1 / 95

Monitoring and treatment iron overload in thalassaemia

Monitoring and treatment iron overload in thalassaemia. Professor John Porter Red Cell Disorders Unit University College London Hospitals and UCL j.porter@ucl.ac.uk. M onitoring and treatment iron overload in thalassaemia. Professor John Porter Red Cell Disorders Unit

xena
Download Presentation

Monitoring and treatment iron overload in thalassaemia

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Monitoring and treatment iron overload in thalassaemia Professor John Porter Red Cell Disorders Unit University College London Hospitals and UCL j.porter@ucl.ac.uk

  2. Monitoring and treatment iron overloadin thalassaemia Professor John Porter Red Cell Disorders Unit University College London Hospitals and UCL j.porter@ucl.ac.uk

  3. Outline • What are the treatment and monitoring options available for iron overload in Thalassaemia Major • On what are guidelines about ferritin targets based and should we be more ambitious? • What are the goals of chelation treatment ? • How can monitoring help to achieve these goals? • What can be achieved ?- a personal perspective

  4. Monitoring options • Iron loading rate • Serum ferritin • Liver Iron concentration • Cardiac evaluation – function & T2* • Endocrine evaluation – growth, function & MRI • Adherence and quality of life

  5. Highly variable iron excretion is required tobalance transfusional iron loading in Thalassaemia Major • Iron accumulation from transfusion in TM (n = 586) • 233mls/kg/y blood (if Hct 0.6) • about 40 units/year for a 70 kg person • 0.4 ± 0.11 mg/kg/day (mean) of iron • < 0.3mg /kg day 19% of patients • 0.3-0.5 mg/kg/day 61% • > 0.5 mg/kg/day 20% Cohen,Glimm and Porter. Blood 2008;111:583-7

  6. Dosing to balance iron transfusional rate D eferoxamine Average transfusion iron intake thalassaemia Average transfusion iron intake SCD Studies 107 and 108 0.8 Deferasirox 0.7 0.6 0.5 Mean total body iron excretion ± SD (mg Fe/kg/day) 0.4 0.3 0.2 0.1 Actual doses (mg/kg/day) 0 0 5 10 15 20 25 30 Deferasirox Deferoxamine (5 days/week) 0 10 20 30 40 50 60 Cohen AR, et al. Blood. 2008;111:583-7.

  7. Change in LIC at low defarasirox doses in NTDT • mean loading rate 0.01 mg/kg/day (primarily from increased GI absorption) LIC change (mg/g dry wt) from baseline Ferritin change (ng/ml) from baseline Taher, Porter,. et al Blood (2012) , 120, 970-7, But at 10mg/kg/day, the mean LIC increased at 1y in TM with mean loading rate 0.4mg/kg/day Cappellini et al, Blood. 2006;107:3455-3462

  8. Use serum ferritin measures to achieve harmless body iron levels? • Clear evidence linking long-term ferritin control to outcome • Convenience and low cost • Permit frequent repeated measurements • Allows early trend recognition • Ferritin trend is increasing; • focus on adherence • consider dose increase • chelator regime change • Ferritin trend decreasing • If rapid, dose adjust to minimise risks of over chelation for ‘soft landing’ • If levels already low- dose reduction to allow maintenance of current level

  9. Limitations of just using serum ferritin ? • Variability in LIC accounts for only 57% of variability in serum ferritin 1 • Raised by inflammation or tissue damage • Lowered by vitamin C deficiency 2 • Origin of serum ferritin differs above values of 4K 3 • Relationship of ferritin to body iron (LIC) varies in different diseases • Low relative to LIC in ThalIntermedia4 • (hepatocellular > macrophages) • Higher and variable in SCD 5 • Relationship of ferritin to LIC differs with different chelators,6,7 • Brittenham et al, Am J Hematol 1993;42:81-5 • Chapman et al, J ClinPathol 1982;35:487-91. • Worwood, M. 1980 Br J Haematol 46,409-16 • Origa, Hamatologica 2007, 92 583 • 5. Porter & Huehns, ActaHaematologica • Fischer et al. Brit J Haem 2003, 121 938-948 • Ai LeenAng, et al, Blood, 201, 116, Abstract 4246.

  10. Why monitor& control liver iron ? • Ferritin alone may not reflect true body iron and chelation trends • LIC predicts total body storage iron in TM1 • Absence of pathology • heterozygotes of HH where liver levels < 7 mg/g dry weight • Liver pathology • abnormal ALT if LIC > 17 mg/g dry weight2 • liver fibrosis progression if LIC > 16 mg/g dry weight3 • Cardiac pathology at high levels • Increased LIC linked to risk of cardiac iron in unchelated patients 2,6 • LIC >15 mg/g dry weight association with cardiac death • all of 15/53 TM patients who died4 • improvement of subclinical cardiac dysfunction with venesectionalone post-BMT5 AngelucciE, et al. N Engl J Med. 2000;343:327-31. Jensen PD, et al. Blood. 2003;101:91-6. AngelucciE, et al. Blood. 2002;100:17-21. BrittenhamGM, et al. N Engl J Med. 1994;331:567-73. MariottiE, et al. Br J Haematol. 1998;103:916-21. Buja LM, Roberts WC. Am J Med. 1971;51:209-21 ALT = alanine aminotransferase; BMT = bone marrow transplantation.

  11. Low Heart T2* inreases risk of low LVEF 90 80 70 60 50 40 30 20 10 0 LVEF (%) Severe cardiac iron Minimal liver iron Severe liver iron Minimal cardiac iron 0 20 40 60 80 Heart T2* (ms) LVEF = left ventricular ejection fraction. Anderson et al. Eur Heart J. 2001;22:2171.

  12. Relationship between cardiac T2* and cardiac failure 0.6 0.5 0.4 0.3 0.2 0.1 0 0 30 60 90 120 150 180 210 240 270 300 330 360 < 6 ms 6–8 ms Proportion of patients developing cardiac failure 8–10 ms > 10 ms Follow-up time (days) Kirk P, et al. Circulation. 2009;120:1961-8.

  13. Other Approaches to assessing Iron overload • Effects on specific organs • Other Organs • Endocrine screening- assessment of function • Growth monitoring, bone age • Role of MRI screening of pancreas 1, 2? • Measurement of NTBI/LPI • Predictive value of response 3 Au WY, et al. Haematologica. 2008;93:785. Noetzli LJ, et al. Blood. 2009;114:4021-6. 3. AydinokY, et al. . Haematologica, 2012, 97,6, 835-41

  14. Au WY, et al. Haematologica. 2008;93:785. MRI and assessment of endocrine complications in Thalassaemia Major – = not analysed; EF = ejection fraction; NS = not significant; Pan = pancreatic; Pit = pituitary; SIR = signal intensity ratio of pituitary to muscle. *p < 0.05; **p < 0.01; ***p < 0.001. n=180 • Cardiac MRI T2* correlates with endocrine dysfunction • Pancreatic T2* poor correlation with diabetes • Pituitary T2 correlates with multiple endocrine dysfunctions

  15. Assessment – when? Observation Frequency Expense Iron intake rate Each transfusion Chelation dose & frequency 3 monthly Growth & sexual development 6 monthly children Liver function 3 monthly Sequential ferritin 3 monthly GTT, thyroid, Ca metab Yearly in adults Liver iron Yearly from age 8-10 Heart function Yearly from age 8-10 Heart iron (T2*) Yearly from age 8-10

  16. Goals of chelation therapy • Prevention of iron mediated damage • Balance input and output - iron balance • Achieve harmless levels of body iron safely • Rescue • patients with high levels of body iron • patients with high levels of cardiac iron • patients with heart dysfunction

  17. Licensed iron chelators

  18. Chelation regimes • DFO monotherapy • Sc 8-12h • continuous (sc or iv) • Deferiprone monotherapy • po 3 x daily • Combined Deferiprone and DFO • Deferiprone daily with DFO nocte n x week • Deferiprone daily + DFO at same time • Deferasirox monotherapy • New combinations and drugs

  19. ‘Harmless body iron levels’ ?what are guidelines based on ? • Experience with thalassaemia major • Experience with DFO • Control of ferritin and LIC • links to risk of cardiac disease • risk of under and over chelation

  20. Guidelines with DFO therapy • Begin • after 10–20 blood transfusions • or when serum ferritin > 1,000 µg/L • Dose adults 40-60mg/kg 8-12h nocte minimum 5x/wk • Maintain • serum ferritin < 2,500 µg/L (1,000 µg/L recommended) • LIC < 7 mg/g dry weight • Intensify dose or frequency if • if severe iron overload • High ferritin values persistently > 2,500 µg/L • High liver iron > 15 mg/g dry weight • or significant cardiac disease • Significant cardiac dysrhythmias • Evidence of failing ventricular function • Evidence of severe cardiac iron loading • Reduce dose if • Ferritin <1000µg/L • Ratio of mean daily dose (mg/kg) / ferritin >0.025

  21. Guidelines based on Risks of over-chelation with DFO • Risks of starting too early • effects on growth • effects on bones, especially < 3 years of age1,2 • Risks of too high a dose • growth affected: > 70 mg/kg/day, normalized ≤ 40 mg/kg/day3 • skeletal/bones: > 70 mg/kg in children1 • eyes: visual symptoms > 80 mg/kg/day4 • otoxicity4,5 • Risks at low iron loads • effects on growth: patients had mean ferritin of 1,300 µg/L3 • otoxicity: with serum ferritin < 2,000 µg/L or when ratio dose/ferritin too high5 • neurotoxicity in non-iron-overloaded RA patients at low doses6 • ocular toxicity in dialysis patient7 1. Olivieri NF, et al. Am J PediatrHematolOncol. 1992;14:48-56. 2. Brill PW, et al. Am.J.Roentgenol. 1991;156:561-5. 3. Piga A, et al. Eur J Haematol. 1998;40:380-1. 4. Olivieri NF, et al. N Engl J Med. 1986;314:869-73. 5. Porter JB, et al. Br J Haematol. 1989;73:403-9. 6. Blake DR, et al. Q J Med. 1985;56:345-55. 7. Rubinstein M, et al. Lancet. 1985;325:817-8.

  22. DFO Chelation therapy has improved patient survival in TM 1985–1997 1.00 1980–1984 1975–1979 1970–1974 0.75 Birth cohort Survival probability 0.50 1965–1969 1960–1964 0.25 (p < 0.00005) 0 0 5 10 15 20 25 30 Age (years) Borgna-Pignatti C, et al. Haematologica. 2004;89:1187-93.

  23. Decline in complications withiron chelation Patients with β-thalassaemia major born after 1960 (N = 977) *DFO i.m., 1975; †DFO s.c., 1980. In 1995, 121 patients switched to deferiprone (censored at this time) Borgna-Pignatti C, et al. Haematologica. 2004;89:1187-93.

  24. Is there a risk of over-chelation with other chelation regimes?How low can we go? • How is risk of chelator toxicity related to • Absolute chelator dose • Dose in relation to • Body iron load • Transfusional iron loading rate • Rate of decrease of load with chelation

  25. Do DFP doses >75mg/kg/d affect tolerability? Unwanted Effect Dose dependence? GI distrurbances 3-24% at 75mg/kg (1-3) 66% at 100mg/kg (n=29) (4) Neutropaenia insufficient human numbers Agranulocytosis insufficient human numbers Thrombocyopenia age <6y (7/44) ? dose effect (5) Arthropathy ? improved arthropathy at 50mg/kg (6) Neurotoxicity Yes with unintended large doses 1. Al Rafae Brit J Haematol, 1995;91:224-9.2. Ceci A, et al. Br J Haematol. 2002;118: 330-6. 3. Cohen AR, et al. Br J Haematol. 2000;108:305-12. 4. Pennell DJ, et al. Blood. 2006;107:3738-44 5. Naithani et al, Eur J Haematol. 2005 ;74:217-20 6. Lucal et a, Ceylon Med, 45, 71-4.J 2000 .

  26. Low serum ferritin without toxicity with long-term combined therapy • 53 patients 5-7y on DFO 20-60mg/kg/day and deferiprone 75mg/kg/day ‘individually tailored’ • Ferritin bl3421µg/L - 87 µg/L at 5-7y • T2* bl28ms - 38 ms at 5-7y • LIC bl12.7 - 0.8mg/g dry wt at 5-7y • GTT normalbl 23% - 64% at 5-7y • Thyroxinereplacement bl34% - 20% at 5-7y • Secondary amen bl19/26 - 3/19 spontaneous ovulation • No toxicity Farmaki et al presentation at ITC 2008 FC07 Pg. 92 Farmaki et al Br J Haematol, 466-75 (2010)

  27. Year 1 Year 2 Year 3 Year 4 Year 5 Experience with serum ferritin < 1,000 μg/L • % of patients achieving serum ferritin < 1,000 µg/L Years The incidence of drug-related AEs did not appear to increase during the periods after serum ferritin levels first decreased < 1,000 μg/L 174 adult and paediatric patients (out of 474) were chelated to serum ferritin levels < 1,000 μg/L Porter JB, et al. Blood. 2008;112:[abstract 5423].

  28. Safety profile of serum ferritin <1000 μg/L • The incidence of drug-related adverse events did not appear to increase during the periods after serum ferritin levels first decreased < 1,000 μg/L • Safety profile was similar to patients with serum ferritin levels > 1,000 μg/L • No increase in the proportion of patients with creatinine increases > 33% above baseline and ULN or with ALTs > 10 x ULN ALT = alanine transaminase. Porter JB, et al. Blood. 2008;112:[abstract 5423].

  29. Combined chelation therapy with DFX and DFO in transfusion-dependent thalassaemia Aim: to explore safety and efficacy of combined deferasirox and DFO in patients with transfusion-dependent thalassaemia who had failed standard chelation therapy with single drug (US24T) 15 patients enrolled and randomized into 3 equally sized groups Group AAdultsLIC <15 mg/g dry wt Group C8–18 yearsLIC >5 mg/g drywt Group BAdultsLIC >15 mg/g dry wt Duration of therapy: 52 weeks Deferasirox 20–30 mg/kg/day DFO 35–50 mg/kg/infusion infused 3–7 days/week Lal, Porter, et al. Blood. 2010;116:[abstract 4269].

  30. 3 2,000 1,500 2 1,000 1 500 0 0 DFX + DFO:improvements in iron overload Cardiac improvements (in three patients who had T2* < 20 ms at baseline) • T2* < 20 ms at baseline (6.5–19.5 ms): improved +2.43 ms (8.8–21.3 ms) (p= 0.027) • LVEF < 60% at baseline (47.4–58.1%): improved to 60.6–64.4% • Median LPI decreased: 0.87 µM to 0.05 µM (p= 0.004) LIC NTBI Serum ferritin 15 43% (p = 0.008) p < 0.001 48% (p = 0.003) 10 Median serum ferritn (μg/L) Median plasma NTBI (µM) Median LIC (mg/g) 5 0 BL 1 year BL 1 year DFO DFO + deferasirox LPI = labile plasma iron. Lal A, et al. Blood. 2010;116:[abstract 4269].

  31. DFX + DFO:improvements in iron overload Lal, Porter et al Blood.CellsMol Dis. 2012 in press.

  32. 34-year-old female with TM, 2 units of packed red blood cells, every 20 days Deferoxamine – failed to comply T2* liver 1.1 ms, cardiac T2* 9.4 ms serum ferritin > 2,800 µg/L Deferasirox, 20 mg/kg for 12 months liver T2* 3.33 ms, cardiac T2* 10.6 ms Deferasirox 30 mg/kg for 24 months liver 7.81 ms, cardiac T2* 13.8 ms serum ferritin 2,080 µg/L Deferasirox 30 mg/kg/day + deferiprone 75 mg/kg/day for 12 months serum ferritin 397 μg/L liver T2* 15.3 ms, cardiac T2* 21.1 ms 25 20 15 10 5 0 DFP + DFX?A patient case Combination MRI T2* (ms) Cardiac Liver 2005 2006 2007 2008 2009 2010 Year Serum ferritin 3,000 2,500 2,000 Serum ferritin (µg/L) 1,500 1,000 500 0 2005 2006 2007 2008 2009 2010 Year Voskaridou E, et al. Br J Haematol. 2011;154:654-6.

  33. Patient selection 16 TM > 20 years old Either intolerance to DFO or ‘inconvenience to DFO’ Serum ferritin > 500 µg/L > 1 iron overload complication (clinical or laboratory) Treatment: up to 2 years of DFX (20–25 mg/kg/day) + DFP (75–100 mg/kg/day) Outcome Reversal of cardiac dysfunction in 2/4 Mean LVEF increased significantly GTT improved in 2/8 with impaired GTT Improvement in gonadal function Tolerability No serum creatinine > ULN No agranulocytosis, neutropenia, thrombocytopenia 3/15 (20%) minor GI disturbance DFP + DFX GTT = glucose tolerance test. * p < 0.001 Farmaki, et al. Blood Cells Mol Dis. 2011;47;33-40.

  34. How has chelation therapy and monitoring impacted on outcome in transfusion dependent thalassaemia- a local perspective in UK

  35. Treatment of Thalassaemia Major in the UK 1960 → 1970 → 1980 → 1990 → 2005 • Cardiac failure secondary to cardiac iron overload is reported as the leading cause of death amongst patients with TM • Survival substantially improved with introduction of iron chelation therapy but despite this by 2000, 50% UK patients died before the age of 35 in 20001. • CMR introduced in London 1999 – what impact has this had • Cohort of 121 patients monitored and treated at UCLH/Whittinton since 1999 1980 – SC desferoxamine standard of care 1987 – Deferiprone 1964 – IM desferoxamine 1999 – CMR Deferasirox 1984 – Bone marrow transplant initiated

  36. Chelation regimes DFP + DFO DFX DFP DFX DFO DFO DFP + DFO DFP + DFO DFP DFP 2010

  37. 70 60 50 40 30 20 10 0 T2* ≤ 20 ms T2* < 10 ms Impact of a decade of cardiac MRI assessment on cardiac T2* Cohort of 132 patients from UCLH/Whittington hospitals p < 0.001 60 Baseline Median 9 years follow-up Proportion of patients (%) p < 0.001 23 17 7 Thomas AS, et al. Blood. 2010;116:[abstract 1011].

  38. Mortality • Total of 8 deaths amongst 132 patients: • 2 female, 6 male • median age at death 35.6 years (range 27.3-48.4) • None directly related to myocardial iron • Mortality rate 1.65 / 1000 patient y (95% CI 0.71-3.24) • Previous reports from UK thalassaemia registry: • 1980-1999: 12.7 deaths / 1000 patient y 2 • 2000-2003: 4.3 deaths / 1000 patient y 3 1. Thomas AS, et al. Blood. 2010;116:[abstract 1011] 2 Modell et al , Lancet 355:2051-2, 2000 3. Modell et al , J. Cardiovas Magnetic Resonance, 2008

  39. Causes of Death and cardiac MRI • Cardiac MRI at death, n = 8 • T2* > 20ms • 3 pt with hepatitis C complications • 1 sudden death • T2* 10-20ms • 1 pt with meningitis • 1 pt with cancer • T2* < 10ms • 2 pt with sepsis

  40. Chelator regime at death • DFO (n= 4) • DFP (n= 2) • Combination DFP + DFO ( n= 1) • DFX ( n= 1)

  41. Causes of death in β-thalassaemia major in the UK 100 90 80 70 60 50 40 30 20 10 0 1950–1959 1960–1969 1970–1979 1980–1989 1990–1999 2000–2003 This cohort Hepatitis C complications Other/unknown Malignancy Infection BMT complication Anaemia Iron overload Patients (%) Mortality rates per cohort Use of modern iron chelation therapy and regular CMR monitoring has dramatically reduced the iron overload-related mortality in the Red-cell Disorders Unit Adapted from UK Thalassaemia Registry data from Modell B, et al. J Cardiovasc Magn Reson. 2008;10:42.Thomas AS, et al. Blood. 2010;116:[abstract 1011]. BMT = bone marrow transplantation;CMR = cardiac magnetic resonance imaging

  42. Optimal Outcome - What else do we need ? • Optimal monitoring and intensification for high risk patients • Recognition that chronic diseases pose special challenges which require targeted resources • Rapidaccess to free care • Staff with expert knowledge & experience • Continuity of care (especially staff) • Systemsorganized to allow best care with minimum disruption to ordinary life • Identity (a ‘unit’) for patients allowing a focus for care but not isolated from hospital • Multidisciplinaryteam with integrated clinics & investigations AND

  43. Conclusions • With modern chelation regimes, used alone or in combination and when applied with modern monitoring techniques, excellent survival can be obtained • The challenge over the next decade will to be to improve quality of life in an ageining population by; • Further decreasing morbidities associated with thalassaemia and iron overload • Further improving infrastructure and delivery of care to thalassaemia patients inside and outside treatment ‘centres’

  44. What can be achieved with transfusion, chelation and optimal monitoring Then andNow

  45. Thankyou

  46. A decade of cardiac monitoring with modern chelation therapies for TM, UCLH/Whittington • Cohort of 132 patients received 1st CMR 1999-2000 • 109 of these available for long term CMR FU • Follow up median 9.2 years (range 7.0-10.6) • Minimum CMR follow up of 7 y • Median age at 1st CMR 27.9 years (range 7.7-49.5) • 58 female, 51 male

  47. Variables studied • % Patients with evidence of myocardial iron • At 1st CMR • At latest CMR • Survival in cohort with baseline CMR 1999-2000 • Cause of death • T2* at death • Modes of chelation • At baseline • At latest follow up • At death • Number of switches in chelator

  48. Causes of Death by cardiac MRI • Cardiac MRI at death, n = 8 • T2* > 20ms • 3 pt with hepatitis C complications • 1 sudden death • T2* 10-20ms • 1 pt with meningitis • 1 pt with cancer • T2* < 10ms • 2 pt with sepsis

  49. Changes in Chelation 69% changed chelator at least once based on: • Iron assessment • Ferritin trend • LIC trend • m T2* trend • Side effects/tolerability • Adherence or patient preference • Availability of new chelators: trials/funding decisions

  50. Impact of monitoring and comprehensive support on outcome

More Related