Report Shows How a t(15; 17) Aberration Typical of APL Was Really Myelofibrosis

July 20, 2019

The authors said their case highlights how t(15; 17) by itself is never sufficient to diagnose acute promyelocytic leukemia (APL) without confirmation by other methods.

A recent case report described a chromosomal t(15; 17) translocation in primary myelofibrosis (PMF), a myeloproliferative neoplasm (MN). While MN is associated with clonal molecular and cytogenetic abnormalities (CA) and varied clinical manifestations, t(15; 17) has not yet been reported in association with PMF.

Writing in OncoTargets and Therapy, physicians at the University of Iowa Hospitals and Clinics reported on the case of a 69-year-old male patient with upper left quadrant pain, abdominal distension, fatigure, weight loss, night sweats, numbness and tingling in his legs, and cytopenias. A bone marrow biopsy revealed immature blasts with fibrosis.

A cytogenetic analysis showed t(15;17), suggesting a diagnosis of acute promyelocytic leukemia (APL).

However, flourescence in situ hybridization (FISH) and reverse transcriptase polymerase chain reaction (RT-PCR) studies were negative for transcripts promyelocytic leukemia (PML) gene and retinoic acid receptor alpha (RARA) or PML-RARA fusion.

Along with these results, a second review of bone marrow histology, flowcytometry and the detection of a calreticulin gene (CALR) mutation helped find the correct diagnosis.

The patient was then treated with ruxolitinib, a JAK (Janus kinase) 1 and 2 inhibitor, and eventually underwent an allogeneic stem cell transplantation (ASCT). At the 6-month follow up, the patient was doing well.

The authors said their case highlights how t(15; 17) by itself is never sufficient to diagnose APL without confirmation by other methods. Relying solely on cytogenetics without confirmatory tests risks a delay in a proper diagnosis, they said. While t(15;17) is diagnostic of APL in most cases, there are exceptions, they said, and it can be associated with other malignancies.

In this case, the patient was first treated for APL, and was started on all-trans retinoic acid (ATRA) therapy. He was also given platelets preemptively for thrombocytopenia. However, the patient suffered an anaphylactic reaction, attributed to either the ATRA therapy or the platelets.

With the FISH and RT-PCR negative for PML-RARA fusion transcripts and with bone marrow fibrosis showing only a 4% blasts, the final diagnosis was thought to be consistent with a chronic MN, and likely MF. Eventually, the NGS myeloid molecular mutation profile from the bone marrow biopsy aspirate revealed a c.1154_1155insTTGTC (5bpins) CALR mutation in 47.6% cells. No other mutations were detected and the patient met the PMF diagnostic criteria.

In this patient, the delay in obtaining the FISH and PCR results delayed the diagnosis of PMF, the authors wrote. The case highlights how classic t(15; 17) (q24; q21) aberration that is typical of APL can sporadically associate with other myeloid malignancies, without an apparent APL phenotype.

Although this patient experienced an adverse event resulting in an ICU admission, the authors said beginning ATRA must be considered with any clinical suspicion of APL, since potential treatment risks outweigh the benefits of preventing early deaths from APL.

But relying solely on cytogenetic markers can be misleading, they said, without conducting a full investigation.

Reference

Nadiminti K, Silverman M, Bhagavathi S, Vikas P. t(15; 17) associated with primary myelofibrosis: a case report of an unusual clinical presentation and diagnostic dilemma [published online July 11,2019]. Onco Targets Ther. doi: 10.2147/OTT.S208290.