From unexplained cytopenias to clonality: Diagnosing T-cell large granular lymphocytic leukemia in rheumatoid arthritis via integrated molecular profiling

Abstract Introduction: Persistent cytopenias in patients with rheumatoid arthritis (RA) pose significant diagnostic challenges and are frequently attributed to medication side effects or Felty syndrome (FS). However, in rare cases, they may reflect an underlying lymphoproliferative disorder such as T-cell large granular lymphocytic (T-LGL) leukemia. This indolent mature T-cell neoplasm, driven by clonal expansion of cytotoxic CD8+ T cells, is commonly associated with autoimmune conditions. Timely recognition requires a high index of clinical suspicion, as FS remains a diagnosis of exclusion. We present a diagnostically complex case of T-LGL leukemia in the setting of longstanding RA, initially misattributed to hydroxychloroquine-induced cytopenia. Case Presentation: A 71-year-old man with seropositive, erosive RA on long-term hydroxychloroquine therapy presented with worsening dyspnea and pancytopenia: ANC 0.02 × 10⁹/L, Hgb 8.4 g/dL, WBC 1.84 × 10³/µL, and Plt 76 × 10⁹/L. He had a >10-year history of intermittent cytopenias, consistently attributed to medication side effects. RF >350 IU/mL and CCP IgG >250 U/mL were markedly elevated, indicating poorly controlled RA. Abdominal imaging demonstrated splenomegaly, raising concern for FS. Diagnostic Workup: Peripheral smear revealed leukopenia and anemia with an increased CD8+ T-cell population (33.1%), concerning for clonal expansion. Bone marrow biopsy showed hypercellularity with increased CD8+ T-cell infiltrates. However, bone marrow flow cytometry for TRBC1 expression indicated a polyclonal T-cell population (23.6% of lymphocytes), mitigating against a T-cell lymphoproliferative disorder. Due to high clinical suspicion, additional molecular studies were pursued. Conventional cytogenetics showed isolated loss of the Y chromosome (46, X-Y[3]/46,XY[17]), an age-related finding. FISH panel for MDS-associated abnormalities was unremarkable. Next-generation sequencing revealed a STAT3 p.Y640F mutation, present in 40–43% of T-LGL leukemia cases, and two TNFAIP3 mutations (E451*, A501Pfs*32), associated with loss-of-function and reported in ~8% of T-LGL cases. Clonal TCRG gene rearrangement was also detected, confirming the presence of a clonal T-cell population. These findings established the diagnosis of T-LGL leukemia in the context of active RA. Clinical Course and Outcome: Hydroxychloroquine was discontinued on admission. The patient was started on prednisone 60 mg daily for 7 days, leading to a prompt rise in ANC to 1.4 × 10⁹/L, followed by tapering. Blood counts had normalized at discharge: ANC 2.1 × 10⁹/L, Hgb 10.8 g/dL, Plt 142 × 10⁹/L. Plans were made to initiate low-dose methotrexate for treatment of both T-LGL and RA. Discussion: This case underscores the diagnostic complexity of persistent cytopenias in RA, especially when attributed to drug-induced myelosuppression or FS. In this case, the clinical suspicion for clonal lymphoproliferative disease remained high despite inconclusive flow cytometry, prompting further molecular testing that ultimately confirmed the diagnosis. An integrated diagnostic approach that includes molecular and clonality testing can help distinguish T-LGL leukemia from reactive or drug-induced cytopenias, enabling timely and targeted immunosuppressive therapy.