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Acquired Aplastic Anaemia – Trends in treatment and Bone Marrow Transplantation

Acquired Aplastic Anaemia – Trends in treatment and Bone Marrow Transplantation. Vikas Gupta, MD Blood and Marrow Transplant Program Princess Margaret Hospital University of Toronto Toronto vikas.gupta@uhn.on.ca. Objectives. Management at Presentation

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Acquired Aplastic Anaemia – Trends in treatment and Bone Marrow Transplantation

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  1. Acquired Aplastic Anaemia – Trends in treatment and Bone Marrow Transplantation Vikas Gupta, MD Blood and Marrow Transplant Program Princess Margaret Hospital University of Toronto Toronto vikas.gupta@uhn.on.ca

  2. Objectives • Management at Presentation • Treatment strategies: Immunosuppressive therapy (IST) or Bone Marrow Transplant (BMT)

  3. Aplastic anaemia bone marrow aspirate

  4. Severe aplastic anaemia Normal

  5. Aplastic anaemia

  6. Etiologic classification • Direct toxicity • Iatrogenic causes • Radiation • Chemotherapy • Benzene • Intermediate metabolites of some drugs • Immune-mediated causes • Idiopathic • Hepatitis associated disease • Pregnancy • Intermediate metabolites of some drugs • Associated with autoimmune disorders

  7. Management at Presentation • Review of morphology • Define disease severity (Camitta 1976; Bacigalupo 1988) • Supportive care • Management plan: BMT or IST

  8. Assessment of Disease Severity • Severe AA (Camitta et al, 1976) • BM cellularity <25% or 25-50% with <30% residual haemopoietic cells • Two of the three of the following: • Neutrophils <0.5 x 109/l • Platelets <20 x 109/l • Reticulocytes <20 x 109/l • Very-severe AA (Bacigalupo et al, 1988) • Same as for SAA but neutrophils <0.2 x 109/l • Non-severe AA

  9. Management at presentation • Review of morphology • Define disease severity (Camitta 1976; Bacigalupo 1988) • Supportive care • Treatment options: BMT or IST

  10. HLA identical sibling BMT Initial treatment of choice if : • severe or very severe aplastic anaemia • HLA identical sibling • age <40 yr Controversy over upper age limit

  11. WP AA Registry: Survival for aplastic anaemia SAA WP March 2004 HLA identical sibling donors (1994 – 2003)

  12. Indications for immunosuppressive therapy (IST) Severe or very severe AA >40y of age Non-severe AA and transfusion dependent Severe or very severe AA <40 y with no compatible sibling donor

  13. What is the Optimum IST?

  14. EBMT randomized study CSA vs. ATG + CSA (Marsh et al, Blood 1999)

  15. German randomised study Frickhofen et al, Blood, 2003 ATG + CsA ATG P = 0.6

  16. German randomised study, Frickhofen et al, Blood, 2003 ATG + CsA ATG P = 0.04

  17. Is there a role for combining long term G-CSF with ATG and CSA?

  18. Randomised study of ATG, CSA ± G-CSF, Gluckman 2002

  19. G-CSF and risk of malignancy • Japanese studies show increased risk • Alarming high risk 45% in children • Small European randomized study did not show increased risk • EBMT observational study • Incidence of AML/MDS • With G-CSF 10.9% • Without G-CSF 5.8% (Socie et al, Blood, 2006, available on line) • Current randomized study by EBMT will probably provide a final answer in the future

  20. Immunosuppressive therapy (IST) • ATG + CSA is current standard of care of IST and is an effective treatment but • 65-70% respond • Delayed response • One third of responders relapse • secondary complications occur • Risk of clonal disorders such as MDS/AML,PNH • Cytogenetic evolution • Solid tumors • Time favours BMT over IST

  21. IST vs. BMT – Q-TwiST Study Viollier et al, Ann Haematol, 2005Re-produced by permission of Andre Tichelli, Basel, Switzerland

  22. Refractory/Relapse after first course of IST • Treatment Options • BMT – Related or unrelated donor • Repeated course of ATG

  23. Response to second course of ATG (Di Bona et al, BJH, 1999)

  24. Response to third course of ATG(Gupta et al, BJH, 2005)

  25. HLA identical sibling BMT - current issues • 1. Graft versus host disease • 2. Graft rejection • How can results be improved further ?

  26. SAA WP March 2004 WP AA Registry - HLA identical sibling donors -

  27. SAA WP March 2004 WP AA Registry HLA identical sibling donors (1994 – 2003) in patients surviving at least 100 days

  28. Is GVHD necessary for AA? • Unlike BMT for malignancies, GVL is probably not necessary in AA • With current protocols, 30-35% develop chronic GVHD • Adverse impact of GVHD on • Well-being • Quality of life • Fertility

  29. Impact of GVHD on Fertility in AA (Deeg et al, Blood, 1997) • Chances of becoming pregnant / fathered a child in long term BMT survivors of AA

  30. An ideal protocol for BMT for AA • Durable Engraftment • Minimal Regimen-related toxicity • Minimal risk of acute and chronic GVHD • Preserves Fertility • Applicable to a wider group of patients especially relatively older patients and those with co-morbidities

  31. Favorable effect on acute and chronic GVHD with cyclophosphamide and in vivo Anti-CD52 Monoclonal antibodies for marrow transplantation from HLA-identical sibling donors for acquired aplastic anaemia V. Gupta, S.Ball, Q-L Yi, D. Sage, S. McCann, M Lawler, M. Ortin, G Hale, H Waldmann, EC Gordon-Smith, J. Marsh (Biology of Blood and Marrow Transplant, 2004: 867-876)

  32. GVHD Chronic (3%) Acute (11%)

  33. Alemtuzumab for prevention of GVHD in AA • The impact on acute and chronic GVHD was favorable • However, graft rejection was 24% • Important Lesson • Graft rejection was higher in patients who received campath both prior and after stem cell infusion (36%) compared to those who received campath only prior to stem cell infusion (16%)

  34. Alemtuzumab for prevention of GVHD in AA • Therefore, timing and dose of anti-CD52 MoAb is important • At PMH, second generation protocols for Campath antibodies were designed and initiated in October 2004 • Day –8 10 mg • Day –7 20 mg • Day –6 30 mg

  35. AA patients receiving alemtuzumab based protocols at PMH

  36. AA patients receiving alemtuzumab based protocols at PMH

  37. AA patients receiving alemtuzumab based protocols at PMH • Infectious complications • Increased CMV reactivation in the campath patients (p=0.008) • Other infections do not appear to be increased

  38. What is the current role of unrelated donor BMT ?

  39. International BMT Registry (IBMTR)

  40. Unrelated donor tx for AA (Deeg et al. Blood 2006)

  41. Low-Dose Cyclophosphamide, Fludarabine and ATG as preparative regimen for aplastic anaemia from alternative donors (Bacigalupo et al, BMT, 2005)

  42. Treatment strategies for newly diagnosed patient with Severe Aplastic Anaemia (Gupta and Marsh, In Press, 2007) Age of patient  40yr > 40 yr HLA identical sibling Yes No ATG (horse)+CSA Response at 4 months HLA id sib BMT Yes No 2nd ATG (rabbit/horse) +CSA Maintain on CSA while FBC rising, then very slow taper, often over one/more years Response at 4 months Yes No MUD available Yes No Adequate performance status Adequate performance status No Yes Yes 1. 3rd ATG if previous response to ATG 2. CRP using novel IST 3. BMT using CRP with UCB 1. 3rd ATG if previous response to ATG 2. CRP using novel IST 3. BMT using CRP with UCB / haplotransplantation Supportive therapy Options Options Supportive therapy MUD BMT MUD BMT

  43. Conclusions • Survival has improved in young patients with AA treated with BMT and immunosuppressive therapy (IST) • Improvements in supportive care such as new antimicrobials, anti-fungals and better transfusion practices have contributed to better outcome • Quality of recovery is different between BMT and IST, need for prospective QOL studies

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