Using PET to guide the therapeutic approach for patients with follicular lymphoma

Follicular lymphoma (FL), despite its indolent biology, can be ¹⁸F-fluorodeoxyglucose (FDG)-avid on positron emission tomography (PET). FDG PET combined with computerized tomography (PET-CT) is an important imaging modality in several FDG-avid lymphomas, where a wide range of FDG avidity has been described. Initially, however, PET was not considered important for staging and response assessment of FL until recently, when it became apparent that FL was universally, though not uniformly, FDG-avid. PET is now considered the gold standard imaging modality for both staging and response assessment of FL.

Judith Trotman, Lymphoma Hub Steering Committee member, recently shared her experience employing PET in indolent FL at the 2021 Pan Pacific Lymphoma Conference¹ and has also published a perspective article on the use of PET-guided therapy in the treatment of patients with FL, in Blood.² The Lymphoma Hub has previously reported on some of the trials discussed by Trotman, including FOLL12 and GALLIUM. Here, we present a summary of Trotman’s key points regarding the advantages and disadvantages of using PET-guided therapy in FL.^1,2

Methods

Studies included in the perspective, published in Blood,² were identified through MEDLINE and Embase by searching the terms ‘positron emission tomography’ and ‘follicular lymphoma’ from 2000 to 2020; only papers published in English were reviewed.²

Findings

Staging and prognosis in newly diagnosed patients^1,2

• PET is more sensitive and specific than a standard CT scan at diagnosis for identification of nodal and extra-nodal disease, with additional sites detected in approximately two-thirds of cases and resulting in upstaging in 10–60% of cases. The 2014 Lugano classification, therefore, recommends PET for staging of all FDG-avid lymphomas.
  • This is applicable to FL, which is almost always FDG-avid (with variability in uptake between and within patients).
• Application of PET to clinical staging was associated with favorable overall survival (OS) and lymphoma-specific survival in a US database study of 5,712 patients.³
• A recent retrospective analysis validated the use of PET staging using a FOLL05 trial cohort⁴ and showed that patients staged using CT had inferior OS despite a similar rate of progression-free survival (PFS). PET staging was also associated with reduced rates of histologic transformation (HT) compared with CT in patients with progression of disease within 1 year of initiating therapy.
• The application of PET in patients with FL who have advanced-stage disease by PET and limited-stage disease by CT poses a challenge due to a lack of knowledge regarding the clinical course and optimal management of these patients.
  • Patients defined by both CT and PET as having limited-stage disease may benefit from local radiotherapy if the radiation field is based on PET. A recent study demonstrated a 5-year freedom from progression of 69% and a 5-year OS of 96% in patients with limited-stage disease using PET to select patients for radiotherapy.⁵
• In patients with asymptomatic advanced-stage disease identified on CT, PET should be deferred until treatment is required.

Role of bone marrow biopsy in the context of PET staging^1,2

• Even though PET is less sensitive in detecting bone marrow involvement in FL, focal lesions are more likely to be detected by PET; therefore, PET and bone marrow biopsy (BMB) can provide complementary information.
• Although both BMB and PET are required for accurate staging, no impact on PFS was observed in the 525 patients included in the GALLIUM study⁶ who had bone marrow involvement identified via BMB.
• BMB may be deferred in patients with FL who do not require immediate treatment, and pretreatment BMB may be omitted altogether if the results will not impact treatment selection.

Quantitative baseline PET measurements in FL^1,2

• Key studies correlating maximal standardized uptake value (SUVmax) with outcomes in FL are summarized in Table 1. These studies do not suggest a clear benefit to biopsy or re-biopsy of lesions based on SUVmax alone.
• The ongoing PETReA study will include all patients diagnosed with FL to address the issue of the confounding effects associated with the exclusion of patients with high SUVmax values.⁷

Table 1. Key studies relating to SUVmax*

bSUVmax; baseline maximal standardized uptake value; HR, hazard ratio; HT, histologic transformation; OS, overall survival; PFS, progression-free survival; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone; ROC, receiver operating curve. *Adapted from Trotman et al.2
Study	Patients, n	Median baseline SUVmax (range)	Histologic transformation, n	PFS
PRIMA8	58	12 (5−36)	0	No association of bSUVmax with PFS; p = 0.53
FOLLCOLL9	181	10 (3−35); ROC and X-tile analysis SUVmax 9.4	2; no correlation with histologic grade; p = 0.66	SUVmax > 9.4: 5-year PFS 62%, median PFS 79 months
SUVmax < 9.4: 5-year PFS 47%, median PFS 49 months; p = 0.0318
No difference in OS, 94% vs 88%; p = 0.15
GALLIUM6	549	12 (8−28) in HT; 12 (3−64) in non-HT	15	No association of bSUVmax with PFS, HR 1.14 (0−1); p = 0.58
Strati et al.10	346	11 (2−42)	Excluded from study population	No effect on PFS if treated with R-CHOP or other chemoimmunotherapy
Inferior 8-year OS if SUVmax >18 (65% vs 89%; p = 0.001)

• Total metabolic tumor volume (TMTV) should not be used for prognostication or patient stratification at this time, as there were contradictory findings regarding the correlation of TMTV with PFS or OS in the GALLIUM study, depending on the method used to assess TMTV (automated vs semiautomated).⁶

Response assessment by PET-CT^1,2

• The 2014 Lugano response criteria recommend assessing metabolic response using a 5-point scale (5-PS). However, there is an ongoing debate on the distinction between Score 4 and 5.
  • In FL, a cutoff of Score ≥4 rather than ≥3 provided better reporter agreement and greater separation of PFS and OS curves. Scores 1−3 are, therefore, considered to represent a complete metabolic response (CMR), and Scores 4 or 5 represent an inadequate end-of-induction (EOI) response.
• Pooled analysis of three trials (PRIMA, FOLL05, and PET-Folliculaire) showed that patients with positive EOI PET had PFS of 23% vs 63% in patients with negative EOI PET (p < 0.0001), and the 4-year OS was 87% vs 97%, respectively (p < 0.0001).¹¹
• The GALLIUM trial⁶ showed patients achieving CMR (PET Score 1−3) had a PFS of 87% at 2.5 years compared with 55% in patients who failed to achieve CMR (p < 0.0001), and achievement of CMR was the only independent predictor of OS on multivariate analysis.
  • At a median follow-up of 77 months, patients who remained PET-positive at EOI had a PFS of 29% vs 70% for those in CMR (p < 0.0001). The 5-year OS was 80% vs 92%, respectively (p < 0.0001).
  • In addition, the risk of progression of disease within 24 months was nine times higher in non-CMR vs CMR patients. This risk remained significant on multivariate analysis.

Use of PET for interim response assessment and remission surveillance²

• Surveillance imaging is discouraged owing to a risk of false positive scans leading to unnecessary biopsies, expense, patient anxiety, and radiation exposure. Even so, patients with residual abdominal disease and concerns for asymptomatic progression may warrant the use of surveillance CT scanning.
• Concerns for symptomatic relapse requiring therapy may permit re-staging with PET and repeat biopsy to exclude HT before re-treatment, but imaging is not required to confirm disease progression outside of a clinical trial.

Conclusion

This perspective provides an overview of the role of PET as the gold standard imaging modality for staging and response assessment of FL. There was no confirmed correlation between high bSUVmax and risk of HT or inferior PFS, suggesting that patients should not be exposed to repeat biopsy. The EOI PET status was a strong predictor of PFS and OS after first-line induction chemotherapy. Patients and clinicians can be more confident in their decision making when CMRs are achieved, especially when considering the compromise between the PFS advantage and toxicity of further treatment. In the absence of data to support preemptive intervention in patients who remain PET-positive, the results from ongoing trials are awaited with interest.