Acute Leukaemias

Dr RA Bolarinwa
MBChB; MSc; FMCPath
 Objectives of the Lecture
• Students should be able to define and classify
acute leukaemias (AL)
• Characterize different types of AL
• Enumerate the diagnostic methods and useful
drugs in the management of AL
• Identify complications associated with AL and
its management
 Lecture Outline

• Introduction/Definition
• Epidemiology and Classifications (FAB, WHO) of Acute Leukaemias
-ALL
-AML
• Aetiologic factors of Acute Leukaemias
-ALL
-AML
• Diagnosis
• Investigations
• Treatment Modalities
• Prognostic Factors
• Conclusion
CASE SUMMARY
AA, 16-year-old Nigerian who presented with 13/12 hx of paraplegia with
associated faecal and urinary incontinence. Previously managed at a
centre before presentation. CNS examination of the lower limbs revealed
symmetrical muscle wasting of the thighs and lower legs, flaccid
paraplegia with complete sensory loss up to T7, bilateral absent plantar
response. Full blood count and differentials showed Haemoglobin
Concentration=12.6g/dl, Leucocyte count = 9.5x103/ul, Platelet count =
225 x 103/ul, Myeloblast = 47%, Lymphocyte = 18%, Eosinophil = 4%
Neutrophil = 31%. Peripheral blood film and Bone Marrow Aspiration
were in keeping with AML (M2), with Myeloblast of 47% and 40%
respectively. These cells were 46% and 32% positive for CD13 and CD33
respectively, Cerebrospinal fluid cytoanalysis showed no malignant
pleocytosis. Total spine MRI done in our facility showed T1 Hypointense
and T2 Hyperintense foci within the spinal cord. She subsequently had 2
cycles of the standard induction therapy (DA) and triple CNS therapy with
no significant improvement. She eventually had high dose Cytarabine
with minimal clinical changes. Patient eventually DAMA, and was reported
to have passed on at home.
 Definition of Acute Leukaemias
• Clonal malignant discorder resulting from genetic
altérations of HSC and characterized by the
proliferation of abnormal leukaemic blast cells and
impaired production of normal blood cells.
3 groups of acute leukaemias:
- acute myeloid leukaemia –AML (M0 –M7).
- acute lymphoblastic leukemia -ALL (L1-L3).
- Biphenotypic leukaemias or Acute undifferentiated
leukaemia
Lymphoblast/Myeloblast
 Classification based on...
- Morphology :appearance of cells under the
microscope.
-Cytochemistry: chemical activity of the cell (ALL
positive for PAS and acid peroxidase and
negative for Sudan Black B)
-immunophenotyping: detection of antigen
present on the cell membrane
- Cytogenetics: chromosomal analysis of the cells
- Molecular biology and immunologic
characterization of the cells
Cytogenetics in Acute Leukaemia

8q deletion, additional long arm of Xm 21, Ph chromosome (T:9;22)

 Acute Leukemia (AL) - Notes

• Short course of symptoms

• Fatigue, fever, easy bruising, bleeding

• Cytopenias - or pancytopenia

• More than 20% blasts in BF and/or bone

marrow

• Blasts in peripheral blood in 90% cases

 Aetiologic Factors for AL
• There is a wide diversity in the behaviour of the various subsets of acute
leukaemias.
• Aetiologic factor different for the disorders.
• There are, however, some accepted risk factors for leukaemogenesis:
-Chemical exposure
Prolonged exposure to benzene & petroleum products.
The interval between exposure and onset of leukaemia is
long (10-30 years). Chromosomal damage is common.
-Pesticide exposure.
-Exposure to hair dyes, smoking & non-ionic radiation may also increase
the risk of leukaemia.
- Previous genetic syndrome abnormality eg Down’s syndrome, Fanconi
anaemia
-Acute T-cell ALL may result from HTLV-1 infection
 Epidemiology of ALL
• Gender
-The incidence of ALL is slightly higher in males than females
• Age
-60% of cases are seen in children, with a peak incidence in
the first 5 years of life and
-A subsequent drop in incidence until age 60
-At 60 years, a second peak emerges
• Race and ethnicity
-The incidence of acute leukaemia is slightly higher in
Europeans. Less common among Arabs and Africans
 Aetio-pathogenesis: ALL
Prior chemotherapy or irradiation
• Use of alkylating agents, such as cyclophosphamide (Cytoxan,Neosar) and
melphalan (Alkeran). Cytogenetic abnormalities, particularly monosomy 5, 7,
11, and 17, are common.
Concurrent radiation exposure slightly increases the risk of leukemogenesis
posed by alkylating agents.
• Topoisomerase II inhibitors (etoposide, teniposide [Vumon], doxorubicin and its
derivatives, and mitoxantrone [Novantrone]), have also been linked with
leukemogenesis. Cytogenetic abnormalities involving chromosome 11q23 or
21q22 are common.
Genetic disorders
• In identical twins younger than age 10, if one child develops leukaemia (usually
ALL), there is a 20% chance that the other twin will develop leukaemia within a
year; subsequently, the risk falls off rapidly and joins that of nonidentical
siblings, which is 3-5 times that of the general population.
 Classification of ALL
• May be pre-B or pre-T in origin
-Lymphoblasts: Blood or bone marrow ≥25%
-cf lymphoblastic lymphoma, with </>25% marrow blasts +
nodal tumour
-The classical FAB subtypes (L1-L3) are no longer recognized by
the new WHO classification
-ALL-L3 is now classified as Burkitt’s lymphoma/leukaemia
(BL) because it expresses surface Ig, does not express TdT &
has the same chromosomal abnormalities as BL.

• Classification is now based on morphologic, immunologic and

cytogenetic characteristics---WHO classification
 Classification of ALL
Immunologic Subtype FAB Type % of Cases Cytogenetic Abnl

Pre-B cell ALL L1, L2 75 t(9:22) t(4:11) t(1:19)

T-cell ALL L1, L2 20 14q11 or 7q34

B-cell ALL L3 5 t(8:14) t(8:22) t(2:8)

L1 - 85% of childhood ALL

L2 - Majority of adult ALL
L3 - Includes Burkitt’s. < 5% of ALL
 Aetio-pathogenesis-AML
• Primary AML
– Increased incidence
• Genetic fragility
– Bloom syndrome
– Faconi anemia
– Wiskott Aldrich
– Down, Klinefelter, Patau syndromes
• tobacco use?
• herbicides?, pesticides?
• benzene exposure

• Secondary AML
– X-Radiation
– Topoisomerase II inhibitors (e.g etopisode), alkylating agents
– MDS
– other cell proliferation disorders
• CML, polycythemia vera, primary thrombocytosis, PNH
 AML - Epidemiology
• 2.3 per 100,000 people per year

• Higher among men than women (2.9 vs 1.9). The

difference is even more apparent in older patients.

• Most common leukemia in adults (80% of cases)

• Vast majority of patients 65 years or older

• AML is more common in whites than in other

populations.
 FAB Classification of AML
• M0 undifferentiated acute myeloblastic leukemia (5%)
• M1 AML with minimal maturation (20%)
• M2 AML with maturation (30%)
– t(8;21)
• M3 Acute promyelocytic leukemia (5%)
– t(15;17)
• M4 Acute myelomonocytic leukemia (20%)
• M4 eos Acute myelomonocytic leukemia with eosinophilia (5%)
– inv (16)
• M5 Acute monocytic leukemia (10%)
– t(9;11)
• M6 Acute erythroid leukemia (3%)
• M7 Acute megakaryoblastic leukemia (3%)
 WHO Classification
• AML with certain genetic abnormalities
– t(8;21), t(16), inv(16), chromosome 11 changes
– t(15;17) as usually seen with AML M3 
• AML with multilineage dysplasia (more than one abnormal myeloid cell type is
involved)
• AML related to previous chemotherapy or radiation
• AML not otherwise specified
– undifferentiated AML (M0) 
– AML with minimal maturation (M1) 
– AML with maturation (M2) 
– acute myelomonocytic leukemia (M4) 
– acute monocytic leukemia (M5) 
– acute erythroid leukemia (M6) 
– acute megakaryoblastic leukemia (M7) 
– acute basophilic leukemia 
– acute panmyelosis with fibrosis 
– myeloid sarcoma (also known as granulocytic sarcoma or chloroma)
• Undifferentiated or biphenotypic acute leukemias (leukemias that have both
lymphocytic and myeloid features. Sometimes called ALL with myeloid markers, AML
with lymphoid markers, or mixed lineage leukemias.)
 Clinical presentation AL:
• Will present with sign or symptoms related to :
– Pancytopenia:
• WBCinfection  infectious syndrome
• Hb anemia  anaemic syndrome
• Platelets bleeding – haemorrhagic syndrome
– Organ infiltration  tumoral syndrome
• Lymphadenopathy.
• Splenomegally. More common with ALL than AML.
• Hepatomegally.
• CNS: 5-10% of patient with ALL
 Clinical features - specifics
• ALL mediastinal tumoral mass/CNS infiltration
• M2 : Chloroma:-presents as a mass lesion ‘tumor
of leukemic cells’
• M3 : DIC
• M4/M5 : Infiltration of soft tissues,
gum infiltration, skin deposits,
Meningeal involvement-headache, vomiting, eye
symptoms
 Acute leukemia - Diagnosis

– Lab evaluation
• The lab diagnosis is based on two things
– Finding a significant increase in the number of immature
cells in the bone marrow including blasts, promyelocytes,
promonocytes (>20% blasts is diagnostic in AML)
– Identification of the cell lineage of the leukaemic cells
 Investigations
• FBC:
– 60% of pts have an elevated WBC.
– Most are anaemic
– Most are thrombocytopenic
– 90%have blast in the periphral blood film.
• electrolytes:
– Hypo/ or hyper kalemia
– Hypomagnesimia
– hyperphosphatemia
• Hypermetabolism:
– LDH.
– uric acid.
• DIC:
– Most common with promyelocytic leukemia, small% monocytic leukemia &ALL
• Bone marrow biopsy and aspirate:
– 30%or more of all nucleated cells are blast.
• Radiology:
– CXR:mediastinal mass (T-cell ALL); CT?MRI in CNS disese
– Osteopenia or lytic lesion 50% of patients with ALL.(intractable pain).
 Acute leukemia - Diagnosis
– Peripheral blood:
• Anaemia (normochromic, normocytic)
• Decreased platelets
• Variable WBC count
– The degree of peripheral blood involvement determines classification:
» Leukaemic – increased WBCs due to blasts
» Sub-leukaemic – blasts without increased WBCs
» Aleukaemic – decreased WBCs
 Acute leukemia - Diagnosis
• Bone marrow aspirate & trephine:
Hypercellular,
– blast cells ( > 20% in AML),
– presence of Auer rods - AML type

• Cytochemistry :
Special stains to differentiate AML from ALL ;
Positivity
with Sudan black & Myeloperoxidase (MPO) in
AML
Jamshidi trephine &
Salah’s BM aspiration needle
 Chemotherapy for acute
leukemias
• Phases of ALL treatment
– induction
– intensification
– CNS prophylaxis post-remission therapy

– maintenance
• Phases of AML treatment
– induction
– consolidation (post-remission therapy)
 ALL Treatment
• 1 – Remission Induction

• 2 – Intensification (Consolidation) Therapy

• 3 – Maintenance Therapy

• 4 – CNS Prophylaxis

• 5 – Allogeneic Stem Cell Transplant

 ALL Treatment
• Remission Induction (targeted to risk of disease)
– Goals: restore normal haematopoiesis, induce a complete
remission rapidly in order to prevent resistance to drugs
– Standard induction regimen
• 4 or 5 drugs: vincristine, prednisone, anthracycline, L-asparaginase, +/-
cyclophosphamide
– 80-90% complete remission

• Intensification (consolidation)
– High doses of multiple agents not used during induction or re-
administration of the induction regimen
 ALL Treatment
• Maintenance Therapy
– Daily po 6MP, weekly MTX, monthly pulses of vincristine
and prednisone for 2-3 yrs

• CNS Prophylaxis
– Given during induction and intensification
– Intrathecal: MTX, Cytarabine, corticosteroids
– Systemic: high dose mtx, cytarabine, L-asparaginase
– +/- Cranial Irradiation
 How we treat ALL
This is based on Magrath et al, Eur J Cancer
2005;41:570-580 with a modified Capizzi MTX
a. Remission Induction (IND 1)-1month
-Prednisolone or Dexamethasone days 1-7
-Prednisolone or Dexamethasone days 8-28
-Vincristine IV days 8,15,22,29
-L-asparaginase SC days 8,10,12,14,16,18,20,22,24,28
-Doxorubicin IV days 8, 15, 29
-*Methotrexate IT for standard and Intermediate risks
-Triple (steroids/methotrexate/cytarabine) IT for HR; days 1,8,15,22
 How we treat ALL
b. Remission Induction 2A
-Cyclophosphamide IV days 1 and 15
-6 mercaptopurine PO days 1-28
` -Cytarabine IV days 1-4, 8-11, 15-18 and 22-25
-IT therapy as in remission induction 1
c. Remission induction 2B
Cyclophosphamide IV days 1 and 15
-6 mercaptopurine PO days 1-28
` -Escalated high dose Methotrexate IV days 1,11,21,31,41 with a
start dose of 100mg/m+ (Capizzi’s modification)
-IT therapy as in remission induction 1
 How we treat ALL
c. Consolidation therapy- 1month
-Cytarabine SC 12hrly days 1-3, 15-17
-Vincristine IV days 1 and 15
-Cyclophosphamide IV day 1
-6-mercaptopurine PO days 1-7, 15-21
-Doxorubicin IV day 15
- IT therapy as in remission induction 1 but for day 1 only
d. Maintenance Therapy 3monthly for 6-8 cycles
-Combination of prednisolone, vincristine, doxorubicin, MTX, L-
asparainase, 6-mercaptopurine and IT MTX at day one of each
cycle
 ALL Treatment
• Stem Cell Transplant
– Done during first CR
– Highly indicated in those with high risk disease:
• Ph Chromosome
• t(4;11) mutation
• Poor initial response to induction therapy
 AML Treatment
• Remission induction therapy (DA)
– Commonly anthracycline (ie, daunorubicin, idarubicin) and cytarabine
→ (“3+7 regimen”)
• Cytarabine has ample CNS penetration so no need for prophylactic
intrathecal chemotx (also, ↓ risk in patients with AML compared to ALL)
• 60-80% achieve complete remission

• Postremission therapy
1. Consolidation
– longer survival than maintence alone
– typically high dose cytarabine
2. Maintenance – continue chemotx monthly for 4-12 months
– nonmyelosuppressive doses

NB: BMT is usually offered at first CR

 Prognostic characteristics in ALL
parameters Good poor
WBC low High(>50x10 9 /l)

Gender Girls Boys

Immunophenotype C-ALL B-ALL

Age Child Adult or infant.

Cytogenetic Normal,hyperdiploid, Ph+,11q23rearrangements.

Time to clear blast from blood < 1week >1week

Time to remission <4weeks >4weeks

Cns disease at presentation Absent Present

Minimal residual disease . Negative at 1-3 months Still positive at 3-6 months.
Prognostic characteristics in AML
parameters Favorable unfavorable

Cytogentics T(15;17). Deletion of chromosome5or7.

T(8;21). 11q23
Inv(16). T(6;9)
Abn(3q)complex
rearrangments
BM response to remission <5% blasts after first course >20% blasts after first course.
induction

age <60yrs >60yrs

 CONCLUSION
• Although the diagnosis of Acute leukaemias is
based on the WHO classification criteria, FAB
morphologic classification is still relevant in
our setting
• Cytochemistry and cytogenetics should always
be done when available
• The treatment of Acute Leukaemia solely rest
on chemotherapy in our environment.
Thank you for your attention