Myeloid/lymphoid neoplasms with eosinophilia and defining gene rearrangement (MLN-TK)
- Method:
- Anticoagulant:
- Recommendation:
- Method:Cytomorphology
- Anticoagulant:EDTA
- Recommendation:obligatory
- Method:Immunophenotyping
- Anticoagulant:EDTA or Heparin
- Recommendation:facultative
- Method:Chromosome analysis
- Anticoagulant:Heparin
- Recommendation:obligatory
- Method:FISH
- Anticoagulant:EDTA or Heparin
- Recommendation:obligatory
- Method:Molecular genetics
- Anticoagulant:EDTA or Heparin
- Recommendation:obligatory
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)
|
Subtype |
Presentation |
Genetics |
|
PDGFRA |
|
Cryptic 4q12 deletion; |
|
PDGFRB |
|
t(5;12)(q32;p13); ETV6::PDGFRB, more than 30 other fusion partners |
|
FGFR1 |
|
8p11 translocation, different fusion partners - 14 described so far |
|
JAK2 |
|
t(8;9)(p22;p24.1); PCM1::JAK2, other fusion partners possible |
|
FLT3 |
|
t(12;13)(p13;q12.2); FLT3::ETV6, other fusion partners described |
|
ETV6::ABL1 |
|
Cryptic t(9;12)(q34;p13); ETV6::ABL1 |
|
MLN mit anderen TK-Fusionsgenen |
|
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 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
MLN-TK: Prognosis and therapy
A proposal on comprehensive therapy response criteria of patients with MLN-TK, which was primarily collected for MLN with FGFR1 rearrangement under pemigatinib in the FIGHT-203 study, is available from the MLN International Working Group (MLN IWG). These criteria are based on the heterogeneous clinical presentations of patients from the FIGHT-203 study and could be helpful in different therapeutic approaches (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).
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
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, if left untreated or in the presence of a blast phase, an unfavorable prognosis has been described (Schwaab et al. 2020, Yao et al. 2021).
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.
Status: September 2023