Myeloproliferative neoplasms Diagnosis and treatment of myeloproliferative neoplasms with

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 (TK) fusion : ‘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 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 , 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 , e.g. KIT D816V positive systemic . For treatment decisions, disease stage Correspondence: (chronic/blast phase), potential clinical course (indolent/aggressive), sensitivity to 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; & 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 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 . 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. 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 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 . 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 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. , 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. count ≥1.5x10 9/L. 2. No Ph 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).

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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). Consequently, a WHO-based diagnosis of advanced KIT D816V positive systemic mastocytosis 22,23 CEL-NOS is only possible infrequently. Other cases (SM). If positive, the serum tryptase level and the mor - which do not fulfil the criteria for MLN-eo or CEL-NOS phological assessment of a BM biopsy with aggregates of but have clear clinical and morphological signs of a spindle-shaped tryptase/CD117 positive mast cells with myeloid neoplasm should be referred to as MPN-eo or atypical expression of CD25 informs the correct diagno - MDS/MPN-eo. sis, e.g. SM-eo or SM-CEL. The presence of JAK2 V617F 24,25 Two recurrent chromosomal translocations are associat - has also been reported in some cases of MPN-eo. At ed with polyclonal eosinophilia due to involvement and present, there are no data from larger series on the pres - subsequent overexpression of the eosinophilopoietic ence or absence of the more recently identified mutations cytokine IL-3. In acute lymphoblastic leukemia, a in MPN-eo such as TET2, SRSF2, SETBP1, CSF3R, t(5;14) (q31;q32) gives rise to an IgH-IL-3 fusion gene ASXL1, RUNX1, RAS, CBL, EZH2, IDH1/2 and others. while a t(5;12)(q32;p13) in a MPN-eo or MDS/MPN-eo Because the clinical phenotype of TK fusion gene nega - like disease may result in an ETV6-ACSL6 fusion gene in tive cases is frequently indistinguishable from those in which eosinophils are polyclonal through overproduction whom a fusion gene is present, it is likely that as yet of IL-3 via positional effects of ETV6 or other as yet uncharacterized mutations or rearrangements that activate 12 intracellular signaling pathways have still to be identi - unknown mechanisms. Because the karyotype of cases 26 with ETV6-PDGFRB or ETV6-ACSL6 fusion is indistin - fied. The cut-off level for the normal eosinophil count ranges guishable, fluorescence in situ hybridization (FISH) m analysis for identification of a rearrangement of PDGFRB between 400-750/ L in PB, and hypereosinophilia is ETV6-PDGFRB defined as a persistent eosinophil count of at least or RT-PCR for identification of an fusion m 2 gene should be performed in patients with a t(5;12)(q31- 1,500/ L. Besides eosinophilia, the dominant clinical 33;p13). feature of cases with PDGFRA , PDGFRB or JAK2 fusion Despite the recent progress in our understanding of the genes, but not FGFR1 , is the male predominance, which molecular pathogenesis of eosinophilia-associated disor - exceeds a 9:1 male/female ratio. The reasons for this are ders, it has become evident that the WHO 2008 classifica - still unknown and it can only be speculated about possible tion contains several problematic and as yet unsolved secondary genetic changes or other gender-related differ - issues for an adequate differentiation between non- ences. In addition to the quantitative and qualitative (e.g. clonal/reactive and clonal/neoplastic eosinophilia, and the nuclear dyssegmentation, vacuoles, abnormal granulation) subsequent classification within reactive conditions, evaluation of eosinophils, PB smears should also be hypereosinophilic syndrome (HES) and the various sub - screened for blasts, , basophils, dysplastic fea - categories of myeloid neoplasms. 2,13,14 tures and leukoerythroblastosis which have repeatedly been reported in association with PDGFRB , FGFR1 and JAK2 fusion genes. 17-21,27-29 Very occasionally, FIP1L1- Clinicial features and diagnostic procedures PDGFRA or other rare TK fusion genes have been described in myeloid neoplasms without obvious Screening for the cytogenetically invisible FIP1L1- eosinophilia. 30 Patients can present with any level of PDGFRA fusion gene from mononuclear cells of PB hemoglobin or platelets from normal to significantly (equal to BM) by nested RT-PCR (through amplification decreased values. Useful serum markers indicating an of the FIP1L1-PDGFRA fusion sequence) or FISH underlying TK fusion and particularly FIP1L1-PDGFRA (through deletion of CHIC2 , a gene that lies between are elevated levels of serum tryptase and vitamin B12 in FIP1L1 and PDGFRA on 4q12) should be performed at an the vast majority but not all patients. 22,31 However, the early stage. Cytogenetic analysis from a BM aspirate is of serum tryptase is rarely over 100 ng/mL, a level which utmost importance for detection of rearrangements at hot would generally be indicative of SM. An elevated IgE in spots such as 4q12 ( PDGFRA ), 5q31-33 ( PDGFRB ), 8p11 the absence of allergies is suggestive of non-clonal (FGFR1 ) and 9p24 ( JAK2 ) indicating the rearranged TK. eosinophilia. Cardiac enzymes (CK, TNI, pro-BNP)

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should be routinely monitored as indicators of potentially with . 15,37,39,40 clinically silent, cardiac involvement. Clonal T-lymphocytes can induce non-clonal eosinophil Tissue infiltration and the effects of eosinophil-derived proliferation through overproduction of eosinophilopoietic mediators may result in a clinically relevant organ dys - cytokines such as IL-3, IL-5 or GM-CSF. Flow cytometric function or even irreversible organ damage. Unfortuna - analysis (through detection of T cells with aberrant pheno - tely, there are no robust immunological markers for the type, e.g. CD3 –/ CD4 +, CD3 –CD8 + or CD3 +/CD4 –/CD8 –) delineation of mature and immature eosinophils, and no or PCR analysis (through detection of T-cell gene aberrant markers indicative for the differentiation between rearrangement) has been recommended for proof of T-cell normal and neoplastic eosinophils. 2,13,14 In MPN-eo, clonality as a potentially underlying disease mechanism splenomegaly represents the most frequently observed for non-clonal eosinophilia. 2,14 However, both methods 15,32-34 organ involvement. Clinical investigation, ultra - and particularly PCR analysis have identified clonal T sound, X-ray, echocardiography, CT/MRI and endo - cells also in reactive conditions, e.g. infections or autoim - scopies should be individually used for the identification mune disorders, and a substantial subset of patients with of additional involvement of organs such as heart, lungs, FIP1L1-PDGFRA positive disease. 34,41,42 In addition to the gastrointestinal tract, lymph nodes, skin, central/peripher - proof of FIP1L1-PDGFRA positive CD3-positive lym - al nervous system and others. The prevalence of cardiac phoblasts in lymph node biopsies, 15,36,37 these results indi - involvement in FIP1L1-PDGFRA positive disease is cate that FIP1L1-PDGFRA may present as a stem-cell dis - 32-34 approximately between 20 and 40%. Typical cardiac order with multilineage involvement. findings and strong indicators for heart involvement include ventricular thrombus and endocardial thickening/fibrosis, while the diagnostic value of valve Treatment

abnormalities, ventricle dilatation and impaired ventricle 33,43 function must be evaluated in consideration of other Data from prospective clinical trials, international col - laborative studies, 44 national registries 32,34 and single cen - potentially underlying heart diseases, e.g. coronary heart 45-47 disease, particularly in older patients with a respective car - ters have shown that imatinib is able to induce complete diac disease history. Whenever possible, a biopsy and his - and durable clinical and hematologic remissions (CHR) in tological evaluation of potentially involved organs (e.g. over 90-95% of FIP1L1-PDGFRA positive patients within skin, lungs) should be undertaken. Biopsies of the heart the first three months. Furthermore, complete molecular are notorious for giving negative results, in these cases the remission (CMR), as determined by nested RT-PCR, is seen extracellular matrix should be carefully checked for in over 80-95% of patients within 12 months (frequently much earlier in individual patients), conferring high rates of deposits of eosinophil-derived proteins, that can some - 32,33,43-47 times be documented by immunostaining. 2,14 With the progression free (PFS) and overall survival (OS). No exception of SM, there is a paucity of reports on gastroin - primary resistance was reported by any of these groups and testinal eosinophilic infiltration in MPN-eo. secondary resistance is very rare (see below) (Figure 2). Bone marrow examinations should include cytomor - PDGFR α and PDGFR β are 100-times more sensitive to phology and histology with reticulin staining and imatinib than to BCR-ABL. Based on informal consensus immunohistochemistry for mast cells. However, there is a rather than on objective clinical data, the initial dose for lack of validated primary morphological features and anti - FIP1L1-PDGFRA positive cases has emerged to be 100 bodies for to differentiate between clonal and non-clonal mg/day. After achievement of CHR or CMR the dose is eosinophilia. 2,14 The term hypereosinophilia should be frequently reduced to: a) 100 mg three times per week or applied when more than 20% of all nucleated cells in the every other day, respectively; or b) 100 mg to 200 mg once BM are eosinophils. Marrow fibrosis and loose aggregates weekly. Both schedules seem to be sufficient to maintain 32,34,45 of mast cells identified by immunostaining with tryptase durable CHR and CMR at low toxicity. Initial reports 43 and CD117 are important characteristics of FIP1L1- indicated that imatinib discontinuation or dose de-escala - 54 PDGFRA positive disease, 3,22,31 although similar features tion leads to molecular relapse in all patients. Patients have also been seen in patients with rearrangements of achieved a second CMR following reinstatement of ima - 43 PDGFRB and JAK2. 18,35 In contrast to SM, the pronounced tinib, although an increased dose was needed in some 54 mast cells are loosely scattered but not found in dense patients to achieve and maintain remission. infiltrates. Subsequently, durable CMR after cessation of imatinib 34,55 34 If present, a biopsy of enlarged lymph nodes is of enor - has been reported in some cases. Legrand et al . mous importance for diagnosis of potentially underlying stopped imatinib in 11 patients after achievement of CHR extramedullary lymphoid blast phase, which is frequently and CMR. Five patients remained in CHR (5 of 5) or CMR primarily diagnosed as T-cell lymphoma. In these cases, (4 of 4 negative by nested RT-PCR, 3 of 4 negative by RQ- the molecular aberration can usually be identified contem - PCR) without hematologic relapse after a median follow poraneously in myeloid cells derived from BM and lym - up of 31 months (range 9-88). In 5 of 6 relapsed patients, phoblasts in lymph node biopsies, indicating a stem-cell reinitiation of imatinib induced CHR and/or CMR, with disorder with multilineage involvement and a disparate the same dose as before discontinuation in 3 of 5 patients. morphological appearance in BM and lymph node. 15,36,37 Helbig et al. 55 stopped imatinib in 2 patients with unde - There is a strikingly high incidence of lymphoid blast tectable FIP1L1-PDGFRA transcripts for more than four phase/lymphoma that may be either of B- or, more com - years and both patients remain free of disease 26 and 24 monly, T-cell phenotype in patients with the months, respectively, off therapy. However, until there are t(8;13)(p11;q12) and a ZNF198-FGFR1 fusion gene. 38 data from more patients with adequate follow up under There are also reports of individual patients and the pres - controlled conditions, the cessation of imatinib cannot be ence of FIP1L1-PDGFRA in cases initially diagnosed generally recommended.

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Similar to BCR-ABL positive CML, where a low versus rapid and durable responses using the same dosing sched - high Sokal score is a predictor for maintained CMR after ules as for patients with FIP1L1-PDGFRA positive dis - cessation of imatinib, 56 it would be interesting to investigate ease (A Reiter, unpublished data, 2014). potential predictors for ongoing CMR by analysis of retro - A key challenge is rapid diagnosis and adequate treat - spective data or even a prospective clinical trial. Serial ment of patients presenting in advanced phase due to sig - measurements by RQ-PCR have proved to be highly effec - nificantly increased numbers of blasts in BM, PB, lymph tive in the management of BCR-ABL positive CML in nodes or various tissues (chloroma). Transformation to which kinetics of response to imatinib has been shown to be accelerated/blast phase occurs after highly variable inter - predictive of outcome, with poor molecular response or ris - vals, rapidly in patients with FGFR1 or JAK2 fusion ing fusion transcript levels frequently indicating treatment genes, much slower in patients with PDGFRA or failure. However, these very encouraging findings in PDGFRB fusion genes. We have recently reported on 17 FIP1L1-PDGFRA disease have to be set against the fact male patients with FIP1L1-PDGFRA (n=13) or various that for many cases the sensitivity with which FIP1L1- PDGFRB fusion genes (n=4) fusion genes with either: i) PDGFRA can be detected is relatively low, 44,48 and that the myeloid blast phase (>20% blasts in PB and/or BM, PCR methodologies are not at all standardized. n=10); ii) extramedullary lymphoid blast phase/lymphoma Excellent clinical responses to imatinib have also been (lymph node infiltration by lymphoblasts of T-cell origin, reported in cases with other PDGFRA and PDGFRB n=5); or iii) chloroma (extramedullary tissue infiltration fusion genes. 17,18,20,21,27,57 The largest series demonstrated by myeloid blasts, n=2) (Figure 2). 37 Without initial rapid normalization of blood counts in 11 of 12 patients knowledge of the underlying fusion gene, 9 patients with complete resolution of cytogenetic abnormalities and received primary or even subsequent allo - decrease or disappearance of fusion transcripts as meas - geneic stem cell transplantation (SCT, n=2), but all ured by RT-PCR in 10 patients after a median of 47 patients were resistant or relapsed. Seven patients received months treatment with imatinib. 27 In addition, updates imatinib as second-line treatment after the underlying were sought from 8 further patients previously described fusion genes were identified as consequence of persisting in the literature; prompt responses were described in 7 and eosinophilia while 8 patients were primarily treated with persist in 6. 57 Perhaps due to the fact that they tend to be imatinib. Rapid CHR was achieved in all 15 patients and associated with more overt myeloid disease, patients with CMR was observed in all 12 FIP1L1-PDGFRA positive PDGFRB fusions are more often treated in the same way patients after a median of 5.4 months (range 2.9-32.0). as patients with BCR-ABL positive CML, i.e. imatinib 400 One patient died of disease-independent causes. Eleven mg/day. 27,57 Meanwhile, we have, however, also observed FIP1L1-PDGFRA positive patients are in sustained CMR

Figure 2. Imatinib in advanced MLN-eo as primary or secondary treatment after failure to intensive chemotherapy or allo - geneic SCT. 37 CR (complete clinical and hematologic remission, patients with PDGFRB fusion genes in complete cytoge - netic remission, FIP1L1-PDGFRA positive patients in complete molecular remission).

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for a median 65 months (range 7-103) and 3 patients with myeloid and lymphoid malignancies which may be sug - a PDGFRB fusion gene are in sustained CHR for a median gested by distinct additional clinical (e.g. splenomegaly), 56 months (range 24-56). biochemical (e.g. elevated serum tryptase), morphological These data not only highlight the excellent long-term (e.g. fibrosis and increased numbers of loosely scattered results of treatment with imatinib in PDGFR fusion gene mast cells) and molecular genetic features of MPN-eo. positive MLN-eo in advanced phase but also the recurrent In contrast to BCR-ABL positive CML, CMR rates for failure to identify pathogenetically relevant TK fusion FIP1L1-PDGFRA seem to be higher and potentially more genes in patients with eosinophilia and supposed ‘acute durable with low rates of acquired resistance due to muta - myeloid leukemia (AML)’ and ‘T-cell lymphoma’ at initial tions within the ATP binding domain. The low frequency diagnosis. In such cases, either diagnosis would not be of clinical resistance might be related to the limited reper - correct as ‘AML’ but should be referred to as myeloid toire of possible PDGFRA kinase domain mutations in blast phase while the ´T-cell lymphoma’ is in fact a stem vitro. 58 Thus far, amongst patients maintained on imatinib, cell disorder in which TK fusion gene positive T-lym - secondary resistance due to point mutations has only been phoblasts predominantly reside in the lymph node. We, reported in a few cases, all of whom had the appearance of therefore, refer to this as ‘extramedullary lymphoid blast a T674I or a D842V in PDGFRA which was phase’. Because the natural history of FIP1L1-PDGFRA shown functionally to confer resistance to imatinib (Figure positive MLN-eo is not well known, these observations 3). 3,49,59 These mutations are analogous to T315I in the also address the important question of whether or not to ABL kinase in imatinib-resistant CML (T674I) and to the treat an asymptomatic and young patient. Early initiation D816V in the KIT kinase in SM (D842V). It was shown of therapy is reasonable because: a) development of symp - recently that the T674I mutant is in vitro effectively inhib - toms or evolution into aggressive disease is inevitable; and ited by PKC412, sorafenib, nilotinib and ponatinib. 59-61 b) targeted therapy results in complete remissions and can, However, clinical responses may only be partial or tran - therefore, prevent complications, including leukemic sient at best, and the prognosis overall is dismal. To the transformation. 1 It is noteworthy that the frequency of best of our knowledge, there is only one long-term surviv - ‘extramedullary lymphoid blast phase/lymphoma’ is sig - ing patient who relapsed with resistant disease and under - nificantly more frequent in patients with FGFR1 fusion went allogeneic SCT (Figure 3). genes, particularly ZNF198-FGFR1 as a consequence of a MPN-eo with involvement of FGFR1 and JAK2 are fre - t(8;13)(p11;q13). Careful attention should, therefore, be quently associated with an aggressive clinical course due paid to the potential presence of these fusion genes in to rapid transformation to blast phase, usually of myeloid

Figure 3. Secondary resistance in FIP1L1-PDGFRA positive MLN-eo in chronic (CP) and advanced (AP) phase. 3,9,48-53

| 260 | Hematology Education: the education program for the annual congress of the European Hematology Association | 2014; 8(1) Milan, Italy, June 12-15, 2014 phenotype. 19,35,38,62 However, we are also aware of occa - sis (≥II°) and loosely scattered, tryptase/CD117/CD25- sional anecdotal reports of cases that have lived much positive mast cells, features which are both associated longer than this despite minimal treatment (e.g. hydrox - with clonal eosinophilia. An increase of blasts is also dis - yurea). FGFR1 and JAK2 are unaffected by imatinib, and tinctive but only rarely found. BM biopsy remains indis - due to the poor prognosis, early allogeneic SCT should be pensable for final diagnosis of SM-eo/SM-CEL through considered for eligible patients with a suitable donor. The presence of dense infiltrates. in vitro and in vivo activity of several promising new TK Imatinib is the treatment of choice for all MPN-eo, inhibitors towards FGFR1 or JAK2 is currently being which are associated with a kinase-activating fusion gene explored. In vitro data for ponatinib towards mutated involving PDGFRA (100 mg/day) or PDGFRB (100-400 FGFR are most encouraging, 63 but so far there are still no mg/day). Rapid and sustained CHR and CMR are to be data to support this contention in patients. In contrast, the expected in the vast majority of patients, even in those JAK1/JAK2 inhibitor ruxolitinib has successfully been who initially present in advanced phase. After achieve - used in at least 2 PCM1-JAK2 positive patients with ment of CMR, the dose for FIP1L1-PDGFRA positive achievement of CHR and complete cytogenetic responses cases can be reduced to 100 mg 1-3 times per week. (CCR). 64,65 As proof of principle, individual patients with Rarely occurring secondary resistance is associated with ETV6-ABL1 and ETV6-FLT3 positive MPN-eo or potentially problematic point mutations ( PDGFRA T674I, MDS/MPN-eo achieved CHR and CCR on imatinib and PDGFRA D842V) which may not be responsive to 2nd- nilotinib or the FLT3 inhibitors sunitinib and/or sorafenib, generation TK inhibitors. Allogeneic SCT should be con - respectively. Of note, one ETV6-FLT3 positive patient sidered, and this is still the primary treatment option for developed secondary resistance due to a secondary FLT3 patients with FGFR1 or JAK2 fusion genes. Initial results N841K point mutation. 7 for ruxolitinib in patients with JAK2 fusion genes and sunitinib/sorafenib in patients with FLT3 fusion genes are encouraging, while we are still awaiting the first results for Practical recommendations and conclusions ponatinib in patients with FGFR1 fusion genes. A key challenge remains the characterization of molec - In articles and reviews on the diagnosis and manage - ular aberrations underlying the majority of MPN-eo ment of eosinophilia, a frequently used initial statement is patients where the causative pathogenetic lesion is that molecular and cytogenetic analyses should be per - unknown. Imatinib is active in only a small minority of formed after exclusion of secondary causes of eosinophil - these patients and usually hematologic responses are only ia. This task is, however, difficult, if not impossible, in a transient; 32,33,43 it thus appears that uncharacterized truly substantial proportion of patients, particularly in those imatinib-responsive abnormalities are very uncommon. with life-threatening disease complications. We, therefore, The recent identification of genes involved in epigenetic recommend that RT-PCR or FISH analysis for FIP1L1- regulators, the spliceosomal machinery, cohesins, calretic - PDGFRA from PB and cytogenetic analysis from BM ulin, etc. in myeloid neoplasms has highlighted the benefit aspirates or PB (if progenitors are present) should be per - of high-throughput screening for mutations by targeted or formed early if readily apparent non-clonal eosinophilia is exome screens. However, this will not identify cryptic absent, e.g. an autoimmune disorder or a malignancy. The rearrangements, and other approaches such as RNAseq or finding of a chromosomal rearrangement through cytoge - paired end whole genome sequencing will be required. A netic analysis is very helpful, indicating the likely pres - particular problem with eosinophilic disorders is that the ence of an underlying fusion gene and facilitating its iden - proportion of cases that are genuinely primary myeloid tification. Interestingly, the formal morphological pheno - neoplasms is unknown (but likely to be a small minority) type may resemble MDS/MPN-eo rather than MPN-eo in and that the clone size may be relatively small. a substantial proportion of patients and eosinophils may be Consequently sequencing coverage needs to be high rather low, if not absent, in association with distinct fusion and/or the analysis may need to be performed on purified genes. We also recommend molecular testing for FIP1L1- cell populations. A concerted effort should be made to PDGFRA and cytogenetic analysis in all cases of more identify suitable cases for high throughput analysis. unusual eosinophilia-associated hematologic malignan - cies, e.g. ‘CBF-mutation negative AML with eosinophilia’ References or ‘T-cell lymphoma with eosinophilia’, because they could represent myeloid or lymphoid blast phase, respec - tively, of a TK-fusion gene associated MPN-eo. Easily 1. Tefferi A, Gotlib J, Pardanani A. 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A tyrosine kinase created by fusion of the PB because multiple lineage involvement in SM-eo/SM- PDGFRA and FIP1L1 genes as a therapeutic target of imatinib CEL regularly leads to a substantial and detectable KIT in idiopathic hypereosinophilic syndrome. N Engl J Med. 2003;348(13):1201-14. D816V allele burden. Unfortunately, BM morphology is 4. Reiter A, Walz C, Cross NC. Tyrosine kinases as therapeutic frequently non-informative for a clear differentiation targets in BCR-ABL negative chronic myeloproliferative dis - between clonal/non-clonal and reactive/neoplastic orders. Curr Drug Targets. 2007;8(2):205-16. 5. Reiter A, Grimwade D, Cross NC. Diagnostic and therapeutic eosinophils due to lack of distinct morphological and management of eosinophilia-associated chronic myeloprolif - immunhistochemical parameters except significant fibro - erative disorders. Haematologica. 2007;92(9):1153-8.

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