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Acute lymphoblastic leukemia (ALL) is a malignancy that occurs in the bone marrow hematopoietic system, most often in children, with a relatively low incidence in adults. In recent years, the complete response rate of all newly diagnosed all has reached 85% to 90%, and the long-term survival rate has ranged from 30% to 50%. The prognosis of relapsed refractory ALL remains poor, with a 5-year survival rate of about 10% and an overall survival (OS) of 2 to 6 months, with a complete response rate of only 5% to 12% for monotherapy. The prognosis of ALL varies widely among different populations, with children having a good prognosis and a poor prognosis for relapsing refractory ALL. Therefore, new drugs are urgently needed.
In this context, blinatumomab came into being. Multiple clinical trial results have shown that bonatuzumab has a good efficacy and well tolerance in relapsed refractory acute lymphoblastic leukemia (B-ALL), and has been approved by the US Food and Drug Administration (FDA) for relapsing refractory and minimal residual disease (MRD) positive B-ALL treatment. This article mainly focuses on the latest research progress of clinical trials and adverse reactions of bonaturumab.
First, the structure of bonatuzumab and its mechanism of action
Bonaturumab is a single-stranded variable region of anti-CD19 and anti-CD3 monoclonal antibodies by using recombinant DNA technology to fuse through a non-immunogenic linker sequence, which can connect CD19+ malignant B lymphocytes with CD3+ T lymphocytes, mediate the lysis of T cells to tumor cells, and the relative molecular mass is 55 kD (Figure 1). Bonatuzumab can be used to treat acute lymphoblastic leukemia, chronic lymphocytic leukemia, and non-Hodgkin lymphoma.
Fig. 1 Structure of Bonaturumab
The results of in vitro activity studies show that bonastumab can specifically bind CD3+ T lymphocytes and CD19+ B lymphocytes, mediating T cells to exert high levels of cytotoxic effects on lymphoma cells. Bonatutuzumab with different drug concentrations was co-incubated with CD8+ T cells and CD4+ T cells, respectively, and the results showed that CD8+ T cells had a lytic effect on target cells, and even at very low drug concentrations, unreimulated T cells could produce strong cytotoxicity to tumor cells. Activated T cells express CD69 and CD25, secrete inflammatory cytokines (such as IFN-γ, TNFα, IL-2, IL-6, and IL-10) and proliferate (Figure 2).
Fig. 2 Mechanism of action of bonaturumab
Second, the clinical application and effectiveness of bonatuzumab
In recent years, clinical studies and efficacy summaries of bonaturumab in the treatment of relapsed refractory B-ALL are shown in Table 1. Clinical studies and efficacy summary of bonatuzumab in the treatment of initial treatment of B-ALL, see Table 2.
1. Bonatuzumab for relapsed refractory ALL
1.1 Ph-negative recurrence refractory ALL
1.1.1 Monotherapy
The results of an early stage II bonatuzumab treatment of adults with Philadelphia chromosome (Ph) negative relapsed refractory ALL showed that 25 (69%) patients achieved complete response (CR) or partial hematologic recovery (CRh) after 2 cycles of treatment, Of these, 22 (88%) patients were MRD negative. Relapse-free survival (RFS) was 6.7 months and OS 9.8 months, with 6 patients developing grade 3 or higher central nervous system toxicity and 2 patients developing grade 4 cytokine release syndrome (CRS). This trial preliminarily verified the safety and efficacy of bonaturumab in ALL.
Another large multicenter Phase II trial (MT103-211) enrolled a total of 189 Ph-negative patients with refractory ALL. After 2 cycles of treatment, 43% of patients achieved CR/CRh (33% CR, 10% CRh). Median RFS (m RFS) was 5.9 months and median OS (mOS) was 6.1 months at median FOLLOW of 8.9 months. Of the 81 patients who received CR/CRh, 32 underwent autologous hematopoietic stem cell transplantation (ASCT). The incidence of toxic adverse reactions in the central nervous system was 12% and the incidence of CRS was 2%. Compared with a long-term survival rate of 5.4% with conventional salvage chemotherapy, bonaturumab can reach 12.4%. The trial pushed the US FDA to accelerate the approval of bonatutuzumab for the treatment of Ph-negative relapsed refractory B-ALL in 2014.
Because bonaturumab exhibits superiority over traditional chemotherapy, a multi-institutional, open-ended phase III clinical trial confirmed that bonatuzumab is more effective than conventional chemotherapy. The trial randomly divided patients into trial and chemotherapy groups in a 2:1 ratio, with 267 patients treated with the blinatumomab regimen and 109 patients receiving conventional second-line chemotherapy. The median mOS of the Bonatuzumab group was longer (7.7 months vs. 4.0 months, P=0.01) and the survival rate was higher (34% vs. 16%, P
1.1.2 Combined drug use
In recent years, the emergence of new treatment methods such as tyrosine kinase inhibitor (TKI), CD20 monoclonal antibody, CD22 monoclonal antibody, chimeric antigen receptor T cell immunotherapy and other new treatment methods has opened up a new path for all multi-drug and multi-treatment forms of combination, and some scholars have tried bonaturumab combined with cytotoxic drugs or other targeted drugs to treat relapsed refractory ALL to achieve greater benefits.
Oletozumab is an antibody-drug conjugate (ADC) that can be effective in improving the response rate of ALL compared to conventional chemotherapy. However, long-term use of oletozumab carries the risk of venous occlusive venosic disease. In a study of mini-hyper-CVD (low-dose CVAD regimen, excluding doxorubicin) plus oletozumab plus bonatuzumab for relapsed refractory Ph-negative ALL, bonatuzumab in combination reduced or interval olattumab reduced the incidence of venous occlusive VEDs (15% vs. 5%) while improving patient survival with a 2-year CR of 52% and an OS of 39%. From the long-term follow-up data of the trial, the 3-year complete response with incomplete hematologic recovery (CRi) was 92%, and the OS was 42%, and the survival data were better in both short-term and long-term.
1.2 Ph positive recurrence refractory ALL
1.2.1 Monotherapy
A positive Ph suggests a poor prognosis, with event-free survival (EFS) and OS significantly lower in Ph-positive patients compared with Ph-negative patients. A Phase II multicenter study evaluating the effectiveness of bonaturumab in the treatment of Ph-positive refractory ALL in 45 patients who had previously undergone TKI failure, 36% of patients achieved CR or CRh, of which 88% were MRD-negative, mRFS was 6.7 months and mOS was 7.1 months, and the results of this trial pushed the US FDA to approve bonatuzumab for the treatment of relapsed refractory Ph-positive ALL in July 2017.
1.2.2 Combined drug use
The mechanism of action of TKI is associated with bcR-ABL1 mutations, while bonaturumab, as a bispecific antibody to CD3 and CD19, has a different mechanism of action than TKI. TKI has a good effect in relapsing refractory Ph-positive ALL, and TKI combined with bonatuzumab may change the treatment mode of relapsing refractory Ph-positive ALL. The goal of Ph-positive ALL therapy is not only to achieve complete remission, but to achieve molecular biological remission. Based on this, a trial of bonatuzumab mainly combined with pronatinib in the treatment of relapsed refractory Ph-positive ALL demonstrated its efficacy and safety, and the molecular biological response rate of the protocol was up to 75%. One study further confirmed that bonaturumab combined with TKI is a safe and effective consolidation regimen for achieving or maintaining molecular biological remission in Ph-positive ALL patients. In the future, comparing the advantages and disadvantages of bonatuzumab plus TKI regimen and bonatuzumab combined with conventional chemotherapy regimen in the treatment of Ph-positive ALL, further clinical trials are still needed to verify.
2. Initial ALL for bonaturumab therapy
2.1 Induction therapy
Given the advantages shown by bonatuzumab in the treatment of relapsed refractory ALL, there have been attempts to use bonatuzumab for the treatment of initial-treated ALL. In order to further improve the prognosis of young patients treated with ALL, Hyper CVAD was sequentially combined with bonatuzumab, that is, 4 cycles of bonastumab induction therapy after 4 cycles of Hyper-CVAD treatment, and 12 cycles of POMM (1 cycle of bonatuzumab cycle alternate after 3 cycles of POP). This trial allows patients with an early high risk of recurrence to use bonaturumab early after 2 cycles of chemotherapy. In the 27 patients included, the complete response rate and MRD clearance were 100% and 96%, respectively, and RFS and OS were 76% and 89%, respectively, after 1 year. According to the results released by the SWOGS1318 trial, the crr/CRi can reach 66% after 1 cycle and 92% of patients can eliminate MRD by using bonatuzumab combined with THE POMP regimen in the newly treated elderly ALL patients.
2.2 MRD cleanup
2.2.1 Monotherapy
A positive MRD is an important marker for predicting disease recurrence. Among adult ALL patients who achieve CR with induction consolidation therapy, 30% to 50% of patients still have MRD positive. MRD cannot detect lesions through traditional cytology, and can only rely on more sensitive detection techniques such as flow cytology, PCR, etc. Several early clinical trials have shown that bonaturumab has the potential for central nervous system toxicity and adverse reactions such as CRS, which may be associated with high tumor burden. The use of bonatuzumab in MRD-positive patients may reduce the occurrence of adverse reactions. Several clinical trials have evaluated the efficacy of bonatuzumab in MRD-positive ALL. In one set of published data, whether Ph positive or negative, 80% of patients achieved MRD response after 1 cycle of bonaturumab, compared with 78% of 1-year RFS. The incidence of grade 3 and above central nervous system toxicity is 19% and the incidence of CRS is 0, which is consistent with the hypothesis that bonaturumab has a low incidence of adverse reactions in low tumor burden disease. This trial accelerated the FDA's approval of bonatuzumab for MRD-positive B-ALL treatment. However, the above-mentioned clinical studies are all small sample size studies, and more large-scale and authoritative clinical trials need to be carried out urgently.
2.2.2 Combined drug use
At present, there is no clear conclusive theory as to whether bonatuzumab is necessary in combination with TKI for MRD-positive ALL. One clinical trial used bonatutuzumab plus TKI as a consolidation regimen to reduce the adverse effects of traditional chemotherapy combined with TKI. Eleven Ph-positive B-ALL patients in the trial received TKI plus bonaturumab consolidation therapy regimen, and after 1 cycle of treatment, 8 (89%) of the 9 MRD-positive patients turned negative, and 2 MRD-negative patients still maintained molecular biological remission, and no grade 3 or higher adverse events were observed. This study suggests that bonatuzumab combined with TKI is a safe and effective consolidation therapy to achieve or maintain molecular biological remission.
Third, the main adverse reactions and safety of bonatuzumab
The most common treatment emergent adverse events (TEAE) that occur (incidence >10%) include fever (62%), headache (32%), edema (32%), febrile neutropenia (25%), nausea (25%), hypokalemia (23%), rash (21%), constipation (20%), tremor (20%), and diarrhea (20%).
Bonaturumab has been reported to cause transient but stable pro-inflammatory cytokine production, or to trigger hemophagocytic lymphostiocytosis/macrophage activation syndrome (HLH/MAS). In one small study, the incidence of infection was 70%, the most common being lower respiratory tract, gastrointestinal tract, and bacteremia. There have also been reports of atypical pneumonia associated with the H1N1 influenza virus caused by bonaturumab. Overall, adverse reactions are controllable and transient, and despite the possibility of reversible central nervous system events and CRS, bonaturumab has a good safety profile.
Fourth, the current listing of bonaturumab and medical insurance price related policies
It is understood that bonaturumab is not currently listed in China, and domestic patients still cannot obtain the drug. Bonatuzumab is not in the Medicare catalog, and the purchased patient is not eligible for Medical Insurance. Depending on your personal circumstances, you can choose drugs exported from different countries.
Fifth, summary and future outlook
With the increasingly hot spot of tumor treatment by immunotherapy, and the emergence of new treatments such as TKI, rituximab, otolizumab, bonatuzumab and CART, the treatment of ALL has made breakthroughs in recent years, but challenges still exist. Bonatuzumab has achieved good efficacy in the treatment of relapsed refractory ALL and MRD-positive ALL whether Ph-positive or negative, and is well tolerated. After a complete response and MRD-positive patients were treated with bonaturumab, 80% achieved MRD-level remission.
There are still many problems that need to be solved urgently in the use of bonatuzumab for the initial treatment of ALL, and clinical research on exploring the optimal combined dosage and medication mode of bonatuzumab + TKI + oxytozumab is currently underway. Judging from the results of real-world research on the application of bonaturumab, its efficacy and safety are roughly equivalent to the results in clinical studies, and more clinical data are urgently needed to evaluate the efficacy of bonatuzumab in the future. Bonatuzumab is also facing the problem of drug resistance, the specific mechanism is still unclear, some studies point out or related to the deletion of target antigens, there are also studies that may be related to the variable splicing of CD19 gene to form a non-immune activity of CD19, bonaturumab combined with immune checkpoint inhibitors may reduce the occurrence of drug resistance.
bibliography
Wu Zhiya, Gu Shuai, Fan Xueting. Research progress of bonatuzumab in the treatment of acute lymphoblastic leukemia[J]. Chinese Journal of Oncology, 48(11):5.
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