1st International Working Group on Thalassemia - Final Effectiveness and saf… · THALASSEMIA...

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

IRAN*

*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. 2015 Jul 7;37:e2015031. doi: 10.4178/epih/e2015031.

TAIWAN **

**Wu HP, Lin CL, Chang Y, et al. Survival and complication rates in patients with thalassemia major in Taiwan. Pediatr Blood Cancer. 2017 Jan;64(1):135-138. doi: 10.1002/pbc.26181.

PAKISTAN *** ITALY ****

***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 major-intermedia dichotomy? Br J Haematol. 2017 Jan;176(1):124-130. doi: 10.1111/bjh.14381.

THALASSEMIA SYNDROMES SURVIVAL PROBABILITY IS IMPROVING WORLDWIDE

EFFECTIVENESS AND SAFETY OF 10 DIFFERENT REGIMENS FOR

CONTROLLING IRON OVERLOADING IN THALASSEMIA 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. 2017 Apr 25. doi: 10.1111/bjh.14712

• 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.

COMPARISON OF CHELATOR PROPERTIES IN PRECLINICAL STUDIES AND THEIR CLINICAL STAGE OF DEVELOPMENT


CURRENT IRON CHELATION REGIMENS FOR THE TREATMENT OF IRON OVERLOAD IN THALASSAEMIA MAJOR


DEFERIPRONE (DFP) AND DEFEROXAMINE (DFO) COMBINEDCHELATION TREATMENT: PUBLISHED SCHEDULES OF ADMINISTRATION


LEVELS OF EVIDENCE FOR INDIVIDUAL CLASS ASSIGNMENTS ACCORDING TOTHE AMERICAN COLLEGE OF CARDIOLOGY AND THE AMERICAN HEART

ASSOCIATION (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.

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)

EVIDENCE FOR THE EFFECTIVENESS OF EACH CHELATION TREATMENT


The evidence for the effectiveness of each chelation treatment has been weighted onthe basis of levels of evidence, according to the American College of Cardiology and theAmericanHeart Association (Ritchie et al, 1995; Klocke et al, 2003) and on the absolutenumberof patients enrolled. Evidence levels A, B and C are shown by green, yellow and redcolour.The absolute number of patients enrolled was used for categorizing three levels onthebasis of median values: Low <1st quartile (<25% distribution), Medium from 1st to 3rdquartile (>25 to 75% distribution), High >3rd quartile (>75% distribution). LIC, liver ironconcentration; DFO, deferoxamine; DFP, deferiprone; DFX, deferasirox.

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 20–40 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 20–40 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 (http://www.ema.eu

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.

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.

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.

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

SERUM FERRITIN

HEART T2*

HEART DAMAGE

SURVIVAL

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).

WELCOME TO PALERMO

1st International Working Group on Thalassemia - Final Effectiveness and saf… · THALASSEMIA...

Documents

Transcript of 1st International Working Group on Thalassemia - Final Effectiveness and saf… · THALASSEMIA...