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Diagnosis and Treatment of Myeloproliferative Neoplasms with Eosinophilia

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Diagnosis and Treatment of Myeloproliferative Neoplasms with Eosinophilia Myeloproliferative neoplasms Diagnosis and treatment of myeloproliferative neoplasms with eosinophilia A. Reiter 1 ABSTRACT G. Metzgeroth 1 Significant eosinophilia is a rare but recurrent morphological feature of all myeloid neoplasms but N.C.P. Cross 2,3 the correct diagnosis of eosinophilia-associated disorders remains problematic. The WHO 2008 clas - sification defines a rare subgroup characterized by selected tyrosine kinase (TK) fusion genes: ‘myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB or FGFR1 ’ (MLN-eo), 1 III. Medizinische Klinik, of which by far the most common fusion gene is FIP1L1-PDGFRA . For other cases, proof of clonality Universitätsmedizin Mannheim, by the finding of increased numbers of blasts and/or cytogenetic or molecular aberrations is the basis Mannheim, Germany 2 for a diagnosis of chronic eosinophilic leukemia, not otherwise specified (CEL-NOS), however this is Wessex Regional Genetics only possible infrequently. To date, over 50 fusion genes encoding deregulated TK have been identified Laboratory, Salisbury, UK 3Faculty of Medicine, University of within the broad spectrum of eosinophilia-associated myeloproliferative neoplasms (MPN-eo) or Southampton, Southampton, UK myelodysplastic/myeloproliferative neoplasms (MDS/MPN-eo). Important to recognize are also those cases that do not fulfil the diagnostic criteria for MLN-eo or CEL-NOS but who may harbor TK point mutations, e.g. KIT D816V positive systemic mastocytosis. For treatment decisions, disease stage Correspondence: (chronic/blast phase), potential clinical course (indolent/aggressive), sensitivity to imatinib or alterna - Andreas Reiter E-mail: andreas.reiter@medma. tive TK inhibitors ( de novo /resistant disease) and eligibility for allogeneic stem cell transplantation uni-heidelberg.de need to be taken into account on an individual basis. Learning goals Acknowledgment: AR and GM were supported by the At the conclusion of this activity, participants should be able to: ‘Deutsche José Carreras Leukämie- Stiftung e.V.’ (grant no. H11/03). - diagnose and classify hematologic and non-hematologic disorders with associated eosinophilia NCPC was supported by Leukaemia correctly; & Lymphoma Research , UK - choose appropriate therapy for disparate subtypes of myeloproliferative neoplasms with eosinophilia. Hematology Education: the education program for the Pathogenesis and classification invisible 800kb interstitial deletion on chro - annual congress of the European 3 Hematology Association mosome 4q12. In addition, cytogenetic analy - Eosinophilia is commonly observed in a sis has identified four distinct recurrent break - 2014;8:255-264 wide range of disparate reactive/non-clonal point clusters that target PDGFRA at 4q12, 1,2 PDGFRB at 5q31-33, FGFR1 at 8p11-12 and and neoplastic/clonal disorders. It is variably 4,5 associated with a potentially life-threatening JAK2 at 9p24. As a consequence of balanced organ dysfunction, e.g. involving the heart, reciprocal translocations or rarely insertions or lungs, gastrointestinal tract, nervous system or complex translocations, fusion genes similar skin, due to release of granular contents from to FIP1L1-PDGFRA are created, e.g. ETV6- infiltrating eosinophils. In the majority of PDGFRB in t(5;12)(q31-33;p12), ZNF198- cases, eosinophilia is reactive through associa - FGFR1 in t(8;13)(p11;q12) or PCM1-JAK2 in tion with atopic conditions, allergies, autoim - t(8;9)(p11;p24). In addition, there are several rare and structurally similar fusions involving mune disorders, infections or malignancies, 6 e.g. lymphomas or solid tumors such as sarco - other TK, e.g. ETV6-ABL1 associated with a 7 ma or melanoma. Reactive eosinophilia is usu - t(9;12)(q33;p12) or ETV6-FLT3 associated ally a response to overproduction of with a t(12;13)(p11;q14). Of note, potential eosinophilopoietic cytokines such as IL-3, IL- fusion genes, with the exception of FIP1L1- 5 or GM-CSF. 2 PDGFRA , are usually indicated by cytogenetic Clonal eosinophilia is frequently associated analysis in combination with the morphologi - with myeloid neoplasms, e.g. myeloprolifera - cal phenotype of a MPN-eo or MDS/MPN-eo tive neoplasms (MPN-eo) or myelodysplas - in chronic or blast phase. tic/myelproliferative neoplasms (MDS/MPN- In the WHO 2008 classification (Table 1), eo). The identification of more than 50 differ - fusion genes with involvement of PDGFRA , ent fusion genes as the consequence of various PDGFRB and FGFR1 are subcategorized as chromosomal and molecular abnormalities has ‘myeloid and lymphoid neoplasms with highlighted the fundamental role of constitu - eosinophilia and abnormalities of PDGFRA , tively activated tyrosine kinases (TK) in the PDGFRB or FGFR1 ’ (MLN-eo). 8 There are no pathogenesis of these disorders (Figure 1). By data from prospective clinical trials or reg - far the most common fusion gene is FIP1L1- istries, but larger retrospective series have PDGFRA , generated by a cytogenetically recently suggested that FIP1L1-PDGFRA is Hematology Education: the education program for the annual congress of the European Hematology Association | 2014; 8(1) | 255 | 19 th Congress of the European Hematology Association likely to be identified in 5-20% of unselected patients with that are required for the transforming activity of the fusion significant eosinophilia. 9 Fusion genes with involvement proteins. Homotypic interaction between specific domains of PDGFRB and FGFR1 are believed to be present in <3% of the partner protein leads to dimerization or oligomeriza - of those patients, if not even less (T Haferlach, Munich tion of the fusion protein mimicking the normal process of Leukemia Lab, personal communication, 2013). ligand-mediated dimerization and resulting in constitutive In fusion proteins, the C-terminal part of a partner protein activation of the TK moiety. 10 Of note, FIP1L1 does not is fused to the N-terminal part of the TK, thus retaining the contain any self-association motifs and it was shown that entire catalytic domain of the kinase. The vast majority of the FIP1L1 moiety is not essential to the transforming activ - partner genes contain one or more dimerization domains ity of the truncated PDGFRA protein. 11 Table 1. WHO 2008 classification of myeloproliferative neoplasms with eosinophilia (MPN-eo). MLN-eo (myeloid and lym - phoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB or FGFR1 ), CEL-NOS (chronic eosinophilic leukemia, not otherwise specified) MLN-eo MPN with prominent eosinophilia and FIP1L1-PDGFA fusion gene. Acute myeloid leukemia, lymphoblastic leukemia/lymphoma with eosinophilia and FIP1L1-PDGFRA fusion gene. MPN often with prominent eosinophilia and sometimes with neutrophilia or monocytosis and presence of t(5;12)(q31-q33;p12) or a variant translocation or demonstration of an ETV6-PDGFRB fusion gene or of rearrangements of PDGFRB . MPN often with prominent eosinophilia and sometimes with neutrophilia or monocytosis or acute myeloid leukemia or precursor T-cell or precursor B-cell lymphoblastic leukemia/lymphoma (usually associated with peripheral blood or bone marrow eosinophilia) and presence of t(8;13)(p11;q12) or a variant translocation leading to FGFR1 rearrangement demonstrated in myeloid cells, lymphoblasts or both. CEL-NOS 1. Eosinophil count ≥1.5x10 9/L. 2. No Ph chromosome or BCR-ABL or other MPN (PV, ET, PMF) or MDS/MPN (CMML or aCML) 3. No t(5;12)(q31-35;p13) or other rearrangement of PDGFRB. 4. No FIP1L1-PDGFRA fusion gene or other rearrangements of PDGFRA. 5. No rearrangement of FGFR1. 6. The blast count in peripheral blood and bone marrow <20% and no inv(16)(p13q22) or t(16;16)(p13;q22) or other feature diagnostic for AML 7. No clonal cytogenetic or molecular genetic abnormality, or blast cells are >2% in the peripheral blood or >5% in bone marrow. Figure 1. Tyrosine kinase fusion genes in MLN-eo and CEL-NOS ( PDGFRA , n=6; PDGFRB , n=25; FGFR1 , n=13). | 256 | Hematology Education: the education program for the annual congress of the European Hematology Association | 2014; 8(1) Milan, Italy, June 12-15, 2014 If patients do not qualify for diagnosis of MLN-eo, then Although highly valuable for proof of clonality and as m the presence of eosinophils over 1,500/ L in peripheral markers for clonal evolution in TK-fusion gene positive blood (PB), increase in number of blasts by more than 2% patients, 15 other chromosomal aberrations, e.g. trisomies, in PB and/or more than 5% in bone marrow (BM), and/or monosomies or deletions, are rare and not useful as indi - the presence of an alternative chromosomal aberration, cators for targeted treatment. RT-PCR or FISH should be e.g. a reciprocal translocation, monosomy, trisomy or performed to confirm the presence of a suspected fusion deletion, leads to diagnosis of chronic eosinophilic gene, not only for diagnosis but also for improved moni - leukemia, not otherwise specified (CEL-NOS). Formally, toring of residual disease at low levels by nested RT-PCR. CEL-NOS would, therefore, also be an adequate subcate - If cytogenetic analysis has failed, e.g. because of dry tap gory for patients with JAK2 , ABL1 and FLT3 fusion genes, and lack of progenitors in PB, we use quantitative RT-PCR although the morphological phenotype and the disease-ini - for the expression of PDGFRA and PDGFRB because sig - tiating pathogenetic mechanisms are similar to MLN-eo. nificantly elevated levels are associated with the presence 16 Fusion genes without involvement of PDGFRA , PDGFRB of respective fusion genes. If the fusion partner is or FGFR1 and any of the alternative non-TK fusion gene unknown, techniques such as RACE-PCR, long-distance 17-21 associated chromosomal abnormalities are overall also inverse PCR or RNA-seq can be used to identify only seen in less than 3% of patients. In addition, an fusions formed by novel cytogenetic abnormalities. increased number of blasts is only evident in a similar We also recommend that FIP1L1-PDGFRA negative small cohort of unselected patients with eosinophilia (T patients with normal karyotype should be screened for KIT Haferlach, Munich Leukemia Lab, personal communica - D816V because eosinophilia is also a frequent feature in tion, 2013).
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