Li Weiming, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Li Weiming, Department of Hematology, Wuhan Union Hospital, Zou Ping
Introduction
Non-Hodgkin’s lymphoma (NHL), which accounts for more than 90% of malignant lymphomas, is a group of highly heterogeneous diseases with complex pathological classification and different clinical manifestations, which often cause great difficulties in diagnosis and treatment. In recent years, with the application of various advanced technologies, the progress of new drug development and the continuous updating of data from various clinical trials, great progress has been made in the understanding of the pathogenesis, the updating of the diagnosis and classification, the prognosis and the therapeutic effect of NHL.
I. Pathology
Histopathological examination is still the gold standard for the diagnosis and staging of lymphoma, and the fourth edition of the WHO classification of lymphohematopoietic tumors (the new classification) released in 2008 is the latest pathological classification system. It is a worldwide consensus on the diagnosis of lymphoma. Since its publication, it has been widely accepted by pathologists and clinicians, and has become the language of communication between pathology and clinical practice. However, the classification still cannot fully meet the need for accurate clinical diagnosis and thus individualized treatment. For example, there are still more controversies in some areas, such as the boundary between monoclonal B-cell hyperplasia and chronic lymphocytic leukemia, follicular lymphoma IIIB, and gray zone lymphoma; while diffuse large B-cell lymphoma and non-specific type (NOS) of peripheral T-cell lymphoma, both of which are still a heterogeneous group of diseases. They cannot be classified precisely and both need to be further studied and improved.
New developments in prognosis and clinical outcome assessment
In the past, the prognosis of NHL was mostly evaluated by the international prognostic index (IPI) or correction index, and corresponding treatment strategies were formulated. In recent years, with the progress of imaging, cytogenetics and molecular biology, various factors have been identified that are closely related to the efficacy and prognosis of NHL. For example, CA125, p53, and SUVmax of PET-CT were negatively correlated with the outcome and prognosis of NHL, and the higher the value, the worse the prognosis and outcome. bcrp and MDR1 were negatively correlated with the outcome of NHL. In contrast, survival protein and Treg were positively correlated with the prognosis of NHL, and the higher their values, the worse their prognosis. In addition, the presence or absence of tissue necrosis, Fas, FasL expression, and the occurrence of EBV infection were also confirmed to be markers of poor prognosis in NHL.
18F-FDG PET/CT imaging has been proven to be of high clinical value in the staging of NHL, early efficacy prediction, efficacy evaluation, identification of the nature of residual masses after treatment, prognosis and survival evaluation, but there is also a certain number of false positives, which cannot be generalized in clinical practice, especially the value of PET/CT in the middle stage of treatment is the focus of current debate and remains inconclusive.
How to develop the most reasonable treatment plan for each NHL patient based on various factors influencing the prognostic efficacy deserves high attention and in-depth study by researchers.
III. Treatment progress of B-cell NHL
“CAR” T-cell therapy
Chimeric antigen receptor (CAR) T-cell therapy is a treatment method in which patient’s T-lymphocytes are collected, modified, and added with viral vectors that target tumor cell surface receptors and promote the expansion of such T-cells, and used to specifically target tumor cells and kill them. Now in its third generation, its clinical efficacy as well as near- and long-term adverse effects deserve further in-depth study.
Recently published results from several studies of CAR-T cell therapy in relapsed refractory B-cell lymphoma have attracted significant clinical attention for their encouraging efficacy. However, similar to most cellular passaging therapies, chills, fever, leukopenia, tumor lysis syndrome, cytokine storm, and hypoimmunoglobulinemia due to B-cell deficiency are common adverse effects that can occur during the application of this therapy. Although the adverse reactions are often reversible and transient, there are reports of cases requiring ICU admission or even death. And because the exogenous gene is randomly integrated into the host genome and persists and is stably expressed in the cell, the treatment also carries the potential risk that mutations at inappropriate insertion sites may cause cells to undergo transformation.
Diffuse large B-cell lymphoma
Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin’s lymphoma, accounting for 35-40% of cases, and is often progressive in nature. In recent years, with the improvement of diagnostic techniques and the application of new drugs, the treatment and prognosis of DLBCL have improved significantly. It has gradually become a curable malignancy, especially for early stage patients, with 5-year PFS ranging from 80% to 85%, and for advanced stage patients, with 5-year PFS around 50%. The significant improvement in efficacy in the last decade should be attributed to the use of the chimeric anti-CD20 monoclonal antibody rituximab. (19-21) Numerous studies have demonstrated that the R-CHOP regimen is currently an irreplaceable option for DLB CL treatment, and combinations with various other targeted agents (e.g., ibrutinib, lenalidomide, etc.) are expected to further improve the efficacy.
Follicular lymphoma
Follicular lymphoma (FL) is one of the common pathological types of non-Hodgkin’s lymphoma, second only to diffuse large B-cell lymphoma. Based on the relative proportions of centroblasts and centroblasts, FL is classified into grades 1-3, with grade 3 subdivided into grades 3A and 3B. Grades 1 through 3A share common histologic and molecular features and inert clinical characteristics, while grade 3B has histology similar to diffuse large B-cell lymphoma, with different molecular features and a more aggressive clinical profile.
Although FL remains incurable, there have been major advances in the treatment of FL in recent years, particularly in the treatment (both initial and maintenance) of rituximab as a single agent and in its combination with conventional chemotherapy regimens. In addition, new technologies, including molecular markers, immunophenotyping and PET imaging, have emerged and are widely used, and diagnostic tools are improving.
The use of rituximab in FL therapy has significantly improved long-term prognosis, and a large number of novel agents entering phase I and II clinical trials, such as novel CD20 monoclonal antibodies, other B-lineage expressing antigen monoclonal antibodies, immunomodulators such as lenalidomide and ibrutinib, may also have good efficacy, thus challenging the previous concept of watch and wait for patients treated with radiation or observation in the limited phase, or asymptomatic patients with low tumor load. The concept of watch and wait for patients with limited stage radiation therapy or observation, or asymptomatic patients with low tumor load, is challenged and its pros and cons need to be reevaluated for better management of FL patients. For the same reason, treatment goals need to be redefined: is the goal to cure FL completely or to make it a manageable chronic disease? Given the older age of most patients, the latter may be more appropriate.
Stromal lymphoma
MCL is a group of B-cell non-Hodgkin’s lymphomas with highly heterogeneous biological and clinical features characterized by t(11; 14)(q13; q32) and cyclin D1 overexpression. mCL is prone to relapse and is the lymphoma subtype with the lowest long-term survival rate, and remains a therapeutic challenge in B-NHL with no standard treatment protocol.
In the last decade, the treatment level of MCL has improved considerably, and the median survival time has been extended from 2.7 years previously to 4.8 years currently. In addition to the use of targeted therapeutic agents (e.g., melphalan) in first-line regimens, the use of higher doses of chemotherapy combined with ASCT for consolidation in younger patients, and the use of attenuated chemotherapy regimens (e.g., melphalan/bendamustine) in older patients, the continued emergence of new drugs (e.g., lenalidomide, ibrutinib, Temsirolimus, etc.) has also brought about a cure for the disease hope.
Further research into the heterogeneity of MCL, more individualized treatment of patients, and the development of new targeted drugs and their combination with conventional chemotherapy regimens will further improve the effectiveness of MCL treatment and increase the cure rate.
Chronic lymphocytic leukemia
Chronic lymphocytic leukemia is a chronic B-lymphocytic proliferative disease characterized by the accumulation of small mature-like lymphocytes in peripheral blood, bone marrow and lymphoid tissues, with corresponding clinical symptoms.
The most advanced area for CLL in recent years has been the introduction of the concept of stratified therapy and the emergence of new therapeutic agents. Stratified therapy is a two-fold approach, based on the patient’s general physical status and concomitant diseases and on the patient’s cytogenetics and molecular biology. The emergence of new highly effective, low-toxic and easy-to-use drugs based on key molecules and pathways in the pathogenesis of CLL, mainly the BCR signaling pathway and its apoptosis-related Bcl-2 signaling pathway, and new anti-CD20 antibodies (such as Ibrutinib, GA101 and Idelalisib), is gradually changing the treatment paradigm of CLL and making CLL patients truly become a chronic disease with a good quality of life.
Advances in the treatment of T-cell NHL
T-cell lymphoma (TCL) is a relatively rare type of malignant lymphoma that is highly heterogeneous, with clinical manifestations, diagnosis, and treatment varying from type to type. Its incidence is about 15% of non-Hodgkin’s lymphoma (NHL) in Europe and the United States, 25% ~ 35% in China, and more common in Taiwan and Japan.
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Treatment of TCL lags significantly behind that of B-cell lymphoma because of the low incidence of TCL and the difficulty of conducting large-scale clinical trials. In recent years, as research on its biological manifestations, cytogenetics, and molecular biology continues to advance, a series of new advances have been made in its diagnosis, treatment, and evaluation of prognostic factors.
Peripheral T-cell lymphoma (PTCL)
PTCL is divided into peripheral T-cell lymphoma-non-specific type (PTCL-NOS), angioimmunoblastoma T-cell lymphoma (AITL), and mesenchymal large cell lymphoma (ALCL), in order of the proportion of PTCL. Peripheral T-cell lymphoma (PTCL) is a relatively new subtype in the pathological classification of lymphoma, with strong heterogeneity, high malignancy, aggressiveness and poor prognosis, and there is no standard treatment plan yet.
The first-line treatment for PTCL is mainly CHOP or CHOP-like regimens, but the results of related studies show that onioncyclines do not improve the prognosis. The prognosis of PTCL has not been changed by increasing the dose or using more toxic chemotherapy regimens that reduce the safety of the treatment process. The development of new drugs (e.g., monoclonal antibodies such as gemcitabine, bevacizumab, alemtuzumab, and proteasome inhibitors) seems to offer hope for PTCL treatment exploration, but more prospective studies are needed to confirm this, and the efficacy of hematopoietic stem cell transplantation needs to be further evaluated.
Extranodal NK/T-cell lymphoma
Extranodal NK/T-cell lymphoma occurs mostly in Asia and Latin America, but is rare in Europe and the United States, and has a high incidence in southern China. Recent studies have shown that EBV infection is closely related to the tumorigenesis mechanism of this disease.
The treatment of extranodal NK/T-cell lymphoma depends on its clinical stage. Currently, radiotherapy followed by chemotherapy is the standard treatment for early stage NK/T-cell lymphoma, and combination therapy can significantly reduce the long-term treatment failure rate and the risk of relapse. Anthracycline-containing regimens have certain effects such as CHOP and EPOCH, but their efficacy is not yet satisfactory; the study of levomucoidase and other new drugs is underway, and their efficacy seems to be better than that of conventional anthracycline-containing chemotherapy.
V. Application of hematopoietic stem cell transplantation in the treatment of NHL
AHSCT is mainly used for relapsed or high-risk NHL after first-line treatment, but it can be used as first-line consolidation therapy for lymphoma subtypes with poor prognosis, such as MCL and PTCL, for which chemotherapy sensitivity is the most important prognostic factor. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is increasingly used in the treatment of NHL, especially reduced-dose pretreatment (RIC) transplantation, which has a promising application due to its lower transplant-related mortality (TRM) along with graft-versus-lymphoma (GVL) effect, but its indications, timing of transplantation, and selection of pretreatment regimens are yet to be further investigated in multicenter, Randomized, prospective clinical trials are needed for further validation.
New radioimmunotherapeutic agents, such as 90Y-tiximab (ibritumomab) and 131 iodine-tosimomab, can use the targeting of antibodies to deliver therapeutic doses of radiation at the tumor site. Some recent studies have attempted to apply this new class of drugs in the pretreatment of ASCT in NHL patients and obtained better results.