ACUTE LEUKEMIAS

CLINICAL PHARMACY IV
BACHELOR OF PHARMACY

MELA DEWI
DEFINITION
• Leukemia is hematological malignancies
• Characterized by the production of excessive numbers of abnormal
white blood cells.

Acute Chronic
Acute Myeloid Chronic Myeloid
Lymphoblastic Lymphocytic
Leukemia (AML) Leukemia (CML)
Leukemia (ALL) Leukemia (CLL)

• Adjectives ‘myeloid’ and ‘lymphoid’ predominant cell involved

• Suffix –cytic  mature and –blastic  immature
EPIDEMIOLOGY
United States - 2016
1.57% of the total
• New cases of cancer incidence
26,540 Acute Leukemia
11,860 deaths per year
• Acute Myeloid 2% of all cancer deaths
19,950 Leukemia (AML)

• Acute Lymphoblastic
6,590 Leukemia (ALL)
EPIDEMIOLOGY
Malaysian National Cancer Registry Report (MNCR) 2007-2011
 Chemicals
• Benzene
ETIOLOGY • Pesticides

Drugs Radiation
• Ionizing radiation
• Alkylating agents
• Anthracyclines Viruses
• Epipodophyllotoxins • Epstein-Barr Virus
• Human T-lymphocyte virus (HTLV-1 and HTLV-2)
Genetic conditions
Social habits
• Down syndrome • Cigarette smoking
• Fanconi anemia • Maternal marijuana use
• Neurofibromatosis type • Maternal ethanol use
1c
• Maternal caffeine consumption
PATHOPHYSIOLOGY ACUTE MYELOID
LEUKEMIA (AML)
Myeloid stem cell

• Erythrocytes
• Platelets
• Monocytes
• Basophils
• Neutrophils
• Eosinophils

Lymphoid stem cells

• Natural killer cells

• B lymphocytes
• T lymphocytes
Normal ACUTE LYMPHOBLASTIC
Hematopoiesis LEUKEMIA (ALL)
PATHOPHYSIOLOGY
• Arise from a single leukemic cell that expands and acquires additional
1 mutations

• Failure to maintain a relative balance between proliferation and

2 differentiation

Lymphoblast Proliferate Myeloblast

uncontrollably
PATHOPHYSIOLOGY
Leukemic Growth and/or “Crowding out” phenomenon
cells survival advantages in the bone marrow

WHY??
vs
Normal • Inhibit normal cellular proliferation and differentiation
Cells • Reduce apoptosis
 What kind of genetic alterations that lead to Leukemia?
Activation of a normally suppressed gene
1 (protooncogene) to create an oncogene
that produces a protein product that
Continuous
PATHOPHYSIOLOGY

signals increased proliferation • Survival

• Replication
Loss of signals for the blood cell to
2 differentiate • Drug resistance

Loss of tumor suppressor genes that

Changes in:
3 control normal proliferation • Signal transduction
• RNA transcription
• Cell cycle control factors
• Cell differentiation
4 Loss of signals for apoptosis
• Programmed cell death
 CLASSIFICATION

WHO

• AL: > 19% blasts in the marrow or blood

• Myeloblast : AML
• Lymphoblast : ALL
• B lymphoblastic
• T lymphoblastic

World Health Organization (WHO) &

Society for Hematopathology and the European Association of Hematopathology
CLINICAL PRESENTATION AND DIAGNOSIS
GENERAL
Recent history of vague symptoms:
• Tiredness
• Lack of exercise tolerance
• Weight loss
• “Feeling unwell”
 CLINICAL PRESENTATION AND DIAGNOSIS
LABORATORY TEST
Complete blood count with differential:
• Thrombocytopenia (severe, <20,000 cells/mm3 [<20 × 109/L])
• Leukopenia or leukocytosis
➢ ALL WBC count ≥50,000 cells/mm3 (≥50 × 109/L)
➢ AML WBC <10,000 cells/mm3 (<10 × 109/L)
Uric Acid elevation  rapid cellular turnover (more common with ALL)
Electrolytes: Na & (PO4)-3 may be elevated with a compensatory decrease in Ca
Coagulation • elevated PT
(more common with AML) • PTT
• D-dimers
 CLINICAL PRESENTATION AND DIAGNOSIS
OTHER DIAGNOSTIC TESTS
Bone marrow aspirate and biopsy:
• Morphologic examination
• Cytochemical staining
• Immunophenotyping
• Cytogenetic (chromosome) analysis

Lumbar Puncture (LP)

ACUTE LYMPHOBLASTIC LEUKEMIA
(ALL)
ALL
-Risk Classification-
• If a patient has clinical and laboratory features
that are associated with a favorable response
Standard Risk to antineoplastic therapy
• Less intensive therapy will be given to reduce
the risk of long term adverse effects

High risk • If a patient is unlikely to respond well to

standard therapy
or Very High Risk • Intensive antineoplastic therapy will be given
ALL
-Risk Classification-
A. Patient Characteristics
• Age
• 1- 9 years having the best Event Free Survival (EFS)
• Presence of CNS disease at diagnosis
• Obesity
• Hepatosplenomegaly and mediastinal mass
ALL
-Risk Classification-
B. Leukemic Cell Characteristics
• Poor prognosis:
• Philadelphia chromosome
• Mixed lineage leukemia (MLL) gene rearrangement (11q23)
• Intrachromosomal amplification of chromosome 21 (iAMP21)
• Hypodiploidy (less than 44 chromosomes)

• Favorable Prognosis:
• High hyperdiploidy (51-65 chromosomes)
• ETV6RUNX1 cryptic translocation, t(12;21)
• NOTCH1 and FBXW7 mutations in patients with T-cell disease
ALL
-Risk Classification-
Risk • Before treatment
Classification • After induction therapy

C. Initial Response to Therapy

Long Term Outcome:
• Rapidity of response
• Level of residual disease at the end
of induction therapy
ALL
-Treatment Goals-
Rapidly achieve a complete clinical and hematologic
Short-term remission
• CR: disappearance of all physical and bone marrow evidence (normal
cellularity with less than 5% blasts) of leukemia, with restoration of normal
hematopoiesis

Long-term Maintain the patient in continuous CR

• Cured : continuous CR for 5 years
 ALL
-Treatment-

• CNS prophylaxis is a mandatory component of ALL

• Total duration of treatment is 2 to 3 years
ALL
-Treatment-
A. INDUCTION
• Vincristine
• Glucocorticoid (dexamethasone or prednisone)
• SE: Low albumin ↑ risk of osteonecrosis
• Asparaginase (or Erwinia asparaginase, Pegaspargase)
• Most likely to cause hypersensitivity reactions
• Pegaspargase is replaced by six doses of Erwinia asparaginase,
given 3x/week.
• Daunorubicin in induction (four-drug induction) for high risk or very
high risk ALL.
• Other chemotherapy regimen  Cyclophosphamide
ALL
-Treatment-
Central Nervous System (CNS) Prophylaxis
• Incorporated throughout all phases of therapy
• Antineoplastic agents do not readily cross the BBB
• Majority of patients with ALL experienced a CNS relapse
• CNS relapse  bone marrow relapse  death from refractory
leukemia

High-dose IV
Cranial
IT Chemotx Dexamethasone methotrexate or
irradiation
cytarabine
ALL
-Treatment-
B. CONSOLIDATION
• Eradicate clinically undetectable disease in order to secure
(consolidate) the remission
• 4 weeks
• Standard: Vincristine, Mercaptopurine, and IT Methotrexate
• Slow early responders during induction/high-risk  intensified
consolidation: addition of pegaspargase, cyclophosphamide, and
low-dose cytarabine to standard therapy
ALL
-Treatment-
C. REINDUCTION (Delayed Intensification
and Interim Maintenance)

• Maintain remission and to decrease cumulative toxicity

• Delayed intensification: cyclophosphamide, methotrexate, and
limited amounts of doxorubicin
• Interim maintenance: dexamethasone, vincristine, weekly
methotrexate, mercaptopurine, and IT methotrexate.
ALL -Treatment-
D. MAINTENANCE THERAPY

• Long-term drug exposure to slowly dividing cells

• Allows the immune system time to eradicate leukemia cells, and
promotes apoptosis (programmed cell death).
• Maintenance therapy:
• Daily mercaptopurine (6-MP)
• Weekly methotrexate for 12 week courses
• Monthly “pulses” of vincristine and a steroid
• Duration: 2 yrs (F children) or 3 yrs (M children)
ALL -Example of Chemotherapy Regimen-

Walker, R., Clinical

Pharmacy and
Therapeutics 5th edition,
2012
ALL -Example of Chemotherapy Regimen-
ALL -Example of Chemotherapy Regimen-
ALL -Example of Chemotherapy Regimen-
A Five-Drug Remission Induction
Regimen With Intensive
Consolidation for
Adults With Acute Lymphoblastic
Leukemia: Cancer and Leukemia
Group B Study 8811

www.bloodjournal.org
ALL
-Treatment-
Late Effect of Treatment

• Older ALL regimens w/ topoisomerase II inhibitors

(etoposide and teniposide)  high risks of development of
secondary leukemia.
• High cumulative doses of anthracyclines 
cardiomyopathy.
• Cranial irradiation  learning deficits, especially in patients
younger than 5 years of age at the time of treatment.
ACUTE MYELOID LEUKEMIA (AML)
AML
-Risk Classification-
Risk Category According to Cytogenetic and Molecular
Abnormalities Present
Good Risk t(8;21)(q22;q22); inv(16); t(15;17); t(9;11) trisomy 21
Mutated NPM1 without FLT3ITD
Mutated CEBPA
Intermediate Normal karyotype; trisomy 8; 11q23; del(7q); del(9q);
Risk trisomy 22; t(9;11)
High Risk Complex karyotype; –5; –7; del(5q); inv(3p)

FLT3 ITD
AML
-Treatment Goals-
Short-term Rapidly achieve a complete clinical and hematologic
remission
• CR:
• Disappearance of all physical and bone marrow evidence (normal cellularity
more than 20% with less than 5% blasts) of leukemia
• Restoration of normal hematopoiesis (neutrophils ≥ 1,000 cells/mm3 & platelets
more than 100,000 cells/mm3

Long-term Maintain the patient in continuous CR

• Cured : survival curve (percentage alive vs time) beyond the 6th years after therapy
shows “survival plateau”.
AML
-Treatment-
 A. REMISSION INDUCTION
AML
-Treatment- 7 + 3 Regimen for AML

Cytarabine

Chemotherapy Agents
24hour infusion of 100-200
mg/m2 per day on days 1 to 7
Daunorubicin

45 to 60 mg/m2 per
day on days 1 to 3

0 1 2 3 4 5 6 7 8
Days
AML
-Treatment-
A. INTENSIVE POSTREMISSION THERAPY
• Risk of relapse after 6-9 months referred to as
• Goals: “consolidation
• Eradicate residual leukemic cells therapy”
• Prevent drug-resistant disease
• Strategies:
• Low-dose prolonged maintenance therapy
• Short-course intensive chemotherapy alone regimens
• High-dose chemotherapy with or without radiation
• Allogeneic or autologous HSCT
AML
-Treatment-
A. INTENSIVE POSTREMISSION THERAPY
HiDAC alone or in
a. Chemoterapy combination with one or
more agents’ (anthracaycline
•  consolidation therapy or etoposide)
• Cytarabine-based consolidation regimens:
• 24hour infusion of 100 mg/m2 per day
• 24hour infusion of 400 mg/m2 per day • days 1, 3, and 5
• 3,000 mg/m2 every 12 hours
• 3 to 4 cycles
 AML –Example of Chemotherapy Regimen-

Walker, R., Clinical Pharmacy and Therapeutics 5th edition, 2012

AML
-Treatment-
A. INTENSIVE POSTREMISSION THERAPY
b. Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)
What’s the
c. Autologous Hematopoietic Stem Cell Transplantation
difference?
• Ablative therapy  to eradicate all traces of disease

• Conditioning Therapy:
• High-dose Cyclophosphamide and total body irradiation
• Other regimen: high dose melphalan, etoposide, busulphan, or
cytarabine

• 2-3 days after conditioning Tx (after total elimination from body) 

previously harvested cell are reinfused peripherally  Stem cells repopulate
the marrow  PB recover after 2-4 weeks.
AML
-Treatment-
A. INTENSIVE POSTREMISSION THERAPY
Allogeneic HSCT
• Human Leucocyte
Antigen (HLA)-matched
donor
Autologous HSCT
• Patients receive their
own cryopreserved
marrow or peripheral
blood sc
• Previously harvested
while they are in CR
SUPPORTIVE CARE
TOXIC EFFECT MONITORING SUPPORTIVE CARE
Marrow Daily CBC & ANC Red cell and platelet transfusions
suppression Platelet transfusions Peripheral counts below 10,000 cells/mm3 (10 × 109/L) or
clinical signs of bleeding
Transfusions of packed red cells Hb <8 g/dL (80 g/L; 4.96 mmol/L), profound fatigue, shortness
of breath, tachycardia, or chest pain
Infection Vital signs monitoring IC strategies
(especially fever) Fungal, Pneumocystis, and bacterial prophylaxis
Daily physical examination Empiric use of broad spectrum antibiotics when
fever occurs
Tumor Lysis Initial WBC presentation Allopurinol or Rasburicase
Syndrome (TLS) Uric Acid Level Adequate hydration prior to and during chemotx
Gastrointestinal Symptoms Parenteral nutrition
toxic effects Physical examination
 EVALUATION OF THERAPEUTIC
OUTCOMES
Monthly for 1 Evidence of
Induction- Post
year disease
Consolidation Remission Tx
Every 3 mos existence

Patient has been in

continuous CR
MONITORING:
• History
• Physical Examination
• Laboratory Test CURED
THANK YOU