IN THE LITERATURE
Gene Therapy Reduces Transfusion Need in Patients
With Beta-Thalassemia
Treatment with LentiGlobin BB305 gene therapy reduced or
eliminated the need for long-term red blood–cell (RBC) trans-
fusions in some patients with severe, transfusion-dependent
beta-thalassemia, according to results of two companion
phase I/II trials (HGB-204 and HGB-205) published in the New
England Journal of Medicine.
“[This treatment] succeeded in overcoming a principal limita-
tion of allogeneic hematopoietic cell transplantation [alloHCT],
which is a lack of a histocompatible donor,” wrote the authors,
led by Alexis A. Thompson, MD, MPH, from the Ann & Robert
H. Lurie Children’s Hospital of Chicago and 2018 president of
the American Society o f Hematology. Their results, though early,
suggest that gene therapy may be an alternative treatment option
for people who lack a suitable donor for alloHCT.
The trials expand on an earlier single-patient, proof-of-concept
study in which investigators established the feasibility of adding
a gene to autologous hematopoietic cells using a lentiviral vector.
The patient was able to safely discontinue transfusions for more
than six years.
In the recently published phase I/II trials, researchers evalu-
ated the safety and efficacy of LentiGlobin BB305 gene therapy
in 22 patients (18 in HGB-204 and 4 in HGB-205) with beta-
thalassemia of any genotype who were transfusion dependent.
Transfusion dependence was defined as the receipt of at least
eight transfusions or at least 100 mL/kg of packed RBCs per year
in the two years before enrollment.
The trial population included nine patients with a β0/β0
genotype (the most severe form of beta-thalassemia), nine with a
βE/β0 genotype, and four with other genotypes.
The investigators obtained mobilized, autologous CD34-
positive cells from participants and transduced the cells ex vivo
with LentiGlobin BB305 vector, which encodes adult hemoglo-
bin (HbA) with a T87Q amino-acid substitution (HbAT87Q).
After undergoing conditioning with single-agent, intravenous
busulfan, modified cells were then re-infused at median doses of:
• 11.0 million CD34-positive cells/kg (range = 6.1 million to
18.1 million cells/kg) in people with a β0/β0 genotype
• 7.1 million CD34-positive cells/kg (range = 5.2 million to
13.0 million cells/kg) in those with other genotypes
Participants had started receiving transfusions at an early age
(median = 3.5 years in HGB-204 and 1.8 years in HGB-205
[range = 0-26 years and 0-14 years, respectively]). Median age at
the time of trial enrollment was 20 years in HGB-204 (range =
12-35 years) and 18 years in HGB-205 (range = 16-19 years).
After a median of 26 months of follow-up after infusion
(range = 15-42 months), the authors reported no serious adverse
events (AEs) related to gene therapy in either study. In HGB-204,
five grade 1 AEs were characterized as related or possibly related
to the drug product; the nine serious AEs reported in this study
were attributed to busulfan conditioning.
Following the infusion of the LentiGlobin drug product,
seven of the 22 treated patients expressed at least 8 g/dL of
HbAT87Q at the last visit, including three patients with a β0/β0
genotype. In addition, all have been free from transfusion for
more than one year.
“Although the studies were not designed to test specific
hypotheses about differences in the characteristics of the patients
or the drug products, clinical outcomes appeared to vary accord-
ing to the underlying genotype,” the authors noted.
All but one of the 13 patients with a non–β0/β0 genotype
stopped receiving RBC transfusions after gene therapy. At the last
study visit (12-36 months after infusion), the median HbAT87Q
level was 6.0 g/dL (range = 3.4-10.0 g/dL), and the median total
hemoglobin level was 11.2 g/dL (range = 8.2-13.7 g/dL) in
these patients.
Of the nine patients with a β0/β0 genotype, six had a median
HbAT87Q level of 4.2 g/dL (range = 0.4-8.7 g/dL) and continued
to receive transfusions. However, they experienced a 74 percent
reduction in their annual number of transfusions and a 73 percent
reduction in their annual transfusion volume (which ranged from
124 to 161 mL/kg in both trials), compared with the transfusion
needs two years before enrollment (p values not reported).
The remaining three patients with a β0/β0 genotype had
not received transfusions for 14 to 20 months, the investigators
added.
While not all patients were able to stop receiving RBC trans-
fusions, the investigators noted that “even the partial reduction
in transfusion requirements that we observed in these patients
may result in a reduction in iron load (and thereby long-term
damage to target organs) and an increased life expectancy.
The findings from these early-phase studies are limited by the
small number of patients enrolled, and the investigators noted
that extended follow-up is necessary to establish the durability
of transduced hematopoietic stem cells and progenitor cells after
a single infusion. “Long-term surveillance of treatment-related
toxicity related to the transfer of genes into hematopoietic stem
cells and progenitor cells, busulfan conditioning, or both will
also be necessary to define the therapeutic profile of this new
treatment approach,” they concluded.
The corresponding authors report financial relationships with
Bluebird Bio, which also supported this study.
REFERENCE
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.
October 2018
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