Acute lymphoblastic leukemia to acute myeloid leukemia: an unusual case report of lineage switching

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Please
cite
this
article
in
press
as:
Pandit
S,
et
al.
Acute
lymphoblastic
leukemia
to
acute
myeloid
leukemia:
an
unusual
case
report
of
lineage
switching.
Hematol
Transfus
Cell
Ther.
2020.
https://doi.org/10.1016/j.htct.2020.06.007
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Hematology,
Transfusion
and
Cell
Therapy
Case
Report
Acute
lymphoblastic
leukemia
to
acute
myeloid
leukemia:
an
unusual
case
report
of
lineage
switching
Sudarshan
Pandit ∗,
Nilesh
Wasekar,
Girish
Badarkhe,
Yasam
Venkata
Ramesh,
Q1
Rajnish
Nagarkar
HCG
Manavata
Cancer
Centre,
Nashik,
Maharashtra,
India
a
r
t
i
c
l
e
i
n
f
o
Article
history:
Received
14
January
2020
Accepted
8
June
2020
Available
online
xxx
Introduction
Cancer
burden
has
raised
from
16.8
million
to
18.1
million
newQ2
cases
with
9.6
million
cancer
deaths
in
2018
alone.1,2 Leukemia
is
the
thirteenth
most
common
cancer
with
4.37
lakh
new
cases,
and
2.11
lakh
related
deaths
globally.2Based
on
the
ori-
gin
of
the
predominant
cell
type
(lymphoid
or
myeloid)
and
the
rate
of
disease
progression
(acute
or
chronic),
leukemia
is
cat-
egorized
into
four
major
subtypes:
acute
lymphoid
leukemia
(ALL),
chronic
lymphocytic
leukemia
(CLL),
acute
myeloid
leukemia
(AML),
and
chronic
myelogenous
leukemia
(CML).3,4
Of
which,
the
incidence
of
ALL
and
AML
are
1.08
lakh
and
1.40
lakh,
respectively.4ALL
is
a
common
cancer
in
children
and
is
caused
by
uncontrolled
production
of
bone
marrow
hematopoietic
precursor
cells.5Advancement
in
the
thera-
peutics
has
increased
the
overall
survival
rate
but
influencing
factors
such
as
lineage
switching
and
the
rise
of
mixed
lin-
eages
at
relapses
or
with
chemotherapy
often
changes
the
∗Corresponding
author
at:
Department
of
Haematology,
HCG
Manavata
Cancer
Centre,
Nashik
422011,
Maharashtra,
India.
E-mail
address:
academics@manavatacancercentre.com
(S.
Pandit).
prognosis
of
the
illness.
Lineage
switching
is
a
rare
phe-
nomenon
in
which
ALL
transforms
from
lymphoid
to
myeloid
lineage
or
vice
versa.
This
situation
rarely
occurs
especially
in
adults,
and
the
prognosis
is
highly
variable.
The
specific
causative
factors,
central
mechanisms
involved
in
these
phe-
nomena
are
still
unclear
and
yet
to
be
identified.
In
the
present
case
report,
we
are
presenting
a
rare
case
of
lineage
switching
of
ALL
to
AML
in
a
young
adult
of
19
years
during
chemother-
apy.
Case
presentation
A
19-year-old
male
was
presented
at
our
hematology
cen-
ter
due
to
weakness,
weight
loss,
and
pancytopenia.
Upon
physical
examination,
he
was
pale,
with
bone
pain,
and
referred
asthenia.
Other
physical
examinations
have
shown
no
other
abnormalities.
Initial
laboratory
tests
were
per-
formed.
From
complete
blood
count
(CBC)
decreased
total
https://doi.org/10.1016/j.htct.2020.06.007
2531-1379/©
2020
Associac¸ ˜
ao
Brasileira
de
Hematologia,
Hemoterapia
e
Terapia
Celular.
Published
by
Elsevier
Editora
Ltda.
This
is
an
open
access
article
under
the
CC
BY-NC-ND
license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
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HTCT
3157
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Please
cite
this
article
in
press
as:
Pandit
S,
et
al.
Acute
lymphoblastic
leukemia
to
acute
myeloid
leukemia:
an
unusual
case
report
of
lineage
switching.
Hematol
Transfus
Cell
Ther.
2020.
https://doi.org/10.1016/j.htct.2020.06.007
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Figure
1
–
Salient
features
of
the
immunophenotype,
at
diagnosis:
(A)
blasts
(red)
co-express
CD19/CD34
and
CD38
antigens,
whereas
they
do
not
express
CD10,
CD20,
CD33
or
CD117
antigens.
The
expressions
of
other
myeolid
and
lymphoid
antigens
of
the
T
lineage
was
not
detected.
(B)
Bone
marrow
aspiration
images
at
diagnosis.
Salient
features
of
the
immunophenotype,
at
relapse:
(C)
blasts
(red)
now
co-express
CD36/CD64/Cy
MPO
and
CD117
while
they
do
not
express
the
CD19
antigen.
Color
indicators:
red
color
–
blasts,
green
–
granulocytes,
blue
–
lymphocytes,
and
violet
–
monocytes.
(D)
Bone
marrow
aspiration
images
at
relapse.
(E)
FISH
study
at
diagnosis
(left
to
right):
interphase
cell
showing
2
orange,
2
green
signals
indicating
BCR/ABL:
Ph
negative
status.
Signal
pattern
showing
2
fusion
(yellow)
signals
indicative
of
negative
status
for
E2A
gene
rearrangement/translocation.
Signal
pattern
showing
2
fusion
(yellow)
signals
indicative
of
negative
status
for
MLL;
t(11q23)
gene
rearrangement/translocation.
Interphase
cell
showing
2
orange,
2
green
signals
indicating
TEL/AML1
ES:
t(12;21)
(p13;q22):negative
status.
(F)
FISH
study
at
replapse:
on
the
left
–
cell
showing
one
orange
and
one
green
signals,
indicating
positive
for
loss
of
chromosome
17p13,
locus
(90%),
nuc
ish
(TP53,
NF1)
×
1[180/200];
on
the
right
–
cell
showing
two
orange
signals,
indicating
negative
for
deletion
of
the
20q12
locus,
nuc
ish
(D20S108
×
3)
[20/200].
Table
1
–
Clinical
and
laboratory
features
of
the
ALL
at
diagnosis
and
AML
at
transformation.
Clinical
data
At
diagnosis
Follow
up
At
relapse
Bone
marrow
blast
count
96%
lymphoblasts
Less
than
3%
blast/hematogones
88%
myeloblast
Flow
cytometry
HLA-DR+,
CD7+
(dim),
CD19+,
CD38+,
MPO−,
CD13−,
CD15−,
CD33−,
and
CD34−
MRD
undetectable
MPO+,
CD13+
(dim),
CD15+,
CD33+,
CD38+,
CD64+,
CD
36+,
CD19-,
CD22−,
and
CD117−
Cytogenetics
Baseline
cytogenetics
normal
Not
tested
t(15
17)
(q21
q22),
Inv
16
(p13
q22),
and
t(8
21)
(q22
q22)
negative
FISH
FISH
for
ALL:
BCR/ABL:
t(9:22)
–
normal
MLL
gene
rearrangement;
t(11q23)
–
normal
E2A
gene
rearrangement
–
normal
TEL/AML1
ES;
t(12;21)
–
normal
Not
tested
17p13
loss
positive
Lumbar
puncture
Negative
Not
tested
Negative
leukocyte
count
was
observed
and
using
peripheral
blood
smear
(PBS)
blast
cells
were
identified
(Figure
1B
and
D).
Bone
and
marrow
aspirate
(BMA)
and
flow
cytometric
analysis
disclosed
CD19
(+),
CD7
(+),
HLA-DR
(+),
and
CD38
(+)
in
sug-
gestive
of
B-ALL
(Table
1
and
Figure
1A).
Fluorescence
in
situ
Hybridization
(FISH)
test
for
BCR/ABL;t(9:22),
MLL
gene
rear-
rangement;
t(11q23),
E2A
gene
rearrangement,
TEL/AML1
ES;
t(12;21)
was
performed
using
TEL/AML1
ES:
t(12;21)
(p13;q22):
45
46
47
48
49
50
51
52

HTCT
3157
1–4
Please
cite
this
article
in
press
as:
Pandit
S,
et
al.
Acute
lymphoblastic
leukemia
to
acute
myeloid
leukemia:
an
unusual
case
report
of
lineage
switching.
Hematol
Transfus
Cell
Ther.
2020.
https://doi.org/10.1016/j.htct.2020.06.007
ARTICLE IN PRESS
HTCT
3157
1–4
hematol
transfus
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x):xxx–xxx
3
(ETV6/RUNX1)
dual
color
translocation
probe,
VYSIS
(Abbott),
Zytolight
SPEC
BCR/ABL1
dual
color
dual
fusion
probe,
E2A
gene
rearrangement:t(19p13);
dual
color
break
apart
probe,
Cytotest,
t(11q23):
LSI
MLL
dual
color,
break
apart
rearrange-
ment
probe,
and
metasystems.
Reports
from
FISH
analysis
was
revealed
to
be
negative
(Figure
1E).
RT-
PCR
for
BCR-
ABL
rearrangements
tests
was
not
done.
Baseline
cytogenetics
was
normal.
Augmented
Berlin-Frankfurt-Munster
(aBFM)-90
regimen
was
initiated.
Induction
phase
was
non-eventful.
However,
Post
induction
marrow
MRD
by
flow
cytometry
was
negative.
So
the
patient
was
proceeded
with
the
consolidation
phase,
with
time
the
patient
has
developed
severe
pain
in
legs
and
body
aches.
Once
again,
all
the
tests
such
as
CBC,
PBS,
flow
cytometry,
cytogenetics
and
FISH
were
performed.
Where
CBC
has
shown
an
increase
in
total
leukocyte
count
with
peripheral
blood
smear
showing
blasts.
Flow
cytometry
results
have
shown
myeloid
and
monocytic
markers
CyMPO,
CD13,
CD33,
CD117,
CD36,
CD64,
CD10,
CD15,
CD38,
CD4
and
CD7confirming
AML
with
monocytic
differentiation
(Table
1
and
Figure
1C).
Whereas
cytogenetics
leukemia
transloca-
tion
panel
was
negative
for
t(15
17)
(q21
q22),
Inv
16
(p13
q22),t(8
21)
(q22
q22)
and
FISH
was
positive
for
loss
of
the
TP
53(17p
13),
confirming
the
lineage
switch
(Table
1
and
Figure
1F).
FLAG-IDA
chemotherapy
regimen
followed
by
allo-
geneic
hematopoietic
stem
cell
transplantation
(HSCT)
was
planned.
As
on
date,
the
patient
is
on
chemotherapy
with
regular
follow-ups.
Discussion
Lineage
switch
from
ALL
to
AML
in
adolescents
and
adults
are
very
rare.
We
present
a
young
adult
patient
case
in
which
de
novo
leukemia
underwent
lineage
switch
from
ALL
to
AML.
The
pathogenesis
for
lineage
switch
in
acute
leukemia
(AL)
is
currently
unknown.
Three
hypotheses
have
been
proposed
to
explain
this
unusual
event.
These
include
mechanisms
of
a
common
progenitor,
trans-differentiation,
and
dedifferentiation.6A
lineage
switch
may
represent
either
the
emergence
of
a
new
leukemic
clone
or
high
plasticity
attributes
or
a
relapse
of
the
original
clone
with
heterogeneity
at
the
morphological
level.5,7 It
has
been
noted
that
in
many
patients,
lineage
switching
occurs
at
relapse.5,8,9
With
respect
to
our
patient,
initial
bone
marrow
aspirate
findings
were
in
favor
of
AL.
Immunophenotyping
by
flow
cytometry
of
bone
marrow
sample
was
also
in
suggestive
of
B-ALL.
FISH
for
ALL
was
negative
and
baseline
cytogenet-
ics
were
normal.
Over
period
of
time,
patient
was
relapsed
during
chemotherapy.
Peripheral
blood
smear
was
performed
and
reappearance
of
blasts
was
observed.
Immunophenotyp-
ing
studies
were
performed,
suggesting
AML
with
monocytic
differentiation.
Further
reports
from
AML
translocation
panel
was
negative,
whereas
cytogenetic
studies
were
positive
for
loss
of
tp
53
(17p
13)
locus
(90%),
confirming
the
lineage
switch-
ing,
as
shown
in
Table
1.
The
mutation
or
loss
of
p53
gene
is
most
frequently
seen
in
solid
tumors
and
many
other
cancer
types.10 However,
their
frequency
in
hematological
malignancies
is
relatively
very
low.
p53
gene
demonstrated
a
pivotal
role
in
disease
development,
progression,
regulation
of
cell
proliferation,
apoptosis,
maintenance
of
genome
integrity,
chromosomal
stability,
resistance
to
DNA-damaging
drugs,
responding,
and
repairing
the
damaged
DNA.
Any
mutation
or
loss
of
p53
function
will
cause
genomic
instability,
chemotherapy
resistance,
and
cell
cycle
deregulation.10,11 Nevertheless,
a
strong
correlation
was
found
to
be
associated
with
muta-
tion
or
loss
of
p53
and
its
related
unfavorable
prognostic
factors
and
resistance
to
chemotherapy
in
hematological
malignancies.12,13 Rossi
et
al.
presented
7
cases
of
lin-
eage
switching
from
B-ALL
to
AML
at
relapse.
In
all
these
7
cases,
11q23/MLL
gene
abnormalities
were
detected.14
In
another
study,
18
pediatric
lineage
switch
cases
were
reported
because
of
chromosomal
aberrations
involving
11q
rearrangements.5
Over
25%
of
leukemia
patients
suffer
relapses
and
among
them
lineage
switching
was
observed
to
be
very
rare.
Cri-
teria
for
such
lineage
switching
might
be
morphological,
immunophenotypic
and
cytogenetic
alterations
in
the
same
original
cell
lineage
(lymphoid
or
myeloid).5,15–17 In
cytoge-
netic
alterations,
very
low
incidence
of
p53
mutations
(5%)
were
reported
in
infants
and
young
adults
with
AML/ALL.18–20
No
studies
have
conformed
the
possible
reasons
for
p53
mutations.
In
many
instances,
p53
mutated
AML
patients
were
observed
to
be
having
a
significantly
inferior
com-
plete
remission
duration,
lower
response
rate,
and
overall
survival.18
Despite
tremendous
progress
and
advancement
in
the
knowledge
and
technology
in
understanding
the
AL,
still
many
questions
to
be
addressed
about
the
mechanisms
driving
this
lineage
switching.
Ultimately
this
phenomenon
leads
to
poor
prognosis
and
resistance
to
therapy.
Hence
much
more
research
has
to
be
done
in
deciphering,
understand-
ing
and
unfolding
the
underlying
mechanisms
of
these
gene
functions,
interrelationships
and
their
role
in
these
cases
for
further
better
management.
Financial
disclosure
The
authors
declared
that
this
study
has
received
no
financial
support.
Conflict
of
interest
The
authors
have
no
conflicts
of
interest
to
declare.
Informed
consent
Written
informed
consent
was
obtained
from
the
patient.
Acknowledgements
The
authors
would
like
to
thank
Dr.
Yasam
Venkata
Ramesh
from
HCG
Manavata
Cancer
Centre,
Centre
for
Difficult
Can-
cers
(CDC),
Nashik,
India,
for
his
medical
writing
assistance.
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HTCT
3157
1–4
Please
cite
this
article
in
press
as:
Pandit
S,
et
al.
Acute
lymphoblastic
leukemia
to
acute
myeloid
leukemia:
an
unusual
case
report
of
lineage
switching.
Hematol
Transfus
Cell
Ther.
2020.
https://doi.org/10.1016/j.htct.2020.06.007
ARTICLE IN PRESS
HTCT
3157
1–4
4
hematol
transfus
cell
ther.
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x
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x):xxx–xxx
r
e
f
e
r
e
n
c
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