Spontaneous tumour lysis syndrome secondary to the transformation of chronic myelomonocytic leukaemia into acute myeloid leukaemia

Abstract

A 78-year-old man, with a 6-year history of stable chronic myelomonocytic leukaemia (CMML), presented with general deterioration and worsening pancytopenia. Bone marrow biopsy showed that his disease had transformed into acute myeloid leukaemia (AML). He was started on a supportive transfusion regimen and did not receive any chemotherapy or corticosteroids. Several weeks later, he developed acute renal failure and was admitted to a medical admissions ward. Spontaneous tumour lysis syndrome (sTLS, grade 1) was diagnosed, as per the Cairo and Bishop criteria. He was treated with intravenous fluids, rasburicase and allopurinol. His renal function improved and he recovered from the sTLS. The authors believe that this is the first published case of sTLS occurring as a result of CMML transforming into AML; it highlights the importance of recognising sTLS as a cause of renal failure and electrolyte disturbance before cancer treatment begins.

Background

Tumour lysis syndrome (TLS) is a complication of highly proliferative malignancies, and is due to the release of cell contents from dying tumour cells.¹ It can be caused either by the start of chemotherapy or by rapid tumour cell turnover. TLS is most commonly seen in ‘liquid’ tumours, such as leukaemia and lymphoma, due to a combination of a high proliferative rate, large tumour burden and sensitivity to chemotherapy.^{1 2} It results in life-threatening electrolyte disturbance and acute kidney injury. Spontaneous TLS (sTLS) is the subset of TLS that occurs before any treatment is started.

The authors believe that this is the first reported case of sTLS occurring as the result of chronic myelomonocytic leukaemia (CMML) transforming into acute myeloid leukaemia (AML). With the availability of drugs such as rasburicase, and good supportive care, sTLS can often be treated successfully if recognised early. Patients may present to haematology/oncology departments, but also to medical admission units. It is important that doctors in acute medicine consider sTLS as a potential cause of acute kidney injury (AKI) and electrolyte disturbance.

Case presentation

A 78-year-old man presented to the haematology outpatient department, with a history of stable CMML. He had never required any chemotherapy or blood product transfusion. He reported weight loss, night sweats, shortness of breath and lethargy over the preceding 6 months. Routine blood tests showed worsening anaemia, thrombocytopaenia and a rising total white cell count (WCC 50.3×10⁹/L, haemoglobin 80 g/L, platelets 33×10⁹/L).

Microscopic review of his peripheral blood smear showed a blast cell count of 8.3%. Alone, this was insufficient for the diagnosis of AML as 20% blast cells are needed for a diagnosis according to the WHO classification.³ A subsequent bone marrow biopsy showed an 80% infiltration of monocytoid blast cells and AML was diagnosed (figures 1 and 2). Cytogenetic analysis of the bone marrow showed trisomy 8, an unfavourable genetic marker.

Figure 1.

Bone marrow aspirate showing monocytoid blasts.

Figure 2.

Bone marrow trephine showing widespread infiltration of blasts in the marrow architecture.

CMML had been diagnosed 6 years before through the haematology out-patient department. The patient's disease had been stable and was therefore not followed up by haematology, but he was regularly seen in primary care. His medical history included coronary artery bypass grafting and appendicectomy; there was no previous history of a hospital admission related to CMML.

Further investigations showed impaired renal function: urea 10.3 mmol/L, creatinine 217 µmol/L and an estimated glomerular filtration rate 25 mL/min (chronic kidney disease stage 4). A blood test taken 3 months earlier showed urea 13.0 mmol/L and creatinine 169 µmol/L.

An epigastric mass was palpated in the haematology clinic and so a CT abdominal scan was arranged. In keeping with his diagnosis of AML, it showed multiple areas of lymphadenopathy (axillary, abdominal and mediastinal), splenomegaly and sclerotic bone marrow foci; there was evidence of neither renal disease nor obstruction (figures 3 and 4).

Figure 3.

Axial CT image showing splenomegaly.

Figure 4.

Axial CT image showing abdominal lymphadenopathy and normal renal size.

Two weeks later, the patient returned to the outpatient department in a clinically deteriorated condition. He was admitted to a medical admissions ward, with worsening constitutional symptoms and deteriorating renal function.

Differential diagnosis

Admission blood tests showed stage 2 AKI: urea 16.0 mmol/L and creatinine 396 µmol/L.

There are numerous differentials of AKI to consider in this case, including: dehydration, sepsis, renal obstruction, for example, from lymphadenopathy, and TLS. The patient was adequately hydrated on clinical assessment. There were no clinical symptoms and no signs of infection, and the C reactive protein was within the reference range. A renal ultrasound scan showed that the kidneys were of normal size and demonstrated no sign of obstruction.

sTLS was considered by the admitting team, and appropriate blood tests were taken (calcium, potassium, phosphate, urate, urea and creatinine). While calcium and potassium levels were within the reference range, urate and phosphate were both raised (table 1).

Table 1.

Initial laboratory investigations for TLS on presentation to medical admissions ward

Investigation	Result	Reference range
Urate	808 µmol/L*	(140–360 µmol/L)
Adjusted calcium	2.29 mmol/L	(2.20–2.60 mmol/L)
Phosphate	2.25 mmol/L*	(0.80–1.50 mmol/L)
Potassium	4.6 mmol/L	(3.5–5.3 mmol/L)
Urea	16 mmol/L*	(2.5–7.8 mmol/L)
Creatinine	396 µmol/L*	(60–105 µmol/L)

*Indicates abnormal results.

TLS, tumour lysis syndrome.

The patient was diagnosed with sTLS, using the Cairo-Bishop classification.¹ This classification combines biochemical findings and clinical signs. Two laboratory criteria and one clinical criterion were met (table 2).

Table 2.

Diagnostic criteria for laboratory and clinical TLS

Laboratory criteria
2 or more needed, occurring ≤3 days before or ≤7 days after chemotherapy	Uric acid >476 µmol/L or a 25% increase
	Potassium >6.0 mmol/L or a 25% increase
	Phosphate >1.45 mmol/L or a 25% increase
	Calcium<1.75 mmol/L or 25% decrease
Clinical criteria
1 or more needed	Creatinine >1.5 times upper limit of normal
	Cardiac arrhythmia or sudden death
	Seizure

Criteria in bold represent raised levels of urate, phosphate and creatinine, respectively, were present in this individual. Adapted from Cairo et al.¹

TLS, tumour lysis syndrome.

Treatment

Initial management focused on prompt rehydration to aid the elimination of urate, using intravenous normal saline and dextrose. Rasburicase was given on the day of admission and allopurinol several days later.

Rasburicase is a synthetic form of urate oxidase that converts uric acid to allantoin; this is more soluble and easier to excrete than urate.⁴ Current British Committee for Standards in Haematology (BCSH) guidelines suggest that it be used in the treatment of established TLS.⁵ Allopurinol, a xanthine oxidase inhibitor, can limit the efficacy of rasburicase by preventing the production of urate, and so was started several days later. The patient's response to this treatment was monitored with twice daily blood tests including: urea, creatinine, urate, calcium and phosphate.⁶

Twenty-four hours into the admission he developed neutropenic sepsis and was treated empirically with intravenous piperacillin/tazobactam (as per current National Institute for Health and Care Excellence guidelines⁷), gentamicin was omitted due to the AKI. Later, a urine culture grew a Proteus species.

Owing to the aggressive fluid therapy, the patient developed peripheral oedema. This was successfully managed with careful monitoring of his fluid balance, and with the advice of intensivists as well as of renal physicians. He did not require dialysis and remained on a general medical ward throughout his admission.

When he had recovered from the neutropenic sepsis, he was started on palliative chemotherapy with subcutaneous cytarabine. The aim of his treatment was to slow the progression of the AML and help to manage his sTLS. He slowly improved and was discharged 19 days following admission.

Outcome and follow-up

This patient was discharged with improved renal function (creatinine 254 µmol/L) and no evidence of ongoing tumour lysis. Unfortunately, he returned 4 days later, unwell and acutely confused. A chest radiograph showed consolidation and he was diagnosed with pneumonia. His renal function had deteriorated slightly, but this was believed to be due to the infection (creatinine 299 µmol/L) and there was no evidence of TLS. Broad-spectrum antibiotics were started and blood products transfused to maintain his haemoglobin >100 g/dL and platelet count >10×10⁹/L. Despite these measures, he continued to deteriorate and died 1 week following readmission.

Discussion

TLS is caused by the release of cell contents from tumour cell breakdown, secondary to either chemotherapy or rapid tumour turnover. It can occur in up to 20% of malignancies.⁸ The specific incidence in haematological malignancies is unknown, but it is seen most commonly in high-grade lymphoma and AML. A recent observational study of 772 patients with AML reported an incidence of 17% during induction chemotherapy, and identified it as the major cause of death in 2% of patients.⁹ Concurrent TLS and AKI is believed to increase mortality rates by up to 51%.¹⁰

Recent BCSH guidelines advise that all individuals with haematological malignancy be risk-assessed before starting any chemotherapy. This then determines their need for prophylactic treatment with either hydration, allopurinol or rasburicase.⁵ This patient was at intermediate risk due to the progression to AML, and would therefore have been given hydration and allopurinol before starting on treatment had he not developed sTLS.

Previously, urinary alkalinisation was used to treat TLS. It aimed to increase the solubility of uric acid and thereby decrease deposition in the renal tubules. There is, however, a lack of evidence to support its use and more recent studies have suggested that the main component of renal injury is from calcium phosphate precipitation, which is exacerbated by urine alkalinisation.^{5 11}

Individuals who have a poor response to TLS treatment should be assessed for the rarer causes of AKI, including direct leukaemic infiltration of the kidney, amyloid deposition, lysozyme deposition and vasculitis.^{12 13} This again highlights the importance of involving renal physicians, as these pathologies would require renal biopsy for diagnosis.

Spontaneous TLS occurs rarely compared to therapy-related TLS. The published literature contains sporadic case reports, occasionally identifying it in less proliferative haematological malignancies such as multiple myeloma.¹⁴ Two case reports of TLS related to CMML were identified from the current literature. Otrock et al¹⁵ reported a case of TLS following hydroxycarbamide therapy with elevated phosphate, creatinine and lactate dehydrogenase. Although the remaining parameters were not sufficiently detailed to allow a formal diagnosis according to the established criteria, it is strongly suggestive of TLS.

Trachsler et al¹⁶ reported a case of known CMML presenting with AKI. Blood tests showed elevated potassium, urate, phosphate and creatinine (1588 µmol/L), in keeping with laboratory and clinical TLS. Despite treatment with rasburicase and allopurinol, the patient deteriorated further and was found at autopsy to have tumourous invasion of the kidney.¹⁶ A bone marrow biopsy performed at the time showed no evidence of transformation into AML.

The authors could find no other cases in the published literature of sTLS occurring due to the transformation of CMML into AML. This case highlights the need to consider TLS in all patients with malignant disease, both prior to and following the initiation of chemotherapy. TLS is associated with significant mortality, but can be successfully managed if recognised early. The prompt involvement of intensivists and renal physicians is critical to the successful management of this condition.

Learning points.

• Tumour lysis syndrome can occur prior to chemotherapy, most often in highly proliferative haematological malignancies.

• Tumour lysis syndrome is associated with significant morbidity and mortality, particularly if there is concurrent acute kidney injury.

• The Cairo-Bishop classification and British Committee for Standards in Haematology guidelines are useful to aid diagnosis, allow risk stratification and guide subsequent treatment.

• Recognised early, tumour lysis syndrome can be successfully managed with hydration, rasburicase and supportive care.

• Early involvement of intensivists and renal physicians is essential.