Histologic Transformation in Follicular Lymphoma Could Signal Poor Outcomes

Patients with follicular lymphoma that responded to rituximab but whose disease later underwent histologic transformation-a series of biologic events that occur before a patient progresses to aggressive lymphoma-were found to have worse outcomes and may benefit from autologous stem cell transplantation (ASCT), according to the results of a study published in the Journal of Clinical Oncology.

“The cumulative incidence was significant within the first year and then diminished compared with the incidence of follicular lymphoma relapse, which continuously increased,” wrote researchers led by Clémentine Sarkozy, of Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, France. “Management after the first progression indicates that there may be a benefit from ASCT for patients with histologic transformation, whereas this strategy was not associated with a better overall survival rate for patients with persistent follicular lymphoma histology at first progression.”

This study included patients taken from the PRIMA trial, a randomized phase III trial evaluating the use of maintenance rituximab in symptomatic patients with follicular lymphoma treated with induction rituximab. Follow-up out to 6 years showed an improvement in progression-free but not overall survival with maintenance therapy.

After 6-years of follow-up, 463 patients in the trial had disease progression and 194 had histologic documentation. Of those with documentation, 40 patients had histologic transformation and 154 had untransformed follicular lymphoma (median time to recurrence, 9.6 months vs 22.8 months; P = .018).

More than half of the histologic transformations found were identified during biopsies performed during the first year of follow-up. Overall, 37% of the biopsies performed in the first year had histologic transformation.

“Interestingly, more than half of the transformations were documented during the first year after induction, which represents a third of the biopsies performed during that period vs 11.8% being documented during the next 4 years,” the researchers wrote. “The recurrence kinetic strengthens the importance of performing a biopsy for any relapse within the first year of follow-up.”

The researchers identified several risk factors associated with histologic transformation including altered performance status, anemia, high lactate dehydrogenase level, B symptoms, histologic grade 3a, and high Follicular Lymphoma International Prognostic Index (FLIPI) scores at diagnosis. However, no link between a patient’s response to rituximab and histologic transformation was found.

Compared with patients with follicular lymphoma histology at recurrence, those patients with histologic transformation were less likely to achieve a complete response with salvage therapy (67.4% vs 50.3%; P = .03), and significantly more of these patients had progressive disease (28.2% vs 9.6%; P < .001).

The median overall survival from the time from recurrence was 3.8 years for patients with histologic transformation compared with 6.4 years for those with follicular lymphoma histology at recurrence (hazard ratio, 3.9 [95% CI, 2.2–6.9]; P < .001).

“Importantly, prolonged treatment with rituximab (ie, maintenance after induction regimen) did not have an impact on the overall survival of the histologic transformation patients after relapse,” the researchers wrote.

After salvage therapy, 17 of the patients with histologic transformation underwent an ASCT. Compared with patients who did not undergo transplant, these 17 patients had improved overall survival. In contrast, transplant had no effect on survival among those patients with recurrence and follicular lymphoma histology.

“As shown here, when achievable, ASCT seems to improve the outcomes of histologic transformation patients; however, this result was not observed in patients with persistent follicular lymphoma histology at progression,” the researchers wrote.

In an editorial that accompanied the study, Brian K. Link, MD, of the University of Iowa, wrote that Sarkozy and colleagues published a well-designed and executed clinical trial, but he added that the advantages of using data from the PRIMA study also come with a price.

“The findings of this study are reliably attributable only to the selected cohort of patients with follicular lymphoma-those who respond to immunochemotherapy for initial management-which represents about half of all patients with follicular lymphoma in the United States, and the investigators only track patients until first progression, thereby leaving some uncertainty about lifelong transformation events,” Link wrote.