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confined to B-lymphoid cells. In contrast,
another subset of patients, perhaps accounting
for 20% to 25%, may have a disease in which
the sentinel Philadelphia chromosome and
BCR-ABL1 fusion occurred in a multipotent
progenitor cell. Treatment with chemotherapy
and a TKI may eliminate the bulk disease in the
lymphoid clone, producing an excellent MRD
response when measured by conventional
MRD methodologies, but leaving a reservoir
of Ph1 cells in other lineages.
Much more work is needed to understand
these findings and particularly their clinical
implications. The current study challenges
us to perform these studies so that we can
understand the frequency of “Ph1 ALL”
subtypes that have multilineage involvement vs
disease restricted to the lymphoid lineage and
the clinical implications of these differences.
Understanding the different potential subtypes
of Ph1 ALL is particularly relevant to adults
with Ph1 ALL because this subtype comprises
a much higher percentage of adult than
pediatric ALL, and because HSCT remains the
most commonly used approach for adults with
Ph1 ALL.9
As observed by the philosopher Roseanne
Roseannadanna, “It just goes to show you,
it’s always something—if it ain’t one thing,
it’s another.”
Conflict-of-interest disclosure: S.P.H. has
received honoraria from Amgen, Jazz Pharmaceuticals, and Erytech and consulting fees from
Novartis. n
REFERENCES
1. Hovorkova L, Zaliova M, Venn NC, et al. Monitoring
of childhood ALL using BCR-ABL1 genomic breakpoints
identifies a subgroup with CML-like biology. Blood.
2017;129(20):2771-2781.
2. Chandra HS, Heisterkamp NC, Hungerford A, et al.
Philadelphia Chromosome Symposium: commemoration
of the 50th anniversary of the discovery of the Ph
chromosome. Cancer Genet. 2011;204(4):171-179.
3. Bower H, Björkholm M, Dickman PW, Höglund M,
Lambert PC, Andersson TM. Life expectancy of patients
with chronic myeloid leukemia approaches the life
expectancy of the general population. J Clin Oncol. 2016;
34(24):2851-2857.
4. Aricò M, Schrappe M, Hunger SP, et al. Clinical
outcome of children with newly diagnosed Philadelphia
chromosome-positive acute lymphoblastic leukemia treated
between 1995 and 2005. J Clin Oncol. 2010;28(31):
4755-4761.
5. Schultz KR, Bowman WP, Aledo A, et al. Improved
early event-free survival with imatinib in Philadelphia
chromosome-positive acute lymphoblastic leukemia: a
children’s oncology group study. J Clin Oncol. 2009;
27(31):5175-5181.
6. Biondi A, Schrappe M, De Lorenzo P, et al.
Imatinib after induction for treatment of children and
adolescents with Philadelphia-chromosome-positive acute
2714
lymphoblastic leukaemia (EsPhALL): a randomised, openlabel, intergroup study. Lancet Oncol. 2012;13(9):936-945.
7. Kolenova A, Maloney KW, Hunger SP. Philadelphia
chromosome-positive acute lymphoblastic leukemia or
chronic myeloid leukemia in lymphoid blast crisis.
J Pediatr Hematol Oncol. 2016;38(6):e193-e195.
8. Hehlmann R, Saußele S, Voskanyan A, Silver RT.
Management of CML-blast crisis. Best Pract Res Clin
Haematol. 2016;29(3):295-307.
9. Fielding AK. Treatment of Philadelphia
chromosome-positive acute lymphoblastic leukemia in
adults: a broader range of options, improved outcomes,
and more therapeutic dilemmas. Am Soc Clin Oncol Educ
Book. 2015:e352-359.
DOI 10.1182/blood-2017-04-776369
© 2017 by The American Society of Hematology
l l l THROMBOSIS AND HEMOSTASIS
Comment on Curtis et al, page 2793
At
last: evidence rather than emotion
----------------------------------------------------------------------------------------------------Paul Monagle
UNIVERSITY OF MELBOURNE
Perinatal stroke is often a devastating and unexpected event for families that leads
them to ask the question of “why?” The study by Curtis et al1 in this issue of
Blood suggests that the answers to this question are not to be found in standard
thrombophilia testing.
T
hrombophilia, a broad term inclusive
of a variety of disorders, has variably
been shown to be associated with venous
thromboembolic diseases in adults, although
the link to arterial disease is more tenuous.
Currently, most guidelines support very
limited clinical usefulness of thrombophilia
testing in adult populations.2
The data supporting thrombophilia testing
in neonatal or perinatal stroke is far from
convincing. One could reasonably extend that
statement to childhood stroke and potentially
childhood thrombosis in general.3 Previous
studies of dubious quality have suggested
a potential association with perinatal stroke,
however, none have demonstrated any impact
of testing on recurrence rates, clinical outcome,
or future therapy.4 Although some studies
have suggested a link to neurological outcome,
most would argue the recommended follow-up
and interventions are unchanged by the
results of thrombophilia testing.4 Yet
thrombophilia testing is frequently performed
in this situation. Many clinicians, in an
attempt to provide some answers for desperate
parents, embark on testing knowing that the
interpretation of any positive results is fraught
with uncertainty. Testing is often driven by
parents who have been scouring the internet for
answers and come asking about thrombophilia.
Childbirth is supposed to be a time of great joy.
An unexplained perinatal stroke that will likely
have lifelong significant consequences for the
infant is incredibly challenging for parents.
There are issues of their fears for their child,
their unfounded feelings of guilt, as well as
concerns about the risks for future children.
Thus, the potential impact of performing
tests of unknown significance for the child’s
future, and, indeed, for future children in the
family, is arguably more negative than positive
because it may increase unfounded fears,
leading to overtreatment and inhibitions or
restrictions on the child. Until now, clinicians
have not had quality data to support making
an argument to parents against doing such
testing.
Curtis et al performed a prospective,
population-based, controlled, disease-specific
study that suggests minimal association
between perinatal stroke and thrombophilia
(specifically, a broad range of thrombophilia
markers). The authors make the relevant point
that this does not exclude a role of disordered
coagulation in the etiology of the event, but that
such a role is unlikely to be found by testing
standard thrombophilia assays. Such a view
is entirely consistent with our knowledge of
developmental hemostasis.5 The coagulation
system changes rapidly in the first few days
of life. In fact, the whole plasma milieu is
fundamentally different when comparing
neonates and adults.6 Placental-released
glycosaminglycans probably contribute to the
overall balance of coagulation, and yet these
factors are no longer detectable after the first
week of life.7 A much greater understanding
the coagulation system in the placenta, fetus, and
BLOOD, 18 MAY 2017 x VOLUME 129, NUMBER 20
From www.bloodjournal.org by guest on June 12, 2017. For personal use only.
premature and term neonates is required. Such
understanding must be an ongoing area of
active research. The aim is to ultimately be able
to provide families with evidence-based
information to explain perinatal events, such
as stroke.
The reported minimal association is
consistent with epidemiological data as well.
The large family cohorts that defined the
original thrombophilias did not report neonatal
events, but rather thrombotic complications
in adult life, and the conclusion is that
thrombophilias interact with patient age in
correlating with the risk of thrombosis and
rarely cause clinical events during childhood.8
So at last we have good quality evidence. As
a result, clinicians who are faced with parents
full of emotion and anxiety can now say that the
available data does not support thrombophilia
testing in their child who has suffered a
perinatal stroke, because any abnormality
found occurs with the same frequency as in the
general population. We do not advocate testing
the general population at birth, despite the
relative frequency of thrombophilias, because
there is no evidence that knowing if a
thrombophilia is present improves the longterm outcome for the child, and such an
approach is clearly not cost effective. Certainly,
being labeled unnecessarily with a diagnosis of
a coagulation abnormality early in life creates
much anxiety and mismanagement. Without
any evidence that results would change
practice, it is impossible to argue that such
testing is cost effective. Thus, there is no
benefit in offering this testing in children who
have suffered a perinatal stroke. No answer
to the question of “why” remains better than
the wrong answer. In the meantime, the search
for the true answers must continue. At least
in regard to thrombophilia, now that we have
some evidence, we can help parents deal
more constructively with their emotions
after perinatal stroke.
Conflict-of-interest disclosure: The author declares
no competing financial interests. n
REFERENCES
1. Curtis C, Mineykol A, Massicotte P, et al.
Thrombophilia risk is not increased in children after
perinatal stroke. Blood. 2017;129(20):2793-2800.
2. Middeldorp S. Inherited thrombophilia: a doubleedged sword. Hematology Am Soc Hematol Edu Program;
2016; 2016(1):1-9
3. Monagle P, Chan A, Massicotte P, Chalmers E,
Michelson AD. Antithrombotic therapy in children:
the seventh ACCP conference on antithrombotic and
thrombolytic therapy. Chest. 2004;126(3 suppl):645S-687S.
BLOOD, 18 MAY 2017 x VOLUME 129, NUMBER 20
4. O’Brien SH. Perinatal thrombosis: implications for
mothers and neonates. Hematology Am Soc Hematol Educ
Program. 2015;2015:48-52.
7. Andrew M, Mitchell L, Berry L, et al. An anticoagulant
dermatan sulfate proteoglycan circulates in the pregnant
woman and her fetus. J Clin Invest. 1992;89(1):321-326.
5. Monagle P, Ignjatovic V, Savoia H. Hemostasis in
neonates and children: pitfalls and dilemmas. Blood Rev.
2010;24(2):63-68.
8. Crowther MA, Kelton JG. Congenital thrombophilic
states associated with venous thrombosis: a qualitative
overview and proposed classification system. Ann Intern
Med. 2003;138(2):128-134.
6. Bjelosevic S, Pascovici D, Ping H, et al. Quantitative
age-specific variability of plasma proteins in healthy
neonates, children and adults [published online ahead of
print 23 March 2017]. Mol Cell Proteomics. doi:10.1074/
mcp.M116.066720.
DOI 10.1182/blood-2017-03-772095
© 2017 by The American Society of Hematology
l l l TRANSPLANTATION
Comment on Lounder et al, page 2801
Vitamin
A to reduce gut leak and GVHD?
----------------------------------------------------------------------------------------------------Paul A. Carpenter
FRED HUTCHINSON CANCER RESEARCH CENTER
In this issue of Blood, Lounder et al report that, in children, vitamin A levels
below the median at 30 days after hematopoietic stem cell transplant (HSCT) are
associated with increased cumulative incidence of gastrointestinal (GI) graftversus-host disease (GVHD).1
V
itamin A is an essential dietary nutrient,
available to humans in 2 forms: preformed
vitamin A (retinol and retinyl ester) and plantbased provitamin A carotenoids. Most of the
body’s vitamin A is stored in the liver as hepatic
retinyl esters. Vitamin A blood levels are
homeostatically regulated to maintain a narrow
range. Preformed and provitamin A must be
metabolized intracellularly by gut mucosal cells
to retinal and retinoic acid, the active forms that
support biological functions. Lounder et al
review vitamin A’s known immunological roles
in the health of the intestinal mucosa; simply
put, most of the existing literature supports
its anti-inflammatory role in limiting chemical
and infectious gut injuries (albeit some
contradictory mouse data exist). Therefore,
to understand their GVHD observation,
Lounder et al explored associations between
higher and lower vitamin A levels and
measurements of retinol-binding protein 4,
intestinal fatty acid–binding protein,
interleukin-22 (IL-22), CCR9, and effector
memory T cells (see figure).
In the last few decades, our understanding
of GVHD pathophysiology has expanded
much beyond conditioning-mediated
disruption of the intestinal mucosa and the
classic interaction of donor T cells with
hematopoietic antigen-presenting cells. We
better appreciate how perturbation of the fecal
microbiota integrates with the cellular immune
system to promote inflammatory disease and
diarrhea. A nonexhaustive list of important
players in this regard includes: intestinal stem
cells and their closely aligned Paneth cells, the
protective intestinal mucous layer, intestinal
fatty acids like butyrate, bacterial composition
of the feces and its regulation by defensins.2,3
Antibiotic therapy and diet can further disrupt
the fecal microbiota and in turn affect mucosal
integrity. It is worth viewing the intriguing
results of Lounder et al through the lens
of this broader understanding of GVHD
pathophysiology and with a shift in focus to
GVHD interventions that move beyond
traditional systemic immunosuppressive
therapies.
Recognizing the critical integration of
fecal microbiota and gut immunology, our
gastroenterology colleagues have also explored
associations with intestinal disease. One study
found that among children diagnosed with
“persistent diarrhea” (.14 days) but not with
inflammatory bowel disease (IBD) per se,
diversity of the gut microbiota and its key
bacterial phylotypes differed significantly
between groups with normal or deficient vitamin
A levels.4 They have also studied alternatives
to systemic immunosuppressive therapy in IBD.
A detailed and well-designed meta-analysis of
therapy in pediatric Crohn disease examined
5 randomized clinical trials and 2 further
nonrandomized trials.5 The authors concluded
2715
From www.bloodjournal.org by guest on June 12, 2017. For personal use only.
2017 129: 2714-2715
doi:10.1182/blood-2017-03-772095
At last: evidence rather than emotion
Paul Monagle
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