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A 21-year-old female presented with fever and bleeding manifestations

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Dr. Al Amin Sabuj

Phase-B resident

Department of Haematology,

BSMMU

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Objective

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Management of high risk Acute promyelocytic leukaemia (APL)

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Salient features

Jannatul Ferdous, 21 years old, female, was admitted with the complains of fever and per-vaginal bleeding for 1 month. She noticed multiple purpuric spot all over the skin which was first appeared on extremities followed by involvement of trunk, painless and non itchy . She also complained generalized weakness. There was no history of cough, joint pain or bleeding from other sites.

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Salient features

No significant-

  • Past history
  • Family history
  • Drug history

H/O 1 unit blood transfusion.

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Salient features

On examination:

the patient was conscious, cooprative , ill-looking

  • mildly anaemic
  • multiple purpura and petechiae all over the skin
  • Pulse-96 b/min
  • BP-110/70 mmHg
  • Temp-980F, respiratory rate- 18 breath/min.

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There was no

  • Oedema
  • Cyanosis
  • bony tenderness
  • Lymphadenopathy
  • Thyromegaly
  • organomegaly

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Complete blood count

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26.01.2022

30.01.2022

Hb

10.2 g/dL

8.3 g/dL

Platelet count

10×109/L

40×109/L

WBC count

30×109/L

103×109/L

N, L, M

10%, 15%

5%, 3%, 2%

Blast/ Atypical cells

75%

90%

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Peripheral blood film

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Features are suggestive of acute myeloid leukaemia

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Bone marrow study

No organized marrow particle is seen. However aspirated marrow blood shows plenty of cells which are morphologically myeloblast (about 60%). Other cell lines are unremarkable.

Comment: suggestive of acute myeloid leukaemia (FAB-AML-M2)

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Flow cytometry for acute leukaemia

CD13, CD33, CD117 and cyMPO were positive

Immunophenotypic findings are compatible with AML

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Coagulation profile

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30.01.2022

06.02.2022

PT

12.80 sec

13.60 sec

APTT

30.00 sec

30.00 sec

D-dimer

4.4 µg/ml

>4.50 µg/ml

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FDP

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15.90 mg/L

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Biochemical profile

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30.01.2022

12.02.2022

(after 7 days of induction)

24.02.2022

Bilirubin

0.3 mg/dL

0.3 mg/dL

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SGPT

33 U/L

975 U/L

87 U/L

SGOT

24 U/L

312 U/L

31 U/L

Creatinine

0.70 mg/dL

0.57 mg/dL

0.61 mg/dL

Uric acid

3.2 mg/dL

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LDH

729 U/L

470 U/L

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ɤ-GT

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168 U/L

54 U/L

ALP

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65 U/L

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Confirmatory diagnosis

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Acute promyelocytic leukaemia (High risk)

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Risk stratification of APL

Risk category

WBC count

Platelet count

Low risk

< 10×109/L

> 40×109/L

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Intermediate risk

< 10×109/L

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< 40×109/L

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High risk

> 10×109/L

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< 40×109/L

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Acute promyelocytic leukaemia (APL)

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Acute promyelocytic leukaemia

  • FAB: AML M3
  • WHO 2008: AML with recurrent genetic abnormalities

APL with t(15;17) (q22;q12); (PML-RARA)

  • 10-15% of all AML cases
  • 80-90% cure rate
  • Morbidity and mortality is high before and during induction
  • DIC is relatively common at diagnosis

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Clinical presentation

  • Fatigue
  • Haemorrhage
  • Petechiae or ecchymotic involvement of the skin
  • Visual changes due to retinal and subconjuctival haemorrhage
  • Overt haemorrhage from the gums, nose, mouth can occur

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Diagnostic approach: key steps

Peripheral blood smear:

  • WBC count often low
  • Thrombocytopenia often present

Morphological appearance of the bone marrow:

  • Hypercellular aspirate
  • Most common form: hypergranular promyelocytes
  • Auer rods present and abundant

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Diagnostic approach (cont.)

Karyotyping/molecular abnormalities:

  • FISH for PML-RARα
  • RT-PCR for PML-RARα
  • Karyotyping for t(15;17)

Morphologic variant can be confused with monocytic leukaemia;

Hypergranular form confused with AML with maturation.

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Management of APL

  • Treatment should be started immediately if APL suspected.
  • ATRA is the cornerstone of treatment irrespective of risk status.
  • Several established protocols offer excellent outcomes.
  • Important not to “mix and match” induction from one trial with consolidation from another.

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Management of APL (high risk)

General supportive care

Specific treatment

Treatment of complications

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Treatment of APL

Confirmed APL

High risk

No cardiac issues

Cardiac issues

(low EF or QT prolongation)

Low risk

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Treatment of newly diagnosed APL (high risk)

Consolidation therapy

BM aspirate and biopsy at day 28 to document remission, consider LP before proceeding with consolidation

Induction with ATRA-based regimen

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Induction (preferred regimens)

ATRA 45 mg/m2 (days 1-36, BD)+ Idarubicin 6-12 mg/m2 on days 2,4,6,8+ ATO 0.15 mg/kg (days 9-36 as 2 h IV infusion)

    • Or

ATRA 45 mg/m2 BD and ATO 0.15 mg/kg IV+ Gemtuzumab ozogamicin 9 mg/m2 may be given on D1, or D2, or D3, or D4

    • Or

ATRA 45 mg/m2 BD and ATO 0.3 mg/kg IV on days 1-5 of week 1 and 0.25 mg/m2 twice weekly on weeks 2-8 + Gemtuzumab ozogamicin 6 mg/m2 may be given on D1, or D2, or D3, or D4

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Induction (other recommended regimens)

ATRA 45 mg/m2 in 2 divided doses daily+

daunorubicin 50 mg/m2 × 4 days (IV days 3-6) +

cytarabine 200 mg/m2× 7 days (IV days 3-9)

    • Or

ATRA 45 mg/m2 in 2 divided doses daily+

daunorubicin 60 mg/m2 × 3 days +

cytarabine 200 mg/m2× 7 days

    • Or

ATRA 45 mg/m2 in 2 divided doses daily+

Idarubicin 12 mg/m2 on days 2,4,6,8

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Maintenance therapy in APL

  • ATRA 45mg/m2 daily 15 days every 3 months
  • 6-MP 60mg/m2 daily
  • MTX 20 mg/m2 weekly
  • Route- oral
  • Duration- 2 years
  • Monitoring- RT-PCR 3 monthly for first 2 years

then 3-6 monthly for next 3 years.

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Management of clinical coagulopathy

  • Platelet transfusion to maintain platelet ≥ 50×109/L
  • Cryoprecipitate or FFP to maintain fibrinogen level > 150 mg/dL and PT and APTT close to normal.

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  • Dialy monitoring until coagulopaty resolves.
  • Invasive procedure such as central venous catheterization, lumber puncture, and bronchoscopy should be avoided.

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Differentiation syndrome (DS)

Clinical features-

  • Unexplained fever
  • Hypotension
  • Weight gain
  • Respiratory distress with interstitial pulmonary infiltrates
  • Pleural or pericardial effusions
  • Acute kidney injury

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Prophylaxis of APL DS:

  • Prednisolone 0.5 mg/kg/day on day 1 until end of induction therapy
  • Dexamethasone 2.5 mg/m2 every 12 hr on day 1-15
  • Taper the steroid over a period of several days.

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Treatment of APL DS:

  • Dexamethasone 10 mg every 12 hour
  • If no improvement within 24 hr, increase frequency to every 6 hr
  • Stop/taper once complete relief of signs/symptoms

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Arsenic trioxide (ATO) monitoring

  • Prior to initiation therapy-
  • ECG for prolonged QTc interval assessment
  • Serum electrolytes (Ca, K, Mg) and creatinine

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Arsenic trioxide (ATO) monitoring

  • During therapy-
  • Minimize use of drugs that may prolong QT interval
  • Maintain K and Mg concentration within normal range.
  • correct electrolytes in patient with QTc interval > 500 ms, and proceed with caution.

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Prognosis

  • Very good prognosis
  • Long-term survival rates up to 90% following treatment
  • Incidence of early death remains high
  • The most common causes of early death in APL are
  • Haemorrhage
  • Differentiation syndrome
  • Infection

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Prognosis

Risk factors for early death:

  • Higher WBC counts
  • Increased serum creatinine level
  • Older age
  • Male sex
  • Elevated fibrinogen level

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Take home message

  1. APL should be managed as a medical emergency
  2. Mortality is high in early disease due to coagulopathy
  3. Excellent long-term outcome with treatment

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Thank you