Philadelphia - positive dimorphic blasts in mixed-phenotype acute leukemia with TET2 mutation

An 85 year old male presented with a 2 week history of epistaxis, bleeding per rectum, easy bruising, progressive weakness and fatigue. He was in remission from a prostate cancer treated with radiation. His physical examination was unremarkable except for pallor. His hemoglobin was 11.2 g/L, white blood cell (WBC) 12.9 ×10⁹/L, and platelets 70 ×10⁹/L. The differential showed 19% blasts, 35% neutrophils, 17% lymphocytes, 16% monocytes and 8% basophils. His blood smear showed 5–6% blasts with left-shift granulopoiesis, basophilia, monocytosis, dysplastic neutrophils, and low platelets. A bone marrow (BM) aspiration and biopsy revealed hypercellular BM (100%) with sheets of blasts (52%). Two distinct blast populations were identified: small blasts (80%) with indistinct nucleoli and scanty cytoplasm, and larger blasts (20%) with distinct nucleoli and moderate cytoplasm. Auer rods were undetectable (Figure 1A). Trilineage dysplasia was noted. The BM biopsy revealed a diffuse increase in coarse reticulin and no collagen fibrosis. Larger blasts were MPO positive (20%) while small blasts were TdT positive (70%). In the BM, lymphoblasts (80%) and myeloblasts (20%) were seen. B-lymphoblasts were positive for CD10 partial, CD19, CD20 partial, CD22, CD25 partial, CD34, CD45dim, CD79a, and TdT and negative for MPO and cIgM. The myeloblasts expressed CD34, CD13, CD33, CD117 and were negative for CD19 and TdT. Conventional cytogenetics showed a complex karyotype with t(9;22) (Figure 1C). FISH analysis demonstrated Philadelphia+ (Ph+) cells. Combined morphologic/FISH analysis demonstrated myeloblasts and lymphoblasts with BCR/ABL1 rearrangement (Figure 1A–B). An e1a2 BCR-ABL1 fusion transcript was detected by real-time-PCR (RT-PCR). Microarray-based comparative genomic hybridization (array CGH) demonstrated numerical losses in chromosomes 1, 6, 7 and 11. A next generation sequencing (NGS)-based analysis from BM for 28 genes commonly mutated in patients with myeloid malignancies showed only a point mutation in exon 3 of the TET2 gene c.2428C>T p.Q810*.

Figure 1. Figure 1 (A–C). Features of the bone marrow aspirate and Cytogenetics/FISH.

A–B: Combined morphologic-FISH analysis. A: Wright-Giemsa stain on bone marrow aspirate smear. There are two types of blasts: myeloblasts (arrow head) and lymphoblasts (arrow), erythrocytes (not marked) show dysplastic feature; B: FISH (Fluorescent in-situ hybridization) analysis using BCR/ABL1 ES probe (Abbott). Myeloblasts, lymphoblasts and erythrocytes show 1 red/1 green/2 fusions signal pattern, indicating a BCR/ABL1 rearrangement (96.5% cells). C) Karyotype. 44,-Y,inv(1)(p13p36.1),-6,-7,t(9;22)(q34;q11.2),+mar. Arrow: chromosomes showing numerical loss; arrow head: chromosomes showing structural abnormalities.

The dimorphic population of blasts and the presence of Ph-chromosome led to a diagnosis of Ph+ mixed phenotype acute leukemia (MPAL). Induction chemotherapy was decitabine, dasatinib, and rituximab-mini-HyperCVAD regimen to address both the myeloid and lymphoid clones. A day-28 BM showed no lymphoblasts with 10% myeloblasts. RT-PCR showed a reduction in the BCR-ABL1 to ABL1% to 45%. Currently the patient is in morphologic remission and receiving consolidation chemotherapy with decitabine, dasatinib, and rituximab-mini-HyperCVAD.

MPAL is a rare variety of leukemia (2% of acute leukemias).¹ Ph+ MPAL is very rare (10–15% of MPAL).^2–4 These patients generally have a poor prognosis. The ideal treatment regimen and long-term responses remain poorly defined in MPAL due to its rarity. Of note, identification of the Ph-chromosome and addition of a tyrosine kinase inhibitor may improve otherwise dismal outcomes. In a series of 117 patients with MPAL¹, Ph+ was seen in 15 patients (13%) and only 1/31 tested patients had a TET2 mutations. To the best of our knowledge, this is the first report of Ph+ MPAL with a TET2 mutation. Whether the TET2 mutations acted as a driver mutation in this patient remains unclear. The methylation imbalance induced by TET2 mutations may be reversible by hypomethylating agents such as decitabine. This patient did receive decitabine and this may have provided therapeutic benefit, especially toward the myeloid clone. Specific interventions/agents to correct the metabolic defect created by TET2 inactivation are currently under investigation and may further improve outcomes in TET2 mutated malignancies⁵.