Philadelphia (Ph) chromosome is a gene abnormality of chromosome 22 generated as a result of the reciprocal translocation t(9;22)(q34.1; q11.2). This rearrangement results in Breakpoint Cluster Region (BCR) at a position juxtaposed to an ABL-1 gene leading to the formation of BCR-ABL1 fusion gene transcripts1. Several BCR-ABL1 fusion transcripts and variant transcripts have been identified including e6a2. Ph is a diagnostic marker for Chronic Myelogenous Leukemia (CML). The appearance of late Ph chromosomes over the course of leukemia often represents disease progression and signifies poor prognosis.
In a report in Leukemia Research Reports, Jinjuan Yao and colleagues from the Memorial Sloan Kettering Cancer Center discuss an uncommon case of a patient diagnosed with Chronic Myelomonocytic Leukemia (CMML) who progressed rapidly to Acute Myeloid Leukemia (AML) with an acquisition of rare BCR-ABL1 fusion transcript e6a22. The article was published ahead of print on 31st Jan 2017.
Patient diagnosed with CMML
- 58-year old male patient with White Blood Cell (WBC) of 24.3 K/µl; no blast present
- Hypercellular; hyperplastic granulopoiesis and dysplastic megakaryocytes present in the Bone Marrow (BM) biopsy
- Normal karyotype and negative for t(9;22)
- Patient was diagnosed with CMML-1
- Patient progressed to AML with 20% BM blasts
- Conventional induction with cytarabine and idarubicin was administered
- Disease progressed with an increase in BM blasts to 41%
- BM blasts reduced to 5% upon re-induction with high-dose cytarabine
- Complete Remission (CR) was not achieved
Transformation to AML
- 83% myeloblasts in the BM
- Ph chromosome was detected
- Single fusion signal detected in 6% (30/500) of Peripheral Blood (PB) cells
- Fusion of BCR exon e6 and ABL exon a2 generating variant e6a2 fusion transcript (~800 bp) was present
- 800 mg/day nilotinib, a Tyrosine Kinase Inhibitor (TKI), was administered
- WBC increased to 91.3 K/µL; 80% blasts
- BCR-ABL1 fusion in 3.4% (17/508) of PB cells
- Palliative care was administered
- Patient died as a result of disease progression
Although the patient’s Ph positive clones decreased significantly upon administration of nilotinib, there was still a high percentage of blasts as well as high selection and uncontrolled proliferation of Ph negative clones. The emergence of these Ph negative clones contributed to disease progression and death of the patient.
In summary, the authors suggest that their study illustrates the importance of detecting rare BCR-ABL fusion transcripts using a combination of karyotype/FISH and molecular studies. Furthermore, personalized therapeutic strategies such as the use of new TKIs and allogenic stem cell transplantation should be considered for patients who are Ph positive. The authors also stressed that it is important to be aware that eradication of Ph positive clones may lead to selection of Ph negative neoplastic clones.
Philadelphia (Ph) chromosome is a cytogenetic hallmark of chronic myelogenous leukemia (CML). Most patients with CML harbor either the e13a2 or e14a2 BCR-ABL fusion product, while small subset of cases expresses e1a2 or e19a2 transcripts. We report a chronic myelomonocytic leukemia (CMML) patient, initially Ph chromosome negative at presentation, with rapid disease progression to AML and appearance of Ph chromosome and BCR-ABL e6a2, a very uncommon fusion transcript. The patient died of the subsequent emergence and dominance of a Ph negative leukemic clone.