Abstract
Background In 2022, the World Health Organization (WHO) and the International Consensus Classification of Myeloid and Lymphoma ( ICC-MLN ) defined a group of rare hematopoietic tumors driven by specific tyrosine kinase gene fusions (PDGFRA/B, FGFR1, JAK2, FLT3, or ETV6::ABL1) as myeloid/lymphoid tumors with eosinophilia and tyrosine kinase gene fusion (MLN-TK). Significant phenotypic and prognostic heterogeneity poses challenges to clinical diagnosis and targeted therapy. The purpose of this study was to analyze the clinical characteristics and treatment outcomes of MLN-TK patients, and to provide reference for clinical diagnosis and treatment.
Methods This retrospective, multi-center study included a total of 71 MLN-TK patients from five clinical centers. Tyrosine kinase gene fusions were detected by RNA-sequencing or FISH and confirmed by qPCR. Next-generation sequencing was performed in 47 patients. We assessed demographic and clinical variables, treatment, and outcomes.
Results Demographic and clinical variables
PDGFRA/B were the most commonly observed fusion genes (PDGFRA, n=27; PDGFRB, n=14), subsequently followed by FGFR1(n=12), JAK2(n=7), FLT3(n=2), ETV6::ABL1(n=8), and RANBP2::ALK(n=1). The median age was 43(6-69) years. 53(74.6%) patients were male.Both patients with PDGFRA and FLT3 fusion genes were male, while only 33% of the FGFR1 group were male (P＜0.01). 68 patients had eosinophil count at the initial diagnosis, of whom 55(80.9%) patients had eosinophilia, including 48(70.6%) diagnosed with hypereosinophilia(HE). Eosinophilia was observed in 5/8(62.5%, P=0.03) ETV6::ABL1 positive and 4/11(36.4%, P＜0.01) FGFR1 rearrangement patients, while more than 90% of patients in other subgroups had eosinophilia. Hypereosinophilia was more common in patients with PDGFRA rearrangement (24/26), FLT3 rearrangement (2/2), and RANBP2::ALK (1/1) positive, while only 4/11 in the FGFR1 rearrangement group(P＜0.01). Overall, a blast phase (BP) in bone marrow (BM) was diagnosed in 15/71 (21.13%) patients (myeloid, 40%; lymphoid, 40%; mixture phenotype, 13.3%; plasma cell leukemia, 6.67%), 5 patients(myeloid sarcoma, 1; T lymphoblastic lymphoma, 4) were diagnosed as extramedullary disease (EMD). Compared with other subgroups, the incidence of BP was higher in the FGFR1 rearrangement group(7/12, 58.33%). 37 mutations were detected in 21 patients, and RUNX1 mutations (8/37, 21.6 %) were the most commonly observed. The main organs involved included the spleen (32/55, 58.2%), lymph nodes (13/55, 23.6%), skin (12/55, 21.8%), liver (11/55, 20.0%) and heart (3/55, 5.4%); 21/55(38.2%) of the patients had two or more organ involvement.
Treatments and outcomes
Treatment follow-up data were available for 63 patients. At a median follow-up of 19.5 months, death occurred in 6 (9.8%) patients..
In MLN with PDGFRA fusion genes, 22 patients in chronic phase(CP) were treated with imatinib, 1 patient with AML received chemotherapy + imatinib, and 1 patient with ALL received dasatinib + chemotherapy. Except for 2 patients who did not reach the 3-month evaluation time, the remaining patients achieved complete molecular remission(CMR) in the 3-month evaluation.
In MLN with PDGFRB fusion genes, CMR was obtained in 10 CP patients after 3 months of imatinib treatment; 2 AML patients failed to benefit from chemotherapy and died 1 month and 3 months after diagnosis;.another AML patient with persistent CR after chemotherapy. One patient with T-LBL received imatinib combined with chemotherapy and achieved CR, followed by allogeneic hematopoietic stem cell transplantation(Allo HSCT).
In MLN with FGFR1, JAK2, FLT3, ETV6::ABL1 and RANBP2::ALK fusion genes (n=28), 11 patients received allo-HSCT after TKI combined with or without chemotherapy. Four patients died of disease progression(FGFR1, n=1; JAK2, n=1; ETV6::ABL1 n=1 and RANBP2::ALK n=1).Two cases of ZMYM2::FLT3 achieved complete hematological remission(CHR) after treatment with giretinib, but did not achieve CMR, and one of them progressed to ALL after 18 months of treatment.
Conclusions: The clinical manifestations of MLN-TK are different, which may involve multiple organs. The increase of eosinophils is more common, and the prognosis of BP or secondary BP seems to be worse.
