2022 CSH Prof. Wei Xu: An Exploration of CLL Diagnosis and Treatment Models in the Era of New Drugs

Listening to the sound of blood and perceiving the rhythm of life, on September 23-25, 2022, the "17th National Hematology Academic Conference of the Chinese Medical Association" was grandly opened
at the National Exhibition and Convention Center in Shanghai.
The conference was hosted by the Chinese Medical Association and the Hematology Branch of the Chinese Medical Association, hosted by the Shanghai Medical Association, co-organized by Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, the First Affiliated Hospital of Soochow University, and the Union Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology, with the theme of "respect, inheritance, collaboration and innovation", specially invited famous experts at home and abroad to talk about the latest progress
in the field of blood diseases.
On this occasion, Professor Xu Wei of the First Affiliated Hospital of Nanjing Medical University was invited to explain the current situation
of diagnosis and treatment and development of chronic lymphocytic leukemia (CLL) for us.

Medical pulse communication: compared with other hematological tumors, the incidence of CLL is relatively low
.
Could you please briefly talk about the current state of diagnosis and treatment of CLL and what clinical needs remain unmet?

First, there are some misconceptions in the diagnosis of CLL so far, and many clinicians are still using bone marrow tests to make the diagnosis
.
In fact, the diagnosis
of CLL is confirmed by peripheral blood monoclonal B lymphocyte count, characteristic manifestations of peripheral blood smear, and peripheral blood flow cytometry immunophenotype.
Second, treatment of CLL requires the mastery of treatment indications, and overtreatment of patients who do not meet the indications does not prolong patient survival
.
In addition, the choice of CLL treatment options is more abundant, although traditional immunochemotherapy is effective for some CLL patients, but for patients with del17p/TP53 mutation, IGHV unmutated, del (11q) and other high-risk factors are not effective, it is difficult to overcome the bad prognosis of such people, and the emergence of new drugs such as BTK inhibitors, BCL2 inhibitors, etc.
, shows a surprising clinical effect
。 Therefore, before the treatment of CLL should be fully evaluated according to the specific situation of the patient, the prognostic risk factors, physical status, concomitant diseases, and combined with the patient's age, economic factors and other circumstances, the most appropriate treatment plan
should be formulated.

CLL is a subtype of lymphoma that is slow to progress and requires long-term treatment management, and oral targeted drug BTK inhibitor therapy is recommended for patients with CLL with high-risk factors, poor physical status, or inability to tolerate chemotherapy
.
In China, a number of BTK inhibitors have been successively included in medical insurance, but the reimbursement ratio of medical insurance in each region may be different, and there is still economic pressure for some patients with lower incomes, and some patients may not be able to complete long-term standardized treatment
for economic reasons.
In addition, the safety of long-term treatment is particularly important, if the patient can not tolerate, it is difficult to adhere to the long-term medication
.
The new generation of BTK inhibitors optimizes the molecular structure and significantly reduces adverse events, but the problem of clonal evolution resulting from CLL continuous treatment that causes resistance remains an unmet need
.

The presence of BTK inhibitors has improved the prognosis of CLL patients, but some patients will develop BTK inhibitor resistance
.
Could you please briefly talk about the mechanism of resistance to BTK inhibitors in CLL patients and the treatment options for CLL patients after drug resistance?

Current studies have found that BTK mutations are the main mechanism by
which BTK inhibitors develop resistance.
The most common BTK mutation is the C481S mutation at the C481 site, resulting in the inability of BTK inhibitors to fully bind to the BTK target, resulting in drug
resistance.
In addition, PLCG2 mutations can also cause CLL to become resistant to BTK inhibitors
.

In patients with CLL who are resistant to first-line BTK inhibitors, the effectiveness of second-line immunochemotherapy is only about
30%.
The novel drug can effectively improve the prognosis of patients with BCL-resistant BTK inhibitors, of which BCL-2 inhibitors have shown good efficacy
in multiple clinical studies.
The remission rate of BCL-2 inhibitors in CLL patients with BTK inhibitor resistance can reach more than 60%, but BCL-2 inhibitors have not yet been approved for CLL indications in China
.
In addition, PI3K inhibitors are also an alternative treatment option, with an effective rate of about 20% to 40%.

Therefore, the choice of BCL-2 inhibitor
is recommended in patients with a condition.

In recent years, the treatment of CLL has developed rapidly, and the continuous emergence of new drugs has given CLL patients more treatment options
.
However, some new drugs require long-term continuous medication, are expensive to treat and may lead to long-term toxicity
.
Therefore, some researchers have explored the limited course of treatment of CLL in order to reduce the economic burden and adverse reactions
of patients.
Could you please briefly talk about the development of limited course treatment in CLL?

There are two main modes of limited course treatment for CLL: one is fixed-course therapy, and you can choose to fix the treatment for 12 months or 24 months; There is also a limited course of treatment driven by minimal residual lesions (MRD), and patients with negative MRD can discontinue the drug; MRD-positive patients continue to take the drug
.
The limited-course treatment regimen has high hopes for reducing the economic burden and adverse reactions of patients, and is currently mainly used for the exploration of BCL-2 inhibitor combination regimens (such as BCL-2 inhibitors combined with BTK inhibitors, BCL-2 inhibitors combined with anti-CD20 monoclonal antibodies).

The combination regimen of the BTK inhibitor ibretinib and the BCL-2 inhibitor Venekla has been approved abroad for CLL therapy, mainly based on the research data of the CAPTIVATE study fixed course (FD) treatment cohort and the results
of the Glow study for elderly CLL patients.
Studies have found that patients treated with a limited course of treatment for one year achieve remission, and if the patient develops disease after discontinuation, the reuse of BTK inhibitors is still effective, and patients rarely develop BTK inhibitor resistance
.
Patients with continuous medication usually develop BTK mutations that lead to BTK inhibitor resistance
.
Limited course of treatment can give patients the opportunity to re-use BTK inhibitors on the one hand, and on the other hand, they can also enter the drug holiday (drug holiday) to rest during treatment, which is also recommended
.

Professor Xu Wei

• Deputy Director of the Department of Hematology, First Affiliated Hospital of Nanjing Medical University (Jiangsu Provincial People's Hospital), doctoral supervisor
• Vice Chairman of the Hematology and Oncology Committee of the Chinese Anti-Cancer Association, and leader of the lymphoma group
• Chairman of the Hematological Lymphoma Committee of the China Junior Insurance Association
• Vice Chairman of the Lymphoma Committee of the Chinese Geriatric Health Care Association
• Vice Chairman of the Lymphoma Committee of the Chinese Medical Education Association
• Member of the Standing Committee of CSCO China Anti-Lymphoma Alliance
• Member of the Standing Committee of the Hematology Committee of the Chinese Association of Women Physicians
• Vice Chairman of the Hematology Society of Jiangsu Medical Association
• Vice President of Hematology Physician Branch of Jiangsu Medical Doctor Association
• Chairman of the Lymphoma Committee of Jiangsu Research Hospital Association
• Chairman of Jiangsu Anti-Lymphoma Alliance
• Vice Chairman of the Hematology Oncology Committee of Jiangsu Anti-Cancer Association
• Vice Chairman of Nanjing Hematology Society

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