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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
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 117
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-
nd/4.0/).
Introduction Methods
One of the most common inherited diseases worldwide is Data sources and searches
b-thalassemia, characterized by a reduced ability to pro-
duce hemoglobin (Hb) [1]. Although b-thalassemia is com- A comprehensive systematic search of the literature was
mon among people originating from the Mediterranean, conducted to evaluate the clinical efficacy and safety of
Middle East, Central Asia, India, and Southern China, it HU in patients with NTDbT. MEDLINE (1946–September
is no longer limited to these geographical areas due to 2016), EMBASE (1974–September 2016), and Cochrane Cen-
migration to different regions of the world [2]. Despite tral Register of Controlled Trials (September 2016) were
the complexity of b-thalassemia genotypes (more than searched using the following keywords: ‘‘hydroxyurea,”
200 different mutations of b-globin genes), two broad ‘‘hydroxycarbamide,” ‘‘hydrea,” or ‘‘droxia” and ‘‘tha-
phenotypes of clinically significant b-thalassemia are rec- lassemia.” Clinical trial registries for the last 5 years were
ognized based on the Hb steady state and the need for searched, including ClinicalTrials.gov, World Health Organi-
blood transfusions: transfusion-dependent b-thalassemia zation International Clinical Trials Registry Platform, and
(TDbT) and nontransfusion-dependent b-thalassemia major conference proceedings (American Society of Hema-
(NTDbT). tology and European Hematology Association). Hand
NTDbT encompasses b-thalassemia intermedia and mod- searches were also conducted using reference lists from pri-
erate E/b-thalassemia [3]. Although NTDbT constitutes the mary studies. Searches were not restricted by language,
moderate form of b-thalassemia and its name may falsely publication date, or publication type, but for human partic-
reassure, it represents a wide spectrum of severity where ipants only.
at the one end there are patients suffering from severe Preferred Reporting Items for Systematic reviews and
symptoms, similar yet milder than TDbT patients; however, Meta-analyses and Meta-analysis of Observational Studies
at the other end, individuals are less affected but more sev- in Epidemiology guidelines for meta-analyses were used as
ere than the minor form [1]. While patients with NTDbT are the basis of our method [5,6]. The meta-analysis protocol
usually not dependent on blood transfusion for their entire for this study was registered with the Prospective Register
lives, they have a wide range of transfusion requirements of Systematic Reviews (registration number:
and suffer from a variety of complications [3]. Such compli- CRD42014010138).
cations are typically related to profound anemia, ineffec-
tive erythropoiesis, and transfusion-related implications Study selection
[3]. In addition, other specific complications have been
ascribed to NTDbT and include pulmonary hypertension One reviewer (A.A.) screened the citations, first by title
and thrombosis [3]. and abstract, and then by a review of the complete article
The common goal in NTDbT management is to correct as indicated. Randomized controlled trials (RCTs) and
the anemia, and allow for normal growth and development observational studies (sample size 10) that assessed the
[3]. To date, blood transfusion is the mainstay of care for clinical efficacy and/or safety of HU alone, for 3 months
patients with the severe form of NTDbT; however, transfu- or longer, in patients with NTDbT of any age were eligible
sions come with the risk of blood-borne infections, iron for inclusion. Exclusion criteria included b-thalassemia
overload, and adverse reactions that could become a major major, severe E/b-thalassemia, any combination therapy
source of morbidity and mortality. As a result, different with HU, and case reports, case series, or studies with a
drugs have been investigated in order to reduce transfusion sample size of <10 patients. If a study included NTDbT
requirements [4]. Hydroxyurea (HU), a fetal Hb inducer that and TDbT patients treated with HU, NTDbT patients were
is expected to improve chronic anemia and decrease the included but remaining patients were excluded. If a study
need for blood transfusions by reducing a/b-globin chain compared two or more treatment arms, the HU-only arm
imbalance, has shown potential [4]. While the current was included. In addition, if a study compared two or more
NTDbT clinical guidelines indorsed HU as a treatment fixed doses of HU in different arms, the most effective arm
option, it restricted the use of HU to certain clinical compli- was selected, as this mimics clinical practice where dose is
cations [3]. Furthermore, there have been no comprehen- titrated to reach the most effective maximum tolerated
sive systematic reviews or meta-analyses that address the dose.
role of HU in patients with NTDbT. Thus, an in-depth assess- While transfusion dependency (TD) may represent a
ment of the efficacy and safety of HU in NTDbT is common feature for both NTDbT and TDbT, this can lead
warranted. to ambiguity about the type of b-thalassemia. As such, we
118 A.H. Algiraigri et al.
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)
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- (pre–post) studies with no control group raised several
sion at least four times per year. Transfusion interval ranged potential methodological limitations. For instance, the lack
from monthly to four times per year. All but four studies of prespecified eligibility/selection criteria for the study
[17,19,20,22] stated their blood transfusion thresholds, population was a common issue in most of the included
although the trigger points were different, ranging from studies, especially for severe NTDbT. Although all the par-
Hb of 6 g/dL to that of 8 g/dL. Most studies based their ticipants in the studies were represented in results, it was
transfusion decisions on the Hb level and/or clinical indica- not clear whether all eligible participants were in fact
tions, such as symptomatic anemia, poor growth, and poor enrolled, raising concerns about a selection bias. A small
quality of life. sample size was a common issue for both types of NTDbT,
which potentially affects the generalizability of their find-
Mild NTDbT ings. All studies did not state whether people assessing
Study characteristics are summarized in Table 2. The stud- the outcomes were blinded to the participants’ interven-
ies were published between 2005 and 2014, and conducted tions. This could bias the results by affecting the actual out-
in seven countries: three in India; two each in Iran and Pak- comes of the participants in the studies. For more details,
istan; one each in Egypt and Italy; and one multinational see Table S1.
study (Canada, UK, and USA) [14,17,23–30]. All studies The two included RCTs [15,23], one for each type of
were single arm (pre–post design) with no control group NTDbT, were of ‘‘fair” quality as they satisfied nine of the
except one RCT, which compared two-dose regimens of 14 NIH criteria used to assess the quality of RCT. As such,
HU (10 mg/kg/day vs. 20 mg/kg/day). Only the superior they are at moderate–high risk of bias as they lack blinding
arm (10 mg/kg/day) was included as per our inclusion crite- and allocation concealment, and were of small size; see
ria. The studies collectively enrolled 373 patients. Sample Table S2.
size ranged from 15 to 106. Study populations were a mix-
ture of children and adults in all studies except one which Intervention and safety
included only adults [26]. The mean or median duration of
the studies ranged from 6 months to 156 months. In all studies, HU was used as a single intervention with no
All studies except one reported the mean Hb increment in other treatment apart from blood transfusions. HU was
the responders, which ranged between 1.5 g/L and 2.4 g/L. given as a single daily oral agent in all studies. The dose
Four studies showed a >2 g/L increment in the mean Hb of HU was similar across all the studies, ranging from
among responders [17,27,29,30], while five studies revealed 10 mg/kg/day to 25 mg/kg/day. The response to HU was
an increment between 1.5 g/L and 2 g/L [14,23,24,26,28]. measured in similar ways and entailed a decrease in the
need for transfusions or increase in Hb. The studies used
Study quality HU for 3–6 months before judging its efficacy.
All studies reported AEs related to HU, which were tran-
For the 15 observational studies, assessment of study qual- sient and improved with temporary cessation of the drug
ity using the NIH quality assessment tool for before–after 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.
121
122 A.H. Algiraigri et al.
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.
Discussion
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 mortality directly related to drug usage in the studies.
depending on institutional policies and blood availability. There were no documented long-term AEs such as leukemia,
However, when the outcome was assessed objectively, as any cancer type, or any chronic organ damage such as liver
in mild NTDbT by measuring Hb, the heterogeneity was or kidney dysfunctions; however, the follow-up duration
moderate as compared with substantial in severe NTDbT was not long enough to completely determine the inci-
where the decision to transfuse is influenced by many dence, if any, of long-term AEs.
factors. The comprehensive search of this meta-analysis identi-
Complete cessation or significant reduction (such as fied only three published cases of leukemia post-HU in
more than 50%) in chronic blood transfusions is a significant b-thalassemia [35–37], two of which were unlikely related
medical gain. Such reduction in blood transfusions will to HU due to a very short interval between the usage of
decrease in the immediate, and short- and long-term risks the drug and development of leukemia in one case and
and complications of blood transfusions. More specifically, the retrospective suspicion of coexistence of chronic leuke-
this leads to reduction in iron overload and its related mia in another case prior to the use of HU [35,37]. This left
end-organ complications and failure, less frequent clinic only one case of suspected association between HU use and
visits, and potentially less frequent monitoring of iron over- leukemia (chronic myelogenous leukemia post 5 years of HU
load. Although quality of life was not assessed in the in b-thalassemia intermedia) despite HU being used for
included studies, it was evident that a decrease or complete other hemoglobinopathies over 2 decades [36]. This reassur-
cessation of blood transfusion could be considered a sub- ing result is consistent with another meta-analysis that
stantial gain for patient quality of life. specifically addressed the long-term carcinogenicity of HU
Blood transfusions can be a significant financial burden, among the nonmalignant conditions, where no association
particularly in developing countries where most thalassemic between long-term use of HU and leukemia was found [38].
patients live. HU is an economical drug and costs approxi- The main limitations of this meta-analysis are the follow-
mately US$95 for a 1-month supply of an average 70 kg adult ing: (A) the conclusions are based on a limited number of
[32]. The cost of one unit of blood is US$316 [33] (minimum studies, with a relatively small sample size; (B) there was
of 2 units per month) and between US$1500 and US$3760 for an absence of control arms in the included studies; (C) there
a 1-month supply of an average 70 kg adult for iron chelators were relatively short follow-up periods for the HU treat-
deferoxamine and deferasirox, respectively [34]. More ment (an average of 1–2 years in most studies, which limits
widespread use of HU in thalassemia could potentially conclusions about the long-term efficacy); and (D) there was
decrease the direct and indirect costs of transfusions as well potential for selection bias across most studies due to a lack
as iron chelation therapies significantly. of prespecified eligibility/selection criteria in most of the
Apart from the transient AEs, most patients tolerated the included studies.
drug well. The most commonly reported AEs included tran- Despite the abovementioned limitations and acknowl-
sient bone marrow suppression, mild elevation of liver edging the significant need to conduct robust experimental
enzymes, nausea, and vomiting. There was no reported studies in this area, the results of this meta-analysis suggest
124 A.H. Algiraigri et al.
potential efficacy of HU therapy in patients with NTDbT. status, b-globin genotype, a-globin genotype, and molec-
Following discussions with individual patients and family ular determinants of increased fetal Hb production.
members along with a structured monitoring plan to ensure Although randomization according to specific predictors
efficacy and safety, we recommend a 3–6-month trial of HU might be challenging, subgroup analysis may reveal cer-
therapy in patients with NTDbT based on the results of this tain associations.
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 Conflicts of interest
of HU; (C) ability to assess efficacy of HU in a short period
(within a few months); and (D) availability and affordability
All authors state that they do not have any conflict of inter-
of HU (especially for the developing countries).
ests to declare.
Conclusions
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