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Current Treatments in MDS; the Scottish Perspective

Current Treatments in MDS; the Scottish Perspective. Dr Dominic Culligan Aberdeen Royal Infirmary. Age-related Incidence of MDS. (per 100,000). Age in 5-year blocks. Williamson PJ, et al. Br J Haematol. 1994 Aug;87(4):743-5. Talk Outline. Therapeutic Options Low Risk MDS High Risk MDS

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Current Treatments in MDS; the Scottish Perspective

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  1. Current Treatments in MDS; the Scottish Perspective Dr Dominic Culligan Aberdeen Royal Infirmary

  2. Age-related Incidence of MDS (per 100,000) Age in 5-year blocks Williamson PJ, et al. Br J Haematol. 1994 Aug;87(4):743-5.

  3. Talk Outline • Therapeutic Options • Low Risk MDS • High Risk MDS • The Scottish Perspective • Scottish Medicine Consortium (SMC) • How it works • What is good & what is bad!

  4. Therapeutic Options • Low Risk MDS – • Main problem is anaemia • High Risk MDS – • Main problem is bone marrow failure & leukaemia

  5. Therapeutic Options • Low Risk MDS • Supportive care/ blood transfusion /iron Chelation • Erythropietic stimulating agent (ESA) • Immunosuppression • Lenalidomide • High Risk MDS • Supportive care • Azacitidine • Chemotherapy • Stem cell transplantation

  6. Best supportive care • Red cell transfusion on demand • Antibiotics for treatment & prevention • G-CSF during infection • Iron chelation therapy

  7. Treatment of Anaemia in MDS Transfusion Growth Factors Symptomatic anaemia in low risk MDS Immunosuppression with Antithymocyte globulin Lenalidomide in 5q-

  8. Treatment of Anaemia in MDS Transfusion Growth Factors Symptomatic anaemia in low risk MDS Immunosuppression with Antithymocyte globulin Lenalidomide in 5q-

  9. Iron chelation is beneficial on survival in thalassaemia Survival by Birth Cohort: University College London Hospitals 100% 1975-97 (n=42) 1.00 1965-74 (n=39) 0.75 1955-64 (n=21) 69% Survival probability 0.50 0.25 Analysis September 2000 0 yrs 10 20 30 40 0 Age (years) Thalassaemia Major treated with desferrioxamine only (N=103) Davis and Porter. Adv Exp Med Biol. 2002;509:91.

  10. Which patients if any should get iron chelation? • IPSS score low or int-1 • Ferritin should be 1000-2000 ng/ml or clinical or radiological evidence of iron loading at the start of chelation • This would often correlate with 20-30 units of red cells transfused • Candidates for allograft in whom there is a significant delay until the procedure

  11. Treatment of Anaemia in MDS Transfusion Growth Factors Symptomatic anaemia in low risk MDS Immunosuppression with Antithymocyte globulin Lenalidomide in 5q-

  12. 20 Years experience of erythropoietin +/- G-CSF therapy in MDS • Overall response rate ~20-40% • Best response group ~ 60-70% • Refractory anaemia • Low endogenous EPO level (<500mU/ml) • Low transfusion requirement (<2u/month)

  13. Prototype model for selecting patients for treatment with EPO + GCSF Score >+1 Good response 74% RA, RARS, RAEB -1 to +1 Intermediate response 23% < -1 Poor response 7% Serum EPO <100 +2 100-500 +1 >500 -3 Unit/mth < 2 +2 = or >2 -2 Hellstrom et al, BJHaem 2003, 120, 1037-46

  14. The ‘nitty-gritty’ of EPO therapy • Is there a quality of life benefit for EPO responders? • Is EPO therapy cost-effective? • Is there a survival advantage for EPO responders?

  15. Your doctors have still not answered two major questions in low risk MDS! • Is erythropoietin therapy more beneficial than transfusion? • Is iron chelation therapy beneficial?:

  16. Our drug companies are trying to answer these questions! • Johnson & Johnson – EPOANE3021 • Erythropoietin versus Placebo • Novartis – TELESTO • Iron chelation (Exjade) versus Placebo

  17. Treatment of Anaemia in MDS Transfusion Growth Factors Symptomatic anaemia in low risk MDS Immunosuppression with Antithymocyte globulin Lenalidomide in 5q-

  18. 5q- Syndrome del(5)(q31q33)

  19. 5q- Syndrome: Diagnostic findings Peripheral blood Anaemia Platelets normal or increased Bone marrow Megakaryocytes with hypolobulated nuclei < 5% blasts, no Auer rods Isolated del(5)(q31) More common in women Median age at diagnosis 68yrs Associated with a favourable prognosis; median survival >5yrs, AML transformation 8-16%

  20. Phase 2 Study of Lenalidomide MDS Del 5q (MDS-003) R E G I S T E R R E S P O N S E Activation date: 7-15-03 Cohorts 10 mg × 21 days10 mg po qd Treatment until progression/relapse Wk: 0 4 8 12 16 20 24

  21. N = 148 Transfusion Independence 99 (67%) Median time to response, wk (range) 4.6 (1 - 49) Transfusion Independence Response Del 5q (MDS-003) See BD for data

  22. Durable Transfusion Independence (ITT) Del 5q (MDS-003) Median not yet reached median FU 104 wks List A et al. N Engl J Med 2006;355:1456-1465

  23. Case1Exceptional in every sense of the word!

  24. Clinical presentation • A 77 year old male retired farmer • 2 year history: • Tired • Lethargic • Poor sleep pattern • Known three vessel coronary artery disease • 2 months more frequent angina • Increasing breathlessness

  25. Laboratory findings • FBC: • Hb 9.1 g/dl; MCV 96fl • WCC 2.6 x 109/l • Neuts 1.2 x 109/l • Plats 117 x 109/l • Myelodysplastic Syndrome (MDS) • Refractory cytopenia with multilineage dysplasia (WHO)

  26. Follow up visit • Cytogenetics failed: • Not keen on repeat bone marrow • Hb 8.5 g/dl

  27. Management • Jehovah’s Witness!

  28. Case 1 Question 2 • What would you recommend? • Tell him not to be so daft and have a blood transfusion? • Tell his wife and daughter (not JWs) to persuade him to have a blood transfusion? • Treat him with a trial of erythropoietic stimulants (EPO, Darbopoietin)? • Try something else?

  29. Case 1 Answer 2 • What would you recommend? • Tell him not to be so daft and have a blood transfusion? • Tell his wife and daughter (not JWs) to persuade him to have a blood transfusion? • Treat him with a trial of erythropoietic stimulants (EPO, Darbopoietin)? (high predicted response) • Try something else?

  30. Initial therapy • Erythropoietin 30,000u once per week x 6wks • Erythropoietin 30,000u once per week + G-CSF 105ug three times per week x 6 weeks • Erythropoetin 60,000u +G-CSF 2 weeks • No response-steady deterioration

  31. March 2009 • Wheelchair- bound • Angina at rest despite maximum medical therapy • Hb 5.7g/dl • Repeat bone marrow: • Gross dysplasia, no increase in blasts • Karyotype 46XY only • IPSS intermediate-1

  32. Case 1 Question 3What would you opt for? 1). Palliative care with no further therapy? 2). Trial of azacitidine if approved? 3). Trial of lenalidomide if approved? 4). Trial of anti-thymocyte globulin (ATG)?

  33. Case 1 Answer 3What would you opt for? 1). Palliative care with no further therapy? 2). Trial of azacitidine if approved? 3). Trial of lenalidomide if approved? 4). Trial of anti-thymocyte globulin (ATG)?

  34. Exceptional Circumstances Group • Approved trial of lenalidomide based on fulfilling local criteria for exceptionality: • ‘Because of his religious beliefs he is unable to receive the standard therapy-blood transfusion’

  35. Case 1 continued • 22/04/09 started first cycle lenalidomide • 10mg od for 21 days out of 28 days • 12/05/09 GP phoned: • Bedridden, home oxygen, not coming to hospital again, no further treatment • Most recent Hb 4.3g/dl

  36. Here is the really exceptional bit! • 22/09/09 FBC from GP!!! • Hb 13.5 g/dl • WCC 6.6 x 109/l • Neuts 3.8 x 109/l • Platelets 166 x 109/l • Contacted GP-It is him and repeat FBC same! • Continued on lenalidomide for two years with normal blood counts and no symptoms of anaemia

  37. Case 1 What should you display in your MDS clinic?

  38. Therapeutic Options • High Risk MDS – Main problems are bone marrow failure & leukaemia • Supportive care • Azacitidine • Chemotherapy • Stem cell transplantation

  39. Azacitidine It has been suggested that azacitidine may switch on important anti-cancer genes

  40. AZA 001:Study design schematic Azacitidine 75 mg/m2 daily for 7 days, every 28 days Investigator selection of conventional care regimen Randomisation • Conventional care regimen • Best supportive care only • Low-dose ARA-C (20 mg/m2 daily • for 14 days every 28-42 days) • Standard chemotherapy (7 + 3)

  41. AZA-001: Vidaza is the only licensed drug that has demonstrated a survival advantage in Int-2 and High-risk MDS • Vidaza – increases the median survival to 24.5 months (compared to 15 months with CCR) providing a 9.4 month benefit • In a post hoc analysis Vidaza doubled 2-yearsurvival rate compared with CCR (p<0.001) • Fenaux P, et al. The Lancet Oncology 2009; 10: 200-01

  42. 100 Vidaza 90 80 CCR 70 33.6% difference p<0.0001 60 % of transfusionIndependent patients 50 40 45.0 30 20 10 11.4 0 AZA-001: Setting a new standard in transfusion independence • Santini V. J Clin Oncol 2008 • Fenaux P, et al. The Lancet Oncology 2009; 10: 200-01 • Vidaza SmPC December 2008.

  43. Azacitidine (Vidaza) • Standard of care for high risk MDS patients who are not candidates for transplantation • Approved by NICE ( great help of UKMDS Patient Forum) • Not approved by SMC

  44. The Scottish Perspective • The Scottish Medicines Consortium • Statutory body which is part of: • Quality Improvement Scotland (QIS) • To advice the NHS in Scotland as to the cost effectiveness of new treatments

  45. SMC vs. NICE • SMC decisions only apply in Scotland • NICE single drug decisions only apply in England, Wales and Northern Ireland • NICE multiple treatment assessments apply in Scotland and replace any existing SMC guidance

  46. The workings of the SMC New Drug Committee Patient Access Scheme Assessment Group (PASAG) Drug Company Main SMC Committee Final Advice Document Exjade Azacitidine

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