CD45+(weak), cyMPO+(strong), CD34-, CD117+, HLA-DR-, CD13+(weak), CD33+(strong), CD15+(weak), CD14-, CD56-

Cells were cultured in supernatans from cell line DSM ACC35

R-banding (RHA)

46,XY,t(1;17)(q42;q21)[9]/46,XY[1]

Probes:

XL PML (O) / RARA (G) (DC DF)[15q24/17q21, Metasystems]

XL RARA (DC BA)[17q21, Metasystems]

Results:

• XL PML (O) / RARA (G) (DC DF): numerical abnormalities

nuc ish(PMLx2,RARAx3)[159/200]

• XL RARA (DC BA): balanced rearrangement

nuc ish(5'RARA,3'RARA)x2(5'RARA sep 3'RARAx1)[154/200]

Conclusion:

Balanced rearrangement of RARA/17q21 without PML/15q24 involvement.

A 74 year old male patient with history of type 2 diabetes, chronic renal failure (baseline creatinine clearance of 27 mL/min), ischemic cardiomyopathy, atrial fibrillation and hypertension was referred to the hematology department because of unexplained neutropenia (ANC: 200/mm³) and anemia (Hb 8.4 g/dL). There was no bleeding tendency nor thrombotic events.

He was diagnosed with an acute promyelocytic leukaemia (low risk disease) with an atypical RARA fusiontranscript (IRF2BP2::RARA).

Treatment was initiated with all trans retinoid acid (ATRA) monotherapy for 7 days followed by the combination of ATRA and arsenic trioxide (ATO).

An extensive superficial vein thrombosis occurred on day 21. A central venous line was placed and low molecular weight heparin was started.

On day 25 a severe differentiation syndrome occurred with fever, severe inflammatory response syndrome, hypotension and oedema. ATRA/ATO was temporally stopped and dexamethasone (2 x 10 mg IV) was administrated. Despite an intial clinical improvement, an ischemic cerebrovascular incident occurred, kidney function declined and anuria developed. The patient further declined  while on dialysis. He declined continuation of therapy and chose to return home where he passed away 36 days after starting therapy.

In addition to the investigations described above, optical genome mapping was carried out on the Saphyr instrument (Bionano Genomics). Two bioinformatic pipelines were used for data analysis: the "Rare Variant Pipeline" and the "Copy Number Analysis Pipeline" (300x coverage). Results were visualized with the Bionano Access software (Genome build GRCh37/hg19).

OGM confirmed the t(1;17)(q42.3;q21.2) leading to the IRF2BP2::RARA fusion transcript. The mechanism behind this fusion was more complex than a simple translocation with occurrence of an additional inversion on chromosome 1.

RNA sequencing was performed and confirmed fusion of exon 1 of IRF2BP2 to RARA exon 3.

References:

• Yin CC, et al. Identification of a novel fusion gene, IRF2BP2-RARA, in acute promyelocytic leukemia. J Natl Compr Canc Netw. 2015;13(1):19-22.

• Alotaibi AS, et al. Acute promyelocytic leukemia (APL) with an IRF2BP2-RARA fusion transcript: an aggressive APL variant. Leuk Lymphoma. 2020;61(12):3018-3020.

• Shimomura Y, et al. New variant of acute promyelocytic leukemia with IRF2BP2-RARA fusion. Cancer Sci. 2016;107(8):1165-8.

• Jovanovic JV, et al. The cryptic IRF2BP2-RARA fusion transforms hematopoietic stem/progenitor cells and induces retinoid-sensitive acute promyelocytic leukemia. Leukemia. 2017;31(3):747-751.

• Mazharuddin S, Chattopadhyay A, Levy MY, Redner RL. IRF2BP2-RARA t(1;17)(q42.3;q21.2) APL blasts differentiate in response to all-trans retinoic acid. Leuk Lymphoma. 2018;59(9):2246-2249.

• Liu Y, et al. A rare case of acute promyelocytic leukemia with IRF2BP2-RARA fusion; and literature review. Onco Targets Ther. 2019;12:6157-6163.

• Zhang X, Sun J, Yu W, Jin J. Current views on the genetic landscape and management of variant acute promyelocytic leukemia. Biomark Res. 2021;9(1):33.