Rasburicase-induced haemolysis and methemoglobinemia: an ongoing issue

Abstract

We report a case of a 91-year-old Caucasian woman with a history of chronic lymphocytic leukaemia who developed acute hypoxic respiratory failure (AHRF) requiring intubation for less than 24 hours after receiving rasburicase. Laboratory workup was significant for methemoglobinemia and acute anaemia, and blood film demonstrated evidence of oxidative haemolysis with bite cells. The patient was given a presumptive diagnosis of glucose-6-phosphate dehydrogenase (G6PD) deficiency and was managed conservatively with successful resolution of AHRF and stabilisation of haemoglobin level. Seven days after admission, she passed away due to subsequent complications; hence, follow-up G6PD level could not be obtained. Haemolytic anaemia and methemoglobinemia in the setting of recent rasburicase administration should raise clinical suspicion for G6PD deficiency. In non-emergent cases, patients should be screened prior to receiving rasburicase regardless of risk factors. Because rasburicase is often needed emergently, patients at high risk of tumour lysis syndrome should be screened early for G6PD deficiency.

Background

Rasburicase is a recombinant form of urate oxidase that is used in the treatment and prevention of hyperuricemia and tumour lysis syndrome (TLS). It facilitates the excretion of urate through the kidneys by converting uric acid into a water-soluble product allantoin, producing hydrogen peroxide as a byproduct.^{1 2} Rasburicase was initially approved in 2002 for the management of elevated uric acid in paediatric patients with haematological malignancies who are receiving chemotherapy. Its use was later expanded by the Food and Drug Administration (FDA) to involve the adult population in 2009.³ Studies have shown that rasburicase is more efficacious in reducing serum urate levels and is associated with less acute kidney injury (AKI) when compared with allopurinol.^4–6

Although rasburicase is generally well tolerated in the general population, individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency are of particular significance. Erythrocytes in patients with G6PD deficiency are rapidly depleted of glutathione, a vital antioxidant. Hydrogen peroxide oxidises the sulfhydryl group on haemoglobin, leading to methemoglobin formation and cell membrane rigidity, thus causing hypoxia and rapid haemolysis of red blood cells (RBCs) by the reticuloendothelial system.^{7 8} Currently, the use of rasburicase in patients with G6PD deficiency is contraindicated with reported incidence of haemolysis and methemoglobinemia occurring in <1% of all patients.³ For that reason, the FDA has recommended testing high-risk individuals for G6PD deficiency prior to administering rasburicase;³ however, this is infrequently done in practice.

Case presentation

The patient is a 91-year-old Caucasian woman with a medical history significant for chronic lymphocytic leukaemia (CLL) on observation and conservative management following previous intolerance to multiple lines of treatment. Routine blood work obtained by her oncologist the day prior to admission revealed elevated lactate dehydrogenase (LDH), uric acid of 12 mg/dL, white blood cell (WBC) count of 55.2 x 10⁹ /L, and stable haemoglobin at 9.2 g/dL. She was given a single dose of rasburicase 7.5 mg for TLS prevention and sent back to the subacute rehab facility. Later in the day, the patient started reporting shortness of breath, was found to have oxygen saturation (SpO₂) in the 80s and was placed on supplemental oxygen with mild improvement in SpO₂. She continued to worsen throughout the night and presented to the emergency department (ED) <24 hours after receiving rasburicase. In the ED, blood pressure was stable, but the patient consistently remained hypoxic despite the use of non-rebreather at 100% FiO₂. Laboratory workup was significant for an acute drop in haemoglobin to 4.6 g/dL from 9.2 g/dL (mean corpuscular volume 98 fL), WBC 242.4 X10⁹ /L, potassium 5.9, and creatinine 1.62 mg/dL. Arterial blood gas (ABG) demonstrated a pH of 7.48, pCO₂ of 22, pO₂ of 38 and methemoglobin level at 6.2% (ref. 0.0%–2.0%). SpO₂ was around 74% despite good waveform on pulse oximetry. When the patient started to become altered, the decision was made to intubate her for airway protection after consent was obtained from family members. CT scan of the chest, abdomen and pelvis was negative for bleeding; however, it was significant for marked lymphadenopathy, consistent with disease progression. A small left-sided subsegmental pulmonary embolism (PE) was also noted, but was disregarded as an inciting factor to the patient’s presentation. No evidence of pneumonia, pulmonary oedema or pneumothorax was noted on CT to justify the patient’s hypoxemia. Echocardiogram revealed an ejection fraction of 60%, normal biventricular function and no evidence of right ventricular (RV) strain. Due to lack of a source of bleeding, haemolysis workup was ordered and the patient was transfused with two units of packed RBCs (pRBCs). Laboratory workuprevealed a low haptoglobin at <8 (ref. 40–250 mg/dL), elevated LDH at 1038 U/L, elevated reticulocyte count, schistocytes <1%, normal international normalized ratio (INR), normal fibrinogen level and a negative direct Coombs test. G6PD levels were within normal limits; however, blood was drawn shortly after transfusion was started and the patient was in acute haemolysis. Thus, the reading was considered unreliable as values can be falsely normal under these circumstances. Blood film was significant for lymphocytosis morphologically consistent with patient’s known CLL, bite cells, smudge cells, and RBC morphology suggestive of oxidative haemolysis (figure 1). Based on these findings, the patient was diagnosed with presumed G6PD deficiency and for that reason, was not given methylene blue for treatment of her methemoglobinemia.

Figure 1.

Peripheral blood smear demonstrating many red blood cells with irregularly contracted haemoglobin (eccentrocytes) and rare bite cells (degmacytes). Mature lymphocytes representing the patient’s chronic lymphocytic leukemia/small lymphocytic lymphoma are also present (Wright-Giemsa stain).

Differential diagnosis

Initial differential diagnosis for the patient’s presentation included PE, pulmonary oedema, pneumothorax and pneumonia. Although a small subsegmental PE was noted on CT scan, it was unlikely the cause of hypoxemia evident by the lack of RV stain, haemodynamic stability and persistent hypoxemia despite supplemental oxygen. The patient’s methemoglobinemia and acute anaemia were also a consideration for the cause of hypoxemia. Imaging did not reveal a concealed haemorrhage, and the patient did not exhibit signs of visible bleeding. The elevated total bilirubin and LDH, and decreased haptoglobin indicated haemolysis. The lack of schistocytes on blood analysis along with normal INR and fibrinogen levels made microangiopathic haemolytic anaemia and disseminated intravascular coagulopathy less likely. Autoimmune haemolytic anaemia was unlikely given that direct Coombs test was negative. Therefore, rasburicase-induced haemolytic anaemia was the most probable cause of the patient’s anaemia, and the presence of oxidative damage with bite cells indicated G6PD deficiency was the likely predisposing factor for this patient’s presentation.

Treatment

She was transferred to the medical intensive care unit (ICU) and was treated conservatively with pRBCs to maintain haemoglobin of 7 mg/dL. Detailed laboratory values during the admission are shown in table 1.

Table 1.

Laboratory values through the first 72 hours of admission

	Normal	Before rasburicase	Admission	12 hours	24 hours	48 hours	72 hours
WBC, x 109 /L	3.3–10.7	55.2	242.4	–	223.3	186.9	95.7
Hgb, g/dL	12.1–15.0	9.2	4.6	8.0	7.1	8.0	7.9
Platelets, x 109 /L	150–400	125	145	–	88	125	85
Potassium, mmol/L	3.5–5.2	4.7	5.9	5.5	5.1	4.9	4.3
Calcium, mg/dL	8.5–10.5	11.3	11.4	9.9	9.0	8.6	8.8
Phosphorous, mg/dL	2.3–4.4	2.5	4.4	–	3.9	4.0	3.7
Creatinine, mg/dL	0.5–1.10	1.25	1.62	1.68	2.17	2.31	2.08
LDH, U/L	100–240	685.2	1038	1252	–	–	–
Total bilirubin, mg/dL	0.3–1.2	0.45	1.9	–	2.2	2.0	1.1
Uric acid, mg/dL	2.6–6.0	12.0	–	–	2.0	–	–
Oxyhaemoglobin, %	95–98	–	91	96	95	98	98
PaO2, mm Hg	80–100	–	389	381	265	95	–
FiO2, %	–	RA	100	100	80	4 L NC	2L NC
Methemoglobin, %	0.0–2.0	–	6.2	2.5	2.5	1.8	–

WBC, white blood cells; Hgb, haemoglobin; LDH, lactate dehydrogenase; PaO₂, arterial oxygen pressure; FiO₂, fraction of inspired oxygen; RA, room air; NC, nasal cannula;.

Given the patient’s initial acute presentation and high WBC count, she was started empirically on antibiotics for concern of an underlying infectious process. After transfusion of pRBCs with stabilisation of haemoglobin to 8.0 g/dL, there was noticeable improvement in respiratory status evidenced by decreased oxygen requirements and ventilatory support. Oncology and nephrology were consulted on admission. On day 2, haemoglobin remained stable, and AKI developed likely due to haemoglobinuria with acute tubular necrosis (ATN), which was treated with intravenous fluids since the patient was non-oliguric. SARS-CoV-2 swab obtained on admission resulted negative. A spontaneous breathing trial was successful and the patient was extubated later that day.

On day 3, the patient developed atrial fibrillation with heart rate (HR) in the 90s and CHA₂DS₂-VAS_c score of 4, so she was started on intravenous heparin. Infectious workup obtained on presentation was negative and antibiotic therapy was de-escalated. In total, four units of pRBCs were transfused, and no additional transfusions were needed to maintain stable haemoglobin

Outcome and follow-up

The patient was transferred out of the medical ICU on hospital day 4 after resolution of acute hypoxic respiratory failure and haemolytic anaemia. A second SARS-CoV-2 swab obtained was negative. The patient continued to be treated conservatively for AKI and hyperkalemia. On day 6, the patient developed an episode of apnoea and bradycardia with HR in the 20s (bpm). Stat ECG was significant for a third-degree heart block. Rapid response team (RRT) was initiated; however, on arrival, the patient reverted back to sinus rhythm with HR in the 90s with stable SpO₂ and blood pressure. The subsequent day, she was noted to have tachypnoea with increased work of breathing, SpO₂ was 85% and chest X-ray demonstrated a left lung base opacity suggestive of aspiration pneumonia. RRT was initiated a second time. The family was notified, and after discussions with the primary team and oncology, code status was changed to ‘do not resuscitate’, and her family opted for comfort measures. Hospice was consulted. The patient expired on day 8, with family members present at bedside.

Discussion

G6PD deficiency is the most common human enzyme deficiency with an estimated 400 million people worldwide carrying the mutation.⁹ Marked geographical and racial variations exist in the distribution of G6PD deficiency, with individuals of Middle Eastern and African descent posing the greatest risk.^{9 10} Men are at especially high risk as G6PD deficiency has an X-linked recessive mode of inheritance. Rasburicase-induced methemoglobinemia and haemolysis are documented side effects that occur due to the production of hydrogen peroxide, an oxidative agent, during conversion of uric acid to allantoin. Patients with G6PD deficiency have a decreased tolerance to oxidative stress and are, therefore, at a greater risk of haemolysis and methemoglobinemia with rasburicase.⁷

Several cases have been reported in the literature demonstrating the occurrence of methemoglobinemia and haemolytic anaemia in patients receiving rasburicase. Since the approval for the use of rasburicase by the FDA was initially granted for paediatric patients, the first reported case involved a 12-year-old boy with G6PD deficiency.¹¹ Subsequently, several reports have been published highlighting the incidence of methemoglobinemia with or without haemolysis in older adults.^12–19 The majority of cases were managed conservatively with blood transfusions and discontinuation of the offending agent with favourable outcomes reported.^15–19 Multiple cases did not have confirmed G6PD deficiency although they were clinically diagnosed as such.^{12 13} Death occurred in two patients^{13 14} of which one was treated with methylene blue in whom G6PD deficiency was not confirmed, but clinically suspected.¹³ One patient had resolution of haemolysis after transfusion of eight units of pRBCs, but eventually developed acute renal failure due to pigment nephropathy, requiring haemodialysis.¹⁵

Methemoglobinemia should be considered on the differential diagnosis when hypoxia develops within 24 hours of rasburicase admission.¹⁶ Potential treatment options for methemoglobinemia include methylene blue and ascorbic acid, in addition to supportive therapy.^{16 20} However, methylene blue should be avoided in patients with G6PD deficiency because they lack the ability to reduce methylene blue, causing it to contribute to oxidative stress and potentially worsening the haemolysis and methemoglobinemia.¹⁷ Therefore, patients presenting with rasburicase-induced methemoglobinemia should be highly suspected of having G6PD deficiency, especially because haemolysis is delayed, typically following the appearance of methemoglobinemia.^{15 18} Haemolytic anaemia can present as jaundice, tachycardia and dyspnoea.¹⁶ Laboratory findings indicating haemolysis include low haemoglobin, low serum haptoglobin and elevated bilirubin. Patients with rasburicase-induced haemolysis should be tested for G6PD deficiency; however, the timing of testing is crucial. During an acute haemolytic crisis, the RBCs severely deficient in G6PD will be the cells that haemolyse, leaving behind RBCs with somewhat normal enzyme activity. Consequently, the G6PD level may be falsely normal.¹⁹ Therefore, full workup with blood count and smear, haemolysis screen and ABG will confirm the diagnosis.

Methemoglobinemia typically presents with decreased SpO_2, but normal pO₂ on ABGs.²¹ This discrepancy leads to the so called ‘saturation gap’’ in which the calculated oxygen saturation from the blood gas varies from the saturation measured by pulse oximetry.²² While in our patient both SpO₂ and pO₂ were significantly decreased, we speculate this might be due to the severe underlying acute haemolysis and the presence of altered mental status, which could have led to decreased inspiratory effect and hypoventilation.

In our case, the patient started experiencing dyspnoea less than 12 hours after receiving rasburicase. After all other causes of hypoxemia were ruled out, acute haemolysis and methemoglobinemia shifted to the top of the differential diagnosis list. Given that the patient’s respiratory status improved after transfusion of pRBCs, methemoglobinemia and anaemia as the cause for the respiratory failure became most likely. Blood film confirmed the diagnosis of oxidative haemolysis and the patient was clinically diagnosed with G6PD deficiency. Although the G6PD level drawn in our patient was in the normal range, she was in acute haemolysis and the blood sample was obtained shortly after transfusion was initiated. For the two aforementioned reasons, the reading was considered unreliable and falsely normal.

To the best of our knowledge, cases of concomitant methemoglobinemia and haemolysis following rasburicase remain rare. After reviewing the literature, our patient was the oldest reported to experience such complications. This highlights the importance of G6PD testing in all individuals prior to receiving rasburicase, regardless of ethnicity or age. In clinical practice, this is infrequently done due to the urgency of TLS and the need for rapid intervention to prevent morbidity and mortality. Therefore, we suggest that a better solution would be to obtain a baseline G6PD level in all individuals considered to be at high risk for TLS. This can be done during routine outpatient visits in patients with lymphoma, leukemia or solid-tumour malignancies planned for antineoplastic therapies, especially those with high tumour burden

Learning points.

• Rasburicase is contraindicated in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency.

• Haemolytic anaemia and methemoglobinemia in the setting of recent rasburicase administration should raise clinical suspicion for G6PD deficiency.

• Baseline G6PD level should be obtained in patients who are considered high risk for tumour lysis syndrome regardless of age or ethnicity.

• Conservative management with blood transfusion and respiratory support is sufficient in patients with methemoglobinemia and acute haemolysis.