Concurrent NPM1::CCDC28A and BCR::ABL1 fusions in extramedullary blast crisis of chronic myeloid leukemia: A case report and literature review

Extramedullary blast crisis (EMBC) is rare, clinically heterogeneous, and often misdiagnosed because routine histology may be inconclusive. We describe a CML-EMBC case in which targeted RNA sequencing uncovered concurrent NPM1::CCDC28A and BCR::ABL1 fusions, refining the diagnosis and suggesting a novel molecular subset.Clinical, laboratory, imaging, histopathology, and outcome data of a 26-year-old man were reviewed retrospectively. Targeted RNA-seq was performed on formalin-fixed, paraffin-embedded sacrococcygeal tissue. PubMed and Google Scholar were searched with "NPM1," "CCDC28A," "fusion," "CML," "myeloid sarcoma," and "extramedullary blast crisis" to contextualise NPM1 rearrangements. The patient achieved deep molecular remission of chronic-phase CML (BCR::ABL1 0.0058% International Scale) while receiving flumatinib, yet developed a painful sacrococcygeal mass. Initial biopsy suggested an undifferentiated small round-cell sarcoma. RNA-seq revealed dual NPM1::CCDC28A and BCR::ABL1 fusions, prompting reclassification as granulocytic sarcoma-type CML-EMBC. Intermediate-dose cytarabine with continued tyrosine-kinase inhibition produced marked metabolic regression on PET-CT, and the patient has been bridged to allogeneic hematopoietic stem-cell transplantation. Literature review uncovered only sporadic reports of NPM1::CCDC28A; experimental data indicate that the fusion up-regulates HOX clusters similarly to mutant NPM1, facilitating leukemogenesis and extramedullary dissemination. Solitary tumours in CML patients who are in marrow remission should prompt suspicion for EMBC. When morphology is ambiguous, integrating molecular pathology, particularly targeted RNA-seq, can confirm myeloid lineage and uncover disease-relevant alterations. Co-occurrence of BCR::ABL1 and NPM1::CCDC28A may delineate a distinct EMBC subset with prognostic and therapeutic relevance. Prospective studies are required to clarify the fusion's pathogenic role and biomarker potential.