Professor Xu Bing: Diagnosis and Treatment of FL|The 4th China Chronic Lymphocytic Leukemia Conference

From March 19 to 21, 2021, the 4th China Chronic Lymphocytic Leukemia Conference was successfully held in Tianjin.

At the meeting, Professor Xu Bing from the First Affiliated Hospital of Xiamen University introduced the diagnosis and treatment of follicular lymphoma (FL).

Professor Xu Bing said that FL is a common indolent lymphoma, accounting for about 20-30% of all newly diagnosed non-Hodgkin's lymphomas (NHL) in European and American countries, and about 8% in China.

The disease progresses inertly, with a median survival time of more than 10 years, but most diseases will eventually relapse or transform, and the consequences are more serious.

Therefore, how to diagnose and treat FL in a scientific way is particularly critical to the survival of patients.

Professor Xu Bing mainly focused on the first-line treatment of newly diagnosed FL and targeted treatment of refractory and relapsed FL.

Newly diagnosed FL: Re-optimization of the first-line treatment plan.
For limited-stage FL, radiotherapy is still the main clinical treatment, and the affected field radiotherapy combined with CD20 monoclonal antibody is the main treatment method.

On the basis of radiotherapy, some new treatment options have been added to the new NCCN guidelines in 2021.
The new guidelines point out that limited-stage patients who are not suitable for radiotherapy for large intra-abdominal or mesenteric masses can be treated with immunochemotherapy with or without chemotherapy.

At the same time, a long-term study of patients with limited-stage FL published in Blood in 2020 showed that age is the only factor that affects the overall survival (OS) of patients, while other indicators such as lactate dehydrogenase (LDH) have no effect on the prognosis.
influences.Figure 1 FL diagnosis and treatment plan For advanced FL, the current clinical practice is mainly 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 treatment.

A study published in Blood in 2020 showed that for newly diagnosed FL patients with high SUV, the R-CHOP treatment plan was significantly better than the BR plan (Figure 2).

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

Figure 2 Comparison of the outcome of R-CHOP and BR treatment regimens.
The clinical "re-optimization" exploration of the first-line regimen mainly includes: BR combined with bortezomib or lenalidomide, rituximab combined with PI3K inhibitor, rituximab Anti-combined BTK inhibitor, R2 regimen combined with ixazomib.

Studies have shown that the combination of BR combined with bortezomib or lenalidomide does not improve the survival rate of FL patients; rituximab combined with BTK inhibitor ibrutinib has significant activity in the treatment of FL, with an overall response rate (ORR) of 75 % Above, and well tolerated; the R2 regimen combined with ixazomib did not significantly improve the survival of patients compared with the R2 regimen alone.

Do FL patients need to undergo autologous hematopoietic stem cell transplantation (ASCT) consolidation therapy after first-line treatment? The latest research data published in 2020 (Blood Adv (2020) 4(18): 4451-4462) shows that ASCT consolidation therapy has no significant improvement in the failure-free survival (FFS) and OS of the general population; subgroup analysis shows that at m7 -Among high-risk populations of FLIPI or POD24-PI, ASCT does not improve survival; this study also constructed a new PReDiCt-FL prognostic model through multivariate analysis.
The analysis found that ASCT in high-risk PReDiCt-FL patients can improve FFS, but not OS. Regarding the maintenance treatment of FL, the latest research data published in 2020 shows that extending the duration of rituximab maintenance treatment does not benefit survival.

Professor Xu Bing pointed out that the “re-optimization” of first-line treatment cannot significantly improve the treatment benefits of patients.
ASCT consolidation treatment and prolonged maintenance treatment time also cannot benefit patients.
Therefore, how to further improve the treatment efficiency of newly diagnosed FL patients? Further research is still needed.

Refractory and relapsed FL: Progress in targeted therapy Professor Xu Bing introduced that there are currently many targeted drugs for refractory and relapsed FL, mainly including EZH2 inhibitors, BTK inhibitors, PI3K inhibitors, cereblon protein modulators, and BCL-2 inhibitors , Bispecific antibodies, PD-1 antibodies, etc.

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

Why are EZH2 inhibitors so "respected" in FL targeted therapy? Professor Xu Bing said that many studies have shown that EZH2 inhibitors have good efficacy.

A study in The Lancet showed that Tazemetostat (EZH2 inhibitor) as a single agent can effectively treat FL (1-3b) patients who relapse after multi-line treatment.
The study included 99 patients who had previously received ≥2 line systemic treatment 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 complete remission (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.

Figure 3 Tazemetostat clinical study results Phase II open single-arm study FLR2002 (DAWN) study used a BTK inhibitor monotherapy to treat patients with relapsed FL.
The study included 110 patients with relapsed FL who had received ≥2 treatments in the past, and these patients received 560mg Ibrutinib was treated with a median follow-up of 27.
7 months.

The results showed that the ORR was 20.
9%, the CR rate was 11%, the duration of remission was 19.
4 months, the median PFS was 4.
6 months, the median OS was not reached, and the 30-month OS rate was 61%.

Therefore, Professor Xu Bing said that although the use of BTK inhibitors to treat patients with relapsed FL has a certain effect, it is relatively limited.

Fig.
4 FLR2002 (DAWN) clinical research results.
Subsequently, Professor Xu Bing said that Ibrutinib combined with venacral (BCL-2 inhibitor) has a certain effect in the treatment of relapsed and refractory FL.
The study shows that the ORR is 69%, CR The rate is 25%, the overall safety is good, and no serious side effects occur.

Professor Xu Bing emphasized that the combination of BTK inhibitors for the treatment of FL still needs further exploration.

Umbralisib is an oral PI3Kδ and casein kinase 1ε (CK1ε) inhibitor.

At the 2020 ASH annual meeting, the results of the Phase II clinical study of Umbralisib were announced.
117 patients with relapsed and refractory FL were enrolled and given Umbralisib monotherapy until the disease progressed or became intolerable.

The median follow-up was 27.
5 months, the ORR was 45.
3%, the CR rate was 5.
1%, and the median PFS was 10.
6 months.

The most common adverse reactions of grade ≥3 included neutropenia (11.
5%), diarrhea (10.
1%), and elevated aminotransferase (7.
2%).

Therefore, this study suggests that Umbralisib is safe and effective in the treatment of relapsed and refractory FL, and it is recommended by NCCN guidelines for the treatment of ≥4-line FL in 2021.

In addition, Avadomide (cereblon modulator), Mosunetuzumab (CD20, CD3 bispecific antibody), nivolumab (PD-1 inhibitor) and other drugs have also played an excellent role in patients with relapsed and 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.

CAR-T treatment of refractory and relapsed FL data update In 2020, ASH updated the relevant data on CAR-T cell treatment of refractory and relapsed FL.
The results showed that Tisagenlecleuc (4-1BB is the costimulatory domain) and Axi-Cel (CD28) The costimulatory domain) showed good therapeutic effects.

Figure 5 ASH's CAR-T therapy update in 2020.
Interestingly, the ZUMA-5 study carried out CAR-T cell retreatment for 11 patients with relapsed FL after CAR-T cell treatment, and found that all patients used CAR-T cells again The treatment can still achieve good results (10 cases of CR, 1 case of PR), which also suggests that the failure of CAR-T cell therapy may be due to insufficient proliferation of CAR-T cells in some patients, but the tumor antigens are not lost.
The patient's re-infusion of CAR-T cells may be a good treatment option.

Finally, Professor Xu Bing said that CAR-T cell therapy has shown a high remission rate and controllable safety in patients with refractory and relapsed FL.
Even in people who relapse after CAR-T cell therapy, CAR-T cell therapy can still make Patient benefits deserve further clinical attention. 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 Hospital 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 Oncology Branch of the Chinese Medical Association Committee members stamp "read the original text", we make progress together