangement to document response (hematologic, cytogenetic, or molecular response) should be considered for all patients after initiation of treatment. However, it should be noted that there are no consensus response criteria for assessment of response.
Monitoring minimal residual disease after allogeneic HCT and maintenance therapy with TKI (eg, ponatinib) or hypomethylating agent (eg, 5-azacytidine) has been shown to be effective for MLN-Eo with FGFR1 rearrangement in single case reports100,101 The role for TKI as maintenance therapy after allogeneic HCT has not been systematically evaluated but may be considered in patients felt to be at high risk for relapse. Additional studies are needed to confirm the efficacy of this treatment approach.
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NCCN CATEGORIES OF EVIDENCE AND CONSENSUS
Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.
Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.
All recommendations are category 2A unless otherwise noted.
Clinical trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
PLEASE NOTE
The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult theNCCN Guidelines is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network® (NCCN®) makes no representations or warranties of any kind regarding their content, use, or application and disclaims any responsibility for their application or use in any way.
© National Comprehensive Cancer Network, Inc. 2020. All rights reserved. The NCCN Guidelines and the illustrations herein may not be reproduced in any form without the express written permission of NCCN.
Disclosures for the NCCN Myeloid/Lymphoid Neoplasms with Eosinophilia and TK Fusion Genes Panel
At the beginning of each NCCN Guidelines Panel meeting, panel members review all potential conflicts of interest. NCCN, in keeping with its commitment to public transparency, publishes these disclosures for panel members, staff, and NCCN itself.
Individual disclosures for the NCCN Myeloid/Lymphoid Neoplasms with Eosinophilia and TK Fusion Genes Panel members can be found on page 1269. (The most recent version of these guidelines and accompanying disclosures are available at NCCN.org.)
The complete and most recent version of these guidelines is available free of charge at NCCN.org.
