FL comprises a group of malignant lymphomas consisting of follicle center cells—a mixture of cleaved cells (centrocytes) and non-cleaved large cells (centroblasts).
FL is a germinal center–derived neoplasm that typically grows in a follicular pattern—hence the name FL.
The histologic grade of FL depends on the number of centroblasts and centrocytes in a given sample.
FL with more than 15 centroblasts per high-power field was defined as FL grade 3.
High-grade follicular lymphoma refers to a more aggressive form of this B-cell lymphoma, typically categorized as grade 3 (with subtypes 3A and 3B) based on the number of large cells present.
Follicular lymphoma is graded from 1 to 3 (low- to high-grade manifestations) based on histology.
The grading system is based on the number of large centroblasts per high-power field.
Grade 3 has the highest concentration of these larger, more rapidly dividing cells.
Grade 3B follicular lymphoma is treated with aggressive chemotherapy regimens, such as R-CHOP
Grade 3A is often treated more similarly to lower-grade follicular lymphoma, while grade 3B behaves more like aggressive lymphomas.
The treatment for high-grade follicular lymphoma depends on the specific subtype:
Grade 3A: Grade 3A FL has comparable radiosensitivity to low-grade FL and may be treated with approaches similar to lower-grade disease, including very low-dose radiation therapy in some cases.
Grade 3B: This subtype is treated more aggressively, typically with chemotherapy regimens like R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).
The higher-grade forms generally have a more aggressive course but may also be more responsive to treatment.
Transformation affects around 2 to 3 in every 100 people with follicular lymphoma annually, where the disease can transform into a more aggressive form.
Transformation is defined by pathologically and clonally related progression to more aggressive lymphoma types.
High grade follicular lymphoma refers to follicular lymphoma (FL) with histologic features indicating a higher proportion of large neoplastic B cells (centroblasts), specifically grade 3A and grade 3B FL.
Grade 3A FL, while histologically high grade, often behaves more like low-grade FL clinically, but may require more aggressive therapy similar to DLBCL in some cases.
High grade FL is associated with greater proliferative activity, variable genetic alterations, and, in the case of grade 3B/FLBCL, a clinical course and treatment approach more akin to DLBCL.
The World Health Organization further divides FL grade 3 into FL3A and FL3B depending on the presence or absence of centrocytes, respectively.
A predominance of centroblasts is, interestingly, a typical cytologic feature of aggressive lymphoma—namely, diffuse large B-cell lymphoma (DLBCL).
Despite the presence of centroblasts, FL3B is typically differentiated from DLBCL by the existence of a focal follicular pattern to a certain degree.
The Ki67 proliferation index is typically higher than 20 in FL grade 3, whereas it is generally less than 20 in most cases of FL grade 1 or 2.
A minority of cases of low-grade FL with a high Ki67 index behave more aggressively than cases with a low Ki67 index and exhibit clinical behavior similar to that of FL grade 3.
Tumor cells in FL have a germinal center origin, they typically express B-cell–related antigens: CD19, CD20, CD22, and CD79a and surface immunoglobulins, IgM with or without IgD, IgG, or rarely IgA.
Additionally, CD10, BCL2, and BCL6 expression is typically positive, whereas CD43 and CD5 expression is typically negative.
The hallmark of FL is BCL2 upregulation caused by the chromosomal translocation t(14;18).
This translocation is expressed in 90% of cases of FL grades 1 and 2.
It is also present less frequently in FL grade 3, occurring in 73% of cases of FL3A and 13% of cases of FL3B.
The incidence of BCL6 rearrangement (3q27 breaks) is higher in FL3B than in FL3A.21,23
The genetic differences between FL3A and FL3B are mirrored in their immunohistochemical status.
CD10 expression is predominantly positive in most cases of FL3A (90%).
Nearly half of cases of FL3B are negative for CD10 expression.
81 genes has been used to distinguish low-grade FL from high-grade FL, with a high accuracy rate of 100%.
FL commonly presents in middle-aged patients.
Most patients present with widespread lymph node enlargement that typically waxes and wanes spontaneously.
Hilar and mediastinal lymph nodes are frequently involved, but bulky disease is quite rare with FL.
B symptoms are encountered in approximately 20% of cases of FL.
FL3B tends to involve the bone marrow or peripheral blood less often, and patients typically have larger lymph nodes.
Approximately 65% to 70% of patients with FL grade 3 present with advanced disease..
Despite the existence of widespread disease at presentation, most patients with FL are asymptomatic at diagnosis.
The management of patients with low-grade FL (grades 1 and 2) depends on the stage of disease at presentation and whether symptoms are present.
Management ranges from a watch-and-wait approach to chemoimmunotherapy.
The most commonly used chemoimmunotherapy regimens are bendamustine and rituximab (BR) and rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP).
The outcomes with BR are comparable to those of R-CHOP, with less toxicity; therefore, BR has been widely adopted as frontline chemotherapy in patients with low-grade FL.
The management of high-grade FL (grades 3A and 3B) is less certain.
Currently, it is uncertain whether patients with FL3A should be treated as if they have aggressive or indolent lymphoma.
95 patients with a diagnosis of FL3A who were treated with R-CHOP or BR.
The response rate was higher (95% vs 76%) and the overall survival (OS) rate at 3 years was also higher (89% vs 73%; P=.008) in the patients who received R-CHOP.
The difference in progression-free survival (PFS) was not statistically significant.
The rate of transformation into aggressive lymphoma was the same in both arms, suggesting a benefit of R-CHOP over BR for FL3A.
A retrospectively assessed the outcomes of 132 patients with FL3A treated with either BR or R-CHOP in the first-line setting.
In contrast to the previous study, the complete remission rates were similar for R-CHOP and BR (97% and 96%, respectively, and the relapse rate was higher in the patients who received R-CHOP than in those who received BR (41% vs 16%, respectively), which translated into a longer PFS in the BR-treated patients (15 vs 11.7 years).
The heterogeneity of FL3A is evident in the published literature, in which FL3A appears to be similar to FL grades 1 and 2 from an immunohistochemical standpoint and also at the molecular level (in the BCL2 and BCL6 translocations) while resembling FL3B in terms of gene expression profiling.
In terms of side effects, rates of grades 3 and 4 neutropenia are lower with BR than with R-CHOP, translating into a significantly reduced occurrence of infections.
However, the risk for nausea, vomiting, and skin reaction is significantly higher with BR than with R-CHOP.
The aggressive nature of FL3B and its molecular similarity to DLBCL, international guidelines have advocated use of the chemoimmunotherapy regimens prescribed for clinically aggressive lymphomas, DLBCL).
No high-quality data are available to guide therapeutic options in patients with FL3B.
The treatment given was rituximab or obinutuzumab plus CHOP, with or without radiation therapy.
With a median follow-up of 4 years, the PFS rate was 72% and the OS rate was 84%.
The survival outcomes of patients with FL3B were similar to those of patients with FL3A/FL3B and patients with FL3B/DLBCL
Both PFS and OS were similar in the 2 groups.
A PFS plateau was observed in the patients with FL3B, confirming a higher cure rate in this patient population.
Despite the improved effectiveness with chemoimmunotherapy regimens in patients with FL, progression of disease(POD) occurs in approximately 20% within 24 months of first-line therapy.
The risk for death within 5 years after diagnosis is substantially greater in patients with POD24 than in patients who do not have disease progression within 24 months.
Autologous stem cell transplant (autoSCT) consolidation after salvage chemoimmunotherapy for eligible patients with relapsed FL can result in sustained remission.
A European phase 3 randomized trial called CUP compared chemotherapy vs autoSCT. At a median follow-up of 69 months, the patients who underwent transplant had a higher 4-year PFS rate (55%-58% vs 26%) and OS rate (71%-77% vs 46%) than those who received chemotherapy(this trial was conducted before the rituximab era.).
Allogeneic stem cell transplant (alloSCT) is a valid option for the treatment of patients with relapsed FL.
AlloSCT is associated with a higher rate of transplant mortality but a lower risk for relapse and a greater potential for cure.
When alloSCT is used for patients with FL, nonmyeloablative preparative regimens are typically the preferred regimens.
Khouri and colleagues published the results of 47 patients with relapsed FL after nonmyeloablative alloSCT in which a fludarabine, cyclophosphamide, and rituximab conditioning regimen was used.
The estimated 5-year OS rate was 85%, and the estimated 5-year PFS rate was 83%.
Chimeric antigen receptor (CAR) T-cell therapy is a treatment option for patients with multiple relapses of FL.
Axicabtagene ciloleucel (Yescarta) also known as axi-cel, received approved from the US Food and Drug Administration (FDA) for patients whose disease progressed through 2 or more lines of therapies.
Treatment with axi-cel resulted in an 80% complete remission rate.
The median PFS and OS were not reached.
Lsocabtagene maraleucel (Breyanzi) also known as liso-cel, in patients with relapsed or refractory large B-cell lymphoma.
Of 44 patients, 3 had FL3B, and all remained in complete response after 1 year of therapy.
Mosunetuzumab is a CD20/CD3 bispecific antibody that redirects T cells to target and eliminate malignant B cells.
In a phase 1/2 trial of a total of 90 patients with FL that had relapsed or was refractory to at least 2 prior lines of therapy, mosunetuzumab was associated with a complete response rate of 60% and a median PFS of 17.9 months.
Mosunetuzumab had a manageable safety profile, with a low discontinuation rate due to adverse events (4%).
Most of the cases of cytokine release syndrome were mild and occurred in cycle 1, and they resolved in all patients after a median of 3 days.53,54
The prognosis in patients with FL is variable.
Some patients have waxing and waning disease for many years without therapy, while others have a more aggressive clinical course and poor outcomes.
Outcomes in patients with FL3B are inferior to those in patients with FL3A.
In a retrospective analysis of 505 patients with FL who had a median follow-up of 10 years, the clinical course for grade 3A disease was similar to that for grades 1 and 2 disease.
Mortality rates were higher for FL3B than for FL grades 1 through 3A, but outcomes were improved after an upfront anthracycline-containing regimen.
Reports suggested a worse prognosis in patients with BCL2 protein expression: Trial results, however, are conflicting regarding the prognostic value of BCL6 expression; some suggest a negative effect on survival, whereas others failed to demonstrate such an effect.
Transformation into aggressive lymphoma and failure to reach a complete or partial response were independent risk factors for shorter OS in a multivariable analysis.
Uptake on positron emission tomography does not seem to correlate with either the grade of lymphoma or the outcome following R-CHOP treatment in patients with FL.
Large, prospective trials evaluating the optimal evidence-based management approach to patients with FL grade 3 are lacking and strongly needed.