A 53-year-old male from Samandağ presented in early 2024 with progressive anemia, fatigue, and splenomegaly. Laboratory evaluation revealed pancytopenia with atypical lymphoid cells on peripheral smear and mildly elevated LDH. Physical examination confirmed palpable splenomegaly without lymphadenopathy.

Bone marrow biopsy performed on August 5, 2024, demonstrated classic hairy cell leukemia with characteristic immunophenotype: CD20+, CD103+, CD25+, Annexin A1+, TRAP+ with negative CD3, CD5, CD23, and CD34. Flow cytometry confirmed 8-10% clonal B-cell population with CD103+, CD25+, CD11c+ expression and aberrant kappa/lambda ratio, establishing HCL diagnosis.

Treatment was initiated with rituximab plus cladribine combination therapy along with G-CSF support and prophylactic antifungal therapy. Post-treatment evaluation on September 17, 2024, demonstrated exceptional response with complete disappearance of all HCL-specific phenotypic markers (0% residual disease) and minimal CD20+ cells (1.8%) reflecting rituximab effect. Bone marrow biopsy confirmed morphologic remission. Imaging showed dramatic spleen size reduction from 22 cm to 14 cm with regression of retroperitoneal lymphadenopathy.

Eight months later, in April-May 2025, the patient developed B-symptoms including persistent fever, weight loss, and dyspnea. HRCT and PET-CT revealed concerning new findings: left lower lobe pulmonary lesion with intense metabolic activity (SUVmax: 34.07), mediastinal involvement (SUVmax: 16.13), and new abdominal lymphadenopathy (SUVmax: 7-10).

Lung biopsy performed on June 16, 2025, revealed diffuse large B-cell lymphoma with non-germinal center phenotype: CD20+, PAX5+, Bcl-6+, MUM1+ with extensive Bcl-2 expression (95%) and low c-Myc expression (10%), confirming systemic DLBCL diagnosis.

Standard R-CHOP chemotherapy (six cycles) was administered from July through November 2025. The patient tolerated treatment well with only mild neutropenia as significant toxicity. Post-treatment PET-CT demonstrated complete metabolic remission with disappearance of all metabolically active lesions, achieving Deauville score ≤2.

At current follow-up, the patient remains in complete remission from both malignancies with excellent performance status and no evidence of disease recurrence.

This case represents a rare scenario of sequential B-cell malignancies with successful treatment outcomes for both conditions. The eight-month interval between HCL remission and DLBCL development, combined with distinct immunophenotypes, suggests either treatment-related secondary malignancy or activation of a dormant malignant clone rather than clonal evolution.

The non-germinal center DLBCL phenotype with high Bcl-2 expression indicates aggressive biology requiring prompt intervention. The excellent response to standard R-CHOP therapy demonstrates that DLBCL following HCL treatment responds comparably to de novo DLBCL, supporting conventional treatment approaches.

This case emphasizes the critical importance of long-term surveillance in HCL patients, as secondary malignancies can develop despite achieving complete remission. The development of new constitutional symptoms or imaging abnormalities warrants thorough evaluation for secondary malignancies.

Sequential development of DLBCL following successful HCL treatment represents a rare but treatable clinical scenario. Standard DLBCL therapy remains highly effective in this setting, achieving complete remission comparable to de novo cases. This case underscores the importance of continued surveillance in HCL survivors and demonstrates excellent outcomes with appropriate treatment of secondary lymphomas.