Endgames Case Report

An unexpected finding after a fall from a horse

BMJ 2013; 346 doi: http://dx.doi.org/10.1136/bmj.f724 (Published 12 February 2013) Cite this as: BMJ 2013;346:f724
  1. Sophie Raby, foundation year 2 doctor1,
  2. Daniel Greaves, core medical trainee1,
  3. Joseph Padayatty, specialist registrar1,
  4. Brian Huntly, consultant haematologist1
  1. 1Haematology Department, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK
  1. Correspondence to: S Raby raby.sophie{at}gmail.com

A 37 year old jockey was admitted with left sided abdominal pain and fullness one week after a fall from a horse. Before this he had been fit and well. On examination, he was tender in the left upper outer quadrant of his abdomen and his blood pressure was 90/55 mm Hg. A computed tomography scan showed an area of active bleeding in the parenchyma of the spleen and a large subcapsular haematoma.

Blood tests showed a white blood cell count of 259×109/L (reference range 4-11) with the following differential: blasts 3%, promyelocytes 11%, myelocytes 28%, metamyelocytes 19%, neutrophils 21%, basophils 10%, lymphocytes 4%, and eosinophils 4%. His haemoglobin was 109 g/L (130-180), mean cell volume was 80 fL (76-96), and platelets were 201×109/L (150-400). Lactate dehydrogenase was 563 IU/L (70-250; 1 mmol/L=9.01 mg/dL) and uric acid was 600 µmol/L (300-470; 1 µmol/L=0.03 mg/dL).

He underwent emergency splenectomy. Macroscopically, the spleen was greatly enlarged, at 22×13×10 cm, and microscopically it showed a dense infiltrate of left shifted immature myeloid cells.

Questions

  • 1 What are the possible causes of a raised white blood cell count?

  • 2 Given the clinical findings, what is the likely diagnosis?

  • 3 What further investigations should be considered?

  • 4 What are the treatment options?

  • 5 Why might allopurinol be started in this patient?

Answers

1 What are the possible causes of a raised white blood cell count?

Short answer

A white blood cell count greater than 50×109/L is caused by a primary haematological disease or, less commonly at such a high value, a leukemoid reaction. A leukemoid reaction may be lymphoid or myeloid in nature and is a physiological response of the bone marrow to a strong stimulus, such as infection, drugs, or an underlying solid cancer.

Long answer

Causes of leucocytosis (>11×109/L) can be classified according to cell lineage (box 1).

Box 1 Causes of leucocytosis (>11×109/L)

Neutrophilia
  • Acute bacterial infections

  • Drugs, such as steroids, dapsone, granulocyte colony stimulating factor

  • Disseminated cancer

  • Myeloproliferative cancers, including chronic myeloid leukaemia and cellular phase of myelofibrosis

  • Tissue necrosis—for example, after myocardial infarction

Lymphocytosis
  • Leukaemia: chronic lymphocytic leukaemia

  • Infection: Epstein-Barr virus, HIV, toxoplasmosis, pertussis

Basophilia
  • Myeloproliferative cancers

  • Viral infections

  • Inflammatory disorders

Monocytosis
  • Chronic infections, such as tuberculosis and brucellosis

  • Inflammatory bowel disease

  • Collagen vascular disease

  • Chronic myelomonocytic leukaemia

Eosinophilia
  • Allergy

  • Parasites

  • Autoimmune disorders, such as Churg-Strauss syndrome

  • Drug reactions

  • Some cancers, such as Hodgkin’s lymphoma

However, a white blood cell count greater than 50×109/L is caused by either a primary haematological disease or, less commonly at such a high value, a leukemoid reaction. A leukemoid reaction may be lymphoid or myeloid in nature and is a physiological response of the bone marrow to a strong stimulus such as infection, drugs, or an underlying solid cancer. Myeloid cells arise from the common myeloid progenitor and when fully differentiated include granulocytes (basophils, neutrophils, and eosinophils), platelets, erythrocytes, and monocytes. In a leukemoid reaction, a sudden increase in cytokines (such as granulocyte colony stimulating factor and tumour necrosis factor α) accelerates the release of cells from the post-mitotic reserve pool in the bone marrow. This is associated with an increase in the number of immature granulocytes—promyelocytes, myelocytes, and metamyelocytes—in the blood (a so called left shift).1 2 These immature cells are usually found only in the bone marrow. In general, however, a white cell count greater than 50×109/L is almost always related to a primary haematological cancer.

Raised uric acid and lactate dehydrogenase (LDH) may reflect a high turnover of bone marrow cells. LDH is a non-specific marker of tissue breakdown, so increased concentrations are of limited diagnostic value. Despite being raised in almost all systemic diseases, LDH is especially likely to be very high in myocardial infarction, hepatitis, haemolysis, and leukaemia. Determining LDH isoenzyme activity may be useful when diagnosis is unclear. However, given the greater specificity of other available diagnostic tests, this is rarely needed.

2 Given the clinical findings, what is the likely diagnosis?

Short answer

The chronic phase of chronic myeloid leukaemia (CML).

Long answer

The chronic phase of CML.

CML is a subtype of myeloproliferative disease. Myeloproliferative disorders (which also include polycythaemia rubra vera, essential thrombocythaemia, and myelofibrosis) are a group of conditions that arise in haematopoietic stem cells and result in clonal proliferation of one or more myeloid cell lineages. CML is characterised by proliferation and continued differentiation of granulocyte cell lines.

CML has an incidence of 1-2 per 100 000 people per year (around 600 cases/year in the UK) and constitutes about 15% of all leukaemias.3 4 It can occur at any age but peaks at 40 to 60 years.5 Ionising radiation is the only recognised risk factor—survivors from Hiroshima and Nagasaki had increased rates of CML.6

Symptoms are typically non-specific—for example, fatigue, night sweats, and weight loss—and insidious in onset. In some cases, a markedly enlarged spleen can cause abdominal discomfort and, as for any cause of splenomegaly, the risk of rupture is increased. In 20-50% of patients, the diagnosis is incidental after a raised white cell count is found on routine blood testing.7 By contrast, acute leukaemias are almost never found incidentally and usually present with serious symptoms arising from bone marrow failure or organ infiltration. Patients with CML are prone to symptoms of hypermetabolism, such as gout, and the high white cell count may result in features of hyperviscosity (headache, dyspnoea, and visual disturbance). Patients also tend to have normocytic normochromic anaemia and may bleed as a result of platelet dysfunction (associated with a normal or raised platelet count) or thrombocytopenia.

Most patients (85%) present in the chronic phase, which is characterised by its indolent nature. Because of the excellent response to recent targeted treatments, which target specific molecules essential for cancer cell growth and survival (in contrast to traditional cytotoxic treatments that target all rapidly dividing cells), the median duration of the chronic phase has yet to be defined. In the latest published data, at eight years’ follow-up 92% of patients taking imatinib (first line treatment) had not yet progressed from the chronic phase.8

Progression occurs through an accelerated phase in half of patients and directly into the blast phase in the other half. This acute leukaemia is characterised by a block in cell differentiation, with greater than 30% blasts, and in 70% of cases it resembles acute myeloid leukaemia. In the remaining 30% of patients it resembles pre-B cell acute lymphoblastic leukaemia, probably because the BCR-ABL translocation seems to arise in the multipotent haematopoietic stem cell that can give rise to both lymphoid and myeloid lineages.9 Rarely, CML may also progress into disease with myelofibrosis-like characteristics. Overall survival in CML is around 85% at five years; prognostic scoring systems identify spleen size, percentage of blasts, age, and percentage of basophils as variables that can help to categorise patients into high and low risk groups.10 11 12 Box 2 shows the phases of CML.

Box 2 Criteria for defining phases of chronic myeloid leukaemia1329

Chronic phase
  • None of the criteria for the accelerated or blast phase are met

Accelerated phase
  • Blast cells 15-29% in the peripheral blood or bone marrow*

  • Blast cells plus promyelocytes in the peripheral blood or bone marrow >30%, with blast cells <30%

  • Basophils in the blood >20%

  • Persistent thrombocytopenia (<100×109/L) unrelated to treatment

Blast phase
  • Blast cells ≥30% in the peripheral blood or bone marrow

  • Extramedullary blast involvement

  • *In the World Health Organization diagnostic criteria, the accelerated phase is defined by ≥10% blasts, and the blast phase by ≥20% blasts.14

3 What further investigations should be considered?

Short answer

In addition to blood count and differential, examination of a blood film and bone marrow biopsy will help to exclude other differential diagnoses, such as other myeloproliferative disorders (polycythaemia rubra vera, essential thrombocytopenia, myelofibrosis) or chronic myelomonocytic leukaemia, and will help determine the stage of CML. Further confirmation can then be obtained using cytogenetics to look for the presence of the Philadelphia chromosome (t(9;22)(q34;q11)) and of the BCR-ABL transcript.

Long answer

It is important to make a blood film and examine the bone marrow to help determine the stage of the disease and to exclude differential diagnoses in which myeloid lineage cells are also increased. For example, clonal proliferation of the myeloid lineage cells can also occur in other myeloproliferative disorders (polycythaemia rubra vera, essential thrombocythaemia, myelofibrosis) or chronic myelomonocytic leukaemia (a disease with both myelodysplastic and myeloproliferative features). However, in myelodysplastic disorders, functional abnormalities of the myeloid cell compartment result in morphologically abnormal “dysplastic cells,” which are not present in myeloproliferative disorders. In addition, low platelet, granulocyte, and red blood cell counts, rather than raised counts, may be present in myelodysplasia. A CML blood film would show leucocytosis, but there should be an absence of dysplasia. The figure shows a typical blood film for CML.

Figure1

Blood film from a patient with chronic myeloid leukaemia. The arrowhead points to a basophil, the black arrow to a myelocyte (immature myeloid precursor cell), and the blue arrow to a neutrophil

Bone marrow aspirate and trephine samples should be obtained. An aspirate is best for showing cellular morphology, whereas a bone marrow trephine core shows the bone marrow architecture and cellularity. Furthermore, a trephine sample may also provide an assessment of cell morphology in the case of a failed bone marrow aspirate (a “dry tap”). In patients with CML, the bone marrow typically has a higher myeloid to erythroid cell ratio—around 15:1, compared with a normal ratio of 3:1. Dysplasia should again be excluded. The percentage of blasts should be calculated in both the blood film and bone marrow to help determine the stage of the disease.

Finally, the diagnosis can be confirmed by cytogenetic analysis of bone marrow cells. This is done using fluorescence in situ hybridisation, which uses fluorescently labelled DNA probes to detect chromosome abnormalities. The Philadelphia chromosome is identified in 95% of patients with CML. This occurs after a reciprocal translocation between chromosomes 9 and 22 results in the fusion of two genes, BCR on chromosome 22 and the ABL on chromosome 9. The remaining 5% of patients have other forms of chromosomal rearrangement that also result in the formation of the BCR-ABL fusion p210 protein. Increasingly, the BCR-ABL rearrangement is also being demonstrated by the polymerase chain reaction. The Philadelphia chromosome is therefore highly sensitive for CML, but it is not specific, being present in about 20% of patients with acute lymphocytic leukaemia. Detection of the Philadelphia chromosome and the BCR-ABL transcript are also important in assessing response to treatment.

4 What are the treatment options?

Short answer

Treatments include disease control with targeted treatment—the tyrosine kinase inhibitors, such as imatinib—and potential cure with allogeneic haematopoietic stem cell transplantation.

Long answer

The identification of the Philadelphia chromosome and the resulting constitutively active tyrosine BCR-ABL kinase fusion protein in CML led to the development of the first targeted treatment in oncology. Imatinib, a tyrosine kinase inhibitor, does not cure the disease but achieves a long term complete cytogenetic response in 51-87% of patients and has increased the 10 year survival from an estimated 20% to greater than 80%.15 16 17 Before the advent of imatinib, overall five year survival was around 68-70%.18 19 Imatinib is therefore the initial treatment for almost all patients diagnosed with CML.20

Second generation tyrosine kinase inhibitors (dasatinib and nilotinib) have recently been developed and evaluated in phase III clinical trials. These produce faster and more durable responses than imatinib and are currently recommended for use in patients who are resistant to or intolerant of imatinib.13 However, although differences in survival between the three drugs have yet to be demonstrated, surrogates for these (haematological, cytogenetic, and molecular responses) suggest that dasatinib and nilotinib may be more successful for first line use in newly diagnosed patients.21 22 For patients resistant to these tyrosine kinase inhibitors, several treatments are being evaluated, including the tyrosine kinase inhibitors bosutinib and ponatinib, and a non-tyrosine kinase inhibitor omacetine.23 24 25 Because new treatments are increasingly becoming available, testing imatinib resistant patients for specific mutational status (such as the T3151 mutation) will help determine future treatment strategies.

Allogeneic stem cell transplantation (between an HLA matched donor and the patient) is a potential curative treatment option, and in the chronic phase it produces an average five year disease-free survival rate of 50%.26 However, this procedure is associated with a relatively high mortality and morbidity. Therefore it now tends to be used only when treatment with tyrosine kinase inhibitors fails or in patients who present in the accelerated or blast phase of CML, when imatinib and other tyrosine kinase inhibitors usually produce a short lived response.27

Before the advent of the tyrosine kinase inhibitors, cytotoxic agents such as interferon alfa, hydroxycarbamide, and busulfan were used.

Interferon alfa produced haematological responses in most patients but complete cytogenetic responses in only a minority. The serious adverse effects associated with this drug meant that many patients were unable to tolerate it.28

Cytotoxic agents such as hydroxycarbamide and busulfan produce haematological responses in almost 90% of patients but they do not prolong survival. They are therefore usually used only for initial reduction of a high white cell count before imatinib is started or when a patient unsuitable for transplantation is refractory or intolerant of imatinib.

Response to treatment may be at the haematological, cytogenetic, or molecular levels (box 3). Patients who do not satisfy one of the criteria for a response are deemed non-responders and their current treatment should be reconsidered.

Box 3 Definitions of haematological, cytogenetic, and molecular response13

Complete haematological response
  • No immature granulocytes and <5% basophils

  • Non-palpable spleen

  • Platelets <450×109/L

  • White blood cell count <10×109/L

Cytogenetic response: Philadelphia positive (metaphase) cells
  • Complete response: 0%

  • Partial response: 1-35%

  • Minor response: 36-65%

  • Minimal response: 66-95%

  • No response: ≥96%

Molecular response
  • Complete response: no BCR-ABL transcripts detected by quantitative PCR

  • Major response: ratio of BCR-ABL to ABL transcripts ≤0.1%

5 Why might allopurinol be started in this patient?

Short answer

To reduce the risk of gout and tumour lysis syndrome in response to cytoreductive treatment.

Long answer

Allopurinol reduces the risk of gout and of tumour lysis syndrome. Tumour lysis syndrome, although rare in CML, is a serious and potentially life threatening condition caused by a large tumour cell mass releasing nucleic acids (which are broken down to uric acid), potassium, cytokines, and phosphate into the bloodstream. It can occur spontaneously or, more commonly, in response to treatment. The main complications are acute kidney injury, cardiac arrhythmias (as a result of hyperkalaemia and secondary hypocalcaemia), and multiorgan failure. The risk of tumour lysis syndrome is particularly high in patients with tumours that have a high cellular proliferation index, such as Burkitt’s lymphoma. Other predisposing factors include the tumour mass (indicated by presence of organ infiltration and raised LDH) and patient features, such as dehydration and pre-existing renal failure.

Unlike tumour lysis syndrome, gout is common in patients with myeloproliferative disorders. It is caused by increased release of uric acid as a result of increased cell turnover and may be precipitated or exacerbated by initial treatment. Allopurinol inhibits xanthine oxidase, inhibiting the breakdown of xanthine to uric acid, therefore decreasing the risk of renal dysfunction from intrarenal crystallisation. Rasburicase, a recombinant formulation of urate oxidase, is used in patients at high risk of tumour lysis (for example, those with acute leukaemias, Burkitt’s lymphoma, or marked renal dysfunction). This drug converts uric acid to allantoin, which is more soluble and can be excreted in the urine. In addition, patients should be kept well hydrated, with accurate monitoring of fluid balance and twice daily measurement of electrolytes to detect any signs of the syndrome developing at an early stage.29

Patient outcome

Our patient developed CML at a relatively young age (37 years), which is outside the peak range of incidence (40-60 years). However, CML can occur at any age. Examination of his blood film before splenectomy showed leucocytosis with numerous myeloid cells, especially myelocytes, at different stages of differentiation. There was a marked basophilia and eosinophilia, and an absence of dysplasia. The bone marrow was hypercellular, with a myeloid to erythroid cell ratio of 15:1, and blasts were less than 5%. He was positive for the Philadelphia chromosome. After splenectomy he was started on hydroxycarbamide, which resulted in a rapid return of the white cell count to near normal. He was then started on dasatinib, a second generation tyrosine kinase inhibitor, as part of a clinical trial. As a result of the raised white blood cell count, raised LDH, and hypotension from the trauma, he was classed as being at intermediate risk of tumour lysis syndrome and started on allopurinol.

At 12 months, he remains a responder at the major molecular level (defined as a >3 log reduction in disease burden) and has returned to work. Because of the splenectomy he was also started on phenoxymethylpenicillin; given meningococcal, pneumococcal, haemophilus, and influenza immunisations; and issued with a splenectomy alert card, in accordance with guidelines.30

Notes

Cite this as: BMJ 2013;346:f724

Footnotes

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

  • Provenance and peer review: Not commissioned; externally peer reviewed.

  • Patient consent obtained.

References