Diagnostics

Myeloid/lymphoid neoplasms with eosinophilia and defining gene rearrangement (MLN-TK)

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Cytomorphology
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Immunophenotyping
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Chromosome analysis
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Classification
Diagnostics
Prognosis and Therapy
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Based on the current guidelines and the current state of research, there are different diagnostic recommendations for patients with myeloid/lymphoid neoplasms with eosinophilia and defining gene rearrangement (MLN-TK). We have summarized the most important info on classification and diagnostic methods at MLL. In addition, we provide further links and literature on prognosis and therapy in MLN-TK, so that you can inform yourself in more detail.

MLN-TK: Classification

Myeloid/lymphoid neoplasms with eosinophilia and gene rearrangement (MLN-TK) are rare specific diseases. Clinical and hematologic manifestation is influenced by the partner gene involved in the rearrangement. Eosinophilia is characteristic but not necessarily present. According to the WHO classification, MLN-TK are divided into the following subtypes:

Table 1: Overview of genetic alterations and clinical presentation in MLN-TK (Reiter & Gotlib 2017, Wang et al. 2020, WHO 2022, Metzgeroth et al. 2023)

Subtype	Presentation	Genetics
PDGFRA	Eosinophilia (91%) ↑ Serum tryptase ↑ Mast cells in bone marrow ↑ Serum vitamin B12	Cryptic 4q12 deletion (incl. CHIC2); FIP1L1::PDGFRA; other fusion partners possible
PDGFRB	Eosinophilia (50%) Possibly with monocytosis (similar to CMML) or neutrophilia	t(5;12)(q32;p13); ETV6::PDGFRB, more than 30 other fusion partners
FGFR1	Eosinophilia (16%) Possibly with monocytosis (similar to CMML) or neutrophilia Phenotypically possible presentation as MPN, MDS/MPN	8p11 translocation, other fusion partners possible
JAK2	Eosinophilia (50%) Bone marrow mostly hypercellular Frequently myelofibrosis	t(8;9)(p22;p24.1); PCM1::JAK2, other fusion partners possible
FLT3	Eosinophilia Frequent in pB: leukocytosis, anemia and thrombocytopenia Variable phenotype (e.g. T-ALL or MPN)	t(12;13)(p13;q12.2); FLT3::ETV6, other fusion partners described
ETV6::ABL1	Eosinophilia (100%) Must be distinguished from B-ALL with ETV6::ABL1 Leukocytosis, anemia, thrombocytosis or thrombocytopenia and basophilia	Cryptic t(9;12)(q34;p13); ETV6::ABL1
MLN mit anderen TK-Fusionsgenen	Eosinophilia Leukocytosis, anemia, thrombocytopenia, and/or monocytosis	Other non-specifically defined TK fusion genes (e.g. ETV6::FGFR2; ETV6::LYN; ETV6::NTRK3; RANBP2::ALK; BCR::RET; FGFR1OP::RET)

All subtypes have in common the constitutive activation of a tyrosine kinase with a highly heterogeneous clinical presentation. Essentially, two disease phases can be distinguished for myeloid/lymphoid neoplasms with eosinophilia and TK gene fusion: the chronic phase and the blast phase. In the chronic phase, the disease usually presents as MPN or MDS/MPN. In the blast phase, it presents more likely as an acute leukemia (AML, ALL, or ALAL (Acute Leukemia of Ambigous lineage)) and/or extramedullary disease (e.g., myeloid sarcoma, lymphoma) (Gerds et al. 2020).

MLN-TK: Diagnostic methods and their relevance

Especially in view of the great heterogeneity of the appearance (see also Table 1), cytomorphology plays an essential role in morphological characterization. It is important for the exclusion of secondary and reactive causes of eosinophilia and, in conjunction with other diagnostic disciplines, for the differential diagnosis of diseases that may also be associated with eosinophilia (Shomali & Gotlib 2024). Follow-up examinations are important for the assessment of hematologic response to therapy and for the exclusion or detection of leukemic transformation.

Immunophenotyping plays a minor role when cases present as myeloproliferative neoplasia in the chronic phase. When cases present as acute leukemia or leukemic transformation, immunophenotyping is important for lineage determination.

Chromosome analysis plays an important role in the diagnosis of myeloid/lymphoid neoplasms with tyrosine kinase fusion. With the exception of the cytogenetically cryptic rearrangements FIP1L1::PDGFRA and ETV6::ABL1, all other rearrangements involving tyrosine kinase coding genes can usually be detected by chromosome analysis. Chromosome analysis is also suitable for identifying both fusion partners (possibly in combination with FISH analyses).

The cytogenetically cryptic FIP1L1::PDGFRA rearrangement as the most common cause of myeloid/lymphoid neoplasia with tyrosine kinase fusion can be detected very well by FISH. The ~800 kB deletion on chromosome 4q12 is detected with a probe that is also directed against the CHIC2 gene, which is located in the deleted region.

In addition, probes are available in modern FISH diagnostics that allow screening for possible rearrangements or aberrations of 4q12 PDGFRA (4q12), PDGFRB (5q32/5q33), FGFR1 (8p11) as well as JAK2 (9p24). Fusion partners can possibly be identified in a further step by chromosomal analysis or molecular genetic characterization.

Molecular genetics can significantly support the diagnosis of these diseases. For example, the most common rearrangements can be detected by RT-PCR, such as FIP1L1::PDGFRA, ETV6::PDGFRB, ZNF198::FGFR1 and PCM1::JAK2, as well as ETV6::ABL1. ETV6::ABL1 and FIP1L1::PDGFRA RT-PCRs provide additional means to detect these cytogenetically cryptic rearrangements besides FISH analysis. In addition, molecular genetics can be used to monitor treatment response.

Differentially, cases with unclear hypereosinophilia (HE) also undergo analyses of the JAK2 (V617F as well as exon 13), KIT (D816V), and STAT5B genes, which would tend to steer the diagnosis toward MPN or mastocytosis or CEL.

Furthermore, the method of RNA sequencing offers the possibility to identify also rare fusion partners.

Little is known about the mutational landscape of MLN-TK compared with other myeloid neoplasms. In a first study, at least one mutation was detectable in 23% of 61 patients examined. The only recurrent mutations were in RUNX1, which was strongly associated with an FGFR1 rearrangement. Additional mutations in MLN-TK were found in the ASXL1, BCOR, DNMT3A, TET2, STAT5, ETV6, NRAS, SRSF2, TP53, and ZRSR2 genes. However, these studies do currently not play a role in diagnosis or prognosis (Baer et al. 2018, Gerds et al. 2020, WHO 2022).

MLN-TK: Prognosis and therapy

Response criteria for neoplasms with eosinophilia and FGFR1 rearrangement

Patients with FGFR1 rearrangement usually show a rather unfavorable prognosis with a heterogeneous clinical presentation. The MLN International Working Group (MLN IWG) developed a proposal for comprehensive treatment response criteria for patients with MLN-TK, which was primarily collected for MLN with FGFR1 rearrangement under pemigatinib as part of the FIGHT-203 study (Shomali et al. 2023).

Good therapeutic response in neoplasms with eosionophilia and PDGFRA and PDGFRB rearrangements

Regardless of the partner gene, the detection of PDGFRA rearrangements is of great importance from a therapeutic point of view, as they usually show a good response to treatment with tyrosine kinase inhibitors (Cools et al. 2003). In particular, patients with FIP1L1::PDGFRA rearrangements achieve deep molecular and long-lasting remission. An overview of this is provided in the Onkopedia guideline. Initial, mostly retrospective, studies are currently evaluating whether, analogous to a TKI stop in CML, a discontinuation of imatinib treatment is possible (Klion et al. 2007, Gerds et al. 2020, Metzgeroth et al. 2020, Rohmer et al. 2020).

A good therapeutic response to tyrosine kinase inhibitors and long-term remissions were also observed in patients with PDGFRB rearrangements (Cheah et al. 2014, Di Giacomo et al. 2022).

High rate of transformation to AML in PCM1::JAK2 rearrangement and FGFR1 rearrangement

Myeloid and lymphoid neoplasms with eosinophilia and PCM1::JAK2 rearrangement or FGFR1 rearrangement have a high transformation rate to acute leukemias.

Aggressive course in FLT3 rearrangements

FLT3 rearrangements are associated with aggressive disease progression. Short-term hematologic and cytogenetic responses can be achieved with FLT3/multikinase inhibitors, and stem cell transplantation should be considered as a curative approach for appropriate patients (WHO 2022).

Unfavorable prognosis for untreated patients with ETV6::ABL1 rearrangement in blast phase

With early diagnosis of the ETV6::ABL1 rearrangement, second-generation tyrosine kinase inhibitors have already been able to induce complete and long-lasting remissions. However, in the presence of a blast phase, an unfavorable prognosis has been described (Schwaab et al. 2020, Yao et al. 2021, Metzgeroth et al. 2023).

MLN-TK: Recommendation

In case of clinical and cytomorphological suspicion of myeloid/lymphoid neoplasms with eosinophilia and defining gene rearrangement, comprehensive screening by cytogenetics (chromosomal analysis & FISH) and molecular genetics should be performed for diagnosis both for classification according to WHO and because of the immense therapeutic consequences.

Due to the rarity of these disorders, inclusion in the Registry of Patients with Rare Myeloid Neoplasms can be recommended.

Baer C et al. Molecular genetic characterization of myeloid/lymphoid neoplasms associated with eosinophilia and rearrangement of PDGFRA, PDGFRB, FGFR1 or PCM1-JAK2. Haematologica 2018;103(8):e348-e350.

Cheah CY et al. Patients with myeloid malignancies bearing PDGFRB fusion genes achieve durable long term remissions with imatinib. Blood 2014;123(23):3574-3577.

Cools J et al. A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. N. Engl. J. Med 2003;348(13):1201-1214.

Di Giacomo D et al. Genomic and clinical findings in myeloid neoplasms with PDGFRB rearrangement. Ann Hematol 2022;101(2):297-307.

Gerds AT et al. Myeloid/Lymphoid Neoplasms with Eosinophilia and TK Fusion Genes, Version 3.2021, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2020;18(9):1248-1269.

Klion AD et al. Relapse following discontinuation of imatinib mesylate therapy for FIP1L1/PDGFRA-positive chronic eosinophilic leukemia: implications for optimal dosing. Blood 2007;110(10):3552-3556.

Metzgeroth G et al. Treatment-free remission in FIP1L1-PDGFRA-positive myeloid/lymphoid neoplasms with eosinophilia after imatinib discontinuation. Blood Adv 2020;4(3):440-443.

Metzgeroth G et al. Myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions: reevaluation of the defining characteristics in a registry-based cohort. Leukemia 2023;37(9):1860-1867.

Onkopedia Leitlinie „Eosinophilie: Primäre klonale Eosinophile und Differentialdiagnosen“ 2023; DGHO 2023.

Reiter A, Gotlib J. Myeloid neoplasms with eosinophilia. Blood 2017;129(6):704-714.

Rohmer J et al. Epidemiology, clinical picture and long-term outcomes of FIP1L1-PDGFRA-positive myeloid neoplasm with eosinophilia: Data from 151 patients. Am J Hematol 2020;95(11):1314-1323.

Schwaab J et al. Response to tyrosine kinase inhibitors in myeloid neoplasms associated with PCM1-JAK2, BCR-JAK2 and ETV6-ABL1 fusion genes. Am J Hematol 2020;95(7):824-833.

Shomali W et al. Comprehensive response criteria for myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions: a proposal from the MLN International Working Group. Leukemia 2023;37(5):981-987.

Shomali W, Gotlib J. World Health Organization and International Consensus Classification of eosinophilic disorders: 2024 update on diagnosis, risk stratification, and management. Am J Hematol 2024;99(5):946-968.

Wang T et al. Identification of a novel TFG-FGFR1 fusion gene in an acute myeloid leukaemia patient with t(3;8)(q12;p11). Br J Haematol 2020;188(1):177-181.

WHO Classification of Tumours Editorial Board. Haematolymphoid tumours [Internet]. Lyon (France): International Agency for Research on Cancer; 2022. (WHO classification of tumours series, 5th ed.; vol. 11). Available from: https://tumourclassification.iarc.who.int/chapters/63.

Yao J et al. Myeloid/lymphoid neoplasms with eosinophilia/ basophilia and ETV6-ABL1 fusion: cell-of-origin and response to tyrosine kinase inhibition. Haematologica 2021;106(2):614-618.

Status: October 2024

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Myeloid/lymphoid neoplasms with eosinophilia and defining gene rearrangement (MLN-TK)

MLN-TK: Classification

Table 1: Overview of genetic alterations and clinical presentation in MLN-TK (Reiter & Gotlib 2017, Wang et al. 2020, WHO 2022, Metzgeroth et al. 2023)

MLN-TK: Diagnostic methods and their relevance

Cytomorphology

Immunophenotyping

Chromosome analysis

Fluorescence in situ hybridisation (FISH)

Molecular genetics

MLN-TK: Prognosis and therapy

Response criteria for neoplasms with eosinophilia and FGFR1 rearrangement

Good therapeutic response in neoplasms with eosionophilia and PDGFRA and PDGFRB rearrangements

High rate of transformation to AML in PCM1::JAK2 rearrangement and FGFR1 rearrangement

Aggressive course in FLT3 rearrangements

Unfavorable prognosis for untreated patients with ETV6::ABL1 rearrangement in blast phase

MLN-TK: Recommendation

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