Follicular lymphoma with histologic transformation may merit ASCT

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Better prognostic measures are needed

In just 3 years, prospective observational studies and [this] clever ancillary analysis of a prospective clinical trial have better informed the lymphoma community about the expected incidence and timing of transformation in patients with follicular lymphoma after being treated with modern management strategies. But we are still limited by clumsy predictive tools for identifying patients at highest risk. Deeper understanding of biologic and genetic factors of FL subclonal populations as well as the tumor microenvironment will allow for more precise identification of patients truly at risk and potentially will provide actionable targets for abrogating that risk. Future [studies of] transformed lymphoma will hopefully replace variables such as anthracyclines, the Follicular Lymphoma International Prognostic Index, lactate dehydrogenase, and ASCT with promising new variables such as IRF-4, miR-31, bcl-2, pleuripotency, and nuclear factor kappa B pathway genes or new therapies that target these variables. Future analyses should not simply prognosticate who is at risk for transformation, but should predict a specific intervention to either prevent or treat such an event.

Dr. Brian K. Link is at the University of Iowa, Iowa City. He reported ties to AbbVie, Gilead Sciences, Genentech, Sandoz, Pharmacyclics, Millennium Pharmaceuticals, Genentech, Kite Pharma, Seattle Genetics, and Dynavax Technologies. These comments are from his editorial accompanying the report (J Clin Oncol. 2016 Jun. doi: 10.1200/JCO.2016.67.4234).



Among patients with high tumor burden follicular lymphoma (FL) that responded to rituximab chemotherapy but then underwent histologic transformation, median overall survival was not reached when patients received autologous stem cell transplantation (ASCT), but was only 1.7 years otherwise, based on results of an ancillary study of a clinical trial.

In contrast, ASCT did not affect overall survival when patients progressed to untransformed FL, said Dr. Clémentine Sarkozy of Centre Hospitalier Lyon-Sud in Pierre Bénite, France, and her associates. Fully 58% of histologic transformations occurred in the first year of follow-up, highlighting “the necessity for biopsy at the first recurrence of FL,” they wrote online June 13 in the Journal of Clinical Oncology.

Histologic transformation in FL signifies progression to aggressive lymphoma. Studies of histologic transformation and subsequent overall survival in the rituximab era have been retrospective, with variable patient populations and initial management regimens, according to the investigators. Therefore, they followed 1,018 patients from the multicenter, randomized, phase III PRIMA (Primary Rituximab and Maintenance) trial, which evaluated maintenance rituximab therapy among patients with symptomatic FL who had responded to induction chemotherapy plus rituximab (J Clin Oncol. 2016 Jun. doi: 10.1200/JCO.2015.65.7163).

A total of 463 patients (45.5%) experienced disease recurrence or progression, and 194 (42%) were biopsied over a median follow-up time of 6 years. A total of 40 (20.6%) biopsies showed histologic transformation, while 154 (79.4%) had untransformed FL. Median time to recurrence was 9.6 months for patients with histologic transformation and 22.8 months for patients with untransformed FL (P = .02). Median overall survival with histologic transformation was worse than with untransformed FL (3.8 years vs. 6.4 years; hazard ratio, 3.9; 95% confidence interval, 2.2-6.9; P = .001). Furthermore, among patients who progressed within 12 months, median overall survival with histologic transformation was 2 years, compared with 6.4 years for patients with untransformed FL (P = .007).

After salvage therapy, 17 (42%) patients with histologic transformation underwent consolidation with high-dose chemotherapy and ASCT. Median overall survival for these patients was not reached, versus 1.7 years when they did not undergo ASCT. In contrast, ASCT did not improve overall survival among patients with untransformed FL. Results were similar after excluding patients with early progression and patients who were older than 65 years, the investigators reported.

Risk factors for histologic transformation in the univariate analysis included performance status, anemia, high lactate dehydrogenase level, “B” symptoms, histologic grade 3a, and high Follicular Lymphoma International Prognostic Index scores at diagnosis. However, only Eastern Cooperative Oncology Group performance status of 2 to 4 (HR, 5.6; 95% CI, 1.7-17.7), and anemia (HR, 3.7; 95% CI, 1.4-9.7) remained significant in the multivariate analysis. Neither the choice of induction regimen nor the quality of response seemed to affect the likelihood of histologic transformation, and rituximab maintenance therapy did not seem to alter response to salvage treatment or survival after histologic transformation. By necessity, the study excluded patients who did not respond to initial immunochemotherapy, which could have limited the generalizability of the findings, the investigators noted.

The study was funded by Sandoz and Takeda Pharmaceuticals. Dr. Sarkozy disclosed research funding from Sandoz and Takeda Pharmaceuticals and honoraria from Gilead Sciences. Twelve coinvestigators also disclosed ties to Takeda and a number of other pharmaceutical companies. The other seven coinvestigators had no disclosures.

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