Professor Yang Shenmiao: Research progress in the treatment of relapsed and refractory CLL|The 4th China Conference on Chronic Lymphocytic Leukemia

From March 19th to 21st, 2021, the 4th China Chronic Lymphocytic Leukemia Conference and the 1st cwCLL and iwCLL Joint Conference of the Hematology and Tumor Professional Committee of the Chinese Anti-Cancer Association was held online.
Participate offline to share the latest research results of hematology.

At this meeting, Professor Yang Shenmiao from Peking University People's Hospital gave a report on "Research Progress in Treatment of Relapsed and Refractory Chronic Lymphocytic Leukemia (CLL)".
Yimaitong organized the main contents as follows.

CLL patients may undergo clonal evolution, bypass activation, and microenvironmental changes after medication, leading to drug resistance.

Among them, the most common clonal evolution is the acquired resistance of BTK inhibitors and Bcl-2 inhibitors, accounting for about 80% of the acquired resistance of CLL.

In order to overcome the drug resistance of CLL patients, many explorations have been carried out on the drug sequence of CLL, the use of new generation drugs, and the application of new treatment methods.

The medication sequence for relapsed and refractory CLL, Professor Yang Shenmiao said that the 2020 ASH conference discussed the medication sequence of CLL patients in detail.
The three studies published at the conference were aimed at the first-line immunochemotherapy, the first-line no chemotherapy regimen, and the first-line vinacola treatment.
After the relapse, research and exploration were carried out.

The choice of treatment for recurrent CLL needs to take into account the patient's basic condition, disease characteristics, previous treatment options, treatment safety and other factors.

At the 2020 ASH conference, there are three studies on the drug sequence for relapsed and refractory CLL.
There are currently many treatment options for patients with drug-resistant CLL after immunochemotherapy.
The RESONATE study compared the BTK inhibitor ibrutinib and the anti-CD20 monoclonal antibody ofatumumab head-to-head.
Efficacy of relapsed and refractory CLL.

The 6-year follow-up results published in the study showed that the median progression-free survival (PFS) of ibrutinib in the treatment of relapsed and refractory CLL was significantly better than that of Ofatumumab (44.
1 months vs.
8.
1 months), and the overall survival of the two groups of patients (OS) No significant difference was seen.

Compared with the real-world research data of immunochemotherapy for the second-line treatment of CLL, patients in the ibrutinib group in the RESONATE study also showed a significant survival advantage.

 In addition to ibrutinib, other BTK inhibitors have also shown good efficacy in relapsed and refractory CLL.

The ASCEND study explored the efficacy of the BTK inhibitor Acalabrutinib in the treatment of relapsed and refractory CLL.

The results of the study show: Acalabrutinib treatment of R/R CLL can further improve the PFS of patients, and it is well tolerated.

At present, Acalabrutinib has been approved in the United States for the treatment of relapsed and refractory CLL.

Professor Yang Shenmiao also pointed out that the domestic BTK inhibitor Zebutinib also showed good efficacy in relapsed and refractory CLL, and looked forward to the announcement of the results after the extended follow-up time of related studies.

 Bcl-2 inhibitors are also a viable treatment option for relapsed and refractory CLL.

The MURANO study explored the efficacy of the Bcl-2 inhibitor Veneclax combined with the anti-CD20 monoclonal antibody rituximab in the treatment of relapsed and refractory CLL.
The 5-year follow-up results of the study showed that the combined regimen was used to treat the median PFS of relapsed and refractory CLL.
It reached 53.
6 months (95%CI: 48.
4-57.
0 months), and the median OS was not reached.

At the same time, the results of the study showed that the MRD-negative status caused by the combined treatment of relapsed and refractory CLL can be transformed into a PFS advantage.

 Based on the relevant research published at the 2020 ASH Conference, Professor Yang Shenmiao believes that CLL patients who are resistant to BTK inhibitors can choose a Venecla-based treatment plan in the future.

For CLL patients who are resistant to Bcl-2 inhibitors, if the resistance appears in the course of treatment, the follow-up treatment can be switched to BTK inhibitors; if the resistance appears after the treatment is completed, relevant studies show that the re-use of Vinekal can still be used Bring benefits to CLL patients.

Treatment options after BTK inhibitors and Bcl-2 inhibitors are resistant.
Related studies have explored the sequential therapeutic efficacy of BTK inhibitors after Vinekalla treatment.
The results show that: for CLL that has not previously been treated with BTK inhibitors For patients, sequential treatment with BTK inhibitors after Venecla treatment can prolong the patient’s PFS for nearly 30 months; for CLL patients who are intolerant to previous BTK inhibitors, changing to other BTK inhibitor treatments can still bring significant Survival benefit; however, for CLL patients who have been resistant to BTK inhibitors, the re-use of BTK inhibitors after Venexa treatment can only bring about 4 months of PFS, and the re-use of BTK inhibitors has limited significance for these patients .

 Some studies have also explored the use of the combined regimen in patients with relapsed and refractory CLL.

The CLARITY study explored the efficacy of Venecla combined with ibrutinib in patients with relapsed and refractory CLL.
The results of the study showed that 40% of CLL patients received the combined regimen and achieved bone marrow (BM) MRD negative.

The "strong combination" of BTK inhibitors and Bcl-2 inhibitors is also a viable treatment option for patients with relapsed and refractory CLL.

The use of a new generation of BTK inhibitors and new treatments Professor Yang Shenmiao then introduced the use of a new generation of BTK inhibitors and new treatments in relapsed and refractory CLL.

Different from Ibrutinib, Acalabrutinib, and Zebutinib, a new generation of non-covalently bound BTK inhibitors has become the focus of research in recent years.

The results of the Phase I/II BRUIN study showed that the new generation of BTK inhibitor Loxo-305 has brought survival benefits to CLL patients who have failed other BTK inhibitor treatments, with an overall response rate (ORR) of 62%.

 Chimeric antigen receptor (CAR)-T cell therapy is a new type of therapy that has attracted much attention in the field of hematological tumors in recent years.
However, Professor Yang Shenmiao said that CAR-T therapy is not as effective in CLL as it is in aggressive lymphoma.
The overall CR rate is about 30%-40%.

Phase I/II TRANSCEND CLL 004 study showed: CAR-T therapy Lisocabtagene Maraleucel (Liso-cel) treatment of CLL patients after BTK inhibitor treatment failed ORR reached 82%, CR/CR with incomplete blood count recovery (CR/ The CRi) rate reached 45%; the ORR of Liso-cel combined with ibrutinib in this part of patients reached 95%, and the CR/CRi rate reached 47%.

The efficacy of Liso-cel in relapsed and refractory CLL needs to be further verified by the follow-up follow-up results of the study.

The future research direction of relapsed and refractory CLL Professor Yang Shenmiao finally looked forward to the possible future research directions of relapsed and refractory CLL.

At present, many diseases in the field of hematology tumors use clinical parameters to establish prognostic models to predict the prognosis of patients and guide clinical practice.

At present, the establishment of CLL-related prognostic models is in the exploratory stage.
Based on the results of a number of ibrutinib-related studies, the relevant research team has established a 4-factor prognostic model for the treatment of CLL with ibrutinib (relapsed and refractory CLL, TP53 mutation, β2MG).
≥5mg/L, LDH＞250U/L).

 In addition to the establishment of a prognostic model, how to prevent drug resistance in CLL patients from the source is also a question that needs to be explored in the future.

Whether it is possible to control the drug resistance of CLL patients through the adjustment of the dosage, the interruption of treatment, and real-world MRD detection, it needs to be further verified by related research in the future.

Summary Professor Yang Shenmiao concluded: In the era of new drugs, the relapse and refractory cases of CLL patients are gradually decreasing, but this does not mean that the treatment dilemma of relapse and refractory CLL has been completely resolved.

I look forward to screening out patients with poor prognosis through more accurate prognostic models in the future, and individualized treatment of these patients earlier to prevent the occurrence of relapse and refractory.
At the same time, I hope that the emergence of more new drugs can make relapse and refractory treatment.
CLL patients bring better treatment options.

Professor Yang Shenmiao, Deputy Chief Physician, Department of Hematology, Peking University People's Hospital, Member of CSCO Anti-Lymphoma Alliance Member, Lymphoma Group, Chinese Medical Association Oncology Branch, Member of the First Chinese Chronic Lymphocytic Leukemia Working Group of the Chinese Anti-Cancer Association Hematology Oncology Committee Youth Committee of Lymph and Hematology, Chinese Society of Geriatric Oncology, Committee of Beijing Society of Integrative Medicine and Hematology