Discussion
We report a rare case of short isoform of PML-RARα and FLT3-ITD with
characteristics of variant APL in terms of elevated WBC, hypogranular
morphology and unique immunophenotype. This is a very distinctive case
that presented with several adverse prognostic factors and yet the
patient achieved remission post induction phase. There are only two case
reports in the literature that have shown PML-RARα and FLT3-ITD in
patients with poor outcome. Both the reported cases carried WT1 gene
mutation and died during induction phase [5,6].
In the diagnostic setting, PML-RARα is detected by qPCR as three
different isoforms: the long bcr-1, the variant bcr-2, and the short
bcr-3 [2]. Approximately, 70% of APL patients express the
long/variant type PML-RARa, whereas the S type isoform is seen in
~30% of APL patients [7]. Patients with bcr-3
subtype of APL are less sensitive to ATRA treatment, take longer time to
achieve complete remission, and are at a higher risk of relapse compared
to patients with other isoforms [8,9]. Additionally, in an in vitro
study, bcr-3 cells showed unique anti-apoptotic properties that were not
seen in bcr-1, which may explain why patients with bcr-3 APL have
stronger drug resistance to ATRA [10]. Several studies have
mentioned that there is a high-degree of correlation between bcr-3
subtype and FLT3 mutations with high incidence in pediatric and yet
better outcome compared to adults [11,12]. It is interesting to note
that our patient is an adult of 32 years who presented with bcr3 and
FLT3-ITD and a good outcome.
FLT3 mutations are often associated with an important adverse marker of
APL, leukocytosis status (WBC count > 10 × 109/L),
low‑fibrinogen concentration, hemoglobin levels and high lactate
dehydrogenase (LDH) level [13]. In a meta-analysis, Picharski et al
conclude that APL patients with FLT3-ITD mutations have significantly
higher WBC counts at diagnosis and higher risk of induction deaths
[14]. Some authors have suggested that FLT3 inhibitor treatment
might potentially intercept differentiation syndrome or coagulopathy
[15,16]. Our patient did not receive any FLT3 inhibitors and
developed both differentiation syndrome and DVT. This suggests the use
of FLT3 inhibitors in the induction regimen of APL patients with
FLT3-ITD may be beneficial.
Our patient presented with variant APL morphology. The morphology of
malignant promyelocyte is classified into 4 types: first, classical or
hypergranular type, which is morphologically diagnostic for APL, has
heavy granular cytoplasm and numerous fused Auer rods, faggot cells;
second, microgranular variant or hypogranular, as our case, has folded
nuclei, fine granules and Auer rods are rarely seen; third, high
nucleocytoplasmic ratio with irregular nuclear borders, with rare
granules and lack Auer rods; fourth, round regular nuclei that lack
granules and subsequently lack Auer rods [17,18].
Our patient expressed CD34, CD2 and CD56 but lacks HLA-DR. These markers
are characteristic of the microgranular variant of APL with CD34 as the
most expressed marker more frequently seen in bcr-3 subtype females
followed by HLA-DR. On the other hand, the immunophenotype of classical
APL is positive for CD13, CD33, CD64, and CD117 but lacks HLA-DR and
CD34 [19]. CD2 and CD56 that are present in our patient are
occasionally expressed and associated with adverse prognosis and
increased risk of thrombosis [20,21,22].
In conclusion, APL patient having several adverse prognostic markers
including PML-RARα short isoform and FLT3-ITD mutation shows a good
response in achieving complete remission to ATRA and ATO plus IDA. The
use of FLT3 inhibitors in the induction regimen of APL patients with
FLT3-ITD may be beneficial to prevent differentiation syndrome and
coagulopathy in such patients.