BMJ 2014;348:g91 doi: 10.1136/bmj.g91 (Published 20 January 2014)
Page 1 of 3
Endgames
ENDGAMES PICTURE QUIZ
Blurred vision and epistaxis 1
Kate Shirley specialist trainee year 2, ophthalmology , Feargal P McNicholl consultant haematologist
2
Department of Ophthalmology, Belfast Health and Social Care Trust, Belfast BT12 6BA, UK; 2Department of Haematology, Altnagelvin Hospital, Altnagelvin, Londonderry, UK 1
A 34 year old man presented with a three month history of blurred vision. He also mentioned nose bleeds, worsening headaches, and pain in the right knee. He had experienced some weight loss and tiredness but had been previously healthy and took no drugs on a regular basis.
His general practitioner carried out full blood tests in light of the recurrent epistaxis: haemoglobin was 127 g/L (reference range 130-180), platelets 111×109/L (140-400), white cell count 275×109/L (3.6-11.0), neutrophils 107×109/L (1.8-7.5), lymphocytes 11×109/L (1.0-4.0), monocytes 5.52×109/L (0.2-0.8), eosinophils 8×109/L (0.1-0.4), and basophils 0×109/L (0.02-0.1). He was subsequently admitted to hospital for investigations. On admission he was apyrexic and his blood pressure was 130/76 mm Hg. His spleen was not palpable, but ultrasonography of his abdomen showed splenomegaly of 16 cm. His coagulation screen was normal: prothrombin time 12.4 s (11-14), activated partial thromboplastin time 27.7 s (26-39), and fibrinogen 18 µmol/L (4.4-11.8). Renal function was slightly impaired, with a creatinine concentration of 136 µmol/L (58-110) and an estimated glomerular filtration rate of 52 mL/min/1.73m2. Uric acid was increased, at 510 µmol/L (200-430). The lactate dehydrogenase concentration was noticeably increased, at 2458 IU/L (105-133), the vitamin B12 level was increased, at >1500 pmol/L (110-664), and C reactive protein was 4.2 mg/L (3 months) is more suggestive of chronic phase CML than of blast crisis CML.
Long answer
Chronic myelogenous leukaemia (CML) is a myeloproliferative neoplasm that results in increased proliferation of granulocytic cell lines, which maintain their ability to differentiate. Most patients with CML are diagnosed in the “chronic phase” and have non-specific symptoms such as fatigue, weight loss, and night sweats. Some patients have abdominal pain due to splenomegaly. Overall, 20-40% of patients are asymptomatic and are diagnosed when a full blood count is done at routine medical examination. CML in the “accelerated phase” or “blast crisis” generally has more severe symptoms related to severe anaemia, bleeding, marked splenic enlargement, or bone pain.1 2 Some patients with CML present with medical emergencies such as pulmonary leucostasis and priapism. The vitamin B12 level is increased in CML owing to increased levels of transcobalamin I on the surface of white cells.
2 How would you confirm your diagnosis? Short answer
Diagnosis is initially based on a blood film and bone marrow aspirate or biopsy sample. The diagnosis is confirmed by cytogenetic identification of the Philadelphia chromosome translocation by routine cytogenetics/FISH (fluorescence in situ hybridisation) or detection of the BCR-ABL fusion gene using polymerase chain reaction.
Long answer
A thorough investigation for suspected CML should include a complete blood count, peripheral blood smear, and bone marrow analysis. The blood count in chronic phase CML shows a leucocytosis (12-1000×109/L, median 100×109/L) mostly as a result of neutrophils in different stages of maturation. Basophilia is characteristic, and eosinophila is usually present. Blasts normally account for less than 2% of the peripheral white cell count in chronic phase CML. The platelet count is often increased. There can be high lactate dehydrogenase, urate, and vitamin B12 levels. The bone marrow biopsy is hypercellular owing to granulocytic proliferation. Blasts usually account for less than 5% of marrow cells in the chronic phase. At diagnosis, 90-95% of cases have the characteristic t(9;22)(q34;q11.2) reciprocal translocation that results in the Philadelphia chromosome. This translocation fuses sequences of the BCR gene on chromosome 22 with regions of the ABL gene from chromosome 9. The enhanced tyrosine kinase activity of the BCR-ABL protein is responsible for constitutive activation of several signal transduction pathways that drive the leukaemic phenotype of CML. In CML, BCR-ABL is found in cells of all myeloid lineage as well as in some lymphoid cells and endothelial cells.1 2
3 What does the fundal photograph show? Short answer
The fundal photograph shows retinopathy of the left eye. Retinopathy is characterised by retinal haemorrhages, some of which have white centres (Roth spots), cotton wool spots, and venous tortuosity (fig 2).
For personal use only: See rights and reprints http://www.bmj.com/permissions
Fig 2 Fundal photograph showing flame shaped intraretinal haemorrhage (blue arrow) in nerve fibre layer; blood vessels throughout retina, which appear more tortuous than normal (black arrow); focal infarcts in nerve fibre layer (yellow arrow), described as cotton wool spots; and Roth spots (green arrow), representing areas of haemorrhage around pale white centres
Long answer
Retinopathy is defined as damage to the retina. It has many signs, which are often non-specific to the cause and therefore require thorough systemic investigation. Many of the signs relate to vascular abnormalities. These abnormalities are usually driven by hypoxia, as in this patient, owing to hyperviscosity causing decreased oxygen transport. On fundal examination, microaneurysms are seen as small round red dots and are the first detectable lesions. Hard exudates lie in the outer plexiform layer and appear as waxy, yellow, distinct lesions. Retinal oedema and haemorrhages may also be detectable. Intraretinal haemorrhages show a dot-blot appearance, whereas haemorrhages of the retinal nerve fibre layer are flame shaped. Cotton wool spots represent focal infarcts in the nerve fibre layer and are small, white, fluffy superficial lesions. The more uncommon sign of Roth spots in this patient is thought to represent fibrin thrombi occluding ruptured blood vessels or leukaemic infiltrates.3
4 What is your differential diagnosis for the fundal appearance of this patient (name three)? Short answer
Hypertension (especially chronic), diabetic retinopathy, or retinal vein occlusion.
Long answer
Retinopathy can be a sign of a wide variety of systemic diseases, the most common being diabetic retinopathy. In diabetic retinopathy the features can range from mild background diabetic retinopathy to proliferative diabetic retinopathy with neovascularisation and maculopathy. Retinopathy may also be a consequence of retinal vein occlusion, which is characterised by venous tortuosity and extensive haemorrhaging. Hypertensive retinopathy can lead to arterial narrowing and vascular leakage. Systemic hypertension is diagnosed by blood pressure readings consistently higher than 140/90 mm Hg. It is important to remember other rare causes of retinopathy such as retinopathy Subscribe: http://www.bmj.com/subscribe
BMJ 2014;348:g91 doi: 10.1136/bmj.g91 (Published 20 January 2014)
Page 3 of 3
ENDGAMES
of prematurity, radiation retinopathy, Purtscher’s retinopathy and, as in this case, blood dyscrasias such as leukaemia, myeloma, and sickle cell anaemia.3 About 10% of patients with CML have eye symptoms at diagnosis.4 5 It is always important to consider and rule out infective endocarditis when Roth spots are identified.
5 How would you manage this patient’s condition? Short answer
The management of CML has been revolutionised recently by the tyrosine kinase inhibitors (TKI) such as imatinib, dasatinib, and nilotinib, which are administered orally and are associated with overall survival rates of more than 90%. Hydroxycarbamide is sometimes also used in the initial period after diagnosis if a more rapid reduction in white cell count is required.
Long answer
Hydroxycarbamide can be used initially to rapidly control white cell count. Tyrosine kinase inhibitors (TKIs, imatinib, dasatinib, or nilotinib) are the mainstay of modern management of CML. TKIs are taken orally and are effective in most cases, resulting in long term remissions if patient compliance is maintained. Some patients have mutations in their CML clones (such as the T513I mutation), which make their CML resistant to first line TKI therapy. Alternative TKI therapy may then be considered. Botusinib may be effective for CML that does not have the T513I mutation. Omacetaxine, given subcutaneously, may be considered for those patients with CML who do not respond to botusinib. Ponatinib has shown efficacy in CML with T513I mutation.6 7 TKIs have been associated with long term overall survival rates of more than 90%, but effective management of CML usually requires patients to take tablets every day. Although side effects during treatment are commonly encountered, they are generally manageable without significantly affecting the quality of life of patients. Each TKI, however, has its specific side effect profile, which may necessitate close monitoring. Allogeneic stem cell transplantation remains the
For personal use only: See rights and reprints http://www.bmj.com/permissions
only “cure” for CML. Although such treatment carries a high risk of transplant related morbidity and mortality, it retains a role in the management of some patients. Leucopharesis is occasionally required if there is life threatening leucocytosis at diagnosis.
Patient outcome This patient was randomised to receive dasatinib in the SPIRIT 2 trial in February 2013,8 resulting in his full blood count normalising by April 2013 (complete haematological remission). He remains on course to achieve a molecular remission; by October 2013 his BCR-ABL/ABL ratio was low, at 0.016% (compared with 73.64% at diagnosis). Competing interests: We have read and understood the BMJ Group policy on declaration of interests and declare the following interests: None. Provenance and peer review: Not commissioned; externally peer reviewed. Patient consent: obtained. 1 2 3 4 5 6 7 8
McCormack PL, Kaem SJ. Dasatinib: a review of its use in the treatment of chronic myeloid leukaemia and Philadelphia chromosome-positive acute lymphoblastic leukaemia. Drugs 2011;71:1771-95. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al. WHO classification of tumours of haematopoietic and lymphoid tissues. 4th ed. International Agency for Research on Cancer, 2008. Kanski JJ, Bowling B. Clinical ophthalmology: a systemic approach. 5th ed. Butterworth Heinemann, 2003. Reddy SC, Jackson N, Menon BS. Ocular involvement in leukaemia: a study of 288 cases. Ophthalmologica 2003;217:441-5. Baccarani M, Deininger MW, Rosti G, Hochhaus A, Soverini S, Apperley JF, et al. European LeukemiaNet recommendations for the management of chronic myeloid leukaemia. Blood 2013;122:872-84. Stein B, Smith BD. Therapeutic options for patients with chronic myeloid leukemia who are resistant to or unable to tolerate imatinib. Clin Ther 2010;32:840-20. Ohkoshi K, Tsiaras WG. Prognostic importance of ophthalmic manifestation in childhood leukaemia. Br J Ophthalmol 1992;76:651-5. Cancer Research UK. A trial looking at imatinib and dasatinib for newly diagnosed chronic myeloid leukaemia (SPIRIT 2). 2013. www.cancerresearchuk.org/cancer-help/trials
Cite this as: BMJ 2014;348:g91 © BMJ Publishing Group Ltd 2014
Subscribe: http://www.bmj.com/subscribe
Page 1 of 3
Endgames
ENDGAMES PICTURE QUIZ
Blurred vision and epistaxis 1
Kate Shirley specialist trainee year 2, ophthalmology , Feargal P McNicholl consultant haematologist
2
Department of Ophthalmology, Belfast Health and Social Care Trust, Belfast BT12 6BA, UK; 2Department of Haematology, Altnagelvin Hospital, Altnagelvin, Londonderry, UK 1
A 34 year old man presented with a three month history of blurred vision. He also mentioned nose bleeds, worsening headaches, and pain in the right knee. He had experienced some weight loss and tiredness but had been previously healthy and took no drugs on a regular basis.
His general practitioner carried out full blood tests in light of the recurrent epistaxis: haemoglobin was 127 g/L (reference range 130-180), platelets 111×109/L (140-400), white cell count 275×109/L (3.6-11.0), neutrophils 107×109/L (1.8-7.5), lymphocytes 11×109/L (1.0-4.0), monocytes 5.52×109/L (0.2-0.8), eosinophils 8×109/L (0.1-0.4), and basophils 0×109/L (0.02-0.1). He was subsequently admitted to hospital for investigations. On admission he was apyrexic and his blood pressure was 130/76 mm Hg. His spleen was not palpable, but ultrasonography of his abdomen showed splenomegaly of 16 cm. His coagulation screen was normal: prothrombin time 12.4 s (11-14), activated partial thromboplastin time 27.7 s (26-39), and fibrinogen 18 µmol/L (4.4-11.8). Renal function was slightly impaired, with a creatinine concentration of 136 µmol/L (58-110) and an estimated glomerular filtration rate of 52 mL/min/1.73m2. Uric acid was increased, at 510 µmol/L (200-430). The lactate dehydrogenase concentration was noticeably increased, at 2458 IU/L (105-133), the vitamin B12 level was increased, at >1500 pmol/L (110-664), and C reactive protein was 4.2 mg/L (3 months) is more suggestive of chronic phase CML than of blast crisis CML.
Long answer
Chronic myelogenous leukaemia (CML) is a myeloproliferative neoplasm that results in increased proliferation of granulocytic cell lines, which maintain their ability to differentiate. Most patients with CML are diagnosed in the “chronic phase” and have non-specific symptoms such as fatigue, weight loss, and night sweats. Some patients have abdominal pain due to splenomegaly. Overall, 20-40% of patients are asymptomatic and are diagnosed when a full blood count is done at routine medical examination. CML in the “accelerated phase” or “blast crisis” generally has more severe symptoms related to severe anaemia, bleeding, marked splenic enlargement, or bone pain.1 2 Some patients with CML present with medical emergencies such as pulmonary leucostasis and priapism. The vitamin B12 level is increased in CML owing to increased levels of transcobalamin I on the surface of white cells.
2 How would you confirm your diagnosis? Short answer
Diagnosis is initially based on a blood film and bone marrow aspirate or biopsy sample. The diagnosis is confirmed by cytogenetic identification of the Philadelphia chromosome translocation by routine cytogenetics/FISH (fluorescence in situ hybridisation) or detection of the BCR-ABL fusion gene using polymerase chain reaction.
Long answer
A thorough investigation for suspected CML should include a complete blood count, peripheral blood smear, and bone marrow analysis. The blood count in chronic phase CML shows a leucocytosis (12-1000×109/L, median 100×109/L) mostly as a result of neutrophils in different stages of maturation. Basophilia is characteristic, and eosinophila is usually present. Blasts normally account for less than 2% of the peripheral white cell count in chronic phase CML. The platelet count is often increased. There can be high lactate dehydrogenase, urate, and vitamin B12 levels. The bone marrow biopsy is hypercellular owing to granulocytic proliferation. Blasts usually account for less than 5% of marrow cells in the chronic phase. At diagnosis, 90-95% of cases have the characteristic t(9;22)(q34;q11.2) reciprocal translocation that results in the Philadelphia chromosome. This translocation fuses sequences of the BCR gene on chromosome 22 with regions of the ABL gene from chromosome 9. The enhanced tyrosine kinase activity of the BCR-ABL protein is responsible for constitutive activation of several signal transduction pathways that drive the leukaemic phenotype of CML. In CML, BCR-ABL is found in cells of all myeloid lineage as well as in some lymphoid cells and endothelial cells.1 2
3 What does the fundal photograph show? Short answer
The fundal photograph shows retinopathy of the left eye. Retinopathy is characterised by retinal haemorrhages, some of which have white centres (Roth spots), cotton wool spots, and venous tortuosity (fig 2).
For personal use only: See rights and reprints http://www.bmj.com/permissions
Fig 2 Fundal photograph showing flame shaped intraretinal haemorrhage (blue arrow) in nerve fibre layer; blood vessels throughout retina, which appear more tortuous than normal (black arrow); focal infarcts in nerve fibre layer (yellow arrow), described as cotton wool spots; and Roth spots (green arrow), representing areas of haemorrhage around pale white centres
Long answer
Retinopathy is defined as damage to the retina. It has many signs, which are often non-specific to the cause and therefore require thorough systemic investigation. Many of the signs relate to vascular abnormalities. These abnormalities are usually driven by hypoxia, as in this patient, owing to hyperviscosity causing decreased oxygen transport. On fundal examination, microaneurysms are seen as small round red dots and are the first detectable lesions. Hard exudates lie in the outer plexiform layer and appear as waxy, yellow, distinct lesions. Retinal oedema and haemorrhages may also be detectable. Intraretinal haemorrhages show a dot-blot appearance, whereas haemorrhages of the retinal nerve fibre layer are flame shaped. Cotton wool spots represent focal infarcts in the nerve fibre layer and are small, white, fluffy superficial lesions. The more uncommon sign of Roth spots in this patient is thought to represent fibrin thrombi occluding ruptured blood vessels or leukaemic infiltrates.3
4 What is your differential diagnosis for the fundal appearance of this patient (name three)? Short answer
Hypertension (especially chronic), diabetic retinopathy, or retinal vein occlusion.
Long answer
Retinopathy can be a sign of a wide variety of systemic diseases, the most common being diabetic retinopathy. In diabetic retinopathy the features can range from mild background diabetic retinopathy to proliferative diabetic retinopathy with neovascularisation and maculopathy. Retinopathy may also be a consequence of retinal vein occlusion, which is characterised by venous tortuosity and extensive haemorrhaging. Hypertensive retinopathy can lead to arterial narrowing and vascular leakage. Systemic hypertension is diagnosed by blood pressure readings consistently higher than 140/90 mm Hg. It is important to remember other rare causes of retinopathy such as retinopathy Subscribe: http://www.bmj.com/subscribe
BMJ 2014;348:g91 doi: 10.1136/bmj.g91 (Published 20 January 2014)
Page 3 of 3
ENDGAMES
of prematurity, radiation retinopathy, Purtscher’s retinopathy and, as in this case, blood dyscrasias such as leukaemia, myeloma, and sickle cell anaemia.3 About 10% of patients with CML have eye symptoms at diagnosis.4 5 It is always important to consider and rule out infective endocarditis when Roth spots are identified.
5 How would you manage this patient’s condition? Short answer
The management of CML has been revolutionised recently by the tyrosine kinase inhibitors (TKI) such as imatinib, dasatinib, and nilotinib, which are administered orally and are associated with overall survival rates of more than 90%. Hydroxycarbamide is sometimes also used in the initial period after diagnosis if a more rapid reduction in white cell count is required.
Long answer
Hydroxycarbamide can be used initially to rapidly control white cell count. Tyrosine kinase inhibitors (TKIs, imatinib, dasatinib, or nilotinib) are the mainstay of modern management of CML. TKIs are taken orally and are effective in most cases, resulting in long term remissions if patient compliance is maintained. Some patients have mutations in their CML clones (such as the T513I mutation), which make their CML resistant to first line TKI therapy. Alternative TKI therapy may then be considered. Botusinib may be effective for CML that does not have the T513I mutation. Omacetaxine, given subcutaneously, may be considered for those patients with CML who do not respond to botusinib. Ponatinib has shown efficacy in CML with T513I mutation.6 7 TKIs have been associated with long term overall survival rates of more than 90%, but effective management of CML usually requires patients to take tablets every day. Although side effects during treatment are commonly encountered, they are generally manageable without significantly affecting the quality of life of patients. Each TKI, however, has its specific side effect profile, which may necessitate close monitoring. Allogeneic stem cell transplantation remains the
For personal use only: See rights and reprints http://www.bmj.com/permissions
only “cure” for CML. Although such treatment carries a high risk of transplant related morbidity and mortality, it retains a role in the management of some patients. Leucopharesis is occasionally required if there is life threatening leucocytosis at diagnosis.
Patient outcome This patient was randomised to receive dasatinib in the SPIRIT 2 trial in February 2013,8 resulting in his full blood count normalising by April 2013 (complete haematological remission). He remains on course to achieve a molecular remission; by October 2013 his BCR-ABL/ABL ratio was low, at 0.016% (compared with 73.64% at diagnosis). Competing interests: We have read and understood the BMJ Group policy on declaration of interests and declare the following interests: None. Provenance and peer review: Not commissioned; externally peer reviewed. Patient consent: obtained. 1 2 3 4 5 6 7 8
McCormack PL, Kaem SJ. Dasatinib: a review of its use in the treatment of chronic myeloid leukaemia and Philadelphia chromosome-positive acute lymphoblastic leukaemia. Drugs 2011;71:1771-95. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al. WHO classification of tumours of haematopoietic and lymphoid tissues. 4th ed. International Agency for Research on Cancer, 2008. Kanski JJ, Bowling B. Clinical ophthalmology: a systemic approach. 5th ed. Butterworth Heinemann, 2003. Reddy SC, Jackson N, Menon BS. Ocular involvement in leukaemia: a study of 288 cases. Ophthalmologica 2003;217:441-5. Baccarani M, Deininger MW, Rosti G, Hochhaus A, Soverini S, Apperley JF, et al. European LeukemiaNet recommendations for the management of chronic myeloid leukaemia. Blood 2013;122:872-84. Stein B, Smith BD. Therapeutic options for patients with chronic myeloid leukemia who are resistant to or unable to tolerate imatinib. Clin Ther 2010;32:840-20. Ohkoshi K, Tsiaras WG. Prognostic importance of ophthalmic manifestation in childhood leukaemia. Br J Ophthalmol 1992;76:651-5. Cancer Research UK. A trial looking at imatinib and dasatinib for newly diagnosed chronic myeloid leukaemia (SPIRIT 2). 2013. www.cancerresearchuk.org/cancer-help/trials
Cite this as: BMJ 2014;348:g91 © BMJ Publishing Group Ltd 2014
Subscribe: http://www.bmj.com/subscribe
