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      News & Perspective Drugs & Diseases CME & Education Academy Video Decision Point
      Drugs & Diseases > Hematology

      Non-Hodgkin Lymphoma (NHL) Medication

      Updated: Aug 03, 2021
      • Author: Sanjay Vinjamaram, MD, MPH; Chief Editor: Emmanuel C Besa, MD  more...
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      Medication

      Medication Summary

      Multiple chemotherapeutic agents are active against non-Hodgkin lymphoma (NHL) and can be used alone or in combination, depending on the histology and stage of the disease and whether the patient can tolerate chemotherapy. In addition, several biological therapies are currently available for these patients, including interferons, rituximab, and radiolabeled antibodies (the newest biological therapy).

      Alkylating agents impair cell function by forming covalent bonds with DNA, ribonucleic acid (RNA), and proteins. These agents are not cell cycle phase–specific and are used for hematologic and nonhematologic malignancies.

      Anthracycline antibiotics bind to nucleic acids by intercalation with base pairs of the DNA double helix, interfering with the DNA synthesis. They cause inhibition of DNA topoisomerases I and II.

      Vinca alkaloids inhibit microtubule assembly, causing metaphase arrest in dividing cells. Vinca alkaloids are also cell cycle phase–specific at the M and S phase.

      Glucocorticoids cause lysis of lymphoid cells, which led to their use against acute lymphoblastic leukemia (ALL), multiple myeloma, and NHL. These agents are also used as adjunctive antiemetic agents, to decrease vasogenic edema associated with tumors, and as prophylactic medication to prevent hypersensitivity reactions associated with some chemotherapeutic drugs.

      Antimetabolites cause tumor cell death by inhibiting enzymes that are important in DNA synthesis.

      Biological response modulators control the response of the patient's immune system to tumor cells, infecting organisms, or both.

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      Cytotoxic agents

      Class Summary

      These agents inhibit cell growth and proliferation.

      Chlorambucil (Leukeran)

      Chlorambucil alkylates and cross-links strands of DNA, inhibiting DNA replication and RNA transcription. It is used mainly to treat indolent lymphomas, particularly chronic lymphocytic leukemia (CLL) and Waldenstrom macroglobulinemia. This agent may be preferable for elderly patients with serious comorbid medical problems who require treatment for lymphoma. It is well absorbed orally.

      Cyclophosphamide

      Cyclophosphamide is chemically related to nitrogen mustards. As an alkylating agent, the mechanism of action of the active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells. This agent can be used alone but is mostly used as a component of multiple combination chemotherapy regimens.

      Doxorubicin

      An anthracycline antibiotic that can intercalate with DNA, doxorubicin affects many of the functions of DNA, including synthesis. It forms DNA-cleavable complexes by interaction with topoisomerase II, which is responsible for the cytocidal activity of the drug. Doxorubicin is administered IV and distributes widely into bodily tissues, including the heart, kidneys, lungs, liver, and spleen. It does not cross the blood-brain barrier and is excreted primarily in bile. It forms an important part of multiple chemotherapeutic regimens for lymphomas, including cyclophosphamide, hydroxydaunomycin (doxorubicin), vincristine (Oncovin), and prednisone (CHOP).

      Vincristine (Vincasar PFS)

      The mechanism of action of vincristine is uncertain. It may involve a decrease in reticuloendothelial cell function or an increase in platelet production; however, neither of these mechanisms fully explains the effect in thrombocytopenic purpura and hemolytic-uremic syndrome. Vincristine is used in hematologic and nonhematologic malignancies. It is a component of CHOP and other regimens for lymphoma.

      Fludarabine

      Fludarabine is a purine analogue that interferes with DNA synthesis by inhibiting ribonucleotide reductase. It is also incorporated into RNA, causing inhibition of RNA and protein synthesis; however, its primary effect may result from activation of apoptosis.

      Pralatrexate (Folotyn)

      This agent is a folate inhibitor. It is indicated for relapsed or refractory peripheral T-cell lymphoma.

      Nelarabine (Arranon)

      Nelarabine is a prodrug of the deoxyguanosine analogue 9-beta-D-arabinofuranosylguanine (ara-G). It is converted to the active 5'-triphosphate, ara-GTP, a T-cell–selective nucleoside analog. Leukemic blast cells accumulate ara-GTP. This allows for incorporation into DNA, leading to inhibition of DNA synthesis and cell death.

      Etoposide (Toposar)

      Etoposide is a glycosidic derivative of podophyllotoxin that exerts its cytotoxic effect through stabilization of the normally transient covalent intermediates formed between DNA substrate and topoisomerase II, leading to single- and double-strand DNA breaks. This causes cell proliferation to arrest in the late S or early G2 portion of the cell cycle.

      Mitoxantrone

      Mitoxantrone inhibits cell proliferation by intercalating DNA and inhibiting topoisomerase II.

      Cytarabine

      Cytarabine is converted intracellularly to the active compound cytarabine-5'-triphosphate, which inhibits DNA polymerase. It is cell cycle S phase specific and it blocks the progression from the G1 to the S phase, in turn killing cells that undergo DNA synthesis in the S phase of the cell proliferation cycle.

      Bendamustine (Bendeka, Treanda)

      Alkylating agent indicated for treatment of indolent B-cell non-Hodgkin lymphoma that has progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen. Included as part of a regimen containing polatuzumab vedotin and rituximab.

      Carboplatin

      Carboplatin is an analog of cisplatin. This is a heavy metal coordination complex that exerts its cytotoxic effect by platination of DNA, a mechanism analogous to alkylation, leading to interstrand and intrastrand DNA cross-links and inhibition of DNA replication. It binds to protein and other compounds containing the SH group. Cytotoxicity can occur at any stage of the cell cycle, but the cell is most vulnerable to action of these drugs in the G1 and S phases. It has same efficacy as cisplatin, but with a better toxicity profile. The main advantages over cisplatin include less nephrotoxicity and ototoxicity, the lack of a need for extensive prehydration, and a smaller likelihood of inducing nausea and vomiting; however, it is more likely to induce myelotoxicity.

      Cisplatin

      Cisplatin is a platinum-containing compound that exerts its antineoplastic effect by covalently binding to DNA, with preferential binding to the N-7 position of guanine and adenosine. It can react with 2 different sites on DNA to cause cross-links. The platinum complex also can bind to the nucleus and to cytoplasmic protein. A bifunctional alkylating agent, once cisplatin is activated to the aquated form in the cell, it binds to DNA, resulting in interstrand and intrastrand cross-linking and denaturation of the double helix.

      Gemcitabine

      Gemcitabine is a cytidine analog. It is metabolized intracellularly to an active nucleotide. It inhibits ribonucleotide reductase and competes with deoxycytidine triphosphate for incorporation into DNA. It is cell-cycle specific for the S phase. Gemcitabine is indicated as first-line treatment for locally advanced (nonresectable stage II or stage III) or metastatic (stage IV) pancreatic adenocarcinoma.

      Bleomycin

      This agent is composed of a group of glycopeptides extracted from Streptomyces species. Each molecule has a planar end and an amine end; different glycopeptides of the group differ in their terminal amine moieties. The planar end intercalates with DNA, while the amine end facilitates oxidation of bound ferrous ions to ferric ions, thereby generating free radicals, which subsequently cleave DNA, acting specifically at purine-G-C-pyrimidine sequences.

      Polatuzumab vedotin (Polivy, polatuzumab vedotin-piiq)

      CD79b-directed antibody-drug conjugate. It is indicated in combination with bendamustine and a rituximab product for treatment of patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) after ≥ 2 prior therapies.

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      Antineoplastic Agents, Histone Deacetylase Inhibitors

      Class Summary

      These agents can induce the termination of cell growth, which, in turn, leads to cell death. Agents include vorinostat and romidepsin.

      Vorinostat (Zolinza)

      Vorinostat is a histone deacetylase (HDAC) inhibitor. HDAC inhibition results in hypoacetylation of core nucleosomal histones, it condenses the chromatin structure, and it represses gene transcription. It is indicated for the treatment of progressive, persistent, or recurrent cutaneous T-cell lymphoma.

      Romidepsin (Istodax)

      This agent inhibits HDAC, which results in the accumulation of acetyl groups. This leads to alterations in chromatin structure and transcription factor activation, causing the termination of cell growth, which, in turn, leads to cell death. Indicated for CTCL in patients who have received at least 1 prior therapy.

      Belinostat (Beleodaq)

      Belinostat is a histone deacetylase (HDAC) inhibitor. HDACs catalyze the removal of acetyl groups from the lysine residues of histones and some nonhistone proteins. Inhibiting this action induces cell cycle arrest and/or apoptosis.

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      Antineoplastics, PI3K Inhibitors

      Class Summary

      This drug class inhibits one or more of the phosphoinositide 3-kinase enzymes, which are part of the PI3K/AKT/mTOR pathway, an important signalling pathway for many cellular functions such as growth control, metabolism and translation initiation. Within this pathway there are many components, inhibition of which may result in tumor suppression.

      Copanlisib (Aliqopa)

      Pan class I phosphatidylinositol-3-kinase (PI3K) inhibitor with predominant inhibitory activity against PI3K-alpha and PI3K-delta isoforms expressed in malignant B cells. By inhibiting several key cell-signaling pathways may induce apoptosis and inhibition of proliferation of premalignant B cells and in turn cause tumor cell death. It is indicated for relapsed follicular lymphoma (FL) in patients who have received at least 2 prior systemic therapies.

      Idelalisib (Zydelig)

      Idelalisib is a phosphoinositide 3-kinase (PI3K) delta inhibitor. Idelalisib induces apoptosis and inhibits proliferation in cell lines derived from malignant B cells and in primary tumor cells; also inhibits several cell- signaling pathways, including B cell receptor (BCR) signaling and the CXCR4 and CXCR5 signaling, which are involved in trafficking and homing of B cells to the lymph nodes and bone marrow. It gained accelerated approval by the FDA (ie, confirmatory clinical trials in progress) in July 2014 for relapsed follicular B-cell non-Hodgkin lymphoma (FL) and relapsed small lymphocytic lymphoma (SLL) in patients who have received at least 2 prior systemic therapies.

      Duvelisib (Copiktra)

      Duvelisib is a selective oral small molecule inhibitor of PI3K-delta and PI3K-gamma. Inhibiting PI3K induces growth inhibition and reduces viability in cell lines derived from malignant B cells. It is indicated for adults with relapsed/refractory follicular cell lymphoma after at least 2 prior systemic therapies. 

      Umbralisib (Ukoniq)

      Umbralisib is a dual inhibitor of PI3K-delta and casein kinase (CK1) 1-epsilon expressed on malignant B cells. It was granted accelerated approval to umbralisib (Ukoniq) for the treatment of adults with relapsed or refractory marginal zone lymphoma (MZL) who have received at least 1 prior anti-CD20-based regimen and for adults with relapsed or refractory follicular lymphoma (FL) who have received at least 3 prior lines of systemic therapy.

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      Monoclonal Antibodies

      Class Summary

      The agents in this class target specific antigens in carcinoma cells and induce cytotoxicity.

      Rituximab (Rituxan, Truxima)

      Rituximab is a genetically engineered chimeric murine/human monoclonal antibody directed against the CD20 antigen found on the surface of normal and malignant B lymphocytes. The binding to CD20 mediates B-cell lysis. The antibody is an immunoglobulin G1 (IgG1) kappa immunoglobulin containing murine light- and heavy-chain variable region sequences and human constant region sequences. It is available as an IV formulation. 

      Rituximab/hyaluronidase (Rituxan Hycela)

      The SC product is combined with hyaluronidase human, which increases subcutaneous tissue permeability. It is indicated for previously untreated diffuse large B-cell lymphoma (DLBCL) in combination with cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) or other anthracycline-based chemotherapy regimens.

      Ibritumomab tiuxetan (Zevalin)

      A murine monoclonal antibody that targets the CD20 antigen, ibritumomab tiuxetan is chelated to the radioisotopes indium-111 or yttrium-90. It is used in conjunction with rituximab to treat B-cell NHL or rituximab-refractory follicular NHL. The regimen consists of 2 low doses of rituximab, an imaging dose, 2-3 whole body scans, and a therapeutic dose, all of which are delivered in an outpatient setting over 8 days.

      Alemtuzumab (Campath)

      Alemtuzumab is a monoclonal antibody against CD52, an antigen found on B cells, T cells, and almost all chronic lymphocytic leukemia cells. It binds to the CD52 receptor of the lymphocytes, which slows the proliferation of leukocytes.

      Ofatumumab (Arzerra)

      Ofatumumab is an anti-CD20 human monoclonal antibody that inhibits B-cell activation in early stages. It is indicated for chronic lymphocytic leukemia refractory to fludarabine and alemtuzumab.

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      Antineoplastic Agents, Proteasome Inhibitors

      Class Summary

      Agents in this class may cause cell-cycle arrest and apoptosis.

      Bortezomib (Velcade)

      This is the first drug approved of the anticancer agents known as proteasome inhibitors. The proteasome pathway is an enzyme complex existing in all cells. This complex degrades ubiquitinated proteins that control the cell cycle and cellular processes and maintains cellular homeostasis. Reversible proteasome inhibition disrupts the pathways supporting cell growth, thus decreases cancer cell survival.

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      Antineoplastic Agents, mTOR Kinase Inhibitors

      Class Summary

      Agents in this class halt the cell cycle at the G1 phase in tumor cells.

      Temsirolimus (Torisel)

      Temsirolimus is a water-soluble ester of sirolimus. It binds with high affinity to immunophilin FKBP (FK506-binding protein). This complex inhibits mammalian target of rapamycin (mTOR) kinase, a key protein in cells that regulate the gene translation responsible for cell-cycle regulation. mTOR also reduces the cell growth factors (eg, vascular endothelial growth factor) involved in new blood vessel development.

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      Antineoplastics, Angiogenesis Inhibitor

      Class Summary

      These agents antagonize or inhibit the development of new blood vessels.

      Lenalidomide (Revlimid)

      Thalidomide analogue; inhibits TNF-alpha production, stimulates T cells, reduces serum levels of the cytokines vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), and inhibits angiogenesis. This agent also promotes G1 cell cycle arrest and apoptosis of malignant cells. Indicated for in combination with rituximab product for the treatment of previously treated follicular lymphoma or marginal zone lymphoma.

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      PD-1/PD-L1 Inhibitors

      Class Summary

      Monoclonal antibodies that bind the programmed cell death-1 protein (PD-1) ligands, PD-L1 and PD-L2, to the PD-1 receptor found on T cells, inhibits T cell proliferation and cytokine production.

      Pembrolizumab (Keytruda)

      Indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy.

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      CAR T-cell Therapy

      Class Summary

      Chimeric antigen receptor (CAR) T-cell therapy is a form of adoptive T-cell therapy in which the patient's T cells are genetically engineered to express a CAR.

      For CAR T-cell preparation, the patient’s T lymphocytes are collected by apheresis and the CAR molecule is introduced into the cells through viral or nonviral approaches. The cells undergo a brief round of expansion in the laboratory and are then infused back into the patient. T cells become activated when they recognize the target antigen on the surface of the tumor, in this case, CD19. When T cells are activated, they undergo massive expansion in the body. The cells start to produce multiple different cytokines and proliferate. These cytokines improve the T cells’ function, help them traffic to the tumor site, and start killing the tumor cells by expressing cytotoxic molecules (eg, granzymes and perforins).

       

      Axicabtagene ciloleucel (Yescarta)

      CD19-directed genetically modified autologous T cell immunotherapy; binds to CD19-expressing cancer cells and normal B cells. After the anti-CD19 CAR T cells bind with target cells, the CD28 and CD3-zeta co-stimulatory domains activate downstream signaling cascades, which eventually leads to killing of CD19-expressing cells. Axicabtagene ciloleucel is approved for relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy. Indications include diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.

      Tisagenlecleucel (Kymriah)

      CD19-directed genetically modified autologous T-cell immunotherapy that involves reprogramming a patient’s own T cells with a transgene encoding a chimeric antigen receptor (CAR) to identify and eliminate CD19-expressing malignant cells. It is indicated in adults with relapsed or refractory large B-cell lymphoma, including DLBCL not otherwise specified, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma, after 2 or more lines of systemic therapy.

      Lisocabtagene maraleucel (Breyanzi)

      CD19-directed CAR T-cell therapy genetically modified autologous cell immunotherapy is administered as a defined composition to reduce variability in CD8-positive and CD4-positive T cell dose. CAR binding to CD19 expressed on tumor and normal B cells induces activation and proliferation of CAR T cells, release of pro-inflammatory cytokines, and cytotoxic killing of target cells. It is indicated for adults with R/R large B-cell lymphoma (LBCL) after two or more lines of systemic therapy, including DLBCL not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B. It is not indicated for primary CNS lymphoma.

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      Antineoplastics, Anti-CD19 Monoclonal Antibodies

      Class Summary

      The monoclonal antibody binds to human CD19, a transmembrane protein expressed on surface of cells of B-lineage origin.

      Loncastuximab tesirine (Zynlonta)

      Indicated for adults with relapsed/refractory large-B-cell lymphoma following 2 or more lines of systemic therapy. Indication includes disuse large B-cell lymphoma (DLBCL) not otherwise specified, DLBCL arising from low-grade lymphoma, and high-grade lymphoma. 

      Tafasitamab (Monjuvi)

      Tafasitamab is a humanized Fc-modified cytolytic CD19 targeting monoclonal antibody. It is indicated, in combination with lenalidomide for the treatment of adults with relapsed or refractory DLBCL not otherwise specified, including DLBCL arising from low- grade lymphoma, and who are ineligible for autologous stem cell transplant (ASCT).

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      Colony-Stimulating Factor Growth Factors

      Class Summary

      These agents can induce an increase in reticulocyte counts, with a subsequent increase in hematocrit and hemoglobin levels.

      Epoetin alfa (Epogen, Procrit)

      This agent is a purified glycoprotein produced from mammalian cells modified with gene coding for human erythropoietin (EPO). Its amino acid sequence is identical to that of endogenous EPO. The biological activity of epoetin alfa mimics human urinary EPO, which stimulates division and differentiation of committed erythroid progenitor cells and induces the release of reticulocytes from bone marrow into the blood stream.

      Darbepoetin alfa (Aranesp)

      This is an erythropoiesis-stimulating protein closely related to EPO, a primary growth factor produced in the kidney that stimulates the development of erythroid progenitor cells. Its mechanism of action is similar to that of endogenous EPO, which interacts with stem cells to increase red blood cell production. It differs from epoetin alfa (recombinant human EPO) in that it contains 5 N-linked oligosaccharide chains, whereas epoetin alfa contains 3. Darbepoetin alfa has a longer half-life than epoetin alfa and can be administered weekly or biweekly.

      Filgrastim (Neupogen)

      Filgrastim is a recombinant methionyl human granulocyte colony-stimulating factor (r-metHuG-CSF) consisting of a 175–amino acid protein with a molecular weight of 18,800 d. It is produced by Escherichia coli bacteria into which the human G-CSF gene is inserted. This protein has an amino acid sequence identical to the natural sequence predicted from human DNA sequence analysis, except for the addition of an N-terminal methionine necessary for expression in E coli. Because it is produced in E coli, the product is nonglycosylated and thus differs from G-CSF isolated from human cells.

      Pegfilgrastim (Neulasta)

      Pegfilgrastim is a long-acting filgrastim created by the covalent conjugate of recombinant granulocyte colony-stimulating factor (ie, filgrastim) and monomethoxypolyethylene glycol. As with filgrastim, it acts on hematopoietic cells by binding to specific cell surface receptors, thereby activating and stimulating the production, maturation, migration, and cytotoxicity of neutrophils.

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      Immunomodulators

      Class Summary

      These drugs regulate key events responsible for immune reactions.

      Interferon alfa-2a (Roferon-A) or alfa-2b (Intron A)

      These drugs regulate key events responsible for immune reactions.

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      Corticosteroids

      Class Summary

      These drugs have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.

      Dexamethasone

      A component of the m-BACOD (methotrexate, bleomycin, doxorubicin [Adriamycin], cyclophosphamide, Oncovin, and dexamethasone) regimen, dexamethasone is a glucocorticoid that acts as an immunosuppressant by stimulating the synthesis of enzymes needed to decrease the inflammatory response. It also acts as an anti-inflammatory agent by inhibiting the recruitment of leukocytes and monocyte-macrophages into affected areas via inhibition of chemotactic factors and factors that increase capillary permeability.

      Dexamethasone is readily absorbed via the GI tract and metabolized in the liver. Inactive metabolites are excreted via the kidneys. Most of the adverse effects of corticosteroids are dose dependent or duration dependent.

      Prednisone (Deltasone)

      A component of several regimens, such as CHOP, prednisone is a glucocorticoid that acts as an immunosuppressant by stimulating the synthesis of enzymes needed to decrease the inflammatory response. It also acts as an anti-inflammatory agent by inhibiting the recruitment of leukocytes and monocyte-macrophages into affected areas via inhibition of chemotactic factors and factors that increase capillary permeability.

      Prednisone is readily absorbed via the GI tract and metabolized in the liver. Inactive metabolites are excreted via the kidneys. Most of the adverse effects of corticosteroids are dose dependent or duration dependent.

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