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Review Articles
Extramedullary
Disease in Acute Promyelocytic Leukemia: Two-In-One Disease
Francesco Albano and Giorgina Specchia
Ematologia con Trapianto,
Università degli Studi di Bari “Aldo Moro“
Correspondence
to: G. Specchia. Ematologia con Trapianto, Università degli
Studi di Bari “Aldo Moro“. E-mail: g.specchia@ematba.uniba.it
Published: December 21, 2011
Received: October 30, 2011
Accepted: November 27, 2011
Mediterr J Hematol Infect Dis 2011, 3(1): e2011066, DOI 10.4084/MJHID.2011.066
This article is available from: http://www.mjhid.org/article/view/9480
This is an Open Access article
distributed under the terms of the
Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits
unrestricted use, distribution, and reproduction in any medium,
provided the original work is properly cited
Abstract
In
acute promyelocytic leukemia (APL), extramedullary disease (EMD) is
particularly rare and shows special clinical and biological features.
It is estimated that about 3–5% of APL patients will suffer
extramedullary relapse. The most common site of EMD in APL is the
central nervous system (CNS). At present, there are still many issues
of EMD in APL needing further clarification, including pathogenesis,
risk factors, prognosis and treatment. A better understanding of the
biological mechanisms underlying EMD is important to be able to devise
more effective CNS prophylaxis and induction-consolidation therapeutic
strategies.
Introduction
Acute
leukemia may present in a
variety of extramedullary tissues with or without bone marrow disease.
Extramedullary involvement by acute leukemia is a relatively rare but
clinically significant phenomenon that often poses diagnostic and
therapeutic
dilemmas. Myeloid sarcoma and leukemia cutis are two well-known EM
manifestations. Extramedullary disease
(EMD) in acute promyelocytic leukemia (APL) is particularly rare and
shows
special clinical and biological features.
How
common is EMD in APL?
The
combination of all-trans retinoic acid (ATRA)
and anthracycline-based chemotherapy, together with maintenance
treatment, has
improved the outcome of APL. In fact, approximately 90% of patients
with newly
diagnosed APL achieve complete remission (CR).[1-2]
and it is
estimated that 70–80% of these patients will remain in remission.[1-3]
However, approximately 20– 30% of patients will eventually relapse.[2] EMD is a rare complication in APL: it is estimated
that about 3–5% of patients
will suffer extramedullary relapse.[4-6] However,
since the
introduction of ATRA in the treatment of patients with APL, EMD disease
has
been increasingly reported; in fact, in the literature fewer than 25
well-documented cases had been described before 1995.[7]
This is most
likely in part due to the following reasons:
a) APL
patients may develop EMD more
frequently because they are achieving longer survival times thanks to
improved
treatment regimens.
b) It is
possible that the drugs
employed in the induction regimens (ATRA, anthracycline and arsenic
trioxide)
do not reach therapeutic concentrations at the anatomical sites where
EMD
eventually develops.
c) It is
also possible that ATRA
therapy might contribute to extramedullary relapses by modulating and
upregulating the expression of adhesion molecules on leukemic cells.
EMD commonly occurs within 1 year of achieving
CR, but it can appear at any time during the disease course and can be
isolated
or can precede systemic relapse.[2-6] As to cases of
EMD at APL
presentation, although a few anecdotal reports have been made this
observation
is very uncommon.[8]
What
are the most frequent anatomical sites of EMD in APL?
The most
frequent site of EMD in APL patients is the central nervous
system (CNS) and at least 10% of hematologic relapses are accompanied
by CNS
involvement.[9] CNS relapse appears in around 1% of
APL patients and
may occur despite hematological remission.[6,10-12] The skin is the
second most common site of EMD.[2] The increased
frequency of EMD
especially in these two sites could be explained by some biological
effects of
ATRA induction treatment. In fact, ATRA-driven differentiation of APL
cells is
associated with a significant upregulation of cellular adhesion
molecules
expressed on the cell surface, like LFA-1 and VLA-4.[13]
The mechanism
of APL blasts adhesion to the endothelium may be further increased by
interleukin-1, via an effect which may be mediated through an increased
expression of ICAM-1 and VCAM-1 on the endothelial cell surface.[14] These
surface proteins have both been demonstrated on the CNS endothelium and
have
been implicated in the migration processes of leukocytes across the
blood–brain
barrier (BBB), through interactions with LFA-1 and VLA-4, respectively.[9]
Since both LFA-1 and VLA-4 are upregulated in APL blasts treated with
retinoids, it is reasonable to suppose that the upregulation of these
adhesion
molecules may promote passage across the BBB of ATRA-treated APL cells,
thereby
creating the conditions for a subsequent CNS relapse (Figure 1).
Moreover, ATRA also stimulates keratinocytes to
proliferate and upregulate their expression of ICAMs.[9]
It has been
suggested that the migration of leukemic cells into the skin and other
tissues
during ATRA induction treatment may leave a reservoir of viable
leukemic cells
in these sites, that eventually may proliferate and cause EMD. These
biological
events could account for the clinical observation of a preferential
skin
localization of APL cells relapsing after ATRA treatment. Moreover, a
high
frequency of EMD in APL may also be related to the ATRA-induced
upregulation of
G-CSF receptors in APL cells, making them more sensitive to endogenous
or
exogenous G-CSF effects.[15] Other described sites of
EMD in APL
include: the testes, sites of vascular access, external ear and
auditory canal,
lung, pleura, heart, lymph nodes, mediastinum, thymus, spine, breast,
pelvis,
mandible and gingiva, bowel. Since in patients affected by ATRA
syndrome APL
cells infiltrate multiple tissues and organs, it has been hypothesized
that
ATRA could promote the migration of differentiating blasts into several
tissues,
constituting a reservoir of viable leukemic cells. These cells could
later
proliferate and result in an extramedullary recurrence.[16-17]
However,
the issue as to whether ATRA promotes EMD in APL is still highly
controversial,
since several studies have reached different conclusions.[5-7,18-19]
Figure 1. ATRA-driven
differentiation of APL cells is associated with the upregulation of
cellular adhesion molecules like LFA-1 and VLA-4. The mechanism of APL
blasts adhesion to the endothelium may be further increased by
interleukin-1, an effect which may be mediated via an increased
expression of ICAM-1 and VCAM-1 on the CNS endothelium. Since both
LFA-1 and VLA-4 are upregulated in APL blasts treated with retinoids,
it is reasonable to suppose that the upregulation of these adhesion
molecules might promote passage across the BBB of ATRA-treated APL
cells, thereby creating the conditions for a subsequent CNS relapse.
Moreover, CD56 expression on APL cells may also foster CNS
relapse.
Are
there risk factors for an EMD onset in APL?
Several
factors have been associated with a higher risk of extramedullary
relapse such as younger age (<45 years), a high WBC count at
diagnosis,
microgranular morphology, expression of CD2 and/or CD56, PML-RARa bcr3
isoform expression, ATRA syndrome, monotherapy regimens, and the
use of therapy schedules that exclude
cytarabine.[24,12,20,21]
Moreover, two recent studies [4,22] reported
a significantly higher incidence of CNS involvement in patients with an
initial
WBC of more than 10 x109/L. In addition to
hyperleukocytosis, the
PETHEMA study also identified a previous CNS hemorrhage during
induction as an
independent risk factor for CNS relapse.[22] It has
recently been
demonstrated that CD56+ APL has a greater risk of extramedullary
relapse.[21]
The higher frequency of coexpression of stem cell (CD117) and NK-cell
antigens
(CD2, CD7) in CD56+ APL cells suggests that in some of these cases APL
might
have arisen in progenitors that did not undergo lineage restriction.[23]
Therefore, it is possible that CD56+ APL may emerge from a more
immature,
undifferentiated and pluripotent leukemic stem cell that is less
sensitive to
the combination of ATRA and anthracyclines. This could explain the
higher
frequency of extramedullary relapse in these cases.[21,24-25]
What
is
the prognosis of EMD in APL?
Which is the best therapy? Because of
the rarity of the disease, the prognosis
of patients with EMD in APL is still unclear. The
GIMEMA study[6] reported that the
outcome was similar to
that of patients who experienced isolated bone marrow relapse, whereas
in the
joint study by the PETHEMA and the European APL groups [4]it
was
found that patients with an
extramedullary relapse had a poorer outcome. EMD can occur in isolation
or
associated with bone marrow involvement as a first relapse, but also
after one
or more hematologic relapses. The molecular status in the peripheral
blood/bone
marrow did not seem to predict the possibility of EMD relapse.[5,6] Management
of relapse in the CNS and other extramedullary sites in APL patients is
a
challenging issue on which there is a strong need for further data. The optimal management of APL
patients in different
situations has not been critically assessed.[26]
Because the majority
of CNS relapses occurs in APL patients with hyperleukocytosis,4
CNS
prophylaxis for patients in this particular high-risk setting may be
appropriate.[26] In these cases CNS prophylaxis
should be performed
after the achievement of CR because lumbar puncture at presentation and
during
induction is extremely hazardous. However, the benefit of this kind of
strategy
has not yet been clearly established.
The role of
ATRA and arsenic
trioxide in the therapeutic management of CNS relapse is still unclear
because
it is not known whether these drugs cross the BBB; nevertheless, some
authors
have reported responses to these agents in patients with meningeal
disease.[27-28]
This may be due to the EMD disrupting the BBB. Arsenic trioxide has
also been
reported to cross the BBB and may be useful as a therapeutic agent to
control
CNS relapse.[29] On the other hand, some reports have
confirmed that
although arsenic crosses the BBB when administered intravenously, the
concentration in CSF is probably not sufficient to treat meningeal
leukemia.[30-31]
Recently, as induction treatment of CNS relapse, the European
LeukemiaNet
recommendations [26] proposed a schedule of weekly
triple intrathecal
therapy (ITT) with methotrexate, hydrocortisone, and cytarabine until
complete
clearance of blasts in the cerebrospinal fluid (CSF), followed by 6 to
10 more
spaced-out ITT treatments as consolidation. In these cases systemic
treatment
should also be given because CNS disease is almost invariably
associated with
hematologic or molecular relapse in the marrow. Chemotherapy regimens
with high
CNS penetrance, such as high-dose cytarabine, have been used in this
situation.
In patients responding to treatment, allogeneic or autologous
transplant is
then recommended as consolidation treatment, together with craniospinal
irradiation.
It was demonstrated that cytarabine during consolidation treatment
significantly reduced the relapse rate in high-risk APL patients.[32-33]Because of the limited numbers of EMD events
reported in these studies, it is
very hard to draw firm conclusions regarding the best schedule of
cytarabine to
use in the consolidation regimen to prevent the EMD in APL. In cases of
promyelocytic sarcoma, wherever it is localized, radiation and
intensive
systemic therapy might be considered. Recently, successful treatment of
relapsed and refractory EMD with Tamibarotene,[34] a
synthetic
retinoid approved in Japan for use in relapsed/refractory APL, has been
reported.[35] Tamibarotene is 10 times more potent
than ATRA as an
inducer of HL-60 and NB-4 leukemia cell lines differentiation. While
tamibarotene has displayed a significant activity in bone
marrow-relapsed APL,
its efficacy in EMD needs to be confirmed in further studies.
Conclusions.
At present,
there are still many
open issues on EMD in APL patients. However, some aspects are becoming
clearer.
An improved understanding of the biological mechanisms that underlie
EMD should
allow us to devise more effective prophylaxis and induction therapeutic
strategies against this severe clinical presentation.
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