Collateral damage

Howard (2011)

A 70-year-old female is seen in the emergency room after being referred by her general practitioner. Since two weeks, she has less energy, a decreased appetite and is out of breath during fairly normal exertion. She also noticed that her gums are bleeding and that they show small bruises. Additionally, there is a large purple bruise on her leg.

Physical examination reveals a pale, fatigued patient with moderate saturation with room air (80%). Her skin shows pinpoint bleeding (purpura) and several small haematomas on arms and legs. She has a normal blood pressure, heart rate and no fever.

Exploratory laboratory tests are requested.

Parameter	ED	Ref.	Units

Hemoglobin	4	7.2-9.5	mmol/L
Thrombocytes	35	150-400	⋅10⁹/L
Leukocytes	358	4-10	⋅10⁹/L

Blasts	63	0	⋅10⁹/L
Promonocytes	28	0	⋅10⁹/L
Monocytes	199	0.2-0.9	⋅10⁹/L
Lymphocytes	45	1-3.5	⋅10⁹/L
Promyelocytes	3.5	0	⋅10⁹/L
Myelocytes	0	0	⋅10⁹/L
Metamyelocytes	1.8	0	⋅10⁹/L
Neutrophils	5	1.5-6.5	⋅10⁹/L
Eosinophils	5	0-0.4	⋅10⁹/L
Basophils	0	0-0.1	⋅10⁹/L

Sodium	141	135-145	mmol/L
Potassium	4	3.2-4.7	mmol/L
Phosphate	0.7	0.7-1.5	mmol/L

AST	106	<30	U/L
ALT	49	<34	U/L
GGT	730	<40	U/L
ALP	265	40-120	U/L
LDH	3054	<248	U/L
Uric acid	1.13	0.14-0.39	mmol/L
Creatinine	149	50-95	µmol/L

CRP	16	<8	mg/L
Albumin	39	32-48	g/L

PT	15.4	9-12	sec
PTT	33	24-33	sec

The first noticeable findings are a very high leukocyte count (hyperleukocytosis), thrombopenia and anaemia. In addition, results show liver damage (elevated ASAT, ALAT, GGT, AF) and impaired renal function (elevated creatinine). The LDH is also strongly increased.

On microscopic differentiation, the following impressive display of cells is seen.

Overview of the patients peripheral blood with an evident proliferation of blasts.

Many monocytes and monocytic blasts are seen. There is acute myeloid leukemia confirmed with immunophenotyping.

Admission

The patient is admitted to the Hematology Department, where she receives oxygen supplementation for her shortness of breath. The respiratory symptoms are caused by large numbers of leukocytes stuck in the vascular bed of the lungs (leukostasis). The previously mentioned bleeding and bruising occur as a result of the low number of platelets.

Hyperleukocytosis is defined as the presence of more than 100*10^9 leukocytes per liter of blood. Although the risk of leukostasis increases with higher numbers of leukocytes, the actual occurrence of leukostasis is difficult to predict; it is often related to the number as well as the size and firmness of the malignant cells.

The patient is treated with a generous infusion of physiological saline (Sodium Chloride 0.9%). Shortly thereafter, chemotherapy is started, after which a sharp increase in LDH, potassium and phosphate is seen (graphs). This increase is caused by the disintegration of the malignant cells (tumor lysis); a sharp decrease in the number of leukocytes takes place (graphs).

Strong decrease in leukocyte count due to chemotherapy, eventually resulting in complete leukopenia.

Huge increase in lactate dehydrogenase (LDH) due to the decay of malignant cells.

Sharp increase in potassium due to tumor lysis after starting chemotherapy. The patient is dialyzed twice shortly thereafter. This shows a sharp decrease in potassium concentration.

Sharp rise in phosphate due to tumor lysis after starting chemotherapy. The patient is dialyzed twice shortly thereafter. This shows a strong decrease in phosphate concentration.

Decrease in calcium running in the opposite direction to phosphate. This is due to the fact that in the circulation calcium is partially bound to phosphate.

Chemotherapy causes malignant cells to break down en masse, with cell contents entering the circulation. Cell breakdown is characterized, among other things, by an increase in LDH. In addition to LDH, DNA, potassium and phosphate are also released. DNA is converted to uric acid by metabolism, which in high concentrations can lead to the formation of uric acid crystals. Uric acid can be suppressed medicamentously using Allopurinol and Rasburicase. High concentrations of phosphate form complexes with calcium. Both crystals and calcium phosphate complexes can cause blockages in organs, leading to damage and loss of function. Hyperkalemia can cause severe cardiac arrhythmias. This complication of chemotherapy is called Tumor Lysis Syndrome (TLS).

The increase in potassium and phosphate is due partly to the tumor lysis and partly to the already poor renal function; the kidney cannot excrete sufficient electrolytes through the urine, causing the concentrations in the blood to rise even more sharply. Therefore, the patient is dialyzed twice (day 1 and day 2 after starting chemotherapy) during which waste products are removed from the blood and the electrolyte balance is restored as much as possible. A temporary improvement in electrolytes is therefore seen after dialysis.

As a result of the chemotherapy, the patient is completely leukopenic from day 4, making it difficult to resist pathogens. The patients respiratory function declines as she appears to have contracted a bacterial infection in the lungs. Her renal function continues to deteriorate, reflected in a continuous rise in creatinine.

Fluctuations in plasma creatinine. Already on admission poor renal function due to (presumably) leukostasis, with temporary decrease in creatinine after dialysis. From day 4 an increase is seen with progressive renal failure.

Given her poor clinical condition, involving the failure of three organs (lungs, kidneys and bone marrow), it is decided in consultation with the patient that more intensive treatment, including dialysis, is not further possible or desirable. An abstinent policy is agreed upon. The patient dies shortly thereafter.

Tumor lysis syndrome is a complication that can occur during the (necessary) treatment of acute leukemia and results in a situation where the patient ends up between hammer and anvil. Not treating is harmful, but so is treating.