Prof. Jianyong Li & Lugui Qiu: The joint program of otolizumab limited courses has brought about a new breakthrough in CLL treatment

Chronic lymphocytic leukemia (CLL) is a mature B lymphocyte clone proliferative tumor that primarily involves peripheral blood and bone marrow

Ottozumab, a new generation of anti-CD20 monoclonal antibody, was approved by the State Drug Administration of China (NMPA) in June 2021 for the treatment of adult patients

With the continuous emergence of new targeted drugs and the rapid development of immunotherapy, CLL treatment has entered the era of individualized targeting, can you please talk about the current unmet clinical needs of CLL treatment?

Small molecule targeted drugs represented by BTK inhibitors are widely used in CLL, oral medication is convenient, the total response rate of first-line treatment is as high as 90%, but the deep response rate is limited, and the results of the 8-year follow-up of the RESONATE-2 ^study1 show that the complete response rate of ibutinib monotherapy for 7 years is only 34%, so patients often need long-term treatment

In order to meet the clinical needs of patients, the exploration of limited courses of treatment is being actively carried

At present, the small molecule targeted drug monotherapy commonly used in CLL first-line treatment is still insufficient in the depth of remission, what impact do you think achieving a negative minimal residual disease (MRD) has on the prognosis of patients? How will MRD-driven CLL treatment change in the future?

There are currently two models of CLL fixed course treatment, one is the "drug holiday" strategy based on MRD status, such as the EU approved ibutinib combined with Venequera fixed treatment program, which may achieve long-term discontinuation and improve the quality of life of
patients.

One is MRD-driven treatment with the aim of eventually achieving a "cure" that prolongs the patient's PFS
as long as possible.

The exploration of MRD-driven and non-MRD-driven fixed treatment regimens raises more promise
for deeper remission and discontinuation in patients with CLL.

Our center is also carrying out MRD-driven CLL treatment-related exploration, through targeted drugs combined with immunotherapy for limited courses of treatment to achieve the purpose of
curing CLL patients.

The purpose of the study was to explore the efficacy and safety of obutinib and otolizumab combined with fludarabine and cyclophosphamide (FCG) regimen in the treatment of patients with CLL, with MRD clearance as the main efficacy index, and it is expected to bring more clinical benefits
to patients with CLL.

The new CD20 monoclonal antibody otolizumab has played an excellent role in the treatment of CLL, can you please talk about its innovative mechanism advantages and clinical application experience?

Otolizumab is a new type II CD20 monoclonal antibody with humanized and glycosylated modification, which significantly reduces immunogenicity and makes the efficacy more stable; Glycosylated modification promotes binding to effector cells, complement-dependent cytotoxicity (CDC) is weaker, direct cell death induction (DCD) and antibody-dependent cell-mediated cytotoxicity (ADCC)/antibody-dependent cell-mediated phagocytosis (ADCP) is significantly stronger
than type I CD20 monoclonal antibody.

The CDC effect is an important route for rituximab to fight tumors, but the lower complement level in CLL patients affects the therapeutic effect
of rituximab.

Type II CD20 monoclonal antibody otolizumab plays a role more through DCD and ADCC, making up for the shortcomings of rituximab in the field of CLL, and its efficacy has been confirmed in early clinical trials and has been approved in the United States for the treatment of FL and CLL
.

The recommended dose of otolizumab is intravenous 1000 mg, and the dose on days 1, 8, and 15 of the first cycle can achieve high target saturation
more quickly.

In CLL treatment, 100 mg is often administered on day 1 of the first cycle, followed by 900 mg on day 2 (or continued on day 1) depending on the infusion situation to improve the safety of infusion
.

Multiple Phase III clinical trials have shown that otolizumab plus chlorambucil (G-Clb) or fludarabine and cyclophosphamide (FCG) regimens for CLL, or cyclophosphamide, doxorubicin, vincristine, and prednisone (G-CHOP) regimens for FL have shown superior effects
over rituximab combination regimens.

Otolizumab has been listed in Western countries for nearly 10 years and in China for one year
.

The combined otolizumab regimen has been recommended by several authoritative guidelines such as the NCCN guidelines as the preferred regimen for first-line treatment of CLL and FL, significantly improving the patient's overall response rate, complete response rate and deep response rate, and as it continues to be applied to Chinese patients, the deep response will be transformed into survival benefits and prolong patient survival
.

Medical Pulse: Both Chinese and foreign guidelines recommend a limited course combination regimen based on otolizumab as the preferred treatment plan for CLL patients, can you please interpret the relevant research on the combination regimen of otolizumab in the treatment of CLL?

The results of the CLL11 ^study2 showed that the G-Clb regimen for first-line CLL treatment benefited more from PFS and OS and was the first-line immunotherapy regimen of older patients without adverse prognosis factors compared with the nitrate monotherapy and rituximab plus chlorambucil (R-Clb) regimens
.

More explorations have been made about the otolizumab combination regimen in the new drug era, such as the combination chemotherapy and BTK inhibitor regimen, the study of FCG combined with ibrutinib (iFCG) regimen for the initial treatment of ^CLL3 found that in young patients with a good prognosis, iFCG treatment achieved a high MRD-negative rate in only 3 cycles, and almost all patients achieved the optimal response
to bone marrow MRD-negative at any time during the study period.

At the same time, the exploration of FCG combined with zebutinib or obertinib treatment options is also in
full swing.

In addition, various chemotherapy-free combination regimens of otolizumab and newer drugs such as the BTK inhibitor Acaabrutinib (Acala) and ibrutinib, the BCL2 inhibitor venequera, have also shown good efficacy
.

Update results from a 5-year follow-up update to the ELEVATE-TN Phase III study ^show that treatment with otolizumab (G-Acala) in combination with otolizumab (G-Acala) conferred more PFS benefits
in patients than acala monotherapy.

As a novel CD20 monoclonal antibody, otolizumab has more clinical advantages in the treatment of CLL, and its combination with various other drugs has shown excellent efficacy, providing new treatment options
for patients with CLL.

Pulse: Can you tell us about your prospects for the use of otolizumab in patients with CLL? What other research directions are worth exploring in the future?

Chemotherapy often causes infection, bleeding and other adverse reactions, long-term chemotherapy will also increase the risk of secondary malignancy, in the physical condition of young patients with good physical condition, otolizumab combined with BTK inhibitors and chemotherapy such as iFCG regimen through limited courses of treatment to achieve a higher MRD negative rate, and reduce long-term chemotherapy-related toxicity, will become an important research direction in
the future.

For very high-risk patients with TP53 abnormalities and chromosomal complex karyotype abnormalities, otolizumab plus BTK inhibitors and venequera may benefit them more
.

In addition, the results of CLL14 ^study5 showed that patients with a fixed course of otolizumab combined with veneerquera for first-line CLL therapy had a significant benefit in survival, but the prognosis of patients with TP53 mutation and IGHV mutation was still poor
.

The G-Acala protocol also benefits PFS in patients with TP53 mutations, providing a better option
.

Overall, otolizumab may become the "cornerstone" of CLL treatment
.

Otolizumab has been included in the "Chinese Chronic Lymphocytic Leukemia / Small Lymphocytic Lymphoma Diagnosis and Treatment Guidelines" first-line treatment recommendations, in the new era of targeted therapy of CLL, otolizumab can be combined with chemotherapy, BTK inhibitors, PI3K inhibitors and BCL2 inhibitors to transform the long-term treatment of small molecule-targeted drugs into limited courses of treatment, helping more patients achieve deep remission
faster.

Our center currently recommends BTK inhibitor therapy for the elderly and patients with poor prognostic factors, and recommends limited courses of CD20 monoclonal antibody combined with chemotherapy for young patients who do not have adverse prognostic factors, such as rituximab combined with fludarabine and cyclophosphamide (FCR) regimen can bring long-term disease-free survival to young patients with IGHV mutations and no high-risk cytogenetic abnormalities, and otolizumab is more effective than rituximab and more promising in CLL treatment
。
Our team's previous study of the combined rituximab regimen and the targeted drug monopharmaceutical alternating application has been enrolled
.

A new exploration of slow shower brake trials is currently underway, in which patients who receive BTK inhibitor monotherapy in combination with otolizumab and chemotherapy for one year and who achieve complete remission and are MRD-negative in bone marrow and peripheral blood discontinue the drug
.

Immunotherapy after the discontinuation of BTK inhibitors to remove tumor cells remaining in the peripheral blood relieves concerns about rapid disease progression/recurrence after discontinuation, may achieve a longer period of remission, and can still be treated again after subsequent recurrences, so that patients can obtain intermittent "cure", hoping that more patients can benefit
from this innovative treatment.

Professor Li Jianyong

• Jiangsu Provincial People's Hospital Pukou Slow Shower Center
  

• Director of the Department of Hematology, Doctoral Supervisor and Postdoctoral Co-supervisor of the First Affiliated Hospital of Nanjing Medical University

• Member of the Standing Committee of the Hematology Branch of the Chinese Medical Association and the leader of the Lymphocytic Disease Group

• He is the chairman of the 4th Hematology and Tumor Professional Committee of the Chinese Anti-Cancer Association, the honorary chairman of the 5th session, and the leader of the lymphoma group

• Leader of the Working Group on Chronic Lymphocytic Leukemia in China

• Vice Chairman of CSCO China Lymphoma Alliance

• Deputy Leader of the Lymphoma Group of the Oncology Branch of the Chinese Medical Association

• Chairman of the Hematology Branch of Jiangsu Geriatrics Association

• President-elect of the Hematologist Branch of Jiangsu Medical Doctor Association

• Former Chairman of the Hematology Branch of Jiangsu Medical Association

• Chairman of the Hematology Branch of Nanjing Medical Association

• Vice Chairman of the Professional Committee of Integrated Hematology of the Chinese Medical Doctor Association

• Member of the Standing Committee of the Blood Immunology Branch of the Chinese Society of Immunology

Professor Qiu Lugui

• Hematology Hospital, Chinese Academy of Medical Sciences
  

• Chief Physician Doctoral Supervisor

• Director of Lymphoma Diagnosis and Treatment Center, Hematology Hospital, Chinese Academy of Medical Sciences

• Medical Director of Tianjin Cord Blood Hematopoietic Stem Cell Bank

• Experts with special government allowances of the State Council and young and middle-aged experts with outstanding contributions to the National Health Commission

• Member of the International Myeloma Society (IMS).
  

• Member of the Expert Committee of the International Myeloma Working Group (IMWG).
  

• Member of the editorial board of Blood Advances magazine

• Honorary Chairman of the Hematology and Tumor Professional Committee of the Chinese Anti-Cancer Association

• Vice Chairman of the Lymphoma Expert Committee of the Chinese Society of Clinical Oncology

• Vice Chairman of the Hematology Branch of the Chinese Hospital Association

• Vice Chairman of the Hematology Professional Committee of the China Medical Education Association

• Vice Chairman of the 6th Council of Tianjin Anti-Cancer Association

• He is a member of the editorial board of 6 core journals, including the Chinese Journal of Hematology

• Completed more than 30 key projects of the National Science and Technology Support Program and the National Natural Science Key Project

• Published more than 50 papers, including more than 150 SCI papers; Editor-in-chief of 5 monographs; It has won 5 national invention patents
  .
  
  

• He has won 2 first prizes for provincial and ministerial achievements

References

[1] Barr PM, et al.
Blood Adv.
2022 Jun 14; 6(11):3440-3450.

[2] Goede V, et al.
HemaSphere.
2018; 2(S1):30.

[3] Jain N, et al.
2022 EHA.
Oral S149.

[4] Sharman JP, et al.
2022 ASCO.
Abstract 7539.

[5] Al-Sawaf O, et al.
2021 EHA.
Abstract S146.

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