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G. Cartron and J. Trotman
Table 6. Summary of chemotherapy regimen: advantages and disadvantages.
Advantages
Bendamustine No alopecia
Less febrile neutropenia
No cardiomyopathy or peripheral neuropathy PFS
TTNT
Lower rate of POD24
CHOP Effective in HT/ 3B disease
Lower rates of stem cell toxicity and
persistent immunodeficiency Lower rates of subsequent HT Effectiveness in 3A disease
CVP Lower infectious toxicity Less fatigue
Minimal alopecia
Disadvantages
Long-term infectious risk and mortality in patients > 70 years
Early and prolonged CD4+ depletion
➝ Increased risk of severe COVID-19
➝ Increased risk of lymphocyte harvest failure for CAR T-cell manufacturing
Increased risk of cardiac toxicity Peripheral neuropathy
Steroid side effects
Alopecia
Lower PFS/TTNT Steroid side effects Peripheral neuropathy
COVID-19; coronavirus-2019 disease; CAR: chimeric antigen receptor; PFS: progression-free survival; TTNT: time to next treatment; POD24: progression of disease by 24 months; HT: histological transformation; CHOP: cyclophosphamide, doxorubicin, vincristine, prednisone; CVP: cyclophosphamide, vincristine, prednisone.
hematologic toxicity. The RELEVANCE study aimed to demonstrate superiority of an immunotherapy combining rituximab and lenalidomide over conventional immunochemotherapy.62 The lack of any advantage on both response rates and PFS has dampened hopes of a chemotherapy-free standard-of-care first-line treatment for FL.
Obinutuzumab offers improved progression-free survival but not overall survival
Obinutuzumab is an anti-CD20 monoclonal antibody modified to improve direct cytotoxicity and antibody- dependent cell cytotoxicity. This antibody has been com- pared to rituximab in a phase III trial (GALLIUM)61 com- bined in induction with different chemotherapy regimens (CHOP, bendamustine, CVP). This immunochemotherapy was followed in responding patients by maintenance treat- ment with rituximab or obinutuzumab every 2 months for 2 years. It is noted that the dose and administration sched- ule of the two anti-CD20 antibodies were different, the pharmacokinetic studies carried out during the develop- ment of obinutuzumab making it possible to optimize its administration. This study showed that obinutuzumab provides a significant improvement in PFS and TTNT for patients. After a follow-up of 57 months, this translated into risk reductions of 27% (HR=0.73, 95% CI: 0.59- 0.90) for progression and 30% (HR=0.70, 95% CI: 0.54, 0.90) for TTNT.63 The advantage of obinutuzumab on PFS and TTNT was especially marked in patients receiving ben- damustine.64 Nonetheless, mindful that TTNT is arguably a more important endpoint in routine clinical practice than in clinical trials, there was no significant TTNT difference at 3 years across all obinutuzumab-chemotherapy arms: obinutuzumab-bendamustine 87%, (83-91%), obinu- tuzumab-CHOP 87% (82-91%), obinutuzumab-CVP 87% (75 - 93%). When using obinutuzumab patients need to be educated about the high probability (59%) of an infusion- related reaction. Reassurance about prompt management of such reactions is important to allay patients’ fears and improve their experience with this monoclonal antibody.
The preferred first-line immunochemotherapy approach is patient-specific.
Choosing between combination immunochemothera- py options requires an individualized, nuanced approach
for each patient, with risk:benefit calculations made both before induction and during treatment. While there is no direct randomized comparison between induction with bendamustine and CHOP for young fit patients in the modern era, accumulated data suggest that where PFS is the overriding priority this may be best achieved with the use of obinutuzumab-bendamustine followed by contin- ued therapy with obinutuzumab maintenance. Where the anticipated bendamustine toxicity (including that which may impair T-cell function, affecting both immune fitness and potential chimeric antigen receptor T-cell collection) creates a preference for CHOP (particularly where con- cerns exist regarding occult transformation) or even CVP, their combination with obinutuzumab results in excellent PFS and TTNT with acceptable toxicity. Nonetheless, the GALLIUM study data are early data, and 5 years of fol- low-up are inadequate for a disease with a median OS beyond 15-20 years. Clinicians are advised to keep this in mind when scheduling first-line therapies for the man- agement of high-tumor burden FL. Mindful of the increased risk of infections related to the use of mainte- nance with anti-CD20 therapy, ongoing use of such maintenance needs careful reconsideration in the event of any infection and meticulous adherence to antimicrobial prophylaxis is encouraged. Because of increased toxicity related to obinutuzumab (first dose infusion-related reac- tions, cytopenia and infections), the lack of a demonstrat- ed OS improvement, and cost considerations, rituximab may remain the preferred anti-CD20 antibody, particular- ly in very frail elderly patients for whom PFS and TTNT are not the overriding clinical objectives. In this setting, the combination of rituximab with CVP offers the lowest toxicity, albeit with a markedly inferior PFS compared to other immunochemotherapy options. Conversely, where chemotherapy toxicity is of concern but PFS remains a priority, pairing less toxic CVP with obinutuzumab with careful management of infusion-related reactions may be a preferred approach for these elderly patients.
Surveillance during first remission in follicular lymphoma
Current guidelines from the European Society for Medical Oncology advise clinical and imaging surveil- lance every 6 months for 2 years after induction and, optionally, annually up to 5 years.65 Surveillance imaging recommendations were mostly based on data from stud-
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