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Individualized first-line management of FL
Table 4. Survival of patients with follicular lymphoma according to FLIPI, FLIPI-2 and PRIMA-PI.
Risk group N. of risk factors
FLIPI30
Low 0-1
Patient distribution (%)
36 37 27
20 53 27
21 36 43
Survival
Intermediate High
2 3-5
78 52
3-year PFS (%)
91 79.5 69 51 51 19
N/A 69 N/A 51 N/A 37
FLIPI-231
Low 0 Intermediate 1-2 High 3-5
PRIMA-PI20
Low b2M≤3mg/LandBM(-) Intermediate b2M ≤ 3 mg/L and BM (+) High b2M>3mg/L
5-year PFS (%)
5-year OS (%)
91 71
10-year OS (%)
51 35.5
FLIPI: Follicular Lymphoma International :Prognostic Index; PRIMA-PI; PRIMA Prognostic Index; OS: overall survival; PFS: progression-free survival; b2M: beta 2-microglobulin; BM: bone marrow.
modify the evolution of these patients whose relapse pro- file is disseminated disease in half of the cases.43
For patients with stage I or II FL with persistent lym- phadenopathy after diagnostic biopsy, there is no consen- sus on appropriate therapy. Alternatives to discuss with the patient include abstention (“wait and watch”), radio- therapy, and rituximab and chemotherapy followed by radiotherapy or immunochemotherapy alone. None of these strategies has demonstrated superiority with regard to OS even if immunochemotherapy,44 chemotherapy fol- lowed by radiation therapy45 or radiation followed by chemotherapy46 results in improved PFS. If radiotherapy is chosen, a dose of 24 Grays (Gy) in 12 fractions gives simi- lar results to a dose of 40-45 Gy.47 Low-dose radiotherapy (4 Gy in 2 fractions) may be preferred for some disease locations to minimize toxicity, particularly when radio- therapy is of palliative intent, but is associated with an inferior PFS.48 Thus, for most patients, the physician could recommend either treatment abstention, radiotherapy (24 Gy) or rituximab (4 weekly infusions).44,45
Some patients with localized FL have poor prognostic characteristics according to GELF/BNLI criteria or FLIPI and FLIPI-2 scores. For these patients, immunochemotherapy as discussed later for advanced stage symptomatic FL could be considered. These patients include subjects with bulky disease (>7 cm according to GELF, or 6 cm according to FLIPI-2), particularly abdominal disease, or a lymphoma- related increase of lactate dehydrogenase or b2-microglob- ulin levels.
Advanced stage follicular lymphoma without treatment-initiation criteria (low-tumor burden)
For advanced stage FL without criteria for treatment ini- tiation (asymptomatic disease), the recommendation is usually to propose therapeutic abstention with dynamic observation. There is no demonstrated OS benefit from initiating early treatment.27,28 The observation that 15 to 20% of patients have still not received treatment 10 years after diagnosis, and that 12% will observe a spontaneous reduction of their disease with an estimated 6% obtaining a complete response, also argues for a “watch and wait” strategy. These patients must, however, be carefully mon- itored because the median time to starting treatment is around 31 months.1 These clinical observations and the unease that some patients and physicians have with this “watch and wait” strategy led to investigations on the use
of rituximab in asymptomatic and disseminated FL. Rituximab monotherapy was examined in two large prospective multicenter trials.1,49 In these trials, rituximab was administered in four weekly infusions followed by maintenance rituximab (infusions every 2 months for 2 years or until progression)1 or with re-treatment according to the same schedule (4 weekly infusions) at progression.49 These two prospective trials demonstrated that after a long follow-up, rituximab monotherapy had no significant side effects. Rituximab increased both PFS and time to the next treatment (TTNT) without having an impact on OS. Ongoing treatment with rituximab maintenance augments the PFS and the TTNT advantage but also the treatment duration (2 years) and increases the rate of grade 1-2 infec- tions.
The USA study also demonstrated that there is no bene- fit from maintenance treatment compared to re-treatment at progression, with four weekly rituximab infusions, lead- ing to a lower utilization of resources for a similar result.
If “watch and wait” is an appropriate strategy for a given patient with asymptomatic disease, the physician must ensure that the objectives of this strategy are well understood and accepted by the patient or risk undermin- ing the patient’s confidence. The patient needs to be aware that this approach does not affect OS and is accompanied by a median time to treatment of 2.5 years.1 The physician who proposes this abstention should not underestimate the psychological consequences for the patient and his or her family of the announcement of a malignant disease, not justifying treatment at the moment but being able to justify it in the near future. The delay in initiating treatment is often seen by patients as time lost in the “fight against the disease” and the physi- cian should not underrate the potential negative impact of this strategy. Instead, with psychologist support, the time can be positioned as a period in which to optimize patients’ health and address social issues that will affect their fitness and tolerance of therapy, such as weight management, physical fitness and smoking cessation and arranging leave from employment and/or securing extra support from caregivers. Efforts must be made to help the patient understand the proposed lymphoma strategy and to reciprocally understand and acknowledge the patient’s experience of their disease. Administration of four weekly injections of rituximab can be an alternative to therapeutic abstention for some patients, for whom compliance with a “watch and wait” proposal appears difficult. The impact of such a strategy on subsequent access to promising first-
haematologica | 2022; 107(1)
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