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Graft vs' Host Disease: Pharmacologic Prevention

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Title: Graft vs' Host Disease: Pharmacologic Prevention


1
Graft vs. Host Disease Pharmacologic Prevention
  • David Kuperman, M.D.
  • Hematology/Oncology
  • Washington University in St. Louis
  • 2/4/05

2
Introduction to Graft vs. Host Disease
  • Graft vs. Host disease is a syndrome that occurs
    when immune cells from a donor attack the hosts
    normal cells.
  • GVHD is one of the major causes of morbidity and
    mortality associated with an allogenic stem cell
    transplant.
  • GVHD occurs in 30 to 50 of HLA-matched sibling
    transplants and 60 to 90 of Mismatched or MUDs.

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Introduction to Graft vs. Host Disease
  • Unfortunately at this time, we can not separate
    GVHD from the beneficial graft vs. leukemia
    effect.

6
Introduction to Graft vs. Host Disease
  • GVHD is divided into acute and chronic depending
    on whether the initial symptoms developed before
    100 days following Bone Marrow Transplant (BMT)
  • The organ systems primarily affected by acute
    GVHD are the skin, liver, and GI tract.

7
Introduction to Graft vs. Host Disease
  • The rash seen in GVHD can be variable.
  • A maculopapular rash affects the palms, soles,
    neck, or ears is commonly seen.
  • The skin changes can be more severe including
    scleroderma-like changes, edema, bullous
    formation, or necrolysis.

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9
Introduction to Graft vs. Host Disease
  • The liver manifestations are primarily increases
    in the bilirubin but can also involve
    transaminitis
  • The GI manifestations are diarrhea, nausea, and
    vomiting.
  • The severity of acute GVHD is staged on a I to IV
    system.

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Proposed mechanism for acute GVHD
  • There appear to be 3 phases to the development of
    acute GVHD.
  • Damage to host tissues.
  • Activation and proliferation of donor
    lymphocytes.
  • Attack on the host cells.

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Damage to the Host
  • The damage primarily comes from the conditioning
    regimen.
  • The damage to the host leads to the release of
    inflammatory cytokines such as TNF-alpha and
    IL-1.
  • In the gut, microbial products such as
    lipopolysaccharide can enter the circulation.

15
Damage to the Host
  • The inflammatory cytokines stimulate antigen
    presenting cells (APC).

16
Activation and proliferation of the donor
lymphocytes
  • The APC present host antigens not recognized by
    the donor lymphocytes.
  • The lymphocytes then multiply and differentiate
    under the influence of IL-2.

17
Attack of Target Tissues
  • GVHD is primarily mediated by cytoxic T
    lymphocytes (CD8) but helper T lymphocytes
    (CD4) and NK cells are also involved.
  • The host cells are destroyed by either direct
    cytotoxic activity or inflammatory cytokines.

18
Decreasing the damage to the host
  • This can be divided into giving less rigorous
    conditioning regimens or blocking the cytokines
    or other products that lead to the activation of
    APCs.
  • Antibiotics have been shown to decrease the
    frequency of acute GVHD.

19
Decreasing the damage to the host
  • TNF-alpha inhibitors have been tried to decrease
    GVHD
  • Holler et alia were able to postpone the
    development of acute GVHD but not reduce the rate
    with the use of prophylactic TNF-alpha inhibitors.

20
Stopping activation and proliferation of donor
lymphs
  • Cyclosporine
  • Methotrexate
  • Tacrolimus
  • Sirolimus
  • Mycophenolate mofetil
  • Steroids
  • Alemtuzamab (Campath)
  • Anti-IL2 antibodies

21
Methotrexate
  • Methotrexate is a folate antimetabolite
  • As a single agent significant GVHD develops in
    70
  • It has found a significant role in prevention
    when used in combination with other immune
    suppressant medications

22
Cyclosporine
  • Cyclosporine is a calcineurine inhibitor
  • Inhibition of calcineurine prevents the
    transcription of NF-at and many cytokines (IL-2,
    TNF-alpha, IL-3, IL-4) which decreases the
    proliferation of lymphocytes
  • Storb et alia showed a rate of development of 40
    for acute GVHD (Grade II-IV) in HLA-matched
    transplants.

23
Methotrexate Cyclosporine
  • In one trial involving HLA identical transplant
    for aplastic anemia, 23 patients were given
    Methotrexate and 23 were given Methotrexate plus
    Cyclosporine
  • In the Methotrexate alone group, 58 developed
    acute Grade II-IV GVHD.
  • In the combination group, 18 developed acute
    Grade II-IV GVHD.

24
Methotrexate Cyclosporine
  • In 3 other trials, a rate of 25 to 33 versus 51
    to 55 were seen for the combination compared to
    solo Methotrexate

25
Tacrolimus
  • Tacrolimus is another calcineurine inhibitor.
  • Is it any better than Cyclosporine?
  • Ratanatharathorn et alia randomized 329 patients
    to either Tacrolimus Methotrexate or
    Cyclosporine Methotrexate

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Tacrolimus
  • There was overall less acute GVHD in the
    Tacrolimus group (32 vs. 44) but the rates of
    Grade III and IV were similar between the two
    groups.
  • There was no difference in the rate of relapse or
    chronic GVHD
  • A survival advantage was seen in the Cyclosporine
    group but this was felt to be due to an over
    representation of less severe disease.

28
Tacrolimus
  • In practice, Tacrolimus and Cyclosporine are
    considered equal.

29
Steroids
  • Steroids are the most effective agents for
    treating acute GVHD once it develops.
  • Chao et alia randomized 150 patients receiving
    HLA matched sibling transplant to either CSA/MTX
    or CSA/MTX/Methylprednisolone.

30
Steroids
  • Only 9 of those receiving the steroid including
    regimen developed grade II-IV GVHD vs. 23 in the
    other group.
  • There was no difference in relapse or disease
    free survival between the two groups.
  • Unfortunately, this data has never been able to
    be repeated.

31
Steroids
  • In another study by Chao published in 2000, 193
    patients receiving HLA matched sibling
    transplants were randomized to receive CSA/MTX/MP
    or CSA/MTX.
  • In this study, there was no statistically
    significant difference in occurrence of acute
    GVHD.

32
Sirolimus
  • Sirolimus is an immune suppressant that appears
    to work synergistically with Tacrolimus.
  • Cutler et alia used Tacrolimus Sirolimus as
    prophylaxis in a phase II trial of 30 patients
    undergoing HLA-matched allotransplant.
  • There was only a 10 risk of Grade II GVHD with
    no grade III or IV.

33
Sirolimus
  • Unfortunately, there was a 10 rate of HUS.
  • Antin et alia used Tacrolimus Sirolimus MTX
    in a phase II of 34 patients undergoing MUDs or
    mismatched allotransplant
  • There was a 26 rate of GVHD.

34
Alemtuzamab (Campath)
  • Alemtuzamab is an anti-CD52 antibody.
  • It depletes host and donor lymphocytes as well as
    APCs.
  • It has been used with success with
    non-myeloablative transplants.
  • Unfortunately significant viral infections have
    occurred with its use.

35
Anti-IL2 monoclonal antibodies
  • A few studies were performed in the early 1990s.
  • There was a delay in the onset of GVHD but no
    decrease in rate.
  • There was a high rate of relapse.

36
Future Directions
  • Randomized trial to assess Sirolimus
    Tacrolimus.
  • Pentastatin.
  • Improved graft manipulation.

37
References
  • J. Antin et alia, Sirolimus, tacrolimus, and low
    dose methotrexate for graft-versus-host disease
    prophylaxis in mismatched related donor or
    unrelated donor transplant. Blood 102 (2003),
    pp.1601-1605.
  • N. Chao et alia, Cyclosporine, methotrexate, and
    prednisone compared with cyclosporine and
    prednisone for prophylaxis of acute
    graft-versus-host disease. NEJM 329 (1993), pp.
    1225-1230.
  • D. Couriel et alia, Acute graft-versus-host
    disease Pathophysiology, clinical
    manifestations, and management. Cancer 101
    (2004), pp. 1936-1946.

38
References
  • J. Davies et alia, New advances in acute
    graft-versus-host disease prophylaxis.
    Transfusion Medicine 13 (2003), pp. 387-397.
  • A. Gratwohl et alia, Current trends in
    hematopoietic transplant in Europe. Blood 100
    (2002), pp. 2374-2386.
  • H. Gokeret alia, Acute graft-versus-host disease
    pathobiology and management. Exp Hematol 29
    (2001), pp. 259-277.
  • E. Holler et alia, Modulation of acute
    graft-versus-host-disease after allogeneic bone
    marrow transplantation by tumor necrosis factor
    alpha (TNF alpha) release in the course of
    pretransplant conditioning role of conditioning
    regimens and prophylactic application of a
    monoclonal antibody neutralizing human TNF alpha
    (MAK 195F). Blood 86 (1995), pp. 890-899.

39
References
  • V. Ratanatharathorn et alia, Phase III study
    comparing methotrexate and tacrolimus (prograf,
    FK506) with methotrexate and cyclosporine for
    graft-versus-host disease prophylaxis after
    HLA-identical sibling bone marrow
    transplantation.Blood 92 (1998), pp. 2303-2314.
  • R. Storb et alia, Cyclosporine v methotrexate for
    graft-v-host disease prevention in patients given
    marrow grafts for leukemia long-term follow-up
    of three controlled trials.Blood 71 (1988), pp.
    293-298.
  • UpToDate
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