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Immunosuppression in Bone Marrow
Transplant
Nwogoh Benedict Department of Haematology/Blood
Transfusion,Federal Medical Centre, Owerri
BBMT Conference, Benin, July 15 - 27, 2013
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
Introduction HSCT is a process of reconstituting the
haemopoietic and immunological system of a recipient using previously harvested stem cells from same individual or a donor HSC.
Allogeneic HSCT involves a complex immunological interplay between donor and recipient immune systems with potentials of both beneficial and serious life threatening complications
Introduction Appropriate manipulation of this
complexity is necessary for a successful transplant.
Immunosuppresion is a important modality of moderating this immunological interaction to ensure a successful HSCT.
Immune System Innate Immunity
Physical Barriers Secretions with microbiocidal activity Phagocytes
Adaptive/Specific Immunity Humoral Cellular: B, T and Plasma cells
Cells of the Immune System
Antigen Major HLA Ags
Class I HLA A, B, C Class II HLA DP, DQ, DR Class III
Minor HLA Ags Non HLA Ags
http://www.rikenresearch.riken.jp/eng/frontline/5028
Use of Immunosuppression Immunosuppression is used in allogeneic
stem cell transplant to:
Prevention of rejection
Prophylaxis for graft versus host disease (GVHD)
Treatment of GVHD
Prevention of rejection Rejection is a consequence of host versus
graft reaction. Immunosuppresants are incuperated into
the conditioning regimen to prevent rejection.
Eradicates host T-cells to allow acceptance of donor cells
Commonly used agents include ATG, Alemtuzimab and Cyclophosphamide.
Prophylaxis for graft versus host disease (GVHD) Pre- & post-transplant medications Suppresses donor T-cells to minimize
recognition of host cells as foreign Post transplant could be
Ex-vivo manipulation of the graft to deplete it of T cells (TCD)
In-vivo
Treatment of GVHD The first line agent is usually steroids
(methylprednisolone 1-2mg/kg) A calcineurine inhibitor (Cyclosporine) may be
used in combination. Second line agent may be indicated when first
line fails. First line agent is adjudged to have failed
when : Features are progressive after 3 days of steroid
therapy Failure to respond after 14 days of therapy
Pathophysiology of GVHD
Ferrara, et al. Lancet 2009;373:1550-61.
Medications used for immunosuppressionClass 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 MethylprednisolonePrednisone
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)
Calcineurin Inhibitors: Adverse Effects Nephrotoxicity Hypertension Hyperglycemia Hypercholesterolemia Hypomagnesemia Hyperkalemia HUS/TTP CNS toxicity
Tremor Posterior reversible encephalopathy syndrome
(PRES)
Calcineurin Inhibitors: Drug Interactions
Many others CYP3A4 inducers and inhibitors
Anti-fungals
Antibiotics GI Agents Anti-convulsants
Others
Fluconazole Metronidazole Metoclopramide Phenytoin Protease inhibitors
Voriconazole Erythromycin Cimetidine Phenobarbital Sirolimus
Posaconazole Clarithromycin Lansoprazole Carbamazepine St. John’s wort
Ketoconazole Rifampin Grapefruit juice
Calcineurin Inhibitors: Cyclosporine Dosing
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 TDM
150-350 ng/ml Adverse effects
Hirsutism/hypertrichosis Gingival hyperplasia
Methotrexate Mechanism of action
Induces apoptosis of activated lymphocytes Blocks dihydrofolate reductase to inhibit purine
synthesis Dosing
5-15 mg/m2 IVP on D+1, 3, 6, 11 +/- leucovorin rescue
Adverse effects Mucositis Myelosuppression Hepatotoxicity
Mycophenolate mofetil Mechanism of action
Inhibits lymphocyte proliferationby blocking purine synthesis
Dosing 1000 mg PO/IV every 12 hours
Drug interactions 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
Inhibits proliferation of lymphocytes by blocking m-TOR
Dosing 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
Infectious complications are common, making appropriate anti-infective prophylaxis important
Stem Cell Unit, Dept of Haematology, Blood Transfusion and Stem Cell Transplantation . Physician:Bazuaye G. N 05.07.2013Patient: Matthew Ebenezer, DOB: 23.11.1997Diagnosis: Sickle Cell Anaemia Donor: Matthew Naomi (MSD), Genotype: AAConditioning: Flu 180 mg/m2, Bu 16mg/kg, ATG (ATGAM) 1500mg total dose over 3days, CSA 5mg/kg/day. (analog EBMT 2005 Sykora und Sauer et al.) Weight. 48 kg, Height 175 cm, BSA 1.53 m2
PROTOCOL
References Ashley Newland. Notes on Immunosuppression in
Bone Marrow Transplant. Eliane Gluckman. Choice of the donor according
toHLA typing and stem cell source. In EBMT HSCT handbook 6th Edition
Jane Appley. Graft versus host disease. In EBMT HSCT handbook 6th Edition
Thank You!