Hematol Oncol Stem Cell Ther (2017) 10, 116– 125

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ORIGINAL RESEARCH REPORT

Hydroxyurea for nontransfusion-dependent

b-thalassemia: A systematic review and
meta-analysis
Ali H. Algiraigri a,b,c,*, Nicola A.M. Wright d, Elizabeth Oddone Paolucci c,
Aliya Kassam c

a
Department of Hematology, King Abdulaziz University Hospital, Jeddah, Saudi Arabia
b
King Faisal Special Hospital and Research Center, Jeddah, Saudi Arabia
c
Department of Community Health Science, University of Calgary, Calgary, Alberta, Canada
d
Department of Pediatrics, Alberta Children’s Hospital, Calgary, Alberta, Canada

Received 20 December 2016; accepted 15 February 2017

Available online 6 April 2017

KEYWORDS Abstract
Non-transfusion dependent Objective/background: Nontransfusion-dependent b-thalassemia (NTDbT) syndromes consist
b-thalassemia;
of b-thalassemia intermedia and moderate hemoglobin E/b thalassemias. They are character-
b-thalassemia intermedia;
ized by varying degrees of chronic anemia and a wide spectrum of complications due to inef-
Hydroxyurea;
Meta-analysis; fective erythropoiesis and iron overload from chronic transfusions. Hydroxyurea (HU), an oral
Blood transfusion chemotherapeutic drug, is anticipated to decrease disease severity.
Methods: We performed a meta-analysis to evaluate the clinical efficacy and safety of HU in
NTDbT patients of any age. MEDLINE, EMBASE, Cochrane databases, and major conference pro-
ceedings for studies that assessed HU in NTDbT patients were searched. Qualities of eligible
studies were assessed by National Institutes of Health tools.
Results: Seventeen studies, collectively involving 709 patients, fulfilled the eligibility criteria.
HU was associated with a significant decrease in transfusion need in severe NTDbT with com-
plete and overall (50%) response rates of 42% and 79%, respectively. For mild NTDbT, HU
was effective in raising hemoglobin by 1 g/L in 64% of patients.
Conclusion: HU appears to be effective, well tolerated, and associated with mild and transient
adverse events. NTDbT patients may benefit from a trial of HU, although large randomized

* Corresponding author at: Wadi An Nakhl, AL Rawdah, Jeddah 23433, Saudi Arabia.
E-mail address: aalgiraigri@gmail.com (A.H. Algiraigri).

http://dx.doi.org/10.1016/j.hemonc.2017.02.002
1658-3876/Ó 2017 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Hydroxyurea for b-thalassemia intermedia
clinical trials assessing its efficacy should be conducted to confirm the findings of this meta-
analysis and to assess its long-term toxicity and response sustainability.
Ó 2017 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. This is an
open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-
Introduction
One of the most common inherited diseases worldwide is
b-thalassemia, characterized by a reduced ability to pro-
duce hemoglobin (Hb) [1]. Although b-thalassemia is com-
mon among people originating from the Mediterranean,
Middle East, Central Asia, India, and Southern China, it
is no longer limited to these geographical areas due to
migration to different regions of the world [2]. Despite
the complexity of b-thalassemia genotypes (more than
200 different mutations of b-globin genes), two broad
phenotypes of clinically significant b-thalassemia are rec-
ognized based on the Hb steady state and the need for
blood transfusions: transfusion-dependent b-thalassemia
(TDbT) and nontransfusion-dependent b-thalassemia
(NTDbT).
NTDbT encompasses b-thalassemia intermedia and mod-
erate E/b-thalassemia [3]. Although NTDbT constitutes the
moderate form of b-thalassemia and its name may falsely
reassure, it represents a wide spectrum of severity where
at the one end there are patients suffering from severe
symptoms, similar yet milder than TDbT patients; however,
at the other end, individuals are less affected but more sev-
ere than the minor form [1]. While patients with NTDbT are
usually not dependent on blood transfusion for their entire
lives, they have a wide range of transfusion requirements
and suffer from a variety of complications [3]. Such compli-
cations are typically related to profound anemia, ineffec-
tive erythropoiesis, and transfusion-related implications
[3]. In addition, other specific complications have been
ascribed to NTDbT and include pulmonary hypertension
and thrombosis [3].
The common goal in NTDbT management is to correct
the anemia, and allow for normal growth and development
[3]. To date, blood transfusion is the mainstay of care for
patients with the severe form of NTDbT; however, transfu-
sions come with the risk of blood-borne infections, iron
overload, and adverse reactions that could become a major
source of morbidity and mortality. As a result, different
drugs have been investigated in order to reduce transfusion
requirements [4]. Hydroxyurea (HU), a fetal Hb inducer that
is expected to improve chronic anemia and decrease the
need for blood transfusions by reducing a/b-globin chain
imbalance, has shown potential [4]. While the current
NTDbT clinical guidelines indorsed HU as a treatment
option, it restricted the use of HU to certain clinical compli-
cations [3]. Furthermore, there have been no comprehen-
sive systematic reviews or meta-analyses that address the
role of HU in patients with NTDbT. Thus, an in-depth assess-
ment of the efficacy and safety of HU in NTDbT is
warranted.
117
nd/4.0/).
Methods
Data sources and searches
A comprehensive systematic search of the literature was
conducted to evaluate the clinical efficacy and safety of
HU in patients with NTDbT. MEDLINE (1946–September
2016), EMBASE (1974–September 2016), and Cochrane Cen-
tral Register of Controlled Trials (September 2016) were
searched using the following keywords: ‘‘hydroxyurea,”
‘‘hydroxycarbamide,” ‘‘hydrea,” or ‘‘droxia” and ‘‘tha-
lassemia.” Clinical trial registries for the last 5 years were
searched, including ClinicalTrials.gov, World Health Organi-
zation International Clinical Trials Registry Platform, and
major conference proceedings (American Society of Hema-
tology and European Hematology Association). Hand
searches were also conducted using reference lists from pri-
mary studies. Searches were not restricted by language,
publication date, or publication type, but for human partic-
ipants only.
Preferred Reporting Items for Systematic reviews and
Meta-analyses and Meta-analysis of Observational Studies
in Epidemiology guidelines for meta-analyses were used as
the basis of our method [5,6]. The meta-analysis protocol
for this study was registered with the Prospective Register
of Systematic Reviews (registration number:
CRD42014010138).
Study selection
One reviewer (A.A.) screened the citations, first by title
and abstract, and then by a review of the complete article
as indicated. Randomized controlled trials (RCTs) and
observational studies (sample size 10) that assessed the
clinical efficacy and/or safety of HU alone, for 3 months
or longer, in patients with NTDbT of any age were eligible
for inclusion. Exclusion criteria included b-thalassemia
major, severe E/b-thalassemia, any combination therapy
with HU, and case reports, case series, or studies with a
sample size of <10 patients. If a study included NTDbT
and TDbT patients treated with HU, NTDbT patients were
included but remaining patients were excluded. If a study
compared two or more treatment arms, the HU-only arm
was included. In addition, if a study compared two or more
fixed doses of HU in different arms, the most effective arm
was selected, as this mimics clinical practice where dose is
titrated to reach the most effective maximum tolerated
dose.
While transfusion dependency (TD) may represent a
common feature for both NTDbT and TDbT, this can lead
to ambiguity about the type of b-thalassemia. As such, we
118
further categorized TD b-thalassemia to either lifelong
TDbT or NTDbT using the primary authors’ definition/labels
of the disease. In cases with no clear distinction in the pri-
mary study (i.e., only provided as TD b-thalassemia), we
asked the primary authors to clarify this issue. If that was
not possible, those patients/studies were excluded.
To limit the expected clinical heterogeneity of NTDbT,
the disease was subcategorized into two groups: mild (no
or <4 transfusions per year) and severe (4 transfusions
per year).
Data abstraction and quality assessment
Two reviewers (A.A. and A.K.) extracted the data indepen-
dently, using data extraction forms for each type of NTDbT.
Key characteristics were extracted from eligible studies and
recorded. These characteristics included author, year and
country of publication, study design, sample size, age of
sample, blood transfusion history, HU dose, response rate
(RR), types of adverse events (AEs), and follow-up duration.
Information was requested from primary authors when it
was not available in the published papers.
The quality of the included studies was assessed indepen-
dently by two reviewers (A.A. and A.K.) using the National
Institutes of Health (NIH) quality assessment tool for con-
trolled intervention studies as well as the NIH tool for
before–after (pre–post) studies with no control group [7].
These tools are composed of multiple questions assessing
the potential risk for selection bias, information bias, mea-
surement bias, and confounding. Reviewers and then used
these questions to judge each study to be of ‘‘good,”
‘‘fair,” or ‘‘poor” quality. Disagreements between review-
ers were resolved by discussion until consensus was
reached.
Data synthesis and analysis
The effect size of our meta-analysis was the proportion of
patients who responded to HU by either decreasing transfu-
sion needs or raising Hb in severe and mild types, respec-
tively. This proportion was called the RR. In severe NTDbT
patients who had a decrease in transfusion needs, complete
response rate (CRR) was defined as complete cessation of
blood transfusion post-HU therapy, and overall response
rate (ORR) was defined as 50% reduction in transfusion
needs post-HU therapy. For mild NTDbT, the RR was defined
as a 1 g/L increase in Hb.
Since most of the included studies were of single-arm
designs with no control arms, pooled estimates of the treat-
ment effect for each outcome (CRR and ORR for severe
NTDbT; RR for mild NTDbT) across the studies were calcu-
lated as proportions (the responders overtreated sample
size with HU), together with their 95% confidence intervals
(95% CIs). These analyses were performed using a recently
published ‘‘metaprop” Stata command developed for the
use of proportions as effect sizes [8]. Owing to the
expected heterogeneity within and between studies, we
used the random effect model, which takes into considera-
tion between- and within-study variations and provides a
more conservative analysis of the studies than the fixed
effect model [9].
A.H. Algiraigri et al.
Heterogeneity and publication bias
Heterogeneity between studies was assessed by visual
inspection of forest plots to detect overlapping 95% CIs,
by a formal statistical test of the significance of the hetero-
geneity (chi-squared test; p < 0.05) and by estimation of the
percentage of heterogeneity between trials that could not
be attributed to sampling error (I2) [10]. The I2 is expressed
as a percentage, with I2 values of 25% indicating low, 50%
indicating moderate, and 75% indicating high heterogeneity
[10].
Publication bias was assessed graphically using funnel
plots and the Egger test, which quantified the asymmetry
of the plot [11,12]. The latter tests the null hypothesis that
small studies give the same results as large studies. An alpha
level of p < 0.05 was deemed significant for the statistical
calculations in this meta-analysis. All data were analyzed
using Stata, version 13.0 [13].
Results
Study selection
The initial literature search yielded 943 references, after
duplicates were removed, and was updated to April 2015.
One author (A.A.) then screened the titles and abstracts,
and 882 were excluded for not meeting eligibility criteria.
The remaining 61 references were assessed on the basis of
their full text for inclusion or exclusion using the criteria
indicated above. Of these, 36 studies were excluded, with
the most common reason being inadequately reported out-
come data. Seventeen studies met our inclusion criteria
for the meta-analysis; see Fig. 1 for Preferred Reporting
Items for Systematic reviews and Meta-analyses study flow
diagram. From the pool of 17 studies available for our
meta-analysis, nine included patients with severe NTDbT
and 10 included those with mild NTDbT.
Study characteristics
Severe NTDbT
All nine studies were published over the last decade
(between 2005 and 2014) and conducted in seven countries:
three in Egypt; two in Iran; one each in India and Pakistan;
and one multinational study (Canada, UK, and USA) [14–22].
All studies were single arm (pre–post design) with no con-
trol group except one RCT [15]. In the single-arm studies,
the prestudy arm used a historical control and the poststudy
arm was the treatment group where HU was given. For the
RCT, HU was compared with HU and erythropoietin, so the
HU-only arm was included [15]. All included studies were
published in English and as full-text papers, except for
one where only the abstract was in English [20]. The studies
collectively enrolled 416 patients. Sample size ranged from
20 to 120. Study populations were a mixture of children and
adults in all studies. The mean or median duration of the
studies ranged from 6 months to 50 months. Study charac-
teristics are summarized in Table 1.
All the studies enrolled b-thalassemia intermedia
patients except one, which enrolled E/b-thalassemia
Hydroxyurea for b-thalassemia intermedia 119

Identified records from the databases ASH and EHA conference abstracts
and bibliographies of relevant articles and bibliographies of relevant articles
(n = 1,210) (n = 11)

Records after excluding duplicates (n = 943)

Records screened (n = 943)

Records excluded according to selection criteria (n = 882)

Full-text articles assessed for eligibility (n = 62)

Full-text articles excluded (n = 37)

Abstract published later as full-text article (n = 3)
Combination therapy (n = 3)
Editorials (n = 2)
Case series (n = 2)
Not enough data to calculate outcome (n =13)
Review (n = 2)
Sample size < 10 (n = 8)
Others (n = 4)

Studies included in qualitative synthesis (n = 25)

Studies included in meta-analysis (n = 17)

Fig. 1 PRISMA flow diagram of literature search. Note. ASH = American Society of Hematology; EHA = European Hematology
Association; PRISMA = Preferred Reporting Items for Systematic reviews and Meta-Analyses.

patients only [22]. All patients were requiring blood transfu-
sion at least four times per year. Transfusion interval ranged
from monthly to four times per year. All but four studies
[17,19,20,22] stated their blood transfusion thresholds,
although the trigger points were different, ranging from
Hb of 6 g/dL to that of 8 g/dL. Most studies based their
transfusion decisions on the Hb level and/or clinical indica-
tions, such as symptomatic anemia, poor growth, and poor
quality of life.
Mild NTDbT
Study characteristics are summarized in Table 2. The stud-
ies were published between 2005 and 2014, and conducted
in seven countries: three in India; two each in Iran and Pak-
istan; one each in Egypt and Italy; and one multinational
study (Canada, UK, and USA) [14,17,23–30]. All studies
were single arm (pre–post design) with no control group
except one RCT, which compared two-dose regimens of
HU (10 mg/kg/day vs. 20 mg/kg/day). Only the superior
arm (10 mg/kg/day) was included as per our inclusion crite-
ria. The studies collectively enrolled 373 patients. Sample
size ranged from 15 to 106. Study populations were a mix-
ture of children and adults in all studies except one which
included only adults [26]. The mean or median duration of
the studies ranged from 6 months to 156 months.
All studies except one reported the mean Hb increment in
the responders, which ranged between 1.5 g/L and 2.4 g/L.
Four studies showed a >2 g/L increment in the mean Hb
among responders [17,27,29,30], while five studies revealed
an increment between 1.5 g/L and 2 g/L [14,23,24,26,28].
Study quality
For the 15 observational studies, assessment of study qual-
ity using the NIH quality assessment tool for before–after
(pre–post) studies with no control group raised several
potential methodological limitations. For instance, the lack
of prespecified eligibility/selection criteria for the study
population was a common issue in most of the included
studies, especially for severe NTDbT. Although all the par-
ticipants in the studies were represented in results, it was
not clear whether all eligible participants were in fact
enrolled, raising concerns about a selection bias. A small
sample size was a common issue for both types of NTDbT,
which potentially affects the generalizability of their find-
ings. All studies did not state whether people assessing
the outcomes were blinded to the participants’ interven-
tions. This could bias the results by affecting the actual out-
comes of the participants in the studies. For more details,
see Table S1.
The two included RCTs [15,23], one for each type of
NTDbT, were of ‘‘fair” quality as they satisfied nine of the
14 NIH criteria used to assess the quality of RCT. As such,
they are at moderate–high risk of bias as they lack blinding
and allocation concealment, and were of small size; see
Table S2.
Intervention and safety
In all studies, HU was used as a single intervention with no
other treatment apart from blood transfusions. HU was
given as a single daily oral agent in all studies. The dose
of HU was similar across all the studies, ranging from
10 mg/kg/day to 25 mg/kg/day. The response to HU was
measured in similar ways and entailed a decrease in the
need for transfusions or increase in Hb. The studies used
HU for 3–6 months before judging its efficacy.
All studies reported AEs related to HU, which were tran-
sient and improved with temporary cessation of the drug
and/or adjustment of the dose. These include transient
 120
Table 1 Study characteristics for severe NTDbT.
Author Country Design Agea (range) Blood HUa N Overall Complete AEs F/Ua Quality
(y) transfusiona (mg/kg/d) response: n (%) response: n (%) (mo) (NIH tool)
El Beshlawy et al. [14] Egypt Pre/postb 12.7 (2–36) 4/y 20 25 23 (92) 11 (44) Transient 35.4 Fair
neutropenia and
transaminitis
Elalfy et al. [15] Egypt RCTc 9.1 (5–17.5) Q 5.8 wk 25 40 25 (62.5) 6 (15) Transient 12 Fair
myelosuppression
Mokhtar et al. [16] Egypt Pre/post 13 (4–25) 6/yd 20.7 40 30 (75) 8 (20)d Transient 18 Fair
myelosuppression
Ishaq et al. [17] Pakistan Pre/post 8.6 (1.8–29) 4/y 15 29 21 (72.4) 16 (55.2) Mild GI symptoms 12 Good
Hashemi et al. [18] Iran Pre/post 16.5 (3–40) 4/y 10–15 20 15 (75) 9 (45) Transient >6 Fair
myelosuppression
and GI symptoms
Italia et al. [19] India Pre/post NR (5–40) 4/y 15–20 35 25 (71.4)d 19 (54.3)d Neutropenia 22 Fair
Yavarian et al. [20] Iran Pre/post 16.8 Regular 10–12 80 69 (83) 30 (37.5) Vomiting and 12 Poor
thrombocytopenia
Karimi et al. [21] Iran Pre/post 13.5 (4–35) Monthly 8–12 120 106 (88.3) 83 (69.2) No significant AEs 50 Good
Singer et al. [22] Canada, UK, Pre/post 15.1 (1.8–35) Regular 18–20 27 NR 12 (44.4) Transient 24 ± 9 Good
and USA myelosuppression
Note. AEs = adverse events; d = day; F/U = follow-up; GI = gastrointestinal; HU = hydroxyurea; mo = month; N = sample size, NIH = National Institutes of Health; NR = not reported;
NTDbT = nontransfusion-dependent b-thalassemia; RCT = randomized clinical trial; wk = week; y = year.
a
Mean or median.
b
Retrospective.
c
Only HU-alone arm was included.
d
Obtained from the primary author.

A.H. Algiraigri et al.

 Hydroxyurea for b-thalassemia intermedia
Table 2 Study characteristics for mild NTDbT.
Author Country Design Agea (range) HUa N Responders: Mean Hba AEs F/Ua (mo) Quality
(y) (mg/kg/d) n (%) (g/dL) (NIH tool)
in responders
Bohara et al. [23] India RCTb 16.7 (NR) 10 32 18 (56.3) 1.7 Transient 6 Fair
myelosuppression and
mild GI symptoms
El Beshlawy et al. [14] Egypt Pre/postc 12.7 (2–36) 4/y 75 56 (74.7) 1.5 Transient neutropenia and 35.4 Fair
transaminitis
Karimi et al. [24] Iran Pre/postc 18.1 (4–45) 8–15 106 56 (52.8) 1.8 No significant AEs 96–156 Good
Ishaq et al. [17] Pakistan Pre/post 8.6 (1.8–29) 15 26 23 (88.5) 2.1 Mild GI symptoms 12 Good
Ansari et al. [25] Pakistan Pre/post 5.4 (3–13) 16 27 12 (44.4)d NR Transient 24 Good
myelosuppression and
mild GI symptoms
Rigano et al. [26] Italy Pre/post 37 (18–59) 14.6 24 17 (70.8) 1.7 No significant AEs 52 Good
Ehsani et al. [27] Iran Pre/post 10.7 (5–19) 20 16 11 (68.8) 2.1 No significant AEs 6 Poor
Singer et al. [28] Canada, Pre/post 13.7 (3–27) 18–20 15 8 (53.3) 1.5 No significant AEs 10.2 Fair
UK, USA
Panigrahi et al. [29] India Pre/post NR (5–32) 10–20 15 8 (53.3) 2.4 No significant AEs 12 Good
Dixit et al. [30] India Pre/post 10 (4–50) 10–20 37 26 (70.3) 2.1 Transient 12 Good
myelosuppression and
mild GI symptoms
Note. AEs = adverse events; d = day; F/U = follow-up; GI = gastrointestinal; Hb = hemoglobin; HU = hydroxyurea; mo = month; N = sample size; NIH = National Institutes of Health; NR = not
reported; NTDbT = nontransfusion-dependent b-thalassemia; RCT = randomized clinical trial; y – year.
a
Mean or median.
b
Only the low-dose arm was included.
c
Retrospective.
d
Obtained from the primary author.

121
122
myelosuppression, transient transaminitis, and mild gas-
trointestinal symptoms such as vomiting and diarrhea. No
long-term AEs such as cancer, infertility, or end-organ dam-
age were reported.
< .001
< .001
Fig. 2 Forest plots of hydroxyurea responses in NTDbT
patients. (A) Complete response rate in severe NTDbT. (B)
Overall response rate in severe NTDbT. (C) Response rate in
mild NTDbT. Note. CI = confidence interval; NTDbT = nontrans-
fusion-dependent b thalassemia; ES = effect size.
A.H. Algiraigri et al.
RR of HU
Severe NTDbT
For severe NTDbT patients, HU was associated with com-
plete cessation of regular blood transfusion with a CRR of
42% (95% CI: 29–56%); heterogeneity was considered high
with an I2 of 86.9%, p < 0.01. In addition, HU was associated
with a significant decrease (50%) in transfusion need
among severe NTDbT patients with an ORR of 79% (95% CI:
71–86%); heterogeneity was moderate with an I2 of 65.3%
and p < 0.01, as depicted in Fig. 2.
Mild NTDbT
HU was associated with an increase in Hb of >1 g/L from
baseline in mild NTDbT patients with an RR of 64% (95%
CI: 55–73%); heterogeneity was considered moderate with
an I2 of 63.9%, p < 0.01, as depicted in Fig. 2.
Analysis of heterogeneity and publication bias
Graphical inspection of forest plots for CRR, ORR, and RR in
Fig. 3 revealed nonoverlapping 95% CIs for CRR, but slightly
overlapping 95% CIs for ORR and RR, suggesting some
heterogeneity among studies. This was confirmed by the
statistically significant high to moderate I2 values.
Owing to an insufficient number of studies that provided
data, it was not possible to perform either subgroup analysis
or metaregression for the age of participants (pediatric vs.
adult), HU dose (10 mg/kg/day vs. 20 mg/kg/day), age at
first blood transfusion, transfusion threshold, and type of
the thalassemias (b-thalassemia intermedia vs. moderate
E/b-thalassemia).
Egger test showed no evidence of publication bias of
studies on CRR (p = 0.24), ORR (p = 0.13), and RR
(p = 0.81). These were consistent with the symmetry of
the funnel plots; see Supplementary Fig. 1.
Discussion
To our knowledge, this study is the first comprehensive
meta-analysis evaluating the clinical efficacy and safety of
HU in NTDbT. Seventeen studies met our inclusion criteria,
but most were observational studies. These studies enrolled
a total of 709 patients. Our meta-analysis concluded that
HU had good clinical efficacy in reducing transfusion
requirements and increasing Hgb in NTDbT, and it was well
tolerated with no major long-term adverse effects. In sev-
ere NTDbT (4 transfusions per year), HU was associated
with complete cessation of blood transfusion in 42% of study
participants. Moreover, there was a >50% reduction in trans-
fusion needs in nearly 80% of study participants. For mild
NTDbT (no or <4 transfusions per year), HU was effective
in raising Hb by at least 1 g/L in nearly two-thirds of study
participants. However, there was moderate heterogeneity
among studies for both types of NTDbT, with higher hetero-
geneity for severe NTDbT.
Heterogeneity was observed despite stringent inclusion/
exclusion criteria and subcategorization of NTDbT. This was
not unexpected given the poor correlation between the
genotype and phenotype of b-thalassemia [31] and blood
Hydroxyurea for b-thalassemia intermedia
Fig. 3 Proposed management algorithm for NTDbT patients. Note. AEs = adverse events; CBC = complete blood count; d = day;
Hb = hemoglobin; HbF = fetal hemoglobin; HU = hydroxyurea; MCV = mean corpuscular volume; mo = month; NTDbT = nontransfu-
sion-dependent b-thalassemia; Retics = reticulocytes; wk = week.
transfusion practices that differ from one region to another
depending on institutional policies and blood availability.
However, when the outcome was assessed objectively, as
in mild NTDbT by measuring Hb, the heterogeneity was
moderate as compared with substantial in severe NTDbT
where the decision to transfuse is influenced by many
factors.
Complete cessation or significant reduction (such as
more than 50%) in chronic blood transfusions is a significant
medical gain. Such reduction in blood transfusions will
decrease in the immediate, and short- and long-term risks
and complications of blood transfusions. More specifically,
this leads to reduction in iron overload and its related
end-organ complications and failure, less frequent clinic
visits, and potentially less frequent monitoring of iron over-
load. Although quality of life was not assessed in the
included studies, it was evident that a decrease or complete
cessation of blood transfusion could be considered a sub-
stantial gain for patient quality of life.
Blood transfusions can be a significant financial burden,
particularly in developing countries where most thalassemic
patients live. HU is an economical drug and costs approxi-
mately US$95 for a 1-month supply of an average 70 kg adult
[32]. The cost of one unit of blood is US$316 [33] (minimum
of 2 units per month) and between US$1500 and US$3760 for
a 1-month supply of an average 70 kg adult for iron chelators
deferoxamine and deferasirox, respectively [34]. More
widespread use of HU in thalassemia could potentially
decrease the direct and indirect costs of transfusions as well
as iron chelation therapies significantly.
Apart from the transient AEs, most patients tolerated the
drug well. The most commonly reported AEs included tran-
sient bone marrow suppression, mild elevation of liver
enzymes, nausea, and vomiting. There was no reported
123
mortality directly related to drug usage in the studies.
There were no documented long-term AEs such as leukemia,
any cancer type, or any chronic organ damage such as liver
or kidney dysfunctions; however, the follow-up duration
was not long enough to completely determine the inci-
dence, if any, of long-term AEs.
The comprehensive search of this meta-analysis identi-
fied only three published cases of leukemia post-HU in
b-thalassemia [35–37], two of which were unlikely related
to HU due to a very short interval between the usage of
the drug and development of leukemia in one case and
the retrospective suspicion of coexistence of chronic leuke-
mia in another case prior to the use of HU [35,37]. This left
only one case of suspected association between HU use and
leukemia (chronic myelogenous leukemia post 5 years of HU
in b-thalassemia intermedia) despite HU being used for
other hemoglobinopathies over 2 decades [36]. This reassur-
ing result is consistent with another meta-analysis that
specifically addressed the long-term carcinogenicity of HU
among the nonmalignant conditions, where no association
between long-term use of HU and leukemia was found [38].
The main limitations of this meta-analysis are the follow-
ing: (A) the conclusions are based on a limited number of
studies, with a relatively small sample size; (B) there was
an absence of control arms in the included studies; (C) there
were relatively short follow-up periods for the HU treat-
ment (an average of 1–2 years in most studies, which limits
conclusions about the long-term efficacy); and (D) there was
potential for selection bias across most studies due to a lack
of prespecified eligibility/selection criteria in most of the
included studies.
Despite the abovementioned limitations and acknowl-
edging the significant need to conduct robust experimental
studies in this area, the results of this meta-analysis suggest
124
potential efficacy of HU therapy in patients with NTDbT.
Following discussions with individual patients and family
members along with a structured monitoring plan to ensure
efficacy and safety, we recommend a 3–6-month trial of HU
therapy in patients with NTDbT based on the results of this
meta-analysis as well as the following implications: (A) seri-
ous consequences of chronic blood transfusions and their
complications; (B) growing evidence of the long-term safety
of HU; (C) ability to assess efficacy of HU in a short period
(within a few months); and (D) availability and affordability
of HU (especially for the developing countries).
Conclusions
Implications for practice
The best available evidence used in this meta-analysis indi-
cates that HU is a potentially effective drug in the manage-
ment of NTDbT. It is well tolerated, and associated with
only mild and transient AEs. A risk/benefit analysis drives
the recommendation to proceed with using the drug in the
clinical setting, where the current therapy (chronic blood
transfusions) is associated with short- and long-term compli-
cations that can increase disease morbidity and mortality.
Prevention or reduction in such complications, using HU,
outweighs the potentially unknown long-term adverse
effects of HU therapy.
We have suggested a clinical algorithm for the use of HU
in NTDbT, as depicted in Fig. 3. These recommendations
were based on the present meta-analysis as well as the pub-
lished guidelines for NTDbT and Sickle cell anemia (SCA)
[3,39].
Implications for research
Although HU appears to be potentially effective in the man-
agement of NTDbT across several studies, more evidence is
needed to further consolidate the validity of this meta-
analysis. The ideal design would be that of a randomized,
placebo-controlled trial. Longitudinal observational studies
that address the long-term sustainability of response and
monitor long-term toxicity are also highly needed, since
such a drug can be used for several years. Additional
research is also required to address the many other ques-
tions that were identified in this meta-analysis. Particular
issues for future trials include the following:
1. The optimal HU dosage in b-thalassemia needs to be
determined, as different investigators used varying doses
of HU in their studies. However, most of the published
studies reported clinical responses using a dose range
of 10–20 mg/kg/day. Whether a fixed low-dose regimen
versus an escalated dose approach according to toxicity
(maximal tolerated dose) is better remains to be
answered.
2. Cost effectiveness and patient quality of life should be
assessed pre- and post-HU therapy. These could be
assessed as secondary objectives of an RCT or observa-
tional study.
3. There is great debate about the predictors of effective
response to HU in NTDbT patients such as splenectomy
A.H. Algiraigri et al.
status, b-globin genotype, a-globin genotype, and molec-
ular determinants of increased fetal Hb production.
Although randomization according to specific predictors
might be challenging, subgroup analysis may reveal cer-
tain associations.
Conflicts of interest
All authors state that they do not have any conflict of inter-
ests to declare.
Acknowledgments
We wish to thank the authors of the studies included in our
meta-analysis for providing additional information about
their studies at our request.
A.A. envisioned and designed the study, wrote the protocol,
searched the literature, extracted the data, evaluated the
quality of eligible studies, analyzed and interpreted the
data, and wrote the manuscript; A.K. edited the protocol,
extracted the data, evaluated the quality of eligible studies,
analyzed and interpreted the data, and edited the manu-
script; and N.W. edited the protocol, interpreted the data,
and edited the manuscript.
Appendix A. Supplementary material
Supplementary data associated with this article can be
found, in the online version, at http://dx.doi.org/10.
1016/j.hemonc.2017.02.002.
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