Myeloid Blast Crisis of Chronic Myeloid Leukemia Followed by Lineage Switch to B-Lymphoblastic Leukemia: A Case Report

Introduction

Chronic myeloid leukemia (CML) is a common myeloproliferative disease characterized by the BCR-ABL fusion gene from the chromosomal translocation t(9; 22)(q34;q11), which is referred to as the Philadelphia (Ph) chromosome.^1–3 There are three stages in the progression of CML: the chronic phase (CP), the accelerated phase (AP), and the blastic phase (BP). The CP can be followed by the AP, or direct progression to the final BP, which occurs more frequently in the cells of myeloid lineage than in those of lymphoid lineage.⁴ Patients with CML are treated with tyrosine kinase inhibitor (TKI) therapy according to the blast phenotype.^5,6 Here, we report a rare case in which the blast lineage switched from myeloid to B-lymphoid.

Case Report

A 35-year-old male was admitted to our hospital in December 2015 because of abdominal distention for more than 1 year and dizziness for 1 week. Prior to his presentation at our hospital, the patient visited a local hospital because of abdominal distention where he was found to have a white blood cell (WBC) count and bone marrow (BM) smear that indicated CML; however, these reports were not available for review. The patient was then transferred to our hospital for further symptomatic treatment. Upon admission, the patient’s vital signs were within normal limits although was pale and had splenomegaly and anemic face on examination.

His initial complete blood count (CBC) showed a hemoglobin level of 71 g/L, a platelet count of 43,000/µL, and a WBC count of 573,090/µL with 17% blasts. A BM study (Figure 1) revealed hypercellular marrow with 25% blasts (Table 1). The neutrophil alkaline phosphatase (NAP) activity was low. A chromosome study revealed a karyotype of 46, XY, t(9; 22)(q34; q11) in all 20 cells analyzed (Figure 1). Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis revealed the presence of genes encoding p210 BCR/ABL1 fusion proteins (Table 1). Immunophenotyping by flow cytometry suggested that the blasts were positive for cytoplasmic myeloperoxidase (MPO), CD4, CD11b, CD15, CD16, CD33, CD34, CD38, CD56, and CD71 (Figure 2). A BM biopsy showed CML in myeloid blast crisis and fibrosis. A diagnosis of myeloid blast crisis from CML was made, and the patient was treated with imatinib (600 mg daily) and hydroxyurea (2000 mg daily). One month after the initiation of therapy, routine laboratory tests revealed a WBC count of 4920/µL with 2% blast cells in both the PB and BM. A treatment in combination with DVCP chemotherapy was recommended to the patient; however, treatment was delayed, and the patient was discharged due to financial reasons and the original treatment plan was maintained. Three months later, the patient was re-admitted to the hospital again for extensive cervical subcutaneous nodules, and PB tests indicated a high leukocyte count with 4% blasts. His BM showed hypercellularity with 62.5% blasts (Table 2). Similar to the first admission, a chromosome study revealed a karyotype of 46, XY, t(9; 22)(q34; q11) in all 20 cells analyzed (Figure 3). RT-PCR analysis revealed the presence of genes encoding p210 BCR/ABL1 fusion proteins (Table 2). Immunophenotyping by flow cytometry suggested that the blasts were positive for cytoplasmic CD22, cytoplasmic CD79a, and CD10, CD19, CD20, CD33, CD38, CD117, HLA-DR with membrane-expressed (Figure 4). Pathological biopsy of the cervical subcutaneous nodules revealed diffuse B-lymphoblastic lymphoma and B-lymphoblastic transformation from CML was diagnosed. Despite chemotherapy with DVCP (daunorubicin, vincristine, cyclophosphamide and prednisone) in combination with dasatinib for three months, the patient did not achieve complete remission. The routine laboratory tests revealed a WBC count of 4020/µL with 6% blast cells in the PB and 20% blast cells in the BM. The patient decided to stop treatment and was discharged from the hospital due to financial reasons.

Table 1 Laboratory Data on First Admission

Table 2 Laboratory Data on Second Admission

Figure 1 Bone marrow aspirate (1000×) using wright stain and chromosome study on first admission. (A) A BM study revealed acute myeloid leukemia. (B) A chromosome study revealed a karyotype of 46, XY, t(9; 22)(q34; q11) in all 20 cells analyzed.

Figure 2 Immunophenotyping by flow cytometry of the blasts at acute myeloid leukemia phase.

Figure 3 Bone marrow aspirate (1000×) using Wright stain and chromosome study on second admission. (A) A BM study revealed acute B-lymphoid leukemia. (B) A chromosome study revealed a karyotype of 46, XY, t(9; 22)(q34; q11) in all 20 cells analyzed.

Figure 4 Immunophenotyping by flow cytometry of the blasts at acute B-lymphoid leukemia phase.

Discussion

There are several previous reports on lineage switch that in Ph chromosome-positive acute leukemia.^7–14 Blast lineage switch has been shown to be related to clonal selection and transformation of multipotent progenitor cells during chemotherapy;⁸ however, lineage switch is rare in CML-BC. Lineage switch often occurs during conventional chemotherapy, although in this case, the switch occurred during treatment with imatinib. Previous studies on the blast lineage switch suggested that the origin was multipotent progenitor cells.^11,15 Our case also suggests that blasts in CML-BC have the potential to change phenotype, which may be related to factors such as gene expression and treatment modality.

The case presented here provides interesting insights into the mechanism of CML-BC. Our findings indicate that the chromosomal translocation t(9; 22)(q34; q11) with p210 BCR-ABL1 fusion gene that exists in multipotent progenitor cells is the primary molecular event in this case. The blastic crisis occurred in the presence of the Ph chromosome in the different multipotent progenitor cells. In our case, it is also possible that blastic crisis arose independently from two different Ph chromosome-positive clones. At the first admission, the blasts were successfully diminished by maintenance therapy with TKI imatinib, suggesting that imatinib may be an effective treatment. At the second admission, TKI dasatinib combined with chemotherapy was ineffective, suggesting that the different Ph chromosome-positive clones were resistant to a combined treatment of dasatinib and DVCP, resulting in B-lymphoid blastic crisis.

This case indicates that the Ph chromosome with p210 BCR-ABL1 fusion gene is a key molecule in CML-BC. However, the Ph chromosome also occurs as a specific primary chromosomal change in acute myeloid leukemia. The mechanisms underlying CML-BC are complex, involving changes to many aspects of the molecular pathology, including the interaction of oncogenes, anti-oncogenes, and other abnormal genes^2,5,16 in addition to the BCR-ABL1 gene. Further research is needed to assess the frequency, treatment, and prognosis of CML-BC patients with lineage switch.