LEUKAEMIAS

DR SAMUEL B. DUROGBOLA MBBS FWACP

NATIONAL HOSPITAL ABUJA
PRESENTED
NPMCN PATHOLOGY PRIMARY REVISION COURSE 2018
INTRODUCTION
Malignant disorders & clonal proliferation of abnormal haematopoietic
precursor cells that accumulates in the bone marrow, suppress normal
haemopoiesis, spill over into circulation and infiltrate tissues with resultant
clinical manifestations
• 2 types based on clinical course & further subdivided into
myeloid & lymphoid origin
• Acute Leukaemias
• Acute myeloblastic leukaemia (AML)
• Acute lymphoblastic leukaemia (ALL)
• Chronic leukaemias
• Chronic myeloid leukaemia (CML)
• Chronic lymphoid leukaemia (CLL)
ACUTE LEUKAEMIA
ACUTE MYELOBLASTIC
LEUKAEMIA
ACUTE MYELOBLASTIC LEUKAEMIA
• Malignant tumour of haemopoietic precursor cells of non-lymphoid
lineage arising in the bone marrow (BM)
• Occurs in all age groups but commoner in adults
• Slightly more in males than females
• Cause is unclear
AML PREDISPOSING CONDITIONS
• Environmental • Chronic myelogenous
leukemias (CML,
• Aplastic anemia
factors • Eosinophilic fasciitis
CMML, CNL) • Myeloma
• Radiation • Primary myelofibrosis
• Other disorders
• Benzene • Essential
• HIV Infection
thrombocythemia
• Alkylating agents, • Langerhans cell
• Polycythemia vera
topoisomerase II histiocytosis
inhibitors • Clonal cytopenias
• Thyroid disorders
• Oligoblastic
• Other cytotoxic drugs myelogenous • Polyendocrine
• Tobacco smoke leukemia disorders
• Paroxysmal nocturnal
• Acquired diseases hemoglobinuria
• Clonal myeloid • Other hematopoietic
diseases disorders
AML PREDISPOSING CONDITIONS
• Inherited or congenital • Diamond-Blackfan • Noonan syndrome
conditions syndrome • Poland syndrome
• Sibling with AML • Down syndrome • Rothmund-Thomson
• Amegakaryocytic • Dubowitz syndrome syndrome
thrombocytopenia, • Dyskeratosis congenital • Seckel syndrome
congenital • Familial (pure, • Shwachman syndrome
• Ataxia-pancytopenia nonsyndromic) AML • Werner syndrome
• Bloom syndrome • Familial platelet (progeria)
• Congenital disorder • Wolf-Hirschhorn
agranulocytosis • Fanconi anemia syndrome
(Kostmann syndrome) • MonoMAC and • WT syndrome
• Chronic Emberger syndromes
thrombocytopenia with (GATA2 mutations)
chromosome 21q 22.12 • Naxos syndrome
• Microdeletion • Neurofibromatosis 1
DIAGNOSIS
• FBC usually shows leucocytosis, anaemia, and thrombocytopenia & may 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
• SB, MPO, and esterase (chloroacetate and non-specific esterase (NSE)) stains are +ve in AML
& −ve in ALL (<3% blasts +ve)
• M0 and M7 AML are MPO −ve; NSE is +ve in monocytic cells; Cytochemistry is not essential if
4-colour flow cytometry and estimation of cytoplasmic MPO is available.
• Cytogenetic analysis to identify prognostic group
• Molecular analysis RT-PCR and FISH in selected cases
IMMUNOLOGIC PHENOTYPES OF AML
FAB CLASSIFICATION (MORPHOLOGY)
2008 WHO AML CLASSIFICATION
CLINICAL FEATURES
• Acutely 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 & epistaxis,
bleeding gums, rectal, retina
• Gum hypertrophy and skin infiltration (monocytic leukaemias (M4, M5))
• Signs of leucostasis: hypoxia, retinal haemorrhage, confusion, or diffuse
pulmonary shadowing
• Hepatomegaly occurs in 20%, splenomegaly in 24% (should raise the
question of transformed CML); lymphadenopathy is infrequent (17%)
• CNS involvement at presentation is rare in adults with AML
TREATMENT
• Remission induction with DA
• Daunorubicin
• Cytarabine (Ara-C)
• Consolidation
• BM transplantation
ACUTE LEUKAEMIA
ACUTE LYMPHOBLASTIC
LUEKAEMIA
ACUTE LYMPHOBLASTIC LEUKAEMIA
• Clonal malignant tumour of haematopoietic precursor cells of
lymphoid lineage (T- or B- cell)
• Most common childhood malignancy & rare in adults
• Dual peaks Age of 2 – 10 years and 15 – 24 years
AETIOLOGY
• Unknown
• Predisposing factors
• Ionizing radiation (AML is more common)
• Congenital predisposition in Down syndrome (20-fold in childhood)
• Bloom, Klinefelter & Fanconi syndromes
• Chemicals, pollution
• Viruses
• Urban/rural migration
• Father’s radiation exposure and radon levels have all been postulated
ALL FAB CLASSIFICATION
2008 WHO ALL CLASSIFICATION
CLINICAL FEATURES
• Acutely ill due to BM failure
• Anaemia: weakness, lethargy, breathlessness, lightheadedness, palpitations
• Infection: chest, mouth, perianal, skin (Staphylococcus, Pseudomonas, HSV, Candida) Fever,
malaise, sweats
• Haemorrhage: purpura, menorrhagia, and epistaxis, bleeding, gums, rectal, retina
• Signs of leucostasis: Hypoxia, retinal haemorrhage, confusion, diffuse pulmonary
shadowing
• Bone or joint pain (more common in children)
• Mediastinal involvement in 15%; may cause SVC obstruction especially T-ALL
• CNS involvement in 6% at presentation; may cause cranial nerve palsies especially
facial nerve, sensory disturbances, and meningism
• Signs include widespread lymphadenopathy in 55%, mild-to-moderate
splenomegaly (49%), hepatomegaly (45%) & orchidomegaly
TREATMENT
• Remission induction
• APO-L (Adriamycin, Prednisolone, Vincristine, L-Asparaginase)
• ALL COAP-L (Cyclophosphamide, Vincristine, Adriamycin, Prednisolone, L-
Asparaginase
• Consolidation
• Same or more intense remission induction chemo
• Several intensification regimen (methotrexate, cytarabine, etoposide, m-
amsacrine, mitoxantrone (mitozantrone), & idarubicin
• CNS prophylaxis
• Maintenance
• Daily 6-MP PO, weekly methotrexate PO, cyclical IV vincristine, oral
prednisolone, & IT methotrexate for 2 years in girls & 3 years in boys
• BMT
CHRONIC LEUKAEMIA
CHRONIC MYELOID LUEKAEMIA
CHRONIC MYELOID LEUKAEMIA
• Clonal malignant tumour of pluripotent haemopoietic stem cell
characterized by increased granulocytes with left shift and the
presence of the Ph chromosome or BCR-ABL chimeric gene
• Classified as a myeloproliferative disease by WHO
• Triphasic disease (chronic, accelerated & blastic phases)
• Rare in children
• Tyrosine kinase inhibitors have made overall survival better
AETIOLOGY
• Unknown
• Irradiation is only known epidemiological factor
• BCR-ABL fusion proteins appear to play a role in the pathogenesis of
CML & have been shown to transform haemopoietic progenitor cells
in vivo and in vitro
PHILADELPHIA CHROMOSOME
• >80% have Ph chromosome
• Reciprocal translocation between chromosomes 9 & 22, (t9;22)(q34;q11)
• Involves 2 genes, BCR and ABL that form a fusion gene BCR-ABL on
chromosome 22
• It is an aberrant 210 kDa protein (p210BCR-ABL), it is active with greater
tyrosine kinase activity than the normal ABL protein
• 10% of patients have variant translocations involving chromosome 22
± 9 & other chromosomes
• 8% with typical clinical features lack the Ph chromosome
• Ph −ve CML: half have the hybrid BCR-ABL gene: Ph −ve, BCR-ABL +ve CML
SUBTYPES OF BCR-ABL1

• Major p210 (e13a2, e14a2) 90% CML patients

• Minor p190 (e1a2) 1% CML, 50% ALL
• Micro p230 e19a2 Chronic neutrophilic leukemia
• Variant e13a3, e14a3 5% CML
• Variant e6a2 (185kDa), e8a2 0.5% CML
WHO CRITERIA FOR ACCELERATED PHASE
WHO CRITERIA FOR BLASTIC PHASE
CLINICAL FEATURES
• 30% asymptomatic at diagnosis found on routine FBC
• Fatigue, lethargy, weight loss, sweats
• Splenomegaly in >75%; may cause (L) hypochondrial pain, (early)
satiety, & sensation of abdominal fullness
• Gout, bruising/bleeding, splenic infarction, and occasionally priapism
• Hepatomegaly (2%), lymphadenopathy unusual
• Occasional signs of leukostasis at presentation
• Low neutrophil alkaline phosphatase (NAP) score
• Increased lactate dehydrogenase (LDH), Uric acid
SOKAL SCORE
EUTOS SCORE
• Predicts complete cytogenetic remission (CCgR) 18 months after the
start of therapy an important predictor of the course of disease
• Patients without CCgR at this point of treatment are less likely to
achieve one later on & are at a high risk of progressing to blastic and
accelerated phase disease
• Formula:
• 7 × basophils (%) + 4 × spleen size (cm under ribcage)
• If the sum is >87, the patient is at high risk of not achieving a CCgR at 18
months, while a sum ≤87 indicates a low risk
EARLY CYTOGENETIC RESPONSE TO IMATINIB
• Another important prognostic factor
• PCyR at 6 months, 80% probability of CCyR at 2 years
• Minor or minimal CyR at 6 months, 50% probability; no CyR at 6 months, 15%
probability
TREATMENT CONSIDERATIONS

• Patient & adherence Counselling

• Appropriate response monitoring
• Management of adverse effects
• Branded vs Generic
• Risk stratification
ADVERSE EFFECT
FOOD INTERACTION

• Citrus fruit increase serum level

• Pomegranate interact with TKI
• Lactose intolerance: nilotinib & dasatinib contain
lactose
DRUG INTERACTION
HAEMATOLOGICAL RESPONSE
CYTOGENETIC RESPONSE (Examination of ≥20 marrow
metaphases)
MOLECULAR RESPONSE (assessed on peripheral blood cells) &
cytogenetic response (assessed on BM aspirate)
 TKI RESPONSE DEFINITION 1st line
TIME OPTIMAL RESPONSE WARNING FAILURE
Baseline High risk
Major CCA/Ph+

3 months BCR-ABL ≤10% BCR-ABL >10% No CHR

Ph+ ≤35% (PCyR) Ph+ 36-95% Ph+ >95%

6 months BCR-ABL <1% BCR-ABL 1-10% BCR-ABL >10%

Ph+ 0% (CCyR) Ph+ 1-35% Ph+ >35%

12 months BCR-ABL ≤0.1% (MMR) BCR-ABL 0.1-1% BCR-ABL >1%

Ph+ >0%

Therefater /Anytime MMR or better CCA/Ph- (-7, or 7q-) Loss of CHR

Loss of CCyR
Loss of MMR x2
Mutations
CCA/Ph+

Courtesy ELN. Key: CCA Clonal cytogenetic abnormality

2nd line response definition
TIME OPTIMAL RESPONSE WARNINGS FAILURE
BASELINE No CHR
Loss of CHR on Imatinib
Lack of CyR to 1st line TKI
High risk
3 months BCR-ABL ≤10% BCR-ABL >10% No CHR or
Ph+ <65% Ph+ 65-95% Ph+ >95% 0r
New mutations
6 months BCR-ABL ≤10% BCR-ABL ≤10% BCR-ABL >10%
Ph+ <35% (PCyR) Ph+ 35-65% Ph+ >65%
New mutations
12 months BCR-ABL <1% BCR-ABL 1-10% BCR-ABL >10%
Ph+ 0 (CCyR) Ph+ 1-35% Ph+ >35%
New mutations
Then & Any time MMR or better CCA/Ph- (-7 or 7q-) or Loss of CHR
BCR-ABL >0.1% Loss of CCyR or PCyR
New mutations
Loss of MMR
CCA/Ph+
RESISTANCE & CHANGING THERAPY
CHANGING THERAPY
• Intolerance to TKI
• SCT; interferon-α ± cytarabine or novel agent
• Hydroxyurea, busulfan
• Failure
• Change to alternate TKI & evaluate for SCT
• Mutation analysis should be done including T315I mutation
• Suboptimal response
• Re-assess and consider imatinib dose-escalation or treatment change now or in near
future
• Warnings
• Features suggesting possible incipient resistance to TKI &/or progression to advanced
phase; needs closer monitoring & consideration of dose escalation, SCT, or
other/investigational agents
CHRONIC LEUKAEMIA
CHRONIC LYMPHOID LUEKAEMIA
CHRONIC LYMPHOCYTIC LEUKAEMIA
• Progressive accumulation of mature-appearing, functionally
incompetent, B lymphocytes in peripheral blood, BM, lymph nodes,
spleen, liver, & sometimes other organs
• Essentially B-lineage lymphocyte malignancy
• Incidence high in Africa, About 40% of all cases of leukaemia in Ile-Ife
(Durosimi)
• Peak age of incidence 60 years and rare below 30 years
• Male:Female 2:1
• More common in Females below 50 years in Africa
CLL
CLL OVERVIEW
• Absolute B-cell count of >5x109/L
• Clonality confirmed by flow cytometry
• Express CD5, CD10, CD19, CD20, CD23, κ, λ
(Immunophenotyping is gold standard for diagnosis)
• Cyclin D1, FISH for t(11:14), t(11q,v)
• Weak SmIg & negative for CD22, FMC7
 RAI & BINET STAGING SYSTEMS
RAI Description Risk Survival (mo)
Lymphocytosis, lymphocytes in
0 blood >5x109/L and >40% Low >150
lymphocytes in the bone marrow
I Stage 0 with enlarged node(s) Intermediate 101
Stage 0-I with splenomegaly,
II Intermediate 71
hepatomegaly, or both
Stage 0-II with hemoglobin <11.0 g/dL or hematocrit
III High 19
<33%
IV Stage 0-III with platelets <100x109/L High 19

BINET Description Survival (mo)

Hemoglobin ≥10 g/dL and platelets ≥100x109/L and
A >120
<3 enlarged areas
Hemoglobin ≥10 g/dL and platelets ≥100x109/L and
B 84
≥3 enlarged areas
Hemoglobin <10 g/dL and/or platelets <100x109/L and
C 24
any number of enlarged areas
Shanafelt. Hematology Am Soc Hematol Educ Program. 2009:421-9
NCCN, 2014..
 PROGNOSTIC FACTORS
Older Prognostic Factors Newer Prognostic Factors

Stage FISH

Pattern of bone marrow involvement ZAP-70 expression

2-microglobulin IgVH gene mutation

WBC doubling time CD38 expression

del(17p)

TP53 mutation

NOTCH1 mutation
Shanafelt TD. Hematology Am Soc Hematol Educ Program. 2009:421-429.
FISH, fluorescence in situ hybridization; ZAP-70, zeta-associated protein 70; IgVH, immunoglobulin heavy chain;
WBC, white blood cell.
 GENETIC ABNORMALITIES VS SURVIVAL

Median =
9 years

11 years

32
months

FISH, fluorescence in situ hybridization.

Döhner H et al. N Engl J Med. 2000;343(26):1910-1916.
INDICATION FOR THERAPY

•Anaemia &/or thrombocytopenia

•Symptomatic disease
•Rapidly progressive disease
TREATMENT OPTIONS
• Observation
• Chlorambucil + Prednisolone
• CVP
• RCHOP
• FCR
 TREATMENT OPTIONS
• <70 years with insignificant comorbidities
• FCR
• Pentostatin + Cyclophosphamide + Rituximab
• Bendamustine + Rituximab
• Obinutuzumab + Chlorambucil
• ≥70 year or <70 + significant comorbidities
• Obinutuzumab + Chlorambucil
TREATMENT OPTIONS
• Del 17q
• Ibrutinib
• HDMP (high-dose methylprednisolone) + rituximab
• FCR
• FR
• Obinutuzumab + chlorambucil
• Alemtuzumab ± rituximab
• Allogeneic transplant
 NEW & EMERGING THERAPIES
Agent MOA Status

Alemtuzumab Anti-CD52 MoAb Approved 2007a

Bendamustine Alkylating agent Approved 2008

Ofatumumab Anti-CD20 MoAb Approved 2009, 2014

Obinutuzumab Anti-CD20 MoAb Approved 2014

Ibrutinib BTK inhibitor Approved 2014

Idelalisib PI3K inhibitor Approved 2014

ABT-199b BCL-2 inhibitor Phase 3

Chimeric antigen receptor T-cell

CART Phase 2
therapy