FEATURE
Confirming the Connection
In 1954, the geneticist Anthony C. Allison, PhD,
confirmed Haldane’s hypothesis while working in Kenya
– though for sickle cell anemia. In sickle cell anemia, the
HBB gene is mutated, but, unlike in beta thalassemia,
the mutation does not affect the abundance of beta
hemoglobin. With his research, Dr. Allison found that
individuals heterozygous for the mutation in the beta
hemoglobin associated with sickle cell anemia have a
relative resistance to malaria. 6
Then, in the late 1970s, when researchers were able
to culture malaria parasites in the laboratory, another
group confirmed Dr. Allison’s observations: P. falciparum
infection of red blood cells with the sickle cell mutation
increased cells’ rate of forming the sickle shape, and the
parasites were killed under these conditions. 7
Yet, for thalassemia, establishing exactly how the
disease protects against malaria has proven challenging,
Dr. Williams said, and efforts are further complicated
by the presence of additional genetic polymorphisms
that are quite common and can reverse the protection.
This occurs despite the presence of a so-called protective
hemoglobin mutation. For example, a beta hemoglobin
mutation on its own is protective against malaria, but if
the individual also has a mutation for sickle cell anemia,
the two mutations essentially cancel each other out and
the individual is susceptible to malaria infection. 8
The proposed mechanisms through which the alpha
and beta hemoglobin mutations guard against malaria are
categorized as either immune-related or cellular. These
include better immune clearance, decreased survival of
malaria parasite inside red blood cells, and decreased par-
asite capacity for invading the red blood cells.
In 2008, a joint team from the New York University
School of Medicine and the University of Oxford, work-
ing with children in Papua New Guinea who have alpha
thalassemia, found that their red blood cells were unusu-
ally small and more abundant, resulting in a mild form of
anemia, compared with red blood cells of children with-
out the genetic mutation that leads to the thalassemia. 9
They went on to show that the alpha thalassemia resulted
in an advantage against malaria infection.
Severe malaria resulted in an as high as a 50-percent
decrease in red blood cells, but children with mild alpha
thalassemia were able to tolerate this loss because they
already had up to 20 percent more red blood cells to start
with, compared with children without thalassemia.
“There has never been a clinical study that has defini-
tively shown that a beta thalassemia mutation is strongly
protective against malaria,” Dr. Williams said, but re-
searchers and clinicians have no doubt that these genes
are indeed protective against malaria, as red blood cell
characteristics are the only traits that come up as positive
in studies of malaria protection. 10
Still, there is no clear and irrefutable mechanism
about how either alpha or beta thalassemia protects
against malaria on which the research community can
agree, according to Dr. Williams. “It is difficult to study
these conditions in the lab because the red blood cells
from patients are inherently prone to oxygen damage
and stress,” he explained. “When we do experiments with
them in the lab, we can find things that look abnormal,
but whether those results actually reflect what is going on
in vivo is difficult to know because the cells become dam-
aged by the lab manipulations,” he explained.
Last but not least, establishing a strong connection
between malaria and beta thalassemia mutations is made
even more difficult by the fact that many of the places
where beta thalassemia has remained are no longer
hotspots for malaria.
“In Greece, malaria was still prevalent about 100 years
ASHClinicalNews.org
ago because there were many more lakes where malaria-
carrying mosquitos could lay eggs,” Antonis Kattamis,
MD, told ASH Clinical News. Dr. Kattamis is head of
the division of pediatric hematology/oncology at the
National and Kapodistrian University of Athens and the
Aghia Sophia Children’s Hospital in Athens, where he
treats patients with thalassemia. “Most of the lakes have
dried up in the last century, so we haven’t had malaria for
many years.”
The Burden of Thalassemia in the
Mediterranean Basin
Like malaria, thalassemia also was once highly prevalent
in these areas: The estimated carrier rate for a thalassemia-
related mutation in the Mediterranean region is between
8 and 15 percent. 11 Based on this rate, Dr. Kattamis said,
clinicians would expect to see about 200 to 250 cases
annually. But awareness campaigns in Greece, Italy, and
other countries have dramatically decreased thalassemia
rates.
In his practice, Dr. Kattamis said he sees about 380
patients with thalassemia on a regular basis, or about 12
percent of the approximately 3,000 patients in Greece
who require regular care for their thalassemia. Most of
the patients are older, given the decreased rate of new
thalassemia cases.
People with severe thalassemia present with symp-
toms a few months to one year after birth, Dr. Kattamis
said. “With severe thalassemia, babies do not grow well
and may have jaundice, and patients bring their children
in because they are seeing a failure to thrive.”
“If a person is homozygous for a beta- or alpha-
thalassemia mutation, he or she has no effective hemoglobin
protection,” Dr. Williams explained, “and after the first
few months of life, the individual is chronically anemic and
dependent on blood transfusions.” Without this therapy,
patients otherwise could die from anemia-related com-
plications, including cardiac failure.
However, lifelong transfusions can lead to complica-
tions, like iron overload. “The red blood cells that patients
receive are rich in iron, and these individuals don’t have
good ways to excrete the iron, so we then have to treat
them with iron-chelating medications,” he explained.
These medications, called chelators, bind to excess iron,
effectively soaking it up. If left untreated, iron overload
can lead to chronic iron toxicity, endocrine problems, and
cardiac or hepatic failure.
Apart from transfusions, a young patient with a sib-
ling donor also can also undergo a curative bone marrow
transplant. According to Dr. Kattamis, approximately one
in five or six patients undergoes such a procedure.
New drug therapies are being developed as
alternatives to chronic red blood cell transfusions and
transplantation. For example, luspatercept, a first-in-class
erythroid maturation agent, is designed to enhance late-
stage erythropoiesis and reduce the need for transfusions.
In the phase III BELIEVE trial, 70 percent of patients
with transfusion-dependent beta thalassemia experienced
a greater-than-33-percent reduction in their transfusion
burden. At the 2018 American Society of Hematology
Annual Meeting, principal investigator Maria Domenica
Cappellini, MD, from the University of Milan in Italy,
commented that the agent is a potential new therapy
for “this very demanding disease. These are young adult
patients transfusing three units of blood every three weeks
for all their lives, so [the reduction in transfusion burden
with luspatercept] has a substantial impact.” 12
Gene therapies also are on the horizon. Earlier this
year in the New England Journal of Medicine, researchers
published results from two companion phase I/II trials
in showing that treatment with gene therapy reduced or
eliminated the need for red blood cell transfusions in
patients with severe disease. 13 “Gene therapy with the
LentiGlobin drug product succeeded in overcoming a
principal limitation of [bone marrow transplant], which
is a lack of a histocompatible donor,” the authors noted.
Together, prevention programs and new therapeutic
options have improved the prognosis for thalassemia, to
the point that it is now considered a chronic disorder. Dr.
Kattamis noted efforts that are under way to identify op-
timal blood transfusion therapies and management of re-
lated complications, noting that, “with treatment, patients
have a fairly good life expectation, and about 70 percent
will live to age 50.” But, as with any other chronic condi-
tion in any other geographic area, he said, survival and
quality of life depend on the development and adherence
to a treatment plan. —By Anna Azvolinsky ●
REFERENCES
1. Haldane JBS. The rate of mutation of human genes. Hereditas. 1949;35:267-73.
2. National Institutes of Health,. Genetics Home Reference. “Beta thalassemia.” Accessed
December 11, 2018, from https://ghr.nlm.nih.gov/condition/beta-thalassemia.
3. Viganó C, Hass C, Rühli FJ, Bouwman A. 2,000 year old β-thalassemia case in Sardinia sug-
gests malaria was endemic by the Roman period. Am J Phys Anthropol. 2017;164:362-70.
4. World Health Organization. “Malaria.” Accessed December 11, 2018, from http://www.who.
int/news-room/fact-sheets/detail/malaria.
5. Opi DH, Ochola LB, Tendwa M, et al. Mechanistic studies of the negative epistatic malaria-
protective interaction between sickle cell trait and α+thalassemia. EBioMedicine.
2014;1:29-36.
6. Allison AC. The distribution of the sickle-cell trait in East Africa and elsewhere, and its ap-
parent relationship to the incidence of subtertian malaria. Trans Royal Soc Trop Med Hyg.
1954;48:312-8.
7. Friedman MJ, Roth EF, Nagel RL, Trager W. Plasmodium falciparum: physiological interac-
tions with the human sickle cell. Exp Parasitol. 1979;47:73-80.
8. Leffler EM, Band G, Busby GBJ, et al. Resistance to malaria through structural variation of
red blood cell invasion receptors. Science. 2017;356:eaam6393.
9. Willcox M, Björkman A, Brohult J, et al. A case-control study in northern Liberia of
Plasmodium falciparum malaria in haemoglobin S and beta-thalassaemia traits. Ann Trop
Med Parasitol. 1983;77:239-46.
10. Fowkes FJ, Allen SJ, Allen A, et al. Increased microerythrocyte count in homozygous α+-
thalassaemia contributes to protection against severe malarial anaemia. PLoS Med.
2008;5:e56.
11. De Sanctis V, Kattamis C, Canatan D, et al. β-thalassemia distribution in the Old World:
an ancient disease seen from a historical standpoint. Mediterr J Hematol Infect Dis.
2017;9:e2017018.
12. Cappellini MD, Viprakasit V, Taher A, et al. The Believe trial: results of a phase 3, randomized,
double-blind, placebo-controlled study of luspatercept in adult beta-thalassemia patients
who require regular red blood cell (RBC) transfusions. Abstract #163. Presented at the 2018
ASH Annual Meeting, December 1, 2018; San Diego, CA.
13. Thompson AA, Walters MC, Kwiatkowski J, et al. Gene therapy in patients with transfusion-
dependent β-thalassemia. N Engl J Med. 2018;378:1479-93.
Highlights of ASH® in the Mediterranean
Athens, Greece
March 15 – 16, 2019
At this new event, co-hosted by the Hellenic Society
of Hematology, internationally recognized experts
will analyze the latest updates in hematology
research from the 2018 American Society of
Hematology annual meeting. Visit hematology.
org/Highlights/Mediterranean.aspx for more
information.
ASH Clinical News
29