Bone marrow biopsy (BMB) provided little information for response assessment in clinical trials of follicular lymphoma (FL) and should be eliminated from clinical trial requirements and diagnostic guidelines, authors of a large retrospective analysis concluded.
Fewer than 1% of 580 patients had a positive baseline BMB, complete radiologic response, and subsequent positive biopsy after treatment. Landmark survival analyses showed no difference in progression-free survival (PFS) or overall survival (OS) between patients with or without a positive BMB at baseline. A sensitivity analysis involving 385 patients showed that 1.3% had biopsies that affected response assessment.
“Therefore, BMB were irrelevant to response in 99% of subjects,” reported Sarah C. Rutherford, MD, of Weill Cornell Medicine in New York City, and co-authors in the Journal of Clinical Oncology.
“We conclude that BMB add little value to response assessment in subjects with FL treated on clinical trials and we recommend eliminating BMB from clinical trial requirements. BMB should also be removed from diagnostic guidelines for FL except in scenarios in which it may change management including confirmation of limited stage and assessment of cytopenias. This would reduce cost, patient discomfort, resource utilization, and potentially remove a barrier to trial enrollment,” they continued.
The study provided new information about the value of BMB in FL, but the analysis has several limitations, according to Paolo Strati, MD, of the University of Texas MD Anderson Cancer Center in Houston.
“In first place, patients enrolled in clinical trials, as in this study, may not be representative of real-world practice,” Strati, who was not involved in the study, told MedPage Today. “In second place, the level of sensitivity of techniques employed to detect bone marrow involvement has changed over time, and the rate of falsely negative cases across trials run at very different times may be very variable. Also the criteria used to determine radiological response have changed over time, and half of the trials included in this study used CT-based criteria, which may have underestimated the rate of patients in complete remission.”
“Finally, this study does not address the interventional implications of positive bone marrow biopsies at the end of treatment, which would be the need for maintenance therapy,” Strati added. “The FOLL12 study has recently shown, in a randomized controlled setting, that patients in complete remission but with positive minimal residual disease benefit from maintenance. And the latter may be represented by positive bone marrow disease, when more sensitive techniques are employed.”
In contrast to aggressive B-cell lymphomas, wherein bone marrow involvement can be reliably determined by noninvasive means, imaging is not sufficient for FL and other indolent lymphomas, he said. “Universal agreement” exists about the need for BMB in early FL but not for advanced disease. The adequacy of flow cytometry to assess bone marrow involvement also remains unresolved.
“While some clinicians may decide to modify or confirm their current practice based on findings from this paper, prospective randomized trials are probably needed to confirm these findings and to make sure that no harm is done to patients by omitting bone marrow biopsies,” he noted.
Rutherford and co-authors reported findings from an analysis of patients enrolled in seven cooperative-group trials of previously untreated FL from 2008 to 2016. The 580 patients included in the analysis had BMB at baseline and during response assessment, as well as best response by imaging. The authors also investigated whether cytopenias were associated with positive findings on baseline BMB, using baseline blood counts from five of the seven trials.
The data showed that 55% of the patients had positive baseline BMB. The analysis of blood counts showed no association between cytopenias at baseline and a positive BMB.
Investigators found that five of the 580 patients had a positive baseline BMB, complete response to treatment on imaging, and a subsequent positive BMB (P<0.0001). Among 344 patients with a complete response on imaging after treatment, five had BMB that affected response assessment.
Rutherford and colleagues also performed landmark survival analyses for 187 patients who had a complete response on imaging at the end of treatment. Neither PFS nor OS differed significantly between 47 patients who had a negative BMB within 60 days of complete response and 140 patients who did not have a repeat BMB within 60 days of imaging (HR 1.10, 95% CI 0.62-1.94 and HR 0.59, 95% CI 0.23-1.53).
Investigators performed a sensitivity analysis using data on 385 patients from a phase III trial of rituximab (Rituxan)-based therapy in low-burden FL. The analysis showed that five patients had BMB that affected response assessment.
“Based upon these results, BMB should be eliminated from diagnostic guidelines in FL and no longer incorporated as response assessments in clinical trials for patients with FL,” the authors concluded. “This strategy is consistent with initiatives including the American Board of Internal Medicine Foundation’s Choosing Wisely Campaign, as well as joint efforts by ASCO [American Society of Clinical Oncology] and Friends of Cancer Research to maximize value of medical interventions and modernize eligibility criteria and therefore make clinical care and trial enrollment more patient focused.”