Immunosuppression in Bone Marrow Transplant
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Transcript Immunosuppression in Bone Marrow Transplant
Objectives
Summarize the principles for use of
immunosuppression in allogeneic stem cell
transplant (SCT)
Compare and contrast commonly used
medications used for immunosuppression
Describe monitoring parameters and
common adverse effects associated with
immunosuppression
Immunosuppression
in Bone Marrow Transplant
Ashley Newland, PharmD
Hematology/Oncology Pharmacist Specialist
VCU Medical Center
November 8, 2011
Cells of the Immune System
http://www.rikenresearch.riken.jp/eng/frontline/5028
Use of Immunosuppression
Allogeneic stem cell transplant
Prevention of rejection
Prevention of graft versus host disease
(GVHD)
Component of conditioning regimen
Eradicates host T-cells to allow acceptance of
donor cells
Pre- & post-transplant medications
Suppresses donor T-cells to minimize
recognition of host cells as foreign
Treatment of GVHD
Pathophysiology of GVHD
Ferrara, et al. Lancet 2009;373:1550-61.
Medications used for immunosuppression
Class
Drug
Immune globulin
Antithymocyte globulin (ATG)
- Equine ATG: Atgam
- Rabbit ATG: Thymoglobulin
Monoclonal antibody
Alemtuzumab
- Campath
Calcineurin Inhibitors
Tacrolimus
- Prograf
Cyclosporine
- Non-modified: SandIMMUNE
- Modified: Gengraf or Neoral
Antifolate antimetabolite
Methotrexate
Immunosuppressant
Mycophenolate mofetil
- CellCept
Corticosteroids
Methylprednisolone
Prednisone
mTOR inhibitor
Sirolimus
- Rapamune
Alemtuzumab
Anti CD52
monoclonal antibody
CD52 expressed on:
B and T lymphocytes
Monocytes
Macrophages
NK cells
Dendritic cells
www.nature.com/reviews/drugdisc
Alemtuzumab Adverse Effects
Infusion related reactions
Chills, dyspnea, fevers, hypotension, rigors
May be fatal
Premedicate with acetaminophen,
diphenhydramine, ± corticosteroid
Hypersensitivity reactions
Cytokine release syndrome
Opportunistic infections
Requires anti-infective prophylaxis
Antithymocyte Globulin (ATG)
Mohty. Leukemia.2007, 21:1387-94.
Antithymocyte Globulin
Polyclonal antibodies active against T cells
Administration
Infuse over at least 6 hours
Premedicate with acetaminophen,
corticosteroids, and an antihistamine
Rabbit ATG (Thymoglobulin®) and equine ATG
(Atgam ®) are NOT interchangeable
Antithymocyte Globulin
Adverse effects
Infusion-related reactions
Fever, chills, headache
Hypersensitivity reactions
Cytokine release syndrome
Increased risk of infections
Serum sickness
Calcineurin inhibitors
http://www.nature.com/nrneph/journal/v2/n12/fig_tab/ncpneph0343_F2.html
Calcineurin Inhibitors
Inhibit T cell activation by suppressing
production of IL-2
IV Administration
Non-PVC tubing
Continuous infusion over 24 hours
IV:PO conversion = ~1:3
Therapeutic Drug Monitoring (TDM)
PO: trough levels (30 min prior to dose)
IV: be sure to waste sufficient amount to avoid
falsely elevated levels
Calcineurin Inhibitors: Adverse Effects
Nephrotoxicity
Hypertension
Hyperglycemia
Hypercholesterolemia
Hypomagnesemia
Hyperkalemia
HUS/TTP
CNS toxicity
Tremor
Posterior reversible encephalopathy syndrome
(PRES)
Calcineurin Inhibitors: Drug
Interactions
Antifungals
Antibiotics
GI Agents
Fluconazole
Metronidazole
Metoclopramide
Phenytoin
Protease
inhibitors
Voriconazole
Erythromycin
Cimetidine
Phenobarbital
Sirolimus
Posaconazole
Clarithromycin
Lansoprazole
Carbamazepine
St. John’s
wort
Ketoconazole
Rifampin
Anticonvulsants
Many others
CYP3A4 inducers and inhibitors
Others
Grapefruit
juice
Calcineurin Inhibitors: Cyclosporine
Dosing
TDM
3 mg/kg CIVI over 24 hours (initial)
5-6 mg/kg PO every 12 hours (initial)
Modified ≠ non-modified
May mix oral solution with
orange juice
150-350 ng/ml
Adverse effects
Hirsutism/hypertrichosis
Gingival hyperplasia
Calcineurin Inhibitors: Tacrolimus
Dosing
0.03 mcg/kg CIVI over 24 hours (initial)
90 mcg/kg PO every 12 hours (initial)
TDM
5-15 ng/ml
Methotrexate
Mechanism of action
Dosing
Induces apoptosis of activated lymphocytes
Blocks dihydrofolate reductase to inhibit purine
synthesis
5-15 mg/m2 IVP on D+1, 3, 6, 11
+/- leucovorin rescue
Adverse effects
Mucositis
Myelosuppression
Hepatotoxicity
Mycophenolate mofetil
Mechanism of action
Dosing
1000 mg PO/IV every 12 hours
Drug interactions
Inhibits lymphocyte proliferation
by blocking purine synthesis
Calcium & magnesium
Adverse effects
Nausea, vomiting, diarrhea
Myelosuppression
Corticosteroids
Mechanism of action
Affect number & function of B-cells & T-cells
Dosing
Systemic
Methylprednisolone or prednisone 0.5-2 mg/kg IV/PO
daily
Taper when applicable
Topical
Budesonide-SR 3 mg PO every 8-12 hours (gut
GVHD)
Triamcinolone cream 0.1% to body +/hydrocortisone 1% to face (skin GVHD)
Corticosteroid Adverse Effects
Short term
Hyperglycemia
Mood disturbance,
psychosis
Insomnia
Hypertension
Fluid retention
Skin atrophy
Gastric ulcers
Long term
Adrenal suppression
Moon facies
Weight gain
Osteoporosis
Buffalo hump
Cataracts
Myopathy
Infections
Sirolimus
Mechanism of action
Dosing
Inhibits proliferation of lymphocytes by
blocking m-TOR
12 mg PO x 1 then 4 mg PO once daily
Therapeutic Drug Monitoring (TDM)
3-12 ng/ml
Trough levels (30 min prior to dose)
http://www.nature.com/nrneph/journal/v2/n12/fig_tab/ncpneph0343_F2.html
Sirolimus
Drug interactions
Similar to calcineurin inhibitors
(CYP 3A4)
Adverse effects
Hyperlipidemia
Myelosuppression
Pneumonitis
Thrombotic microangiopathy
Additional Immunosuppressants:
Treatment for GVHD
TNFα blockers
Etanercept, infliximab
Pentostatin
Alefacept
Many drugs under investigation for
treatment of acute and chronic GVHD
Infection Prevention
Use appropriate anti-infective prophylaxis
throughout immunosuppressive therapy
Pneumocystis carinii pneumonia
Fungal infections
Viral infections
Summary
Immunosuppression is utilized in
allogeneic SCT to prevent rejection and
GVHD, and for the treatment of GVHD
Calcineurin inhibitors and sirolimus require
TDM and close monitoring for side effects
and drug interactions
Infectious complications are common,
making appropriate anti-infective
prophylaxis important
Thank You!
Ashley Newland, PharmD
[email protected]