ASH News Daily 2017 - Issue 4 - A-6

Page A-6

ASH News Daily

Tuesday, December 12, 2017

GENE THERAPY

And Lions Lie Down With Lambs
By hugh young rienhoFF, Jr., Md

f ever there were a better parallel to Isaiah beating swords into
ploughshares and spears into
pruning hooks, it would be the use
of lentivirus to serve as a vector for
gene therapy. The Ernest Beutler
Lecture presented Monday by Dr.
Luigi Naldini of the San Raffaele
Telethon Institute for Gene Therapy
and Dr. Marina Cavazzana of the
Hopital Necker-Enfants Malades,
serves as evidence.
This journey began in the 1980s
when the HIV virus was first associated with AIDS. Coincident were
the first attempts to treat with retroviral or adenoviral vectors monogenic diseases such as adenosine
deaminase deficiency (ADA) and
hemoglobinopathies. These delivery systems posed serious challenges such as antigenicity, small payload sizes, insertional mutagenesis,
and frank oncogenesis and integration restricted to dividing cells. The
development of lentivirus as a gene
delivery system became prominent
with the 1996 Science publication

Myeloid

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World Health Organization classification of PV and ET were reviewed
including the new identification of
prefibrotic/early primary myelofibrosis (MF) as a distinct entity and
significant changes in the diagnostic criteria for PV, particularly the
lowering of hemoglobin thresholds
from 18.5 g/dL to 16.5 g/dL in men
and 16.5 g/dL to 16.0 g/dL in women to identify early-phase cases.
Earlier and more accurate diagnosis of PV and ET, improved risk
stratification for disease-related
morbidities, tailored treatment approaches, and novel therapeutics
have all converged to improve survival and quality of life for patients
dealing with these MPNs. Dr. Vannucchi discussed algorithms to use
in risk stratification and in choosing
first- and second-line therapy in patients. The talk ended with a call for
physicians to encourage patients to
consider participating in trials and
for industry to continue to invest in
innovation in PV and ET.
The most challenging MPN was
saved for the last talk, with Dr. Harrison providing an update on MF.
Increased therapeutic options, particularly the JAK inhibitor ruxolitinib and increased insight into the
genetic landscape of MF, have created a need for more complex treatment schemas. This complexity is
likely to escalate with emerging

of Dr. Naldini's work showing that
lentivirus could be successfully
used to achieve stable in vivo gene
delivery in nondividing cells using
a replication defective virus.
Similar to the development of
any new medicine, much work
lay in modifying and optimizing
the vectors and their method of
manufacture that led to the successful treatment of mouse models
of Mendelian diseases by the mid2000s. Along with that came a complement of valuable experimental
tools employing lentivirus vectors.
A series of observational papers describing the effects of gene transfer
on the biology of the recipient cells
provided guidelines as to expectations in the clinical setting. The clinical reality became clear with Dr.
Cavazzana's report in 2009 using
a lentivirus to transduce hematopoietic stem cells for the treatment
of X-linked cerebral adrenoleukodystrophy. The clinical benefit was
comparable to that of hematopoietic stem cell transplantation. With
that publication, Dr. Naldini in a
moment of triumph announced the
treatments and potential avenues
to more targeted therapeutic approaches. Dr. Harrison highlighted
the MIPSS70 as an important new
risk stratification tool in MF incorporating genetic factors. In addition
to discussing the specific role of
watch and wait, IFNα, ruxolitinib,
and stem cell transplantation in different risk groups, she stressed the
importance of taking an individualized approach with each patient.
Dr. Harrison stated that one of
the important questions surrounding MF at this year's annual meeting is now that we're six years from
ruxolitinib approval, what do we
understand about response and loss
of response? She reviewed updated
ruxolitinib data and discussed strategies to manage treatment-related
issues, including hematologic toxicity and infection risk. She lastly
reviewed the checkered results of
recent clinical trials with other JAK
inhibitors with a focus on the continued potential for several of these
agents.
Moving ahead, Dr. Harrison
believes the MF community is
"looking forward to other agents,
knowing that we will need a better
understanding of disease heterogeneity and pathophysiology at many
levels (stem cell, microenvironment, etc.) to identify new targets
and surrogate endpoints."
Dr. Forsberg and Dr. Shah indicated
no relevant conflicts of interest.

comeback of gene therapy and the
recovery of the field plagued with
skepticism and haunted by the earlier death of a recipient patient.
Drs. Naldini and Cavazzana discussed the long and winding path
each took. In addition to the promise of lentivirus gene therapy, they
addressed the current outstanding
issues in the field including the
ongoing optimization of vectors,
precision targeting, the durability
of clinical effects, the concerns of
genotoxicity, modifications to the

standard conditioning regimens,
and factors such as inflammation
that affect transduction efficiency.
What remains clear is that the vision of gene therapy as it began to
take hold in the 1980s was right; the
irony is that the heart of the plague
of AIDS is today a source of salvation thanks to the persistence of
Drs. Cavazzana and Naldini, and
their colleagues.

CLL

tion in the setting of kinase inhibitor
(KI) failure. The authors suggest that
patients failing KI tend to have more
metabolically active disease, and
PET scan readouts can be unreliable
in that setting.
In addition to this tremendous
body of work, abstract #263 detailed
the use of whole-exome sequencing
in identifying recurrent mutations in
patients who develop resistance to
venetoclax. Despite the small numbers, there are indictions that recurrent mutations in CDKN2A/B and
BTG1 can be found in these patients.
Although their functional significance remains to be determined, that
may not be an issue if we also start
patients on statins when we start
them on venetoclax, since that was
shown to improve the depth of response, not just for CLL patients but
also those with multiple myeloma
as reported in abstract #1737. Add
statins to the drinking water, I say.
In conclusion, the list of phenomenal abstracts focused on CLL
is long and cannot possibly be covered in this short piece; but a consistent theme that was observed
across various reports was the utility and efficacy of combinations of
novel therapeutic agents, resulting
in deep remissions that could be
used as a stopping rule for therapy.
Collectively this provides the optimism for a great future for patients
with this disease.

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abstract #387 suggested, could be
enhanced by ibrutinib through its
disruption of the IL-4 axis.
As to the waning use of chemoimmunotherapy (CIT) for patients with
CLL, while CIT is decreasing, ibrutinib use and the use of other similar
novel agents is on the rise and so is
our understanding of related issues.
Abstract #1743 compiled the bleeding data from earlier ibrutinib trials and suggested a low incidence
of bleeding. However, these data
should be interpreted with caution
since they do not reflect the realworld patient population that will
be treated with ibrutinib. They also
should not be used as a justification
for the routine use of antiplatelet
agents or anticoagulants with ibrutinib. Similarly, there is growing concern about the risk of invasive fungal infections in patients with CLL.
Abstract #4323 reported on 28 patients who developed invasive fungal infections while on ibrutinib and
was suggestive of a higher risk in
this cohort. However, a large study
of 566 patients with a long follow-up
revealed the incidence of all opportunistic infections to be low (<5%),
which appears to be consistent with
previous clinical experience (abstract #830). Similarly, abstract #834
casts doubt on the utility of PET
scan and a standardized uptake value cut-off higher than 10 to diagnose
patients with Richter's transforma-

Dr. Rienhoff indicated no relevant
conflicts of interest.

Dr. Awan indicated no relevant conflicts of interest.

Today's Remote Session Viewing Schedule
ASH Central: Hall B1
7:30-9:00 a.m.

Late-Breaking Abstracts Session (Channel 5)

9:30-9:45 a.m.

Announcement of Awards: William Dameshek
Prize and Henry M. Stratton Medal (Channel 1)

9:45-11:15 a.m.

Presidential Symposium (Channel 2)

11:15-11:30 a.m.

Business Meeting (Channel 3)

11:30 a.m.-1:00 p.m.

Best of ASH (Channel 4)

Table of Contents for the Digital Edition of ASH News Daily 2017 - Issue 4

ASH News Daily 2017 - Issue 4 - A-1
ASH News Daily 2017 - Issue 4 - A-2
ASH News Daily 2017 - Issue 4 - A-3
ASH News Daily 2017 - Issue 4 - A-4
ASH News Daily 2017 - Issue 4 - A-5
ASH News Daily 2017 - Issue 4 - A-6
ASH News Daily 2017 - Issue 4 - A-7
ASH News Daily 2017 - Issue 4 - A-8
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