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Current Medical Research and Opinion

ISSN: 0300-7995 (Print) 1473-4877 (Online) Journal homepage: http://www.tandfonline.com/loi/icmo20

Complications pattern and burden of the diseasein patients affected by beta-thalassaemia major

Fedele Bonifazi, Rosa Conte, Paola Baiardi, Donato Bonifazi, MariagraziaFelisi, Paola Giordano, Viviana Giannuzzi, Angela Iacono, Rosa Padula,Alessia Pepe, Maria Caterina Putti, Lucia Ruggieri, Giovanni Carlo DelVecchio, Aldo Filosa, Aurelio Maggio, Adriana Ceci & on behalf of the HTA-THAL Multiregional Registry, funded by the Italian Ministry of Health andFondazione Giambrone

To cite this article: Fedele Bonifazi, Rosa Conte, Paola Baiardi, Donato Bonifazi, MariagraziaFelisi, Paola Giordano, Viviana Giannuzzi, Angela Iacono, Rosa Padula, Alessia Pepe, MariaCaterina Putti, Lucia Ruggieri, Giovanni Carlo Del Vecchio, Aldo Filosa, Aurelio Maggio, AdrianaCeci & on behalf of the HTA-THAL Multiregional Registry, funded by the Italian Ministry ofHealth and Fondazione Giambrone (2017): Complications pattern and burden of the diseasein patients affected by beta-thalassaemia major, Current Medical Research and Opinion, DOI:10.1080/03007995.2017.1326890

To link to this article: http://dx.doi.org/10.1080/03007995.2017.1326890

View supplementary material Accepted author version posted online: 04May 2017.

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Complications pattern and burden of the disease in patients affected by beta-thalassaemia

major

Running Heads: Complications and burden of the disease in TM

Authors

Fedele Bonifazi1, Rosa Conte1, Paola Baiardi2, Donato Bonifazi3, Mariagrazia Felisi3, Paola

Giordano4, Viviana Giannuzzi1, Angela Iacono5, Rosa Padula3, Alessia Pepe6, Maria Caterina

Putti7, Lucia Ruggieri1, Giovanni Carlo Del Vecchio8, Aldo Filosa9, Aurelio Maggio10 and Adriana

Ceci1, on behalf of the HTA-THAL Multiregional Registry, funded by the Italian Ministry of

Health and Fondazione Giambrone.

Corresponding author: Fedele Bonifazi, Via Abate Eustasio 30, 70010 Valenzano (BA), Italy. Phone

+39 0802021169. E-mail address: fb@benzifoundation.org

Authors’ affiliations 1Fondazione per la Ricerca Farmacologica Gianni Benzi Onlus, Valenzano (BA), Italy

2Fondazione Salvatore Maugeri, Pavia, Italy

3Consorzio per Valutazioni Biologiche e Farmacologiche, Via L. Porta 14 27100 Pavia, Italy

4Dipartimento di Biomedicina e oncologia umana Sezione pediatrica, Università 'A. Moro 'di Bari, Italy

5Fondazione ''Leonardo Giambrone'' per la Guarigione dalla Thalassemia, Castelvolturno (CE), Italy

6Fondazione G. Monasterio C.N.R.- Regione Toscana, Pisa, Italy

7Azienda Ospedaliera Padova Centro Leucemie Oncoematologia Pediatrica, Padova, Italy

8Azienda Ospedaliera Universitaria Consorziale Policlinico di Bari, Unità Operativa di Pediatria Generale e

Specialistica "Federico Vecchio" Bari, Italy

9Azienda Ospedaliera "A. Cardarelli" UOS Talassemia Pediatrica e Emoglobinopatie Pediatriche, Napoli, Italy

10Azienda Ospedaliera Ospedali Riuniti Villa Sofia Cervello, Palermo, Italy

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ABSTRACT

Objectives: Despite the correct application of blood transfusions and chelation treatments,

beta-thalassaemia patients have many complications. Systematic population analyses on types

and frequency of these complications are very few. The aim of this study is to characterize the

complications,their risk factors and their clinical and economic impact.

Methods: Complications at baseline and events occurred during 1 observational year were

analysed in 272 patients aged >12 years. Risk factors were analysed through chi-squared and

unpaired t-tests. Logistic regression was applied to perform the risk factors multivariate

analysis.

Results: 82.3% of patients were affected by 1 to 6 complications for a total of 554. Cardiac

complications were less represented than expected. Musculoskeletal diseases have been the

most represented complications followed by hepatic, sexual and endocrine diseases.

Splenectomised patients, born before 1970 and aged >40 years, starting iron chelation therapy

when aged >4 years or after receiving more than 20 blood transfusions presented a significantly

higher number of complications.

885 adverse events requiring 3425 additional medical services occurred in 1 year. Of these,

34.9% were related to treatments and 65.1% to other causes. Events number, additional

medical intervention and costs increase progressively in patients that are affected by 1

complication or more with respect to patients with no complications.

Conclusions: The pattern of complications is changing according to the birth cohort and

differentiates the older from the younger patients. The burden of the disease and its costs

increase after the onset of the first complication, therefore prevention of complications is

fundamental in these patients.

Key words. Thalassaemia, Complications, Adverse Reactions, Risk Factors, Cost of the Disease.

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INTRODUCTION

In the last decades for the large majority of patients affected by beta-thalassaemia major (BTM)

the prognosis has significantly improved thanks to the introduction of regular transfusion

regimens associated to iron chelation treatments (ICT), the increase of the availability of

diagnostic methods to monitor iron overload, the dissemination of evidence based guidelines

on supportive therapy, splenectomy, antibiotic prophylaxis, patients management and

treatment1,2.

However, despite the correct application of these diagnostic and therapeutic interventions,

thalassemic patients may experience secondary diseases or complications, which have taken a

new and important role in the course of this disease in recent years3,4. Common complications

related to blood trasfusions are allergic reactions, febrile haemolytic and delayed reactions,

transfusion-related acute lung injury and transfusion-transmitted infections such as hepatitis B

and C (HBV and HCV), Human Immunodeficiency Virus (HIV), new viruses5. Among these, HCV

infection is assuming a relevant role. In fact, even if the incidence of new infections was

significantly reduced after the discovery of the virus C1, HCV infections remain very common in

the thalassaemia population6 leading to an increased haepatocarcinoma rate7,8,9. The most

important complications related to iron overload are liver10, cardiac and endocrine diseases11.

Noteworthy, cardiac complications still represent the first cause of death in these patients12. In

fact, cardiac complications are reported to be the cause of the deaths in 71% of the patients

with beta-thalassaemia major13. In addition, splenectomy, often used in the past, demonstrated

to increase complications such as bleeding, atelectasis and subphrenic abscess, thrombosis and

uncontrollable sepsis.

Patients can be also affected by Adverse Drug Reactions (ADRs) that differ by type of drug. For

example local skin reactions, severe allergy, hearing loss, visual impairment, and skeletal

damage are frequently reported after Deferoxamine (DFO) treatment;

neutropenia/agranulocytosis are the most feared in Deferiprone (DFP) and increase in serum

creatinine, gastrointestinal disorders, hypertransaminasemia and rarely renal impairment and

liver failure are reported for Deferasirox (DFX).

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Moreover, with increasing patients’ age, new life-threatening complications are being

recognized, including severe Deep Venous Thrombosis (DVP), pulmonary hypertension,

pseudoxanthoma elasticum9,14,15,16.

Types and frequency of complications in the thalassaemia population have been described in

many high quality publications. However systematic population analyses and a standardized

methodology to describe patients complications and their impact on the every day life, are very

few. To the aim of this study we performed an observational study on a significant patients sub-

population with beta-thalassaemia that is part of the Italian Multiregional Thalassemia Registry

(HTA-THAL) collecting almost 2.000 patients in Italy17 to characterize the complications affecting

adolescent and adults patients with beta-thalassaemia major globally and in relation with

identified risk’s factors increasing complications. In addition the 1 year occurred Adverse

Events (AEs) including Blood Acute Transfusion Reactions (ATRs) and ADRs were observed in

order to calculate the burden of the disease both in term of number of additional medical

interventions needed in patients with complications and of their costs.

For the aim of the study, complications were defined as “any well defined medical condition

not directly related to the thalassaemia status and classified according to international

guidelines”2,18.

AEs and ADRs were defined according to Directive 2001/83/EC on the Community code relating to

medicinal products for human use19 as 'any untoward medical occurrence in a patient or clinical

trial subject administered a medical product and which does not necessarily have a causal

relationship with this treatment' and any 'response to a medicinal product which is noxious

and unintended and which occurs at doses normally used in human’ respectively.

Definitions

Complications were defined as any well defined medical condition not directly related to the

thalassaemia status and classified according to international guideline2,18 and literature.

Adverse events (AEs) were defined as 'any untoward medical occurrence in a patient or clinical

trial subject administered a medical product and which does not necessarily have a causal

relationship with this treatment' (Directive 2001/20/EC)21.

Adverse Drug Reactions (ADRs) were any 'response to a medicinal product which is noxious and

unintended and which occurs at doses normally used in human ' (Directive 2001/83/EC)19.

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Blood Transfusion Reactions (ATRs) were defined according to national (CNS-ISS) and

international Guidelines

METHODS

Study Design

Prospective multicentre observational study, consisting of 272 patients from 13 clinical centres

observed for a period of 12 month (first visit April 2009, last visit April 2011).

Population

272 confirmed BTM patients, aged >12 years and balanced according to gender and 5 ICT

regimens (DFO, DFP, DFX, DFO-DFP sequential/combined) that fully understood and signed

written informed consent (in the case of minors, consent provided by parents or guardians)

were included. Patients were excluded in case of not confirmed BTM, prior Bone Marrow

Trasplantation or other experimental studies.

Data Collection

The following information was collected at recruitment:

demography, age at beginning of transfusion and ICT, interval between the first

transfusion and the first ICT, ICT regimen); clinical status and complications,

splenectomy, age of splenectomy, medium in the life HB land ferritin level.

On a quarterly basis the following information have been collected: new AEs, medical

interventions provided by type (drugs, visits, laboratory and instrumental examinations given as

inpatients and outpatients care).

Cost assessment

Costs’ sources considered by the analysis were:

1) transfusion sessions, including medical visits, laboratory and instrumental tests,

ICTs and other drug’s prescription, iron overload monitoring according to protocols of

care;

2) costs for the management of new AEs, including visits, imaging and lab tests,

pharmacological treatments.

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All health resources were assessed according to market prices and tariffs that were operative

during the study period and referred to Sicily current tariffs, as applicable also in Apulia,

Basilicata and Campania.

Data analyses

Descriptive statistics of all measured variables, including frequencies and percentages of

qualitative variables, means and standard deviations of quantitative variables, were measured.

Univariate analyses were performed by means of chi-square or unpaired t tests according to

the qualitative or quantitative nature of the variable, respectively. A logistic regression model

was applied to assess the association between potential risk factors and occurrence of

complications.Results have been reported as both raw and adjusted odds ratios and 95%

Confidence Intervals Statistical significance was set at p<05.

Statistical analyses were performed by SPSS Statistical Software.

Ethics

In compliance with the AIFA Guidelines on observational studies20, the Legislative Decree, D.L.

196/2003 for the protection and treatment of personal data the study received approval by

each competent Ethics Committee and a Consent Form was signed by each participant. For

minors, the informed consent was provided by parents or legal representative.

Electronic database governance and maintenance

An electronic system was developed using a three tier architecture (Apache, PHP, and MySQL).

The study’ forms were accessible on internet to the investigators through an user-friendly

interface. Access for data entry was controlled by user authentication system. Standardised

security measures were adopted such as password strength and auto logoff after 20 minutes of

inactivity.

Each centre was enabled to access only its own patient’s data.

Patients’ data were anonymised: name and surname were replaced by a numeric code

automatically generated by the system. Database server was accessible only through the

application server and no other direct access to database was allowed. Periodic database

backup was automatically performed.

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RESULTS

Patients characteristics at onset

The main characteristics of enrolled patients were reported in Table 1 (see supplemental data).

Briefly:

272 patients (145 females, 53.3%) aged 12 to 50 years with an average of 30.6 ± 7.7 years

were enrolled. Paediatric patients (aged 12-17 years) were 6.6% of the whole population;

All patients received diagnosis between 1 months to 6 years. Most of the subjects (n=187,

68.7%) were diagnosed within their first year of life, while 21.3% were reported as

diagnosed when 1 to 2 years old. 9.9% was reported as diagnosed when > 2 years old; 9

patients have reported as receiving diagnosis when > 3 years;

The age at the beginning of transfusions was variable from 2 months to 6 years: 228

patients (83.8%) started the transfusional treatments early in childhood (< 2 years) and 146

(53.7%) of these under one year of age. 34 patients (16.2%) started between 2 and 3 years

and 15 of these after 3 years.

The majority of patients were transfused at a < 20 days interval (n=183, 67.3%), 84 patients

(30.9%) were transfused at a 20 but < 30 days interval and 4 patients (1.5%) were

transfused at a > 30 days interval;

At the time they started ICT, 70 patients were aged less than 2 years, 145 patients (53.3%)

were older than 3 years and 57 patients (20.9%) were older than 6 year;

The interval between the starting of transfusions and the starting of ICT was lower than 12

months for 70 patients (25.7%) whilst it was higher then 18 months for 179 patients

(65.8%). As shown in Figure 1, the number of transfusions before starting ICT was less than

10 in 33 patients and >10 <20 in 77 patients while in the other cases patients received a

higher nymber up to 100 and more;

The average ferritin level during the whole patients life as reported to the registry was

ranging from 100 ng/ml to 8000 ng/ml with half of patients having ferritin level equal to

1000-2000 ng/ml, 13 patients (4.8%) having ferritin level > 4.000 ng/ml, and 22 < 500;

The average level of haemoglobin (HB) during the whole patients life as reported to the

registry was 9-9.8 mg%ml in 195 patients (71.7%), 10-10.5 mg%ml in 73 patients (26.8%)

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and 8-8.7 mg%ml in 4 (2.9%).

Patients characteristics by birth cohort

Some patients characteristics significantly modify by birth cohort. In particular modifications

relate to number of trasfusions before starting ICT and splenectomy. As reported in Figure 1

patients received a high number of trasfusions (more than 20 or 40) before starting ICT were

all, but 3, born before 1980; similarly of the 139 patients (51.1%) that underwent splenectomy

all were born before 1958 and after the year 1995 no further patients were splenectomised.

Complications

A total of 224 patients out of 272 (82.3%) were affected by at least one complication, for a total

of 554 complications at baseline.

In particular, 126 patients had ≤ 2 complications, 90 patients had 3-6 complications and 8

patients had 6 complications, while 48 patients (17.7%) had no complications.

As shown in Figure 2, musculoskeletal diseases (osteoporosis, osteopenia, lordosis, etc) are the

mostly represented complication (n=134 pts, 59.8%), followed by hepatic diseases (n=113

patients, 50.4%), sexual development diseases (n=88 pts, 39.3%) and endocrine diseases (n=56

patients, 25%). Cardiovascular complications were present in 46 patients (20.5%). Blood system

diseases (secondary thrombocytosis) were reported in 11 splenectomised patients.

Details on type of complications are shown in Table 2 (see supplemental data). The most

interesting findings in this table are: a) osteoporosis and osteopaenia affect almost half of

patients, b) a very high number of patients resulted affected by HCV infection (data on status of

the disease and virus genotype were not reported in the Registry); c) All patients with HCV

infection received almost 1 blood transfusion before 1990; d) sexual impairment affected men

more than women (hypogonadism versus amenorrhea p < 0.001); e) cardiomyopathy is

reported less frequently than expected. The global number of cardiac diseases remains relevant

if cardiac arithmiae and atrial fibrillation are also taken into account (13.2%); f) among the

endocrine diseases, hypothiroidism is reported in 40 patients, while growth retardation and/or

growth hormone deficit is reported only in few cases.

Univariate analysis applied to different variables (Table 3) demonstrated that increasing age (p

< 0,001), age > 4 years at starting of ICT, splenectomy (p < 0,001) and a high number of blood

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transfusions before initiation of ICT (p < 0,002) increase significantly the risk to have at least 1

complication. Sex, ferritin and Hb level during the whole life, demonstrated limited or not

impact on complications.

Table 3. Complications by risk factors (univariate analysis)

ORraw 95%CI ORAdjusted 95%CI

Lower Upper Lower Upper

Sex* (ref. M)

Female

1.30

0.69

2.43

-

Age (ref 12-17 yrs)

18-25 yrs 26-40 yrs > 40 yrs

2.34 11.94 57.36

0.78 4.02 10.54

7.11 35.52 312.2

2.22 10.40 34.01

0.69 3.35 6.01

7.10 32.28 193.5

Age at stating ICT* (ref 2-3 yrs)

≥ 4 yrs

3.11

1.54

6.28

-

No. transfusions* (ref <10)

10-20 20-40 40-100 > 100

0.81 0.86 2.80 11.82

0.28 0.36 1.01 1.44

2.29 2.08 7.74 97.21

-

Splenectomy (ref NO)

Yes

4.05

2.00

8.21

2.52

1.14

5.57

In addition the logistic regression analysis followed by a stepwise selection of variables

demonstrated that the risk of developing complications increases significantlly by age and is

almost 2.5 times higher in splenectomised patients than non-splenectomised patients.

Patients follow-up during 1 observation year

During the observation year 234 out 272 patients reported a total of 885 AEs often requiring

medical care. These included:

- 35 AEs in 25 patients related to a (BTRs) (more in details they were: febrile non-hemolytic

reaction (20 cases), Acute Hemolytic Transfusion Reaction (AHTR) (5 patients), urticarial

transfusion reaction (10 cases).

- 129 reported ADRs potentially related to the ICT therapy regimens (Table 4, see supplemental

data). The ICT regimen with the highest number of ADRs is represented by the DFX therapy with

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41 ADRs, while the DFP alone had the lowest number with only 10 ADRs. Globally these events

required hospitalization for a total of 47 days. Details are described in Table 4.

Three ADRs were reported with reference to HCV ribavirine or interferon treatments.

The remaining AEs were associated to different intercurrent medical conditions both related or

not related to an existing complication. More in detail we noted that the prevalent symptom was

pain mainly related to musculoskeletal system (it was present in 245 reported cases), followed by

gastrointestinal disturbances (145 reported cases) and other diagnosis included intercurrent viral

or bacterial infections, gastroenteric aspecific disturbances, traumatic episodes, etc. Eight

patients received medical interventions following a suspected or confirmed dyagnosis of tumors:

1 benign lipoma, 3 lymphoproliferative disease, 1 myeloproliferative disease, 1 hepatic nodule

and 2 breast nodules.

Three cases of Deep Venous Thrombosis were also reported.

Costs of the 1 year treatment

The cost of current standard therapy and the additional costs due to the observed AEs occurred

duting 1 year were assessed.Routine therapy

During the observation year, patients underwent a mean of 20.2 transfusional sessions (±4.9

SD); which corresponds to a transfusion session every 2.5 weeks. All sessions were performed

in Day Hospital; during these sessions the visits, common laboratory analysis and diagnostic

procedure were performed, as the protocols of care require.

For the routine therapy the followings have been considered:

-The costs of transfusional sessions corresponding to what quated in the related DRG. It has

been equal to 5679.5±1366.3 euro in the year

-The costs of chelation as detailed in Table 5 (see supplemental data). When the chelation costs

have been calculated we have also taken into account the variation of the chelation therapy

during the year that occurred in the 55.1% of subjects at least once during the study and the

cases of 7 patients that prematurely interrupted the study.

-The cost of the iron overload monitoring, including cardiac MRI, hepatic MRI or SQUID and

considering that in our study only 67 patients underwent instrumental examination during the

year.

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In conclusion our data demonstrate that the mean patient cost by year for standard therapy

and routine tests has been equal to 15,751 ±1907.6 and the total year cost is equal to 4,235,312

euro. Variations are related to the cost of chelators while other cost categories are

omogeneous (Table 6, see supplemental data).

Costs for additional AEs during 1 year (other than routine therapy)

During the study period (1 year), patients required a total of 3.125 additional services other

than routine treatment. The total costs for management of these services is mainly due to the

clinical management of the complications including a high consuming of pharmaceuticals

accounting for 44% of the total additional cost. Hospitalisation accounts for another 50%. 43

patients were admitted to Day Hospital (DH) with a total cost of 11,998 euro and 55 received

Hospital care for a total of 428 days for 55 events with a total cost of 170,268 euro (Table 7, see

supplemental data).

Hospitalisation was mainly related to surgical reasons and gallstones treatment result the more

frequent diagnosis in this group of patients; benign tumour were present in 11 cases. The

observed BTRs lead to hospitalization for a total of 15 days while a total of 43 days of

hospitalisation were required for treatment of iron chelators related ADRs.

With reference to pharmaceuticals, we noted that the highest pharmaceutical cost has

concerned the treatment of gastro-intestinal and hepatic complications, especially interferon

for hepatitis (Table 8, see supplemental data).

Concluding the need to provide additional care to thalassaemia patients has led to an increase

of both the burden of the diseases in term of visits, laboratory, DH, hospitalization, additional

pharmaceutical, and of the cost of the disease. This increase can be calculated as an additional

7.7 % over the routine cost.

However both burden of the disease and additional cost are different in complicated and not

complicated patients; in particular these increases of 10 and 15 folders respectively in patients

having 3 to 6 and more of 6 complications but a significant increase is observed in patients with

only 1 complication.

In table 9 we calculate the progressive costs related to the need of medical interventions in the

different groups of patients demonstrating the relevance of the number of complications on

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both the costs and the burden of the disease. Results are done also as percentage of the

increased cost over the routine therapy costs.

Table 9. Progressive costs related to the need of medical interventions in the complicated and

not complicated patients

No complications n= 48 patients

1-2 complications n= 126 patients

3-6 complications n= 90 patients

> 6 complications n=8 patients

All groups

N° of medical interventions In 1 year

48/90 126/469 90/292 8/34 272/885

Medical interventions /pts/year

1.8 3.7 3.2 4.2 3.3

Total medical interventions costs excluding pharmaceuticals)

7,746.46 74,145.40 80,586.72 22,466.87 184,943

Medical intervention cost/patient/year

86.06 588.70 896.62 2,808.87 676.93

Total pharmaceutical cost

4,644.30 60,266 72,365 13,899.22 151,295.07

Pharmaceutical cost by patient by year

96.75 478.30 804.05 1,737.37 556.00

Total additional cost over routine by patients

183 1,067 1,700 2,454.50 1,232

% additional cost over routine cost

1.16 6.77 10.79 15,58 7.82

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DISCUSSION

The population of these study represents approximately 10% of the thalassemic population

enrolled in the HTA-THAL registry with similar age, sex, education, occupation rate

characteristics. The paediatric age groups < 12 years is not part of this study. This exclusion has

been motivated by the evidence that in thalassemic patients complications usually appear after

the 1st decade of life and increase with age22,23.

Data collected demonstrate that more than 90% of patients have received the diagnosis of BTM

when aged less than 2 years, and that they started transfusions in the 83.8% during early

childhood (< 2 year and in particular 62.1% < 1 years, 169 patients) while the median age at

starting chelation therapy was 3 years and in the 65.8% of cases the interval between the first

transfusion and the beginning of chelation treatment was higher than 18 months, thus leading

to a very high nymber of blood transfusions done before starting ICT (> 100).

These results are not in line with the thalassaemia’ national/international guidelines

recommending to start ICT after not more than 10-20 blood transfusions usually received in 8-

12 months. However the current guidelines have became well known and largely applied only

in the last 2 decades while our population mean age is 30.63 with an interval varying from 12 to

50 years with the majority of patients (60.7%) born before 1980.

The main result of this study is the detailed quali-quantitative description of the very high

number of complications affecting thalassaemia patients and on this issue we consider of

interest the followed considerations:

Cardiac problems, such as heart failure and arrhythmias, are the main cause of mortality

in patients with thalassaemia24. On the contrary, in our study, the presence of

cardiovascular diseases was lower than expected with a prevalence inferior also to

hepatic complications thus suggestingthat a reduced mortality is to be anticipated in

this patients subpopulation that seems to be generally well-controlled and well-treated.

However this expectation could be only confirmed by a longer follow-up that should

include the estimation of the mortality rate due to all the cardiac events.

On the other hand the very high frequency of the observed osteoporosis and osteopenia

confirms the literature data reporting these as the commonest problems among

thalassaemic patients due to the increased marrow erythropoiesis and extensive iron

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deposition resulting in expansion of bone marrow cavities and reduced trabecular bone

volume, leading to decreased bone tissue and osteoporosis10,25,26,27. Also high dose

desferrioxamine therapy causes decrease in the differentiation and proliferation of

bone-forming cells and collagen formation, and increases osteoblast programmed cell

death. The presence of other endocrinopathies like hypothyroidism,

hypoparathyroidism, diabetes mellitus, and hypogonadism also contributes to bone

disease.

A relevant complications’ group is represented by hypogonadism affecting 68.2% of the

males’ population and amenorrhea affecting 30.7% of females. In many cases these

complications affect people with osteopenia or osteoporosis confirming that an

adequate follow up of the musculoskeletal diseases is very important since the

adolescence2,28 together with the management of endocrine functionality.

Other endocrine diseases such as deficiency of growth hormone, diabetes mellitus,

hypothyroidism, parathyroid gland dysfunction as reported by many other authors2,29,30

were also relevant in our population. In particular, our data confirm that hypothyroidism

is one of the more frequent complications observed in adult patients suffering from beta

thalassaemia31,32. Infact 71.4% of patients with endocrine disease were affected by

hypothyroidism and 87.5% of them were 26-40 years old.

Hepatic disease, reported as the second cause of mortality in BTM33, also represent the

second cause of morbility in our study. In particular a total of 100 patients (88.5%)

affected by hepatic diseases is HCV positive confirming the relevance of this infection in

thalassaemia patients34,35 in patients that received transfusions in lack of the advanced

diagnostic test. It shoud be noted that in our population we didn’t observe any HCV

positivity in patients transfused after the 1990 year. In addition the launch on the

market of the new families of anti HCV infections drugs (sofosbuvir and other drugs)

hasa completely changed the prognosis of chronic hepatitis C affected patients.

However the thalassaemia population living in Italy at today need to be carefully

monitored with reference to the HCV status that includes information on the

immunological status, the virus genetic characteristic, the response to previous

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treatment, etc. This information is planned to be included in the next data collection on

the thalassaemia population included in the HTA-THAL registry.

We have observed a relatively high number of thrombotic complications that are

considered more common in thalassaemia intermedia than in regularly transfused

thalassaemia major36; thus the number observed in our series should be considered and

discussed.

With reference to the identification of specific risk factors our study confirms that the number

of complications increases with age as already reported in literature23, especially whith

reference to hepatic and cardiovascular complications.

Sex, age at first transfusion, type of the chelators and (curiously) average ferritin level do not

seem to have influence on the number or type of complications. In particular our data seem to

demonstrate that the predictive value of serum ferritin greater than 1,000 ng/mL is limited and

lower than the number of transfusions received before ICT. In fact in patients that received

more than 20 transfusions before starting ICT the number of complications is significantly

higher and this confirms the need to anticipate the age at whom patients should be chelated.

This is also in accordance with the current literature data guidelines recommending that ICT

should be started after a cumulative transfusion of 10 units of Prbc2,37,38,39,40.

Also splenectomy was confirmed as a relevant and significant risk factor for complications

(41.5% of splenectomised patient developed > 2 complications versus 25% of non

splenectomised patients), as pulmonary hypertension, silent brain infarcts, venous thrombosis,

etc. Even with reference to this risk factor it is to be noted that splenectomy has been

abandoned and in our population the younger splenectomised patient is aged 14 years.

In our study, the patients population has been followed for 1 year in order to evaluate the

incidence ofall AEs and their impact on the patients clinical status. A very large amount of AEs

often required additional medicalinterventions and sometime hospitalization.

The main conseguence is that in their daily life the thalassemic patients are forced to live with

other disabling diseases and to undergo further treatments, additional medical interventions

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and hospitalisation. These, along with the significant burden from chronic treatment with

transfusions and chelation, can adversely impact patient's quality of life.

Thus it seems that, even if the patients survival is significantly icreased, the medical burden of

the disease remain very high for patients affected by 1 or more complication. Complications are

also associated to a higher costs for the Health Care System with a significant difference versus

non complicated patients.

In particular, considering the additional costs derived by new AEs during 1 observational year,

we observed that patients without complications have a global additional cost very low (equal

to 1% ) while this cost increased up to 10-15% in complicated patients.

This observation prolonged for 1 year with regular medical and laboratory assessments, also

enable us to calculate the occurrence of AEs related to blood transfusions and chelation

therapy. We consider these last data only speculative, since the study was not designed as a

formal pharmacovigilance or transfusion vigilance study. However, we consider of interest that

25 patients presented a total of 35 BTRs (mainly non-hemolytic febrile reaction), that

represents an valuable quote in our small group of patients (>10%). Maybe a more extensive

follow up of patients could describe the specific transfusional risks in the thalassemic

population and identify appropriate programs to prevent/reduce this risk. Even this aspect is

planned to be included in the next HTA-THAL Registry data collection.

Despite the study is not designed as a pharmacovigilance monitoring study, ATRs and ADRs

have also been collected as producing additional medical needs.

Regarding the occurrence of ADRs related to ICT therapy we noted that:

The use of chelation is affected by a number of ADRs but serious reaction are very rare. The

majority of these reactions are ‘class-related’ but in our population we noted some unexpected

features that need to be discussed. As an example, neutropaenia has resulted mainly related to

the use of DFO instead that of DFP that, on the contrary, used alone, has been the drug less

associated with ADRs. Patients treated with combined DFO+DFP therapy presented a higher

number of ADRs (40.4%) in comparison with single chelation regimen. This combined use is well

consolidated in the Italian population, where it is estimated that not less than 25% of patients

are using the DFO+DFP combination and that the whole risk/benefit of this regimen remains

positive 17,41,42,43. Moreover, the slow increase in some ADRs linked to both DFP or DFO (like

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tubulopathy observed in 4 cases) could be related with the great variability in dosage and

schedules with the consequent risk of underdosing or overdosing these patients44. Thus, this

observation open the door to perform a large and Good Pharmacoepidemiological Practice

(GPP) based study to identify safe/efficacious dosages and schedules.

CONCLUSION

This study has many weakness and needs for improvement. The observation is limited by age

(children < 12 years are not included), and diseases (only thalassaemia major patients were

recruited). We believe that in some cases the diagnosis of thalassaemia major, done many

years before this data collection, was not appropriate and that patients included in this study

could be affected by different forms of thalassaemia (intermediate, other genetic variants, etc).

Finally the population description in this paper corresponds to a relatively old patients’

population that received during a large part of their life, treatments responding to protocols

and guidelines in use years ago and no more currently adopted. However this is the patients

population we are to currently deal with, hoping that the number and seriousness of

complications will strongly decrease following the application of good therapeutic practices

such as starting ICT early, avoiding splenectomy, monitoring from childhood and adolescence

the functioning of systems at higher risk of complication (endocrine, muscoloscheletric, etc).

Moreover by collecting a large amount of data in this long-term observational study we have

been able to demonstrated that:

- complications represent the real crucial problem of the thalassaemia patients with a huge

impact on burden and costs of the disease;

- cardiac diseases are no more the 1° cause of morbidity but infections, osteopathies and

endocrinopathies are increasing;

- splenectomy, the age of patients > 40 years and delay in starting ICT treatment after 10-20

blood transfusions is a relevant risk factor for complications;

- just after the first complication arises, the burden of the disease and its cost multiply.As

conclusive consideration we underline that these information could be only collected using

long-term studies including a large patients population. More efforts and more longitudinal

observational studies are necessary to better identify strategies to prevent or reduce

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complications and their impact. Patients Registries, including all patients age and diseases

groups, could represent the optimal way to facilitate these studies and make available relevant

information without submit this population to more complex and costly experimental

procedures.

TRANSPARENCY SECTION

1. Declaration of funding

This manuscript has been published on behalf of HTA THAL project, funded by the Italian Ministry of

Health (art 12 D.LGS. 502/1992) and cofunded by the Fondazione Giambrone.

2. Declaration of financial/other relationships

AP declares: MIOT and E-MIOT received “no profit” support from Chiesi spa, Apopharma Inc

and Bayer. The authors have no other relevant affiliations or financial involvement with any

organization or entity with a financial interest in or financial conflict with the subject matter or

materials discussed in the manuscript apart from those disclosed. CMRO peer reviewers on this

manuscript have no relevant financial or other relationships to disclose.

3. Authors’ contributions

All authors fulfil the authorship criteria and contributed as following described:

F. Bonifazi designed the research study, evaluated data and wrote the manuscript

R. Conte analyzed the data and wrote the manuscript

P. Baiardi performed the statistical analysis and collaborated to data evaluation

D. Bonifazi designed the research study and commented on the manuscript

M. Felisi analyzed the data and commented on the manuscript

P. Giordano collaborated to data collection and commented on the manuscript

V. Giannuzzi collaborated to research study design and commented on the manuscript

A. Iacono provided comments from the patients point of view and collaborated to data

collection and evaluation

R. Padula collaborated to research study design, to the data collection and evaluation

A. Pepe collaborated to data collection and commented on the manuscript

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M.C. Putti collaborated to data collection and commented on the manuscript

L. Ruggieri supported the data analysis and the writing of the manuscript

G.C. Del Vecchio collaborated to data analysis and evaluation and commented on the

manuscript

A. Filosa collaborated to data analysis and evaluation and commented on the manuscript

A. Maggio collaborated to data collection and commented on the final version of the

manuscript

A. Ceci designed the research study, analyzed the data and provide the final version of the

manuscript

4. Acknowledgements

The manuscript has been published on behalf of HTA THAL project, funded by Ministry of Health and

Fondazione Giambrone. The authors wish to thank Fondazione Giambrone for its contribution.

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Supplemental data Table 1. Patients characteristics Patients characteristics N, %

Total 272 (100%)

Sex Males Females

127 (46,7%) 145 (53,3%)

Age groups 12-17 years 18-25 years 26-40 years > 40 years

18 (6.6%) 56 (20.6%) 177 (65.1%) 21(7.7%)

Age at diagnosis of beta-thalassaemia Mean ± SD (min-max) Median (IR)

< 1 year 1-2 years > 2 years

1.0± 1.0 years (Prenatal-6 years) 0.8years (0.4 - 1.5years) 187 (68.7%) 58 (21,3%) 27 (9.9%)

Age at starting of transfusions Mean ± SD (min-max) Median (IR) ≤ 2 years > 2 years

1.2± 1.1 years (2 months -6 years) 0.8 years (0.5 - 1.5 years) 228 (83.8%) 44 (16.2%)

Age at starting of ICT Mean ± SD (min-max) Median (IR) ≤2 years > 3 years > 6 years

4.7 ± 3.8 years (1 - 23 years) 3 years (2 - 6 years) 70 (53.7%) 145 (53.3%) 57 (20.9%)

Transfusion - ICT interval lower than 12 months beetwen 12-18 months longer than 18 months

70 (25.8%) 23 (8.4%) 179 (65.8%)

Transfusions received before ICT < 10 10-20 20-40 40-100 > 100 Not declared

43 (15.8%) 34 (12.5%) 72 (26.5%) 82 (30.1%) 40 (14.7%) 1 (0.4%)

Average ferritin level in the whole patients life < 1000 ng/ml 1000-2000 ng/ml 2000-4000 ng/ml > 4.000 ng/ml Not declared

55 (20.2%) 121 (44.5%) 69 (25.4%) 13 (4.8%) 14 (5.1%)

Average level of HB 8-8.7 mg%ml 9-9.8mg%ml 10-10.5 mg%ml

4 (2.9%) 195 (71.7%) 73 (26.8%)

Age at splenectomy ≤ 3 years 3-6 years 6-12 years

21(15.1%) 32 (23%) 37 (26.6%)

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Patients characteristics N, %

12-18 years > 18 years Not Not declared

22 (15.8%) 27 (19.4%) 130 (47.8%) 3 (1.1%)

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Table 2. Type and description of complications Type Description Number and % on a total

of complications

Musculoskeletal disease (n=134,

24.2%)

osteoporosis,

osteopenia,

lordosis, scoliosis, platyspondyly.

82 (61.2%)

44 (32.8%)

8 (6%)

Hepatic disease (n=113, 20.4%) HBV

HCV

chronic active hepatitis,

Gilbert syndrome.

2 (1.8%)

100 (88.5%)

49 (43,4%)

4 (3.5%)

Endocrine disease (n=56, 10.10%) hipothyroidism,

thyroid nodules, chronic lymphocytic thyroiditis,

hypoparathyroidism,

dyabetes ,

GH deficiency, growth failure.

40 (71.4%)

2 (3.6%) 1 (1.8%)

4 (7.1%)

4 (7.1%)

3 (5.3%)

Sexual development disease (n=88,

15.9%) secondary amenorrhea:

associated to hipothyroidism

hypogonadism:

associated to hipothyroidism

associated to dyabetes.

27 (30.7%)

9 (10,2%)

60 (68.2%)

20 (22.7%)

5 (5.7%)

Cardiovascular disease and

thromboembolic complications

(n=46, 8.3%)

cardiomyopathy

arrhythmia, atrial and ventricular fibrillation,

heart failure,

pulmonary hypertension,

blood hypertension.

24 (52.2%)

10 (11.8 %)

3 (6.5%)

3 (6.5%)

2 (4.3%)

Gallstones (n=20, 3.6%) renal,

biliary.

12 (60%)

8 (40%)

Metabolic disease (n=10, 11. 2 %) intolerance to carbohydrates. 10 (90.9%)

Blood system disease (n=11, 11. 2%) primary and secondary thrombocytosis. 11 (100%)

Hearing damage (n=26, 4.7%) sensorineural hearing loss,

hearing loss.

19 (73.1%)

7 (26.9%)

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Type Description Number and % on a total

of complications

Immune system disease (n=7, 1.3%)

asthma, rhinitis,

immunoglobulinophaties.

3 (42.9%)

4 (68.3%)

Table 4. ADRs related to ICT therapy

Observed Adverse Drug Reactions

DF

O

D

FP

D

FX

DFO+

DFP

associated

DFO+DF

P

sequentially

T

otal

Neutropenia 9 2 2 3 7 2

3

Nausea, vomit, abdominal pain 8 8 8 3 _ 2

7

Laboratory test abnormalities 8 _ 1

7

12 6 4

3

Dizziness 2 _ _ 4 _ 6

Urticaria 2 7 _ _ 9

Hypertensive crisis 1 _ _ _ _ 1

Severe Agranulocitosis 1 _ _ _ _ 1

Cardiac events 2 _ _ 8 _ 1

0

Gallstones and related biliary

disorders

_ _ 5 _ _ 5

Renal tubulopathy _ _ _ 4 _ 4

Total 33 1

0

3

9

34 13 1

29

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Table 5. Cost of chelation

Therapeutic regimen Cost by patient

DFO

DFP

DFP

DFO+DFP sequentially

DFO+DFP combined

5,360.1±1,173.

5

23,629.7±7,555

.9

4,519.6±1,184.

9

5,029.5±1,127.

6

7,049.6±2,393.

Mean cost 9,117±2,449.6

Table 6. Costs categories N° /year Mean cost per patient

Transfusion sessions 20.2/year 5,679.5±1,366.3

Cardiac MRI 1/year 516.3

Hepatic MRI/SQUID 1/year 279.9/160.1

Mean cost for chelation 5-7time/week

9,117±2,449.6

Total 15, 751 ±1907.6

Table 7. Cost for treatment of AEs in 1 year: cost categories

Type of service

N° Cost for unit Total cost in 1 year

DH 43 279 11,998.00

Hospitalisation

55 (428 days) 257.16/day 170,268.48

Pharmacological treatments

2,776 54.50 mean 151,295.07

Others 251 35.70 2,678.96

Total 3,125 336,238.21

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Table 8. Costs for treatment of additional AEs: pharmaceuticals

Diseases categories N°

prescriptions Total 1 year cost

(€)

Endrocrine diseases 826 34,349.91

Musculoskeletal disease 698 27,697.59

Cardiovascular disease and thromboembolic complications 575 13,747.17

Blood system disease 279 9,698.43

Gastrointestinal and hepatic disease 199 52,408.96

Sexual development disease and urinaire system 87 4,650.06

Respiratory diseases 26 526.06

Nervous system disease and behaviour 47 4,001.54

Hearing damage 14 321.80

Tumours 11 306.11

Infective disease 8 3,213.95

Other 6 273.47

Total 2776 151,295.07

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