Literature Scan
Gene Therapy Alleviates Transfusion Burden in Patients
With Beta-Thalassemia
Treatment with gene therapy reduced or eliminated the
need for long-term red blood cell (RBC) transfusions
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.
“We found that gene therapy with
LentiGlobin drug product succeeded
in overcoming a principal limita-
tion of allogeneic hematopoietic cell
transplantation, which is a lack of a
histocompatible donor,” wrote the
authors, led by Alexis A. Thompson,
MD, MPH, from Ann & Robert
H. Lurie Children’s Hospital of
Chicago and 2018 president of
the American Society of Hematol-
ogy. Their results, though early,
suggest that gene therapy may be
an alternative treatment option for
people who lack a suitable donor
for allogeneic hematopoietic-cell
transplantation.
“[This
approach]
succeeded in
overcoming
a principal
limitation of
[alloHCT],
which is
a lack of
a histo-
compatible
donor.”
—ALEXIS A. THOMPSON, MD, MPH
The trials expand on an earlier
single-patient, proof-of-concept
study in which investigators estab-
lished the feasibility of adding a
gene to autologous hematopoietic
cells using a lentiviral vector. The
patient was able to safely discon-
tinue transfusions for more than six
years.
In the recently published phase I/II
28
ASH Clinical News
trials, the researchers evaluated the safety and efficacy of
such gene therapy (BB305 vector) in 22 patients (18 in
HGB-204 and 4 in HGB-205) with beta-thalassemia of
any genotype who were transfusion-dependent. Transfu-
sion 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
BESPONSA™ (inotuzumab ozogamicin) is indicated for the treatment of adults
with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL)
AIM FOR DEEP
REMISSION
Deep remission refers to MRD-negative
remission, defi ned in the INO-VATE
ALL study as leukemic cells comprising
<1 x 10 -4 of bone marrow nucleated
cells per fl ow cytometry. 1
The effi cacy of BESPONSA was established on the basis of CR (35.8% [39/109; 95% CI,
26.8-45.5] with BESPONSA vs 17.4% [19/109; 95% CI, 10.8-25.9] with SC), the duration of
CR (8.0 months [95% CI, 4.9-10.4] with BESPONSA vs 4.9 months [95% CI, 2.9-7.2] with SC),
and the proportion of MRD-negative CR (89.7% [35/39; 95% CI, 75.8-97.1] with BESPONSA
vs 31.6% [6/19; 95% CI, 12.6-56.6] with SC) in the fi rst 218 randomized patients. 1
IMPORTANT SAFETY INFORMATION
WARNING: HEPATOTOXICITY, INCLUDING HEPATIC VENO-OCCLUSIVE
DISEASE (VOD) (ALSO KNOWN AS SINUSOIDAL OBSTRUCTION
SYNDROME) and INCREASED RISK OF POST–HEMATOPOIETIC STEM
CELL TRANSPLANT (HSCT) NON-RELAPSE MORTALITY (NRM):
• Hepatotoxicity, including fatal and life-threatening VOD, occurred in
patients who received BESPONSA. The risk of VOD was greater in
patients who underwent HSCT after BESPONSA treatment. The use
of HSCT conditioning regimens containing 2 alkylating agents and
last total bilirubin ≥ upper limit of normal (ULN) before HSCT were
signifi cantly associated with an increased risk of VOD
• Other risk factors for VOD in patients treated with BESPONSA
included ongoing or prior liver disease, prior HSCT, increased
age, later salvage lines, and a greater number of BESPONSA
treatment cycles
• Elevation of liver tests may require dosing interruption, dose
reduction, or permanent discontinuation of BESPONSA.
Permanently discontinue treatment if VOD occurs. If severe
VOD occurs, treat according to standard medical practice
• There was a higher post-HSCT non-relapse mortality rate in patients
receiving BESPONSA, resulting in a higher Day 100 post-HSCT
mortality rate
Hepatotoxicity, Including Hepatic VOD: Hepatotoxicity, including fatal and
life-threatening VOD, occurred in 23/164 patients (14%) during or following
treatment with BESPONSA or following subsequent HSCT. VOD was reported
up to 56 days after the last dose during treatment or follow-up without an
intervening HSCT. The median time from HSCT to onset of VOD was 15 days.
Patients with prior VOD or serious ongoing liver disease are at an increased
risk of worsening liver disease, including development of VOD, following
treatment with BESPONSA. Monitor closely for signs and symptoms of VOD;
these may include elevations in total bilirubin, hepatomegaly (which may be
painful), rapid weight gain, and ascites. For patients proceeding to HSCT,
the recommended duration of treatment with BESPONSA is 2 cycles. A third
cycle may be considered for patients who do not achieve a CR or CRi and
MRD-negativity after 2 cycles. Monitor liver tests closely during the fi rst
month post HSCT, then less frequently thereafter, according to standard
medical practice.
Grade 3/4 increases in aspartate aminotransferase, alanine aminotransferase,
and total bilirubin occurred in 7/160 (4%), 7/161 (4%), and 8/161 (5%)
patients, respectively.
Increased Risk of Post-HSCT Non-Relapse Mortality (NRM): There was a
higher post-HSCT NRM rate in patients receiving BESPONSA, resulting in a
higher Day 100 post-HSCT mortality rate. The rate of post-HSCT NRM was
31/79 (39%) with BESPONSA and 8/35 (23%) with investigator’s choice of
chemotherapy. In the BESPONSA arm, the most common causes of post-
HSCT NRM included VOD and infections. Monitor closely for toxicities post
HSCT, including signs and symptoms of infection and VOD.
Myelosuppression: Myelosuppression, and severe, life-threatening, and
fatal complications of myelosuppression, including hemorrhagic events
and infections, have occurred with BESPONSA. Thrombocytopenia and
neutropenia were reported in 83/164 patients (51%) and 81/164 patients
(49%), respectively. Febrile neutropenia was reported in 43/164 patients (26%).
Monitor complete blood counts prior to each dose of BESPONSA and
monitor for signs and symptoms of infection, bleeding/hemorrhage, or
other effects of myelosuppression during treatment and provide appropria