Case presentation

A 20-year-old male patient presented with a two-week history of abdominal pain, accompanied by fever, abdominal distention, a significantly enlarged spleen (approximately 6.5 cm below the umbilicus), and tenderness in the left upper abdomen upon admission. The blood routine showed leukocytes at 379 × 10^9/L, eosinophils at 18.77 × 10^9/L, hemoglobin at 78 g/L, and platelets at 541 × 10^9/L. Upon further examination, reverse transcription-polymerase chain reaction (RT-PCR) identified positive results for BCR::ABL1 (P210, IS quantification 86.34%), while the JAK2-V617F mutation tested negative. The results of bone marrow (BM) morphology revealed a remarkably active proliferation of nucleated cells, with a predominant population of myelocytes and metamyelocytes exhibiting intense proliferation and displaying normal morphology. Additionally, there was an observed increase in eosinophils and basophils. Furthermore, the evaluation of the peripheral blood smear displayed a significant elevation in white blood cells, primarily characterized by a left shift in the population of mature neutrophils. The BM biopsy morphology reveals an active proliferation of nucleated cells, with an increase in the granulocytic lineage (Fig. 1A). Chromosome results showed clonal chromosome abnormalities: 46, XY, t(5; 12) (q33; q24.1), t(9:22)(q34.1; q11.2)[20] (Fig. 1B). These results suggest the coexistence of BCR::ABL1 and GIT2::PDGFRB. The patient was diagnosed with the chronic phase of chronic myelogenous leukemia (CML-CP) at a local hospital and was treated with 400 mg of imatinib orally daily.

Fig. 1
figure 1

Morphologic, cytogenetic, and molecular findings in a patient with myeloid proliferative neoplasm with coexisting BCR::ABL1 and PDGFRB rearrangement. (A) The bone marrow biopsy morphology reveals an active proliferation of nucleated cells, with an increase in the granulocytic lineage. The cells predominantly observed are in a more mature stage of development, with a sparse presence of less mature, immature cells. (B) G-banded bone marrow karyogram at diagnosis showing 46, XY, t(5; 12) (q33; q24.1), t(9:22)(q34.1; q11.2)[20]. (C) G-banded bone marrow karyogram at 4 months post-treatment showing 46,XY [18]/46,XY, t(9:22)(q34.1; q11.2)[2]. (D) Quantification of the BCR::ABL1 trend in bone marrow by reverse transcription-polymerase chain reaction

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His symptoms gradually improved and he was discharged to continue oral therapy with imatinib 400 mg daily. Four months later, a follow-up examination revealed a normal blood count, a karyotype of 46,XY [18]/46,XY, t(9:22)(q34.1; q11.2)[2] (Fig. 1C), and a decrease in BCR::ABL1^IS copies to 5.3% in the BM. The patient came to our hospital for reexamination 10 months after diagnosis, showing that the copies of BCR::ABL1 had decreased to MMR (BCR::ABL1^IS level of 0.0704%) and normal karyotype in the BM. He achieved BCR::ABL1 MR5 (BCR::ABL1^IS level less than 0.001%) 18 months after diagnosis. The trend graph illustrating quantify of BCR::ABL1 is presented in Fig. 1D.

Discussion

This is a rare case in which BCR::ABL1 and PDGFRB rearrangement coexist in a patient with MPN. Despite the identification of an additional chromosomal abnormalities (ACA), 5q33, in Philadelphia chromosome-positive cells at the initial diagnosis, the patient remains in the CML-CP, as the findings do not meet the diagnostic criteria for CML-AP [1]. A myeloid or lymphoid neoplasm, often with prominent eosinophilia and sometimes with neutrophilia or monocytosis, combined PDGFRB rearrangement should be diagnosed as myeloid/lymphoid neoplasms associated with rearrangement of PDGFRB [2]. The diagnosis was updated to myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions (MLN-TK) in the 5th edition of the WHO classification. MLN-TK may present as chronic myeloproliferative tumors, but the frequency of presentation as lymphoid tumors or acute myeloid leukemia varies [3]. For MLN-TK with PDGFRB rearrangement, usually there is t(5; 12)(q32; p13.2) with the formation of an ETV6::PDGFRB fusion gene. In uncommon variants, other translocations with a 5q31-33 breakpoint led to the formation of other fusion genes, such as GIT2::PDGFRB [4]. In the setting of PDGFRB-related disease, the characteristics are more variable, which can manifest as chronic myelomonocytic leukemia, atypical chronic myeloid leukemia, or MPN, often accompanied by eosinophilia, or manifest as chronic eosinophilic leukemia [3]. So far, there have been no reports of CML associated with other clonal chromosomal abnormalities such as PDGFRA, PDGFRB, FGFR1, or PCM1-JAK2 [5]. Meanwhile, no MLN-TK has manifested as BCR::ABL1-positive MPN.

For the first time, we present a case of an eosinophilia-associated MPN patient with coexisting BCR::ABL1 and PDGFRB rearrangements, along with neutrophilia and splenomegaly, who exhibited an excellent response to daily imatinib at 400 mg. This patient meets the diagnostic criteria for both CML and MLN-TK, indicating the uniqueness of this case and warranting further investigation. It is believed that both CML and MLN-TK originate from abnormal pluripotent stem cells. In this particular case, the origins of the two genetic abnormality clones remain unknow. There are two possible explanations: the first involves CML associated with ACA, while the second entails a distinct entity characterized by concurrent BCR::ABL1 and PDGFRB rearrangements.

We are inclined to believe that this patient represents a coexistence of BCR::ABL1 and PDGFRB rearrangements. Firstly, at the initial diagnosis, all metaphases of the patient exhibited Philadelphia chromosome-positive cells combined with a translocation involving 5q33, which suggests a pre-existing condition rather than an acquired one post-treatment. Secondly, the patient’s response to imatinib closely mirrors that of MLN-TK patients with PDGFRB rearrangements rather than CML. Notably, the patient achieved a profound molecular response (MR5) within just 18 months, a notably rapid progression. The 12-year incidences of achieving molecular responses MR4.5 and MR5 are reported as 72% and 54% in patients with CML, respectively [6]. Conversely, in patients with myeloid/lymphoid neoplasms with eosinophilia and PDGFRB rearrangements in the chronic phase receiving imatinib therapy, all patients achieved complete hematologic remission within a median of 2 months. Additionally, complete cytogenetic and/or molecular remissions were achieved in 92% and 86% of cases, respectively, over median durations of 10 and 19 months [7]. It is evident that compared to CML, patients with myeloid/lymphoid neoplasms with eosinophilia and PDGFRB rearrangements achieve a faster attainment of deep molecular remission when treated with imatinib. The patient’s response pattern to imatinib closely resembles that of myeloid/lymphoid neoplasms featuring eosinophilia and PDGFRB rearrangements. Moreover, subsequent chromosomal metaphases during treatment showed disappearance of the 5q33 translocation preceding the Philadelphia chromosome, potentially indicating greater sensitivity of the PDGFRB rearrangement to imatinib.

Regrettably, the patient did not undergo testing for PDGFRB rearrangement via fluorescence in situ hybridization (FISH) or GIT2-PDGFRB by RT-PCR during the initial diagnosis at a regional hospital. This lack of diagnostic findings hindered our ability to provide direct evidence of PDGFRB fusion and left us with only a strong suspicion. However, considering the patient’s rapid molecular response to imatinib, it lends support to the presence of a concomitant PDGFRB rearrangement.

In summary, our report underscores a rare and distinctive case of MPN with both BCR::ABL1 and PDGFRB rearrangements, achieving rapid and profound remission following imatinib treatment. While further research is needed to confirm this, we lean towards considering it a unique subtype simultaneously harboring both BCR::ABL1 and PDGFRB rearrangements, rather than classical CML with ACA.