Professor Fan Lei: First-line treatment of chronic lymphocytic leukemia|Jinling Lymphatic Tumor Forum 2021

In the past 20 years, the treatment of chronic lymphocytic leukemia (CLL) from alkylating agents to rituximab, fludarabine and cyclophosphamide (FCR) regimens has prolonged the progression-free survival (PFS) of patients.

New targeted drugs and immunotherapy are also constantly developing, including anti-CD20 monoclonal antibodies (rituximab, otuzumab), BTK inhibitors (ibrutinib, zebutinib, acatinib) , BCL-2 inhibitors (Venecla), etc.
, CLL treatment has gradually entered the era of chemotherapy-free, but it seems that it is still impossible to achieve disease control and deep remission at the same time.

At the "2021 Jinling Lymphatic Tumor Forum" meeting held in Nanjing, Jiangsu Province from May 14th to 16th, 2021, Professor Fan Lei from Jiangsu Provincial People's Hospital shared the first-line treatment of CLL.

Yimaitong organizes the main content as follows for the reference of readers.

Exploring the development of immunochemotherapy regimens to BTK inhibitors CLL8, CLL10 and CLL11 clinical studies have established the important position of immunochemotherapy in the treatment of different CLL patients.

The CLL8 study shows that the FCR regimen is the standard treatment regimen for young fit patients; the CLL10 study supports the results of the CLL8 study and also supports the BR regimen as a treatment option for elderly fit patients; the CLL11 study shows that the CD20 antibody (rituximab, Otto Rizumab) combined with chlorambucil is the treatment option for elderly unfit patients.

Professor Fan Lei said that although immunochemotherapy has improved the overall prognosis of CLL patients, the prognosis of CLL patients with high risk [IGHV not mutated and/or del(11q) or del(17p)] after standard FCR treatment is still not optimistic.
, High-risk CLL patients still need to improve the efficacy of the treatment plan.

In addition, the FCR regimen has a high incidence of serious infections, and the occurrence of secondary tumors cannot be ignored.

Therefore, the treatment of CLL urgently needs drugs with better curative effects and fewer side effects, and BTK inhibitors have emerged as the times require.

In the CLL12 study, ibrutinib significantly prolonged the event-free survival (EFS) of early-stage asymptomatic CLL patients, but there is still no overall survival (OS) data.

As a result, Professor Fan Lei said that for CLL patients with no indications for treatment, it is still not recommended to prematurely intervene in treatment.

The researchers also explored the treatment of other CLL populations with BTK inhibitors.
The RESONATE-2 study compared the efficacy of ibrutinib and chlorambucil in the treatment of CLL.
The results showed that ibrutinib significantly improved the patient's remission rate.
And PFS, and significantly improved the prognosis of patients with high-risk [IGHV without mutation and/or del(11q) or del(17p)] CLL.

In addition, the 5-year long-term follow-up data showed that the 5-year PFS rates of the ibrutinib group and the chlorambucil group were 70% vs 12%, respectively, confirming the excellent efficacy of ibrutinib.

In addition, the benefit of ibrutinib compared to FCR regimen has also been verified in the E1912 study.
The results show that compared with FCR regimen, IR regimen can further prolong PFS and OS in newly treated young CLL patients.

And the 4-year long-term follow-up data of the study confirmed the continued survival benefit of ibrutinib.

Professor Fan Lei said that if the side effects are handled properly during the treatment process, the survival rate can be further improved.

It is worth mentioning that at the 2020 ASH annual meeting, a meta-analysis analyzed the efficacy of ibrutinib in the first-line treatment of CLL patients with TP53 mutations.
The results showed that the 4-year PFS rate and OS rate were 79% and respectively.
88%, in addition, other high-risk (such as no IGHV mutation, BIRC3 mutation, SF3B1 mutation, etc.
) CLL patients have improved to varying degrees after treatment with BTK inhibitors.

Professor Fan Lei said that for newly diagnosed CLL patients with high-risk molecular biology, BTK inhibitors are a good treatment option.

Exploration of multi-drug combination regimens Although BTK inhibitors have a better disease control rate in the treatment of CLL, there are fewer patients with deep remission, and continuous treatment is required.

Therefore, achieving deep relief, reducing side effects, and a fixed course of treatment has become an ideal goal for the treatment of CLL.

Combined limited-time treatment emerged at the historic moment, opening a new era of non-chemotherapeutic drugs limited-time treatment mode.

Through the combined use of targeted drugs, more CLL patients are expected to be cured.
At the same time, a limited-time treatment model for minimal residual disease (MRD) has been established for the purpose of elimination to solve various problems of long-term medication.

01Ibrutinib+Veneclax A study published in 2019 explored the efficacy of ibrutinib combined with veneclaline in the treatment of newly treated patients with high-risk CLL.
At 12 weeks of treatment, the overall response rate (ORR) was 100% Among them, the complete response (CR) rate was 88%, and 61% of patients reached MRD negative.

In addition, the efficacy of this combination regimen on non-high-risk patients has been verified in the CAPTIVATE study.
The CAPTIVATE study evaluated the efficacy of Ibrutinib+Venecla in the first-line treatment of CLL patients.
Among evaluable patients, the negative rate of peripheral blood MRD The negative rate of bone marrow MRD is 72%, and the negative rate of peripheral blood MRD gradually increases with the extension of the combined treatment.
The results of subgroup analysis show that patients with different risks can benefit from the treatment.

02BTK inhibitor+Venecla+Otuzumab The short-term remission rates of different BTK inhibitors (Ibrutinib, Zebutinib, Acatinib)+Venecla+Otuzumab in the treatment of CLL are all Almost close to 100%, and the negative rate of MRD is relatively high.

Professor Fan Lei expressed his expectation for the excellent results of his long-term follow-up.

03Ibrutinib+FCG regimen In the study of ibrutinib+fludarabine, cyclophosphamide and otuzumab (FCG) regimens for newly-treated CLL patients, 45 patients were enrolled and 44 patients The patients completed the study treatment; the median follow-up was 22.
3 months and the ORR was 89%; 32 patients after 1 year of follow-up, all achieved bone marrow MRD negative, and after the discontinuation of Ibrutinib, the median follow-up was 13.
6 months.
Clinical recurrence.

The French ICLL07 FILO study also used Ibrutinib+FCG to treat newly diagnosed CLL patients.
The bone marrow MRD negative rate was 62%, the 3-year PFS rate was as high as 96.
5%, and the 3-year OS rate was 97.
7%.

Professor Fan Lei said that the data of the study is relatively good, and he looks forward to its long-term follow-up results.

04Veneclax+Otuzumab CLL14 study compared the efficacy and safety of veneclair combined with otuzumab and chlorambucil combined with otuzumab in newly-treated CLL patients with comorbidities .

Studies have shown that the combination of otuzumab and venecla in CLL patients is safe, and PFS benefits more (3-year PFS rate: 82% vs 50%); MRD negative rate is higher (12 after treatment is completed) Monthly MRD negative rate: 81% vs 27%), its remission is deeper and lasts longer.

Professor Fan Lei emphasized that the combination regimen is ever-changing, but it seems that all patients can benefit from the combination regimen.

However, the existing evidence does not support the clinical cure of CLL, and longer follow-up is still needed.
We look forward to more clinical research data in the future.

Finally, Professor Fan Lei concluded that in the past two years, the first-line treatment of CLL has shown a precise stratified treatment model.
BTK inhibitors still have an important position, but venexa and otuzumab are also alternative treatment options.

Professor Fan Lei, Deputy Director of the Department of Hematology, Jiangsu Provincial People's Hospital, Doctor of Medicine, Chief Physician, and Associate Professor, The First Youth Executive Director of the Chinese Anti-Cancer Association Member of the Hematology Oncology Professional Committee of the Chinese Anti-Cancer Association The 11th Youth Member of the Hematology Branch of the Chinese Medical Association United States New York Columbia and Cornell University's New York Presbyterian Hospital's postdoctoral research direction is the precise diagnosis and treatment of lymphatic tumors.
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