Graft vs' Host Disease: Pharmacologic Prevention

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Graft vs. Host Disease Pharmacologic Prevention

• David Kuperman, M.D.
• Hematology/Oncology
• Washington University in St. Louis
• 2/4/05

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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.

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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.

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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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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.

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Damage to the Host

• The inflammatory cytokines stimulate antigen
  presenting cells (APC).

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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.

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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.

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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.

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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.

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Stopping activation and proliferation of donor
lymphs

• Cyclosporine
• Methotrexate
• Tacrolimus
• Sirolimus
• Mycophenolate mofetil
• Steroids
• Alemtuzamab (Campath)
• Anti-IL2 antibodies

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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

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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.

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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.

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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

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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.

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Tacrolimus

• In practice, Tacrolimus and Cyclosporine are
  considered equal.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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Future Directions

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

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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.

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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.

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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.
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