Non-Hodgkin lymphoma (NHL) is a malignancy arising from differentiated lymphocytes. The disease most commonly involves lymph nodes, but any organ with lymphocyte activity (such as the respiratory and gastrointestinal mucosa, for example), as well as the bone marrow and extralymphatic tissues, can also be involved.
There are many subtypes of lymphomas and lymphoproliferative diseases, each with its own histological features, genetic alterations and clinical manifestations. According to the latest WHO classification published in 2022, lymphomas are divided according to the cell of origin – most of them are of B-cell origin and a minority of T-cell or NK-cell origin.
The reported incidence in the United States is 22 cases per 100,000 people, which constitutes approximately 5% of all malignancies, and the median age at diagnosis is 63. In Israel, in 2012, approximately 6% of patients diagnosed with malignancy were diagnosed with NHL, which is the fourth highest incidence rate. It is a disease whose incidence increases with age, and the male-to-female ratio is approximately 1.4:1 in favor of men.
The risk factors for morbidity are similar to risk factors for other malignancies, such as smoking, obesity, exposure to pesticides, and working in certain industries, but the statistical relationship between the risk factors for morbidity is low, and many patients had no known risk factors. Immunosuppression due to HIV or drug treatment (such as that given to organ transplant recipients), as well as a family predisposition, are also recognized. There is an etiological link between certain subtypes of NHL and infectious agents, such as hepatitis C virus and marginal zone lymphoma (MZL), Helicobacter pylori and gastric MALT lymphoma, or Chlamydia trachomatis and ocular MZL. In some of these cases, treatment of the infectious agent alone can bring the lymphoma into remission.
The clinical presentation ranges over a wide spectrum. Many patients, especially with indolent lymphomas, are asymptomatic for long periods. In others, the first sign is painless lymphadenopathy or local pressure on a limb that causes pain. In advanced or racing lymphomas, severe B symptoms (weight loss, systemic fever, and night sweats) may be present.
In general, diagnosis is made from a biopsy of an involved site (often a lymph node), based on the architecture of the tissue and immunohistochemical staining that identifies the expression of specific proteins on the tumor cells. The architecture of the tissue is critical for diagnosis, and therefore a biopsy of a whole gland or a TRU CUT biopsy with a thick needle is desirable.
After diagnosis, staging is required to estimate the extent of the disease spread, which includes a whole-body CT scan and, in some lymphomas, a bone marrow biopsy. In most types of lymphoma, a PET-CT scan with radioactively labeled glucose injection is preferred, which provides information on the metabolic activity of the tumor, in addition to the anatomical information provided by the standard CT scan. The information provided by PET upstaging up to 31% of cases at diagnosis, and better differentiates in follow-up examinations between scarred sites of old disease and active disease sites. Following STAGING, there are prognostic indices based on disease activity and blood tests of the patients, which create the international prognostic index (IPI), and for many lymphomas there are IPI-based indices adapted to the specific subtype. In the era of HeptCity and genetic information, the various IPI indices are losing their importance as prognostic indices, but are still widely used.
Subtypes of lymphomas
There are many subtypes of lymphoma, and they are usually divided into “indolent”/indolent lymphomas, and aggressive lymphomas. The distinction between these types is also related to the dynamics of the disease and sometimes to the clinic, but greatly influences therapeutic decisions.
Indolent lymphomas are lymphomas that usually develop slowly over years and are usually diagnosed at an advanced stage (stage 3–4). They behave clinically as a chronic disease, and cannot be cured with standard chemotherapy, but are also usually characterized by long survival of most patients. Therefore, early treatment is often not necessary upon diagnosis, and only when a clear indication for treatment appears, such as damage to nearby organs, damage to the bone marrow, or B signs (fever, weight loss, or night sweats), should treatment be started. Several studies on early treatment of these diseases have found that early treatment does not improve the life expectancy of patients (does not extend overall survival). The most common lymphoma in the group of indolent lymphomas is follicular lymphoma (FL).
The most common lymphoma in the group of aggressive lymphomas (and generally the most common within NHL) is DLBCL. Lymphomas Aggressiveness requires rapid treatment after diagnosis, and most patients will suffer from various complaints and symptoms related to their disease at the time of diagnosis. Thanks to treatment, about 70% of patients will recover after the first line of treatment, and will not require further treatments in the future. As described above, information about genetic changes in the disease cells and its different subtypes provide important prognostic information and influence the therapeutic decision, and in particular which treatment protocol is appropriate for the disease.
T-cell or NK-cell lymphomas are a minority of all lymphomas, and even in this category there are diseases that behave in an indolent manner, such as cutaneous lymphoma of the type Mycosis fungoides. However, a significant number of them are very aggressive, and often the prognosis is worse than that of aggressive B-cell lymphomas.
Lymphoma Treatment Methods
For many years, the first line of treatment for lymphoma was based on chemotherapy, plus antibodies against a protein on the disease cells. This is still the recommended first line in many of the diseases, such as DLBCL, FL. However, a large number of non-chemotherapy treatment options have entered, mainly in advanced lines but also in early lines. These treatments, and in particular their combinations, can lead to excellent and long-lasting responses, with a safer side effect profile.
Chemotherapy or radiation-based treatment
The mechanism of action of these treatments is damage to dividing cells. In light of the fact that in tumors the cells divide at a faster rate, and there is less genomic stability, the treatment damages the tumor more than in healthy tissues, and can only lead to prolonged remissions. However, there is significant damage to healthy cells as well, and this leads to many side effects such as damage to the immune system, gastrointestinal disorders, and hair loss.
Targeted therapies
These therapies interfere with a specific pathway or enzyme in the cell proliferation pathway, or with a mechanism related to controlled cell death (apoptosis). For example, Bruton tyrosine kinase inhibitors prevent the action of the kinase that causes uncontrolled B-cell division. In contrast, inhibitors of the BCL-2 protein, a protein that protects cells from programmed cell death, cause increased apoptosis.
Immunotherapy therapies
The first treatment to show a prognostic improvement in combination with chemotherapy, compared to chemotherapy alone, was treatment with clonal antibodies such as Rituximab. These antibodies, directed against CD20, are added to the chemotherapeutic backbone, and mark disease cells for recognition by immune system cells that destroy them, and even cause tumor death themselves. As mentioned, the addition of rituximab treatment improved patient survival compared to chemotherapy alone in both indolent and aggressive lymphomas.
Sometimes these antibodies are given for a long time after the end of intensive treatment, as maintenance therapy to prevent the disease from returning. In follicular lymphoma, maintenance therapy for 2 years with a monoclonal antibody against CD20 alone, after the end of the combination phase with chemotherapy, improved progression-free survival, although not life expectancy of patients.
Antibody conjugates and biphasic
Another family of antibody-based therapies is antibody-drug conjugates. These antibodies are conjugated to cytotoxic substances, and when they bind to the target cell, the antibody is introduced into the cell, and with it the drug that causes disruption of cell division and death. There are antibodies of this type against CD30 (Brentuximab vedotin) used to treat T-cell lymphomas and Hodgkin lymphoma, as well as against other targets found on B-cell lymphoma cells, such as CD79a.
A new group of immunotherapies are bispecific T-cell engager (BiTE) antibodies. These bispecific antibodies target an antigen on the tumor, as well as an antigen on T cells – usually CD3. Adherence to tumor cells on the one hand and to T cells on the other hand, causes the activation of T cells against the tumor, and an immunological response against them. These antibodies have already been approved by the FDA, and some of them are in the Israeli health basket as advanced lines of treatment for B-cell lymphomas.
Cellular therapies – CAR T
Another treatment method that has entered clinical use is the use of immune system cells that have undergone genetic engineering, and have had a gene inserted into them which encodes a chimeric receptor. The receptor targets a specific target on the tumor, activating T cells to multiply and kill the tumor cells. These cells – chimeric antigen receptor T cells (CAR-T) – are transplanted into the patient after a process of collection and production in the laboratory, and after being returned to the body, multiply, and attack the tumor cells. Some of them can remain in the body for many years, effectively creating long-term protection against the recurrence of the disease. These treatments have been approved in the United States and included in the Israeli health basket for several B-cell lymphomas, and have even been promoted from third-line to second-line in DLBCL (Axicabtagene ciloleucel and lisocabtagene maraleucel), and are also approved for third-line mantle cell lymphoma (Brexucabtagene autoleucel), for second-line B-ALL (Brexucabtagene autoleucel for all ages, and Tisagenlecleucel for those under 26), and for follicular lymphoma (Axicabtagene ciloleucel and Tisagenlecleucel). There are studies regarding the future introduction of cellular therapies, as well as bi-head antibodies, to early lines and even first-line in B-cell lymphomas.
In conclusion
NHL lymphoma contains many subtypes of lymphomas, with different clinical behavior and prognosis between types. These diseases are characterized by biopsy, and for most of them a more accurate prognostic diagnosis can be reached by the genetic changes found in the tumor. After performing STAGING, usually by PET CT, it must be decided whether treatment is necessary, and sometimes – in indolent lymphomas – only monitoring is necessary. After progression, or in aggressive diseases, it is necessary to choose a treatment protocol, and beyond chemotherapy treatments – there are many options of targeted therapies or immunotherapies for treating lymphoma.
