I cured my own GVHD

1
I cured my own GVHD

• Jeevan Sekhar
• Hem/Onc Grand Rounds
• March 20, 2009

2
Outline

• Case
• Overview of GVH
• Clinical
• Pathophysiology
• Overview of current aGVH management
• Potential of autologous stem cell infusion as
  treatment

3
Case

• A 29 year old male was diagnosed with acute
  promyelocytic leukemia in March 2005. He was
  successfully induced and consolidated with
  standard therapy including ATRA.
• Autologous stem cells collected in 8/06
• 3/07 he relapsed and dz persisted despite 2
  cycles of arsenic. Gemtuzumab (Mylotarg) worked.
  
• Concern that dz was too refractory so got allo
  transplant w/ bu/cy conditioning

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Case contd

• D 30, he developed grade IV GI acute GVH
• Treated w/ methylpred, pentostatin, tacrolimus,
  budesonide, beclomethasone. Nothing worked.
• Then idea to ablate the graft. Reconditioned with
  fludarabine, cytarabine, and 200 cGy TBI and
  reinfused with autologous stem cells in 12/07.
• In 4-6 weeks, GVH improved
• In 11/07, chimerism studies revealed full donor
  engraftment. In 12/07 chimerism studies after
  autologous SCT showed only recipient cells. At
  the end of 12/07, biopsy revealed grade II GVH.

5
Acute GVH

• Mainstay of treatment is high dose steroids
• However, only about 50 respond, the rest are
  steroid refractory.
• Mortality with steroid refractory GVH is about
  50
• Thus, intense area to be addressed to improve
  post-transplant survival

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Overview of acute GVH

• Risk up to 50-60 in matched related donors
  despite immunosuppresant prophylaxis
• Risk factors
• Increased age
• Degree of mismatch
• Doses of prophylactic immunosuppresants
• Source of cells
• Conditioning regimen more intense, the greater
  the risk

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Clinical Manifestations of Acute GVH

• Skin
• First manifestation
• Most common
• Si/Sx
• Maculopapular rash usually at the time of
  engraftment.
• Involves epidermal and dermal layers
• T cell infiltrate
• Severe disease includes bullae formation and
  desquamation

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Clinical Manifestations contd-Liver-

• Second most common
• Unlikely to have liver manifestation without
  skin.
• Manifested as abnormal liver tests
• Definitive diagnosis only by Bx

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Clinical Manifestations Contd- GI Tract-

• GI Tract
• Most commonly lower GI tract
• Non-specific symptoms
• Diarrhea
• Abd Pain
• Diagnosis by rectal bx showing crypt necrosis and
  epithelial denudation similar to skin GVH

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Pictures
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Pathophysiology

• Primarily T cell mediated process
• 3 step process
• Step 1
• Recipient antigen presenting cells are activated
  by conditioning regimen
• Increased recognition by donor T cells
• Step 2
• Donor T cells activate, proliferate, release
  cytokines
• Step 3
• LPS translocation of microbes through viscous
  wall 2/2 conditioning regimen recruits monocytes
  causing even more inflammation and thus more
  cytokine release
• All these cytokines recruit cytotoxic lymphocytes
  and NK cells

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Graft versus leukemia

• GVHD is tightly associated with GVL
• One of the therapeutic benefits of allogeneic
  transplant
• Primarily mediated by cytotoxic pathway
• Inflammatory cytokines allow CTLs and NK cells to
  amplify GVH
• Possibility of interrupting inflammatory cascade
  but maintain GVL

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Schematic of GVH vs. GVL
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Current Treatment Strategies

• Prevention
• Relapse rate is higher in those without GVHD
• Grade II-IV GVHD carries its own risks for
  mortality
• Balance of upregulating GVL while lowering GVH is
  the ideal goal

15
Treatment contd

• Steroids

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Treatment contdSecond line agents

• No standard order
• Etanercept anti-TNF antibody
• Daclizumab anti IL-2R
• Pentostatin Purine analog inhibiting T cells
• Ontak diptheria toxin combined with IL-2
  interacting protein
• OSIRIS study mesencymal stem cells

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Treatment contd

• Steroid refractory portends a poor prognosis
• Responders 50 alive at 2 years
• Non-responders 10
• Survival benefit is minimal at best
• Although drugs can cause good early response
  rates, long term outcomes are similar to
  steroids.
• Blood and Marrow Transplant Clinical Trials
  Network

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None of that worked, now what?

• Rescue autologous transplant
• Ablate the allo-graft and rescue patient with
  their own cells, i.e. if you cant solve the
  problem, eliminate the problem
• 7 patients had resolution of GVH 3 are alive, 4
  died of a combination of relapse and infection
• 3 patients had minor improvement all died of GVH
• Pseudoautologous transplant

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Post-transplant chimerism

• Unpredictable
• 3 cases had 100 patient cells post transplant
• 1 myeloablative,
• 2 nonmyeloblative
• 5 cases had 100 donor cells
• 4 w/o conditioning regimen
• 1 non-myeloblative
• 1 mixed myeloablative
• 1 pseudoauto non-myeloablative
• 2 unknown

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Autologous stem cells and GVH

• T cell immunological balance
• Maybe similar to inducing a mixed chimera.
• Mouse model
• Whole blood re-transfused resulted in 50
  survival
• CD8, CD4 depleted cells infused resulted in 100
  survival
• CD4CD25 known to regulate immune system
• Mesenchymal stem cells
• Have immunoregulatory properties
• Secrete cytokines that suppress lymphocyte
  proliferation
• Induce T cell anergy
• Induce production of CD4CD25 cells

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Conclusion

• Autologous stem cell transplant can possibly
  improve outcomes for steroid refractory aGVHD
• Chimerism status is not a determinant of success
• Can be recipient or donor
• May affect primary disease control
• Studies underway using exogenous therapeutics
• OSIRIS
• BM Network
• Could do a study pheresing patients for stem
  cells before their allo

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