Case 127

Submitting Author: Yin, C. Cameron, MD, PhD
Institution: University of Texas MD Anderson Cancer Center
Additional authors:Daniela Hoehn, Gary Lu, Sergej Konoplev, Carlos E. Bueso-Ramos, Zhuang Zuo, L. Jeffrey Medeiros, C. Cameron Yin
Session: AML secondary to myeloproliferative neoplasms and other types of disease progression in MPN

HISTORY

The patient was a 72-year-old woman with a history of chronic myelogenous leukemia (CML) who was in complete cytogenetic remission on imatinib 23 months after diagnosis when she suddenly developed coagulopathy. Bone marrow (BM) aspiration and biopsy revealed a hypercellular marrow with numerous promyelocytes that had Auer rods and strong myeloperoxidase positivity. Conventional cytogenetic analysis showed 46,XX,der(3)t(3;15)(q21;q15)t(15;17)(q24.1;q21.2),t(9;22)(q34;q11.2),der(15)t(3;15),del(17)(q21)[20]. The presence of BCR-ABL1 and PML-RARA was confirmed by fluorescence in situ hybridization (FISH) and reverse transcription-polymerase chain reaction (RT-PCR). Molecular studies showed no mutations in ABL1, FLT3, NPM1, RAS, KIT, IDH1, IDH2 and JAK2 genes. The patient received all trans retinoic acid and arsenic trioxide and achieved complete cytogenetic remission with low level of BCR-ABL1 fusion transcript detected by RT-PCR. PML-RARA was not detected by FISH or RT-PCR. Two months later, however, the patient expired as a result of multiorgan system failure.

DETAILS

The initial peripheral blood (PB) smear showed markedly left-shifted leukocytosis with absolute monocytosis, basophilia, eosinophilia, and 1% blasts. There was normochromic, normocytic anemia and marked thrombocytosis. The BM aspirate and biopsy specimens showed hypercellular (95%) BM with left-shifted granulocytic hyperplasia and small hypolobated (“dwarf”) megakaryocytes. No significant fibrosis was noted and blasts were not increased.

The PB smear 23 months after CML diagnosis showed markedly left-shifted leukocytosis with numerous promyelocytes. There was normochromic, normocytic anemia and thrombocytopenia. The BM aspirate and biopsy specimens showed a hypercellular (~95%) marrow with trilineage hypoplasia and markedly increased blasts and promyelocytes (90%). The promyelocytes had occasional Auer rods and cytochemical analysis showed strong positivity for myeloperoxidase. The overall morphologic findings are similar to that of the microgranular variant of de novo APL.

IMMUNOHISTOCHEMISTRY AND FLOW CYTOMETRY

Flow cytometric immunophenotypic analysis of the BM aspirate specimen revealed a population of promyelocytes that were positive for CD2 (partial), CD13, CD15 (dim partial), CD33, CD34 (dim partial), CD38, CD56, CD64 (partial), CD117 (partial) and myeloperoxidase, and were negative for HLA-DR and other markers assessed, consistent with a promyelocytic immunophenotype.

CYTOGENETIC FINDINGS

Conventional cytogenetic analysis of the initial BM aspirate specimen showed 46,XX,t(9;22)(q34;q11.2)[20].

Karyotypic analysis performed 23 months later showed 46,XX,der(3)t(3;15)(q21;q15)t(15;17)(q24.1;q21.2),t(9;22)(q34;q11.2),der(15)t(3;15),del(17)(q21)[20].

FISH analysis using probes specific for BCR and ABL1 showed BCR-ABL1 fusion signals with an extra red signal in 85.5% of cell nuclei, and FISH using PML and RARA probes showed PML-RARA fusion signals with an extra RARA signal in 81.5% of cell nuclei.

MOLECULAR FINDINGS

Both b3a2 type of BCR-ABL1 and the short form of PML-RARA fusion transcripts were detected by RT-PCR. The BCR-ABL1/ABL1 and PML-RARA/ABL1 ratios were 99.73% and 13.28%, respectively. Additional molecular studies showed no mutations in ABL1, FLT3, NPM1, RAS, KIT, IDH1, IDH2 and JAK2 genes.

INTERESTING FEATURES

To our best knowledge, this is the second confirmed case of t(15;17)(q24.1;q21.2)/PML-RARA in CML blast phase (BP). This case illustrates that t(15;17)(q24.1;q21.2) can occur in CML patients at time of BP and probably reflects a rare form of cytogenetic evolution. Although the BP resembled de novo acute promyelocytic leukemia (APL) morphologically, this patient had a more aggressive clinical course (compared with de novo APL) and died of complications of therapy.

PROPOSED DIAGNOSIS

t(15;17)(q24.1;q21.2)/PML-RARA in blast phase of chronic myelogenous leukemia: a unique clonal evolution

CONSENSUS DIAGNOSIS

Chronic myelogenous leukemia, BCR-ABL1 positive, blast phase with t(15;17)(q24.1; q21.2); PML-RARA and t(9;22)(q34;q11.2); BCR-ABL1