Reassessing bone marrow staging practices in limited-stage follicular lymphoma in the PET era

Abstract Introduction: Bone marrow (BM) involvement is present in approximately 50% of patients with follicular lymphoma (FL) and is associated with an inferior prognosis. Although BM aspiration and biopsy (A&B) have traditionally been recommended as staging investigations for FL, emerging evidence indicates that routine BM A&B at diagnosis or follow-up rarely affects clinical management and may be safely omitted for most patients with advanced-stage disease. Nevertheless, international guidelines continue to recommend BM sampling alongside F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) imaging to confirm cases of suspected limited-stage FL, particularly when curative-intent treatment with radiation therapy (RT) is being considered. However, the diagnostic utility of routine BM A&B in patients with suspected limited-stage FL as defined by PET remains uncertain. Methods: This retrospective population-based study included consecutive patients with PET-defined limited-stage FL who underwent BM sampling in Alberta, Canada between 2017 and 2023. Provincial guidelines recommended BM A&B for confirming limited-stage disease or investigating unexplained cytopenias, although this decision was ultimately at the discretion of the treating physician. The primary objective of this study was to determine the diagnostic utility of BM A&B in the study population. Results: Among 1,209 patients diagnosed with FL during the study period, 295 (24%) presented with radiographically-defined limited-stage disease by PET (n=114) or CT (n=181). A staging BM A&B was performed in only 84 (28%) of suspected limited-stage cases, including 50/113 (44%) patients who received RT, largely reflecting variation in practice between physicians. A total of 60 patients with PET-defined limited-stage FL underwent BM aspiration (n=59) and/or biopsy (n=60) and were included in this study. The median age of these patients was 65 years (range 31-82). The PET-defined Lugano disease stage was I in 31 (52%), IE in 5 (8%), and II in 24 (40%) patients. Treatment strategies included 24-30 Gray of RT (n=44), active surveillance (n=11), chemoimmunotherapy (n=4), or rituximab monotherapy (n=1). The results of the BM A&B were negative for FL in 56 (93%) cases, including 3 (5%) patients who exhibited an unrelated low-level B-cell clone (e.g. monoclonal B-cell lymphocytosis) detected by flow cytometry of the BM aspirate. Only 4 (6%) patients had FL detected on BM aspirate (n=1), biopsy (n=1), or both (n=2), despite having no evidence of marrow involvement on PET. Notably, none of these 4 patients displayed abnormalities in routine bloodwork, including CBC, LDH, β2-microglobulin, or SPEP, other than a single patient with a monoclonal protein related to a plasma cell neoplasm. The calculated number of patients required to undergo BM A&B to identify one case of marrow involvement with FL was 15. Importantly, the positive findings from the BM A&B did not alter the clinical management of any of the 4 patients; specifically, 2 patients received RT despite their low-level BM involvement, while 2 patients were not planned to receive RT from the outset due to a concurrent plasma cell neoplasm or disease extending beyond a single radiation field. Conclusions: Despite provincial and international guidelines recommending staging BM A&B to confirm suspected cases of limited-stage FL, the findings of this study indicate that BM sampling is widely perceived by physicians to have limited value and is frequently omitted in routine clinical practice, including in over 50% of patients treated with curative-intent RT. Additionally, among the 60 patients in this cohort with PET-defined limited-stage disease, BM A&B identified unexpected marrow involvement in only 1 in 15 (6%) patients and did not lead to a change in clinical management for any individual. These results call into question the utility of routine BM A&B in PET-defined limited-stage FL, particularly given the associated healthcare costs, resource demands, and discomfort of this invasive procedure. These findings may assist patients and physicians in engaging in informed discussions regarding the utility of BM sampling in this setting.