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
anewland@mcvh-vcu.edu