Intensive Literature Reading: Rituximab-Resistant Treatment Options in NHL Patients

"Qunyinghui - Lymphoma Diagnosis and Treatment Research Interpretation Series" is an exclusive academic exchange platform created for young and middle-aged hematologists, through the intensive reading of influential research literature in the field of lymphoma, discussing hot topics in lymphoma diagnosis and treatment, jointly exploring and summarizing the optimal diagnosis and treatment strategy of lymphoma, in order to improve the survival rate

Rituximab is a type I anti-CD20 monoclonal antibody, which is currently the standard treatment for FL and other lymphoma subtypes, but some patients are still resistant to rituximab or relapse

The purpose of the study was to further study the pharmacokinetics (PK) of otolizuma in different CD20+ B cell lymphomas; It also explores whether differences in otolizumab exposure in patients with relapsed/refractory (R/R)NHL in rituximab in GADOLIN studies affect pharmacodynamics (PD), safety, or efficacy

>>>>

Population PK analysis of CLL, DLBCL and NHL

A total of 16,301 serum otolizumab concentrations were collected from 961 patients for population PK analysis, including 469 patients with iNHL (406 patients with FL and 183 cases from the GADOLIN study), 342 patients with CLL, 130 patients with diffuse large B-cell lymphoma (DLBCL), and 20 patients

Table 1 Effects of covariates on key pharmacokinetic parameters in the final covariate model

>>>> the relationship between otolizumab exposure and findings in patients with R/R FL in the GADOLIN study This analysis used data

Exploratory analysis of otolizumab exposure-efficacy

Exploratory analysis
of exposure-efficacy was conducted using BOR and PFS data from 128 FL patients treated with otolizumab in the GADOLIN study.

The results found that patients with complete remission (CR) had a higher otolizumab C_mean (Figure 1) compared to other types of patients (partial response, disease stabilization, or progression), and higher otolizumab exposure may be associated
with better efficacy.

Figure 1 Relationship between PFS and otolizumab exposure (Cmax) in patients with FL

Multivariate Cox regression analysis showed no effect
on baseline tumor size on PFS or OS.

Compared with the bendalmustine monotherapy group, the risk of disease progression was lower and the PFS was longer in all three exposure groups of otolizumab (Table 2, Figure 2), and the progression-free survival benefit of the otolizumab plus bendamustine group was not related to
exposure.

Table 2 Final Cox scale risk model

Figure 2 Kaplan–Meier curve: Relationship between PFS and otolizumab exposure in patients with FL

ConclusionsThe population PK model updated in this study accurately describes otolizumab PK
in patients with NHL and CLL.

In the GADOLIN study, no correlation between otolizumab exposure and AEs was found, confirming that the currently approved fixed dose of otolizumab (ottozumab 1000 mg, given at days 1, 8, and 15 days in the first cycle) combined with the bendamustine regimen was suitable for patients with rituximab R/R FL, with good safety and more clinical benefits
for patients.

After Professor Feng Ru's wonderful interpretation, many experts discussed
the mechanism of action of otolizumab.

Professor Ren Jinhai and Professor Feng Ru discussed the effect of CD20 expression on the efficacy of otolizumab and rituximab, Professor Feng Ru added that from the perspective of the binding mode with CD20 antigen, otolizumab requires less CD20 antigen, and rituximab is more dependent on CD20 expression, so if CD20 expression is reduced, the effect on the efficacy of rituximab is greater, and the effect
on otuximab is almost no.

Professor Hu Jianda said that as a humanized type II anti-CD20 monoclonal antibody, otolizumab has a higher affinity with tumors, stronger lethality to tumors, and better efficacy, and patients with R/R FL who are resistant to rituximab can still benefit
from the treatment of otolizumab.

Intensive Literature Reading (2)

Mechanism of action of rituximab, mechanism analysis of drug resistance and exploration of a new generation of anti-CD20 monoclonal antibodies

Professor Huang Yan shared an article published by Critical Reviews in Oncology/Hematology as "A molecular perspective on rituximab: A monoclonal antibody for B cell non Hodgkin lymphoma and other.
" affections (Molecular analysis of rituximab: a monoclonal antibody for the treatment of B-cell NHL and other diseases)" article ^[2].


This review summarizes the mechanism of action and resistance mechanism of rituximab, and explores a new generation of anti-CD20 monoclonal antibodies
.

CD20 is expressed in the vast majority of B-cell malignancies and is an ideal therapeutic target

Multiple studies have shown that CD20 is expressed
on the surface of the vast majority of B cell NHL (B-NHL) cells.

And CD20 is only present on the surface of the cell, not in plasma in a free form, so it does not bind
competitively with antibodies.

Moreover, after CD20 binds to the antibody, there is no obvious endocytosis and shedding, and the number of CD20 on the cell surface will not be significantly reduced
due to binding to the antibody.

Therefore, CD20 is considered an ideal target for the treatment of B-cell lymphoma
.

Mechanism of action of rituximab The mechanism of action of rituximab mainly includes 3 aspects (Figure 3) :(1) antibody-dependent cell-mediated cytotoxicity (ADCC), (2) complement-mediated cytotoxic reaction (CMC) / complement-dependent cytotoxic effect (CDC), (3) direct induction of apoptosis
.

The study found that in a single patient, it may not be one mechanism that works, and that these three mechanisms interact in synergy or antagonism, with CDC being the most dominant mechanism
for rituximab to kill tumor cells.

Fig.
3 Schematic diagram of the mechanism of action of rituximab

Mechanism of resistance to rituximab is reported to be about 50%
of the probability of the first treatment response of rituximab.

The mechanism of rituximab resistance includes five aspects (Figure 4), the most important of which are three: (1) CDC resistance, (2) CD20 target loss, and (3) adverse effects of the tumor microenvironment
.

Figure 4 Mechanism of rituximab resistance

In the past 20 years, researchers have continued to deepen their research on CD20 molecules and anti-CD20 monoclonal antibodies and develop new drugs
.

There are currently a variety of anti-CD20 monoclonal antibodies that have been approved by the FDA, and some are in clinical or preclinical studies
(Table 3).

Table 3 New generation anti-CD20 monoclonal antibody

Among them, the third generation of anti-CD20 monoclonal antibody otolizumab has been humanized, reducing immunogenicity; Moreover, the Fc segment is modified to promote effector cell binding and enhance ADCC/antibody-dependent cell-mediated phagocytosis (ADCP) action
.
In addition, according to the different structure and function, anti-CD20 monoclonal antibody can be divided into type I and II, rituximab is type I anti CD20 monoclonal antibody, and otularzumab is type II antiCD20 monoclonal antibody
.

The mechanism of action of the two types is different, type I monoclonal antibody is mainly complement-dependent cytotoxicity (CDC) and ADCC, which does not lead to direct cell death; Type II monoclonal antibodies exert antitumor effects mainly through direct cell death action (DCD) and ADCC, with CDC having a weaker
effect.

SummaryThe immunotherapy of type I anti-CD20 monoclonal antibody rituximab is the main treatment for a variety of B-cell malignancies, and its value is beyond doubt
.

However, further research is needed to determine the mechanism of rituximab resistance and to develop a new generation of anti-CD20 monomers
with more desirable efficacy.

After Professor Huang Yan's wonderful interpretation, a number of experts discussed
the treatment plan after rituximab resistance.

For the future application of anti-CD20 monoclonal antibody in clinical practice, Professor Zhang Xudong said that type II anti-CD20 monoclonal antibody otolizumab can overcome the mechanism of rituximab resistance: otolizumab mainly exerts anti-tumor activity (overcoming CDC resistance) by directly inducing cell death and ADCC; ADCC/ADCP effect and inducing direct cell death are stronger (overcoming the adverse effects of the tumor microenvironment); Better clinical outcomes
may be possible in patients with weak CD20 expression or drug resistance due to CD20 antigen loss (overcoming CD20 target loss).

Professor Zhao Xia also said that in the current clinical practice, patients with relapse and refractory treatment will try to use otularzumab more, and Professor Li Zengjun said that the first course of otularizumab is administered on the 1st, 8th and 15th days, which can achieve a higher stable blood concentration faster, and the treatment effect is better, and it is recommended to standardize the administration according to the standard mode of administration to ensure the expected efficacy
.

Past Issues Review: Heroes of the Crowd No.
1 | Literature Intensive Reading of the Initial Diagnosis and Treatment of DLBCL New Thinking
Group Yinghui· No.
2 | Intensive literature reading focuses on the treatment
of indolent lymphoma, Issue 3, | New Advances
in the Treatment of Rituximab Refractory iNHL in Intensive Literature Reading Group Yinghui No.
4 | New Advances
in the Treatment of Relapsed Refractory DLBCL, No.
5 | Intensive reading of the literature focuses on the treatment of CLL

Qunyinghui No.
6 | Application of anti-CD20 in lymphoma in intensive literature

Qunyinghui No.
7 | Application of bendamustine combined with anti-CD20 monoclonal antibody regimen in iNHL

QunyingHui No.
8 | Intensive reading of the literature on otolizumab plus chemotherapy in the first line treatment of FL and MCL

Qunyinghui No.
9 | Intensive reading of the literature: The Advanced Path to DLBCL First-Line Therapy

Qunyinghui No.
10 | A new direction for targeted therapy for B-cell lymphoma in the literature

References: [1] Gibiansky E, Gibiansky L, Buchheit V, Frey N, Brewster M, Fingerle-Rowson G, Jamois C.
Pharmacokinetics, exposure, efficacy and safety of obinutuzumab in rituximab-refractory follicular lymphoma patients in the GADOLIN phase III study.
Br J Clin Pharmacol.
2019 Sep; 85(9):1935-1945.
doi: 10.
1111/bcp.
13974.
Epub 2019 Jul 12.
PMID: 31050355; PMCID: PMC6710522.
[2] Seyfizadeh N, Seyfizadeh N, Hasenkamp J, Huerta-Yepez S.
A molecular perspective on rituximab: A monoclonal antibody for B cell non Hodgkin lymphoma and other affections.
Crit Rev Oncol Hematol.
2016 Jan; 97:275-90.
doi: 10.
1016/j.
critrevonc.
2015.
09.
001.
Epub 2015 Sep 30.
PMID: 26443686.
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