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Follicular lymphoma (FL) is the second most common non-Hodgkin lymphoma and is clinically and molecularly heterogeneous
.
In recent years, there have been many advances in FL treatment, but about 20% of patients still have early progression or recurrence and poor
prognosis.
Early identification of high-risk patients with early treatment failure (ETF) and optimization of treatment regimens are of great
significance to reduce recurrence and improve survival outcomes for patients with FL.
Recently, the team of Professor Bai Ou of the First Hospital of Bethune of Jilin University published a study that uses a nomogram composed of three indicators such as SUVmax to predict high-risk patients with ETF in FL, which helps to screen out subgroups
of patients who may benefit from individualized targeted therapy.
To this end, Professor Bai Ou was invited to combine years of clinical experience and research results to share the prognostic model exploration and individualized treatment
of FL.
Yimaitong: In recent years, FL treatment has made great progress, but there are still some patients with poor prognosis, please talk about what unmet needs still exist in FL diagnosis and treatment based on clinical experience? What factors are associated with poor FL prognosis?
Professor Bai Gull
FL is derived from mature B cells, accounting for more than 20% of non-Hodgkin lymphoma (NHL) patients in Europe and the United States, and the proportion is slightly lower in China, about 10%, but the incidence is increasing year by year
.
With the application of anti-CD20 monoclonal antibodies, the therapeutic efficacy of FL has been significantly improved, and the median survival time can reach 18 years1
.
However, there are still many unmet clinical needs, and the following problems that seriously affect the prognosis of FL need to be paid great attention to in the treatment: (1) Pay attention to the early progression of FL disease, about 20% of patients progress (POD24) or relapse within 2 years of initial treatment, that is, early treatment failure (ETF), and POD24/ETF is an independent risk factor for poor prognosis of FL patients, and the survival prognosis of these patients is very poor
.
(2) At present, most FL patients cannot be completely cured and will experience repeated recurrences
.
With the increase in the number of recurrences, the prognosis of patients with FL is getting worse and worse, so the time of
first disease progression and recurrence should be extended as much as possible in treatment.
(3) Pay attention to FL large cell transformation, FL patients will have macrocytic transformation every year after diagnosis, and compared with patients initially diagnosed with diffuse large B-cell lymphoma (DLBCL), patients diagnosed with DLBCL after transformation have a worse
prognosis.
Yimaitong: FL is highly heterogeneous in clinical and molecular aspects, and early identification of high-risk patients of ETF is crucial to the selection of treatment options and improvement of prognosis.
Professor Bai Gull
Since the first prognostic evaluation model FLIPI-1 came out in 2004, there have been nearly 20 prognostic evaluation models, including FLIPI-1, FLIPI-2, PRIMA-PI, 23-gene, POD24-PI, FLEX, Bio-FLIPI, etc.
, each prognostic model evaluates FL prognosis from different angles, each with its own merits
.
However, the existing prognostic models still have certain limitations in predicting ETFs, and FLIPI-1 and FLIPI-2 predict ETFs purely from clinical factors, which is less accurate; Other models may require patients to undergo genetic testing, molecular biomarker testing, etc.
, which is difficult to popularize in primary hospitals and increases the economic burden of patients, so their promotion in clinical practice is limited
.
In conclusion, there is a lack of convenient, simple, accessible predictive models that do not increase the burden on doctors and patients, and there is currently no method to accurately predict the risk of early patient progression at the time of
diagnosis.
Yimaitong: It is understood that you and your team have established a nomogram composed of 3 independent variables (SUVmax≥12, Ki67>40%, β2MG>3 mg/L) to predict high-risk patients of ETFs in FL.
Professor Bai Gull
As early as 2012, our center has begun to evaluate FL patients with PET/CT before treatment, and by 2021 has accumulated more than 200 patients
.
A total of 127 eligible patients with FL were included in this review, and the initial treatment regimen for these patients was a combination regimen containing anti-CD20 monoclonal antibodies, i.
e.
, immunochemotherapy
.
In this study2, we constructed a nomogram (Figure 1) using three indicators≥ SUVmax12, β2MG>3mg/L, and Ki67>40% to predict the ETF risk of these 127 FL patients (training cohort), and validated it using data from Duke University Medical Center (validation cohort, n=95).
Figure 1 FL prognostic evaluation nomogram
The results showed that the nomogram could accurately predict high-risk ETF patients, and the sensitivity and specificity of the training cohort were 70.
8% and 83.
5%.
The validation cohort had a sensitivity of 84.
2% and a specificity of 68.
4%.
In addition, we divided patients in the two cohorts into three subgroups of ETF low-risk, intermediate-risk, and high-risk ETF (scores: 0-57.
5, 67.
5-100, and >100), and the results showed that the corresponding 5-year progression-free survival (PFS) and 5-year overall survival (OS) rates in the three subgroups of the two cohorts were significantly different (Figure 2).
Figure 2 PFS and OS of three subgroups of training cohort and validation cohort
It is worth mentioning that the three indicators SUVmax, β2MG and Ki67 used in the prognosis model are commonly used indicators of PET/CT, blood test and pathology, respectively, which are relatively easy to obtain in clinical practice, so the prognosis model is more simple, convenient, practical and highly
accessible.
.
Yimaitong: Based on your clinical experience, please talk about how to carry out individualized treatment for high-risk patients with ETF to reduce disease recurrence and early progression? Can high-risk patients benefit from the novel anti-CD20 monoclonal antibody obinutuzumab treatment?
Professor Bai Gull
If POD24/ETF is predicted prior to treatment, we usually prefer a regimen
containing the novel anti-CD20 monoclonal antibody obinutuzumab.
This is mainly based on the results of the global phase III GALLIUM study3, which showed that obinutuzumab can overcome early treatment failure and reduce the risk
of POD24 in treatment-naïve FL patients.
At a median follow-up of 34.
5 months, the obinutuzumab combination chemotherapy regimen (G-chemotherapy) reduced the risk of POD24 by 46% in treatment-no-treated FL patients (HR 0.
54; 95% CI: 0.
39, 0.
75; P=0.
0003) (Figure 3).
It can be seen that for patients at high risk of POD24/ETF, obinutuzumab-containing regimens are a good treatment option
.
Figure 3 GALLIUM findings: POD24
In addition, after screening high-risk patients of ETF/POD24, we will urge patients to undergo next-generation sequencing of genes, and then accurately select targeted therapy combination regimens in combination with next-generation sequencing results, such as patients with EZH2 mutations, it is recommended to choose CHOP regimens (cyclophosphamide, doxorubicin, vincristine, prednisone), and avoid choosing bendamustine-containing regimens, because the regimen combined with CHOP can overcome the poor prognosis caused by EZH2 mutations; If the patient has an abnormal BCL-2 gene or a mutation in the TP53 gene, choose BCL2-inhibitor combination therapy as soon as possible; If the patient is accompanied by PI3K gene mutations, it is recommended to choose PI3K inhibitors
.
In summary, we will combine the results of prognostic assessment models and next-generation sequencing to carry out individualized and precise targeted therapy for high-risk patients, so as to improve the efficacy of patient treatment and reduce disease progression or recurrence
.
Yimaitong: In the era of precision therapy, please talk about your prospects
for the future of FL personalized therapy.
Professor Bai Gull
With the gradual refinement of the classification of lymphoma, it has now developed to combine the patient's cell morphology (Morphology), immunology (Immunology), cytogenetics and molecular biology (Molecular) four aspects of MICM classification, its treatment also tends to be based on MICM molecular typing for precise targeted therapy, the future treatment of lymphoma will be based on standard treatment based on individualized precision targeted therapy
。 In short, on the one hand, standard and standardized treatment is carried out for patients without high-risk factors; On the other hand, individualized and precise targeted therapy
is carried out for high-risk patients.
With the continuous optimization of treatment options, there are now a variety of lymphomas that can be cured and become curable tumors; Lymphoma, such as FL, which cannot yet be cured, can also become a chronic disease
that can be managed and controlled like hypertension and diabetes.
Whether it is FL or other lymphomas, the goal of treatment is the same, that is, for low-risk patients, the proportion of patients who achieve cure or can be controlled like chronic diseases is increased; For high-risk patients, the proportion of life-threatening patients is reduced
.
In addition, it should be noted that patients with FL with low, intermediate, or no indications for treatment should not be over-treated, so as to avoid adverse factors caused by treatment affecting the quality of life and survival of
patients.
In short, the ultimate goal is to greatly improve
the overall treatment efficacy of lymphoma patients.
brief summary
FL is still difficult to cure, and early treatment failure seriously affects the prognosis of
patients.
The nomogram composed of SUVmax, Ki67 and β2MG by Professor Baiou's team is simple and convenient, which can effectively identify high-risk patients with early treatment failure of FL during diagnosis and guide the optimization of clinical treatment
.
The novel anti-CD20 monoclonal antibody obinutuzumab can significantly reduce the early progression of FL patients, and the selection of individualized precision targeted therapy regimens combined with genotyping is expected to further improve clinical efficacy and benefit more FL patients
.
Professor Bai Gull
Deputy Director of the Department of Hematology, Bethune First Hospital, Jilin University
Head of the Lymphoma Specialist Alliance of Bethune First Hospital of Jilin University
Member of the Lymphocytic Disease Group of the 11th Committee of the Hematology Branch of the Chinese Medical Association
The third director of the Chinese Society of Clinical Oncology (CSCO).
Member of the Standing Committee of the Lymphoma Professional Committee of the Chinese Anti-Cancer Association
Member of the Standing Committee of CSCO China Anti-Lymphoma Alliance (UCLI).
Member of the Standing Committee of the 5th Oncology Clinical Chemotherapy Professional Committee of the Chinese Anti-Cancer Association
Member of the Standing Committee of the First Committee of the Hematology Branch of the Chinese Geriatrics Society
Member of the Standing Committee of the Medical Oncology Branch of the China Association for the Promotion of International Exchanges in Healthcare
Member of CSCO China Anti-Leukemia Alliance (UCLI).
References:
1.
Tobin JWD, Keane C, Gunawardana J, et al.
Progression of Disease Within 24 Months in Follicular Lymphoma Is Associated With Reduced Intratumoral Immune Infiltration.
J Clin Oncol.
2019 Dec 1; 37(34):3300-3309.
2.
Wan X, Guo W, Wang X, et al.
Improving the prognostic ability of PET/CT SUVmax to identify follicular lymphoma with early treatment failure.
Am J Cancer Res.
2022 Aug 15; 12(8):3857-3869.
3.
Seymour JF, Marcus R, Davies A, et al.
Association of early disease progression and very poor survival in the GALLIUM study in follicular lymphoma: benefit of obinutuzumab in reducing the rate of early progression.
Haematologica.
2019 Jun; 104(6):1202-1208.
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