Graft Versus Host Disease Medication

Therapy includes immunosuppressive agents, antimetabolite and/or chemotherapeutic agents, antibodies and/or Igs, immunomodulating agents, and photoactive agents.

Class Summary

Corticosteroids are the mainstay for treatment of GVHD. Corticosteroids cause profound and varied metabolic effects. In addition, they modify the body's immune responses to diverse stimuli. Complications associated with glucocorticoid therapy depend on the dose and duration of treatment. A risk-benefit decision is made to determine the dose, duration, and frequency (daily or intermittent) of treatment.

The lowest possible dose of corticosteroid is used to control the condition and then gradually reduced when possible. Most patients undergoing allogeneic stem-cell transplantation are receiving prophylaxis for GVHD with CSP or tacrolimus in combination with methotrexate (MTX) and/or prednisone. Acute GVHD is treated with IV methylprednisolone for as long as 14 days. Subsequent tapering of the dose or switching to an oral agent is continued over several weeks to months. Chronic GVHD is treated with oral prednisone alone or in combination with CSP. If the response is positive, it is continued and tapered over 6-9 months.

Methylprednisolone (Solu-Medrol)

Synthetic analog of naturally occurring glucocorticoids. Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing increased capillary permeability. Greater anti-inflammatory potency than that of prednisolone and less likely than prednisolone to induce sodium and water retention.

Prednisone (Sterapred)

Synthetic analog of naturally occurring glucocorticoids. Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing capillary permeability.

Cyclosporine (Sandimmune, Neoral)

Cyclic polypeptide. Suppresses some humoral immunity and more so cell-mediated immune reactions. Dosages for children and adults based on ideal body weight. Sandimmune and Neoral not bioequivalent.

Sirolimus (Rapamune)

Inhibits lymphocyte proliferation by interfering with signal-transduction pathways. Binds to immunophilin FKBP to block action of mammalian target of rapamycin (mTOR). Approved by Food and Drug Administration for prophylaxis of organ rejection in patients receiving allogeneic renal allografts. Prolonged survival of allografts (kidney, heart, skin, islet, small bowel, pancreaticoduodenal, bone marrow) in mice, rats, pigs, and primates. Reversed acute rejection of heart and kidney allografts in rats and prolonged graft survival in presensitized rats. Immunosuppressive effect may last up to 6 mo after discontinuation. Tolerization effect is alloantigen specific. Also used for treatment of GVHD and for prophylaxis in combination with tacrolimus and/or MTX.

Tacrolimus (Prograf)

Previously known as FK506. Macrolide immunosuppressant produced by Streptomyces tsukubaensis. Prolonged host and transplant survival in animal models. Adults should receive doses at low end of dosing range. Concomitant adrenal corticosteroid therapy recommended early after transplantation.

Mycophenolate mofetil (CellCept)

The 2-morpholinoethyl ester of mycophenolic acid (MPA), an immunosuppressive agent. Inhibits purine synthesis and proliferation of human lymphocytes. Prolonged survival of allogeneic transplants in animal models.

Class Summary

Thalidomide exerts an immunologic effect. Its effectiveness is thought to be due to suppression of excessive TNF-alpha production and downmodulation of selected cell-surface adhesion molecules involved in leukocyte migration.

Thalidomide (Thalomid)

Immunologic effects vary substantially in different conditions but may be related to suppression of excessive TNF-alpha production and downmodulation of selected cell-surface adhesion molecules involved in leukocyte migration.

Class Summary

Methoxsalen, a psoralen, and PUVA may be beneficial in treating cutaneous lesions of GVHD and may improve survival in some patients with steroid-resistant GVHD.

8-MOP, methoxsalen, 8-methoxypsoralen (Oxsoralen)

Naturally occurring photoactive substance that acts as photosensitizer. Subsequent exposure to UVA can cause cell injury. PO dose reaches skin by blood, and UVA penetrates well into skin. If sufficient cell injury occurs in skin, inflammatory reaction occurs. Most obvious manifestation is erythema, which may not begin for several h and peaks at 48-72 h. Over days to weeks, inflammation followed by repair manifested by increased melanization of epidermis and thickening of stratum corneum.

Exact mechanism of action with epidermal melanocytes and keratinocytes not known. Best-known biochemical reaction is with DNA. On photoactivation, conjugates and forms covalent bonds with DNA, which leads to formation of monofunctional (addition to single strand of DNA) and bifunctional adducts (cross-linking of psoralen to both strands of DNA).

Class Summary

These agents inhibit cell growth and proliferation.

MTX is used to treat certain neoplastic diseases, severe psoriasis, and adult rheumatoid arthritis. A short-course MTX is administered for the prophylaxis of acute GVHD. It is used in combination with CSP or tacrolimus.

Azathioprine is an antimetabolite that suppresses cell-mediated hypersensitivities and causes variable alterations in antibody production. It is used in combination with steroids and CSP to treat chronic GVHD.

Newer antineoplastic treatments include novel fusion proteins carrying a toxin or chemotherapeutic agents are engulfed into target cells, delivering a highly toxic molecule and leading to cell death.

Pentostatin (Nipent)

Inhibits adenosine deaminase resulting in deoxyadenosine and deoxyadenosine 5+-triphosphate accumulation that may inhibit DNA or RNA synthesis causing cell death.

Methotrexate (Rheumatrex)

Formerly amethopterin. Antimetabolite used to treat certain neoplastic diseases, severe psoriasis, and adult rheumatoid arthritis. Interferes with DNA synthesis, repair, and cellular replication. Actively proliferating tissues (eg, malignant cells, bone marrow, fetal cells, buccal and intestinal mucosa, cells of urinary bladder) generally most sensitive to this effect. May impair malignant growth without irreversible damage to healthy tissues when cellular proliferation in malignant tissues is greater than that of most healthy tissues. Preservative formulation contains benzol alcohol and must not be used for intrathecal or high-dose therapy.

Azathioprine (Imuran)

Imidazolyl derivative of 6-mercaptopurine. Many of its biologic effects similar to those of the parent compound. Suppresses hypersensitivities of cell-mediated type and variably alters antibody production. Immunosuppressive, delayed hypersensitivity, and cellular cytotoxicity suppressed more than antibody responses. Considered slow-acting drug, and effects may persist after discontinuation.

Denileukin diftitox (Ontak)

Molecule in which diphtheria toxin and receptor-binding domain of human IL-2 fused. Fusion protein selectively delivers cytotoxic activity of diphtheria toxin to targeted cells. Used only in T-cell lymphoma in which malignant cells express CD25 component of IL-2 receptor. Binds to the IL-2 receptor (measured by CD25). Internalized by receptor-mediated endocytosis, and inhibits protein synthesis by translocating active portion of diphtheria toxin into cytosol. This, in turn, causes cell death.

Class Summary

These agents are monoclonal antibody directed against specific antigens found on surface of normal and/or malignant cells. They may also be directed against specific molecules to render them inactive.

Infliximab (Remicade)

Chimeric IgG1k monoclonal antibody that neutralizes cytokine TNF-α and inhibits its binding to TNF-α receptor. Reduces infiltration of inflammatory cells and TNF-α production in inflamed areas.

Rituximab (Rituxan)

Antibody genetically engineered chimeric murine/human monoclonal antibody directed against the CD20 antigen found on surface of normal and malignant B lymphocytes. Antibody is an IgG1 kappa immunoglobulin containing murine light- and heavy- chain variable region sequences and human constant region sequences.

Daclizumab (Zenapax)

Humanized monoclonal antibody that specifically binds to and blocks interleukin-2 (IL-2) receptor on surface of activated T cells.

Class Summary

Antithymocyte globulin-equine (Equine, Atgam) is an Ig-containing immunosuppressive agent that principally inhibits cell-mediated immune responses and inhibits humoral immune response to an extent.

IVIG (human) is a sterile, highly purified polyvalent antibody product containing, in concentrated form, all the IgG antibodies that regularly occur in the donor population.

Muromonab-CD3 is a murine monoclonal antibody to the CD3 antigen of human T cells that functions as an immunosuppressant. It is thought to reverse graft rejection by blocking the function of T cells that play a major role in acute allograft rejection.

Newer monoclonal antibodies directed against particular targets such as cytokines or antigens on cells that may have a role in GVHD initiation and propagation include alemtuzumab, daclizumab, infliximab, and other agents being investigated.

Antithymocyte globulin-equine (Atgam)

Ig-containing immunosuppressive agent. Immunosuppressive action generally similar to that of other antilymphocyte preparations. May differ qualitatively and/or quantitatively in extent of specific effects, partly because of factors such as source of antigenic material, animal used to produce antiserum, and method of production.

Intravenous immune globulin, human (Sandoglobulin, Gammagard, Gammar-P, Gamunex)

Sterile, highly purified polyvalent antibody product containing, in concentrated form, all IgG antibodies that regularly occur in donor population. Do not mix with other medications or fluids; administer in separate infusion line.

Muromonab-CD3 (Orthoclone OKT3)

Murine monoclonal antibody to CD3 antigen of human T cells, which functions as immunosuppressant. Monoclonal antibody preparation; therefore, homogeneous, reproducible antibody product with consistent, measurable reactivity to human T cells. Reverses graft rejection, probably by blocking function of T cells, which play major role in acute allograft rejection. In in-vitro cytolytic assays, blocked generation and function of effector cells. Binding to T lymphocytes results in early activation of T cells, which leads to cytokine release then blockage of T-cell functions. After termination, T-cell function usually returns to normal within 1 wk.

Alemtuzumab (Campath)

Monoclonal antibody against CD52, antigen found on B-cells, T-cells, and almost all chronic lymphocytic leukemia (CLL) cells. Binds to CD52 receptor of lymphocytes, which slows proliferation of leukocytes.

Class Summary

Preclinical studies have shown the importance of tumor necrosis factor-α (TNF α) as an effector of experimental GVHD. TNF inhibition can be accomplished by either antibodies against soluble and membrane-bound TNF α or by competitive binding using soluble TNF α receptors (such as etanercept) to render the molecule inactive.

Etanercept (Enbrel)

A dimeric fusion protein made up of the extracellular ligand-binding portion of tumor necrosis factor receptor linked to the Fc portion of human IgG1. It binds specifically to TNF and blocks its interaction with cell surface TNF receptors. TNF is a naturally occurring cytokine involved in normal inflammatory and immune responses. It is also implicated in mediating GVHD both through amplification of donor immune response to host tissues as well as direct toxicity to target organs.