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those treated with the agent for a longer duration,
Dr. Al-Samkari reported.
In the efficacy analysis, researchers examined
the change in HSS from pretreatment to maintenance
during a designated timeframe of up to 36
weeks, as well as changes in the individual patient
mean hemoglobin, average maintenance epistaxis
severity score (ESS), individual RBC transfusion
requirements, and individual patient intravenous
iron infusion requirements.
In the year following bevacizumab administration,
patients achieved significantly higher mean
hemoglobin levels, which increased by 3.2 g/dL
from pre- to post-treatment (8.6 g/dL vs. 11.8 g/
dL, respectively; p<0.0001). In addition, bevacizumab
was associated with a significant 3.4-point
reduction in the mean ESS (6.8 vs. 3.4; p<0.0001).
Bevacizumab also led to an 82% reduction in
the median number of transfused RBC units, from
9 units during the 6 months before treatment to
0 units during the first 6 months of treatment
(p<0.0001). Participants experienced a similar
reduction in the need for iron transfusions, from
8 to 2 units in the first 6 months of treatment
(p<0.0001). No difference was found between disease
severities or underlying pathogenic gene
mutation (ENG vs. ACVRL1) in terms of treatment
efficacy or outcomes.
Overall, Dr. Al-Samkari said, approximately
two-thirds of patients who were anemic at baseline
achieved freedom from anemia following
treatment with bevacizumab. These “significant
and striking improvements” were observed in a
“cohort of patients with a rare disease treated with
a biologic therapy,” he added, “and [the study] had
the size and scope capable of doing subgroup
analyses to compare maintenance strategies and
treatment effects by underlying genotype.”
However, he noted that the study was limited
by its lack of a control group, retrospective
design, and the lack of assessment of patientreported
quality of life both before and after bevacizumab
treatment.
The authors report relationships with Agios, Dova,
and Amgen.
Reference
Al-Samkari H, Kasthuri R, Albitar H, et al. An international multicenter study of systemic
bevacizumab for bleeding in hereditary hemorrhagic telangiectasia: The InHIBIT-
Bleed study. Abstract S320. Presented as part of EHA25 Virtual, June 12, 2020.
CRISPR-Based Therapy Targeting BCL11 Shows Clinical Benefit
in SCD and Beta-Thalassemia
Treatment with the CRISPR/Cas9 gene-editing
therapy CTX001 was associated with successful
neutrophil and platelet engraftment in 2 patients
with transfusion-dependent β-thalassemia (TDT)
and 1 patient with severe sickle cell disease (SCD),
according to early results from a phase I/II trial. The
therapy also led to long periods of transfusion independence
in all 3 patients.
Findings from this study, which were presented
at the remotely held 25th European Hematology
Association Annual Congress (EHA25 Virtual)
by Selim Corbacioglu, MD, of the Regensburg
University Hospital in Germany, offer insight into
a promising, first-of-its-kind strategy for the management
of hemoglobinopathies.
Clinically meaningful
increases in fetal and
total hemoglobin were
achieved early and
maintained.
CTX001 is designed to suppress BCL11A, which
results in an upregulation of fetal hemoglobin
(HbF), Dr. Corbacioglu explained, adding that elevated
HbF is associated with decreased disease
severity in both thalassemia and SCD. Increases in
HbF may reduce or eliminate a patient’s requirement
for transfusion and decrease the incidence of
vaso-occlusive crises (VOCs) in patients with SCD.
Dr. Corbacioglu and colleagues enrolled 2 patients
with TDT who had received packed red blood cell
(pRBC) transfusions of ≥100 mL/kg per year or ≥10
units per year in the 2 years prior to enrollment.
Another patient with severe SCD (defined as ≥2 VOCs
per year in the previous 2 years) also was enrolled.
Following mobilization with the granulocyte
colony-stimulating factor filgrastim and plerixafor
(for TDT) or plerixafor alone (for SCD), the investigators
collected CD34-positive hematopoietic
stem/progenitor cells by apheresis. Next, they
used CRISPR-Cas9 to edit the CD34-positive cells,
using a guide RNA specific for BCL11A’s erythroid
enhancer region. Patients then received myeloablative
conditioning with busulfan, followed by
CTX001 infusion on day 1.
Patients were monitored for the following:
• stem cell engraftment/hematopoietic recovery
• adverse events (AEs)
• hemoglobin production
• hemolysis
• HbF and F-cell expression
• pRBC transfusion requirements for TDT
• VOCs for SCD
After CTX001 infusion, follow-up occurred at
12 months for the participants with TDT and 6
months for the participant with SCD.
The patients with TDT received CTX001 infusions
of 17.0×10 6 cells/kg and 12.3×10 6 cells/kg.
Successful engraftment of neutrophils occurred on
days 33 and 36, while engraftment of platelets was
achieved on days 37 and 34 post-infusion. In the
patient with severe SCD, who received a CTX001
infusion of 3.3×10 6 cells/kg, successful neutrophil
and platelet engraftment was achieved on day 30.
“Clinically meaningful increases in HbF and
total Hb were achieved early and maintained,” Dr.
Corbacioglu reported. For example, in the patient
with TDT and 15-month follow-up, total Hb levels
increased from 9.0 g/dL at baseline to 12.7 g/dL,
which included an HbF level of 12.4 g/dL. The
authors added that this patient has been transfusion
free since day 30 following CTX001 infusion.
The other patient experienced an Hb increase
from 10.1 g/dL to 12.5 g/dL at month 5 – 12.2 g/dL
of which was HbF – and remained transfusion free
for 3.5 months at last follow-up.
Similarly, in the patient with SCD, total Hb
increased from 7.2 g/dL to 11.3 g/dL at 6 months,
and HbF levels increased to measure 47.3% of
total Hb at 6 months. Again, this patient remained
transfusion independent since day 19 after study
treatment. Dr. Corbacioglu added that there were
no VOCs in this patient during the 6 months following
infusion.
Regarding safety, Dr. Corbacioglu reported that
“AEs were generally consistent with myeloablation
and autologous stem cell transplantation, so [there
was] nothing unexpected in these patients.”
The patient with TDT experienced 2 serious
AEs, but both events were deemed unrelated to
CTX001. The 2 serious AEs – busulfan-associated
veno-occlusive liver disease and pneumonia in the
presence of neutropenia – resolved.
A total of 3 post-CTX001 infusion serious AEs
occurred in the patient with SCD, including sepsis
while neutropenic, cholelithiasis, and abdominal
pain. All the serious AEs were considered unrelated
to CTX001.
The investigators agree that the findings offer a
promising new gene therapy option for this patient
population, but the study was limited by its small
sample size. Dr. Corbacioglu noted that enrollment
and manufacturing of CTX001 for TDT and SCD is
ongoing, with further dosing planned later in 2020.
The authors report relationships with Vertex
Pharmaceuticals and CRISPR Therapeutics, which
sponsored the trial.
Reference
Corbacioglu S, Cappellini MD, Chapin J, et al. Initial safety and efficacy results
with a single dose of autologous CRISPR-CAS9 modified CD34+ hematopoietic
stem and progenitor cells in transfusion-dependent B-thalassemia and sickle
cell disease. Abstract S280. Presented as part of EHA25 Virtual, June 12, 2020.
26 ASH Clinical News
July 2020 Bonus Mid-Year Edition