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A 50 year old hairdresser attends her GP practice complaining of worsening tiredness. Work through the case to reach the diagnosis.

History

Presenting complaint

“It all started about 3 months ago when I was late to work after sleeping through my alarm clock, despite having had an early night. Since then I’ve been feeling tired most of the time, regardless of how much sleep I have. I’m struggling to make it through a full shift at work and I only work from 9am-3pm. Yesterday I fell asleep during my lunch break and the manager told me I need to get checked out by the doctor, so that’s why I’m here. Oh I’ve also not got much of an appetite.”

What questions might be useful to elicit further details surrounding the presenting complaint?

Tiredness – get specific

  • How many hours is she sleeping a day?
  • Does she wake frequently when sleeping?
  • Did the tiredness come on suddenly or has it gradually gotten worse?
  • Does she take any sleep medications or any medications with drowsiness as a side effect?

 

Appetite:

  • When did her appetite change?
  • Is her appetite getting worse, better or remaining the same?
  • How much is she managing to eat on an average day?
  • Does she stop eating because she feels nauseated or just “full” (early satiety)
  • Is she experiencing nausea or vomiting?
  • What is her normal bowel habit? Has this changed? Bleeding?
  • Has she lost any weight?
  • Does she have any reflux symptoms or abdominal pain?

 

General health:

  • Any recent illnesses?
  • Any current infective symptoms – fever / cough / dysuria / diarrhoea 
  • Any contact with others who are unwell or have similar symptoms?
  • Any significant psychological stress at present? Current mood?
  • Menstrual history
  • Diabetic symptoms – polydipsia / polyurea 
  • Hypothyroid symptoms – cold intolerance / weight gain / memory impairment

 

Past medical history / Drug history

  • Any known medical conditions?
  • Any regular medication?
  • Any over the counter medication?
  • Any recreational drug use?

 

Social history / Family history

  • Current living situation
  • Job details – role / responsibilities 
  • Smoking history
  • Alcohol history
  • Impact of symptoms on activities of daily living
  • Family history of disease?

 

Ask the patient about other new symptoms that haven’t already been covered.

Patient’s response…

“I’ve been sleeping around 14 hours a day, which is a far more than the 7 hours I was sleeping a few months ago. It didn’t suddenly switch to 14 hours though, it’s just been gradually increasing over the last few months. I don’t remember waking frequently, I seem to sleep pretty well and I’m not taking any regular medication or anything over the counter. “

“My appetite is generally pretty good, but for the last 4-6 weeks it’s definitely decreased. I don’t feel particularly nauseated, I just seem to feel full quicker than usual. I might have a piece of toast and then feel like I don’t need anything else for another 6-8 hours, it’s really weird. I haven’t had any vomiting either. My bowels haven’t really changed, I go on average once a day and there’s no blood or anything. My weight has decreased, I’m not sure by how much, but I’ve started wearing a belt with my jeans as they were slipping down. I haven’t noticed any abdominal pain though and certainly no acid reflux type symptoms.”

“I’ve been fairly well otherwise, no recent colds or anything like that. I haven’t had any coughs or burning when passing water. I have woken up feeling quite hot and sweaty on a few occasions. Nobody I’ve been in close contact with has been unwell from my knowledge and psychologically I’m feeling a bit stressed about the sleeping at work, but my mood is generally pretty good. I don’t really have periods as I have a Mirena coil. I haven’t noticed that I’m particularly thirsty or passing more water than usual. Also haven’t noticed any cold intolerance or memory problems.”

“I have some eczema, but no other medical problems and I don’t take any medication. I’ve smoked Marijuana a few times over the last few months, but I don’t take any other drugs”

“I live with my boyfriend in a flat and I obviously work as a hairdresser. I’ve never smoked and I only drink at weekends, maybe 6-8 units. There’s no illness that runs in my family as far as I’m aware.”

“Well now that you mention it, I have noticed a few weird bruises in random spots where I don’t remember hurting myself, there was one or two last week, but this week there’s about 6.”

Examination

What systems would you be particularly interested in examining?

Gastrointestinal system – given the reduced appetite, weight loss and tiredness

Lymphoreticular system – given the history of weight loss, night sweats and early satiety 

Examination findings

On examination…

Inspection

  • Conjunctival pallor 
  • Multiple patches of  petechial bruising across the limbs and trunk

 

Cardiovascular / respiratory systems

  • Pulse95 bpm – regular
  • Capillary refill time <2
  • Heart auscultation – normal heart sounds with no added sounds
  • Lungs – good air entry, no crackles or wheezes, resonant on percussion

 

Gastrointestinal system / lympho-reticular system

  • No gross abdominal distension on inspection
  • Palpation:
    • Abdomen is soft, with some tenderness in the left upper quadrant
    • On deep palpation you note some fullness in the left upper quadrant
  • Lymph nodes –  2 enlarged cervical lymph nodes are noted
  • Nil else of note on examination.

 Differential diagnosis

What is your differential diagnosis?

Lymphoma

Leukaemia 

Infectious mononucleosis – can cause splenomegaly, malaise, weight loss, fever, lethargy (however duration is often much shorter than 3 months)

Investigations

Which bedside investigations would you like to perform?

Full blood count – ?low Hb /  ?low platelets / ?raised WCC

Blood film – ?haematological malignancy 

U&E – ?renal function

Coagulation studies – given findings of bruising, need to rule out coagulopathy

Random blood glucose – ?diabetes – however wouldn’t explain bruising / night sweats

Thyroid functiongiven the tiredness / reduced appetite 

VirologyEBV antibodies

Results

FBC¹

Hb – 7.9 g/dL (13.5-18.0 g/dL)

WCC – 250 x 109  (4.0-11.0 x109)

MCV – 90 fL (76-96 fL)

Hct – 0.32/L (0.4-0.54/L)

Neutrophils – 180 x 109/L (2.0-7.5 x 109/L)

Basophils – 2 x 109/L (0.0-0.10 x109/L)

Eosinophils – 4×109/L (0.04-0.44 x 109/L)

Myeloblasts – 8.8 x 109/L (usually undetectable)

 

U&Es – No abnormalities noted

Coagulation¹

Platelets – 13  x109/L (150-400 x109/L)

PTT – 11 seconds (10-14 s)

APTT – 37 seconds (35-45 s)

 

Random blood glucose – 4.8mmol/L

TFTs – T3, T4 and TSH normal

Virology – EBV antibodies negative

 

Blood film

What does the blood film show?

This blood film shows increased numbers of neutrophils, basophils and eosinophils as well as an increased number of immature myeloid cells. Overall this is referred to as leukocytosis.²

Diagnosis

What is the provisional diagnosis?

Chronic myeloid leukaemia

Chronic myeloid leukaemia (CML) is a malignancy of white blood cells.  It is characterised by increased numbers of myeloid cells in the bone marrow and peripheral blood (leukocytosis). This can cause a number of signs and symptoms, however this depends on the degree of leukocytosis.

85-95% of patients are diagnosed incidentally in the chronic stage of the disease via routine blood tests.  As a result about 50% of patients are asymptomatic at diagnosis. Read our chronic myeloid leukaemia article here.

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Symptoms of CML:

  • Fatigue
  • Night sweats
  • Abdominal fullness (due to splenomegaly)
  • Low grade fever

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Clinical signs can include:

  • Splenomegaly (if it can be palpated it’s already 3x its normal size)
  • Hepatomegaly
  • Lymphadenopathy
  • Signs of anaemia – conjunctival pallor / glossitis 
  • Easy bruising
What causes this disease?

The overproduction of myeloid cells occurs as a result of a chromosomal translocation (9;22) which produces the characteristic Philadelphia chromosome.  When the translocation between chromosomes 9 and 22 occurs it results in the production of a hybrid gene known as BCR-ABL.  This gene produces substances which activate a cascade of proteins triggering the speed of cell division to increase.  In addition the BCR-ABL gene produces proteins which inhibit DNA repair, making the cell more susceptible to developing further genetic abnormalities 4. Read more about CML in our article HERE .

What is the natural history of the disease?

Chronic myeloid leukaemia progresses through 3 stages

 

Chronic phase

In this phase the immune system remains competent and the patient often has no symptoms.  

The chronic phase typically lasts around 4-5 years.

In the absence of any treatment it will eventually progress to the accelerated phase.

 

Accelerated phase

Around two thirds of patients will progress to the accelerated phase.

This is often when patients become symptomatic (as in this case).

Features of the accelerated phase involve:

  • ↑ Blasts in the bone marrow & periphery
  • ↑ Basophils and Eosinophils in the bone marrow and periphery
  • Worsening anaemia
  • Thrombocytopenia
  • Increasing splenomegaly
  • Additional genetic mutations in haematopoietic stem cells
The accelerated phase varies in length but typically lasts a number of months, then progressing to a blast crisis.
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Blast crisis
Blast crisis is the final phase in the evolution of CML.  It is similar to an acute leukaemia and is very aggressive with large numbers of blasts flooding the blood and bone marrow. As a result the bone marrow becomes exhausted and production of immune cells and platelets is significantly reduced. This leaves the patient vulnerable to infection and bleeding which explains why this phase is often rapidly fatal.  Patients in blast phase often respond very poorly to chemotherapy.
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Features of the blast phase include:
  • Large numbers of blasts in peripheral blood and bone marrow (>30%)
  • Severe weight loss
  • Fever, night sweats, bone pain
  • Infection (due to incompetent immune system)
  • Bleeding (due to lack of platelet production)
  • Foci of blasts causes local tissue destruction
How would you confirm the diagnosis?

Cytogenetic testing of bone marrow aspirate for the Philadelphia chromosome.

The testing for the chromosome can be done via various methods:

  • FISH (fluorescent in-situ hybridisation)
  • PCR for the BCR-ABL gene

Management

What is the 1st line of treatment

BCR-ABL tyrosine kinase inhibitors (TKIs)

There are multiple TKIs available for first line treatment to allow switching if resistance occurs to one particular agent. Treatment is usually continued indefinitely in patients who respond well to treatment.

High levels of relapse have been observed in patients who stop therapy.5

What is the treatment's mechanism of action?

TKIs specifically target BCR-ABL, blocking the ability of the gene to phosphorylate a tyrosine . As a result it inhibits proliferation of cells and induces apoptosis in cells with the BCR-ABL fusion gene.  It is better tolerated and more effective than previous therapies due to its specificity to the exact pathway responsible for CML.

What other treatment options exist?

Stem cell transplantation

Stem cell transplantation is  a treatment option for those who do not respond well to drug treatments. This tends only to be used in younger, otherwise healthy patients. It does offer the possibility of a cure however there are significant risks involved, therefore it is often kept as a last resort

Prognosis

What is the prognosis?

TKIs have revolutionised CML treatment and now the 5 year survival for those treated is around 90%³

References

Click to show

1. Reference intervals – Oxford handbook of Clinical Medicine – 7th edition

2. Blood Film Photo – http://library.med.utah.edu/WebPath/HEMEHTML/HEME022.html

3. Druker BJ, Guilhot F, O’Brien SG et al. (2006). “Five-Year Follow-up of Patients Receiving Imatinib for Chronic Myeloid Leukemia”New England Journal of Medicine 355 (20): 2408–17

4. Hehlmann R, Hochhaus A, Baccarani M; European LeukemiaNet (2007). “Chronic myeloid leukaemia”. Lancet 370 (9584): 342–50.

5. Baccarani M, Cortes J, Pane F, et al; Chronic Myeloid Leukemia: An Update of Concepts and Management Recommendations of J Clin Oncol. 2009 Nov 2. [abstract]

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