Objectives Summarize the principles for use of immunosuppression

Objectives Summarize the principles for use of immunosuppression in allogeneic stem cell transplant (SCT) p Compare and contrast commonly used medications used for immunosuppression p Describe monitoring parameters and common adverse effects associated with immunosuppression p

Immunosuppression in Bone Marrow Transplant Ashley Newland, Pharm. D 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 p Prevention of rejection p n n p Prevention of graft versus host disease (GVHD) n n p 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: Sand. IMMUNE - Modified: Gengraf or Neoral Antifolate antimetabolite Methotrexate Immunosuppressant Mycophenolate mofetil - Cell. Cept Corticosteroids Methylprednisolone Prednisone m. TOR inhibitor Sirolimus - Rapamune

Alemtuzumab Anti CD 52 monoclonal antibody p CD 52 expressed on: p n n n B and T lymphocytes Monocytes Macrophages NK cells Dendritic cells www. nature. com/reviews/drugdisc

Alemtuzumab Adverse Effects p Infusion related reactions n Chills, dyspnea, fevers, hypotension, rigors p n May be fatal Premedicate with acetaminophen, diphenhydramine, ± corticosteroid Hypersensitivity reactions p Cytokine release syndrome p Opportunistic infections p n Requires anti-infective prophylaxis

Antithymocyte Globulin (ATG) Mohty. Leukemia. 2007, 21: 1387 -94.

Antithymocyte Globulin Polyclonal antibodies active against T cells p Administration p n n n 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 p Adverse effects n Infusion-related reactions p n n Fever, chills, headache Hypersensitivity reactions Cytokine release syndrome Increased risk of infections Serum sickness

Calcineurin inhibitors http: //www. nature. com/nrneph/journal/v 2/n 12/fig_tab/ncpneph 0343_F 2. html

Calcineurin Inhibitors Inhibit T cell activation by suppressing production of IL-2 p IV Administration p n n Non-PVC tubing Continuous infusion over 24 hours IV: PO conversion = ~1: 3 p Therapeutic Drug Monitoring (TDM) p n n 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 p Hypertension p Hyperglycemia p Hypercholesterolemia p Hypomagnesemia p Hyperkalemia p HUS/TTP p CNS toxicity p n n 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 p Anticonvulsants Many others n CYP 3 A 4 inducers and inhibitors Others Grapefruit juice

Calcineurin Inhibitors: Cyclosporine p Dosing n n p TDM n p 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 n n Hirsutism/hypertrichosis Gingival hyperplasia

Calcineurin Inhibitors: Tacrolimus p Dosing n n p 0. 03 mcg/kg CIVI over 24 hours (initial) 90 mcg/kg PO every 12 hours (initial) TDM n 5 -15 ng/ml

Methotrexate p Mechanism of action n n p Dosing n n p Induces apoptosis of activated lymphocytes Blocks dihydrofolate reductase to inhibit purine synthesis 5 -15 mg/m 2 IVP on D+1, 3, 6, 11 +/- leucovorin rescue Adverse effects n n n Mucositis Myelosuppression Hepatotoxicity

Mycophenolate mofetil p Mechanism of action n p Dosing n p 1000 mg PO/IV every 12 hours Drug interactions n p Inhibits lymphocyte proliferation by blocking purine synthesis Calcium & magnesium Adverse effects n n Nausea, vomiting, diarrhea Myelosuppression

Corticosteroids p Mechanism of action n p Affect number & function of B-cells & T-cells Dosing n Systemic Methylprednisolone or prednisone 0. 5 -2 mg/kg IV/PO daily p Taper when applicable p n Topical Budesonide-SR 3 mg PO every 8 -12 hours (gut GVHD) p Triamcinolone cream 0. 1% to body +/hydrocortisone 1% to face (skin GVHD) p

Corticosteroid Adverse Effects p Short term n n n n Hyperglycemia Mood disturbance, psychosis Insomnia Hypertension Fluid retention Skin atrophy Gastric ulcers p Long term n n n n Adrenal suppression Moon facies Weight gain Osteoporosis Buffalo hump Cataracts Myopathy Infections

Sirolimus p Mechanism of action n p Dosing n p Inhibits proliferation of lymphocytes by blocking m-TOR 12 mg PO x 1 then 4 mg PO once daily Therapeutic Drug Monitoring (TDM) n n 3 -12 ng/ml Trough levels (30 min prior to dose)

http: //www. nature. com/nrneph/journal/v 2/n 12/fig_tab/ncpneph 0343_F 2. html

Sirolimus p Drug interactions n p Similar to calcineurin inhibitors (CYP 3 A 4) Adverse effects n n Hyperlipidemia Myelosuppression Pneumonitis Thrombotic microangiopathy

Immunosuppressants: Treatment for GVHD p TNFα blockers n Etanercept, infliximab Pentostatin p Alefacept p p Many drugs under investigation for treatment of acute and chronic GVHD

Infection Prevention p Use appropriate anti-infective prophylaxis throughout immunosuppressive therapy n n n Pneumocystis carinii pneumonia Fungal infections Viral infections

Summary p Immunosuppression is utilized in allogeneic SCT to prevent rejection and GVHD, and for the treatment of GVHD p Calcineurin inhibitors and sirolimus require TDM and close monitoring for side effects and drug interactions p Infectious complications are common, making appropriate anti-infective prophylaxis important

Thank You! Ashley Newland, Pharm. D anewland@mcvh-vcu. edu