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Non-Responders to Iron Chelation Therapy

Non-Responders to Iron Chelation Therapy. John B. Porter, MA, MD, FRCP Professor, Department of Haematology University College London London, United Kingdom Kai-Hsin Lin, MD Professor of Paediatrics National Taiwan University Hospital Taipei, Taiwan. The Non-Responder.

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Non-Responders to Iron Chelation Therapy

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  1. Non-Responders to Iron Chelation Therapy John B. Porter, MA, MD, FRCP Professor, Department of HaematologyUniversity College LondonLondon, United Kingdom Kai-Hsin Lin, MDProfessor of PaediatricsNational Taiwan University HospitalTaipei, Taiwan

  2. The Non-Responder John B. Porter, MA, MD, FRCP 2

  3. What Does “Non-Responder” Mean? • Balance • Failure to balance transfusional iron input with excretion? • Failure to excrete more iron than transfusional iron input? • Ferritin • Failure to decrease serum ferritin? • Failure to control serum ferritin (or LIC) to target levels? • Myocardial iron (T2*) • Failure to control T2*? • Failure to improve T2* if abnormal?

  4. What Information Do We Need to Predict “Response Rate” with a Chelation Regimen? • The average change of a given measure in a group of patients does NOT tell you the probability of response in an individual • This can only be predicted when the proportion of patients showing the desired effect is shown

  5. What Evidence Do We Have About the Percentage of Patients Who “Respond” to Different Regimens? • With desferrioxamine monotherapy • With deferiprone monotherapy • With combination therapy of the above • With deferasirox monotherapy

  6. “Non-Response” to Desferrioxamine (DFO)

  7. % Responders to DesferrioxamineIron Balance SC 5x/Week % of Patients in Negative Balance Dose mg/kg 25 – <35 35 – <50 ≥50 Low Transfusion <0.3 mg/kg/d 17 76 100 High Transfusion >0.5 mg/kg/d 17 52 89 Medium Transfusion 0.3–0.5 mg/kg/d 43 75 86 Cohen AR, et al. Blood. 2008;111:583-587. 7

  8. Responders to DesferrioxamineAverage Response withSerum Ferritin • At 30 mg/kg • Negative iron balance at transfusion rate of 22.2 mg/d (0.44 mg/kg/d), only if iron stores >4g (LIC >8mg/g wt) • At 40 mg/kg • Negative iron balance at transfusion rate of 26.7 mg/d (0.53 mg/kg/d), if body iron >2g (LIC 4 mg/g dw) • At 50 mg/kg • Negative iron balance at transfusion rate of 31.1 mg/d (0.62 mg/kg/d), if body iron >2g (LIC 4 mg/g dw) Fischer R, et al. Br J Haematol. 2003;121:938–948.

  9. Non-Responders to DesferrioxamineMonotherapyConclusions • 35 mg/kg (dose used in several comparative studies) unlikely to induce negative iron balance unless transfusion rate is low • If poor response (LIC or ferritin), consider increasing dose or frequency (but max 40 kg/mg in children) • As iron load falls, chelation will be less efficient and larger doses will be required to achieve the same response rate (especially <2g, LIC<3.8mg/g dw) • However, this is not practical with DFO because of riskof toxicity

  10. “Non–Responders” to Deferiprone (DFP)

  11. Mean Iron Balance with DeferiproneLinked to Degree of Iron Load Changes in LIC by SQUID over 2 y at 75 mg/kg • Low LIC (<1500 µg/g wet wt) • Negative balance in 24% (13/54) • At higher LICs (>1500 µg/g wet wt) • Negative balance in 50% (12/24) Fischer R, et al. Br J Haematol. 2003;121:938–948.

  12. LIC Responders to Deferiprone Effects of Transfusion Rate and Iron Stores • At low transfusion rate (22.2 mg/d) • At 75mg/kg negative iron balance only if iron stores >2g • Intermediate transfusion rate (26.7 mg/d) • 75 mg/kg insufficient at any level of iron loading • 100 mg/kg negative iron balance if body iron >2g • At high transfusion rate (31.1 mg/d) • 75mg/kg, negative iron balance only if body iron >3g Fischer R, et al. Br J Haematol. 2003;121:938–948.

  13. Does Ferritin Response Rate Parallel the LIC Response with Deferiprone Monotherapy?

  14. Ferritin vs LICPercent Responders to DFP Monotherapy • Population and treatment • Italian poor compliers with DFO • 29 patients at 70 mg/kg • Response by LIC • 6/20 (30%) responders • 70% non-responders • Response by ferritin • 24/29 (83%) responders • 17% non-responders Mazza A, et al. Haematologica. 1998;83:496-501.

  15. Responders to DFPSerum Ferritin vs SQUID LIC stores Changes in ferritin and stores (LIC + spleen ) by SQUID over 2 yrs •Correlation between changes in ferritin and changes in iron stores • BUT whereas 43% (23/54) of patients show decrease in ferritin • Only 24% (13/54) show decrease in iron stores Fischer R, et al. Br J Haematol. 2003;121:938-948.

  16. Continued treatment (n = 26) Mean treatment duration 39.4 months Non-response 61% 8/26 (31%) remain >2500 µg/L Discontinued (n = 25a) Mean treatment duration 18.7 months Non-response 72% 20/25 (80%) remain >2500 µg/L Ferritin Response with Long-Term Deferiprone 58 Patients in total treated with DFP aIncluding 5 deaths. Hoffbrand AV, et al. Blood. 1998;91:295-300.

  17. Ferritin Response Rates to DFP by Starting Ferritins • 151 patients completing 3 years of therapy • Mean serum ferritin level declined from 2579 ng/mL at baseline to 2320 ng/ml at 3 years (P = 0.01) • If initial ferritin levels higher than 2500 ng/mL, the ferritin level declined significantly • If initial values <2500 ng/mL, the mean ferritin level did not change significantly • Overall, 18% passed to a more severe class of ferritin Ceci A, et al. Br J Haematol. 2002;118:330-336.

  18. Long-Term Ferritin Response to DFP What Factors Affect Response Rate? 58 patients on DFP at least 3 years DFP 75 mg/kg/d • At baseline • Group 1 (n = 8): Ferritin <2000 • Group 2 (n = 21): Ferritin 2000-4000 • Group 3 (n = 29): Ferritin >4000 • Overall response at 3 years • 29% patients showed rise in serum ferritin • 52% remained stable • 19% showed decline • Group 1: Significant ferritin increase (7/8 increased) (88% non-responders) • Group 2: Significant ferritin increase (19/21 increased) (90% non- responders) • Group 3: 8/29 decreased (ie, responded); (75% non-responders) Goel H, et al. Hematology. 2008;13:77-82.

  19. Non-Responders to DFP Monotherapy Conclusions • Highly variable reports of response rates - likely due to • Variations in baseline iron stores1,2 • Variations in transfusion rates3 • Variations in metabolism UGT1A64 • Variable follow-up time • More non-responders with LIC than ferritin, why? • Hypothesis • Greater ferritin response than LIC3,5 response because  Ferritin changes reflect macrophage (RE) iron changes  RE iron mobilised more rapidly than hepatocellular iron  Because DFP inactivated by glucuronidation iron binding site in hepatocytes • Practical point • Ferritin changes may not fully reflect iron balance • May explain late rise in ferritin observed by several groups Abbreviation: RE, reticuloendothelial. 1. Ceci A, et al. Br J Haematol. 2002;118:330–336. 2. Goel H, at al. Hematology. 2008;13:77-82. 3. Fischer R, et al. Br J Haematol. 2003;121:938–948. 4. Haverfield, Blood. 2005 106: Abstract 2703. 5. Mazza A, et al. Haematologica. 1998;83:496-501.

  20. Responders to Combined DFP + DFOIron Balance (LIC) DFP Monotherapy Combination Therapy Decrease in 7/8 Non-response 13% Decrease in 5/12 Non-response 58% Baseline 12 months Baseline 12 months With permission from Aydinok Y, et al. Haematologica. 2007;92:1599-1606.

  21. Responders to Combined DFP + DFOSerum Ferritin • Effect of deferiprone (75 mg/kg/d) + DFO (2 g/d twice weekly) on serum ferritin levels • Iron intake reported in each patient (mean 0.31mg/kg/d, n = 11) • 9/11 decreased ferritin • In 2/11 no decrease (iron intake 0.39 and 0.30 mg/kg/d) Mourad FH, et al. Br J Haematol. 2003;121:187-189.

  22. “Non-Responders” to Deferasirox(DFX)

  23. Change in LIC by Deferasirox Dose and Ongoing Transfusion Burden % of Patients in Negative Balance Dose mg/kg 10 20 30 Low Transfusion <0.3 mg/kg/d 29 76 96 High Transfusion >0.5 mg/kg/d 0 47 82 Medium Transfusion 0.3-0.5 mg/kg/d 14 55 83 Cohen AR, et al. Blood. 2008;111:583-587.

  24. Pharmacokinetics of Deferasirox in Patients with Adequate/Inadequate Response • 10 transfused patients with inadequate response (rising ferritin or rising LIC) on >30 mg/kg per day vs 5 control transfusion-dependent patients with adequate response • Compared to controls, patients with inadequate had significantly lower systemic drug exposure (P <.00001) Chirnomas D, et al. Blood. 2009;114:4009-4013.

  25. Pharmacokinetics of Deferasirox in Patients with Adequate/Inadequate Response • No differences observed between adequate and inadequate responders in • Cmax • Volume of distribution/bioavailability (Vd/F) • Elimination half-life (t½) • Conclusion • Bioavailability is the likely discriminant Chirnomas D, et al. Blood. 2009;114:4009-4013.

  26. Relationship of Ferritin to LIC Changes with Deferasirox? • Change in ferritin correlates with change in LIC across diagnoses (TM n = 85, MDS n = 47, DBA n = 30, rare anaemias n = 22) • Intersect of correlation suggests that when no change in ferritin, there is a fall in LIC of about 4-7mg/g d wt • So when body iron falls, there may be a decrease in LIC (negative iron balance) without a significant change in ferritin • Ferritin may also increase in the absence of a positive trend in LIC Porter J, et al. EJH. 2008;80:168-176.

  27. Liver Tissue Iron Scores Following Therapy with Deferasirox • Method • Tissue Iron Score (TIS) on liver iron biopsies • Change in score after 1 year of chelation • Change in distribution of iron after 1 year of chelation • Deferasirox n = 224, Desferrioxamine n = 230 • Results • Fall in TIS correlated with fall in LIC • Greater removal from hepatocellular than • macrophage compartment (cf DFO) Porter J, et al. 10th International Conference on Thalassaemia and Haemoglobinopathies, January 7-10, 2006.

  28. Hepatocytic—Total Liver Iron Ratio Reflects Tissue Distribution of Iron LIC 8.0 mg/Fe g dw Total, TIS 24 Hetatocyte, HIS 24 Sinusoidal, SIS 0 Portal, PIS 0 Hepatocytic:total liver iron ratio 1 LIC 9.1 mg/Fe g dw TIS 19 HIS 3 SIS 10 PIS 6 Hepatocytic:total liver iron ratio 0.16 Prussian blue stain Abbreviations: HIS, hepatocytic iron score; PIS, portal iron score; SIS, sinusoidal iron score; total tissue iron score. Deugnier YM, et al. Gastroenterology.1992;102:2050–2059. Turlin B, Deugnier Y. J Clin Pathol. 1997;50:971.

  29. Deferasirox But Not DesferrioxamineShowed a Tendency to Reduce Hepatocytic:Total Liver Iron Ratio 0.4 0.2 0 -0.2 Mean ± 95% CI Change in Hepatocytic: Total Liver Iron Ratio n= 6 27 86 10 9 48 83 191 <25 25–<35 35–<50 ≥50 5 10 20 30 DFO (mg/kg 5 days/week) DFX (mg/kg/day) Porter J, et al. 10th International Conference on Thalassaemia and Haemoglobinopathies, January 7-10, 2006.

  30. Serum FerritinResponse to Different Chelators Hypothesis • With DFO • Iron removal is approximately equal in hepatocytes and RE cells • So changes in ferritin reflect changes in LIC and RE iron • With DFP • Iron removal is preferential in RE cells compared with hepatocytes • Explains why may see response with ferritin but not with LIC • Explains late secondary resurgence of ferritin • With DFX • Iron is removed preferentially from hepatocytes compared with RE cells • Body iron (LIC) may fall even though ferritin may lag

  31. Possible Reasons for “Non-Response” • The measure used may not reflect iron balance in that individual • The patient may have a high transfusion requirement • The dose/frequency may be insufficient • The patient may not be taking the treatment regularly • The PK and metabolism of the chelator may not be favorable (very limited data)

  32. Non-RespondersPracticalQuestions to Ask • How are you assessing “non-response”? Is this the correct measure? • How long have you been assessing response? Is it long enough? • Is the patient on a high, low, or average transfusion schedule? • Is the patient taking the prescribed dose and frequency of chelator?

  33. The Non-ResponderPractical Things to Do • Quantitate current transfusional iron loading rate • Consider additional measures of “response” (e.g., changes in LIC) • Carefully interview the patient about adherence patterns • Consider whether administration of drug is optimal (e.g., timing of oral dose relative to food, number of hours of DFO infusion) • Consider whether the dose can be safely increased • Consider alternative chelation

  34. Management of Non-Responders to Iron Chelation Therapy Kai-Hsin Lin, MD 34

  35. Contributing Factors in Inadequate-Responders Poor drug compliance Inadequate drug dose due to side effects Poor drug efficacy Comorbid diseases confounding the assessment of iron overload 35

  36. Case 1: Ms H 36

  37. Ms. H—Treatment History 18-year-old female diagnosed with thalassaemia major at age 1 year Received regular transfusions 4 units washed RBC every 2 weeks (250 cc whole blood) Has been receiving iron chelation therapy with desferrioxamine since 3 years old Poor desferrioxamine compliance (4-5 nights per week) due to inconvenience and discomfort No hepatitis B or C or diabetes mellitus No puberty 37

  38. Initiation of Deferasirox Ms. H started take deferasirox as iron chelation therapy at 20 mg/kg/day in Feb 2007 Baseline assessments Serum ferritin: 5037 ng/mL AST: 19 U/L, ALT: 21 U/L Creatinine: 0.7 mg/dL 38

  39. Deferasirox Therapy Patient found once-daily oral administration of deferasirox to be more convenient than SC or IV desferrioxamine Improved drug compliance Improved iron chelation and reduced total iron burden 39

  40. Deferasirox Treatment CourseSerum Ferritin (Months 1–36) Deferasirox therapy (mg/kg/day) 20 30 35 40 35 Start 40 Courtesy of Dr. Lin

  41. Poor Drug Compliance Forgetting to take the drug Not understanding or misinterpreting instructions Experiencing side effects (the treatment may be perceived as worse than the disorder) Disliking the drug taste or smell Finding restrictions on treatment inconvenient Not caring about getting better 41

  42. Poor Injection Compliance Two main reasons are Lack of disease knowledge Incorrect injection method Lin SS. Presented at 12th TIF, January 7-10, 2006. 42

  43. Serum Ferritin Level vs Injection Days (Before & After Disease Education) 43 Lin SS. Presented at: 12th TIF, January 7-10,2006. Courtesy of Syi Su Lin, MD

  44. Poor Drug Compliance: Management *Medication diary *Family support group *Patient peer support group *Disease education *Treatment guideline 44 Courtesy of Kai-Hsin Lin, MD

  45. Case 2: ML 45

  46. ML: Treatment History 15-year-old male diagnosed with thalassaemia major at age 8 months Received regular transfusions 2 units washed RBC every 2 weeks (250 cc whole blood) Started iron chelation therapy with desferrioxamine at age 1 year No hepatitic B or C or diabetes mellitus 46

  47. Initiation of Deferasirox Began iron chelation therapy with deferasirox at 20 mg/kg/day in March 2006 Baseline assessments Serum ferritin: 3693 ng/mL AST: 24 U/L, ALT: 16 U/L Creatinine: 0.5 mg/dL Good compliance but had mild GI upset when taking deferasirox 47

  48. Reduced Bioavailability 40 mg/kg/day once-daily deferasirox only maintained total iron burden and led to GI upset in this patient Bioavailability of deferasirox in this patient may be reduced, as individuals with inadequate response to deferasirox have been found to have significantly lower systemic drug exposure compared with those having an adequate response1 Reduced drug bioavailability in this patient may be the result of patient variability in Oral absorption Distribution Metabolism Excretion 1. Chirnomas D, et al. Blood. 2009;114:4009-4013. 48

  49. Managing Inadequate Bioavailability In this patient, twice-daily deferasirox at the same total dose increased bioavailability, relieved GI upset, and further reduced total iron burden 49

  50. Deferasirox Treatment CourseSerum Ferritin(Months 1 - 48) Deferasirox therapy (mg/kg/day) 40 40 BID 30 20 Start 50 Courtesy of Kai-Hsin Lin, MD

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