【Am J Hematol】Diagnosis and Treatment of Follicular Lymphoma (2023 Update)

Since 2011, the American Journal of Hematology has updated a review of the diagnosis and treatment of follicular lymphoma every few years, first by Professor Arnold Freedman of Dana Farber Cancer Institute (a cancer specialist hospital at Harvard Medical School), and in 2020 by Professor Arnold Freedman and Professor Eric Jacobsen.
Recently, the journal published the 2023 update, and the author is only Professor
Eric Jacobsen.
The 2023 update includes diagnosis, risk stratification, and risk adaptation treatment, and the main contents are translated below for teachers' reference
.

Overview and clinical manifestations of the disease

Follicular lymphoma (FL) is the second most common lymphoma in the United States and Western Europe, accounting for about 35% of all non-Hodgkin lymphomas (NHLs) and 70%
of indolent lymphomas.
The median age at diagnosis was 65 years, and there was a slight increase
in incidence among relatives of patients with FL.

FL is a low-malignant B-cell tumor derived from follicular germinal center cells, and approximately 85% of FL patients carry t(14;18), leading to overexpression of the BCL-2 protein, a member of the protein family that blocks apoptosis.

However, the development of FL is likely to require multiple genetic events, as there is a t(14;18) translocation
in B cells in both normal humans and patients with diffuse large B-cell lymphoma (DLBCL).
Chromatin modification gene mutations (KMT2D, CREBBP, EZH2) are common features of FL, and studies have shown that changes in normal T cell function in the malignant microenvironment also play a role in the pathobiology of the disease, including changes in gene expression, especially the upregulation of PMCH, ETV1, and TNFRSF9, and changes
in T cell motility in vitro.

Patients with FL often present with asymptomatic lymphadenopathy that can wane for years
.
Bone marrow involvement is present in at least 70% of patients, and other organ involvement is less common; Less than 20% of
patients have B symptoms or elevated serum lactate dehydrogenase (LDH).
The peculiarity of FL is in the gut, which is usually early and has an excellent
prognosis.
The mutated features of duodenal FL and lymph node FL suggest that the immune microenvironment is different
.
Children with FL are different, presenting with localized lesions with grade 3 histology and no bcl-2 rearrangement; FL in children is highly curable and invasive treatment
should be avoided.

diagnosis

Tumor cells of FL are composed of a mixture of central cells (small to medium-sized cells) and central blasts (large cells) in different proportions, and their clinical aggressiveness increases
with the number of central blasts 。 The WHO classification adopts a 1-3 grading system, which increases based on the number of centroblasts per high power field count: grade I FL has 0-5 centroblasts/hpf (follicular clevas), grade II FL has 6-15 centroblasts/hpf (follicular mix), and grade III FL has more than 15 centroblasts/hpf (follicular macrocytes); Grade III is further divided into grade III.
a in the presence of central cells and grade III.
b in the presence of sliced central blasts, and grade III.
b FL is more clinically and biologically similar to diffuse large B-cell lymphoma, so it is treated
accordingly.

Bone marrow involvement is very common and is characterized by
paratrabecular lymphatic aggregation.
FL cells expressed monoclonal immunoglobulin light chains, CD19, CD20, CD10, and BCL-6, and CD5 and CD23 were negative; Because t(14;18), almost all FL cells overexpress the BCL-2 protein
.
There is also clonal Ig gene rearrangement in FL, with extensive somatic mutations
in most cases.

Histological transformation of FL to DLBCL occurs in 10% to 70% of patients over time, with a risk of 2% per year, associated with rapid progression of lymphadenopathy, extranodal lesions (other than bone marrow), B symptoms, hypercalcaemia, elevated serum LDH, high FLIPI score, and failure to respond to initial therapy
.

prognosis

Overall survival (OS) in patients with FL improved significantly with the advent of rituximab
.
Data from the Swedish Lymphoma Registry report 10-year OS from 2003 to 2010, 92%, 83%, 78% and 64%
of the 18-49, 50-59, 60-69 and ≥70 age groups, respectively.
A US and French cohort analysis also reported OS improvement in the rituximab era, with approximately 80%
OS at 10 years.
However, lymphoma (particularly histologic transformation) remains the leading cause of death, with a 10-year disease-specific mortality rate of 10%.

Indicators of outcomes in patients with FL include FLIPI and tumor grade, and there is also evidence that features of relevant cells in the FL tumor microenvironment influence disease behavior and prognosis
.

FLIPI includes five prognostic factors: age, stage, number of lymph node regions affected, serum LDH, and hemoglobin (Table 1).

FLIPI was developed
based on an international study of survival data on 4167 patients with FL diagnosed in the pre-rituximab era between 1985 and 1992.
The modified version of FLIPI2 also contains 5 parameters and has some overlap with FLIPI: β-2 microglobulin, bone marrow involvement, age, hemoglobin, and maximum diameter
of affected lymph nodes.
The utility of FLIPI2 compared to the original FLIPI remains uncertain, and even in the era of rituximab, FLIPI remains a useful prognostic model (Table 2).

One study analyzed 74 gene mutation states in 151 treatment-novice FL patients treated with R-CHOP and found that combining seven gene mutation states with a FLIPI score (known as m7 FLIPI) was a better predictor of 5-year failure-free survival
.
Another study analysing genomic alterations found that deletions of TP53 and CREBBP were associated
with shortened survival.

Another risk stratification model, GELF criteria, includes tumor burden and clinical outcome parameters
.
Analysis of prospective PRIMA studies of chemoimmunotherapy yielded a simple prognostic model of PFS based on bone marrow involvement and β2-microglobulin (β2m), known as PRIMA-PI, classified as low-risk (β2m≤3 mg/L, BM-negative), intermediate-risk (β2m≤3 mg/L, BM-positive), and high-risk (β2m>3 mg/L) with 5-year PFS of 69%, 55%, and 37%,
respectively.

The prognostic index above does not include initial treatment DOR in the prognostic model, while analysis of patients receiving R-CHOP as initial therapy has reported that relapse within 2 years of completion of treatment is associated with a poor prognosis (50% and 90% 5-year survival, respectively).

FL tumor grade is grade 1~3, which has a certain prognostic effect, but pathologists generally have a poor consensus on FL grade, and there is no evidence to support the different treatment of grade 1 and grade 2 FL, which has historically been called follicular large cell lymphoma
.
As many studies may include both grade IIIa and IIIb, this heterogeneity may affect the interpretation
of outcomes.
Despite the structural integrity of the follicular, many patients with FL class IIIb have closer clinical presentation, behavior, and therapeutic outcomes to DLBCL; FL grade IIIb has a higher recurrence rate but longer
survival compared with DLBCL.

Studies of the FL cellular microenvironment also provide interesting insights
into prognosis.
It has been suggested that FL is an immunological disease, and the interaction of tumor cells with the microenvironment determines the overall clinical behavior
.
These studies have observed tumor-associated invasions of macrophages, T cells, and T cell subsets to affect prognosis, but additional studies are needed in larger datasets and prospective validation
in a uniformly treated patient population 。 In addition, the 2016 edition of the WHO classification of lymphoid malignancies added four additional FLs: pediatric FL, FL in situ, primary intestinal FL, and predominantly diffuse FL with IRF-4 rearrangement
.

18F PET can be used to assess response to CHOP-R in patients with treatment-naïve FL, and PET after 4 cycles and at the end of treatment predicts PFS and OS
.
When used as an interim or end-of-treatment scan, 2-year PFS was significantly higher in PET-negative patients than in PET-positive patients, and 2-year OS was also significantly higher in PET-negative patients than in PET-positive patients
.
A recent study reported a controversial association between MRD testing (identified by monitoring BCL-2-IGH translocations in the bone marrow
) and long-term outcomes.

Initial treatment of early FL

Less than 10% of patients with FL have stage I/II, radiation therapy (RT) is often the first choice for limited-stage FL, with a 10-year OS rate of 60% to 80%, a median survival of about 19 years, and a significant proportion of deaths due to non-lymphomatic causes
.
The 24 Gy dose appears to be effective, and there is no benefit
in increasing the dose.
A recent phase III study showed that 24 Gy was superior to 2 Gy
in disease control (although not OS).
In addition, patients who staged FDG-PET before RT had better
progression-free outcomes than those staged with CT.
In a large study of more than 6000 patients with stage I to II FL, 34% of whom received initial radiation therapy had higher
disease-specific survival rates at 5 years (90% vs.
81%), 10 years (79% vs.
66%), 15 years (68% vs.
57%), and 20 years (63% vs.
51%) 。 A retrospective study comparing RT alone with RT plus chemotherapy monotherapy (CVP) or the addition of rituximab (RCVP) showed that systemic therapy plus RT improved PFS compared with RT alone (10-year PFS of 59% and 41%, respectively), but had no effect
on OS.

Selected early-stage patients can be observed without initial radiation therapy
.
In one report, the median OS for a given untreated patient was 19 years; At a median follow-up of 7 years, 63% of patients still did not require treatment
.
In an analysis of early-stage patients with FDG PET before radiation therapy, OS was 91.
4% 3 years after relapse; Patients who relapsed ≤ 12 months had worse OS than those who relapsed > 12 months after diagnosis (88.
7% vs.
97.
6%, respectively).

Despite good radiotherapy outcomes and low toxicity, the majority of stage I patients treated in the US surprisingly did not receive radiotherapy, but instead rituximab monotherapy or chemoimmunotherapy
.
Based on OS data, most patients with stage I FL are recommended for field RT involvement, and the prognosis for patients with relapse after radiation therapy is excellent
.

Initial treatment of advanced FL

Most patients with FL are diagnosed with advanced disease, and patients with advanced FL do not require immediate treatment
unless there is symptomatic lymphadenopathy, impaired end-organ function, B symptoms, symptomatic extranodal lesions, or cytopenias.
The strategy of watchful waiting is supported by randomized prospective studies comparing observation with immediate treatment, the largest of which compared immediate treatment with chlorambucil with observation, with no differences
in OS and cause-specific survival observed between groups at a median follow-up of 16 years.
Similar results
were observed in other prospective studies comparing initial treatment with observation.

A major question is whether rituximab may change the observation strategy to benefit
asymptomatic patients through early treatment.
One retrospective analysis included low-risk patients under observation or rituximab monotherapy, with no harmful effects
on the OS from watchful waiting.
A prospective study comparing rituximab monotherapy or sequential maintenance therapy with rituximab in treatment-new FL did not observe a difference
in the incidence of OS or histological transformation.
However, these studies do not address important questions
such as time, cost, toxicity, and future response to rituximab to secondary treatment.
RESORT includes low-risk patients suitable for treatment given rituximab once a week for a total of 4 times a week, followed by randomization (retreatment with observation and progression, or rituximab maintenance therapy for 2 years); There was no difference in time to treatment failure, histological transformation, and OS, but rituximab was used more in the maintenance group; There was a difference in the duration of cytotoxic therapy, with rituximab maintenance therapy being preferred
.
Close observation is therefore still appropriate advice for many newly diagnosed patients; If initial treatment with rituximab monotherapy is used, retreatment at progression may be consistent with
the response to 2 years of rituximab maintenance therapy.

Although rituximab is not indicated in asymptomatic patients without disease-related symptoms or complications, it has changed the treatment paradigm
for FL.
As previously noted, the improvement in FL survival over the past 20 years is mainly due to the use of anti-CD20 antibody-based therapies (most commonly rituximab), and multiple randomized trials have demonstrated the benefit of adding rituximab to combination chemotherapy for the initial treatment of advanced FL, all of which have demonstrated improvement in response rate, time to progression, and OS in
the rituximab plus chemotherapy group.
In addition, subcutaneous rituximab is as effective as intravenous rituximab with fewer adverse events and is a viable alternative to
intravenous administration.

In addition to rituximab, advances in chemotherapy have improved outcomes
for FL.
A first-line randomized phase III study comparing bendamustine + rituximab (BR) with R-CHOP in 513 patients with advanced indolent lymphoma, most of whom were FL, had a better median PFS for BR (69.
5 months vs.
31.
2 months), less toxic, including lower incidence of grade 3-4 neutropenia and leukopenia; There was no difference
in OS at a median follow-up of 45 months.
BRIGHT found that BR is not inferior to R-CHOP and R-CVP, and BR is similar in CR and ORR; PFS was also thought to be longer in the BR group but similar in OS, and there were more secondary
malignancies in the BR group.
These studies support BR as the mainstay of treatment for FL, but a Medicare database review has demonstrated that bendamustine > treatment-related mortality unacceptable in patients aged 60 years with low tumour burden, so bendamustine should be used with caution in older patients, particularly those with comorbidities, and should be tapered
if necessary.

Another randomized phase III study assigned treatment-new-stage II-IV FL patients to R-CHOP or R-CVP or R-fludarabine-mitoxantrone (R-FM) showed that both R-FM and R-CHOP were superior to R-CVP in 3-year PFS and TTF, but there was no difference
in OS.
Considering the results of the BR versus R-CHOP studies and the subsequent widespread adoption of BR as the preferred chemoimmunotherapy for FL, this study had no significant impact
on the treatment strategy for FL.

A phase III study evaluated chemoimmunotherapy containing obinutuzumab or rituximab in treatment-naïve patients with FL with a chemotherapy regimen of bendamustine, CHOP, or CVP, followed by maintenance therapy with obinutuzumab or rituximab for 2 years
.
Omotulumab and rituximab had similar response rates to OS, but obinutuzumab had a higher PFS, and similar benefits
were observed with all three chemotherapy regimens.
Grade 3 to 5 adverse events (cytopenias) were highest in the CHOP group, compared with grade 3 to 5 infection and secondary malignancy and higher death in the bendamustine group
.
Both bendamustine plus obinutuzumab regimens have been approved for treatment-tactic-new FL, but the toxicity
of this regimen should be carefully weighed before use, given the absence of OS benefit.
In general, bendamustine plus obinutuzumab regimen should be reserved for young, healthy patients with large mass lesions, although the authors still prefer BR, even in this patient population
.

Rituximab monotherapy has been used as initial treatment in patients with indolent lymphoma with an ORR of approximately 70% and a CR rate of more than 30%.

The most impressive data on single-agent rituximab is the update of the SAKK study, in which 202 patients received rituximab administered 4 times weekly and subsequently patients ≥ SD randomized to observation or 4 doses of rituximab maintenance therapy (given every 2 months).

Results At 12 weeks, 151 patients with disease remission or SD were randomized, and at a median follow-up of 35 months, event-free survival increased 2-fold in patients receiving rituximab maintenance therapy (23 months vs.
12 months).

With longer follow-up, 35% of respondents remained in remission at 8 years, and 45% of newly diagnosed patients remained in remission at 8 years after the addition of rituximab maintenance therapy
.
In addition, there was no benefit
from increasing rituximab maintenance therapy to 5 years.

One large randomized study evaluated the use of
rituximab maintenance therapy following chemoimmunotherapy in patients with FL.
Although rituximab maintenance therapy appears to improve PFS, toxicity (although tolerated) also increases, and the effect on the
OS is unclear to date.
In a PRIMA phase III study of 1018 FL patients who had not previously received chemotherapy, patients in response to immunochemotherapy (CVP-R, CHOP-R, or FCM-R) were randomly assigned to receive rituximab (375 mg/^m2 every 8 weeks for 24 months) or placebo maintenance therapy
。 At a median follow-up of 36 months after randomization, PFS rates were higher in the rituximab maintenance group (75% vs.
58%), and the OS was currently the same in both groups; The percentage of patients with CR/CRu was higher at 24 months (72% vs.
52%) in the rituximab maintenance group 2 years after randomization; The proportion of patients with grade III/IV adverse events and infections was also significantly higher
.

Another randomized phase III study using fludarabine, cyclophosphamide, and mitoxantrone evaluated whether rituximab simplified maintenance therapy has clinical benefit in treatment-new patients aged 60 to 75 years with FL, with no statistically significant PFS benefit
from rituximab maintenance therapy.
A retrospective analysis of patients treated with 4 cycles of BR found that patients who achieved PR after completing BR had improved DOR after R maintenance compared with no maintenance therapy, but no benefit in patients who achieved CR, but this was not a prospective randomized study
.
Therefore, the role of maintenance regimens after R-CHOP or R-CVP, especially after bendamustine, remains uncertain
.
Rituximab does reduce the antibody response to the SARS-CoV-2 vaccine, so maintenance therapy with rituximab during the coronavirus pandemic must combine the increased risk of severe coronavirus infection with the benefit
of PFS prolongation.

Among the immunomodulators combined with rituximab to enhance activity, the most impressive is lenalidomide combined with rituximab (^R2).

The combination phase II study in treatment-naïve patients had a ORR of 95% and a CR rate of 72%, a 2-year PFS rate of 86% and 70% at 5 years, and a 5-year OS of 100%.

In a phase III study comparing chemoimmunotherapy with^R2, response rates and 3-year PFS were similar
in both groups.
Similar results
were reported by the SAKK Collaboration Group from Europe.
Therefore,^R2 in treatment-new patients with FL is a viable chemotherapy-free alternative
.

In a study of lenalidomide plus obinutuzumab in treatment-new-cure FL patients, patients received induction therapy with lenalidomide 20 mg and obinalizumab for 6 months, followed by 1 year of dose reduction therapy with lenalidomide and obinutuzumab (every 8 weeks), followed by 1 year of maintenance therapy
with obinalidomab.
The ORR at the end of induction was 92% and the CR was 47%; 3 years PFS is 82% and OS is 94%.

Neutropenia was the most common adverse event, but febrile neutropenia
occurred in only 2% of patients.
Given a randomized study comparing this regimen with standard chemotherapy immunotherapy, authors generally still prefer no chemotherapy regimen
with future alidomide and rituximab as first-line therapy.

Radioimmunotherapy alone should only be used as initial treatment
for patients with limited FL.
Two radioimmunotherapy drugs have been studied, but 131I tositumomab is no longer commercially available
.
90 Yttrium-ibritumomab-tiuxetan was also used as the sole initial treatment, with excellent results but limited
follow-up.

Radioimmunotherapy is also used for consolidation therapy
after induction of conventional chemotherapy in patients with FL.
Results from a phase III trial comparing 90 yttrium-ibritumomab tiuxetan with induction chemotherapy CR or PR followed by observation in patients with treatment-novice FL
are reported.
It is important to note that most patients did not receive rituximab and induction chemotherapy
at the same time.
At year 8, patients with PR or CR treated with 90 yttrium-ibritumomab tiuxetan had a median improvement of about 36 months
.
In contrast to this study, a randomized trial comparing CHOP + rituximab with CHOP + 131I tositumomab did not observe any difference
in PFS between the two groups.
Based on these and other studies, and the lack of general availability of these treatment modalities, radioimmunotherapy is rarely used in patients with
FL.

High-dose chemotherapy and autologous stem cell transplantation (SCT) have been used for consolidation after the first remission in specific FL patients, with many studies often predating the widespread use
of rituximab.
About 50% of patients are disease-free for 10 years or more after autologous SCT, but an increased
risk of secondary malignancies, including MDS, AML, and solid tumors, is found at long-term follow-up.
Several randomized trials evaluating the role of autologous SCT following induction therapy in patients with treatment-naïve FL have demonstrated significant improvement in PFS but no effect on OS; One of the reasons for the lack of effect on the OS is the excessive
number of secondary malignancies.
Although allogeneic SCTs may cure patients with FL, allogeneic SCTs are mostly reserved for patients with multiple relapses or refractory because
treatment-related mortality is significantly higher than autologous SCTs.

Indolent NHL can progress to high-grade histologic subtypes such as DLBCL, with a post-diagnostic risk of 2%
per year.
Patients with BR and rituximab who progressed within 24 months of maintenance therapy had a higher incidence of
histological transformation.
In a recent retrospective analysis, 13% of patients progressed early, of which 76% underwent histological transformation
.

A subgroup of indolent NHL patients transitioning to more aggressive histologic may achieve complete remission with CHOP-like chemotherapy, particularly at the time of initial treatment, where approximately 30% to 50% of patients can be cured
with high-dose chemotherapy followed by autologous hematopoietic cell transplantation.
Retrospective studies of patients with histologically transformed rituximab in the era have shown that autologous SCT consolidation remission after chemoimmunotherapy is superior to chemoimmunotherapy alone, with 55 versus 40 percent
of 5-year OS.
However, r-chop has a favorable outcome even in the absence of autologous SCT, with a 5-year OS of 64%, particularly in patients
who have not previously received FL therapy.
In addition, patients who have transformed at diagnosis have a higher 5-year survival rate than those who convert late (84% and 51% of 5-year OS, respectively).

The authors' practice is that consolidation therapy is performed after R-CHOP if the patient has transitioned after prior FL therapy, whereas for treatment-naïve patients with histological transformation who achieve CR after R-CHOP therapy, R-CHOP therapy is used
alone.

Treatment of relapsed FL

There are many options for the treatment of patients with relapsed FL, ranging from rituximab monotherapy to combination chemotherapy plus rituximab, radioimmunotherapy, kinase inhibitors, and, in selected patients, SCT
.

The SAKK study evaluated rituximab monotherapy in patients with relapsed FL and included patients with newly diagnosed, relapsed, or refractory FL who were treated
with rituximab administered 4 times a week.
Patients in remission or stabilization at week 12 were randomly observed or maintained once every 2 months for a total of 4 sessions
.
At long-term follow-up, 35% of respondents remained in remission at 8 years
.
However, it is uncertain whether response data for rituximab monotherapy are as high or durable
as in patients who did not receive rituximab plus chemotherapy induction therapy.

The response rate for patients refractory to rituximab with obinutuzumab was 55%, with a median PFS of 11.
9 months
.
Studies of obinutuzumab in combination with chemotherapy have shown response rates of 93% to 98%
in patients with relapsed and refractory FL.

Chemotherapy combined with rituximab enhances the efficacy
of recurrent FL.
The largest of these studies treated selected patients with relapsed FL who had not previously received anthracyclines or rituximab-containing regimens, randomized patients to CHOP or R-CHOP, and patients in remission randomized to rituximab maintenance therapy for 2 years or observation
.
Results The overall and CR rates in the R-CHOP group were significantly improved, and the median PFS improved for about 12 months.
At a median follow-up of 6 years, rituximab maintenance therapy also improved PFS by 2.
4 years; OS at 5 years after maintenance was 74% compared with 64%
in the observation-only group.
It is important to note that patients have not been treated with rituximab and anthracyclines, so their current utility is limited
.

PFS advantages
of adding rituximab were also confirmed in a randomized study using fludarabine, cyclophosphamide, and mitoxantrone (FCM) with or without rituximab.
Phase II studies of many other drugs in combination with anti-CD20 antibodies have shown high response rates, including the BR study, where the ORR was 90% and the median PFS was 2 years; In contrast, bendamustine monotherapy has an ORR of only 77% for recurrent FL, and the median duration of response is 6.
7 months
.
Bendamustine + obinutuzumab for 6 cycles followed by ocinutuzumab maintenance therapy for 2 years, which was better than bendamustine monotherapy for 6 cycles, and the toxicity was similar; PFS was 26 months in the bendamustine + obinutuzumab group compared with 14 months in the bendamustine monotherapy group; In addition, combination therapy has significant OS advantages
.
All of these studies support the inclusion of rituximab in chemotherapy regimens
for relapsed FL.

Lenalidomide + rituximab has also been explored
in patients with relapsed and refractory FL.
The combination therapy had a higher ORR (70% vs.
53%) and a longer time to disease progression by 1 year
.
A phase III randomized study comparing lenalidomide + rituximab versus rituximab monotherapy in previously treated FL patients showed a non-statistically significant
improvement in PFS compared with rituximab monotherapy (39% and 14%, respectively).

Lenalidomide + obinutuzumab is also being explored
in relapsed and refractory FL.
All patients in the study had previously received at least one rituximab-based regimen with 6 cycles of lenalidomide 20 mg induction therapy combined with monthly obinutuzumab 1000 mg for 6 cycles, followed by 12 months of lenalidomide 10 mg + obinutuzumab 1000 mg maintenance therapy (given every 2 cycles), followed by 1 year of maintenance therapy with obinalidomb (every 8 weeks).

。 The ORR was 79% and the CR was 38% at the end of induction; Event-free survival at 2 years was 62%, PFS 65%, and OS 87%; The most common adverse events were weakness, neutropenia, bronchitis, diarrhoea, and muscle cramps, with neutropenia being the most common grade ≥ grade 3 adverse event, with one patient dying of febrile neutropenia
.

Anti-CD20 radioimmunotherapy agents are also used in patients with relapsed and refractory FL with response rates ranging from 60% to 80% and a median PFS of 12 months, but about 20% to 37% of patients achieving CR have a median to progression time of about 4 years
.
These radioimmunoconjugates are rarely used for logistical reasons, and 131I preparations have been withdrawn from the market
.

Despite the general lack of use of radioimmune conjugates, FL remains extremely responsive
to radiation therapy.
Low-dose RT (eg, 4 Gy total) is an excellent choice for relieving patients with symptoms associated with a single disease site, with a CR rate of 57% and an ORR of 82%.

Potential toxicity is site-dependent but generally very well
tolerated.

The use of autologous or allogeneic hematopoietic cell transplantation in FL is controversial and the subject of
many clinical trials.
Numerous pre-marketing phase II studies of rituximab, including high-dose chemotherapy and autologous SCT, suggest that PFS and OS prolongation
may occur in approximately 40% of patients with recurrent disease with good performance status and sensitivity to chemotherapy.
The only phase III randomized study comparing autologous SCT with conventional chemotherapy in patients with relapsed FL (CUP study) demonstrated higher PFS and OS with autologous SCT but no benefit
from clearing stem cell grafts.
A retrospective analysis of patients receiving autologous SCT after salvage therapy with rituximab did not show a benefit of autologous SCT compared with usual care; Unfortunately, as with autologous SCT in initial remission, secondary malignancies, including solid tumors and MDS/AML
, have been reported after autologous SCT.

A phase III study of rituximab in patients with relapsed FL for in vivo tumor cell clearance prior to autologous SCT followed by maintenance of rituximab therapy for 2 years after autologous SCT resulted in PFS improvement but no OS benefit
in patients receiving rituximab for in vivo clearance, maintenance, and a combination of both, compared with those not receiving rituximab.
This option has not yet been widely adopted
.

Allogeneic SCT is also being studied in patients with recurrent FL, and both myeloablative and reduced-intensity pretreatment (RIC) methods have been used; Unfortunately, however, treatment-related mortality with myeloablative pretreatment is as high as 40%, although the recurrence rate is less than 20%.

RIC allogeneic SCT is favored due to the low treatment-related mortality, but relapse rates have been reported to be higher than with conventional myeloablative pretreatment
.
The role of allogeneic SCT versus autologous SCT in the treatment of FL remains uncertain
.
A retrospective analysis of the NCCN database found that the 3-year OS of autologous SCT was significantly higher than that of allogeneic SCT (87% vs.
61%)
.
Of course, for younger patients with greater drug resistance, allogeneic SCT remains a potential treatment option
for recurrent FL.
However, given the wide diversity of other treatment options, autologous and allogeneic SCTs are used in FL less frequently than in the past
.

Autologous SCT may be most beneficial
in patients with early relapse.
Several retrospective analyses have reported a 5-year OS of 70%
in this patient population after autologous SCT.
Data generated by the International Center for Blood and Bone Marrow Transplantation Research and the National Lymphatic Care Study suggest that patients who have failed early treatment with early autologous SCT have a higher 5-year OS than those who do not receive autologous SCT (73% vs.
60%)
.
However, with the advent of CAR-T therapy in FL, the role of autologous SCT in early recurrence will need to be re-evaluated, as this may ultimately be a patient population
that can benefit from CAR-T cell therapy.

New solutions

There are many new protocols for treating patients with FL, including monoclonal antibodies, individual genotype vaccines, immunomodulators, kinase inhibitors, and CAR-T cells
.

Immunostimulants, including IL2 and CpG, to enhance the activity of rituximab have been explored, but have so far had limited
effect on enhancing the therapeutic efficacy of rituximab.
Another area is active immunity, which focuses on unique forms as antigens, with 3 randomized studies using KLH-conjugated unique forms after induction of remission in patients with follicular NHL, of which only 1 study showed improvement
in PFS.
However, induction chemotherapy is intensive, and remission must continue until 12 months
before vaccination begins.
Based on these studies, no further individual genotype vaccination
was performed in FL.
Vaccine research using neoantigens and other methods is ongoing
.

B-cell kinases are targets for FL therapy, and kinase inhibitors targeting PI3 kinase and BTK have been extensively studied
.
In patients with relapsed and refractory FL, idelalisib (PI3 kinase δ subtype inhibitor) was the first kinase inhibitor studied, with an ORR of 57% and a median DOR of 12.
5 months
.
Copanlisib is an intravenous PI3 kinase pan-I inhibitor with similar
response rates to idelalisib in relapsed FL.
The other two PI3 kinase inhibitors, duvelisib (targeting γ and δ subtypes) and umbralisib, have similar
activities to idelalisib and Copanlisib.
In fact, idelalisib, copanlisib, idelalisib, and umbralisib were all originally approved by the FDA for the treatment of relapsed/refractory FL.

However, all drugs currently have been voluntarily withdrawn from FDA approval due to the increased risk of death from these drugs in CLL studies
, with the exception of copanlisib.

The CHRONOS-3 study compared copanlisib + rituximab with rituximab + placebo in relapsed indolent non-Hodgkin lymphoma (including FL) with a median PFS of 21.
5 and 13.
8 months, respectively (statistically significant difference), but no improvement
in OS.
The most common grade 3 or 4 adverse events in the copanlisib group were hyperglycemia and hypertension, with 47% experiencing serious adverse events during treatment compared with 18% of those receiving placebo; One patient in the Copanlisib group died of pneumonia
.
In general, common toxicities of PI3 kinase inhibitors include infections, bone marrow suppression, and inflammatory toxicities such as pneumonia, hepatitis, and colitis
.
The authors recommend prevention of opportunistic infections (e.
g.
, Pneumocystis jirovecii) in CMV IgG-positive patients and monitoring for CMV reactivation
.

Overall, the future of PI3 kinase inhibitors in B-cell malignancies remains uncertain
.
Due to safety concerns with other PI3K kinase inhibitors, authors typically retain copanlisib for patients who
are not suitable or have exhausted other treatment options.

The BTK inhibitor ibrutinib has limited efficacy in FL (ORR 21%)
.
A randomized study of patients with FL who had received at least 2 prior current therapies, including alkylating agents and anti-CD20 antibodies, compared zebrutinib plus obinutuzumab with obinutuzumab monotherapy, yielded an ORR of 68.
3% in the combination group versus 45.
8% in the obinutuzumab monotherapy group; The median PFS was 27.
4 months and 11.
2 months
, respectively.
The incidence of atrial fibrillation and major bleeding in the zebrutinib group was 0.
7% and 1.
4%, respectively, while 5.
6% of patients in the combination group and 9.
9% of patients in the obinutuzumab group experienced adverse events
in treatments that led to death.
A combination of aclotinib and obinutuzumab is also being studied
in FL.
Although some studies of BTK inhibitors in combination with anti-CD20 antibodies have yielded promising results, and studies of combination therapies and non-covalent BTK inhibitors in FL are ongoing, the authors did not use BTK inhibitor-based therapies for the treatment of recurrent FL
outside of the clinical trial context.

TAZEMETOSTAT

EZH2 is a histone methyltransferase that is essential for germinal center formation, and approximately 20% of FLs carry EZH2-activated mutations that promote lymphoma proliferation and immune evasion
.
Even FL cases of wild-type EZH2 are presumed to rely on EZH2 for growth and survival
.

Tazemetostat is an oral inhibitor of mutant and wild-type EZH2 in an open-label, non-randomized study of patients with relapsed or refractory grade 1 to 3B FL after at least 2 prior systemic therapies receiving Tazemetostat 800 mg orally twice daily for 2 years
。 Patients were divided into EZH2 mutation and EZH2 wild-type cohorts, with an independent radiological review ORR of 69% in the EZH2-mutated cohort and 35% in the EZH2 wild-type cohort; The median DOR was 10.
9 months in the EZH2 mutation cohort and 13 months in the EZH2 wild-type cohort; The median PFS was 13.
8 months and 11.
1 months
, respectively.
However, despite the initial difference in responses based on EZH mutation status, subsequent propensity-score match analysis suggests that response rates may be similar
if the 2 groups are closer to a match.

CAR T-cell therapy

In the pivotal ZUMA-5 study, 124 patients with FL who had received at least 2 prior FL treatments, including alkylating agents and anti-CD20 antibodies, received fludarabine and cyclophosphamide cleansing, followed by axicabtagene ciloleucel (axi-cel).

。 Results The ORR of FL was 94%, CR was 77%, and the median DOR was not reached.
At 18 months, the estimated proportion of patients who maintained remission was 65.
6%; The most common grade ≥ 3 adverse events were cytopenia (70%) and infection (18%), with grade 3 cytokine release syndrome occurring in 7% of patients ≥and grade ≥ neurological events
occurring in 19% of patients.
Four patients died from adverse events, one of which was considered treatment-related
.

In the pivotal ELARA study, 97 patients with FL who had previously received at least 2 prior systemic therapies or relapsed after autologous SCT received fludarabine and cyclophosphamide cleanse, followed by tisagenlecleucel (tisa-cel).

The ORR at week 8 was 86.
2% and the CR was 69.
1%; There was no ≥ grade 3 cytokine release syndrome, and 3.
3% of patients ≥developed grade 3 neurological adverse events; No dosing-related deaths occurred; The 1-year PFS was 67%, but 86%
of patients achieved CR.
Disease progression, high metabolic tumor volume, and ≥ 5-line prior treatment within 24 months of prior treatment predict worse response
.

There are no head-to-head trials of CAR-T products to definitively compare efficacy and toxicity
.

Other immunotherapies

Polatuzumab vedotin is an antibody-drug conjugate
.
In a small group of patients with relapsed FL, polatuzumab vedotin plus rituximab had an ORR of 70% and a CR of 45%.

Polatuzumab vedotin in combination with lenalidomide and rituximab also showed favorable activity
in the treatment of recurrent FL.

Bispecific T cell adaptors (BiTEs) exhibit excellent activity
in relapsed/refractory B-cell malignancies, including FL.
For example, in a phase II trial of anti-CD3/CD20 BiTE mosunetuzumab, the CR rate was 60%; Cytokine release syndrome occurs in 44% of patients, but is predominantly grade 1 (26%) or grade 2 (17%), usually occurring only in the first cycle; No neurotoxic or fatal adverse events
were reported.
In the phase I/II trial against CD3/CD20 BiTE epcoritimab, patients with FL had an ORR of 90% and a CR of 50%; CRS occurs in 59% of patients, but all are grade
1 or 2.
In phase I/II trials, the ORR of anti-CD3/CD20 BiTE glofitimab was 70.
5% and FL was 47.
7% pre-treatment with obinutuzumab; The incidence of grade 3 CRS and neurological events is low
.

summary

FL is the most common form of indolent B-cell lymphoma, and most FL is a chronic, incurable disease, although it has a long natural history and often decades of survival
.
A small proportion of patients presenting with limited-stage disease can be cured with radiation therapy, many patients with advanced disease can be observed without disease-related symptoms or complications, and rituximab alone or in combination with chemotherapy is very effective but not curable
for patients requiring treatment.
Recent studies have shown that lenalidomide and rituximab are chemotherapy-free alternatives
in both first-line and relapsed patients.

Depending on previous treatment and DOR, most patients with recurrent FL can receive anti-CD20 with or without chemotherapy
.
Even in the absence of an obvious EZH2 mutation, Tazemetostat is an option
for later treatment.
Although copanlisib is still on the market for the treatment of recurrent FL, the role of PI3 kinase inhibitors in FL remains uncertain due to the increased risk of death observed in the CLL study of PI3 kinase inhibitors and the voluntary withdrawal of idelalisib, duvelisib, and umbralisib in FL, but the authors reserved copanlisib for patients who
have exhausted other treatment options.

Patients with relapse or prior severe pretreatment within 24 months of chemoimmunotherapy should be referred to a specialized center for evaluation
for CAR-T cell therapy or autologous SCT.
Allogeneic SCT is highly effective but rarely necessary and should be reserved for intensive pretherapy patients
who have exhausted other treatment options, including CAR-T cells.
Despite the excellent prognosis of FL, the disease can be fatal in a subgroup of patients, and histologic transformation remains a major problem
.

References

Eric Jacobsen.
Follicular lymphoma: 2023 update on diagnosis and management.
Am J Hematol .
2022 Sep 17.
doi: 10.
1002/ajh.
26737.

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