Abstract
Platelet-derived growth factor receptor beta (PDGFRB)-rearranged myeloid/lymphoid neoplasms (MLNs) are rare hematologic malignancies typically responsive to tyrosine kinase inhibitors (TKIs) such as imatinib. However, resistance—particularly in the context of co-occurring high-risk mutations—is uncommon and poorly characterized. We report a case of a 65-year-old man diagnosed with a ETV6::PDGFRB-translocated MLN, presenting as atypical chronic myeloid leukemia (aCML), who exhibited a brief response with development of resistance to imatinib. Although the patient initially achieved hematologic and partial cytogenetic remission, residual fibrosis and cytogenetic abnormalities persisted despite dose escalation. Molecular profiling revealed high-risk mutations in ASXL1, KRAS, NRAS, SETBP1, and SRSF2, along with a variant of uncertain significance (VUS) in IDH2. The patient progressed to acute myeloid leukemia (AML) within 11 months despite sequential therapies including dasatinib and azacitidine-venetoclax, ultimately succumbing to sepsis. This case highlights the limitations of TKI monotherapy in MLNs with PDGFRB rearrangements and co-existing high-risk mutations, underscoring the importance of early molecular profiling and consideration of allogeneic hematopoietic stem cell transplantation in cases with poor risk features.
Introduction
Platelet-derived growth factor receptors alpha (PDGFRα) and beta (PDGFRß) are members of the class III receptor tyrosine kinase family, playing central roles in cellular growth, differentiation, and proliferation (). Myeloid/lymphoid neoplasms with eosinophilia and PDGFRB rearrangements typically present as chronic myeloid neoplasms and are classified as a distinct entity in the World Health Organization (WHO) classification. The ETV6 gene is the most common fusion partner ().
These rearrangements result in constitutive tyrosine kinase activation, rendering most cases highly sensitive to imatinib (, ). Over 40 different fusion partners have been reported, with ETV6 being the most frequent ().
Patients with PDGFRB translocations may lack eosinophilia, only low grade in this case, and rarely present with additional cytogenetic or molecular abnormalities (, –).
Although most cases respond well to TKIs, resistance—either primary or acquired—remains poorly understood. Proposed mechanisms include secondary kinase domain mutations or disease progression to AML (). TKI resistance has also been described in lymphoid malignancies with PDGFRB rearrangements (, ), though B-cell acute lymphatic leukemia with such fusions appears highly TKI-sensitive ().
Here we describe a patient with a ETV6::PDGFRB translocation presenting as aCML, developing resistance to imatinib. The presence of high-risk mutations likely contributed to the resistance and rapid progression to AML. This case emphasizes the need for comprehensive molecular profiling, clonal monitoring, and early consideration of allogeneic stem cell transplantation in MLN cases with PDGFRB rearrangements that do not respond as expected to treatment.
Case description
A 65-year-old man with a history of prostate cancer treated by radical prostatectomy 12 years prior, without adjuvant therapy, presented with splenomegaly (12 cm below the left costal margin), 8-kg weight loss over 2 months, and gout. Laboratory studies revealed leukocytosis (69 × 109/L), mild peripheral eosinophilia (2%), and mild anemia. Bone marrow biopsy showed hypercellularity with myeloid proliferation, dysgranulopoiesis, and grade 2 fibrosis, without increased blasts or significant eosinophilia (Figure 1). Cytogenetics revealed t(5;12)(q33;p13) as the sole abnormality. Fluorescence in situ hybridization (FISH) examination confirmed PDGFRB rearrangement. RNA sequencing confirmed the presence of an ETV6::PDGFRB fusion transcript involving exon 4 of ETV6 (NM_001987.5) and exon 9 of PDGFRB (NM_002609.4). Accordingly, whole genome sequencing identified the translocation breakpoint within intron 4 of ETV6 (NM_001987.5) and intron 8 of PDGFRB (NM_001355017.2). BCR::ABL1 was negative. Targeted sequencing revealed pathogenic mutations in ASXL1, KRAS, NRAS, SETBP1, SRSF2, and a VUS in IDH2 ().
Figure 1
Imatinib at 100 mg/day was initiated. Hematologic remission and spleen size normalization occurred within 2 months. However, at 10 months, a follow-up marrow showed only partial response, persistent patchy fibrosis, and 17% FISH positivity for the PDGFRB rearrangement. Imatinib was escalated to 400 mg/day, and transplantation workup was initiated.
Repeat marrow and FISH at 3 months later showed no further cytogenetic improvement and no blast increase. PDGFRB kinase domain sequencing showed no secondary mutations. Dasatinib at 100 mg/day was briefly trialed, but increasing leukocytosis necessitated azacitidine plus venetoclax. Despite therapy, the patient progressed to AML 15 months after diagnosis and died of sepsis with multiorgan failure during a neutropenic episode.
Serial sampling using the same targeted sequencing panel () in parallel with FISH for PDGFRB-rearrangement showed a decrease in PDGFRB-rearranged clone burden and parallel decreases in KRAS/NRAS variant allele frequency (VAF) (see Figure 2). In contrast, ASXL1, SETBP1, and SRSF2 VAFs remained stable. Interestingly, the IDH2 VUS VAF declined with the PDGFRB clone, suggesting that the variant was part of that clone. The two NRAS variants were consistently detected at low VAFs. Cytogenetics at AML transformation revealed monosomy 7 in 19/21 metaphases and a 17p11.2 locus loss in seven metaphases, alongside the persistent t(5;12), indicating clonal evolution. No TP53 mutations or new molecular abnormalities were found (Figure 2).
Figure 2
Discussion
Chronic-phase PDGFRB-rearranged neoplasms are typically sensitive to TKIs such as imatinib. Resistance is rare. Byrgazov et al. reported one imatinib-resistant NDEL1::PDGFRB case with a D850E mutation in the activation loop—a mechanism excluded in our case (). Other reports describe TKI resistance predominantly in advanced-stage AML or lymphoid malignancies (, , ).
PDGFRB translocation alone appears to be a leukemogenic driver (), explaining the usual absence of additional mutations or cytogenetic anomalies—similar to BCR::ABL1 in CML. Among the rare cases of TKI failure, few underwent molecular profiling (, ), and no previously identified mutations have been clearly linked to resistance (, ).
An exception is a case by Gou et al., who described an ETV6::PDGFRB-positive patient with concurrent NPM1, TET2, and NOTCH3 mutations and 46,XY,del(12)(p13p11.2), who developed a PDGFR-translocation positive T-lymphoblastic lymphoma while on imatinib ().
In our case, ASXL1, SETBP1, and SRSF2 VAFs remained unchanged during treatment, indicating their independence from the PDGFRB-positive clone. While ASXL1 and SRSF2 mutations may reflect age-related clonal hematopoiesis, SETBP1 is more strongly associated with secondary AML, CMML, and aCML—often co-occurring with ASXL1 and SRSF2 in those neoplasms (, ). Given the unusual clinical course with an initial partial response to TKI followed by TKI-insensitive relapse and progression to AML, it is difficult not to think that the co-occurring mutations, in some way, contributed to the dismal outcome, even if it is impossible to conclude this in a single observational study such as this.
This case report has certain limitations, particularly in terms of generalizability—for example, the possibility of a pre-existing myeloproliferative neoplasm (MPN) with adverse mutations preceding the acquisition of the PDGFRB rearrangement cannot be excluded. Therefore, these findings should be interpreted with caution and may serve as a basis for further investigation.
The key message is to consider broad mutational profiling—even in the presence of targetable lesions like PDGFRB rearrangements and especially if signs of poor treatment response occur. In cases with poor molecular risk, rapid TKI response should not be assumed. While similar concerns have been raised in CML (), this is, to our knowledge, the first report of primary TKI resistance in chronic-phase PDGFRB-rearranged MLN associated with high-risk mutations and adverse outcome.
Statements
Data availability statement
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.
Ethics statement
The requirement of ethical approval was waived by Etikprövningsmyndigheten for the studies involving humans because Case reports are waived from ethical approval in Sweden. The patients closest relative (only daughter) approved the case study in writing and the patient approved it orally previous to his demise. The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required from the participants or the participants’ legal guardians/next of kin because Please see the previous answer (8). Written informed consent was not obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article because The patient provided oral consent to publish his case as a case report prior to his demise. His closest relative (the only daughter) was present at the time and has provided written informed consent in the patients absence. Written informed consent was obtained from the participant/patient(s) for the publication of this case report.
Author contributions
LC: Data curation, Formal Analysis, Investigation, Methodology, Writing – original draft, Writing – review & editing. LS: Formal Analysis, Investigation, Supervision, Validation, Writing – original draft, Writing – review & editing. BS: Data curation, Visualization, Writing – original draft, Writing – review & editing. SD: Conceptualization, Data curation, Funding acquisition, Investigation, Supervision, Visualization, Writing – original draft, Writing – review & editing.
Funding
The author(s) declare that no financial support was received for the research, and/or publication of this article.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Summary
Keywords
platelet-derived growth factor receptor beta-rearranged myeloid/lymphoid neoplasms, treatment resistance, imatinib, case report, acute myeloid leukemia
Citation
Cavelier L, Saft L, Sander B and Deneberg S (2025) Resistance to imatinib in a ETV6::PDGFRB rearranged myeloid/lymphoid neoplasm with high-risk mutations: a case report. Front. Oncol. 15:1611747. doi: 10.3389/fonc.2025.1611747
Received
14 April 2025
Accepted
21 October 2025
Published
07 November 2025
Volume
15 - 2025
Edited by
Anjali Mishra, Sidney Kimmel Cancer Center, United States
Reviewed by
Nicholas Cross, University of Southampton, United Kingdom
Liqiong Liu, Affiliated Nanshan Hospital of Shenzhen University, China
Updates
Copyright
© 2025 Cavelier, Saft, Sander and Deneberg.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Stefan Deneberg, stefan.deneberg@regionstockholm.se
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.