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Recent developments for patients with R/R FL
ing in mind our goals (prolongation of OS while preserv- ing quality of life) as well as patients’ own priorities, which might differ according to their age and their per- sonal history.8
Prognostic factors in patients with relapsed or refractory disease
While many discoveries have advanced our under- standing of the biology of FL, from patterns of gene muta- tions to the immune microenvironment, efforts to estab- lish biological parameters that predict individual patients’ outcomes have yielded few reliable indicators to date. The extreme clonal heterogeneity and diversification of FL over time point towards the frequent emergence of divergent clones originating from a common progenitor cell, rather than a selective, directional evolutionary process. One suspects that rapidly resistant and evolutive disease may accumulate alterations accounting for chemoresistance, but such alterations have yet to be iden- tified, aside from genetic changes occurring at the time of histological transformation.9,10
The Follicular Lymphoma International Prognostic Index (FLIPI) has been shown to be predictive of the out- come of patients at the time of first lymphoma progres- sion, and one usually assumes that clinical or biological features identified as prognostic factors at diagnosis may apply at the time of progression, although this has not been properly examined in the last decade in large series.11 The clinical impact of biological characteristics (genomic gain or loss, point mutations, immune and microenvironment changes) present at the time of disease progression has not been evaluated extensively, and rep- resents an area for further investigation, especially given the growing accessibility of therapies with distinct mech- anisms of action.
In recent years, attention has been drawn to the poor outcome of patients experiencing early disease progres- sion after their initial treatment. This has been well doc- umented after immunochemotherapy, with worse out- comes associated with disease progression within 12 or 24 months of initial treatment, described in shorthand as EFS12 or EFS24/POD24 disease, respectively.12,13 These findings have been reproduced in patients treated with rituximab as a single agent or in combination with lenalidomide, as well as in those having received radia- tion therapy for localized disease.14,15 Patients under observation for whom an event such as treatment initia- tion or clinical progression within 12 months occurs were similarly found to have a shorter survival.13 These find- ings have led some to advocate for more intensive thera- py (such as autologous stem cell transplant – ASCT) in patients with POD24 disease.16 However, most of these retrospective studies did not account for cases with histo- logical transformation, which are associated with poor outcomes.17 Notably, recent data indicate that a high pro- portion of patients with early progression present with histological transformation, with numbers ranging from 20 to 40% in patients having received CHOP (cyclophos- phamide, adriamycin, vincristine, prednisone) or CVP (cyclophosphamide, vincristine, prednisone) regimens (containing an anti-CD20 antibody) and from 20 to 75% of those having received bendamustine as a cytotoxic backbone.3,17
The precise evaluation of treatment efficacy in patients with POD24 is hampered by the lack of pre-treatment biopsy requirements in some studies, as well as subtle variations in the definition of POD24 disease in others. However, some new agents or combinations remain active in this setting, suggesting that new approaches might potentially circumvent this adverse disease feature.
Old tools remain useful in the relapsed and refractory settings
Repeating chemoimmunotherapy: still a standard of care
While promising targeted agents and immunotherapies are now available, treatments incorporating chemothera- py and anti-CD20 monoclonal antibodies remain a main- stay of treatment for the management of relapsed/refrac- tory FL. The choice of agents depends on patients’ initial therapy, with preference for a non-cross-resistant option.
We have the most robust clinical data to guide decision- making in patients who received first-line therapy with rituximab plus CHOP (R-CHOP) or rituximab plus CVP (R-CVP), wherein bendamustine-based therapy is most frequently utilized. The StiL study demonstrated superior progression-free survival (PFS) with rituximab plus ben- damustine (B-R) over rituximab plus fludarabine in a ran- domized study of relapsed/refractory indolent non- Hodgkin lymphoma, with a PFS of 34.2 months for B-R versus 11.7 months for rituximab plus fludarabine, and an OS benefit with B-R.18 In this study, 50% of patients had FL, with the majority having been previously treated with first-line CHOP-based therapy. The GADOLIN phase III clinical trial established the efficacy of obinutuzumab plus bendamustine with obinutuzumab maintenance as another second-line option in patients with rituximab- refractory FL, defined as primary resistance or relapse within 6 months of rituximab-containing therapy. Compared to bendamustine alone, obinutuzumab plus bendamustine and obinutuzumab maintenance demon- strated PFS and OS benefits in the overall cohort of non- Hodgkin lymphoma patients and in the subset with FL.19,20 Of note, bendamustine regimens were associated with prolonged T-cell depletion in other studies, and precau- tions, including anti-microbial prophylaxis, should be considered.21
Important gaps remain in our knowledge regarding sec- ond-line therapy. In rituximab-sensitive individuals, ritux- imab and obinutuzumab have not been compared direct- ly. While GADOLIN investigated rituximab-refractory disease, the lack of rituximab in the control arm also raises questions about whether obinutuzumab is truly superior to rituximab in disease defined as rituximab-refractory.
Treatment after first-line bendamustine-based therapy is poorly established as there are no dedicated trials eval- uating this population. Large long-term outcome studies in FL have included very few patients receiving first-line B-R, likely representing its more recent adoption.22,23 Convention has been to use non-cross-resistant chemotherapy, such as rituximab or obinutuzumab (R/O) with CHOP or R/O-CVP. One small retrospective study of bendamustine-based re-challenge in patients with chronic lymphocytic leukemia or lymphoma showed a response rate of 78% with B-R in lymphoma, with grade
haematologica | 2022; 107(1)
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