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D. Qualls and G. Salles
3-4 hematologic toxicity following 35% of treatment administrations.24 Given the availability of alternative agents, along with concerns regarding cumulative hema- tologic toxicity and risk for secondary malignancies, we continue to favor R/O-CHOP or R/O-CVP over B-R re- treatment if chemotherapy is needed. However, this remains a major information gap in FL therapy. Given the increased use of first-line B-R, more studies in this area are needed.
As for B-R, few data are available regarding second-line therapy after the rituximab-lenalidomide (R2) combination has been used as first-line treatment.25 A recent retrospec- tive study evaluated outcomes in patients with relapsed or progressive FL who received R2 as first-line therapy.26 The overall response rate was 78% and median PFS was 38 months after salvage therapy, and the use of chemoim- munotherapy (B-R or R-CHOP) was associated with a sig- nificantly longer PFS compared to that achieved with bio- logical agents, supporting the use of immunochemothera- py regimens in this second-line context.
Other chemoimmunotherapy regimens have demon- strated activity in relapsed/refractory FL, although they are less commonly implemented. These include fludarabine- based combinations (with cyclophosphamide, mitox- antrone, or both), rarely utilized because of their substan- tial hematologic toxicities, immunosuppression, and risk of secondary neoplasias.27 Cytarabine-containing regimens (such as R-DHAOX [rituximab, dexamethasone, cytara- bine, oxaliplatin] and R-DHAP [rituximab, dexametha- sone, cytarabine, cisplatin]) showed encouraging results in a retrospective study in patients with early relapsed or refractory disease, often as a path towards high-dose ther- apy and ASCT.28 The use of chlorambucil (and less com- monly cyclophosphamide) in combination with rituximab represents an alternative in comorbid or frail patients.29,30
The role of anti-CD20 maintenance after second line chemoimmunotherapy
Following successful second-line treatment with response, maintenance therapy with rituximab or obinu- tuzumab is often considered. Two large randomized clin- ical trials by the European Organisation for Research and Treatment of Cancer and the German Low Grade Lymphoma Study Group demonstrated PFS benefit with maintenance rituximab after second-line chemoim- munotherapy.31,32 A subsequent meta-analysis of individ- ual patients’ data from randomized clinical trials evaluat- ing maintenance rituximab found an OS benefit with the use of maintenance rituximab after second-line induction therapy.33 However, many patients in these trials had not received rituximab during their frontline management (and specifically no anti-CD20 maintenance), and since these trials were completed a number of new treatment options for FL have been approved, which may affect any survival benefit with maintenance rituximab.
The decision of whether to pursue maintenance ritux- imab or obinutuzumab should be based on prior therapy and the most recent progression-free interval might be considered. For patients with rituximab-refractory dis- ease, obinutuzumab-based treatment as per GADOLIN would be preferred, whereas in rituximab-sensitive dis- easecontinuedrituximabisreasonable.Inthesestudies, maintenance treatment was generally well tolerated, although with an increase in grade 3-4 infections.
Should a therapeutic response in the relapsed or refractory setting be consolidated with transplantation?
Consolidation high-dose chemotherapy with stem cell rescue can be considered in the relapsed/refractory set- ting, particularly in those with high-risk disease. An early randomized study of relapsed/refractory FL noted PFS and OS benefits with high-dose chemotherapy and ASCT after initial response to chemotherapy (predominantly CHOP), as opposed to additional chemotherapy alone, although it is difficult to extrapolate these findings which preceded the routine use of rituximab.34 Other studies have demonstrated durable responses following consol- idative autologous transplant (with a median PFS exceed- ing 5 years in one large study), with a suggestion of greater benefit in patients with early progression.35-38 It should be considered that better disease control in patients presenting with histological transformation may have contributed to some of the benefit seen with ASCT in early progression, given the high rates of such transfor- mation in POD24. One study stratifying outcomes by his- tological transformation showed a clear OS benefit with ASCT in those with transformation, while in those with- out, ASCT was not associated with improved survival.39 Overall, the sustained PFS benefit achieved with ASCT for patients with FL should be balanced with the immedi- ate and long-term toxicities of the procedure, particularly the risk of secondary malignancies.40 Indications for ASCT also need to be interpreted in the context of alter- native treatment options, such as antibody-based thera- pies and, more recently, chimeric antigen receptor (CAR) T-cell therapy.
Allogeneic transplant with reduced intensity condition- ing also remains a viable option with prolonged periods of disease-free survival. However, this must be balanced with the relatively high treatment-related morbidity and mortality, with other options including chemoim- munotherapy, CAR T cells, and other immune-based therapies offering more favorable toxicity profiles. We consider this option for patients with multiply refractory FL, particularly younger, otherwise healthy patients with good performance status and adequate candidate donors.
Radiation and radioimmunotherapy: potent tools for local and systemic treatment
FL is a highly radiosensitive disease, and both external radiation and radio-immunotherapies are effective tools in the management of relapsed or refractory FL.
While extended-field radiation with high doses might expose patients to long-term sequelae, focal radiotherapy to symptomatic lymph nodes represents an efficacious approach which is easy to administer. The optimal dose of radiation in this scenario is an area of active discussion. A recent study comparing standard 24 Gy dosing with a 2 x 2 (4 Gy) regimen demonstrated significantly superior local control with higher dose therapy (5-year progres- sion-free rates of 89.9 vs. 70.4%, respectively), although no difference in OS was observed, and more acute toxic- ity was seen in the 24 Gy arm.41 In our hands, a 2-year local control rate of 70% has been achieved with 2 x 2 Gy in patients with recurrent disease, and this option appears remarkably versatile in patients with lesions <6 cm (Imber B et al., Blood Adv, in press). Based on the lack of curative intent in the relapsed/refractory setting, reduced
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haematologica | 2022; 107(1)