Chronic myeloid leukaemia (CML) in children is rare, accounting for 2–3% of childhood leukaemia cases. The natural history of CML progresses through three phases. Approximately 95% of children present in chronic phase (CP), with the remainder presenting in accelerated phase or blast crisis (BC) (Millot et al, 2005). CML-BC is defined as the presence of greater than 20% blasts of either white blood cells in peripheral blood or of nucleated cells in bone marrow (BM), or extramedullary blast proliferation (Vardiman et al, 2009). Extramedullary BC is an infrequent event, affecting 3–7·9% of patients (Raanani et al, 2005), and BC with lymph node (LN) early precursor T-lymphoblastic transformation as initial presentation of CML is extremely rare.
A 12-year-old, previously healthy boy presented with pallor and fatigability for two months, without fever, bleeding or significant weight loss. He had no history of antecedent infections, or taking any medication. He was the only child from healthy parents, with an uneventful family history. Physical examination revealed a developmentally normal boy, with no acute distress except for pallor. His right inguinal lymph nodes (LNs) were identified as being enlarged up to 2 cm in diameter, firm and non-tender. There was no petechia noted on the skin. Examinations of the head, ears, eyes, nose and throat (HEENT), chest and abdomen were negative.
Complete blood counts (CBC) and differential showed red blood cell (RBC) count 1·44 × 1012/l, haemoglobin (Hb) level 50 g/l with normal mean cell volume (MCV) and mean cell haemoglobin concentration (MCHC); white blood cell (WBC) count 7·1 × 109/l with 43% neutrophils, 0·1% eosinophils, 0·3% basophils, 47·9% lymphocytes; platelets of 357 × 109/l, and reticulocytes of 0·017 × 1012/l. A BM aspiration revealed granulocytic hyperplasia with suppression of erythroid cells (Fig 1). Cytogenetic analysis of the marrow showed a metaphase karyotype of 46,XY,t(9;22)(q34;q11·2)/46,XY. Fluorescent in situ hybridization (FISH) revealed BCR-ABL1 fusion signals in 80% of nuclei analysed. Multiple reverse transcription polymerase chain reaction (RT-PCR) demonstrated p210 BCR-ABL1 fusion gene. Sequencing results revealed that the breaks in the major breakpoint cluster region (M-bcr) occur between b2 and b3, generating fusion transcripts with a b2a2 junction. Real time RT-PCR was performed for BCR-ABL1 p210 with the result of 10240 copies/10000 ABL1 copies. Cytomegalovirus, Epstein-Barr virus and parvovirus B19 were negative by RT-PCR. A computerized tomography scan of the chest, abdomen and pelvis was normal with no evidence of lymphadenopathy or organomegaly. Magnetic resonance imaging of the cranium and skeletal survey were unremarkable.
Given that a definitive diagnosis could not be ascertained at that point, the patient was not given any specific cancer treatment except transfusion support for a total four units of pure red blood cells over the next three months follow-up.
The patient was then re-admitted due to enlargement of inguinal LNs. Physical examination showed a pale looking boy, with enlargement of LNs in right groin (about 4 cm in their greatest diameters) and splenomegaly (2 cm palpable below the left rib cage). CBC showed RBC count 3·08 × 1012/l, Hb level 96 g/l (after RBC transfusion), WBC count 8·4 × 109/l and platelet count 137 × 109/l. Ultrasound of the abdomen revealed splenomegaly measuring 129 mm × 37 mm and abdomen lymphadenopathy up to 3·0 cm in their greatest diameters. The inguinal LN measuring 2·0 × 3·5 × 4·0 cm3 was biopsied, which was well-encapsulated and without necrosis. Morphologically, diffuse lymphocytic infiltrates were seen with mostly small to medium sized lymphocytes, which showed high nucleated cell ratio and open chromatin. Immunohistochemistry studies indicated early precursor T-lymphoblastic leukaemia/lymphoma (pre-T ALL/LBL) that was positive for CD3, CD5, CD34, and terminal deoxynucleotidyl transferase (TdT), mostly double CD4/CD8 negative, CD1a negative, and negative for myeloid and mature lymphoid antigens (Fig 2). Fusion gene levels for BCR-ABL1 p210 with the biopsied tissue was detected at 50843 copies/10000 ABL1 copies. Both IGH@ gene and TRG@ gene rearrangement were not identified by PCR using multi-specific commercially available primers.
Based on the presence of the transcription for BCR-ABL1 p210 both in LNs and BM, the patient was treated with imatinib at 340 mg/m2 orally once daily. One and half months later, the lymphadenopathy had resolved and CBC was improved with Hb 122 g/l, WBC count 4·9 × 109/l, and platelet count 170 × 109/l. The BM evaluation demonstrated a low level of BCR-ABL1 (1013 copies/10000 ABL1 copies) and the M:E ratio decreased to 1·2:1. BCR-ABL1 was monitored after 6 and 12 months, and showed 264 copies/10000 ABL1 copies and 118 copies/10000 ABL1 copies, respectively.
The presentation of our case demonstrates the challenge for the diagnosis of paediatric CML. Due to the profound anemia with normal platelet count and no prominent leucocytosis, it would not be possible to reach the diagnosis of CML, except for the identification of BCR-ABL1 p210, which is pathogenomonic of CML (Foroni et al, 2009). Paediatric CML is a very rare disease, and involvement of extramedullary tissues, such as the LNs, is generally limited to blast crisis (Kobayashi et al, 2011).
When CML enters BC, the prognosis is extremely poor, with an overall survival of 4 months for patients treated with conventional chemotherapy or interferon-α, and 7·5 months for patients treated with imatinib (Hehlmann & Saussele, 2008). About 30% of CML-BC are lymphoid, of which T lineage is very uncommon. The median survival of these patients is poor at about 4 months from the diagnosis of BC (Raanani et al, 2005). As a child with isolated LN early pre-T lymphoblastic transformation, and high BCR-ABL1 p210 copies both in the BM and LN, our patient had dramatic response to imatinib and, to date, has been progression free for nearly 15 months. However, the issue of long-term control versus cure is important when discussing therapy for paediatric CML. Stem cell transplantaion (SCT) remains the only proven cure for CML (Andolina et al, 2012), therefore, allogenic SCT was taken into consideration for our patient.
In summary, our case may represent a window of opportunity to identify the progression of an early stage of paediatric CML. The treatment of targeting BCR-ABL1 yielded satisfactory clinical outcome, underscoring the importance of detailed molecular cytogenetic examinations and targeted therapy in malignant haematological disorders.