Therapy-related chronic lymphocytic leukemia/small lymphocytic lymphoma (t-CLL/SLL) is uncommon compared with therapy-related AML/MDS. We report a breast-cancer survivor who evolved from a CD5-negative low-grade B-cell lymphoproliferative disorder (LPD) to classical CLL/SLL with unmutated IGHV, underscoring why targeted BTK inhibition may supersede chemo-immunotherapy in this setting.

Single-patient case review of prospectively collected data. We extracted longitudinal clinical, imaging (PET-CT), bone-marrow histology, multiparameter flow cytometry, and cytogenetics (FISH, IGHV mutation testing). Treatment decisions were individualized by a multidisciplinary team.

A 1959-born woman had invasive ductal breast carcinoma (2009) treated with adriamycin–cyclophosphamide, weekly paclitaxel, and radiotherapy, achieving long-term remission. In 2018 bone marrow was normal; in 2019 splenectomy for progressive splenomegaly revealed florid follicular hyperplasia. Between 2020–2022, bone-marrow biopsies showed a low-grade B-cell LPD (CD20⁺, CD5–/CD23–/CD10–), managed with rituximab–bendamustine (8 cycles), yielding metabolic complete remission.

In 2025 she re-presented with profound fatigue and anemia. Labs showed marked lymphocytosis (WBC 46 × 10⁹/L), hemoglobin severely reduced, and PET-CT consistent with medullary disease. Bone marrow showed 40–50% intertrabecular lymphoid infiltration. Flow cytometry now demonstrated classical CLL/SLL (CD19⁺, CD20⁺, CD5⁺, CD23⁺, κ-restriction). Molecular work-up: IGHV unmutated; FISH: monoallelic del(13q); del(17p)/del(11q) negative. Given prior anthracycline exposure/radiation and the high-risk biology conferred by unmutated IGHV despite isolated 13q deletion, the tumor board selected acalabrutinib plus rituximab rather than re-exposure to chemo-immunotherapy. Transfusion support and infection prophylaxis accompanied therapy planning.

This case is notable for: (i) Therapy-related CLL/SLL emerging years after breast-cancer treatment—an under-recognized survivorship risk; (ii) Phenotypic evolution from an initially CD5-negative indolent B-cell LPD to typical CD5⁺/CD23⁺ CLL/SLL, highlighting clonal drift and the need for repeat immunophenotyping at relapse; (iii) Risk adjudication where unmutated IGHV outweighs the generally favorable isolated 13q deletion, steering first-line choice away from bendamustine-rituximab toward BTK-inhibitor–based therapy; and (iv) pragmatic considerations in a previously anthracycline-exposed patient, favoring targeted agents for efficacy and tolerability. Educationally, the case adds to scarce real-world documentation of t-CLL, illustrates immunophenotypic switch over time, and provides a clear management rationale aligned with modern risk biology.

In this therapy-related CLL/SLL with unmutated IGHV and prior breast-cancer treatment, acalabrutinib + rituximab was selected as the preferred front-line strategy over chemo-immunotherapy. The case emphasizes the importance of serial phenotyping and genomics to detect evolution and to personalize therapy in cancer survivorship.