mgt of acute leukemias

1. ACUTE LEUKAEMIAS
BY
DR ABUBAKAR SAIDU
FMCP
A paper presented at the
Faculty of Internal Medicine,
National postgraduate Medical College
of Nigeria
General Medicine Update course
28TH JANUARY, 2023.

2. INTRODUCTION
• Acute leukaemias are heterogenous disorders that result from
malignant transformation of haematopoietic stem cells with loss or
abnormal differentiation resulting in accumulation of immature cells
in the marrow. These differences also reflect in response to therapy.
• The malignant cells may also infiltrate other tissues and organs.
• The disease is rapidly fatal without intervention and recent advances
have improved survival.
• They can be myeloid, lymphoid or rarely biphenotypic but share
many characteristics and the general discussion can be taken
together.

3. EPIDEMIOLOGY
• Acute leukaemia incidence generally increase with age except for the
acute promyelocytic variety whose incidence is not age related. AML
has an annual incidence of 2-3% in children rising to 15% in adults.
Though ALL is commoner in children, incidence increases from 40
years. In Africa, the typical under 5 ALL of the Western world is rare.
• There is a slight female preponderance in the myeloid variety while
the reverse is true for the lymphoid.
• Whites are generally more affected than blacks and Jews are more
commonly affected than non Jews.
• Regional variation in incidence is both by genetic and environmental
factors.

4. ETIOLOGY/RISK FACTORS
• Genetic factors- Down’s, Klinefelter’s, Fanconi anaemia
• Radiation- Hiroshima/Nagasaki, prior radiotherapy
• Chemicals-Benzene, Chemotherapeutic agents
• Viruses- HTLV 1, EBV
• Pre existing myelodysplastic syndrome or myeloproliferative
neoplasm

5. CLINICAL FEATURES
• Constitutional
• Cytopaenias
• Tissue/organ infiltration
• Bone/joint pains
• DIC

6. INVESTIGATIONS
• Full blood count/peripheral film
• Coagulation profile
• Bone marrow aspiration/biopsy
• Full biochemistry
• Stool microscopy
• Viral screening
• Chest radiogram

7. CLASSIFICATION
• Traditional FAB based on morphology is still in use. Myeloid from M0 to M7
and lymphoid from L1 to L3
• WHO classification based on immunophenotypes, cytogenetic studies,
clinical features in addition to morphology and cytochemistry of FAB.
• WHO AML classification-
1. Well characterised cytogenic or molecular abnormalities
2. Multilineage dysplasia
3. Therapy related
4. Others eg acute basophilic, acute panmyelosis/fibrosis, acute
biphenotypic etc

8. CLASSIFICATION Contd.
• WHO ALL classification-
1. B lineage ALL
Progenitor B
Common B-precursor
Pre-B
Burkitt type
2. T lineage ALL

9. CYTOCHEMISTRY AND IMMUNOPHENOTYPES
• AML- Positive cytochemical stains
Myeloperoxidase
Sudan black B
Non specific esterase
• Immunophenotypes
Specific myeloid CD13,CD33,CD117
Monocytic CD14,CD64
Erythroblast Glycophorin A
Megakaryoblast CD41
• ALL- Positive cytochemical stains
Periodic Acid Schiff
Terminal deoxynucleotidyl
transferase
• Immunophenotypes
B-cell CD10,CD19,CD20,CD22,HLA
DR
T-cell CD2, CD3, CD7

10. CYTOGENETIC RISK GROUPS IN AML
• Favourable- inv(16), t(15,17) (q22;q21)/PML RARα with any
abnormality, t(8,21)(q22;q22)/RUNX1-RUNX1T1, lack of del(9q),
complex karyotype
• Intermediate- Normal, +8, +21 or other numerical abnormalities
• Unfavourable- -5/del(5q), -7/del(7q), inv(3q)
abnormality of11q, 20q, 21q, 17p
del(9q), t(6,9), t(9,22), FLT3-ITD
complex karyotypes with ≥3 abnormalities

11. CYTOGENETIC RISK GROUP IN ALL
• Good risk- t(12,21), ETV6/RUNX1
Hyperdiploidy
• Poor risk-
t(9,22) (BCR-ABL1)
t(4,11) (MLL/AF4)
Complex karyotype (5 or more chromosomal abnormalities)
Low hypodiploidy/near triploidy

12. OTHER RISK FACTORS
• Age
• Response to induction chemotherapy
• Performance score
• White cell count
• Resistance proteins
• CNS involvement
• Immunophenotype

13. TREATMENT
• Supportive
• Chemotherapy
Remission induction
Remission consolidation(Intensification)
Maintenance
• Stem cell transplant

14. AML CHEMOTHERAPY
• Induction- Daunorubicin, Ara C ( 3+7)
• Consolidation- Daunorubicin, Ara C (2+7) or High dose Ara C

15. ALL CHEMOTHERAPY
• Pre-phase- Oral steroids
• Induction- Steroids, Asparaginase, Anthracycline, Cytarabine,
Cyclophosphamide and IT Methotrexate
• Intensification- High dose IV Methotrexate
• Consolidation- Four or more courses of induction drugs
• Maintenance- Two years of 6 Mercaptopurine, Oral Methotrexate,
Pulses of Vincristine, Oral Steroids and 3 monthly IT Methotrexate

16. SPECIAL CASES
• CNS Prophylaxis mainly for ALL
• Short course intensive chemotherapy for Burkitt’s type
• Tyrosine kinase inhibitors for Philadelphia chromosome positive ALL
• Anti CD19 and CD22 monoclonal antibodies in ALL
• Early SCT for Progenitor B ALL with t(4,11)
• Demethylation agents eg azacitidine in the elderly
• Gemtuzumab ozogamicin in relapse or the elderly
• All-trans retinoic acid for acute promyelocytic leukaemia
Presence of t(15,17)(q22;q21) and PML RARα makes it sensitive
to differentiation by ATRA and sensitivity to apoptosis by Arsenic
trioxide(As2O3)

17. CONCLUSION
• Acute leukaemias are diseases that need rapid assessment and quick
institution of treatment
• Despite adverse outcomes, improvement in diagnosis and treatment
modalities has given hope to patients
• Availability of adequate supportive measures is a sine qua non to
improved outcomes
• Advocacy still plays a vital role in resource poor environments

18. REFERENCES
• Hoffbrand AV, Higgs DR, Keeling DM, Mehta AB, editors. Postgraduate
Haematology. 7th edition. WILEY Blackwell. 2016. p 352-398.
• Durosinmi MA. Acute leukaemias in: Durosinmi MA, editor. A design
handbook of haemato-oncology chemotherapy for medical students and
doctors. 3rd edition. Amkra books. 2013. p 7-14.
• Furie B, Cassileth PA, Atkins MB, Mayer RJ, editors. Clinical Haematology
and Oncology. 1st edition. Churchill Livingstone. 2003.p521-565.
• Ghorab, A., Al Kali, A., Elliot, M. et al Clinical outcome of myelodysplastic
syndrome progressing on hypomethylating agents with evolving frontline
therapies: continued challenges and unmet needs. Blood Cancer J. 12,
93(2022)
• https://www.cancer.gov