Acute Promyelocytic Leukaemia (APML) (Blood 2009)

CD45+, MPO+, CD117+, CD33+, Aberrant CD9+

CD34-, HLADR-

Intro

 

10-15% of AML cases

Usually young, with leukopenia and life-threatening coagulopathy

A balanced translocation between PML (Promyelocyte) & RARA (Retinoic Acid Receptor-a) generates a fusion protein —> leukaemic promyelocytes have the unique ability to differentiate when exposed to retinoic acid.

 

Diagnostic Investigations

 

Morphology

  • Kidney-shaped/bi-lobed nucleus, cytoplasm densely packed with granules/auer rods

  • Hypogranular variant exists, differential diagnosis of acute monocytic leukaemia

Immunophenotype

  • CD45+, MPO+, CD117+, CD33+, CD13+, CD64+/-, Aberrant CD9+

  • CD34-, HLADR-, CD11b-, CD11c-

Cytogenetics

  • t(15;17)

  • PCR as gold standard – able to detect PML-RARA in leukopenic patients. Takes 48 hours.

  • FISH – can give an answer in 6 hours

  • Karyotyping – expensive and time consuming

 

Risk Classification

 

WBC <10 – Low to intermediate risk disease

WBC >10 – High risk disease

 

Supportive Treatment

 

Coagulopathic bleeding responsible for 50-60% of early deaths (CNS, lung and GI)

Risk of bleeding may persist up to 20 days

  • Twice or thrice daily FBC, PT, APTT and FGN

  • Keep platelets >30-50

  • Keep PT/APTT normal

  • Keep FGN >1.5g/l

 

Definitive Treatment

 

Treatment should start based on morphological assessment, do not wait for FISH

1st line options

  • ATRA + Idarubicin (AIDA)

  • ATRA + Arsenic (ATO) - NICE approved 1st line for low risk disease only (as of June 2018)

 

ATRA

  • Overrides the t(15;17) protein induced blockade of the retinoic acid receptor

  • 45mg/m2 daily in two divided doses to start on day 1

  • Continued until haematological CR and for a maximum of 60 days

 

Idarubicin

  • 12mg/m2 on days 2,4,6 and 8. Or start on day 1 if WBC >10

 

Arsenic

  • Arsenic degrades the fusion protein and induces apoptosis

  • ATRA + Arsenic is a highly effective (97% CR) non-chemo regimen

 

ATRA Toxicity

 

Pseudotumour Cerebri

  • Usually patients <20 y.o.

  • Severe headache, nausea, vomiting and visual disturbance

 

Hepatoxicity

  • Bili/ALT/AlkP >5x the ULN

 

ATRA/APL Differentiation Syndrome

  • 10 days after starting ATRA

  • Fluid retention, capillary leak – cough, hypoxia, effusion, oedema, weight gain, fever

  • Associated with rising WBC count. Risk lower when ATRA given with chemo.

  • Rx: Stop ATRA, give IV Dexamethasone, Cautious re-introduction when Sx resolve

 

Other adverse effects

  • Rash (Sweet’s Syn)

  • Pancreatitis, hypercalcaemia, bone marrow necrosis

 

Consolidation & F/up

 

>90% CR after induction + 2 cycles of consolidation.

No role for transplant in CR1

MRD monitoring 3-monthly for two years after completion of treatment

Relapse inevitable if PCR positive in two consecutive samples —> treat at molecular relapse.

 

At relapse

Induce 2nd CR with aim to harvest PCR negative cells for autograft

Consider Allograft in patients in whom PCR negativity cannot be achieved.