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Follicular lymphoma (FL) is the most common indolent B-cell non-Hodgkin lymphoma, although some patients show long-term remission after anti-CD20 monoclonal antibody-based immunochemotherapy, 20-30% still have FL Patients experience early progression, and 2-3% of patients transform into aggressive lymphoma each year
.
How to identify patients at high risk of treatment failure at an early stage has become a challenge in FL management
.
The FL International Prognostic Index (FLIPI) and FLIPI2 scores, including baseline clinical and standard biological parameters, do not accurately identify patients with early relapse associated with an increased risk of death
.
FDG positron emission tomography (PET) is used in routine practice to stage disease prior to FL treatment and to identify sites of FDG uptake with high risk of transformation
.
PET status after induction therapy appears to be more predictive of outcomes in patients with FL than FLIPI or FLIPI2 scores, with most patients achieving a PET-negative first remission for several years
.
However, a key challenge in the management of FL is to identify those patients at higher risk of failure with standard therapy prior to treatment
.
Among the baseline PET measures, total metabolic tumor volume (TMTV) was a strong predictor of FL outcome independent of FLIPI2
.
Systemic maximal standardized uptake (SUVmax) at baseline has been used to predict outcomes in patients with mantle cell lymphoma (MCL), but pretreatment SUVmax is significantly more important for patients receiving rituximab(R) in combination with chemotherapy followed by R maintenance (Rm) therapy The predictive value of prognosis in FL patients remains unclear
.
Based on this, some researchers have carried out related studies to determine the value of PET indicators at baseline in predicting the prognosis of FL patients, and to establish a link with the molecular markers of FL tumor cells and their immune cell infiltration
.
STUDY METHODS The study training cohort included 48 FL patients and the validation cohort included 84 FL patients
.
Gene expression analysis was performed by extracting RNA from available frozen tumor samples (N=38/48), after DNA extraction from 51 available FL FFPEs (n=33 from the training cohort, n=18 from the validation cohort), using participating Lymphopanel for 43 genes in B-cell lymphomagenesis samples were sequenced on Illumina MiSeqDx
.
POD24 was defined as primary refractory disease (partial response not achieved) that had progressed, transformed, or relapsed within 24 months of diagnosis
.
Findings 01 Study Population The median age of the entire study population was 61.
8 years (range: 28-87 years)
.
The majority of patients (84%) were clinically advanced; 54% were high-risk and 34% were intermediate-risk according to FLIPI
.
Ninety-one percent of patients had histological grades 1-2
.
Treatment received was comparable between groups, with the majority (89%) receiving R in combination with CHOP or CHOP-like and Rm
.
During a median follow-up of 43.
4 months, 10 patients died from disease progression and 3 from secondary malignancies
.
02 SUVmax at baseline was associated with risk of progression in FL patients The median baseline SUVmax of the 132 patients enrolled in the study was 9.
15
.
Baseline SUVmax was independent of neither baseline TMTV nor maximum lymph node size
.
Notably, the median SUVmax of the 12 FL grade 3A patients was not significantly different from that of grade 1-2 patients
.
The investigators determined that an SUVmax of 14.
5 was an accurate threshold that could distinguish patients with different outcomes
.
Patients with SUVmax>14.
5 had significantly worse PFS than those with SUVmax≤14.
5 (P=0.
00046), with 2-year PFS rates of 54% vs 86% (P=0.
006), respectively (Figure 1A and 1B)
.
The results of univariate analysis showed that the factors associated with patients' PFS were SUVmax, FLIPI, elevated lactate dehydrogenase (LDH), and elevated β2-microglobulin (β2-MG); treatment type (R combined with chemotherapy vs R combined with lena) hydrazine), and baseline TMTV had no effect on patient PFS (Figure 1A)
.
Multivariate Cox model analysis showed that SUVmax was the only factor affecting the prognosis of patients with PFS (P=0.
0066)
.
POD24 patients accounted for 25%, and POD24 events were more common in patients with SUVmax>14.
5 than patients with SUVmax≤14.
5, 55% and 15%, respectively
.
The median overall survival (OS) of patients with SUVmax>14.
5 and SUVmax≤14.
5 was 23.
9 months and not reached, respectively (P=0.
06)
.
Figure 1: Clinical impact of SUVmax and TMTV at baseline in FL patients at baseline 03 Baseline SUVmax is not associated with FL immune infiltration To investigate whether immune infiltration markers in baseline biopsies are associated with increased FDG uptake, we compared SUVmax >14.
5 and ≤ 14.
5 patients with immune profiles determined by immunochemical (IHC) and transcriptomic methods
.
The 38 available frozen FL samples from the training cohort and 148 of the 1446 NHL samples had higher IEGS33 scores, indicating upregulation of immune escape genes
.
Scatter plots of "IEGS33" versus "T cell activation" for all samples showed that FL samples clustered together, in contrast to most other NHLs (Fig.
2)
.
Tumor-infiltrating lymphocyte (TIL) PD-1 expression was found in 46%, 20%, and 34% of cases with perifollicular, intrafollicular, and diffuse patterns, respectively
.
PD-1+ cells and PD-L1+ cells accounted for 16% and 5% of CD3+ immune cells, respectively (Fig.
3A)
.
All ICP protein expression by IHC score in each sample closely correlated with their respective IEGS33 scores (Fig.
3B)
.
Figure 2: Functional immune status of FL samples from training cohort and previously published lymphoma cohort Figure 3: Immunohistochemical validation of IEGS33 overexpression in FL samples IHC analysis demonstrated CD3+ T cells, CD8+ T cells and CD163+ monocytes The median percentage of cells was 35%, 14%, and 11% of total immune cell infiltration, respectively (Fig.
4A)
.
As shown in Figure 4B, 20% of cases had high CD8+ T cell abundance (>30% immune cells) by IHC score, 40% had low (<10%), and 40% were moderate ( 10-30%)
.
Transcriptomic evidence of T cell activation in FL samples was consistent with and correlated with cytotoxic CD8+ T cells observed by IHC (Fig.
4C)
.
Figure 4: Immunohistochemical validation of T cell activation in FL samples by SES 04 DNA repair/tumor proliferation signature and SUVmax relationship We observed a relationship between SUVmax levels and DNA repair/proliferation signature scores (Figure 5A)
.
These findings were then validated at the protein level by scoring Ki-67 staining in FFPE samples
.
Ki67 staining was scored according to the percentage of Ki-67+ tumor cells determined by optical evaluation and quantified by automated image analysis solutions (Fig.
5B)
.
Using a cutoff value of 10%, Ki-67 immunostaining was found to be significantly associated with GO cell cycle DNA replication SES, BER SES and G2M checkpoint SES (Fig.
5C)
.
Furthermore, using an optimal Ki-67 cutoff value of 10%, we found that patients with FL grades 1-2 and 3A with ≥10% Ki-67 staining had significantly increased SUVmax levels (Fig.
5D)
.
Figure 5: Correlation between tumor proliferation signature and SUVmax in FL samples.
05 Baseline SUVmax may be influenced by tumor cell mutational signature.
Of the 33 available FL samples in the training cohort, targeted NGS identified 243 of 32 genes Non-synonymous changes (Fig.
6A)
.
The most common genetic mutations are KMT2D, CREBBP and BCL2
.
A recurrent missense mutation in EZH2 tyrosine 646 (Y646) was also found in 21% of cases
.
Ninety-four percent of patients carried mutations in genes related to epigenetic regulatory pathways, with lower frequencies of mutations in genes related to apoptotic pathways or immune response (Fig.
6B)
.
Mutation frequencies in these pathways did not vary with SUVmax levels (Fig.
6C)
.
Figure 6: Molecular analysis of FL samples.
Conclusions of the study.
The results of this study showed that SUVmax >14.
5 at baseline PET was associated with poorer PFS and higher risk of POD24 events in FL patients
.
Additionally, high SUVmax levels correlated with tumor cell proliferation, but not with cellular content in the tumor microenvironment
.
References: Cédric Rossi, Marie Tosolini, Pauline Gravelle, et al.
Baseline SUVmax is related to tumor cell proliferation and patient outcome in follicular lymphoma.
Haematologica.
2022 Jan 1;107(1):221-230.
Review: Quinta typesetting : Wenting execution: Wenting pokes "read the original text", we make progress together
.
How to identify patients at high risk of treatment failure at an early stage has become a challenge in FL management
.
The FL International Prognostic Index (FLIPI) and FLIPI2 scores, including baseline clinical and standard biological parameters, do not accurately identify patients with early relapse associated with an increased risk of death
.
FDG positron emission tomography (PET) is used in routine practice to stage disease prior to FL treatment and to identify sites of FDG uptake with high risk of transformation
.
PET status after induction therapy appears to be more predictive of outcomes in patients with FL than FLIPI or FLIPI2 scores, with most patients achieving a PET-negative first remission for several years
.
However, a key challenge in the management of FL is to identify those patients at higher risk of failure with standard therapy prior to treatment
.
Among the baseline PET measures, total metabolic tumor volume (TMTV) was a strong predictor of FL outcome independent of FLIPI2
.
Systemic maximal standardized uptake (SUVmax) at baseline has been used to predict outcomes in patients with mantle cell lymphoma (MCL), but pretreatment SUVmax is significantly more important for patients receiving rituximab(R) in combination with chemotherapy followed by R maintenance (Rm) therapy The predictive value of prognosis in FL patients remains unclear
.
Based on this, some researchers have carried out related studies to determine the value of PET indicators at baseline in predicting the prognosis of FL patients, and to establish a link with the molecular markers of FL tumor cells and their immune cell infiltration
.
STUDY METHODS The study training cohort included 48 FL patients and the validation cohort included 84 FL patients
.
Gene expression analysis was performed by extracting RNA from available frozen tumor samples (N=38/48), after DNA extraction from 51 available FL FFPEs (n=33 from the training cohort, n=18 from the validation cohort), using participating Lymphopanel for 43 genes in B-cell lymphomagenesis samples were sequenced on Illumina MiSeqDx
.
POD24 was defined as primary refractory disease (partial response not achieved) that had progressed, transformed, or relapsed within 24 months of diagnosis
.
Findings 01 Study Population The median age of the entire study population was 61.
8 years (range: 28-87 years)
.
The majority of patients (84%) were clinically advanced; 54% were high-risk and 34% were intermediate-risk according to FLIPI
.
Ninety-one percent of patients had histological grades 1-2
.
Treatment received was comparable between groups, with the majority (89%) receiving R in combination with CHOP or CHOP-like and Rm
.
During a median follow-up of 43.
4 months, 10 patients died from disease progression and 3 from secondary malignancies
.
02 SUVmax at baseline was associated with risk of progression in FL patients The median baseline SUVmax of the 132 patients enrolled in the study was 9.
15
.
Baseline SUVmax was independent of neither baseline TMTV nor maximum lymph node size
.
Notably, the median SUVmax of the 12 FL grade 3A patients was not significantly different from that of grade 1-2 patients
.
The investigators determined that an SUVmax of 14.
5 was an accurate threshold that could distinguish patients with different outcomes
.
Patients with SUVmax>14.
5 had significantly worse PFS than those with SUVmax≤14.
5 (P=0.
00046), with 2-year PFS rates of 54% vs 86% (P=0.
006), respectively (Figure 1A and 1B)
.
The results of univariate analysis showed that the factors associated with patients' PFS were SUVmax, FLIPI, elevated lactate dehydrogenase (LDH), and elevated β2-microglobulin (β2-MG); treatment type (R combined with chemotherapy vs R combined with lena) hydrazine), and baseline TMTV had no effect on patient PFS (Figure 1A)
.
Multivariate Cox model analysis showed that SUVmax was the only factor affecting the prognosis of patients with PFS (P=0.
0066)
.
POD24 patients accounted for 25%, and POD24 events were more common in patients with SUVmax>14.
5 than patients with SUVmax≤14.
5, 55% and 15%, respectively
.
The median overall survival (OS) of patients with SUVmax>14.
5 and SUVmax≤14.
5 was 23.
9 months and not reached, respectively (P=0.
06)
.
Figure 1: Clinical impact of SUVmax and TMTV at baseline in FL patients at baseline 03 Baseline SUVmax is not associated with FL immune infiltration To investigate whether immune infiltration markers in baseline biopsies are associated with increased FDG uptake, we compared SUVmax >14.
5 and ≤ 14.
5 patients with immune profiles determined by immunochemical (IHC) and transcriptomic methods
.
The 38 available frozen FL samples from the training cohort and 148 of the 1446 NHL samples had higher IEGS33 scores, indicating upregulation of immune escape genes
.
Scatter plots of "IEGS33" versus "T cell activation" for all samples showed that FL samples clustered together, in contrast to most other NHLs (Fig.
2)
.
Tumor-infiltrating lymphocyte (TIL) PD-1 expression was found in 46%, 20%, and 34% of cases with perifollicular, intrafollicular, and diffuse patterns, respectively
.
PD-1+ cells and PD-L1+ cells accounted for 16% and 5% of CD3+ immune cells, respectively (Fig.
3A)
.
All ICP protein expression by IHC score in each sample closely correlated with their respective IEGS33 scores (Fig.
3B)
.
Figure 2: Functional immune status of FL samples from training cohort and previously published lymphoma cohort Figure 3: Immunohistochemical validation of IEGS33 overexpression in FL samples IHC analysis demonstrated CD3+ T cells, CD8+ T cells and CD163+ monocytes The median percentage of cells was 35%, 14%, and 11% of total immune cell infiltration, respectively (Fig.
4A)
.
As shown in Figure 4B, 20% of cases had high CD8+ T cell abundance (>30% immune cells) by IHC score, 40% had low (<10%), and 40% were moderate ( 10-30%)
.
Transcriptomic evidence of T cell activation in FL samples was consistent with and correlated with cytotoxic CD8+ T cells observed by IHC (Fig.
4C)
.
Figure 4: Immunohistochemical validation of T cell activation in FL samples by SES 04 DNA repair/tumor proliferation signature and SUVmax relationship We observed a relationship between SUVmax levels and DNA repair/proliferation signature scores (Figure 5A)
.
These findings were then validated at the protein level by scoring Ki-67 staining in FFPE samples
.
Ki67 staining was scored according to the percentage of Ki-67+ tumor cells determined by optical evaluation and quantified by automated image analysis solutions (Fig.
5B)
.
Using a cutoff value of 10%, Ki-67 immunostaining was found to be significantly associated with GO cell cycle DNA replication SES, BER SES and G2M checkpoint SES (Fig.
5C)
.
Furthermore, using an optimal Ki-67 cutoff value of 10%, we found that patients with FL grades 1-2 and 3A with ≥10% Ki-67 staining had significantly increased SUVmax levels (Fig.
5D)
.
Figure 5: Correlation between tumor proliferation signature and SUVmax in FL samples.
05 Baseline SUVmax may be influenced by tumor cell mutational signature.
Of the 33 available FL samples in the training cohort, targeted NGS identified 243 of 32 genes Non-synonymous changes (Fig.
6A)
.
The most common genetic mutations are KMT2D, CREBBP and BCL2
.
A recurrent missense mutation in EZH2 tyrosine 646 (Y646) was also found in 21% of cases
.
Ninety-four percent of patients carried mutations in genes related to epigenetic regulatory pathways, with lower frequencies of mutations in genes related to apoptotic pathways or immune response (Fig.
6B)
.
Mutation frequencies in these pathways did not vary with SUVmax levels (Fig.
6C)
.
Figure 6: Molecular analysis of FL samples.
Conclusions of the study.
The results of this study showed that SUVmax >14.
5 at baseline PET was associated with poorer PFS and higher risk of POD24 events in FL patients
.
Additionally, high SUVmax levels correlated with tumor cell proliferation, but not with cellular content in the tumor microenvironment
.
References: Cédric Rossi, Marie Tosolini, Pauline Gravelle, et al.
Baseline SUVmax is related to tumor cell proliferation and patient outcome in follicular lymphoma.
Haematologica.
2022 Jan 1;107(1):221-230.
Review: Quinta typesetting : Wenting execution: Wenting pokes "read the original text", we make progress together
