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!