Approach to Treatment in Lymphoma

Treatments by Lymphoma Type

Hodgkin Lymphoma

The initial approach to the treatment of Hodgkin lymphoma is determined by the disease histology, anatomical stage, and the presence or absence of poor prognostic factors, constitutional symptoms, and bulky disease.⁹

Because patients with a positive FDG-PET scan at the end of treatment have a significantly increased chance of recurrence, FDG-PET scanning is used during treatment to increase or decrease intensity or repeat biopsy based on results. FPG-PET done early in the course of treatment is a better predictor of outcome than stage or extranodal disease.⁹

Treatment for Hodgkin lymphoma is generally differentiated by early-stage disease and favorable prognostic favors, early-stage disease and poor prognostic factors, advanced disease. Early-stage disease is often treated with a combination of chemotherapy and involved-field radiation therapy, while advanced disease is more often treated with a longer course of chemotherapy without the addition of radiation therapy. Newer agents such as brentuximab vedotin and anti-PD-1 antibodies may also play a role in combination therapy.⁹

Non-Hodgkin Lymphoma

As NHLs are a more heterogeneous group of disease than Hodgkin lymphoma, there is more variability in treatment protocols. The approach to treatment differs between indolent forms of NHL and aggressive forms, which are the two broad categories into which B-cell NHL is divided.⁷

Aggressive forms of NHL, such as DLBCL and Burkitt lymphoma, generally require immediate combination chemotherapy for treatment. These chemotherapy regimens have the potential to cure the disease. By contrast, more indolent forms of NHL, such as follicular lymphoma, hairy cell leukemia, lymphoplasmacytic lymphoma, and marginal zone lymphoma, can be asymptomatic and require treatment only once they cause symptoms or organ impairment. However, indolent forms of NHL are not usually curable.⁷

Of note, mantle cell lymphoma is considered an intermediate-grade lymphoma that requires urgent combination chemotherapy, but is not readily curable with this regimen.

Management of Complications by Lymphoma Type

Hodgkin Lymphoma

Hodgkin lymphoma is associated with both short- and long-term treatment complications. Long-term complications are of particular concern in Hodgkin lymphoma due to the high survival rate and, therefore, higher risk of occurrence than with other malignancies.⁸

Pretreatment complications of Hodgkin lymphoma may include superior vena cava syndrome secondary to mediastinal mass or cytopenias due to bone marrow involvement. Early treatment complications include opportunistic infections, cardiotoxicity, hyperglycemia or diabetes mellitus, psychosis, mood alteration, and osteonecrosis.⁴

Late treatment effects of Hodgkin lymphoma include infertility, thyroid dysfunction, secondary malignancies, and cardiopulmonary disease. In fact, mortality from secondary malignancies and cardiopulmonary disease are the leading causes of death for survivors of Hodgkin lymphoma.¹⁴

A variety of second cancers can occur in patients following treatment for NHL. These include solid tumors, as well as leukemia and NHL. The 40-year cumulative incidence of secondary malignancies is 43.6% and the younger a patient is at the time of diagnosis, the higher chance they have of developing a secondary malignancy over their lifetime.¹⁴

Cardiac mortality is a significant concern for survivors of Hodgkin lymphoma and these patients have increased risk of death from coronary artery disease and myocardial infarction. Valvular disease, pericardial disease, conduction defects, arrhythmias, and cardiomyopathy are also long-term risks of Hodgkin lymphoma treatment.¹⁴

Non-Hodgkin Lymphoma

The initial treatment of NHL depends on the histologic subtype of disease and the stage and may include chemotherapy, immunotherapy, radiation therapy, or a combination of these. Some patients are also treated with autologous hematopoietic stem cell transplantation. Therefore, short-term effects of treatment will vary widely based on the method of treatment.¹⁵

Side effects commonly associated with chemotherapy regimens used in the treatment of NHL include alopecia, stomatitis, nausea, vomiting, anorexia, diarrhea, constipation, opportunistic infections, and cytopenias.¹⁶

Fatigue is a common long-term effect of NHL treatment and occurs in two-thirds of patients. Although long-term fatigue often improves in the year following treatment, some patients continue to have symptoms for months or years.¹⁵

Like patients who have undergone treatment for Hodgkin lymphoma, there is a risk for secondary malignancies in patients following treatment for NHL. Again, because of the greater variety of treatments for this more diverse disease, the types of second cancer and risk for each varies based on the subtype of NHL and treatment regimen used.¹⁵

Long-term cardiovascular effects are linked to the use of both chemotherapy and radiation for treatment of NHL. The risk for chronic heart failure and stroke is increased in patients who have undergone treatment for NHL. Additional cardiac risks exist and monitoring for cardiac effects should be a part of ongoing surveillance following treatment.¹⁵

Infertility, hypothyroidism, and neurocognitive impairment are additional long-term complications of NHL treatment.¹⁵

Lymphoma Medications

Historically, classical Hodgkin lymphoma became the first curable malignancy, owing to the use of extended-field radiotherapy (EFRT). However, the substantial rates of long-term effects following EFRT led to the development of different treatment regimens that included chemotherapy. As chemotherapy regimens for Hodgkin lymphoma evolved, so too did the use of imaging studies to monitor response to therapy and adjust protocols accordingly.¹⁴

More recently, the use of novel agents such as brentuximab vedotin, nivolumab, and pembrolizumab has been incorporated into frontline Hodgkin lymphoma therapy in combination with chemotherapy and used for the treatment of relapsed or refractory disease.¹⁴

Treatment for NHL encompasses a greater number of agents and combinations than Hodgkin lymphoma treatment due to the large number of subtypes with variable treatment regimens. Chemotherapy, immunotherapy, targeted drug therapy, radiation therapy, high-dose chemotherapy and autologous hematopoietic stem cell transplantation, and (rarely) surgery may be used for the treatment of NHL depending on the subtype of disease and staging.¹⁶

In contrast to Hodgkin lymphoma, indolent forms of NHL may not require any treatment if a patient is asymptomatic. For these patients, observation may be an appropriate choice with future initiation of treatment if symptoms or organ dysfunction develops. Treatment in such circumstances is generally effective, but does not offer a cure.⁷

Chemotherapeutic Agents

The most common chemotherapy regimen used for Hodgkin lymphoma treatment in the United States is ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine). Other chemotherapy regimens that are used in certain protocols include AVD, Stanford V, BEACOPP, CHOP, and CVP.^4,17

For relapsed or refractory Hodgkin lymphoma, potential chemotherapy options include bendamustine, DHAP, ESHAP, gemcitabine/bendamustine/vinorelbine, GVD, ICE, IGEV,

C-MOPP, MINE, mini-BEAM, GEMOX, and GCD.^4,17

Multiple types of chemotherapy are used for treating NHL, including alkylating agents, platinum drugs, purine analogs, anti-metabolites, and anthracyclines. Choice of chemotherapy regimen depends on categorization of NHL as indolent, aggressive, or highly aggressive among other factors.^5,16

Intrathecal chemotherapy may also be required for patients with NHL affecting the central nervous system. Methotrexate and cytarabine are the agents used for this purpose.¹⁶

For treatment of both Hodgkin lymphoma and NHL, chemotherapy is often combined with other modalities of treatment including radiation therapy and immunotherapy.^13,16,17

Corticosteroids

Corticosteroids may be used in combination with chemotherapeutic agents in the treatment of both Hodgkin lymphoma and NHL.^4,5,13,16,17

Prednisone, prednisolone, methylprednisolone, and dexamethasone are incorporated into a number of chemotherapy combination treatments for Hodgkin lymphoma and NHL. However, it is important to note that not all combination chemotherapy regimens for lymphoma have a corticosteroid component.^4,5,13,17

Monoclonal Antibodies

Antibodies Targeting CD20

Rituximab is an anti-CD20 antibody used for the treatment of multiple types of NHL, often in combination with chemotherapy.¹⁶ It is also used for treatment of nodular-lymphocyte predominant Hodgkin lymphoma.^4,18

Obinutuzumab, ofatumumab, and ibritumomab tiuxetan are also anti-CD20 antibodies used for the treatment of certain types of NHL.¹⁶

Antibody Targeting CD19

Tafasitamab is an anti-CD19 antibody that can be used in combination with lenalidomide for the treatment of refractory or relapsed DLBCL in patients who are ineligible for stem cell transplantation.^16,19

Antibody-Drug Conjugate with CD19 Antibody

Loncastuximab tesirine is an anti-CD19 antibody attached to an alkylating agent. It is used for the treatment of relapsed or refractory large B-cell lymphoma after the use of two or more systemic agents.^16,20

Antibody Targeting CD52

Alemtuzumab is an anti-CD52 antibody that can be used as a single agent treatment for B-cell chronic lymphocytic leukemia.^16,21

Antibody Targeting CD30

Brentuximab vedotin is an anti-CD30 antibody-drug conjugate used in the treatment of both NHL and Hodgkin lymphoma. It is approved for use in certain circumstances for multiple subtypes of NHL, including anaplastic large cell lymphoma and mycosis fungoides.^16,18,22

Antibodies Targeting CD79b

Polatuzumab vedotin is an anti-CD79b antibody-drug conjugate that is used in combination with bendamustine and a rituximab product for the treatment of relapsed or refractory DLBCL after two or more prior therapies.^16,23

Immune Checkpoint Inhibitors

Pembrolizumab is a PD-1 monoclonal antibody that inhibits cell death by attaching to the PD-1 receptor. It is used for the treatment of relapsed or refractory Hodgkin lymphoma and relapsed or refractory primary mediastinal large B-cell lymphoma after two or more prior therapies (unless urgent cytoreductive therapy is indicated).^16,18,24

Nivolumab is also a PD-1 monoclonal antibody that can be used in certain cases of Hodgkin lymphoma, but it is not used for treatment of NHL. Nivolumab is indicated for adults with classical Hodgkin lymphoma that has relapsed or progressed after autologous stem cell transplantation and brentuximab vedotin, or after three or more 3 lines of systemic therapy that included autologous stem cell transplantation.^18,25

Immunomodulating Agent

Lenalidomide is an immunomodulating agent that demonstrates both antiangiogenic and antineoplastic properties. It works through multiple mechanisms including secreting proinflammatory cytokines, enhancing cell-mediated immunity, and inhibiting trophic signals to angiogenic factors in cells. It is indicated for treatment of follicular lymphoma, mantle cell lymphoma, and marginal zone lymphoma in certain circumstances.^16,26

Chimeric Antigen Receptor (CAR) T-Cell Therapies

CAR T-cell therapy uses a patient’s own genetically modified T cells to direct their own T cells against lymphoma cells.²⁷

Axicabtagene ciloleucel, tisagenlecleucel, lisocabtagene maraleucel, and brexucabtagene autoleucel are all CAR T-cell therapies that are used to treat different subtypes of NHL in certain circumstances, including follicular lymphoma, DLBCL, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, and mantle cell lymphoma.¹⁶

Proteasome Inhibitors

Proteasome inhibitors work by inhibiting proteasomes, which are protein complexes that divide cellular proteins into peptides. The mechanism by which this leads to cell death is not entirely clear.²⁸

Bortezomib is a proteasome inhibitor that is used for the treatment of mantle cell lymphoma in adults.^16,29

Histone Deacetylase (HDAC) Inhibitor

Histone deacetylases are epigenetic modifiers that are active in gene transcription. The alteration or mutation of their expression contributes to tumorigenesis in a variety of tumors. HDAC inhibitors target histone deacetylase.³⁰

Belinostat is an HDAC inhibitor that is approved for treatment of relapsed or refractory peripheral T-cell lymphoma.^16,31

Bruton Tyrosine Kinase (BTK) Inhibitors

BTK functions in cell signaling and regulates cell proliferation and survival in B-cell malignancies.³²

Ibrutinib, acalabrutinib, and zanubrutinib are used to treat a variety of B-cell NHLs in certain circumstances, including mantle cell lymphoma, marginal zone lymphoma, and small lymphocytic lymphoma.¹⁶

PI3K Inhibitors

The PI3K pathway plays a role in cell growth, apoptosis, metabolism, and survival. There are multiple isoforms of PI3K and mutations in these are found in a variety of cancers. PI3K inhibitors target this pathway to stop cancer cell survival.³³

Idelalisib, copanlisib, duvelisib, and umbralisib are PI3K inhibitors used for treatment of multiple forms of NHL in certain circumstances, including follicular lymphoma, small lymphocytic lymphoma, and marginal zone lymphoma.¹⁶

EZH2 Inhibitor

EZH2 plays a role in cell proliferation, apoptosis, and senescence and has been associated with cancer initiation, progression, metastasis, metabolism, drug resistance, and immunity regulation. EZH2 inhibitors treat cancer by targeting these functions of EZH2.³⁴

Tazemetostat is an EZH2 inhibitor that can be used for the treatment of relapsed or refractory follicular lymphoma in patients with an EZH2 gene mutation who have received more than two prior systemic therapies or those without an EZH2 gene mutation who have no satisfactory alternative treatment options.^16,35

Selective Inhibitor of Nuclear Export

The XPO1 export receptor transports proteins and RNA species. It is often overexpressed or mutated in malignancies and drives oncogenesis. Therefore, targeting this export process is valuable for cancer treatment.³⁶

Selinexor is a nuclear export inhibitor that blocks exportin 1 and reversibly inhibits the nuclear export of tumor suppressor proteins, growth regulators, and mRNAs of oncogenic proteins. It is used for the treatment of relapsed or refractory DLBCL after at least two lines of systemic therapy.³⁷

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