Focusing on AML and APML.

1. Acute Leukaemia
- AML and APL -
Farah Adibah Kasmin
Master in Internal Medicine
Hematology CME UMMC
19.1.2024

2. Acute Leukaemia
• A group of disorders characterized by the accumulation of malignant
white cells in the bone marrow and blood.
• It is the result of a series of mutational events occurring in an early
hematopoietic precursor that prevents the progeny of that precursor
from maturing normally but allows them to proliferate in an
uncontrolled fashion.
• These abnormal cells cause symptoms because of:
- Bone marrow failure (e.g. anaemia, neutropenia, thrombocytopenia);
- Infiltration of organs (e.g. liver, spleen, lymph nodes, meninges, brain,
skin or testes).

3. Acute Myeloid Leukaemia -AML

4. Introduction
• Acute myeloid leukaemia (AML) refers to a group of hematopoietic
neoplasms involving cells committed to the myeloid lineage.
• Most common acute leukaemia in adults.
• Incidence rate 3 per 100 000 annually.
• The median age at diagnosis is 68 years.

5. Aetiology
- Pre existing myelodysplasia
- Prior cytotoxic chemotherapy
- Ionizing radiation
- Benzene exposure
- Constitutional chromosomal abnormalities: Down or Fanconi
syndrome

6. Clinical presentation
• Acute presentation usual; often critically ill due to effects of BM failure.
• Symptoms of anaemia: weakness, lethargy, breathlessness, lightheadedness, and
palpitations.
• Infection: particularly chest, mouth, perianal, skin (Staphylococcus, Pseudomonas, HSV,
Candida).
• Fever, malaise, sweats.
• Haemorrhage (especially APL due to DIC): purpura, menorrhagia and epistaxis, bleeding
gums, rectal, retina.
• Gum hypertrophy and skin infiltration (monocytic leukaemias (M4, M5)).
• Signs of leucostasis, e.g. hypoxia, retinal haemorrhage, confusion, or diffuse pulmonary
shadowing.
• Hepatomegaly occurs in 20%, splenomegaly in 24%; the latter should raise the question of
transformed CML; lymphadenopathy is infrequent (17%).

7. Diagnosis of AML
• FBC—usually shows leucocytosis, anaemia, and thrombocytopenia.
Can show pancytopenia.
• Blood film—usually contains blasts.
• BM aspirate—≥20% blasts
• Trephine biopsy—to exclude fibrosis and multilineage dysplasia.
• Immunophenotyping to differentiate AML from ALL: CD3,
CD7, CD13, CD14, CD33, CD34, CD64, CD117, cytoplasmic myeloperoxidase
(MPO).
• Cytochemistry—MPO or Sudan Black (SB), combined esterase.
• Cytogenetic analysis—to identify prognostic group.
• Molecular analysis—RT-PCR and FISH in selected cases.

8. Immunophenotyping
It is done by multiparameter flow cytometry (MFC) and required
to diagnose AML accurately by identifying cell surface and
intracellular markers.

9. Cytogenetic analysis
• Conventional cytogenetic analysis is mandatory in the
evaluation of AML.
• It detects translocations and deletions that define disease and risk
categories or that are needed for targeted treatment modalities.
• If conventional cytogenetics fails, fluorescence in situ
hybridization (FISH) is an alternative to detect specific
abnormalities.

11. Molecular analysis
• It is any testing that reveals the changes in the nucleotide in a DNA
and RNA sequence.
• It can be karyotyping, fluorescence in situ hybridization (FISH),
polymerase chain reaction (PCR)–associated testing, traditional
sequencing, and next-generation sequencing (NGS).
• APL is an AML with t(15;17) translocation that leads to a chimeric
gene (PML–RARA) on the long arm of derivative chromosome 15.
• AML with t(8;21) translocation leads to a transcriptionally active
chimeric gene on the 8q-derivative chromosome (RUNX1–RUNX1T1).

12. Morphological classification
• The French-American-
British (FAB)
classification, based on
predominant
differentiation pathway
remains useful for
preliminary classification
of a newly diagnosed
patient before the
cytogenetics result is
known.

13. WHO classification
• Recommendation for the definitive
diagnosis and classification of AML:
1. The blast threshold for the
diagnosis of AML is reduced from
30% to 20% BM blast compared to
older classification systems.
2. Patients with clonal recurring
abnormalities t(8;21)(q22;q22),
inv(16)(q13q22), t(16;16)(p13;q22),
or t(15;17)(q22;q12) should be
considered to have AML regardless of
the blast percentage.

14. Hierarchical classification of the International
Consensus Classification of AML

15. Additional adverse prognostic factors for
AML
• Age at diagnosis. Remission rates in adult AML are inversely related to
age, with an expected remission rate of more than 65% for those
younger than 60 years.
• CNS involvement with leukemia.
• Systemic infection at diagnosis.
• Elevated white blood cell count (>100,000/mm3) at diagnosis.
• Therapy-related myeloid neoplasms, resulting from alkylating agents
and radiation therapy.
• History of myelodysplastic syndrome or another antecedent
hematologic disorder.

16. Treatment
• The general approach to cure in AML is to achieve CR to reduce the
leukemia burden by several orders of magnitude and then administer
post remission therapy, which could be chemotherapy and/or alloSCT.

17. • The choice of the most appropriate induction and post-remission
therapy is based on multiple parameters:
1. Comorbidities
2. Past medical history including prior myeloid disease and/or cytotoxic
chemotherapy exposure
3. AML cytogenetic and molecular risk profile
4. Post-therapy MRD status
5. Donor availability
6. Patients' goals of care

18. Supportive treatment
• Explain diagnosis and offer counselling—the word ‘leukaemia’ and
prospect of prolonged chemotherapy are distressing.
• RBC and platelet transfusion support will continue through treatment.
• Start neutropenic infection prophylaxis regimen. Prompt antibiotic
• treatment might be required if febrile/septic.
• Start hydration aiming for urine output >100mL/h throughout induction
therapy.
• Start allopurinol or consider rasburicase to prevent
hyperuricaemia/tumour lysis syndrome.
• Insert tunnelled central venous catheter

19. Chemotherapy
• AML treatment consists of two phases which are remission and
consolidation.
1. Remission induction to achieve CR:
Most commonly as “7 + 3” regimen using daunorubicin at a dose of 60–
90 mg/m2 for 3 days and cytarabine at a dose of 100200 mg/m2 for
7 days
Then assess BM response after 3–4 weeks.
2. Consolidation therapy: Essential to reduce risk of relapse; optimum
number unknown Standard 2 cycles, example: HD cytarabine.

20. Response criteria

21. Stem cell transplantation (SCT)
• Allogeneic SCT7 from a HLA-compatible donor should be offered to
younger/fitter patients with poor-risk AML in 1st CR.
• Allo-SCT is an option for those with intermediate (standard) risk AML.
• Autologous transplantation in AML has been abandoned.

22. Treatment Failure of AML

23. Induction:
• HIDAC
• Young : Ara-C 3g/m2 over 1 hour every 12 hours for 6 days
• Other patients : Ara-C 1.5g/m2 over 1 hour every 12 hours for 5 days
If no response → Mitoxantrone 12mg/m2 and T AraC 100mg/m2 X 5
→ FLAG
Consolidation:
• Allogeneic or Autologous Transplant or HIDAC (2 cycles)
• If not for transplant → maintenance chemotherapy : VP-16
100mg/m2 D 1-3 and Ara-C 1gm/d D 1 monthly

24. Acute promyelocytic leukaemia (APL/APML)

25. • A medical emergency
• High rate of mortality due to bleeding. Untreated, will lead to
pulmonary/ cerebrovascular hemorrhage in 40% of patients, up to
20% of early hemorrhagic death.
• Unique presentation of bleeding due to DIVC.

26. Pathology
• Caused by reciprocal translocation; t (15,17)
involving the promyelocytic leukeamia (PML)
gene on chromosome 15 and the retinoic
acid receptor alpha (RARα) gene on
chromosome 17.
• This translocation begets the formation of
the PML-RARα fusion gene which acts as a
transcriptional repressor inhibiting normal
myeloid differentiation.

27. APL-DIVC

28. Diagnosis
Suspected if patient has coagulopathy, and PBF/
marrow shows characteristic morphology of the
leukemic cells or immunophenotyping.
Confirmed with identification of PML-RARA
gene either with FISH, RT-PCR or conventional
karyotyping

29. Hypogranular APML - Morphology

30. Risk Stratification
• APML can be risk stratified into:
1.High risk (WBC >10,000/μl)
2.Low risk (WBC <10,000/μl)
• Patients with leukocytosis on presentation are known to experience a higher rate of early
death and life-threatening complications before or during induction.

31. Management
• Start ATRA 45mg/m2 /day (All transretinoic acid) IMMEDIATELY
when a diagnosis of APML is suspected.
• Treatment consists of:
a. Induction: ATRA + Anthracycline (Idarubicin)
b. Consolidation
c. Maintenance chemotherapy

33. Supportive Therapy
• Supportive therapy plays a very important role in the survival
of patients
• Platelets should be maintained above >30-50k ×103/l and
fibrinogen above 100-150 mg/dl with aggressive blood
product support.
• Avoid invasive procedures if possible.
• High suspicion should be maintained for systemic infections as
the patients are routinely immunosuppressed.
• In neutropenic patients with fever, an empiric antibiotic
regimen to treat gram-negative bacteria should be instituted.

34. Differentiation Syndrome
A complication of all-trans retinoic acid (ATRA) therapy in patients with acute promyelocytic
leukeamia (APML).

35. Differentiation Syndrome

36. • Thank you.