1st International Working Group on Thalassemia:

Transcription

1 1st International Working Group on Thalassemia: Effectiveness and safety of 10 different regimens for controlling iron overloading in Thalassemia Major CAMPUS OF HEMATOLOGY "Franco e Piera Cutino" A.O.R. "Villa Sofia - V. Cervello" Palermo (Italy) Prof. Aurelio Maggio

2 THALASSEMIA SYNDROMES SURVIVAL PROBABILITY IS IMPROVING WORLDWIDE IRAN* TAIWAN ** PAKISTAN *** ITALY **** *Rajaeefard A, Hajipour M, Tabatabaee HR, Hassanzadeh J, Rezaeian S, Moradi Z, Sharafi M, Shafiee M, Semati A, Safaei S, Soltani M. Analysis of survival data in thalassemia patients in Shiraz, Iran. Epidemiol Health Jul 7;37:e doi: /epih/e **Wu HP, Lin CL, Chang Y, et al. Survival and complication rates in patients with thalassemia major in Taiwan. Pediatr Blood Cancer Jan;64(1): doi: /pbc ***For kind concession of Dr. Saqib Hussain Ansari, National Institute of Blood Disease & Bone Marrow Transplantation, Karachi (Pakistan): 1996: data from HBB Karachi, 2006: data from BTIHS, Karachi ****Vitrano A, Calvaruso G, Lai E, et al. The era of comparable life expectancy between thalassaemia major and intermedia: Is it time to revisit the majorintermedia dichotomy? Br J Haematol Jan;176(1): doi: /bjh

3 EFFECTIVENESS AND SAFETY OF 10 DIFFERENT REGIMENS FOR CONTROLLING IRON OVERLOADING IN THALASSEMIA MAJOR This review outlines the effectiveness and safety of 10 different regimens for controlling iron overloading in thalassaemia major TM For each treatment, the strength of the evidence was documented according to the guidelines of the American College of Cardiology and the American Heart Association Serum ferritin (SF), liver iron concentration (LIC), heart T2* signal, heart damage and survival were used to assess effectiveness. Di Maggio R, Maggio A. The new era of chelation treatments: effectiveness and safety of 10 different regimens for controlling iron overloading in thalassaemia major. Br J Haematol Apr 25. doi: /bjh.14712

4 COMPARISON OF CHELATOR PROPERTIES IN PRECLINICAL STUDIES AND THEIR CLINICAL STAGE OF DEVELOPMENT Di Maggio R, Maggio A. The new era of chelation treatments: effectiveness and safety of 10 different regimens for controlling iron overloading in thalassaemia major. Br J Haematol Apr 25. doi: /bjh.14712

5 CURRENT IRON CHELATION REGIMENS FOR THE TREATMENT OF IRON OVERLOAD IN THALASSAEMIA MAJOR Di Maggio R, Maggio A. The new era of chelation treatments: effectiveness and safety of 10 different regimens for controlling iron overloading in thalassaemia major. Br J Haematol Apr 25. doi: /bjh.14712

6 DEFERIPRONE (DFP) AND DEFEROXAMINE (DFO) COMBINED CHELATION TREATMENT: PUBLISHED SCHEDULES OF ADMINISTRATION Di Maggio R, Maggio A. The new era of chelation treatments: effectiveness and safety of 10 different regimens for controlling iron overloading in thalassaemia major. Br J Haematol Apr 25. doi: /bjh.14712

7 LEVELS OF EVIDENCE FOR INDIVIDUAL CLASS ASSIGNMENTS ACCORDING TO THE AMERICAN COLLEGE OF CARDIOLOGY AND THE AMERICAN HEART ASSOCIATION (Ritchie et al, 1995; Klocke et al, 2003). Di Maggio R, Maggio A. The new era of chelation treatments: effectiveness and safety of 10 different regimens for controlling iron overloading in thalassaemia major. Br J Haematol Apr 25. doi: /bjh.14712

8 LEVELS OF EVIDENCE FOR EFFECTIVENESS ACCORDING TO DIFFERENT OUTCOMES FOR THE 10 DIFFERENT IRON CHELATION REGIMENS IN THALASSAEMIA MAJOR. THE LEVELS OEVIDENCEWERE BASED ON AMERICAN COLLEGEOF CARDIOLOGY AND THE AMERICAN HEART ASSOCIATION GUIDELINES (Ritchie et al, 1995; Klocke et al, 2003) NA, not available; ( ), liver iron concentration (LIC) determined by T2* or Liver Biopsy; ( ), heart damage if ejection fraction <50% or proven cardiac disease; RCT, randomised clinical trial; NRCT,none randomised clinical trial; CoE, consensus opinion of expert; Pts, patients (this number includes subjects in the experimental and control arms); LoE, level of evidence according to Ritchie et al(1995) and Klocke et al (2003); DFO, deferoxamine; DFP, deferiprone; DFX, deferasirox.*maggio et al (2009a), although in this study 275 patients were randomised, only 54 patients underwent T2* heart signal determination.

9 EVIDENCE FOR THE EFFECTIVENESS OF EACH CHELATION TREATMENT The evidence for the effectiveness of each chelation treatment has been weighted on the basis of levels of evidence, according to the American College of Cardiology and the AmericanHeart Association (Ritchie et al, 1995; Klocke et al, 2003) and on the absolute numberof patients enrolled. Evidence levels A, B and C are shown by green, yellow and red colour.the absolute number of patients enrolled was used for categorizing three levels on thebasis of median values: Low <1st quartile (<25% distribution), Medium from 1st to 3rd quartile (>25 to 75% distribution), High >3 rd quartile (>75% distribution). LIC, liver iron concentration; DFO, deferoxamine; DFP, deferiprone; DFX, deferasirox. Di Maggio R, Maggio A. The new era of chelation treatments: effectiveness and safety of 10 different regimens for controlling iron overloading in thalassaemia major. Br J Haematol Apr 25. doi: /bjh.14712

10 INITIATING CHELATION TREATMENT SF is >1000 ng/l or LIC >7 mg Fe/g dw or > 1000g RBC transfused or Transferrin Saturation >90% with less than 1000 g of RBCs transfused (Danjou et al., 2014) ; DFO at a dose of mg/kg/day 5 7 times per week as the recommended chelator for first-line treatment of children between the ages of 2 and 6 years in Europe, the UK and Canada(Saliba et al, 2015) ; DFX at mg/kg/day may be used as a first-line treatment in the US and Australia; The evaluation of DFP in the paediatric population is ongoing thanks to the DEEP European Grant Project ( ropa.eu/ema/index) chaired by Adriana Ceci. Bellanti et al., 2016 suggest that the same dosages of DFP that are used in adults may be used in these cohorts.

11 PREGNANCY DFO: caution during pregnancy (Bosque et al, 1995). The majority of the women who are treated with this drug during second and third trimesters have normal pregnancy outcomes (McElhatton et al, 1991).The risk of spontaneous abortion is low, but it cannot be excluded (McElhatton et al, 1991). FDA Risk Category: C. DFP: treatment has not been adequately studied (Shilalukey et al, 1997), and no carcinogenetic studies have been conducted in animals. FDA Risk Category: D. DFX: animal studies have revealed evidence of embryo fetotoxicity. These studies showed decreased offspring viability and increased renal anomalies (Anastasi et al, 2011; Vini et al, 2011; Diamantidis et al, 2016). FDA Risk Category: C.

12 COMPLIANCE The survival of TM patients has improved to levels that are comparable to thalassaemia intermedia (TI) patients (Vitrano et al, 2017).However, heart damage still remains the major cause of death (Vitrano et al, 2017), and this scenario can only be explained by compliance failure. This may be explained because humans often do not act consistently or obey the laws of rational choice theory (Gowdy, 2008). Therefore, to be effective, each intervention aimed at changing behaviour must take into account the emotional sphere of the patient.

13 EFFECTIVENESS AND SAFETY OF 10 DIFFERENT REGIMENS FOR CONTROLLING IRON OVERLOADING IN THALASSEMIA MAJOR CONCLUSIONS I Five chelation regimens are able to control SF levels with Level A Evidence Five chelation regimens are able to control LIC levels with Level A Evidence Three chelation regimens are able to control heart iron levels, as determined by T2* signals with Level A Evidence Two chelation regimens are able to improve/reverse heart damage with Level B Evidence Four chelation regimens increased of survival with Level B Evidence Di Maggio R, Maggio A. The new era of chelation treatments: effectiveness and safety of 10 different regimens for controlling iron overloading in thalassaemia major. Br J Haematol Apr 25. doi: /bjh.14712

14 SERUM FERRITIN

15 HEART T2*

16 HEART DAMAGE

17 SURVIVAL

18 LIC

19 Effectiveness and safety of 10 different regimens for controlling iron overloading in Thalassemia Major CONCLUSIONS II Chelation therapy has advanced since 1962 when DFO was first shown to be effective. By 2006, 10 different chelation treatments had been identified, which initiated a new era of chelation In terms of effectiveness and safety, these advances are very impressive and, combined with the improved safety of red cell transfusions, may explay how today survival in TM is now similar to that in TI (Vitrano et al, 2017) These findings, if confirmed on larger setting of patients, merit consideration for revisiting our approach to the classification of the thalassemia syndromes (TS). Di Maggio R, Maggio A. The new era of chelation treatments: effectiveness and safety of 10 different regimens for controlling iron overloading in thalassaemia major. Br J Haematol Apr 25. doi: /bjh.14712

20 WELCOME TO PALERMO