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Poor outcomes for histologically transformed follicular lymphoma warrant use of salvage HSCT
Patients with follicular lymphoma who experienced histologic transformation after immunochemotherapy experienced poor outcomes and may be candidates for intensive salvage hematopoietic stem cell transplantation, according to analysis of a randomized phase 3 trial.
“Histologic transformation is the culmination of a series of biologic events leading to aggressive lymphoma; it is histologically defined by the documentation of increased numbers of large cells that eliminate the follicular structure, the most frequent manifestation being diffuse large B-cell lymphoma,” Gilles Salles, MD, PhD, professor of medicine at Centre Hospitalier Lyon Sud in France, and colleagues wrote. “The overall role of transformation reported in patients with follicular lymphoma ranges from 16% to 60%, depending on the number of serial biopsies and the duration of follow-up in the different historical series.”
Brian K. Link
Salles and colleagues sought to evaluate outcomes of patients with histologic transformation who had previously responded to immunochemotherapy.
They accessed data from the Primary Rituxumab and Maintenance (PRIMA) trial, in which 1,018 patients with follicular lymphoma were assigned to induction chemotherapy with rituximab (Rituxan; Genentech, Biogen). After a median follow-up of 73 months, outcomes showed maintenance rituximab vs. no treatment significantly extended PFS, but not OS.
At the end of the follow-up period, 463 patients had experienced disease progression, 194 of whom (42%) underwent biopsy at the time of first progression.
Biopsies confirmed histologic transformation in 40 patients (20.6%); the remaining 154 patients had untransformed follicular lymphoma.
In 66 biopsies that occurred during the first year of follow-up, 24 (36.4%) showed histologic transformation.
Of the total documented cases of transformation, 58% occurred during the first year of follow-up, with a shorter median time to progression (9.7 months vs. 22.8 months; P = .018).
At the end of follow-up, 4.1% of patients had confirmed histologic transformation compared with a 15.9% documented incidence of progression with follicular lymphoma histology. The researchers cautioned that these numbers are not representative of patients who did not undergo biopsy.
Risk factors that may predict histologic transformation include altered performance status, anemia, high lactate dehydrogenase level, a histologic grade of 3a, the presence of “B” symptoms and high Follicular Lymphoma International Prognostic Index scores at the time of diagnosis.
The researchers observed similar responses to the induction regimen among the histologic transformation and follicular lymphoma groups for complete response (42.5% vs. 42.2%), unconfirmed complete response (30% vs. 31.6%) and partial response (27.5% vs. 25.3%).
All but one patient (97.5%) with histologic transformation received therapy at first recurrence, compared with 87.7% (n = 135) of patients with recurrent follicular lymphoma.
Patients with histologic transformation had a significantly lower likelihood of achieving a complete response or unconfirmed complete response (50.3% vs. 67.4%; P = .03), and were more likely to experience progressive disease during salvage therapy (28.2% vs. 9.6%; P < .001).
These patients also had a shorter OS interval from recurrence (median, 3.8 years vs. 6.4 years; HR = 3.9; 95% CI, 2.2-6.9).
Seventeen patients with histologic transformation proceeded to autologous hematopoietic stem cell transplantation with high-dose consolidation chemotherapy. These patients achieved better survival outcomes than patients who did not undergo HSCT (median OS, not reached vs. 1.7 years).
Patients without histologic confirmation who underwent HSCT did not have significant OS improvements over those who did not undergo HSCT (median OS, 6.4 years vs. not reached).
The researchers acknowledged that they only analyzed patients from the PRIMA trial who achieved a response after induction therapy, which may have contributed to selection bias and the exclusion of biopsied patients with histologic transformation.
“Our results further emphasize the need to perform a new biopsy at the time of first progression in patients with follicular lymphoma,” Salles and colleagues wrote. “Although intensive treatment may represent a good option for younger patients and those who are eligible for autologous HSCT, the remaining population still represents a group of patients with an unmet medical need.”
More research into the molecular nature of follicular lymphoma is needed to improve outcomes and understanding of the disease, Brian K. Link, MD, professor of internal medicine at University of Iowa Carver College of Medicine, wrote in an accompanying editorial.
“Future opportunities to reduce the impact of transformed follicular lymphoma on patients likely will require more than just routine clinical observations such as those the above studies largely rely upon,” Link wrote. “Future observational studies and clever ancillary analyses of prospective clinical trials that study transformed lymphoma will hopefully replace variables such as anthracyclines, the Follicular Lymphoma International Prognostic Index, lactate dehydrogenase and autologous HSCT with promising new variables such as IRF-4, miR-31, bcl-2, pluripotency and nuclear factor kappa B pathway genes, or new therapies that target these variables.” – by Cameron Kelsall
Disclosure: Salles reports institutional research funding and travel expenses from Genentech; honoraria from Amgen, Genentech and Mundipharma; and consultant roles with Amgen, Celgene, Genentech, Gilead Sciences, Janssen, Mundipharma and Novartis. Please see the full study for a list of all other researchers’ relevant financial disclosures. Link reports institutional research funding from and/or consultant roles with AbbVie, Dynavax Technologies, Genentech, Gilead Sciences, Kite Pharma, Millennium, Pharmacyclics, Sandoz and Seattle Genetics.