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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