Most often, the treatment is chemotherapy (chemo), usually with a regimen of 4 drugs known as CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), plus the monoclonal antibody rituximab (Rituxan). For DL BCL that is only in 1 or 2 lymph node groups on the same side of the diaphragm (the thin muscle that separates the chest from the abdomen), R-CHOP is often given for 3 to 6 cycles, which might be followed by radiation therapy to the affected lymph node areas.
After several cycles, doctors may get imaging tests such as a PET/CT scan to see how well treatment is working. People who have a higher risk of the lymphoma coming back later in the tissues around the brain and spinal cord may be treated with chemo injected into the spinal fluid (called intrathecal chemotherapy).
For younger patients with a higher risk of the lymphoma coming back based on the International Prognostic Index (IPI) score, high-dose chemo followed by a stem cell transplant might be an option. Most doctors feel that if a transplant is done as part of the first treatment, it should be done in a clinical trial.
Stem cell transplants are not effective unless the lymphoma responds to chemo. DL BCL can be cured in about half of all patients, but the stage of the disease and the IPI score can have a large effect on this.
Sometimes, the doctor will order a biopsy of the chest tumor to confirm that lymphoma is still present before starting radiation. Another treatment option is 6 cycles of dose-adjusted topside, doxorubicin and cyclophosphamide with vincristine, prednisone and rituximab (DA-EPOCH-R) which typically does not require any radiation.
If the primary mediastinal B cell lymphoma does come back or does not respond to chemo, immunotherapy with the drug pembrolizumab may be an option. This type of lymphoma often grows slowly and responds well to treatment, but it is very hard to cure.
If treatment is needed for follicular lymphoma that is only in 1 lymph node group or in 2 nearby groups that are both above or below the diaphragm (the thin muscle separating the chest from the abdomen), the preferred treatment is radiation therapy to the lymph node areas affected by lymphoma (called involved site radiation). If treatment is needed, the most common option is a monoclonal antibody (rituximab or obinutuzumab) combined with chemo.
The chemo can be a single drug (such as bendamustine) or a combination of drugs, such as the CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or CVP (cyclophosphamide, vincristine, prednisone) regimens. This might include continuing the monoclonal antibody (rituximab or obinutuzumab) for up to 2 years, or treatment with ibritumomab.
Further treatment may lower the chance that the lymphoma will come back later and may help some patients live longer, but it can also have side effects. The main difference is where the cancer cells are (the blood and bone marrow for CLL, and the lymph nodes and spleen for SLL).
If the lymphoma isn’t growing quickly or causing any problems, it can be watched closely without treatment for a time. Which treatment is used depends on a person’s age and health, as well as on whether the cancer cells have certain chromosome changes.
Because current treatments for this type of lymphoma aren't likely to cure it, patients might want to consider taking part in a clinical trial. Mantle cell lymphomas that have spread more widely when they are first diagnosed are treated with chemo plus rituximab.
If the lymphoma responds well to these initial treatments, a stem cell transplant may be a good option, followed by rituximab for 3 years. Less intense chemo regimens, such as bendamustine with rituximab, may be used for people who are older or who have other health issues.
For mantle cell lymphomas that don’t respond or that come back after initial treatment, chemo with drugs such as bendamustine, bortezomib (Decade), carbine, clofarabine, or thalidomide (Realized) may be used, sometimes along with other chemo drugs or with rituximab. Other options include the use of a targeted drug, such as ibrutinib (Imbruvica), acalabrutinib (Sequence), or zanubrutinib (Bruins), as well as the CAR T-cell therapy brexucabtagene autoleucel (Tenants).
Other targeted drugs such as venetoclax (Vendetta) and idealism (Zelig) have also shown promising results in some early studies. Early-stage gastric MALT lymphomas are treated with antibiotics combined with drugs that block acid secretion by the stomach (called proton pump inhibitors).
About 2 out of 3 of these lymphomas go away completely with antibiotic treatment, but it can sometimes take several months to be effective. For these early-stage gastric MALT lymphomas, treatment is usually either radiation therapy to the stomach or rituximab.
If the lymphoma is large, is causing symptoms, or is growing, it can be treated with radiation therapy to the stomach, rituximab, chemo, chemo plus rituximab, or the targeted drug ibrutinib (Imbruvica). The chemo drugs used are the same as those used for follicular lymphoma, and may include single agents such as chlorambucil or clofarabine or combinations such as CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or CVP (cyclophosphamide, vincristine, prednisone).
This rare type of lymphoma is generally slow growing (indolent), and it often doesn’t need to be treated right away. If it does need treatment, it is usually treated the same way as follicular lymphoma (which also tends to grow slowly).
If treatment is needed for lymphoma that is only in 1 lymph node group or in 2 nearby groups on the same side of the diaphragm (the thin muscle separating the chest from the abdomen), the preferred treatment is radiation therapy to the lymph node areas affected by lymphoma (called involved site radiation). Other choices include treatment with rituximab (Rituxan), chemo, or both, which might be followed by radiation therapy.
The chemo can be a single chemo drug (such as bendamustine or clofarabine) or a combination of drugs, such as the CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or CVP (cyclophosphamide, vincristine, prednisone) regimens. Other options for initial treatment include rituximab alone or chemo alone (either one or several drugs).
Further treatment may lower the chance that the lymphoma will come back later and may help some patients live longer, but it can also have side effects. Nodal marginal zone B-cell lymphoma can also change into a fast-growing diffuse large B-cell lymphoma (DL BCL), which would require more aggressive chemotherapy (see above).
About 1 in 3 people with this type of lymphoma have chronic hepatitis C virus (CV) infection. If that doesn’t work, or if a person isn’t infected with CV, surgery to remove the spleen can sometimes lead to a long-term remission.
Hyper-CVAD (cyclophosphamide, vincristine, doxorubicin , and dexamethasone), alternating with methotrexate and cytarabine (Arab) CODEX (cyclophosphamide, vincristine , doxorubicin, and high-dose methotrexate), alternating with IVAN (ifosfamide, topside , and cytarabine ) EPOCH (topside, prednisone, vincristine , cyclophosphamide, and doxorubicin) An important part of the initial treatment of this disease is making sure a person gets plenty of fluids, as well as drugs like allopurinol, to help prevent tumor lysis syndrome (described in Chemotherapy for Non-Hodgkin Lymphoma).
This lymphoma begins in the brain or spinal cord. It often develops in older people or those with immune system problems caused by AIDS or drugs given to keep transplanted organs from being rejected. For people in reasonably good health, high IV doses of the drug methotrexate have been shown to be the most effective treatment.
This is given along with the drug leucovorin and IV fluids, which help limit serious side effects. For those who aren’t able to tolerate this treatment, other, less intensive chemo regimens or radiation therapy alone may be tried.
An issue with radiation therapy to the brain, especially in older patients, is that it can often cause mental changes. If CNS lymphoma keeps growing or comes back after treatment, further options may include chemo (using different drugs), radiation therapy, or a stem cell transplant if the person is healthy enough.
Most often doctors treat these cancers with radiation therapy, chemotherapy (chemo), or a combination of the two. Problems with thinking, concentration, and memory are possible side effects from radiation to the brain and spinal cord.
Depending on the type of lymphoma, chemo may be used alone or in combination with radiation therapy, especially if it has grown outside the eye or spread to other places in the body. Intraocular chemo gets higher doses of the drug to the tumor without causing severe side effects in other parts of the body.
Patients with MALT lymphoma have a varied presentation depending on the primary site of disease. Common sites include the stomach, small intestines, lacrimal glands/orbit, thyroid, lungs, skin, and salivary glands.
Despite proliferation of lymphoid tissues, patients are often asymptomatic and the disease may present as an incidental finding. Patients with splenic marginalzonelymphoma (SML) commonly present with splenomegaly and bone marrow involvement, both of which may produce cyclopedias.
Patients with DL BCL typically experience rapid progression of disease and are often symptomatic at the time of diagnosis. Physicians should consider searching for loci of transformation in patients with marginalzonelymphoma who experience rapid disease progression, or increase in clinical symptoms.
However, MCL is typically CD5+ and is characterized by the over expression of cycling D1 and/or the presence of t(11;14) by cytogenetics or fluorescent in situ hybridization (FISH). MCL is typically more aggressive than marginalzonelymphoma, although up to one third of cases may follow an indolent course for several months or years.
A para protein, usually immunoglobulin M (IGM), is common but is not diagnostic of LPL and can also occur in cases of marginalzonelymphoma with plasmacytoid differentiation, although usually to a lesser degree. Morphologically, marginalzonelymphoma is characterized by small to medium-sized lymphocytes surrounding a reactive follicle.
SML typically produces infiltrates of small lymphocytes in both the white and red pulp of the spleen. The exception is primary cutaneous marginalzonelymphoma, which appear to undergo class switching and more commonly express Egg, IGA, and IGE (immunoglobulins G, A and E).
Extra nodal marginal zone lymphomas are commonly associated with chromosomal abnormalities, including t(11;18)(q21;q21), t(14;18)(q32;q21), t(1;14)(p22;q32), t(3;14)(p12;q32), and trisomy 3 or 18. The nuclear factor kappa B (NFL) pathway is frequently involved in the pathogenesis of marginal zone lymphomas.
Mutations leading to constitutive activation of NFL have been detected in splenic and extra nodal marginal zone lymphomas including BIRC3 and TRAF3. The tumor suppressor genes responsible for histone modification, KMT2D and MLL2, are often mutated in nodal marginalzonelymphoma.
Similarly, testing for Chlamydia pitta in ocular adnexal lymphoma or B. burgdorferi in cutaneous marginalzonelymphoma is reasonable. Standard Ann Arbor lymphoma staging and response assessment is performed using computed tomography (CT) imaging of the neck, chest, abdomen, and pelvis.
The utility of PET (positron emission tomography) imaging remains unclear, with a high false negative rate. Nonetheless, PET imaging can occasionally be useful to help identify sites of extra nodal disease in patients that were previously felt to have nodal lymphoma.
Similarly, dissemination of MALT lymphoma to regional nodes can occasionally be detected by PET scan in patients with normal CT imaging. Nonetheless, PET imaging is not considered standard of care and generally has limited clinical utility.
MRI imaging is often helpful in assessing the extent of disease in patients with ocular adnexal MALT lymphoma. Due to the slow nature of progression, most patients present before developing significant complications.
In the rare cases of life or organ-threatening marginalzonelymphoma, high dose corticosteroids (for example, dexamethasone 40 mg daily) can be used to temporize matters before starting more definitive (immune) chemotherapy or radiotherapy. Treatment of indolent lymphoma should be individualized according to the disease subtype, presentation, comorbid conditions, and patient preferences.
Most patients with nodal marginalzonelymphoma present with advanced stage disease and are not likely to achieve cure, even with aggressive chemotherapy regimens. Asymptomatic patients with slowly progressive, non-bulky disease may be safely observed, often for many months, before developing indications for therapy.
Similarly, there are reports of resolution of ocular adnexal MALT lymphoma following antibiotic therapy of Chlamydia pitta. Patients with early stage MALT lymphoma with no underlying infectious etiology, or those for whom antibiotic therapy has failed, can be effectively managed with external beam radiotherapy.
Surgery is rarely the primary mode of therapy for localized disease, but may be the only treatment necessary in cases where the entire tumor was removed during a diagnostic biopsy. Patients with symptomatic advanced stage disease, or those with symptomatic early stage disease not amenable to radiation therapy, may be managed with rituximab +/- chemotherapy, depending on comorbid conditions and urgency for treatment response.
Observation with deferred initial therapy should be considered in most patients with SML without cyclopedias or symptoms. Traditionally, splenectomy has been considered the best first-line therapy for patients with SML and symptomatic splenomegaly or severe cyclopedias.
However, treatment with rituximab +/- chemotherapy may be equally likely to yield clinical benefit and will also result in a reduction in tumor bulk outside the spleen (that is, the bone marrow). These patients require aggressive therapy and may benefit from autologous stem cell transplantation.
Gastric MALT lymphoma is the sole subtype for which strong evidence of response to antibiotic therapy exists. However, among patients with early stage gastric MALT lymphoma, the response to H. pylori eradication can vary significantly.
Second, tumors that demonstrate the t(11;18) abnormality are unlikely to respond to H. pylori eradication and should probably be managed with alternative therapies (for example, radiation). Patients that respond but subsequently relapse may benefit from another course of H. pylori eradication in cases where reinfection occurs.
Patients with other subtypes of nodal and extra nodal marginalzonelymphoma are at high risk for relapse following initial therapy (advanced stage disease is rarely, if ever, curable). Nonetheless, there is typically a lag between relapse of disease and the point at which patients develop clinically relevant symptoms sufficient to warrant therapy.
The Burton’s tyrosine inhibitor ibrutinib is indicated for treatment of relapsed/refractory marginal lymphoma based on the results of a phase 2 clinical trial in which it was dosed continuously at 560 mg daily. As has been observed in other lymphomas, ibrutinib was associated with side effects including fatigue, anemia, and infections and should therefore be reserved for patients with symptomatic relapsed or refractory disease.
Patients with limited stage extra nodal MALT lymphoma should be treated with curative intent with antibiotics or locally directed therapy when possible. In circumstances where such therapy is not feasible, when patients present with advanced stage lymphoma, or when patients relapse at sites distal to their original presentation, cure is unlikely with anything short of allergenic stem cell transplantation (something that is usually not indicated).
Nonetheless, patients typically live for many years, requiring intermittent therapy when the disease becomes symptomatic. Despite similar International Prognostic Index (IPI) scores at presentation and rates of aggressive transformation, patients with nodal marginalzonelymphoma fare somewhat worse than patients with MALT lymphomas, with a reported 5-year OS closer to 60%.
In a large retrospective series from Italy, hemoglobin less than 12g/L, lactate dehydrogenase (LDH) greater than the upper limit of normal, and albumin less than 3.5g/DL were associated with a 5-year OS of 88%, 73%, and 55% for one, two, or three factors. Patients experiencing transformation will typically manifest new constitutional symptoms, rapid tumor growth, or resistance to less aggressive forms of therapy.
Radioimmunotherapy may be appropriate for those patients that are not candidates for tetracycline based regimens, if hematologic and bone marrow parameters allow. Such patients should be considered for aggressive second-line regimens, followed by autologous stem cell transplantation.
Although the tumor microenvironment clearly plays a role in the biology of many cancers, rarely is the relationship as strong as that which exists in marginalzonelymphoma. The association of MALT lymphomas with infectious/autoimmune conditions, the restricted variable gene repertoire, and ongoing somatic hypermutation, all strongly suggest a role for chronic antigenic stimulation.
Moreover, expression of chemokine receptor CXCR3 on tumor cells (except maybe primary cutaneous marginalzonelymphoma) is consistent with the suggestion that they are dependent on inflammatory cytokines. It is likely that there is a stepwise progression from reactive B-cell, to localized antigen-dependent tumor, to antigen independence, and more aggressive phenotypes.
For example, it has been hypothesized that the t(11;18) may be an early event that results in antigen independence, but is also associated with low incidence of transformation to DL BCL. These data support the hypothesis that aberrant NFL activation plays an important role in the pathogenesis of marginal zone lymphomas.
Additional studies will be required to determine whether the components of this signaling pathway could be targeted with novel therapeutic agents. No sponsor or advertiser has participated in, approved or paid for the content provided by Decision Support in Medicine LLC.