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Indian Pediatr 2021;58: 609-610 |
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Management of Thalassemia: Blood and Beyond
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Rashid Merchant
Thalassemia Clinic, Nanavati Max Super Specialty
Hospital, Mumbai, Maharashtra. [email protected]
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I t has been almost a
century since cases of thalassemia were reported by Cooley and
Lee for the first time globally [1], and over eighty years since
they were reported by Mukerjee and Coelho for the first time in
India [2,3]. India has come a long way since then in reducing
thalassemia-related morbidity and mortality, through
collaborative efforts between govern-ment bodies, medical
institutions and NGOs. Societies run by affected individuals and
their parents have played an incredible role in spreading
awareness and helping the thalassemia community navigate the
medical and psychosocial complexity of adapting to the condition
[4]. Numerous novel therapies, diagnostics, and approaches to
management – stemming from decades of biomedical research – are
on the horizon and hold great promise for improving the
status-quo.
Though better management has substantially
reduced morbidity and mortality, the consequent increase in life
expectancy necessitates multidisciplinary care to mitigate the
clinical sequelae of iron overload such as endocrine dysfunction
and nutritional deficiencies. A study in this issue conducted by
Bhat, et al. [5] suggests that low levels of vitamin C might be
very common amongst individuals affected by
transfusion-dependent thalassemia. In the study group a large
majority of children were found to have vitamin C deficiency,
which was in turn found to be associated with iron overload and
higher oxidant levels. Supplementation with vitamin C in
deficient patients led to a safe reduction of oxidant levels,
which suggests that supplementation of vitamin C along with
dietary counse-ling might reduce oxidative stress and thereby
protect against myocardial damage. Another study in this issue
by Singh and colleagues [6] reported that over a quarter of
patients in their study cohort required hormone replace-ment
therapy due to pubertal arrest/failure despite regular
transfusions, intensive chelation, and regular follow-up. High
systemic iron load was found to be the only statistically
correlated determinant of pubertal arrest/failure, signaling the
need for further personalization of iron chelation regimes based
on genetic susceptibility to higher iron-overload.
Novel treatments such as Hb-F induction
therapy and gene therapy are eagerly awaited as they have the
potential to reduce the need for frequent blood transfusions and
consequent iron overload. The use of hydroxyurea (hydroxycarbamide)
has been studied in India [7], where the authors found a mixed
response to hydroxyurea in cohorts of thalassemia intermedia and
thalassemia major patients. The correlation of certain
haplotypes with response to hydroxyurea supported the hypothesis
that response was governed by variable genetic mutations,
biochemical interactions, and
g/g
globin chain production. In a unique study included in this
issue, Chandra and colleagues [8] report that over 75% of
transfusion-dependent thalassemia patients in their cohort
experienced a significant reduction in transfusion requirement
and serum ferritin levels after administration of thalidomide
over a 6-month period. Though encouraging, larger studies will
be required to establish a safe and effective dosage regime,
adverse event profile, drug interactions, and long-term effects
of this intervention.
Repurposing drugs such as hydroxyurea and
thalidomide might provide an effective way to reduce dependence
on blood transfusions and iron chelation therapy; however,
purpose-built novel therapies can take this a step further.
Luspatercept, the activin II receptor trap, targets ineffective
erythropoiesis and thereby decreases transfusion frequency in
transfusion-dependent thalassemia patients – other similar
therapies undergoing trials include Sotatercept and JAK2
inhibitors [9]. Minihepcidin, Ferroportin and TMPRSS6 inhibitors
are promising novel therapies that improve iron dysregulation,
especially in non-transfusion-dependent thalassemia patients
[9]. In this issue, Soni [10] reviews gene therapy treatment
strategies including gene insertion-based lentiviral vectors
such as the recently EU-approved Zynteglo, and CRISPR-Cas9 based
gene-editing of BCL11A, amongst others; these novel
therapies will provide a long-awaited alternative to patients
who do not have an HLA-matched donor for allogeneic
hematopoietic stem cell transplant.
There is a high cost associated with
thalassemia management, novel therapies, and allogeneic
hemato-poietic stem cell transplants, hence reducing the burden
of thalassemia will simultaneously necessitate robust and
multi-pronged preventive interventions including precon-ception,
prenatal, and newborn screening. India’s regional heterogeneity
of HBB mutations has been studied by Colah, et al. [11]
amongst others and has led to the establishment of such programs
at various centers in India. It is important that such programs
also include appropriate counselling to address fear and stigma
associated with being diagnosed as a carrier and enable informed
reproductive decision-making amongst high-risk couples [12].
In India,
b-thalassemia
poses a significant socio-economic burden [13]. The discoveries
and innovations covered in this issue have the potential to
greatly reduce this burden and improve the quality of life of
affected individuals. Simultaneous public health interventions
that improve access and adherence will be necessary to tap into
this potential. Given India’s underdeveloped reimbursement
landscape, relatively low healthcare expenditure, and myriad
public health priorities, successful implementation of new
therapies, management strategies, and prevention programs will
require structured and sustained collaboration between
stakeholders across healthcare, government, social, and private
sectors. All in all, innovative public health interventions
coupled with cross-sector collaboration will enable translation
of the exciting new research published in this issue and
elsewhere into better outcomes for India’s large thalassemia
community.
Funding: None; Competing interests:
None stated.
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