Non-Hodgkin lymphoma medical therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Preeti Singh, M.B.B.S.[2]; Sowminya Arikapudi, M.B,B.S. [3]

Overview

The predominant therapy for non-Hodgkin lymphoma is chemotherapy. Adjunctive radiation, immunotherapy, and stem cell transplantation may be required.

Medical Therapy

• The optimal therapy for non-Hodgkin lymphoma depends on:

• Age
• The type of non-Hodgkin lymphoma
• The stage of non-Hodgkin lymphoma
• Growth of the tumor, slow growing (indolent) or fast growing (aggressive)
• Prognostic factors
• Other medical conditions that may interfere with treatment
• Previous treatment

Medical therapy for non-Hodgkin lymphoma

Stage	Watchful waiting	Chemotherapy	Radiotherapy	Biological therapy	Stem cell transplant
Indolent Lymphoma
Limited stage	Offered to patients who do not have symptoms	Offered if patients cannot have radiation therapy If lymphoma is causing symptoms	External beam radiation therapy is used most often	May be offered along with chemotherapy	---------
Advanced stage	Offered to patients who do not have symptoms	Offered to patients who have symptoms Single Drug Regimen: Chlorambucil OR Fludarabine OR Cyclophosphamide Combination Drug Regimen: (CVP) Cyclophosphamide AND Vincristine AND Prednisone	May also be given to specific areas to control symptoms	May be offered	---------
Recurrent	---------	Single Drug Regimen: Fludarabine Combination Drug Regimen: (CHOP) Cyclophosphamide AND Doxorubicin AND Vincristine AND Prednisone (CVP) Cyclophosphamide AND Vincristine AND Prednisone (FND) Fludarabine AND Mitoxantrone AND Dexamethasone	May be given to relieve pain or to control the symptoms	May be offered	May be offered
Aggressive Lymphoma
Limited stage	----------	Chemotherapy is usually the main treatment Combination Drug Regimen: (CHOP) Cyclophosphamide AND Doxorubicin AND Vincristine AND Prednisone	Radiation therapy is usually given after chemotherapy Used if the lymphoma is localized in one area of the body	Used in combination with chemotherapy	----------
Advanced stage	----------	Combination Drug Regimen: (CHOP) Cyclophosphamide AND Doxorubicin AND Vincristine AND Prednisone CNS Prophylaxis: Drug Regimen (Intrathecal or Intravenously): Methotrexate OR Cytarabine	May be offered	May be offered	May be considered
Recurrent	---------	Combination Drug Regimen: (DHAP) Dexamethasone AND Cytarabine AND Cisplatin (EPOCH) Etoposide AND Prednisone AND Vincristine AND Cyclophosphamide AND Doxorubicin (ESHAP) Etoposide AND Methylprednisolone AND Cytarabine AND Cisplatin (GDP) Gemcitabine AND Dexamethasone AND Cisplatin (ICE) Ifosfamide AND Cisplatin AND Etoposide (mini-BEAM) Carmustine AND Etoposide AND Cytarabine AND Melphalan	---------	May be offered	May be recommended

Watchful waiting

• May be a treatment option for some people with asymptomatic lymphomas and patients with slow-growing (indolent) non-Hodgkin lymphoma (NHL) who are otherwise healthy.
• Patients have regular checkups and follow-up with their doctor during this time.
• Treatment is given when the signs and symptoms of the lymphoma appear or change or the lymphoma looks like it is progressing.

Chemotherapy

• Chemotherapy may be used:

• As the primary treatment, with or without radiation therapy, to destroy cancer cells

• Alone or along with biological therapy or radiation therapy, depending on the type and stage of non-Hodgkin lymphoma
• Early stage, slow-growing (indolent) lymphomas may be treated with radiation therapy by itself or with chemotherapy or biological therapy, if the person has symptoms
• Aggressive lymphomas are usually treated immediately with combination chemotherapy and biological therapy with or without radiation therapy. This treatment offers the best chance of success.

• In people with a lymphoma that tends to spread to the brain and spinal cord.
• In combination with biological therapy or radiation therapy to treat recurrent or relapsed lymphoma.
• To relieve pain or to control the symptoms of advanced non-Hodgkin lymphoma.

CNS Prophylaxis

• To treat primary CNS lymphoma
• As preventive for lymphomas that tend to spread to the CNS:

• Lymphoma that involves paranasal sinuses or the testicles
• Very aggressive lymphomas, such as Burkitt lymphoma or lymphoblastic lymphomas

Radiation therapy

Radiation may be used for non-Hodgkin lymphoma:

• As the main treatment for early stage (stage I or sometimes stage II) indolent non-Hodgkin lymphoma

• Radiation therapy may be used when non-Hodgkin lymphoma is in 1 or 2 lymph node areas in the same part of the body
• Early stage non-Hodgkin lymphoma often responds very well to radiation therapy

• With chemotherapy to destroy lymphoma cells

• Radiation therapy is often given with chemotherapy, either after or along with chemotherapy, to help destroy lymphoma cells and to reduce the risk of the cancer recurring
• Radiation therapy to certain areas is usually combined with chemotherapy to treat aggressive lymphomas or for large tumors

• To relieve pain or to control the symptoms of advanced lymphoma (palliative radiation therapy)

• Radiation can be used to shrink tumors that are pressing on or spreading into other organs or structures
• It can also be used to shrink enlarged lymph nodes and relieve symptoms caused by tumors

External beam radiation therapy

• Radiation therapy treatment is usually given each day for 5 days a week.
• The dose and schedule for the radiation therapy is determined by:

• The type of non-Hodgkin lymphoma
• The extent of the disease
• Whether the treatment is being given to cure the lymphoma or relieve symptoms.

Radiation fields

• Radiation treatments are given to different areas of the body when treating non-Hodgkin lymphoma. The radiation field is the part of the body that receives the radiation. Some of the fields where radiation is given for treating lymphoma are:
• Involved field – most commonly used

• Radiation is given to only 1 or a few lymph node areas known to contain lymphoma and is used for localized, early stage non-Hodgkin lymphoma. Involved field radiation therapy is also called IFRT. When radiation is given to a larger area to cover nearby or the next level of lymph node sites, this may be called extended field radiation therapy (EFRT).

• Mantle field

• Radiation is given to the lymph nodes in the neck, chest, and underarms

• Upper abdominal field

• Radiation is given to lymph nodes around the heart and aorta (para-aortic area) and possibly the spleen (unless it has been removed)

• Pelvic field

• Radiation is given to lymph nodes in the pelvis and groin
• A large amount of bone marrow is also radiated because the hip bones, which contain the most bone marrow, are in this field

• Inverted (upside down) Y field

• Radiation is given to lymph nodes in the upper abdominal and pelvic fields

Hematopoietic stem cell transplantation

• Stem cell transplants may be considered for people with non-Hodgkin lymphoma in the following cases:

• To treat people with high-grade or aggressive non-Hodgkin lymphoma that has recurred or relapsed, depending on the type of lymphoma.
• High-dose chemotherapy and a stem cell transplant may be useful, especially if the lymphoma was sensitive or responded to chemotherapy in the past.
• Used in some cases when the person's lymphoma is not responding to other treatments or standard treatment has failed to work.
• Occasionally considered to treat people with non-Hodgkin lymphoma who are in remission, but have a high risk of the lymphoma recurring.

Immunotherapy

Biological therapy (also called immunotherapy) is a form of treatment that uses the body's immune system, either directly or indirectly, to fight cancer or to lessen the side effects that can be caused by some cancer treatments. It uses materials made by the body or made in a laboratory to boost, direct, or restore the body's natural defenses against disease. This approach is under close investigation. Biological therapy is sometimes also called biological response modifier therapy.

• Biological therapy may be used:

• To treat advanced indolent non-Hodgkin lymphoma or aggressive non-Hodgkin lymphoma.
• To treat recurrent or relapsed non-Hodgkin lymphoma.
• In certain cases when chemotherapy no longer seems to be working.
• To treat B-cell lymphomas.

• The most common biological therapy drugs used to treat non-Hodgkin lymphoma are:

• Rituximab
• Ibritumomab
• Alemtuzumab
• Interferon alfa

Chimeric antigen receptor T (CAR-T) cell therapy

• Chimeric antigen receptor T (CAR-T) cell therapy has recently been approved by the Food and Drug Administration for the treatment of non-Hodgkin lymphoma (specifically diffuse large B cell lymphoma) in the second- or third-line settings.
• This form of therapy involves the engineering of a patient's own T lymphocytes to create genetically engineered cells that have anti-tumor immune responses.
• The process of CAR-T construction involves first performing leukapheresis to collect peripheral blood mononuclear cells, which contain the T cell population.
• The T cells are stimulated to proliferated via treatment with interleukin-2 (IL-2) or anti-CD3 agonist antibody.
• A lentivirus or retrovirus is transfected into the T cells, and this lentivirus contains the DNA sequence that encodes for the CAR gene.
• The final CAR-T cell product is usually composed of 3 components: a single-chain variable fragment, a transmembrane domain, and an intracellular signal transduction domain.
• This structure allows for antigen recognition that parallels B lymphocyte activity and effector function that parallels T lymphocyte activity, hence the name "chimeric."
• CAR-T cells are a combination of T cells and antibodies and are thus sometimes known as "T-bodies."
• In non-Hodgkin lymphoma, the specific tumor antigen against which CAR-T cells are engineered is CD19, which is a B cell marker.
• The current FDA-approved products are tisagenleclucel and axicabtagene ciloleucel.

Measuring response to treatment

After treatment for non-Hodgkin's lymphoma, the response is classified as follows:

• Complete Response (CR). This indicates the disappearance of all detectable disease.
• Partial Response (PR). A reduction in the bulk of disease by at least 50%, but with some remaining disease.
• Stable Disease. Less than a partial remission, but no progression of disease and no new sites of disease.
• Progressive Disease. Growth in bulk of disease by >50%, or the appearance of new sites of disease.

• If a complete remission is achieved, the patient is watched closely for any evidence of recurrent disease. Standard guidelines dictate that a patient be monitored for relapse every three months in the first year following a complete remission, every six months in the second year, and finally once annually in the third and later years.
• Diffuse large b-cell lymphoma is the most common type of lymphoma that is considered curable.
• Currently, if a patient maintains a complete remission for 3 years, the patient is considered cured.
• Generally most relapses of diffuse large b-cell lymphoma occur within the first year after a complete remission is obtained.
• Recurences after 3 years are rare but they do occur.
• The effect of Rituximab on relapse rates for diffuse large b-cell lymphoma is still largely unknown, though initial relapse rates since 2003 have been much lower than expected.
• Patients with follicular lymphoma are generally not considered cured. Instead, they are categorized as in ongoing complete remission. Relapses occur steadily over time. Relapse rates are estimated to be 33%, 66%, and 100% for follicular lymphoma's Grades I, II, and III respectively.
• Research has indicated that relapse rates can be lowered on patients with follicular lymphoma by giving supplemental radiation therapy, however, it is known that this additional therapy increases the chances of a second malignancy of unknown type later in life.
• If the response to treatment falls short of a complete response, more treatment may be administered (using a different chemotherapy regimen), or watchful waiting may be utilized, depending on the goals of treatment.