Professor Xu Bing: Progress in the treatment of follicular lymphoma|The First National Lymphocytic Disease Academic Conference of the Chinese Medical Association

Lymphocytic disease is currently one of the most vigorously developing fields in hematology at home and abroad.
In recent years, remarkable achievements have been made in disease pathogenesis, targeting and immunotherapy.

In order to promote domestic and international peer exchanges, the First National Lymphocytic Disease Academic Conference of the Chinese Medical Association and the 2021 International Lymphoma Update Symposium will be held in Chengdu, Sichuan Province from April 16-18, 2021.

At the meeting, Professor Xu Bing from the First Affiliated Hospital of Xiamen University introduced the progress of the treatment of follicular lymphoma (FL).
Yimaitongxian organized the following for readers.

FL is a common indolent lymphoma.
In European and American countries, the 5-year overall survival (OS) rate can reach 89%; in my country, the 5-year OS rate can reach more than 80%.

The overall efficacy of FL is good, and the mortality rate shows a downward trend year by year.

Professor Xu Bing mainly focused on the problems of newly diagnosed FL, relapsed/refractory FL treatment and other issues.

First-diagnosed FL treatment strategy Early FL treatment options Professor Xu Bing said that the treatment goals of FL patients in different stages are different, and stratified treatment is particularly important.

The treatment goal of early FL patients (approximately 5%-10%) is "cure", and radiotherapy is still the main clinical practice.

Studies have shown that radiotherapy in the affected field combined with CD20 monoclonal antibody can further improve the efficacy and reduce the recurrence rate.

The new NCCN guidelines in 2021 added some new treatment options.
The new guidelines point out that immunochemotherapy can be used for limited-period patients who are not suitable for radiotherapy for large intra-abdominal or mesenteric masses.

Treatment options for advanced FL For patients with advanced FL (approximately 90%-95%), if there are indications for treatment, the treatment plan will be individualized; if there are no indications for treatment, wait for observation and follow-up regularly.

Individualized treatment options include BR regimen (rituximab combined with bendamustine), R-CHOP regimen (rituximab combined with cyclophosphamide, doxorubicin, vincristine and prednisone), R -CVP regimen (rituximab combined with cyclophosphamide, vincristine and prednisone) or no chemotherapy regimen R2 (rituximab + lenalidomide), followed by sequential maintenance therapy.

Professor Xu Bing said that there is no difference between the first-line options to improve OS, and different clinicians may choose treatment options based on different clinical conditions and patient wishes.

In addition, for FL 3b patients, clinically refer to the treatment strategy of diffuse large B-cell lymphoma (DLBCL).

01Otuzumab vs.
rituximab GALLIUM study compared the new generation of CD20 monoclonal antibody otuzumab (G) combined with chemotherapy and traditional rituximab (R) combined with chemotherapy.
It has not been received in the past Efficacy in treated CD20-positive FL patients.

The results showed that compared with R-chemotherapy, G-chemotherapy reduced the risk of progression, recurrence, and death in FL patients by 34%, and reduced the relative risk of disease progression (POD24) events within 24 months by 46%; There is no significant difference between the two solutions in terms of safety.

In addition, the results of the Chinese subgroup of patients are consistent with the results of the overall patient.

Professor Xu Bing said that G-chemotherapy is the world's first regimen that surpasses R-chemotherapy in first-line FL treatment.

At present, the NCCN guidelines and the CSCO guidelines have included the otuzumab combined chemotherapy regimen as the first-line treatment recommendation for FL.

02BR regimen vs R-CHOP regimen STiL-1 study and Bright study both show that BR regimen is superior to R-CHOP regimen (p values ​​are 0.
0072 and 0.
582, respectively).
In addition, GALLIUM study also shows that BR regimen has complete metabolic remission (CMR) The rate is better than that of the R-CHOP regimen, and the incidence of adverse events (AE) of BR regimen≥3 is lower than that of the R-CHOP regimen.

However, a study published in the Journal of Blood in 2020 showed that for newly diagnosed FL patients with high SUV, the R-CHOP regimen is significantly better than the BR regimen.

The results of the 03R2 vs R-chemo (R-CHOP, BR, R-CVP) RELEVANCE study (R2 vs R-chemo) showed that there was no significant difference in progression-free survival (PFS) and OS between R2 and R-chemo.

Subgroup analysis showed that the efficacy of R2 was similar to that of R-CHOP, inferior to BR, and superior to R-CVP.

The latest data in 2021 shows that the 8-year PFS rate of R2 first-line treatment of FL is 65%, the 8-year OS rate is 98%, and the disease progression (POD24) rate within 24 months is 13%.
The long-term follow-up data of this study It is proved that the "chemo-free" program can achieve similar effects as the "R-chemo" program.

04Exploration of "re-optimization" treatment plan Clinically, some exploration of "re-optimization" plan is also carried out for the first-line treatment plan.

Studies have shown that BR combined with bortezomib or lenalidomide regimen does not improve the survival rate of FL patients.
In addition, the combination of R2 regimen and ixazomib does not significantly improve the survival of FL patients compared with R2 regimen alone.

The results of the Phase 2 study of otuzumab combined with lenalidomide in the first-line treatment of FL were more eye-catching.
The results showed that the overall response rate (ORR) reached 96%, the complete response (CR) rate reached 94%, and the 2-year PFS rate reached More than 90% and only 6% of patients have POD24.
Professor Xu Bing expressed his expectation for the results of the Phase 3 study.

Treatment strategies for relapsed/refractory FL Professor Xu Bing emphasized that for patients with relapsed/refractory FL, evaluation before initiation of treatment is particularly important, including retaking biopsy to rule out transformation, assessing the patient’s general condition and disease status, and understanding previous treatment options and To alleviate the situation, choose individualized treatment strategies according to different situations.

For patients who have not received chemotherapy before, BR and R-CHOP can be selected; for patients who have previously received BR, the most common alternative is R-CHOP, but there is no clinical evidence to suggest its effectiveness.
Xu Bing The professor said that for patients with recurrence time> 2 years, you can consider repeating the BR regimen; for patients who have previously received R-CHOP therapy and are resistant to rituximab, otuzumab can be selected for treatment. The results of a phase 1/2 study of otuzumab combined with lenalidomide (Glen regimen) in patients with relapsed/refractory FL showed that the median follow-up was 17.
7 months, the ORR reached 100%, and the CR rate reached 75%, 2 years The PFS rate is 74%, and Professor Xu Bing said that the program is worth looking forward to.

Subsequently, Professor Xu Bing introduced the progress of targeted therapy drugs for relapsed/refractory FL.
There are many targeted drugs for relapsed/refractory FL, mainly including EZH2 inhibitors (Tazemetostat), PI3K inhibitors (Parsaclisib, Umbralisib), and cereblon Modulator (Avadomide), BCL-2 inhibitor (Venecla), bispecific antibody (Mosunetuzumab), CAR-T cell therapy, etc.

A study published in The Lancet showed that Tazemetostat as a single agent can effectively treat FL (1-3b) patients who relapse after multi-line therapy.
The study included 99 patients who had previously received ≥2 line systemic therapy.
Among them, 45 cases were EZH2 mutant and 54 cases were EZH2 wild type.

The results showed that the EZH2 mutant group had an ORR of 69%, a CR rate of 13%, and a median PFS of 13.
8 months; the EZH2 wild-type group had an ORR of 35%, a CR rate of 4%, and a median PFS of 11.
1 months.

In short, no matter whether EZH2 is mutated or not, the use of EZH2 inhibitors can achieve better PFS.

Therefore, the NCCN guidelines recommend: For patients with EZH2 mutation-positive and refractory and relapsed FL patients who have received more than 2 lines of treatment, EZH2 inhibitors may be considered; and patients with EZH2 mutation-negative but no other alternative treatment options may also choose EZH2.
Inhibitor.

Currently, the study of Tazemetostat combined with rituximab in the treatment of patients with relapsed/refractory FL is underway.

In addition, Umbralisib, Avadomide, Venecla, Mosunetuzumab and other drugs have also played an excellent role in patients with relapsed/refractory FL.

Professor Xu Bing said that targeted therapy is still the current research hotspot for refractory and relapsed FL.
With the deepening of research, it is expected that in the future, individualized treatment plans will be selected according to the different genetic characteristics of patients.

In 2020, ASH updated relevant data on CAR-T cell therapy for refractory and relapsed FL.
Both Tisagenlecleuc and Axi-Cel showed good therapeutic effects.

Professor Xu Bing said that CAR-T cell therapy has shown a high remission rate and controllable safety in patients with relapsed/refractory FL.
Even in people who relapse after CAR-T cell therapy, CAR-T cell therapy can still make patients Benefits deserve further clinical attention.

In the end, Professor Xu Bing emphasized that in the era of new drugs, attention should be paid to the standardized and individualized treatment of FL.

In addition, I believe that with the deepening of clinical research, more treatment plans will be approved for clinical use in the future, benefiting patients.

Professor Xu Bing, Chief Physician, Professor, and Doctoral Supervisor, Director of the Institute of Hematology, Xiamen University School of Medicine, Director of the Department of Hematology and Director of the Department of Internal Medicine, Xiamen University First Affiliated Hospital, Visiting Scholar, University of Cambridge, UK Cooperative Supervisor for Doctoral Students, Wolverhampton University, UK Chinese Society of Geriatrics Chairman of the Leukemia Academic Working Committee Member of the Standing Committee of the Hematology and Oncology Professional Committee of the Chinese Anti-Cancer Association Member of the Standing Committee of the Lymphoma Professional Committee of the Chinese Anti-Cancer Association Member of the Standing Committee of the Anti-Leukemia Alliance of the Chinese Society of Clinical Oncology Member of the Lymphoma Group of the Chinese Medical Association Oncology Branch Committee members stamp "read the original text", we make progress together