Isolated Neutropenia as a Sentinel of High-Risk Clonal Evolution: A Case of Acute Myeloid Leukemia-Myelodysplasia Related Changes harboring TP53 deletion via Isochromosome 17q and deletion 20q mimicking Myeloproliferative Neoplasm

Introduction/Background/Significance: Isolated neutropenia is often dismissed as benign, particularly in elderly patients where it is typically attributed to age-related marrow changes, medications, nutritional deficiencies, or immune-mediated processes. However, when persistent and unexplained, it may represent early clinical footprint of clonal hematopoiesis or a precursor to myeloid malignancy. While acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) typically arises from antecedent cytopenias or myelodysplastic syndrome (MDS), its presentation with isolated neutropenia and myeloproliferative neoplasia (MPN)-like features is exceedingly rare and diagnostically challenging. This case underscores the diagnostic complexity of such presentations and highlights the urgent need to re-evaluate conservative approaches in favor of a more risk-adapted strategy—especially in resource-limited setting.

Materials and Methods/Case Presentation/Objective: A 69-year-old woman initially presented with isolated mild neutropenia and occasional easy bruising. Aside from a low absolute neutrophil count (ANC 1188/μL), her complete blood count and coagulation profile were within normal limits. Over the next several months, neutropenia persisted without other cytopenias or constitutional symptoms. In the absence of transfusion requirements or overt clinical decline, bone marrow biopsy was deferred—a decision influenced by clinical stability and limited diagnostic access. This period of observation continued despite subtle hematologic changes in the white blood cell count. Six months later, she presented with new-onset abdominal discomfort, anorexia, and weakness. Physical examination revealed massive splenomegaly measuring 14cm below subcostal margin, and extending beyond midline.

Results/Description/Main Outcome Measures: Laboratory workup showed leukocytosis with marked left shift, anemia, thrombocytopenia, and nucleated red blood cells—findings consistent with a leukoerythroblastic reaction. Bone marrow aspiration revealed hypercellular marrow with >40% myeloblasts, multilineage dysplasia, and mild reticulin fibrosis. Cytogenetic analysis demonstrated the rare coexistence of isochromosome 17q and deletion of chromosome 20q. JAK2 mutation and BCR-ABL FISH were negative. Fluorescence in situ hybridization (FISH) detected TP53 deletion in 81.91% of nuclei, establishing the diagnosis of acute myeloid leukemia with myelodysplasia-related changes (AML-MRC), harboring high-risk cytogenetic abnormalities.

The patient was initiated on fixed-dose azacitidine and low-dose venetoclax. Despite dose adjustments due to hematologic toxicity, day 28 bone marrow examination showed minimal residual disease. Repeat cytogenetic studies, however, demonstrated no metaphase growth, supporting continuation of treatment. She is currently on her 3rd cycle of treatment.

Conclusions: This case exemplifies the clonal dynamics of aging hematopoiesis—demonstrating that isolated neutropenia, even in the absence of other cytopenias, can represent the earliest clinical footprint of high-risk myeloid neoplasia. The patient's aggressive evolution to AML-MRC with rare coexistent i(17q), del(20q), and TP53 deletion highlights the malignant potential of what is perceived as a benign finding.

Notably, in well-resourced settings, prevailing guidelines recommend conservative management and serial CBC monitoring for isolated neutropenia without overt dysplasia, delaying bone marrow evaluation until additional cytopenias or clinical deterioration emerge.

This case challenges that paradigm and calls for a re-evaluation of current diagnostic thresholds—particularly in older adults—regardless of setting. In resource-limited environments, where access to advanced diagnostics is delayed or unavailable, this inertia may be even more pronounced. Our findings argue for a more vigilant, risk-adapted approach to persistent neutropenia, recognizing it as a possible sentinel of clonal evolution with potential for early interception before leukemic transformation.