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The treatment model for chronic lymphocytic leukemia (CLL) is undergoing a historic change. From traditional immunotherapy to non-chemotherapy, from single-agent uncertainty therapy to new drug-deterministic therapy. CLL's treatment model and strategy have undergone tremendous changes.
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CLL belongs to the B-cell-derived chronic lymphoproliferative disease, which has a high incidence age of 65 to 70 years. The incidence of CLL in mainland China is lower than that in Western countries, but with the aging of the population and the popularization of routine physical examination, the incidence of chronic lymphocytic leukemia is increasing year by year. Rituximab-based combination immunotherapy, such as FCR (fludarabine, cyclophosphamide, and rituximab), BR (bendamustine, rituximab), and nitrobutyric acid merlot, are the mainstay of treatment for CLL in the pre-new drug era.
These regimens remain the standard first-line treatment regimens for patients with chronic lymphocytic leukemia in China. Novel CD20 monoclonal antibodies of ofomaumab and obinutuzumab; CD52 monoclonal antibody alenzumab; small molecule targeted drugs such as Bruton's tyrosine kinase (BTK) inhibitors, phosphatidylinositol 3-kinase (PI3K) inhibitors, B cell lymphoma-2; Bcl-2) application of the inhibitor venetoclax; And the application of a new immune system therapy such as a chimericantigen receptor (CAR) T cell has ushered in a new era for the treatment of CLL.
1. BTK inhibitors
BTK is a member of the family of non-receptor protein tyrosine kinases, and BTK inhibitors bind to cysteine residues (Cys-481) in the BTK active center, blocking the activation of BTK by inhibiting phosphorylation of BTK.
1. Irutinib
Ibrutinib is the first generation of small molecule irreversible BTK inhibitors taken orally, mainly metabolized by the liver in the body. In a phase II multicenter study, 85 patients with R/RCLL were treated with different doses of irutinib (51 patients 420 mg/day, 34 patients 840 mg/day). The dose of ilutinib is recommended for patients with CLL at 420 mg/day according to the efficacy and toxic side effects of 2 groups of patients. At 26 months of follow-up, the estimated progression-free survival (PFS) rate was 75% and the overall survival (OS) rate was 83%. And the toxic effect is mild.
However, the problem of drug resistance of irutinib gradually emerged. Elutinib resistance is often associated with mutations in irutinib's BTK binding site C481 and mutations in PLCγ2, which lead to sustained activation of the BCR signaling pathway, thereby promoting leukemia cell growth and proliferation and elutinib resistance.
2. Akatinib
Acalabrutinib is a specific, irreversible second-generation BTK inhibitor that, similar to irutinib, covalently binds to C481 in BTK to inhibit its activity. However, its inhibitory effect is highly specific, reducing the non-targeted inhibition of the epidermal growth factor receptor (EGFR) of a generation of irutinib and interleukin-2-induced tyrosine kinase (ITK), so its toxicity is low.
In a Phase I.-II. multicentre study conducted by Byrd et al., 61 patients with R/RCLL were given different oral doses of akatinib (an incremental dose of 100 to 400 mg/day) in the first stage, and no dose-limiting toxic reactions occurred. The study recommended a phase II trial dose of akatinib at 100 mg, 2/day based on efficacy. In the second stage, 100 mg of akatinib was given twice daily for treatment with R/R CLL, with a median follow-up time of 14.3 months and an ORR of 95%. In patients with 17P deficiency, their ORR was 100%. There were no cases of Richter's transformation during the follow-up period. Therefore, akatinib has a good efficacy and safety in patients with R/R CLL (including those with 17P deficiency).
Bcl-2 inhibitors
The mitochondrial apoptosis pathway is the most classic apoptosis pathway and is regulated by the Bcl-2 protein family. Overexpression of anti-apoptotic proteins such as Bcl-2 is one of the important reasons for the obstruction of apoptosis and drug resistance in tumor cells, and the study found that Bcl-2 overexpression is often detected in leukemia stem cells. Therefore, small molecule inhibitors that target Bcl-2 have become one of the most promising drugs in the field of AML therapy.
Vinacla
As the first Bcl-2 inhibitor on the market, venetoclax (Ven) has a good safety profile in monotherapy with AML, but the efficacy is limited. Ven is a powerful oral Bcl-2 selective inhibitor, as an important small molecule drug in the field of protein-protein interaction, it can directly bind to Bcl-2 and replace Bim, thereby changing the permeability of the outer membrane of the mitochondrial body, activating caspase, repairing the apoptosis pathway of tumor cells, and regulating related genes to promote the release of inflammatory factors to exert anti-tumor effects.
Studies have shown that AML cells vary widely in sensitivity to Ven, and Mcl-1 is a key factor contributing to Ven endogenous resistance. Therefore, the combination of Ven with other drugs is a key therapeutic strategy to improve the anti-tumor effect and prevent drug resistance. Demethylated drugs (HMAs) azacitidine (Aza) or decitabine (Decitabine, Dec) as first-line treatments of AML, combined with Ven are superior to two-agent monotherapy.
III. Panatinib
Panatinib is a third-generation multi-target tyrosine kinase inhibitor (TKI), approved by the US FDA in December 2012, clinically used for the treatment of adults with T315I mutation-positive CML (CP, AP and BP) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) with T315I mutation positive; It is also used to treat CML and Ph+ALL in adults who have not been treated with other TKIs. Panatinib is currently the only marketed drug that is effective against bcr-Abl kinase T315I mutations.
4. PI3K inhibitors
PI3K has three subtypes: PI3Kα, PI3Kδ, and PI3Kγ, which are mainly expressed in white blood cells. PI3K promotes activation and maturation of B cells by activating the BCR signaling pathway. In addition, PI3K can propagate activation signals to other downstream targets through PI3K-AKT-mTOR signal cascading, mediating the regulation of the cell cycle. Therefore, inhibition of PI3K has become a hot spot for CLL targeted therapy. At present, common PI3K inhibitors are Idelalisib, Duvelisib, Umbralisib and so on.
Adrani
Idelalisib is an oral reversible PI3Kγ inhibitor that inhibits its activity by non-covalent binding to PI3K. Brown et al. conducted a Phase I clinical trial in which 54 patients with R/R CLL were treated with different doses of Idelalisib, and the dosing regimen of Idelalisib was recommended at 150 mg, 2/day according to efficacy and toxic side effects. In a Phase II clinical study, 24 patients treated with CLL were given oral monotherapy Idelalisib for 2 months, followed by 6 months of Idelalisib plus ofatumumab. After a median follow-up of 14.7 months, a total of 13 subjects (54%) experienced ≥ grade 3 aminotransferase elevations that occurred prior to ofatumumab use (median incidence was 28 d). Hepatotoxicity is a common and serious adverse event of Idelalisib, so Idelalisib is not currently being considered for use in patients with primary CLL.
In patients with R/RCLL, the Idelalisib-related regimen can lead to treatment-related serious adverse reactions. Currently, the treatment-related toxic side effects of Idelalisib are thought to be autoimmune-mediated and associated with the regulation of the release of CD8+ cytotoxic T cells by inactivated PI3Kδ. Compared with Ibrutinib, Idelalisib is relatively less safe, so it is currently more likely to apply Idelalisib to patients with R/R CLL who have contraindications to the use of Ibrutinib, cannot be tolerated, or progressed.
Fifth, alkylating agent
Among the many anti-cancer drugs, alkylating agents are the earliest drugs applied to cancer treatment, and they are also drugs that are widely used in tumor treatment. The alkylating agents commonly used in clinical practice mainly include nitrogen mustard, nitrosoureas, triazoles, hydrazine derivatives and platinum drugs.
Mephalan (melphalan)
Melphalan is a nitrogen mustard alkylating agent that can be decomposed spontaneously or hydrolyzed enzymatically to generate active electron-loving reagents that attack DNA, RNA, or proteins and inactivate these biological macromolecules. Dna alkylation damage produced by these alkylators is thought to be the main cytotoxic damage to their anti-tumor activity, and if not properly repaired, these damages can inhibit double-strand separation during DNA replication and transcription or induce DNA double-strand breakage, ultimately leading to apoptosis. Monofunctional alkylating agents have poor targeting of cancer cells, alkylating sites are easy to repair, and toxic side effects that patients cannot afford at large doses, so their clinical application is greatly limited.
6. Monoclonal antibodies
Monoclonal antibodies are highly homogeneous antibodies produced by a single B cell clone that target only a specific epitope. Hybridoma (hybridoma) antibody technology is usually prepared by using hybridoma (hybridoma) antibody technology, which is based on cell fusion technology, which fuses sensitized B cells with the ability to secrete specific antibodies and myeloma cells with unlimited reproductive ability into B cell hybridomas. Cultured into a cell population with a single hybridoma cell with this property prepares a specific antibody against an epitope of one antigen, a monoclonal antibody.
1. Offamumab
Ofatumumab is a fully humanized, targeted anti-CD20 monoclonal antibody for the treatment of refractory CLL with fludarabine combined with alemmab. The drug induces cell lysis by binding to small ring antigens on CD20-sized molecules, inducing apoptosis of CD20 cells, specifically killing B lymphoma cells, but having no adverse effects on other normal tissues. Dillon, CEO of NICE, said: "Offamumab is the first drug to treat untreated CLL, the main purpose of which is to prevent disease progression and delay the next treatment."
2. Allenumab
Alenumab (ALM) is a completely humanized anti-CD52 monoclonal antibody. ALM can kill all cells expressing the CD52 molecule through antibody-dependent cytotoxic and complement-mediated cell lysis processes. Because CD52 is widely distributed on all human lymphocytes, it is anchored to the surface of the cell membrane by glycosylated phosphatidyl inositol, but CD52 is not expressed in hematopoietic stem progenitor cells. ALM is an effective drug that produces lymphocyte lysis without affecting hematopoietic stem cells. ALM was initially used in the treatment of lymphocyte line tumors and can produce a good lymphocyte lysis effect. In 2001, ALM has been used as a second-line treatment for chronic lymphocyte leukocytes. ALM is also used as a treatment for other gonorrheal proliferative tumors.
Summary and outlook
The advent of a range of new targeted drugs has revolutionized the treatment of CLL and is replacing traditional standard immunotherapy regimens, especially for elderly and frail patients with poor prognosis. As key kinases in the BCR signaling pathway, BTK, PI3K, and SYK are essential for the growth, proliferation, and survival of B lymphoid leukemia cells, and inhibiting their activity can greatly improve the prognosis of CLL patients. At present, Ibrutinib, Idelalisib and Duvelisib have been approved by the FDA for CLL treatment, and the long-term application of these targeted drugs has also brought some toxic side effects and led to the occurrence of drug resistance. At present, the continuous development of a new generation of kinase inhibitors or new combination therapies will be committed to solving these problems. More findings are expected to emerge, thus providing more treatment options for CLL patients.
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