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.