Tumour lysis syndrome in a neonate with transient abnormal myelopoiesis

Abbreviations

1 Introduction

Tumor lysis syndrome (TLS) is an oncological emergency characterized by hyperuricemia, hyperkaliemia, hyperphosphatemia, and hypocalcemia due to rapid destruction of tumor cells [1]. It may be defined clinically or by laboratory investigations [2]. Cairo and Bishop proposed a laboratory definition which requires two or more abnormal values of uric acid, potassium, phosphorus, and calcium within three days before or seven days after cytotoxic therapy [2].

Meanwhile, clinical TLS is defined as laboratory TLS plus at least one clinical complication that was not directly or probably attributable to a therapeutic agent, namely increased serum creatinine concentration (≥1.5 times the upper limit of normal), cardiac arrhythmia/sudden death, or a seizure [2]. These are the most used definitions of TLS, although no universal consensus has been reached [1].

TLS is generally associated with hematological malignancies or high proliferative and sensitive solid tumors [3]. It rarely occurs in transient abnormal myelopoiesis (TAM) [4]. TAM is a disorder of fetal hematopoiesis occurring mostly in neonates with Down Syndrome, that results in a preleukaemic state [4]. It is typically self-limiting but may cause significant complications occasionally [5]. We report a case of a patient with TAM who developed tumor lysis syndrome.

2 Case report

A baby girl was born prematurely at 34 weeks by spontaneous vertex delivery with a birth weight of 2390 g. Her mother is a healthy 28-year-old lady. Detailed scan performed at 24 weeks showed a ventricular septal defect with hyperechogenic bowel. Thus, amniocentesis was performed and revealed Trisomy 21.

The patient was admitted to the neonatal intensive care unit (NICU) after delivery. She exhibited clinical features of Down Syndrome, namely single palmar crease, wide sandal gap, hypotonia and loose skin folds at posterior neck. Initially she was saturating well under room air however, at 12 hours of life she started to develop respiratory distress requiring supplemental oxygen. An ejection systolic murmur grade 3/6 was heard on chest auscultation. Echocardiography revealed complete balanced atrioventricular septal defect with moderate bilateral branch pulmonary artery stenosis. On day 6 of life, the patient exhibited signs of heart failure, namely persistent tachypnoea with a displaced apex beat, requiring non-invasive ventilation. Pharmacological treatment was commenced on day 6 of life, with initiation of oral Furosemide 1 mg/kg/dose twice a day, and oral Spironolactone 3.125 mg BD. Subsequently, Captopril was added as a third anti-failure medication a fortnight later and doses were gradually increased to maximum therapeutic dose.

Initial laboratory reports on the day of birth revealed hemoglobin of 17.8 g/dL, total white count of 65×10³/uL and platelet count of 93×10³/uL. A full blood picture (FBP) performed at 48 hours of life suggested Transient Abnormal Myelopoiesis (TAM) with a blast percentage of 42% as shown in Fig. 1. There was no coagulopathy at this time.

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Fig.1

Full blood picture showing leucoerythroblastic picture with presence of large blasts with high nuclear: cytoplasmic ratio and multiple prominent nucleoli.

Other blood investigations taken at day 4 of life showed hypocalcemia and hyperphosphatemia with normal potassium and serum uric acid levels. Here, two out of four criteria for laboratory TLS were fulfilled. Hyperkalemia and hyperuricemia became evident at day 7 and day 9 of life respectively and remained elevated on repeated readings. Her serum creatinine on day 9 of life was 62μmol/L which was more than 1.5 times from the upper limit of normal. It was at this stage that criteria for both laboratory and clinical TLS were fulfilled. Table 1 shows results of her serial blood investigations throughout admission.

The patient was managed by a careful balance between maintaining adequate kidney perfusion and preventing fluid overload to the heart with a total fluid of 140 ml/kg/day. He was supported with non-invasive ventilation, with highest positive inspiratory pressures of 22 cm H₂O and positive end-expiratory pressures of 6 cm H₂O. Throughout the period of biochemical tumor lysis syndrome, the clinical manifestation of heart failure did not become worse. Serum electrolytes normalized after resolution of leukocytosis on day 16 of life. No other end organ impairment was observed. Both allopurinol and rasburicase were not accessible for this patient at that point of time. Serial peripheral blood examination showed complete resolution in the number of circulating blasts by day 79 of life.

The patient’s heart failure worsened, and she was put on the waiting list for surgical correction. However, at 2 months old, she developed an acute life-threatening event requiring cardiopulmonary resuscitation and prolonged ventilatory support. This resulted in a multidisciplinary team decision for palliative care. She was eventually discharged at 3 months with three anti-failures.

We report a case of a neonate who developed spontaneous tumor lysis syndrome associated with transient abnormal myelopoiesis, complicated by concomitant heart failure.

Transient Abnormal Myelopoiesis is considered a pre-leukemic disorder occurring mainly in infants of Down Syndrome. The occurrence of trisomy 21 with an additional single GATA1 mutation, drives fetal liver hematopoiesis leading to proliferation of megakaryoblastic progenitor cells [6, 7]. The transient nature is thought to be due to the switching of fetal liver to bone marrow at the site of hematopoiesis as the infant matures [7]. However, 10-20% of these patients will develop Acute Megakaryoblastic Leukaemia [6].

Leukocytosis and presence of blast cells more than 10% on a peripheral blood smear suggest the diagnosis of TAM [8]. Thrombocytopenia may be present in 40% of cases [9]. Diagnosis is confirmed by spontaneous regression of blast cells on peripheral blood film within weeks to months [5]. Neonates with TAM may have hepatomegaly, splenomegaly, jaundice, bleeding tendencies, ascites, pleural effusion, and renal failure [5]. They are usually managed conservatively. In patients with evidence of end-organ dysfunction, exchange transfusion, chemotherapy and leukapheresis may be carried out [10].

The mainstay management of tumor lysis syndrome is also supportive. Allopurinol, and rasburicase have been suggested as potential pharmacological therapy by reducing the plasma levels of uric acid. Allopurinol reduces uric acid formation by inhibiting xanthine oxidase, which catalyzes oxidation of hypoxanthine to xanthine and xanthine to uric acid [11]. Rasburicase is recombinant form of urate oxidase, that catalyzes enzymatic oxidation of uric acid to allantoin [12]. Rasburicase has been demonstrated to be clinically superior to allopurinol [12], however it is costly and remains inaccessible to many resource-limited settings. The patient gradually recovered after treatment with diuretics and a small increment in fluid volume.

While most cases resolve spontaneously, there are several risk factors that warrant therapeutic interventions, including signs of hyperviscosity, extremely high blast count, respiratory compromise due to hepatosplenomegaly or heart failure not due to congenital heart disease, and disseminated intravascular coagulation [13]. The risk of TLS is higher in patients with high tumor burden, rapidly proliferating cells, sensitivities to chemotherapy agents or those with underlying renal impairment, and mortality is associated with organ failure [13]. In our case, prematurity and hyperleukocytosis were significant factors that stratified her into the high-risk category. Interestingly, a high blast percentage count at time of presentation is not a determinant for therapeutic interventions or a risk factor to predict early death in these infants [13].

In addition, this patient had higher physiological and hemodynamic demands on her kidneys, due to prematurity and concomitant heart failure. The immature cells i.e., blasts in transient abnormal myelopoiesis are easily ruptured. Consequently, this will lead to massive spillage of intracellular contents such as potassium, phosphate and nucleic acid into the extracellular space resulting in hyperkalemia, hyperphosphatemia and hyperuricemia due to increased catabolism of nucleic acid into uric acid. These electrolytes are renally excreted and their capacity to compensate for these changes is markedly reduced in this patient. Therefore, excess uric acid will form stones causing obstructive uropathy and subsequently progress into acute kidney injury.

To our knowledge, only four cases of tumor lysis syndrome in association with TAM have been reported. Kato et al. [14] reported a case successfully treated with allopurinol and diuretics. Abe et al. [4] reported a patient who subsequently succumbed despite treatment with diuretics and pressor agents. Tragiannidis et al. [10] treated a neonate with TLS and TAM with rasburicase and the patient made complete recovery. Singh et al. [5] described three case reports, one of which was a neonate with Down Syndrome phenotype and atrioventricular septal defect who developed tumor lysis syndrome. The patient succumbed due to obstructive cholangiopathy.

Evidently, while TAM is often self-limiting, it may rarely cause tumor lysis syndrome. Clinicians should have a high index of suspicion of its manifestation with careful consideration of all treatment options. Reports of such rare cases are informative for clinicians in decision-making of management strategies.