Spontaneous Tumor Lysis Syndrome as the Initial Presentation of Chronic Lymphocytic Leukemia: A Case Report

Abstract

Background

Tumor lysis syndrome (TLS) is an oncologic emergency that most commonly follows cytotoxic treatment of highly proliferative hematologic malignancies; spontaneous TLS as the presenting manifestation of chronic lymphocytic leukemia (CLL) is rare but can cause life-threatening metabolic disturbance and acute kidney injury (AKI).

Case presentation

A 68-year-old man from rural Oromia presented with 48 hours of progressive weakness, oliguria, and confusion, and a several-month history of weight loss and painless lymphadenopathy. Initial testing showed leukocytosis (WBC 148 ×10⁹/L; absolute lymphocyte count 130 ×10⁹/L), marked hyperuricaemia (14.5 mg/dL), hyperphosphataemia (8.5 mg/dL), severe hyperkalaemia (6.8 mmol/L) with peaked T-waves, elevated LDH (980 U/L), and AKI (serum creatinine 4.9 mg/dL). Flow cytometry confirmed CLL; there was no prior cytotoxic therapy.

Management and outcome

The patient received emergent cardioprotective and potassium-lowering measures, aggressive isotonic fluids, serial monitoring, and oral allopurinol. Oliguria and progressive uraemia prompted urgent haemodialysis on the day of admission. Rasburicase was not available. After stabilization, inpatient cytoreduction with oral chlorambucil and a short steroid taper was started on day 8. The patient was discharged clinically improved on day 10 with monitoring and outpatient follow-up. Renal function and metabolic parameters progressively normalized, with serum creatinine 1.4 mg/dL and marked hematologic improvement at 6 weeks.

Conclusion

This case illustrates that spontaneous TLS can unmask previously undiagnosed CLL and cause severe, but potentially reversible, AKI. Early recognition, prompt metabolic stabilization, and timely renal replacement therapy, adapted to local resource availability, are critical to optimize renal and overall outcomes.

Introduction

Tumor lysis syndrome (TLS) is a life-threatening metabolic complication of malignant cell breakdown, typically following cytotoxic therapy for high-grade hematologic cancers.^1,2 Massive tumor cell lysis releases intracellular potassium, phosphate, and nucleic acids, leading to hyperkalemia, hyperphosphatemia, hypocalcemia, and hyperuricemia.^2,3 These derangements can cause cardiac dysrhythmias, seizures, and acute kidney injury (AKI) from uric acid and calcium-phosphate crystal nephropathy.^1,4 The Cairo–Bishop criteria define laboratory TLS as ≥25% change in two or more serum values (uric acid, potassium, phosphate, calcium) within 3 days before or 7 days after therapy, and clinical TLS when such laboratory changes are accompanied by organ dysfunction (e.g., AKI or arrhythmias).^4,5 TLS is most often reported after treatment of highly proliferative malignancies (e.g., acute leukemias, Burkitt lymphoma). ² Spontaneous TLS (STLS) can occur without therapy in about one-third of TLS cases, ¹ but it is exceedingly rare in CLL. Indeed, only a handful of STLS cases in treatment-naïve CLL have been reported.^6,7

Chronic lymphocytic leukemia is the most common leukemia in adults, predominantly affecting older individuals (median age ∼65–70). ⁸ It is often indolent and discovered incidentally, and most patients can be managed with “watchful waiting” if asymptomatic.^8,9 Therapy is reserved for active disease, defined by the International Workshop on CLL (iwCLL) as massive or symptomatic lymphadenopathy/splenomegaly, disease-related constitutional symptoms (≥10% unintentional weight loss, fevers, night sweats) or progressive marrow failure (declining hemoglobin <10 g/dL or platelets <100×10^9/L).^9,10 Common clinical features prompting treatment include B-symptoms (fever, night sweats, weight loss), symptomatic organomegaly or lymphadenopathy, and worsening cytopenias.^8,11 When CLL requires therapy, historically, chemoimmunotherapy regimens such as fludarabine-cyclophosphamide-rituximab (FCR) or bendamustine-rituximab (BR) were standard, but newer targeted agents (Bruton tyrosine kinase inhibitors like ibrutinib, PI3K inhibitors, or BCL-2 inhibitors such as venetoclax) have dramatically improved outcomes.^9,12,13 For elderly or frail patients who cannot tolerate intensive therapy, gentler options like chlorambucil (often combined with anti-CD20 antibodies) may be used. ¹⁴ In practice, access to therapies and comorbidities strongly influence regimen choice.

Tumor lysis syndrome (TLS) is an oncologic emergency defined by specific laboratory and clinical criteria. ⁴ CLL only rarely provokes TLS in the absence of prior therapy, with isolated case reports describing this presentation.^6,7 Spontaneous TLS is often under-recognized, and diagnostic delay is associated with a higher risk of irreversible organ injury and mortality. ¹⁵ Reporting such cases, therefore, expands the limited evidence base, highlights key diagnostic pitfalls, and informs management decisions in settings where rasburicase and targeted agents may be unavailable. ¹⁶

Case Presentation

A 68-year-old male farmer from a rural district in Oromia, Ethiopia, was referred to the medical ward of a tertiary teaching hospital with 48 hours of progressive generalized weakness, markedly reduced urine output, and confusion. He had been well until one week before admission, when he developed nausea, vomiting, and poor oral intake. The family reported several months of increasing fatigue, easy bruising, and unintentional weight loss (∼6 kg), and they noted painless neck and axillary swellings for several weeks. There was no history of prior cytotoxic therapy or immunotherapy. Past medical history was otherwise unremarkable, with no known hypertension, diabetes, or chronic kidney disease, and the patient was not taking any regular prescription medications, over-the-counter drugs, or herbal remedies. Baseline renal function was not available prior to this illness, as no previous serum creatinine measurements were documented.

On arrival, the patient was drowsy but arousable (Glasgow Coma Scale 13/15). Vital signs were: temperature 36.7°C, blood pressure 105/68 mmHg, heart rate 102/min, and respiratory rate 22/min. General examination showed pallor and scattered petechiae. Multiple non-tender, mobile lymph nodes were palpable in the cervical and axillary regions (largest ≈2.5 cm). There was no clinically evident hepatosplenomegaly. Neurological examination revealed reduced attention but no focal deficit.

Initial bedside investigations identified a life-threatening metabolic disturbance. Point-of-care and laboratory tests demonstrated acute kidney injury and severe electrolyte abnormalities: serum potassium 6.8 mmol/L with peaked T waves on 12-lead ECG, marked hyperuricaemia, hyperphosphataemia, and hypocalcaemia. Lactate dehydrogenase (LDH) was also markedly elevated (Table 1). A working diagnosis of tumour lysis syndrome (TLS) was made. The diagnosis of spontaneous tumour lysis syndrome was favored because the patient met the Cairo–Bishop laboratory criteria on admission (marked hyperuricaemia, hyperphosphataemia, hyperkalaemia, and an acute rise in serum creatinine) in the absence of prior cytotoxic therapy. Urinalysis on admission showed no evidence of active sediment (no significant hematuria or pyuria, and no casts suggestive of glomerulonephritis), and renal ultrasound demonstrated no hydronephrosis, making obstructive uropathy unlikely. A Direct Antiglobulin Test (Coombs test) was performed and was negative. There were no clinical or microbiological features to suggest a septic cause of the acute kidney injury (no source of infection identified, and cultures were negative).

Table 1.

Key Investigations Showing the Trend From Admission Through Follow-Up

Test	Admission (Day 0)	Post-HD (Day 0)	Day 7	6-week follow-up	Reference range
Serum creatinine	4.9 mg/dL	3.4 mg/dL	2.3 mg/dL	1.4 mg/dL	0.6–1.3 mg/dL
Blood urea nitrogen (BUN)	82 mg/dL	58 mg/dL	34 mg/dL	22 mg/dL	7–20 mg/dL
Serum potassium (K+)	6.8 mmol/L	4.8 mmol/L	4.4 mmol/L	4.1 mmol/L	3.5–5.0 mmol/L
Serum sodium (Na+)	134 mmol/L	136 mmol/L	138 mmol/L	139 mmol/L	135–145 mmol/L
Serum bicarbonate (HCO3-)	16 mmol/L	18 mmol/L	22 mmol/L	24 mmol/L	22–28 mmol/L
Serum uric acid	14.5 mg/dL	9.2 mg/dL	5.8 mg/dL	4.5 mg/dL	3.5–7.0 mg/dL
Serum phosphate	8.5 mg/dL	6.2 mg/dL	4.2 mg/dL	3.5 mg/dL	2.5–4.5 mg/dL
Corrected serum calcium	5.9 mg/dL	7.0 mg/dL	8.1 mg/dL	8.6 mg/dL	8.4–10.2 mg/dL
Lactate dehydrogenase (LDH)	980 U/L	780 U/L	520 U/L	350 U/L	140–280 U/L (lab dependent)
White blood cell (WBC) count	148 ×109/L	140 ×109/L	137 ×109/L	18 ×109/L	4.0–11.0 ×109/L
Absolute lymphocyte count (ALC)	130 ×109/L	125 ×109/L	60 ×109/L	18 ×109/L	1.0–3.5 ×109/L
Haemoglobin (Hb)	8.7 g/dL	10.2 g/dL	9.0 g/dL	10.1 g/dL	13.5–17.5 g/dL (male)
Platelet count	110 ×109/L	105 ×109/L	110 ×109/L	140 ×109/L	150–400 ×109/L
Serum Albumin	3.0 g/dl	3.1 g/dL	3.3 g/dL	3.8 g/dL	3.5-5.0 g/dL
Beta-2 microglobulin	6.8 mg/L	—	4.2 mg/L	3.2 mg/L	<2.5 mg/L (lab dependent)
Urine output (mL/kg/hr)	0.2 mL/kg/hr (Oliguric)	0.8 mL/kg/hr	0.7 mL/kg/hr	1.0 mL/kg/hr	>0.5 mL/kg/hr desirable
ECG	Peaked T waves	Normalized	Normal	Normal	—
Peripheral blood film	Small mature lymphocytes; smudge cells	—	—	—	—
Flow cytometry	—	Diagnostic for CLL	—	—	CD19+, CD5+, CD23+, dim CD20

Immediate management focused on stabilization of TLS. The patient received 10 mL of 10% intravenous calcium gluconate for cardioprotection, 10 units regular insulin with 25 g dextrose, and nebulised salbutamol to lower serum potassium, and aggressive isotonic crystalloid infusion to improve renal perfusion. Serial electrolytes and ECGs were monitored every 2–6 hours. Allopurinol was administered to prevent further uric-acid formation. Because oliguria and progressive uraemia persisted despite medical management, urgent haemodialysis was initiated on the day of admission to rapidly correct hyperkalaemia and uraemia and to remove pre-existing uric acid and phosphate. Immediate post-dialysis serum potassium measured 4.8 mmol/L, and urine output increased markedly following haemodialysis. Rasburicase was not available at our centre, and therefore, a combined approach of pharmacologic prevention plus early dialysis was used. He remained on telemetry with serial electrolytes and ECGs every 6–12 hours until biochemical stabilization. Supportive care continued (IV fluids as tolerated, allopurinol, electrolyte correction, analgesia, nutritional support); he required one unit of packed red blood cells for symptomatic anaemia (nadir Hb 8.7 g/dL). There were no dialysis-related complications.

While TLS was being treated, diagnostic investigations to identify an underlying malignancy were performed. Full blood count revealed marked leukocytosis with lymphocytic predominance. Peripheral blood film showed abundant small mature lymphocytes and numerous smudge cells. Flow cytometric analysis of peripheral blood performed identified a clonal B-cell population expressing CD19, CD5, and CD23 with dim CD20 and light-chain restriction, confirming chronic lymphocytic leukaemia (CLL). Representative peripheral blood film and flow cytometry images were not available for inclusion because of archival/technical limitations. Serum beta-2 microglobulin was elevated. Abdominal ultrasonography showed no clinically significant hepatosplenomegaly, and kidney sizes were within normal limits without hydronephrosis. The chest radiograph was unremarkable. Based on the presence of anemia at presentation (hemoglobin 8.7 g/dL), the patient’s CLL was classified as Rai stage III and Binet stage C.

Haematology confirmed chronic lymphocytic leukaemia by flow cytometry and, after multidisciplinary discussion, inpatient cytoreductive therapy with oral chlorambucil plus a short steroid taper was started on day 8 (targeted agents unavailable). Chlorambucil was chosen as the inpatient cytoreductive agent because it was available, orally administered, and considered better tolerated in our patient and setting than more intensive regimens; newer targeted agents were not available locally. The patient tolerated treatment without immediate adverse effects.

By hospital day 10, he was clinically improved (alert, ambulating with assistance, taking oral intake) and was discharged with oral allopurinol (to complete 4 weeks), ongoing oral cytoreductive therapy and steroid taper, a monitoring plan (electrolytes twice weekly for 2 weeks then weekly for 4 weeks), and arranged haematology follow-up within 1 week. Palliative/social support services were engaged for symptom control and assistance with access to medication and transport.

At the 6-week outpatient review, the patient reported marked symptomatic improvement. Laboratory reassessment showed continued renal recovery and a haematologic response to therapy (see table). The plan was to continue outpatient cytoreduction, monitor closely for relapse or complications, and consider escalation to targeted therapy should it become available.

The patient and his family expressed gratitude for the care provided and reported relief after his clinical improvement and discharge. They described the course of illness as frightening because of the sudden onset of weakness, confusion, and reduced urine output, but they appreciated the explanation of the diagnosis and the stepwise management. They also valued the follow-up plan and counseling provided at discharge.

Discussion

Spontaneous TLS in treatment-naïve CLL is exceptionally uncommon. Verma-Saluja et al. recently noted that STLS has “never been reported in a patient with stable CLL” aside from a few individual case reports. ⁷ In fact, literature reviews identify only a handful^4,5 of STLS cases in CLL to date.^6,7,17,18 Most reported TLS events in CLL have been therapy-related (e.g., after chemotherapy or novel agent initiation).^19,20 The rarity of STLS likely reflects CLL’s typically indolent course; however, large tumor burden or additional stressors (e.g., corticosteroids) may trigger rapid cell death even without cytotoxic therapy. ⁶ In our patient, marked lymphocytosis and bulky lymphadenopathy created a context for fulminant cell lysis. The elevated beta-2 microglobulin level (6.8 mg/L) likely reflected a combination of increased tumor burden from CLL and reduced renal clearance in the setting of acute kidney injury. A summary of previously reported cases of spontaneous TLS in CLL is provided in Table 2.

Table 2.

Published Cases of Spontaneous Tumor Lysis Syndrome in Chronic Lymphocytic Leukemia: Clinical Presentation, Management, and Outcomes

Author/year	Age/sex	CLL status	Presentation	Key findings	Treatment	Outcome
Gogia et al., 2014 20	57/M	Newly diagnosed CLL	Nausea, vomiting, anuria, lymphadenopathy, splenomegaly	AKI, hyperuricemia, hyperkalemia	IV hydration, furosemide, bicarbonate, allopurinol	Renal recovery; later treated for CLL
Armaly et al., 2019 6	Adult patient with stable CLL	Stable CLL	STLS with AKI; steroid exposure considered possible trigger	Metabolic TLS with renal failure	Hemodialysis ×3; supportive care	Resolved without sequelae
Desai et al., 2020 18	68/M	Newly diagnosed CLL	Abdominal pain, anuria	Smudge cells, hyperuricemia, hyperphosphatemia, hyperkalemia	Fluids, allopurinol, rasburicase	Improved; recurrent episode within 1 month
Menakuru et al., 2022 21	Adult	Bulky CLL	STLS with AKI	Bulky lymphadenopathy and TLS	Prompt intervention/supportive care	End-organ damage prevented
Verma Saluja et al., 2024 7	Adult male	Undiagnosed CLL	Vomiting, diarrhea, dyspnea, and oliguria	Hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcemia, AKI	Prompt diagnosis and intensive monitoring	Successful stabilization

Although no single precipitating factor could be identified, several subclinical or physiological stressors may have contributed to the spontaneous lysis in this patient, including dehydration, poor oral intake, and the large underlying tumor burden. ²² In spontaneous TLS, hyperphosphatemia may sometimes be less pronounced because rapidly proliferating viable tumor cells can reutilize released phosphate; however, our patient had marked hyperphosphatemia (8.5 mg/dL), which is consistent with severe TLS and further supports the diagnosis. ²³

Diagnostically, distinguishing TLS-related AKI from other causes in CLL is challenging. Differential diagnoses include prerenal or septic AKI, leukemic kidney infiltration, glomerular disease, and obstructive uropathy. ⁸ In hematologic malignancies, common AKI precipitants include hypoperfusion (e.g., from sepsis), direct tumor infiltration, TLS, infections, and treatment toxicity.^8,24 Our patient was afebrile with negative blood and urine cultures, making sepsis unlikely. Indeed, TLS may mimic septic shock with systemic inflammatory response and organ failure, ²⁵ but the lack of infection favored TLS. Renal ultrasound ruled out obstruction. Leukemic infiltration of the kidney is often seen in autopsy series (60–90% of cases) but is typically asymptomatic. ⁸ Importantly, biopsy series show that infiltration often does not correlate with blood lymphocyte count, and renal function can improve with CLL therapy.^8,26 In this case, the rapid development of severe hyperuricemia with accompanying electrolyte shifts and AKI strongly supported TLS as the primary etiology.

Management of TLS centers on aggressive supportive care. International consensus emphasizes vigorous IV hydration, diuresis, and urate-lowering therapy to prevent uric acid nephropathy. ¹ Allopurinol (a xanthine oxidase inhibitor) prevents new uric acid production but does not remove existing uric acid, whereas rasburicase (recombinant urate oxidase) rapidly degrades uric acid to soluble allantoin ²⁷ . In our resource-limited setting, intravenous rasburicase was not available; we initially used oral allopurinol, phosphate binders, and aggressive fluids. Despite this, the patient’s uric acid remained high and renal function worsened, prompting eventual transfer for dialysis. Published evidence supports rasburicase’s efficacy: matched studies show significantly lower TLS-related mortality with rasburicase (2.1%) compared to allopurinol (7.1%, p<0.05), ²⁷ and rasburicase prevents uric acid nephropathy and may improve renal outcomes. ¹ If rasburicase is unavailable, febuxostat is an alternative xanthine oxidase inhibitor shown to reduce uric acid levels, though data in acute TLS are limited. ³ In all cases of severe TLS, renal replacement therapy is indicated for refractory hyperkalemia, acidosis, or volume overload. In an ICU series, over half of TLS patients required dialysis.^1,8 We performed emergency hemodialysis for our patient’s life-threatening hyperkalemia, which contributed to full renal recovery.

CLL-specific therapy must follow stabilization of TLS. In our patient, the indications (B-symptoms and marrow failure) necessitated treatment. In Western practice, first-line options would include FCR or targeted agents like ibrutinib or venetoclax.^9,19 However, due to local drug availability, we chose chlorambucil plus low-dose prednisone. ¹⁴ Notably, induction of apoptosis via treatment can exacerbate TLS, so concomitant management is crucial.^12,19 One recent report of steroid-induced TLS in CLL emphasizes that even mild cytoreductive therapy can trigger TLS. ⁶

Prognosis in TLS depends on prompt management and underlying disease. Historical data showed TLS mortality around 20–25%.^27,28 In one large database, overall TLS in-hospital mortality was 21%, and ∼15% of patients required dialysis. ²⁸ Risk factors for worse outcomes include older age, multiorgan failure, and spontaneous TLS.^1,3 Indeed, in the ICU cohort by Darmon et al., spontaneous TLS was independently associated with higher 1-year mortality (hazard ratio ∼1.65). ¹⁵ Our patient’s ultimate renal recovery is consistent with reports that AKI from TLS often resolves once the malignancy is treated.^1,3 However, delayed recognition or limited resources can lead to irreversible damage.^15,16 Importantly, resource-limited settings face challenges: Rasburicase is costly and often unavailable, and advanced therapies (BTK or BCL2 inhibitors) may be inaccessible.^12,13,16 A South African study found that rasburicase use significantly shortened hospital stay and reduced costs compared to dialysis, ²⁹ underscoring its value where available. In contrast, reliance on dialysis and older drugs may increase morbidity and length of hospitalization. ¹⁶

This case has some limitations. Cytogenetic/FISH analysis and bone marrow biopsy were not performed because of resource constraints, so full prognostic characterization of the leukemia was not possible. Nevertheless, the diagnosis of CLL was established by peripheral blood smear and flow cytometry, and the clinical course was consistent with spontaneous tumor lysis syndrome in the setting of untreated CLL.

Conclusion

This case highlights several key points. Spontaneous TLS can occur in treatment-naïve CLL, especially in patients with a large disease burden, despite its rarity. High clinical suspicion is warranted when a CLL patient presents with unexplained AKI and characteristic metabolic abnormalities, once more common causes (infection, obstruction) are excluded. Prompt initiation of aggressive hydration, urate-lowering therapy, and early dialysis when indicated can reverse TLS-related AKI and improve outcmes. Finally, in resource-constrained environments, lack of novel agents and rasburicase may worsen prognosis; this underscores the importance of adaptable management strategies and global access to life-saving TLS therapies.