Drawing First Blood
sibling donor, we strongly recommend that approach.
However, even if there is a perfectly matched sibling,
there remains a 3% to 5% risk of transplant-related
mortality. For most parents of young children with
beta-thalassemia, the only acceptable number is zero
percent. Adequate management with transfusion and
iron control gives the patient and his family the time
and opportunity to discuss options.
Dr. Thompson: Any of these cures has a cost. In
addition to the risk of transplant-related mortality,
all curative approaches carry the risk of infertility.
No matter what kind of transplant – gene therapy,
alloHCT, or autologous hematopoietic cell trans-
plantation – infertility is still a burden we are not
able to alleviate. I am encouraged by some of the
progress in fertility cryopreservation in young
children, but this is still experimental. In our
experience, if fertility is a high priority, parents
of children with sibling matches have deferred
transplant to ensure that they allow the child time
to participate in that decision.
Dr. Coates: Another concern about gene therapy
are the less-exciting outcomes seen in patients with
the ß 0 genotype, compared with those in patients
with the ß + genotype. We also have seen that some
patients who receive gene therapy are developing
thalassemia intermedia instead, when only sporadic
or no transfusions are required. These represent
some of the most complicated patients to follow,
even for physicians with extensive experience in
managing thalassemias.
If patients undergo gene therapy and their
hemoglobin levels are at 11 or 12 g/dL, I anticipate
gene therapy will continue to provide long-term
clinical benefit; however, if patients undergo gene
therapy and their hemoglobin levels linger at 8 or
9 g/dL, they might develop the same long-term
complications seen with thalassemia intermedia.
In contrast, after a sibling or unrelated donor
alloHCT, patients essentially no longer have
thalassemia.
Dr. Thompson: We have managed a fair number
of patients who have thalassemia intermedia, and
I am struck by how severely their quality of life
worsens over time compared with some of our
patients with transfusion-dependent thalassemia
– irrespective of transplantation. As we look to
improve gene therapy, it must be with the intent
to normalize hemoglobin and iron homeostasis.
Without achieving those goals, we may see im-
provements in terms of scientific measures, but we
will fall short in terms of clinical improvement.
Dr. Coates: Thalassemia intermedia brings me to
another topic: the current enthusiasm for luspa-
tercept. 3 This drug is thought to work by inhibit-
ing ineffective erythropoiesis. The BELIEVE trial
showed that it was efficacious in transfusion-
dependent patients, meeting all major transfusion
burden–related endpoints. Data from the pre-
liminary studies in non–transfusion-dependent
patients also are quite exciting, showing that, while
the approach did not cure the disease, it markedly
improved disease burden – particularly in those
with hemoglobin levels of 8 to 9 g/dL. 4
Again, this is a huge problem in the U.S. because
patients with non–transfusion-dependent beta-
thalassemia are often not recognized as having
44
ASH Clinical News
thalassemia by many hematologists or general prac-
titioners. Luspatercept will probably be an exciting
option for them, but I wonder what effect luspater-
cept would have on patients with hemoglobin levels
of 8 or 9 g/dL who have received gene therapy.
Dr. Thompson: That is an intriguing idea. It could
very well be that a treatment like luspatercept
could be added post–gene-therapy infusion to
increase hemoglobin levels and perhaps eliminate
the need for transfusion.
It’s hard not to be thrilled with the early out-
comes of gene therapy, yet the approach clearly is
not for every patient with transfusion-dependent
thalassemia. Certain patients feel that there are still
too many questions about gene therapy, and they
are concerned about the lifestyle changes neces-
sary to undergo this procedure. I can imagine that
a patient who is finishing college, has a first job, or
is raising a young family might not want to put his
or her life on hold for even two or three months to
undergo a potential curative therapy for which we
don’t have long-term data.
Luspatercept, understandably, would be more
appealing for these types of patients: We could
give them an injection when they come in for a
transfusion and minimize or eliminate their need
for future transfusions, and they can continue with
their lives as usual.
Dr. Coates: When we talk about potentially curing
thalassemia, we also must consider the other option:
long-term maintenance. Again, I come back to the
issue of the availability of physicians who under-
stand how to manage thalassemia because it is such
a rare disease.
At our center, we are aggressive with transfu-
sions, so many patients receiving transfusions
actually have beta-thalassemia intermedia and
would be considered by other centers to have
non–transfusion-dependent disease. We see
few complications when patients’ iron levels are
controlled.
We also have to consider that, as patients with
beta-thalassemia intermedia age, they do not
tolerate their anemia as well and later become
transfusion dependent. Luspatercept will prob-
ably help a substantial portion of these “borderline
transfusion-dependent” patients, without the need
for transfusion. Therefore, luspatercept is going to
make the prospect of a non-transplant option even
more attractive to certain patients.
In clinical trials, the drug was shown to decrease
RBC transfusion requirements by approximately
30%, including among patients with thalassemia
intermedia and the β 0 genotype. My hope is that
luspatercept will allow us to achieve the same degree
of hemoglobin increase with less transfusion, which
would make the non-transplant approach even more
palatable for patients with thalassemia intermedia.
Dr. Thompson: This is a remarkable time in the
treatment of thalassemias. We have made it over
the big hurdles of providing safe transfusions,
monitoring iron noninvasively, and developing
more convenient chelators, but I can’t help but
think there is room for other advances for patients
with thalassemia. For example, the newer oral che-
lators have represented such an improvement over
the onerous medications like deferoxamine, which
required nightly subcutaneous infusion. Given the
dosing schedules and side-effect profiles of the oral
options, though, compliance and adherence are
still issues. Unfortunately, we do not have an ideal
chelator for some patients. Similarly, we don’t yet
know whether there is a role for drugs like hepci-
din to help with balancing iron load in patients.
The trials of gene-editing in thalassemia also are
just preparing to launch.
Dr. Coates: The major challenge to overcome with
chelation therapy is finding a chelator that can
be administered in a less-frequent schedule. Of
course, all these medications have the same fatal
flaw: They don’t work if you don’t take them. The
beauty of transplant is that, once a patient gets
through the process, the daily drug therapy falls
away.
Dr. Thompson: With gene therapy, at least in the
current research setting, patients must adhere to a
certain regimen postinfusion, but for a fairly fixed
period. Many patients will need to resume iron
chelation to fully unload residual tissue iron after
gene therapy, but most will not need long-term
medications. They will require close follow-up at a
specialized center postinfusion, then less frequent
monitoring after a few years. Compared with the
burdens of transfusion, chelation, and management
of other thalassemia complications, gene therapy
should give most patients remarkable freedom.
Dr. Coates: That freedom is also one of the advan-
tages of luspatercept; it is an injection administered
approximately once every three weeks, so adher-
ence should be a bit higher.
Iron is the factor I am always at the pulpit
about. Pediatric patients who undergo transplant
are now expected to survive for decades, so my big-
gest concern is the long-term consequences of ma-
lignant transformation. Research has shown that
patients receiving transfusions have an elevated
risk of developing leukemia and lymphoma later in
life, compared with those who were not transfused.
Dr. Thompson: We can both agree that we need
long-term follow-up to evaluate late effects of gene
therapy, as well as the consequences of pre-existing
organ injury from thalassemia. It is easy to talk
about the intent of curative therapies, but the
question we need to answer is, “Does this person
still have thalassemia?” Patients want to consider
themselves disease-free, and it is incumbent upon
us to remind them that, even after one of these
curative approaches, they will need surveillance for
a long time. ●
REFERENCES
1. 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.
2. Locatelli F, Walters MC, Kwiatkowski JL, et al. Lentiglobin gene therapy for
patients with transfusion-dependent β-thalassemia (TDT): results from the
phase 3 Northstar-2 and Northstar-3 studies. Abstract #1025. Presented at the
2018 ASH Annual Meeting, December 1, 2018; San Diego, CA.
3. 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.
4. Piga A, Perrotta S, Gamberini MR, et al. Luspatercept improves hemoglobin
levels and blood transfusion requirements in a study of patients with
β-thalassemia. Blood. 2019;133:1279-89.
June 2019