Management of acute graft versus host disease

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  • Steps of Transplantation :
    Conditioning
    Stem cell infusion
    Neutropenic Phase
    Engraftment Phase
    Post- Engraftment Phase

    Overall aGVHD cascade
    Initiation and maintenance of aGVHD has been conceptualized into 4 phases with feedback loops that self-sustain the process. Although the effect of conditioning phase in aGVHD is not absolutely necessary, in many of the models it activates APCs, via tissue destruction, and improve APC capacity. It also, through release of gut bacteria, PAMPS and chemokines, can activate cellular components of innate immune system that can participate in direct tissue damage and contribute in cytokine storm. Host hematopoietic APCs have perhaps the most important role in initiation of GVHD, but this may depend on the model and the potential role of recipient APCs as well host non-hematopoietic APCs should not be ignored. Following antigen presentation, a strong cytokine response is initiated, promoting greater antigen presentation and recruitment of Teffs, and innate immune cells further contributing to the inflammatory cytokine milieu. Finally, the Teff cells, NK cells, macrophages and pro-inflammatory cytokines (e.g. TNF-α), will result in end organ damage, clinically recognized as aGVHD in the skin, lung, gut and liver. The resulting tissue damage, if not treated, will further escalate the disease, spiraling up the process to higher and more severe stages of GVHD pathology, which is extremely difficult to control.

  • Although initial definitions of acute GVHD required an onset of symptoms before 100 days post transplantation, the current National Institutes of Health (NIH) consensus criteria use clinical findings, rather than a set time period, to differentiate between acute and chronic GVHD. 
  • Scale Index allows patients to be classified as to their functional impairment

    40Disabled; requires special care and assistance.
    30Severely disabled; hospital admission is indicated although death not imminent.
    20Very sick; hospital admission necessary; active supportive treatment necessary.
    10Moribund; fatal processes progressing rapidly.
    0Dead
  • Liver biopsy is poses a significant risk of major bleeding since most patients are thrombocytopenic at the time of presentation with GVHD. Transjugular liver biopsy is a safer alternative if it can be adequately performed.
  • In Grade 1: No systemic Steroids is used.
     the most common prophylaxis regimen is the combination of cyclosporine and methotrexate. The cyclosporine is administered to reach a therapeutic target concentration, which varies according to the time from transplantation. A target concentration of 200 to 300 mcg/L is used during the first three to four weeks post transplant; then, if there is no GVHD, the target concentration is decreased to 100 to 200 mcg/L until three months after transplantation, and then tapered further. Patients who develop GVHD of any grade should have their cyclosporine dose adjusted to ensure a therapeutic level
  • The mechanism of prednisolone their effects may because of lympholytic effects and anti-inflammatory properties
    Gradual tapering is important to prevent a flare of GVHD.
    These efficacy and toxicity data suggested the use of mycophenolate plus glucocorticoids as the most promising combination
  • Day 28 post initiation of treatment complete response rates for methylprednisolone plus either etanercept, or mycophenolate, or denileukin, or pentostatin were 26, 60, 53, and 38 %, respectively.
    9 month overall survival rates for these four treatment regimens were 47, 64, 49, and 47 percent, respectively.
    Cumulative incidences of severe infection were 48, 44, 62, and 57 percent, respectively.
  • Etanercept plus methylprednisolone as initial therapy for acute graft-versus-host disease, 2008 by Department of peds in Michigan medical school
    Showed that : Patients treated with etanercept plus steroids were significantly more likely to attain complete remission (CR) after 28 days than those treated with steroids alone (69 versus 33 percent)
  • Management of acute graft versus host disease

    1. 1. MANAGEMENT OF ACUTE GRAFT VERSUS HOST DISEASE (GVHD) Mahmoud A. Hashim Ahmed Khalaf Visiting Students UAB School of Medicine Hem-Onc Department Bone Marrow Transplantation Unit
    2. 2. DEFINITION  Multisystem Disorders due to immune reaction caused by transplanted cells from a non-identical donor (the graft) that recognize recipient cells (the host) as foreign, thus disease is caused in the recipient organs.  It can be fatal in up to 15% of HSCT recipients.
    3. 3. PATHOGENESIS
    4. 4. CLASSIFICATION  Patients with GVHD are sub classified based upon the timing of presentation and the features present:  Classic acute GVHD  Cases present within 100 days of hematopoietic cell transplant (HCT).  Shows features of acute GVHD.  Diagnostic features of chronic GVHD are absent.  Persistent, recurrent, late onset acute GVHD  Cases present greater than 100 days post-HCT.  Shows features of acute GVHD.  Diagnostic features of chronic GVHD are absent.  Classic chronic GVHD  Cases may present at any time post-HCT.  Diagnostic features of chronic GVHD are present.  There are no features of acute GVHD.  Overlap syndrome “Acute on Chronic GVHD”  Cases may present at any time post-HCT .  Shows features of both chronic GVHD and acute GVHD.
    5. 5. CLINICAL MANIFESTATIONS AND GRADING I. Maculopapular rash. “ 1st and most common symptom” II. GI Symptoms “ 2nd commonest symptoms”  Diarrhea with or without Abd. Pain.  Persistent nausea and/or emesis. III. Jaundice “Glucksberg Criteria”
    6. 6. Overall Grading of Acute GVHD If Karnofsky Performance <30%, then Grade 4
    7. 7. DIAGNOSES I. Clinical Evaluation The diagnosis of aGvHD is predominantly based on clinical findings. II. Histological Tests A. Skin Biopsy is important in absence of the classic symptoms.  Skin biopsy was not found to be useful in predicting severity of disease. B. Rectosigmoid Biopsy was found to be the most informative. C. Transjugular liver biopsy can show Endothelialitis, Lymphocytic infiltration of the portal area, pericholangitis and Bile duct obstruction. III. Imaging  upper GI endoscopy as well as lower endoscopic biopsy may show Luminal Dilatation and Thckening of small bowel wall. IV. Biomarkers  There are many candidate biomarkers but none are ready for clinical application.
    8. 8. MANAGEMENT  The choice of initial therapy for patients with acute graft-verus-host disease (GVHD) depends upon : Overall grading of Acute GVHD. Grade 1 GVHD Management A. Topical steroids are the most commonly used skin-directed therapy for acute GVHD. B. Antihistamines may be used as supportive therapy for patients with pruritus. C. In Resistant grade 1 aGVHD, Topical Tacrolimus may be useful. D. Optimizing prophylactic agents When acute GVHD of any grade develops, to ensure a therapeutic level. For those no longer receiving prophylaxis, the prior prophylactic agent should be restarted again.
    9. 9. GRADE 2-4 GVHD  Patients with grade 2-4 disease are likely to require addition of Systemic agents to achieve a response and Optimizing prophylactic calcineurin inhibitors agents. A. First Line of Treatment: Corticosteroids  Most centres used 2 mg/kg /day of methylprednisolone to be the standard primary dose.  Oral beclomethasone, a non- absorbable glucocorticoid, is added for most patients with GI involvement.  Topical steroids can be added for further control of Skin lesions.  Steroids are continued for several weeks in responders and then gradually tapered over a period of several months.  Patients who shows progression of disease by day 5 or non-response by day 7 are considered to have corticosteroid resistance.  Use of Steroids results in complete response rates ranging from 25 to 40 %.
    10. 10. HOW TO TAPER THE STEROIDS AFTER INITIAL RESPONSE? Conclusion I. Tapering of steroid doses should begin as soon as GVHD manifestations show major improvement. II. Inappropriately rapid taper rates carry a risk of GVHD exacerbation or recurrence, while inappropriately slow taper rates increase the risk of steroid-related complications. III. Doses should be gradual reduced 0.2 mg/kg/day every 3–5 days, after prednisone doses are decreased to less than 20–30 mg/day, slower tapering rate is required.
    11. 11. B. Second Line of Treatment:  Given in Patients who fail to respond to 2 mg/kg/day Methylprednisolone for 5 d or progressive symptoms after 72 h.  There is nostrong comparative data showing superior efficacy for any particular agent over others, so the choice of a second-line regimen should be guided by 1. Considerations of potential toxicity, interactions with other agents 2. Expense 3. The familiarity of the physician with the agent 4. The prior experience of the physician  Includes: 1. Mycophenolate mofetil (MMF) 2. Etanercept “ Anti TNF Antibodies” 3. Pentostatin 4. Sirolimus 5. Basiliximab 6. Extracorporeal Photopheresis
    12. 12. I. MYCOPHENOLATE MOFETIL (MMF) Mechanism of Action: I. MMF is a prodrug of mycophenolic acid (MPA), an inhibitor of inosine monophosphate dehydrogenase (IMPDH).  This is the rate-limiting enzyme in de novo synthesis of guanosine nucleotides.  T- and B-lymphocytes are more dependent on this pathway than other cell types are. II. MPA can induce apoptosis of activated T-lymphocytes. III. MMF dose in Adults is 2 gm/kg/day.  Side Effects  Dose related Cytopenia and gastrointestinal toxicity.  Moderate High possibility of Viral reactivation.
    13. 13. II. ETANERCEPT  A recombinant human TNF-alpha receptor fusion protein.  Given SC at a dose of 0.4 mg/kg per dose, Twice/ week. (maximum dose, 25 mg/week).  Mechanism  A purine analog, a potent inhibitor of adenosine deaminase.  T and NK Cells Death occurs due to accumulation of 2-deoxyadenosine 5-triphosphate.  Dose: 1.5 mg/m2 IV /day for three days.  Pentostatin should be used with caution in patients with renal insufficiency.  A 50 % dose reduction has been suggested for patients with an estimated creatinine clearance of 30 to 50 mL/min/1.73 m2 III. Pentostatin
    14. 14. IV. SIROLIMUS (RAPAMYCIN)  Mechanism  Exerts its immunosuppressive effect through inhibition of mTOR.  Loading dose of 6 mg/m2 followed by a daily dose of 3 mg/m2 daily for 13 days .  At a dose of 4 -5 mg/m2 without a loading dose for 14 days.  Reversible cytopenia, hypertriglyceridemia, and nephrotoxicity (HUS) and neurotoxicity when combined with calcineurin inhibitors.  The use of Sirolimus has also been associated with sinusoidal obstruction syndrome (SOS) following conditioning regimens especially, Busulfan.  Mechanism  Humanized monoclonal antibodies directed against the interleukin-2 receptor leading to prevention of T- cell proliferation. V. BASILIXIMAB VI. DENILEUKIN DIFTITOX  Mechanism Recombinant fusion molecule of human IL-2 and diphtheria toxin that binds to the IL-2R-α and triggers apoptosis in activated T cells.
    15. 15. VII.EXTRACORPOREAL PHOTOPHERESIS  Infusion of ultraviolet-A irradiated autologous peripheral lymphocytes which have been collected by apheresis and incubated with 8- methoxypsoralen.  ECP induces apoptosis of all leucocytes (including activatedn T- cells) within 24 h of return.  Several studies have suggested that ECP may have a role in the treatment of acute GVHD.  Better results are expected in patients with disease limited to the skin.  Side effects is mild including hypotension, fevers and reduced hemoglobin level.
    16. 16. GvHD Diagnosing and Grading Grade 1 Topical steroid Grade 2-4 First Line Systemic steroids 2mg/kg/day Second Line CONCLUSION MMF Etanercept Pentostatin Sirolimus Extracorporeal Photopheresis BASILIXIMAB
    17. 17. REFERENCES I. Advances in graft-versus-host disease biology and therapy,2013, Bruce R. Blazar, William J. Murphy, and Mehrdad Abedi http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3552454/ II. Diagnosis and management of acute graft-versus-host disease, 2012, Fiona L. Dignan et al. http://www.bcshguidelines.com/documents/bjh_9129_Rev_EV.pdf III. First and Second-Line Systemic Treatment of Acute Graft-versus- host Disease: Recommendations of the American Society of Blood and Marrow Transplantation, Paul J. Martin et al. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3404151/ IV. Management of Acute GVHD, Uptodate.com V. Extracorporeal photopheresis in the management of graft-versus- host disease, Bredeson C et al. http://www.ncbi.nlm.nih.gov/pubmed/24764713

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