From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
l l l PLATELETS & THROMBOPOIESIS
Comment on Zhou et al, page 1541, and Lim et al, page 1526
ITP and TTP: interpreting evidence
in
light of patient values
----------------------------------------------------------------------------------------------------Adam Cuker
UNIVERSITY OF PENNSYLVANIA
In this issue of Blood, data presented by Zhou et al1 and Lim et al2 on the use
of rituximab (RTX) to treat immune thrombocytopenia (ITP) and thrombotic
thrombocytopenic purpura (TTP), respectively, illuminate the importance of
considering patient values and preferences in the interpretation of clinical
evidence.
Z
hou et al randomized 123 adults with
persistent or chronic ITP who failed
to respond to or relapsed after tapering
corticosteroids to open-label RTX 100 mg
weekly, alone, or in combination with
recombinant human thrombopoietin (rhTPO),
for 4 weeks. Treatment was well tolerated in
both arms. The rate of complete response
(platelet count $100 3 109/L) was greater
(45.4% vs 23.7%, P 5 .026) and time to
response was shorter (7 vs 28 days, P 5 .004)
in the combination therapy arm. At first
blush, these findings suggest important
potential advantages of the combination
regimen. However, evaluation of evidence
in light of patient values and preferences
offers a different perspective.
ITP is associated with reduced healthrelated quality of life.3 Although individual
patient experiences vary, important sources
of diminished quality of life include fear of
bleeding and the unpredictable and disruptive
nature of relapse. The addition of 4 weeks of
rhTPO to RTX did little to address these
patient-important outcomes. A platelet count
$30 3 109/L is sufficient for prevention
of serious bleeding in most patients and
situations. Although the rate of complete
response was augmented in the combination
therapy arm, overall response (platelet count
$30 3 109/L and doubling from baseline)
was not (79.2% vs 71.1%, P 5 .36). In
keeping with this observation, there was no
significant difference in bleeding between the
two treatment arms. Neither did the addition
of rhTPO reduce relapse; sustained response
rates were not significantly different in the
treatment arms at 6, 12, or 24 months. Only
24.6% and 18.5% of patients remained relapse-
1514
free at 24 months in the combination and
monotherapy arms, respectively, confirming
the disappointing long-term platelet responses
with RTX reported by other investigators.4,5
Lim et al provide a timely systematic
review on RTX for the management of
acquired TTP.2 They evaluated evidence
regarding RTX for 3 distinct indications: (1)
as initial therapy along with plasma exchange
(PEX) and corticosteroids; (2) as supplemental
therapy in patients with disease refractory
to PEX and corticosteroids; and (3) as
prophylactic therapy in asymptomatic patients
with severe ADAMTS13 deficiency (,10%)
following recovery from a clinical episode of
TTP. Evidence is extremely limited and of
poor quality for all 3 indications, highlighting
the need for well-performed prospective
studies in this area. Indeed, only one
(historically) controlled study was identified
for each indication. Based on their review,
the authors suggest that RTX be considered
for initial therapy (grade 2C) and recommend
its use in refractory patients (grade 1C) along
with PEX and corticosteroids.
On the contrary, Lim et al make a
strong recommendation against the use of
prophylactic RTX in asymptomatic patients
with low ADAMTS13 activity (grade 1C).
This recommendation is based primarily on
a single cohort study comparing outcomes in
30 patients treated with RTX to 18 patients
who did not receive RTX.6 Although median
ADAMTS13 activity rose to 46% at 3 months
and relapse-free survival was longer (P 5 .049)
in the RTX group, Lim et al rightly point
out limitations of the data. These include
the use of immunosuppressive therapies in
addition to RTX in the RTX group and longer
follow-up in the control group, where both
could have biased results in favor of the RTX
group. They also note that ADAMTS13
activity did not increase in all patients after RTX
and that activity measurement may vary based
on the assay system.2 These are crucial limitations
that undoubtedly undermine the strength of
the evidence. Nevertheless, one is forced to reexamine the recommendation against prophylactic
RTX when the evidence is viewed through the
lens of patient values and preferences.
Relapse is not uncommon in patients with
acquired TTP. In the Oklahoma registry, 34%
of patients with TTP accompanied by severe
ADAMTS13 deficiency (,10%) at the time
of presentation relapsed over a median of
4.7 years.7 Several studies suggest that the risk
of relapse is magnified in patients with severe
ADAMTS13 deficiency in remission.8-10 TTP
relapses are life-changing events. At best,
they are terrifying and highly disruptive to
patients’ lives. At worst, they remain fatal in
approximately 10% of cases. Emerging
evidence suggests that survivors manifest
long-term cognitive and physical deficits.11 On
the other hand, RTX, while not without toxicity,
is safe and well tolerated by most patients. Faced
with these facts, many patients (particularly
those with multiply relapsed disease), in my
experience, are willing to accept the uncertain
benefits and potential harms of RTX for a shot at
staving off relapse. I cannot say I blame them.
The reports by Zhou et al and Lim et al
provide important contributions to our
understanding of the management of ITP
and TTP, and highlight the need for further
studies. They also remind us that such studies
should be designed with patient-important
outcomes in mind and interpreted in the light
of patient values and preferences.
Conflict-of-interest disclosure: The author
declares no competing financial interests. n
REFERENCES
1. Zhou H, Xu M, Qin P, et al. A multicenter randomized
open-label study of rituximab plus rhTPO vs rituximab in
corticosteroid-resistant or relapsed ITP. Blood. 2015;125(10):
1541-1547.
2. Lim W, Vesely SK, George JN. The role of rituximab in
the management of patients with acquired thrombotic
thrombocytopenic purpura. Blood. 2015;125(10):1526-1531.
3. McMillan R, Bussel JB, George JN, Lalla D, Nichol
JL. Self-reported health-related quality of life in adults
with chronic immune thrombocytopenic purpura. Am J
Hematol. 2008;83(2):150-154.
4. Patel VL, Mahévas M, Lee SY, et al. Outcomes 5 years
after response to rituximab therapy in children and adults
with immune thrombocytopenia. Blood. 2012;119(25):
5989-5995.
BLOOD, 5 MARCH 2015 x VOLUME 125, NUMBER 10
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
5. Khellaf M, Charles-Nelson A, Fain O, et al. Safety and
efficacy of rituximab in adult immune thrombocytopenia:
results from a prospective registry including 248 patients.
Blood. 2014;124(22):3228-3236.
6. Hie M, Gay J, Galicier L, et al; French Thrombotic
Microangiopathies Reference Centre. Preemptive
rituximab infusions after remission efficiently prevent
relapses in acquired thrombotic thrombocytopenic
purpura. Blood. 2014;124(2):204-210.
7. Kremer Hovinga JA, Vesely SK, Terrell DR, Lämmle
B, George JN. Survival and relapse in patients with
thrombotic thrombocytopenic purpura. Blood. 2010;115(8):
1500-1511.
8. Ferrari S, Scheiflinger F, Rieger M, et al; French
Clinical and Biological Network on Adult Thrombotic
Microangiopathies. Prognostic value of anti-ADAMTS
13 antibody features (Ig isotype, titer, and inhibitory
effect) in a cohort of 35 adult French patients undergoing
a first episode of thrombotic microangiopathy with
undetectable ADAMTS 13 activity. Blood. 2007;109(7):
2815-2822.
9. Peyvandi F, Lavoretano S, Palla R, et al. ADAMTS13
and anti-ADAMTS13 antibodies as markers for recurrence
of acquired thrombotic thrombocytopenic purpura during
remission. Haematologica. 2008;93(2):232-239.
10. Jin M, Casper TC, Cataland SR, et al. Relationship
between ADAMTS13 activity in clinical remission and
the risk of TTP relapse. Br J Haematol. 2008;141(5):
651-658.
11. Lewis QF, Lanneau MS, Mathias SD, Terrell DR,
Vesely SK, George JN. Long-term deficits in healthrelated quality of life after recovery from thrombotic
thrombocytopenic purpura. Transfusion. 2009;49(1):
118-124.
© 2015 by The American Society of Hematology
l l l PLATELETS & THROMBOPOIESIS
Comment on Meng et al, page 1623, and Sharda et al, page 1633
Defective platelet autocrine
signaling
in HPS
----------------------------------------------------------------------------------------------------Brian Storrie
UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES
In this issue of Blood, Meng et al1 and Sharda et al2 use the Hermansky-Pudlak
syndrome (HPS) as a model to show that adenosine 59-diphosphate (ADP)
released by dense granules serves as an autocrine signal to potentiate platelet
release of a-granule and lysosome cargo and protein disulfide isomerase (PDI),
all of which serve to stabilize thrombus formation.
G
enetic defects in bleeding present a clinical
challenge and a handle to understand the
underlying molecular basis of disease. Inherited
platelet bleeding disorders represent one such
example of a chronic disease as well as a research
opportunity.3 Many of these disorders affect the
formation of specialized storage compartments
within platelets, termed lysosome-related
organelles (LROs).4 These organelles include
the a-granule, a protein storage site, the dense
granule in which small molecules such as ADP,
serotonin, and polyphosphates are stored, and the
lysosome itself. The a-granule is much more
abundant than other LROs and has long been
considered a key organelle with respect to platelet
function. HPS, a defect in platelets specific for
dense granule formation that produces a distinct
bleeding disorder, provides strong evidence for
the importance of the dense granule. The HPS
patient and mouse model are then an attractive
research example.
Working independently, Meng et al in
Philadelphia and Sharda et al in Boston reveal
BLOOD, 5 MARCH 2015 x VOLUME 125, NUMBER 10
a surprising answer to the puzzle of the HPS
phenotype. In essence, the 2 groups find that
the dense granule is important here, not for
its direct role in building a platelet plug, but
rather because ADP released from dense
granules potentiates a-granule cargo release
and to some extent lysosome and T-granule
secretion. In brief, ADP is a signaling molecule
released locally from dense granules as an
autocrine regulator of platelet a-granule
cargo release. How we know this experimentally
builds from the molecular basis of HPS,
a rare bleeding disorder caused by a series
of single-gene mutations that affect the
biogenesis of LROs including melanosomes
and dense granules. In mice, there are
16 loci that independently produce the HPS
phenotype.5 These typically affect the
machinery for protein sorting and delivery
to LROs and often go by colorful names such
as gunmetal, light ear, pallid, or sandy because
of their effects on melanosome formation.
In fact, work with the ruby-eye HPS model
foreshadowed some of these overall
conclusions.6
Experimentally, the 2 groups emphasized
different aspects and somewhat different
approaches in arriving at what are the same
general conclusions. The Philadelphia group,
led by Michael Marks, concentrated on the
relationship between mutations in 3 HPS loci,
AP-3, BLOC-3, or BLOC-1, and defects in
the secretion by other LROs, namely, the
a-granule and lysosome.1 The formation
of a-granules and lysosomes was normally
to minimally affected. However, ex vivo
secretion from both was impaired. High
agonist doses or most significantly in this
case, supplemental ADP, restored normal
a-granule secretion, suggesting that the
defect in a-granule secretion was secondary
to the dense granule defect. Rescue of
lysosome enzyme secretion was incomplete.
Intravital microscopy after laser-induced
vascular injury in HPS mice confirmed that
in vivo a-granule secretion was reduced. The
authors conclude that secondary reductions
in a-granule and lysosome secretion are
contributors to the pathology of HPS. In
contrast, the Boston group, led by Barbara
and Bruce Furie, places more emphasis on
intravital microscopy in a mouse model of
HPS, wild-type platelet-rescue experiments,
and the use of model gene-silencing
experiments in human vascular endothelial
cells.2 In addition to variations in the
experimental approach, the Boston group
concentrates on PDI secretion. PDI catalyzes
disulfide-bond formation that is essential to
the formation of stable platelet plugs. The
authors found that extracellular PDI was
greatly reduced along with platelet deposition
and fibrin generation in HPS6– mice after
vascular injury. As was seen in the Philadelphia
study, ADP supplementation corrected
impaired exocytosis of a-granules, lysosomes,
and T granules. Again, based on ADP rescue,
many of the traits of LRO secretion were
found to be secondary to defective dense
granule formation and ADP release in HPS.
In sum, impaired secretion of many proteins
including PDI contributes to the bleedingdefect phenotype.
If we take HPS as a hereditary disease in
which much of the phenotype, including
bleeding defects, is a secondary consequence
of defective dense formation, what does the
secreted ADP do and how can one small
signaling molecule produce such a myriad
1515
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
2015 125: 1514-1515
doi:10.1182/blood-2015-01-622555
ITP and TTP: interpreting evidence in light of patient values
Adam Cuker
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