Chronic myeloid leukaemia with pulmonary leucostasis in a young Down syndrome patient

Introduction

Down syndrome (DS) patients are at a higher risk of haematological malignancies compared to the general population, albeit at a lower risk of contracting solid-tissue malignancies. ¹ Common haematological disorders encountered in DS include transient myeloproliferative disease (TMD), acute megakaryocytic leukaemia (AMKL) and acute lymphoid leukaemia (ALL). Chronic myeloid leukaemia (CML) is rare in the young population. While people with trisomy 21 or DS have an increased risk of developing acute myeloid or lymphoid leukaemia, CML in DS is very rare, and the pathogenesis behind this association is yet to be fully understood.

Case report

An 11-year-old boy was referred to us with worsening symptoms of cough, fever and lethargy for three months. He was diagnosed with DS at birth but was reportedly healthy before the current presentation. He did not have any clinic follow-up. He had skipped schooling since a young age due to his learning disability.

Upon review, the patient was tachypnoeic with a respiratory rate of 30 breaths per minute. He had DS facies characteristics which included a large tongue, small chin, slanted eyes, flat nose and short neck. He was obese, with an estimated body weight of 50 kg and a height of 130 cm. His blood pressure was 136/60 mmHg, pulse rate 130 bpm, temperature 39^oC and oxygen saturation 100% under nasal Optiflow. Lung auscultation revealed bilateral wheeze with a prolonged expiratory phase. Hepatosplenomegaly could not be appreciated due to his thick abdomen. Other physical examinations were unremarkable.

Initial full blood count showed the following values: haemoglobin 7.9 g/dL, leucocytes 229.67×10⁹/L and platelets 136×10⁹/L. The differential counts revealed neutrophils 67.9%, lymphocytes 9.5%, monocytes 19.9%, eosinophils 0.6% and basophils 2.1%. Blood film revealed predominantly granulocytic hyperleucocytosis with all stages of myeloid maturation and 17% circulating blast (Figures 1 and 2). Peripheral blood polymerase chain reaction for BCR–ABL fusion transcript types was b2a2, while peripheral blood for immunophenotyping revealed 15% of cells at blast window expressing positivity towards myeloid markers (i.e. CD13, CD33, CyMPO and CD56). Cytogenetic study from peripheral blood showed t(9;22) (q34;q11) (Ph chromosome) with trisomy 21. Of note, bone marrow aspiration and trephine procedure were not done at diagnosis in view of the patient’s unstable condition and rapid clinical deterioration. C-reactive protein was elevated (51 mg/L). Liver function and renal function were normal. Serial blood and sputum cultures were negative for growth.

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Figure 1.

Peripheral blood film. Granulocytic hyperleucocytosis with all stages of myeloid maturation and circulating blast. Anaemia and thrombocytopenia are also seen.

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Figure 2.

Peripheral blood film (magnified). Granulocytic hyperleucocytosis with all stages of myeloid maturation and circulating blast. Anaemia and thrombocytopenia are also seen.

Spleen size was 22 cm by ultrasound measurement. Chest x-ray showed bilateral lung heterogenous alveolar opacities and cardiomegaly (Figure 3).

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Figure 3.

Chest x-ray. Bilateral lung heterogenous alveolar opacities and cardiomegaly.

A diagnosis of CML in the accelerated phase was made based upon available evidence. However, the possibility of CML in the blast phase could not be totally excluded, since the patient was already in impending pulmonary leucostasis. A cytoreduction agent (i.e. hydroxyurea) was initiated, and later imatinib was introduced after the detection of BCR–ABL fusion transcript. A broad-spectrum antibiotic was started as well for suspected superimposed pneumonia. He was intubated on day 3 of admission due to worsening type 1 respiratory failure. The decision for leukapheresis on day 4 of admission was based upon respiratory deterioration, despite the cytoreductive agent and adequate lung infection control.

The patient showed a slight improvement in terms of white blood cell (WBC) count reduction after being started on the combination of cytoreductive agent and leukapheresis. However, the patient’s condition deteriorated on day 9 of admission. He developed shock, acute anuric renal failure and acute liver injury. The patient succumbed on day 11 of admission.

Discussion

DS is a genetic disorder caused by trisomy of chromosome 21. It is the most common human aneuploidy, occurring in 1/700 births. ² The risk of giving birth to a baby with DS increases with maternal age. DS manifestations include cognitive impairment, gastrointestinal tract anomalies, craniofacial dysmorphism, congenital heart defects, endocrine abnormalities, neuropathology, immune system defects as well as haematological abnormalities. Haematological abnormalities in DS range from macrocytosis, platelet count disorder, TMD to acute leukaemia. Common leukaemia encountered in DS includes AMKL and ALL, with prognosis less favourable in the latter. ³ It has been recognised that blasts in both TMD and AML associated with DS have common genetic abnormalities, namely trisomy 21 and GATA binding protein 1 (GATA1) mutation. Trisomy 21 is considered the ‘first hit’ in leukemogenesis, whereas GATA1 mutation is the ‘second hit’. ⁴

The median age at diagnosis of CML is 60–65 years, and it is rare among children and adolescents. CML in children is aggressive in nature, especially in DS patients. ⁵ Such an occurrence has been reported in two case reports. The first case was reported by Cawein et al. in 1965 and involved a 42-year-old woman with typical CML features. Despite having the DS phenotype, she had a normal karyotype. Karyotyping also revealed the Ph chromosome. She succumbed at home two years later. ⁶ The second case, reported in 1996 by Seghezzi et al., was that of an 11-year-old Italian DS patient with Ph-positive CML in the blast phase. He was also found to have an additional chromosomal abnormality of monosomy 7, which is a frequent acquired clonal abnormality in other haematological disorders such as AML and myelodyspastic syndrome. The patient unfortunately succumbed one year later due to fungal bronchopneumonia after a series of cytoreductive hydroxyurea and intensive chemotherapy. ⁷

Little was known about our patient’s pre-existing illness history. TMD during infancy could hypothetically play a role as a pre-leukemic state in this scenario, even though it is only reported as a pathogenetic role in the development of AML in children with DS. ⁴ Unfortunately, further genetic mutation analysis apart from the conventional cytogenetic testing was not done due to the patient’s rapid clinical deterioration. The other limitation of our case report is the lack of bone marrow investigation to confirm whether it was indeed a blast phase CML. Regardless of different CML phases, physicians should note that CML in DS is aggressive in nature as depicted in our case report and other previous reported cases.^6,7

Pulmonary leucostasis was diagnosed empirically in the setting of impending respiratory distress, despite adequate antimicrobial coverage and negative cultures. Symptoms of leucostasis, either pulmonary or neurological, are typically absent in CML in the chronic phase but can be seen in the accelerated or blast phase. Therapeutic leukapheresis is the aim for immediate cytoreduction, an adjunct to cytoreductive agents such hydroxyurea. The critical leucocyte count resulting in leucostasis may differ in various hyperleucocytic leukaemias. In AML, leucocyte counts ranging from 100 to 200×10³/mm³ could result in severe symptoms, whereas in CML, a patient with a leucocyte count as high as 900×10³/mm³ can still be asymptomatic. ⁸ Therefore, the exact timing of initiating leukapheresis depends upon clinical judgement rather than being determined by a specific leucocyte count.

Cytoreduction with cytarabine and steroids could rapidly decrease the circulating leucocyte count, as well as target the leukaemia cells in the bone marrow. However, the benefit of chemotherapy agents should outweigh the risk of overwhelming infection, which is usually co-existent upon presentation. Hydroxyurea is preferred for patients who are unable to receive immediate induction chemotherapy.

Conclusion

CML is rare in DS patients, and it is usually aggressive in nature. Prompt identification and rapid referral to haematologists for intensive treatment should be done whenever physicians encounter DS patients with elevated WCC.