Case 117 update 2

Bone marrow trephine shows a hypocellular trephine throughout the specimen, supporting your suspicion of aplastic anaemia. There are no dysplastic features present

There is no evidence of a PNH clone.

How would you classify this patient?

What are your immediate management plans?

What are your longer term treatment options for this patient?

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Case 117 update 1

So far our investigations have shown:

  • Normal haematinics
  • Negative viral screen
  • Negative autoimmune screen
  • Blood film – no blasts/no dysplasia. Anisopoikilocytosis
  • Normal LDH
  • Negative abdominal ultrasound
  • Reticulocytopenia

Patient has no significant past medical history and is not taking any regular medications

A bone marrow is performed and bone marrow aspirate results are available:

Hypocellular particles and trails. Erythropoiesis, granulopoesis and megakarycytes appears reduced.

What is your differentials diagnosis? Are there any further investigations you would perform?

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Case 117

31 year old man attends GP feeling tired. Bloods show

HB 65

Platelets 45

WCC 1.2

What further test would you advise? Immediate management??

Please reply to us (@TeamHaem) on Twitter and always include #TeamHaem to allow others to follow your comments. Please join in the debate and learn about haematological problems along the way. The case will continue to  evolve over the coming week so keep checking #TeamHaem on Twitter for more information.

Please note – all cases on TeamHaem are entirely fictional to protect patient confidentiality.

TeamHaem are not a position of authority.  It is an educational platform to allow discussion and learning.

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Case 116 – Summary!

Thank you for everyone’s involvement in the case this week. We discussed a 56 year old man who presented with an acute stroke. This was managed with oral aspirin as his NIHSS score was low at 3 and he presented at 4.5 hours after his symptoms developed.

His initial investigations revealed polycythaemia with iron deficient picture (Hb 122, HCT 0.52, MCV low) and mild thrombocytosis (480).

We took a thorough history to assess for potential secondary causes and cardiovascular risk factors. The only identifiable factors were a renal transplant 6 months ago (no prior dialysis and acute renal disease necessitating need for transplant) and smoking history. However he only smoked 5 cigarettes per day and had normal saturations so it wasn’t felt this was a significant contributory cause although he has obviously been recommended to stop. We also assessed cardiovascular risk status.

An important learning point from our case is the need to repeat the FBC/look back at previous results to ensure it is not just an erroneous result. Doing so highlighted that his polycythaemia was longstanding and pre-dated his renal disease and transplant. This prompted us to perform JAK2 V617F mutation analysis which was present confirming the diagnosis of polycythaemia vera.

Our patient was stratified as high risk due to his acute stroke and underwent venesection to try promptly reduced his HCT as well commencing hydroxycarbamide therapy. We discussed the importance of optimizing other cardiovascular risk factors and continuing anti-platelet therapy.

Below is a summary of polycythaemia and post-renal transplant erythrocytosis.

Polycythaemia

Polycythaemia is a frequent finding in general medicine and general practice. The vast majority of causes are due to relative/apparent polycythaemia (reduced plasma volume making the blood more concentrate) or secondary or reactive to other causes.

Causes

PV causes

Investigations

Those with a persistently raised venous haematocrit (male >0.52; females >0.48) should be reviewed and investigated. However, if there is a clear secondary cause no further investigations may be necessary.

 BSH guidelines recommend using the following investigative algorithm: https://onlinelibrary.wiley.com/doi/full/10.1111/bjh.15648

Polycythaemia algorithm

 Stage 1 Investigations:

  • History and examination
  • FBC/film (NB film not generally helpful in diagnosing polythaemia but needed to look for signs of myelofibrosis)
  • Ferritin, U&E, LFT (frequently patients are iron deficient)
  • Serum erythropoietin
  • ABG (or Sp02 but beware if at risk of carbon monoxide poisoning, sleep apnoea or high affinity haemoglobins as may be normal). An SaO2 <92% is associated with absolute erythrocytosis
  • JAK2V617F mutation (allele burden equivalent in bone marrow and peripheral blood)

Stage 2 investigations (if JAK2 negative):

  • Red cell mass
  • Abdominal USS (splenomegaly, renal pathology etc)
  • JAK2 exon 12 analysis (can have discrepancy between allele burden in bone marrow and peripheral blood)
  • Marrow aspirate/trephine/cytogenetics
    • – Marked increased erythropoiesis, moderate increase in granulopoiesis and megakaryopoiesis. Highly variable megakrycocyte including hyperlobulated nuclei, absent iron stores.
    • – Abnormal karyotype, SH2B3 mutation, TET2, DNMT3A

 

Polycythaemia Vera

 Polycythaemia vera is a clonal haematopoietic neoplasm which presents usually in the 60s with a slight male predominance. The substitution of phenylalanine for valine at position 617 of the JAK2 gene is responsible for approximately 95% of cases of polycythaemia vera and costs approximately £50. Progenitor cells have increased sensitivity to growth factors as the V617F mutation allows the JAK protein to become active even when no growth factor is bound leading to increased cell survival and proliferation. The incidence is approximately 2-3 per 100 000 per year.  When the V617F mutation is not found, mutations in exon 12 should be looked for as these account for a further 2-4% of cases of polycythaemia vera.

Clinical features:

  • Night sweats
  • Weight loss, lethargy
  • Splenomegaly
  • Aquagenic pruritis
  • Thrombosis (venous/arterial/microvascular) and bleeding
  • Arterial thrombosis more common (75%)
  • Abdominal vein thrombosis should be investigated for the JAK2v617F and exon 12 mutations even with a normal FBC.
  • Headache/visual disturbance
  • Dizziness
  • Erythromelalgia

 

Diagnostic criteria

JAK2-positive polycythaemia vera (requires both criteria)

  • High HCT (>0.52 in men, >0.48 in women) OR raised red cell mass (>25% above predicted)
  • Mutation in JAK2

JAK2-negative polycythaemia vera (requires A1-A4) plus another A or two B criteria)

  • A1 Raised red cell mass (>25% above predicted) OR HCT >0.6 in men; >0.56 in women
  • A2 Absence of mutation in JAK2
  • A3 No cause of secondary erythrocytosis
  • A4 Bone marrow histology consistent with PV
  • A5 Palpable splenomegaly
  • A6 Presence of an acquired genetic abnormality (excluding BCR-ABL1) in the haemopoietic cells
  • B1 Thrombocytosis (Plts >450 x 109/l)
  • B2 Neutrophil leukocytosis (neutrophil count >10 x 109/l in non-smokers, >12.5 x 109/l in smokers)
  • B3 Radiological evidence of splenomegaly
  • B4 Low serum erythropoietin

 

Risk stratification (of thrombotic risk based on ECLAP data):

  • Low risk: <65 years and no PV-associated thrombotic history
  • High risk: >65 years and/OR prior PV-associated arterial or venous thrombosis
  • NB: other factors contributing to thrombotic risk include: WCC >15 x 109/l, smoking, diabetes mellitus, hypertension, hypercholesterolaemia. Patients with these features even if stratified as low risk should be considered as high risk.
  • Mortality is predominantly based on thromboembolic events

 

Factors associated with an increased risk of transformation to myelofibrosis

~Incidence of transformation 5-10% in 10 years

  • Longer disease duration
  • Splenomegaly
  • Raised LDH
  • Presence of reticulin fibrosis at diagnosis
  • JAK2 V617F allele burden >50%

Factors associated with an increased risk of transformation to AML

  • Age
  • WCC >15 x 109/l
  • Splenomegaly
  • Abnormal karyotype

Management

 All Patients

  • HCT target <0.45
    • based on CYTO-PV data on reduction of major thrombosis/cardiovascular death
  • Aspirin 75mg – 100mg per day (+ PPI if high bleeding risk including age >75)
  • Optimisation of other cardiovascular risk factors e.g hypertension
  • Avoid excess of dietary iron

Low risk patients

  • Venesection alone to achieve target HCT
  • In the acute setting this may be needed frequently e.g. alternate days and concomitant fluid replacement may be necessary
  • ≥3 venesections per year is associated with higher thrombotic risk. If maintenance venesection frequency high cytoreductive treatment should be considered.
  • Patients otherwise catergorised as low risk should be managed with cytoreductive therapy if extreme thrombocytosis (>1500 – haemorrhage risk), progressive splenomegaly/progressive leukocytosis. Or marked constitutional symptoms.

High risk patients

  • Require use of cytoreductive therapy
  • Hydroxycarbamide or interferon are first line

 

  • Hydroxycarbamide
    • No definitive evidence that it increases risk of transformation to leukaemia.
    • Advise to stop 3 months prior to conception

European LeukaemiaNet criteria for hydroxycarbamide intolerance and resistance:

  1. Need for phlebotomy to keep haematocrit <0·45 after 3 months of at least 2 g/day of hydroxycarbamide OR
  2. Uncontrolled myeloproliferation, i.e. platelet count >400 × 109/l AND white blood cell count >10 × 109/l after 3 months of at least 2 g/day of hydroxycarbamide OR
  3. Failure to reduce massiveasplenomegaly by more than 50% as measured by palpation OR failure to completely relieve symptoms related to splenomegaly, after 3 months of at least 2 g/day of hydroxycarbamide OR
  4. Absolute neutrophil count <1·0 × 109/l OR platelet count <100 × 109/l OR haemoglobin <100 g/l at the lowest dose of hydroxycarbamide required to achieve a complete or partial clinico‐haematological response OR
  5. Presence of leg ulcers or other unacceptable hydroxycarbamide ‐related non‐haematological toxicities, such as mucocutaneous manifestations, gastrointestinal symptoms, pneumonitis or fever at any dose of hydroxycarbamide.

 

  • Interferon
    • Safe in pregnancy

 

  • Other cytoreductive agents
    • Ruxolitinib (JAK2 inhibitor)
      • Second/third line if HC intolerant/resistant
    • Radioactive phosphorus / busulfan
      • Increased risk of leukaemia transformation so should only be administered to thse with a limited life expectancy.
    • Anagrelide
      • Can be used in combination if plt count not controlled with hydroxycarbamide

 

Post renal transplant erythrocytosis

  • Incidence ~5-20%
  • Various definitions ranging from HCT >0.50 -0.52 persisting for between 1 and 6 months.
  • It typically occurs within the first year post transplant
  • The erythrocytosis is related to EPO levels. Risk factors for developing post transplant erythrocytosis include:
    • Male > female
    • Native kidney in situ
    • Renal artery stenosis
    • Reduced need for EPO pre-transplant or transfusions
    • Poor allograft function
  • It is usually considered to be a benign condition as it is not associated with thrombosis or increased mortality. It can also spontaneously resolve over 1-4 years.
  • Management:
    • ACEi or ARB as these suppress the renin-angiotensin system
    • Treat hypertension
    • No benefit of aspirin
    • Consider venesection if persistent symptoms to target HCT 0.5 (no evidence of benefit)

References

  1. McMullin MF. A guideline for the diagnosis and management of polycythaemia vera. A Britich Society for Haematology Guideline. 184(2):176-191. 2019.
  2. Landolfi R et al. European Collaboration on Low-dose aspirin in polycythaemia vera (ECLAP): A randomised trial. Seminars in Thrombosis and haemostasis. 23(5):473-8. 1997.
  3. Marchioli R et al. Cardiovascular events and intensity of treatment in polycythaemia vera. New England Journal of Medicien. 368:22-33. 2013
  4. McMullin MF. A guideline for the management of specific situations in polycythaemia vera and secondary erythrocytosis. A Britich Society for Haematology Guideline. 184(2):161-175. 2019.
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Case 116 – Update 3!

Thank you for everyone’s contributions.

Due to his history of renal disease and renal transplant it is important that we consider these as potential secondary causes of polycythaemia. However, taking a thorough history and review of previous blood results has identified that he has been polycythaemic for the past 3 years which preceded his renal issues. It is important to note that we can’t exclude post transplant polycythaemia as a contributing cause. There was nil else on his history which was indicative of another secondary cause.

We now have the outstanding blood results that you have all requested:

Erythropoietin: Low

JAK2 V617F: Present

Questions:

  1. What is the main cause of his polycythaemia and how what would your management be for this patient?
  2. What is the management of post-transplant polycythaemia and would you institute it in this case?

Please reply to us (@TeamHaem) on Twitter and always include #TeamHaem to allow others to follow your comments. Please join in the debate and learn about haematological problems along the way. The case will continue to  evolve over the coming week so keep checking #TeamHaem on Twitter for more information.

Please note – all cases on TeamHaem are entirely fictional to protect patient confidentiality.

TeamHaem are not a position of authority.  It is an educational platform to allow discussion and learning.

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Case 116 – Update 2!

Thank you for everyone’s contributions so far!

It has been noted that our patient who presented with an ischaemic stroke has a raised HCT and you have mentioned that we need to ensure this is an absolute polycythaemia and if so whether there is a primary or secondary cause.

To recap the FBC result taken at the time of his stroke was Hb 122, HCT 0.56, MCV 72, Plts 480, WCC 9.8, Neuts 7.5. NB we have repeated the FBC and th results are similar (lets not forget this!!)

Various information/investigations to determine the aetiology of his polycythaemia have been requested by yourselves as follows:

  • Current smoker: 5/day
  • Lives in the UK at sea level
  • PMH: renal transplant 6 months ago secondary to rapidly progressive glomerulonephritis. Native kidneys in situ. No prior CVA, diabetes, hypertension, or hypercholesterolaemia.
  • On examination: Saturations 99%. BP 139/68.
  • ECG: normal sinus rhythm.
  • Electrolytes normal. Ferritin 13. Albumin 37. Lipid profile unremarkable. Glucose NAD
  • JAK2 V617F, EPO levels pending.

 

The main differentials suggested are:

  • Primary polycythaemia
  • Polycythaemia post renal transplant

 

Questions:

  1. What further information from the patients history/examination would be useful to  help determine potential secondary causes of polycythaemia?
  2. What are the risk factors for polycythaemia post renal transplant? How would you treat it?

Please reply to us (@TeamHaem) on Twitter and always include #TeamHaem to allow others to follow your comments. Please join in the debate and learn about haematological problems along the way. The case will continue to  evolve over the coming week so keep checking #TeamHaem on Twitter for more information.

Please note – all cases on TeamHaem are entirely fictional to protect patient confidentiality.

TeamHaem are not a position of authority.  It is an educational platform to allow discussion and learning.

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Case 116 – Update 1!

Thanks for everyone’s contributions so far.

Our 56 year old man was commenced on aspirin by the acute stroke team. He was not suitable for thrombolysis (presented later than 4.5hours of onset of symptoms) and it was felt thrombectomy was not required due to a low NIHSS score of 3. He remains on the acute stroke unit under their care.

Following his renal transplant 6 months ago he has a good baseline function. He has never had a TIA/stroke previously.

Work-up investigations requested by yourselves revealed:

  • BP and glucose: Normal
  • ECG: Normal sinus rhythm
  • FBC: Hb 122, HCT 0.56, MCV 72, Plts 480, WCC 9.8, Neuts 7.5

Question:

  1. What abnormality is apparent and what further investigations would you want to perform?

Please reply to us (@TeamHaem) on Twitter and always include #TeamHaem to allow others to follow your comments. Please join in the debate and learn about haematological problems along the way. The case will continue to  evolve over the coming week so keep checking #TeamHaem on Twitter for more information.

Please note – all cases on TeamHaem are entirely fictional to protect patient confidentiality.

TeamHaem are not a position of authority.  It is an educational platform to allow discussion and learning.

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Case 116 – The Beginning!

A 56 year old man presents with left sided arm weakness and slurred speech. His symptoms started 6 hours prior to presentation. He has a significant past medical history of a renal transplant 6 months ago. A CT confirms a partial anterior circulation stroke.

Questions:

  1. What further information would you want?
  2. What would be your acute management at this stage?

Please reply to us (@TeamHaem) on Twitter and always include #TeamHaem to allow others to follow your comments. Please join in the debate and learn about haematological problems along the way. The case will continue to  evolve over the coming week so keep checking #TeamHaem on Twitter for more information.

Please note – all cases on TeamHaem are entirely fictional to protect patient confidentiality.

TeamHaem are not a position of authority.  It is an educational platform to allow discussion and learning.

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Case 115 summary

Our patient presented with MAHA, thrombocytopenia and neurological symptoms which prompted further investigations and confirmation of TTP.

Teamhaem have covered TTP previously in case 7, with a different clinical scenario. Therefore the majority of this summary is taken from the previous case. However key areas to this case are pregnancy, refractory diseaseand new advances in treatment.

Acquired TTP is a potentially life threatening thrombotic microangiopathy, caused by a severe deficiency in ADAMTS13 due to the presence of inhibitory autoantibodies. In our case we demonstrated low levels or ADAMTS13 in the presence of antibodies. This results in aggregation of platelets to ultra large vonwillebrand factor multimers causing micro vascular thrombosis which results in organ ischaemia.

Differential

  • Haemolytic uraemic syndrome
  • Malignant hypertension
  • HELLP (haemolysis elevated liver enzymes low platelets)
  • Pre-eclampsia
  • Disseminated intravascular coagulation
  • Autoimmune diseases e.g. anti-phospholipid syndrome, SLE

TTP – clinical syndrome

The classic clinical presentation is often insidious in inset and consists of the pentad:

  • Pyrexia
  • MAHA
  • Fluctuating neurological impairment – may include personality change and drowsiness to seizures and coma
  • Renal failure
  • Thrombocytopenia

TTP – Investigations

The below are to help in the diagnosis of other MAHA and also to point towards a potential cause.

  • Biochemistry: U&E/LFT/Ca/indirect bili/LDH/troponin/amylase
  • Haematology: FBC, film, reticulocyte count/coag/DAT
  • Viral: HIV/Hep B/C
  • Immunology: Autoimmune screen/haptoglobin
  • ADAMTS13 assay
  • Urinalysis
  • ECG
  • CXR
  • TFTs
  • CT head
  • CT chest abdo pelvis, pregnancy test and stool sample if indicated

Management

Taken from BsH guidelines 2014

New therapies

Caplacuzimab may be used in acquired TTP. An anti-vonwillebrand factor nanobody, inhibits the interaction be ultra large Von willebrand factor multimers and platelets. This results in reduce aggregation, producing faster recovery of the platelet count and reduced incidence of thrombosis, and shortening of the acute episode of TTP.

HERCULES trial – Caplacuzimab treatment for acquired thrombotic thrombocytopenic purpura. NEJM January 2019 Scully, M et al

https://t.co/KNjhbSumYo Link to podcast discussing the role of caplacizumab

TTP and pregnancy

Pregnancy can be the initiating event for TTP. This may be acquired or late onset congenital TTP. Patients may present at any point during pregnancy, but the majority of presentation occur at 30+ weeks gestation a or in the immediate post-part in period.

Diagnosis of TTP can be challenging especially in pregnancy. PEX should be started immediately if there is uncertainty in the diagnosis.

Treatment

  • Delivery is the definitive treatment in pregnancy, however it may not guarantee remission.
  • Congenital TTP may be managed with plasma infusions alone.
  • Steroids and PEX comprises main treatment plan
  • PEX can be continued throughout pregnancy and may allow continuation of pregnancy and delivery of a live foetus
  • Rituximab has been used in pregnancy in other conditions (autoimmune/lymphoma) but there is no data available for its use in pregnancy in acute TTP, although it would be considered in a case such as ours.

The following can be considered when managing a pregnancy in a patient with previous TTP

  • Low dose aspirin
  • LMWH
  • Azathioprine
  • Rituximab can be given pre-conceptually to reduce the risk of relapse during pregnancy
  • PEX

Baseline ADAMTS13 level and IgG should be taken and monitored regularly during pregnancy. Treatment plan will depend upon baseline ADAMTS13 levels and often patients will required additional treatments by the third trimester. The obstetric team would require early and regular reviews to perform foetal ultrasound +\- uterine artery doppler. Delivery should be planned for 37weeks gestation.

Pregnancy outcomes are closely related to gestation with pregnancy loss typically occurring in the second trimester.

ADAMTS13 levels may be reduced in other TMAs related to pregnancy I.e HELLP and pre-eclampsia, but ranging from 12% to 40%, and antibodies to ADAMTS13 are not found.

References

HERCULES trial – Caplacuzimab treatment for acquired thrombotic thrombocytopenic purpura. NEJM January 2019 Scully, M et al

Diagnosis and management of thrombotic thrombocytopenic purpura and other thrombotic microangiopathies. BSH guideline 2014

Thrombotic thrombocytopenic purpura and pregnancy: presentation, management and subsequent pregnancy outcomes. Blood 2014 Scully et al.

TTP diagnosis and management in pregnancy. Thrombosis UK. Prof Marie Scully. https://m.youtube.com/watch?v=-c8BFywDGbs

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Case 115 update 3

Our patient improves clinically with PEX/steroids/rituximab.

Unfortunately she also suffers a miscarriage.

What is your ongoing treatment plan?

How would you council her for future pregnancies? Would you offer any treatment pre.conceptually?

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Case 115 update 2

TTP is confirmed by ADAMTS13 level of 2%. What further information would be useful and why?

Plasma exchange was initiated promptly along with methylprednisone. The patient has had 1.5 plasma volume exchange over the first 3 days of admission. Platelet count is 30. How would you continue to manage this patient?

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Case 115 update 1

You have reviewed the film and concur with the finishing of marked red cell fragmentation. Thrombocytopenia is also confirmed.

You contact the A&E doctor who has reviewed the patient and they confirm as history of a possible seizure prompted hospital review. A history of alcohol excess has also been reported by the patient partner.

Patient usually fit and well, no recent travel, no new medications

Further blood tests undertaken include:

Na- 134

K- 5.4

Crest – 231

Urea – 9

DAT- negative

LDH – elevated

Coagulation screen – PT 12 APTT 33 fibrinogen 3.4

Trop T- elevated

Amylase – within normal range

Hep B/Hep C/ HIV – negative

BetaHCG- elevated

ADAMTS13- awaited as not available out of hours in your area

What is your differential diagnosis?

How would you manage this patient?

Please remember to include #teamhaem in your reply!

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Case 115

As the haematology registrar on call, you are contacted at 2am by the lab scientist. He has reviewed a film of a patient and reports marked red cell fragmentation.

What else would you like to know?

What is your response?

Please reply to us (@TeamHaem) on Twitter and always include #TeamHaem to allow others to follow your comments. Please join in the debate and learn about haematological problems along the way. The case will continue to  evolve over the coming week so keep checking #TeamHaem on Twitter for more information.

Please note – all cases on TeamHaem are entirely fictional to protect patient confidentiality.

TeamHaem are not a position of authority.  It is an educational platform to allow discussion and learning.

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Case 114 – Summary!

Acute Promyelocytic Leukaemia

Thank you for everyone’s contributions throughout our case this week!

It started as a seemingly simple advice call regarding a platelet count of 51. However the clinical history of marked bleeding was inconsistent with this platelet count prompting a prompt review. Further investigations identified a progressive pancytopenia and DIC. Acute Promyelocytic Leukaemia (APL) was diagnosed following a bone marrow biopsy.

The patient had non-high risk APL (WCC <10) and began induction therapy with ATRA/Arsenic. Our patient experienced a WCC rise from 3.6 to 18 secondary to therapy prompting the need for dexamethasone prophylaxis for differentiation syndrome. Unfortunately she developed prolonged QTc and arrhythmias. Her arsenic was temporarily withheld until the QTc <460ms. She had also been commenced on other medications that prolong the QTc which were stopped – highlighted the importance of cautious prescribing.

Below is a summary of APL:

APL is a subtype of acute myeloid leukaemia (AML) accounting for approximately 5-8% of all AML cases. It has better outcomes than most forms of AML with ~90% achieving long-term remission.

Clinical features:

  • Bleeding / bruising (haemorrhagic manifestations are a common presentation and often more marked than non-APL AML due to DIC)
  • Symptoms of anaemia
  • Infections
  • Thrombosis (less commonly)
  • Often symptoms have developed reasonably rapidly prior to diagnosis (days / weeks)

 

Investigations:

FBC: typically cytopenias. The WCC is not usually greatly elevated.

Coag screen (Clauss fibrinogen), DDimer

U+Es, LFTs, CRP.

Viral screen

Blood film: may not be diagnostic.

Bone marrow

 

Morphology

Acute hypergranular promyelocytic leukaemia

  • Abnormal promyelocytes: large cells, pink/purple granules, faggot cells (bundles of Auer rods)

Variant hypogranular form

  • WCC is usually elevated
  • Abnormal promyelocytes : fine granules or agranular. Nucleus is frequently bilobed.

Immunophenotype: CD45+, CD33+, MPO+, CD117+, CD13+/-, CD34-, HLA-DR-, CD2+/-, CD56+/-

Molecular diagnosis of PML-RARA fusion

  • Mandatory
  • t(15;17) resulting in PML-RARA fusion protein (NB rarer variants of this are also reported). This functions as a transcriptional repressor resulting in arrested differentiation.
  • Various techniques available
    • Reverse transciptase polymerase chain reaction – must be performed to enable definition of type of PML/RARA isoform and quantification for subsequent MRD evaluation. Other techniques provide a more rapid diagnosis and are often performed in tandem.
    • Conventional karyotype
    • FISH
    • (Alternative for genetic diagnosis: PML nuclear staining in leukaemic cells using anti-PML monoclonal antibodies)

 

Management

 Blood transfusion Support – To be started as soon as APL suspected

  • Essential as haemorrhage is main cause of early death
  • To be initiated prior to genetic confirmation of diagnosis
  • Frequent monitoring of coagulopathy (coag screen/DDimer) required
  • Platelet transfusion: aim plt >30-50×109/L
  • FFP/cryoprecipitate/fibrinogen: aim INR <1.5, fibrinogen >1-1.5g/l
  • Invasive procedures should be avoided whilst coagulopathic

 

All trans retinoic acid (ATRA) – To be started as soon as APL suspected

  • ATRA causes the differentiation of the abnormal promyelocytes. In rare variants RARA is fused to other genes and ATRA is not successful.
  • To be started as soon as APL suspected (do not wait until genetic confirmation)
  • Prophylactic corticosteroids to be considered if WCC >5-10 x 109/L (or if WCC increases after ATRA started due to ATRA-induced differentiation). However no definitive evidence showing clinical benefit.
  • Monitor for Differentiation syndrome
    • Unexplained fever, weight gain, peripheral oedema, hypoxia, interstitial pulmonary infiltrates, hypotnsion, acute kidney injury
    • Management: dexamethasone 10mg IV twice daily. Temporarily withhold ATRA/ATO in severe cases.

 

Non-high-risk APL (WCC <10×109/L)

  • NB risk based on WCC not on other leukaemic characteristics e.g CD56 expression, FLT3 mutation
  • ATRA and ATO for induction (daily until CR or for a maximum of 60 days)
  • ATRA + ATO vs ATRA + chemo: associated with greater efficacy, less myelosuppression, fewer infections but increased rates of deranged LFTs and QTc prolongation.
  • If WCC rises >10 x 109/L after ATRA/ATO started this should be considered as ATRA/ATO-induced differentiation. The case should not be reclassified as high-risk disease. The median peak occurs at ~10 days after starting treatment
  • Consolidation: 4 courses of ATO (4 wks on, 4 off) and 7 courses ATAR (2wk on, 2 off)
  • No maintenance required

 

Specific treatment considerations with ATO:

  • If significant WCC rise (10 x 109/L) cytoreductive therapy can be considered (hydroxycarbamide, or in severe hyperleukocytosis idarubicin or mylotarg)
  • Maintain serum K>4, Mg >1.8
  • Perform ECG minimum x2/week. Calculate QTc using Bazett formula
  • Avoid medications that prolong QTc interval if possible
  • If QTc >500ms or develop syncope, tachycardia or arrhythmia
  • Admit patient
  • Optimise electrolytes
  • Temporarily withhold ATO
  • Stop other medications that prolong QTc interval if possible
  • When QTc <460ms and electrolytes replete restart ATO at 50% with intention of increasing to 100% if stable.
  • Time to achieve complete remission (CR) is often longer than with ATRA+ATO vs ATRA+chemo. Treatment should be continued until CR is achieved – this can be up to 8-10 weeks.

 

High-risk APL (WCC >10X109/L)

  • ATRA + chemotherapy (idarubicin or daunorubicin alone or in combination with cytarabine)
  • (In Europe ATO is not approved for high risk APL but otherwise could consider ATRA/ATO + chemo regimens)
  • Cytoreductive chemotherapy should be started promptly even if molecular confirmation is still awaited.
  • Avoid leukapheresis due to the risk of haemorrhage

 

MRD monitoring

  • Use RT PCR with sensitivity 104
  • Based on bone marrow sample.
  • To be performed at completion of consolidation
  • In non-high risk patients who achieve CR MRD negativity prolonged MRD monitoring is not required due to very low risk of relapse
  • In high risk patients perform BM MRD every 3 months for 3 years post completion of treatment
  • If PCR+ post completion of consolidation repeat within 2 weeks.

 

Relapsed disease

  • Molecular relapse (2 successive PCR+ assays analysed in 2 laboratories) is highly predictive of frank haematological relapse and should be treated promptly
  • Salvage therapy is based upon on patients 1st line therapy (if CR1 lasted <2years):
    • Relapse post ATRA/ATO treat with ATRA+chemo
    • Relapse post ATRA+chemo treat with ATRA/ATO
    • Aim to consolidate with autologous HSCT providing MRD negativity achieved
  • If CR1 >2 years can consider repeating original regimen
  • If CNS relapse weekly triple intrathecals should be performed alongside systemic therapy until by complete clearance of blasts in CSF. A further 6-10 intrathecals should be performed.

 

References

  1. Sanz MA et al. Management of acute promyelocytic leukaemia: updated recommendations form an expert panel of the European LeukaemiaNet. Blood. 133(15): 1630-1643. 2019.
  2. Bain BJ et al. Bone Marrow Pathology. Fourth Edition. Wiley-Blackwell. 180-183. 2014.
  3. Sanz MA and Montesinos P. How we prevent and treat differentiation syndrome in patients with acute promyelocytic leukaemia. Blood. 123:2777-2782. 2014.

 

 

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Case 114 – Update 5!

Thanks to everyone’s advice our patient didn’t develop differentiation syndrome following administration of dexamethasone prophylaxis. She also received hydroxyurea in addition to ongoing ATRA / arsenic to reduce the WCC. Her DIC is also improving. She has had issues with nausea/vomiting which is predominantly controlled on antiemetics and a infection for which she is on oral antibiotics.

However she is currently week 4 of induction and informs the staff that for the last few days she has been experiencing intermittent marked dizziness. She is currently asymptomatic and her observations are stable. There is no evidence of sepsis.

Questions:

  1. How would you want to investigate the dizziness? What is your likely differential?

 

Please reply to us (@TeamHaem) on Twitter and always include #TeamHaem to allow others to follow your comments. Please join in the debate and learn about haematological problems along the way. The case will continue to  evolve over the coming week so keep checking #TeamHaem on Twitter for more information.

Please note – all cases on TeamHaem are entirely fictional to protect patient confidentiality.

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Case 114 – Update 4!

Thank you for the ongoing contributions to our case. Following everyones input our 43 year old female patient has been commenced on intravenous arsenic alongside ATRA. This decision was made as her APL is considered non-high risk as initial WCC <10. However on day 8 her WCC has increased to 18.

She continues to have ongoing blood product support to achieve:

  • Plts >30-50
  • Clauss Fib >1-1.5
  • INR <1.5

Questions:

  1. What is the likely cause of the WCC rise?
  2. Do we need to alter treatment and if so how?
  3. How long would you aim to maintain the above plt / coag thresholds provided the patient doesn’t have any significant bleeding?

Please reply to us (@TeamHaem) on Twitter and always include #TeamHaem to allow others to follow your comments. Please join in the debate and learn about haematological problems along the way. The case will continue to  evolve over the coming week so keep checking #TeamHaem on Twitter for more information.

Please note – all cases on TeamHaem are entirely fictional to protect patient confidentiality.

TeamHaem are not a position of authority.  It is an educational platform to allow discussion and learning.

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Case 114 – Update3!

Thanks for everyones contributions to our case so far! We now have confirmation of our suspected diagnosis of Acute Promyelocytic Leukaemia by FISH. We have already began discussing initial management. Following the suggestions to date we have instituted the following:

  • ATRA treatment. With monitoring for differentiation syndrome. We have not started prophylactic dexamethasone as WCC 3.6 when ATRA started.
  • Intensive blood product support

There is some debate from responses of what definitive treatment to commence between arsenic, chemotherapy or combination of arsenic and chemotherapy.

Questions:

  1. How do we risk stratify patients with APL? How does this influence our treatment decision?
  2. What other factors/investigations would you consider/perform prior to commencing your chosen treatment?

 

Please reply to us (@TeamHaem) on Twitter and always include #TeamHaem to allow others to follow your comments. Please join in the debate and learn about haematological problems along the way. The case will continue to  evolve over the coming week so keep checking #TeamHaem on Twitter for more information.

Please note – all cases on TeamHaem are entirely fictional to protect patient confidentiality.

TeamHaem are not a position of authority.  It is an educational platform to allow discussion and learning.

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Case 114 – Update 2!

As highlighted by our followers the patients degree of bruising is out of proportion to a platelet count of 51. As requested a thrombin time and ddimer have been performed and are both prolonged.

Thrombin time: 19 Ddimer 6320 (reminder: PT 27, APPT 45, Clauss Fib 0.9)

We’ve also been informed that the patient is also developing new mucosal blood blisters. A repeat FBC is more deranged Hb 95, plts 34, WCC 3.6, Neuts 0.6. Film still not diagnostic. Viral screen as requested already in progress.

Questions:

  1. What is the explanation for the clotting results?
  2. How would you want to further investigate this progressive pancytopenia and above deranged clotting?

 

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Case 114 – Update 1!

Thank you for all your contributions. Following your requested information and initial investigations you now know:

Our 43 year old patient has previously been fit and well with no prior significant medical history. Over the past 2 weeks she has developed marked bruising – the largest of which is approximately 10cm on her thigh. She has no history of trauma and no personal or family bleeding history. She is feeling tired but has no other associated symptoms. She has no relevant travel history. She is not on any regular medications and does not drink in excess. She has Apart from the bruises her examination is unremarkable.

FBC: Hb 106, Plts 51, WCC 3.7, Neuts 1.2.

Blood film: confirms the above FBC differential but is otherwise unremarkable.

Coag: PT 27, APPT 45, Clauss Fibrinogen 0.9.

LFTs, UEs, Haematinics all normal.

Questions:

  1. What further investigations would you want to perform in this outpatient?

 

Please reply to us (@TeamHaem) on Twitter and always include #TeamHaem to allow others to follow your comments. Please join in the debate and learn about haematological problems along the way. The case will continue to  evolve over the coming week so keep checking #TeamHaem on Twitter for more information.

Please note – all cases on TeamHaem are entirely fictional to protect patient confidentiality.

TeamHaem are not a position of authority.  It is an educational platform to allow discussion and learning.

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Case 114 – The Beginning

You are the haematology registrar on-call and a GP contacts you for advice regarding investigation and management of a platelet count of 51. The GP performed a FBC on a 43 year old woman who had presented to him with marked bruising.

FBC differential: Hb 106, Plts 51, WCC 3.7, Neuts 1.2

Questions:

  1. What further information from the history would you want?
  2. What initial investigations would be relevant?

 

Please reply to us (@TeamHaem) on Twitter and always include #TeamHaem to allow others to follow your comments. Please join in the debate and learn about haematological problems along the way. The case will continue to  evolve over the coming week so keep checking #TeamHaem on Twitter for more information.

Please note – all cases on TeamHaem are entirely fictional to protect patient confidentiality.

TeamHaem are not a position of authority.  It is an educational platform to allow discussion and learning.

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