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Acute & Chronic Leukemi
a Therapy
Presented to:
Prof. Dr. Khalid Hussain JanbazDean, Faculty of PharmacyB. Z. University Multan.
Presented by:Irfan HamidPh.D.
Pharmacology 2nd Semester
Roll No. 05-PhDL-12
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Leukemia
Group of malignant disorders of the hematopoietic tissues characteristically associated with increased numbers of white cells in the bone marrow and / or peripheral blood
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Development of Leukemia in the Bloodstream
Stage 1- Normal Stage 2- Symptoms Stage 3- Diagnosis
Stage 4- Worsening
Stage 5a- Anemia
Stage 5b- Infection
Legend
White Cell
Red Cell Platelet Blast Germ
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Hematopoieticstem cell
Neutrophils
Eosinophils
Basophils
Monocytes
Platelets
Red cells
Myeloidprogenitor
Lymphoidprogenitor
B-lymphocytes
T-lymphocytes
Plasmacells
naïve
ALL
AML
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Types of Leukemia Acute Lymphoblastic Leukemia (ALL)
Acute Myeloblastic Leukemia (AML)
Chronic Lymphocytic Leukemia (CLL)
Chronic Myelocytic Leukemia (CML)
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Myeloid vs Lymphoid
Any disease that arises from the myeloid elements (white cell, red cell, platelets) is a
myeloid disease ….. AML, CML Any disease that arises from the lymphoid elements is a lymphoid disease ….. ALL, CLL
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Acute vs. chronic leukemia Leukemias are classified according to cell of origin: Lymphoid cells ALL - lymphoblasts CLL – mature appearing lymphocytes Myeloid cells AML – myeloblasts CML – mature appearing neutrophils
On a CBC, if you see: Predominance of blasts in blood consider an acute leukemia Leukocytosis with mature lymphocytosis consider CLL Leukocytosis with mature neutrophilia consider CML
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Chronic and AcuteChronic Leukemia:
accumulation of mature granulocytes or lymphocytes
longer clinical course (several to many years)
Progress slowly (runs a slow course)
Not immediately fatal.
Acute Leukemia:
excess myeloblasts or lymphoblasts
short clinical course (weeks to months)
Progress rapidly (runs a fast course)
Life expectancy short without treatment.
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Acute leukemias
Definition: Malignancies of immature hematopoietic cells. (> 20% blast cells in the bone marrow)
Types: Acute Myeloid Leukemia (AML)
Acute Lymphoblastic leukemia (ALL)
Groups: Childhood (< 15) > 80% ALL
Adult (> 15) > 80% AML
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Chronic Myeloid Leukaemia The myeloproliferative diseases (MPDs)
are clonal stem cell disorders characterised by leukocytosis, thrombocytosis, erythrocytosis, splenomegaly, and bone marrow hypercelularity
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Acute Lymphoblastic Leukemia (ALL)
• Clonal proliferation and accumulation of blast cells in blood, bone marrow and other organs
• Disorder originates in single B or T lymphocyte progenitor
• Incidence in adults : 20% of acute leukemias
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Bone Marrow Pathology
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Acute Leukemia
accumulation of blasts in the marrow
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Acute leukemias - laboratory findings. Blood examination
- anemia,- thrombocytopenia,- variable leukocyte count, usually increased,- blood morphology: presence of blast cells
2. Bone marrow morphology- presence of blast cells,- suppression of normal haematopoiesis
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Acute leukemias - clinical features1. Bleeding2. Fever/infection3. Bone/joint pain4. Hepatomegaly5. Splenomegaly6. Lymphadenopathy7. CNS involvement
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Acute leukemias - Laboratory findings
1. Cytochemical stains2. Immunophenotyping3. Cytogenetics4. Molecular studies
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Differentiation between AML and ALL
Age AML - mainly in adults ALL - common in children
Blood AML - anemia, neutropenia, thrombocytopenia, myeloblasts and
promyelocytes ALL - anemia, neutropenia, thrombocytopenia, lymphoblasts and
prolymphocytes Morphology
AML - blasts are medium to large with more cytoplasm which may contain granules, Auer rods, fine nuclear chromatin, distinct nucleoli
ALL - blasts are small to medium with scarce cytoplasm, no granules, fine nuclear chromatin and indistinct nucleoli
Cytochemistry AML - positive peroxidase and Sudan black, negative TdT ALL - negative peroxidase and Sudan black, positive TdT
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Acute Leukemia:Clinical Manifestations
Constitutional & Metabolic effects:
Weight loss Fever Hyperkalemia Hyperuricemia
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Acute Leukemia:Clinical Manifestations Marrow replacement, organ
infiltration & metabolic effects
Marrow replacement Neutropenia: infection Anemia: pallor, fatigue, dyspnea Thrombocytopenia: abnormal
bruising and bleeding
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Acute Leukemia:Clinical Manifestations Organ infiltration
Bone pain Hepatosplenomegaly Lymphadenopathy Gingival hypertrophy Leukemic meningitis
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AML:FAB classification French American British classification
M0-M7 based on morphology, and special cytochemical studies
Historically, distinguishing AML M0 from ALL was a major clinical problem
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AMLFAB classification M0,M1, M2: Myeloblasts with no, little or
some granulocytic maturation M3: Promyelocytic leukemia M4: Myelomonocytic or eosinophilic M5: Monocytic M6: Erythroleukemia M7: Megakaryoblastic
Not all that useful except for M3
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AML – M1 Note the myeloblasts and the auer rod:
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AML – M2 Note myeloblasts and hypogranulated
PMNs:
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AML – M3 Note hypergranular promyelocytes:
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AML – M4 Note monoblasts and promonocytes:
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AML – M5A Note monoblasts:
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AML – M6 Note M1 type monoblasts
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Morphologic subtypes of acute lymphoblastic leukemias (FAB classification
Subtype Morphology Occurrence (%)L1 Small round blasts 75
clumped chromatinL2 Pleomorphic larger blasts 20
clefted nuclei, fine chromatinL3 Large blasts, nucleoli, 05
vacuolated cytoplasm
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FAB ClassificationL1
Small, uniform lymphoblastsScant cytoplasm, indistinct nucleoli, occassional clefting of nucleus, chromatin is clumpedAffects primarily children
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FAB Classification: L2L2
Large, pleomorphic lymphoblastsAbundant cytoplasm, predominant nucleoli, nuclear clefting and indentationAffects adults
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FAB Classification: L3L3: Burkitt’s type
Uniform population of large lymphoblasts with deeply basophilic cytoplasm, vacuoles, round to oval nuclei without indentationAffects adults and children
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CHRONIC LEUKEMIAS
Definition: Neoplastic proliferations of mature haemopoeitic cells.
Types: Chronic lymphocytic leukemia (CLL) Chronic myeloid leukemia (CML)
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CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL) Neoplastic proliferations of mature
lymphocytes. Distinguished from ALL by
A. Morphology of cells.B. Degree of maturation of cells.C. Immunologically immature blasts
in ALL.D. CLL affects mainly elderly.
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SYMPTOMS of CLL
Weakness, fatigue, vague sense of
being ill
Night sweat
Infections esp pneumonia
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TREATMENT OF CLL Observation Chemotherapy. Oral chlorambucil
Fludarabine, Immunotherapy Anti-CD 20 (rituximab), Anti-CD 52 (Alemtuzumab)Indications for starting chemotherapy
a. Progressive Symptomsb. Progressive Anemia or Thrombocytopeniac. Bulky LN, large spleend. Recurrent Infections
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CHRONIC MYELOID LEUKEMIA CML is a clonal stem cell disorder
characterised by increased proliferation of myeloid elements at all stages of differentiation.
Incidence increases with age, M > F.
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CML is characterised by 3 distinct phases
a) Chronic Phase:Proliferation of myeloid cells, which show a full range of maturation.
b) Accelerated Phase decrease in myeloid differentiation occurs.
c) Blast crisis (acute leukemia)
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CLINICAL PRESENTAITON OF CMLSymptoms
Asymptomatic (50% of patients) Fatigue Weight loss Abdominal fullness and anorexia Abdominal pain, esp splenic area Increased sweating Easy bruising or bleeding
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CYTOGENETICS OF CMLPhiladelphia (Ph) chromosome is an
acquired cytogenetic abnormality in all leukaemia cells in CML
Reciprocal translocation of chromosomal material between
chromosome 22 and chromosome 9.
t(9;22)
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Treatment
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ACUTE LYMPHOBLASTIC
LEUKEMIA ( ALL)
DOSE ROUTE
REGIMEN
Induction ( 4 weeks)VincristinPrednisoloneL- AsparaginaseDaunorubicin
1.5 mg/m240mg/m26000u/m245mg/m2
I.VOralI.MI.V
Weekly for 4 weeksDaily for 4 weeks3xWeekly for 3 weeksDaily for 2 days
Intensification(1 week)VincristinDaunorubicinPrednisoloneEtoposideCytarabineThioguanine
1.5mg/m245mg/m240mg/m2100mg/m2100mg/m280mg/m2
I.VI.VOralI.VI.VOral
1 doseDaily for 2 daysDaily for 5 daysDaily for 5 days2x daily for 5 daysDaily for 5 days
CNS Prophylaxis( 3 weeks)Cranial irradiationMethotrexate
24 GyI.T weekly for 3 weeks
Maintenance Therapy ( 2 years)Methotrexate6-MercaptopurinePrednisolonevincristine
20mg/m275mg/m240mg/m21.5mg/m2
OralOralOralI.V
WeeklyDaily5days/ MonthMonthly
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(Treatment of acute leukemias)Induction Obtained by using high doses of chemotherapy1 Severe bone marrow hypoplasia
2 Allowing regrowth of normal residual stem cells to regrow faster than leukemic cells. Remission
Normal neutrophil count Normal platelet count Normal hemoglobin level
Remission defined as < 5% blast in the bone marrow
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(Treatment of acute leukemia)
Consolidation• Different or same drugs to those used during
induction
• Higher doses of chemotherapy
• Advantage: Delays relapse and improved survival
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(Treatment of acute leukemias) Maintenance• Smaller doses for longer period
• Produce low neutrophil counts & platelet counts
• Objective is to eradicate progressively any remaining leukemic cells.
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(Treatment of acute leukemias)
Supportive Care Vascular access (Central line) Prevention of vomiting Blood products (Anemia, ↓Plat) Prevention & treatment of infections (antibiotics) Management of metabolic
complications
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ALL vs AMLALL
Induction
Consolidation
Maintenance
CNS prophylaxis all patients
AML
Induction
Consolidation
No maintenance
CNS – Selected group only
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DRUGS USED TO TREAT ACUTE MELOBLASTIC LEUKEMIA ( AML) AnthracyclineDaunorubicinDoxorubicinIdarubicinMitoxantrone
AntimetaboliteCladribineCytarabineFludarabineHydroxyureaMethotrexate6-Mercaptopurine6-Thioguanine
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DRUGS USED TO TREAT ACUTE MYELOBLASTIC LEUKEMIA ( AML)
TOPOISOMERASE INHIBITORS
ETOPOSIDETOPOTECAN
o DNA DAMAGING( ALKYLATING AGENT)
CYCLOPHOSPHAMIDECARBOPLATINTEMOZOLOMIDE
CELL MATURING AGENT
ALL-TRANS RETIONIC ACID (ATRA)ARSENIC TRIOXIDE
o HYPOMETHYLATING AGENT
AZACITIDINEDECITABINE
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Treatment of Chronic Lymphoblastic Leukemia (CLL)
Alkylating agents : Chlorambucil intermittently (10 mg/m2
x 7 days, monthly ) or continously ( 5 -10 mg / day )
Combinations : COP : Cyclophosphamide, Oncovin,
Prednisolone( 5 day – monthly course ) Chlorambucil + Epirubicin CHOP : COP + Doxorubicin
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Treatment of Chronic Lymphoblastic Leukemia (CLL)
Corticosteroids : Prednisolone : 30 mg / m2 for 3 weeks + 1 week tailing
off for initial treatment of pts with Stage C disease. High – dose Methylprednisolone IV at 1 g/m2 ( 5-day
monthly course ) Nucleoside analogues : Fludarabine ( 25 mg / m2 IV daily as 30 min infusion for
5 days every 28 days ) Fludarabine + Cyclophosphamide Pentostatin ( 2 mg/m2/day IV for 5 days every 28 days) Cladribine ( IV infusion over 2 hrs dose of 0.12
mg/kg/day for 5 consecutive days )
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Nucleoside analogues Studies have shown FLUDARABINE
superior to Chlorambucil in CLL with higher clinical response rates, superior time to treatment failure, better tolerance in pts > 65 yrs.
FLUDARABINE – Currently 1st line of treatment in CLL
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Monoclonal Antibodies Alemtuzumab ( monoclonal antibody directed at
CD 52 ) : 1st line agent For salvage in pts with fludarabine refractory
disease Effective in CLL with p53 mutations Very effective in clearing Bone Marrow disease Limited activity in clearing bulky
lymphadenopathy Has role in consolidation therapy for elimination
of minimal residual disease.
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Monoclonal Antibodies Anti-viral prophylaxis and prophylactic antibiotics for
Pneumocystis carnii are recommended for pts receiving Alemtuzumab and for 2 – 4 months after treatment
Rituximab – (monoclonal antibody specific for CD 20) used extensively in combination with chemotherapy.
Fludarabine combined with Rituximab – shown higher clinical remission rates than fludarabine alone .
FCR – ( Fludarabine, Cyclophosphamide, Rituximab ) – shown clinical response rates of 76% in trials.
CFAR – ( Cyclophosphamide, Fludarabine, Alemtuzumab, Rituximab ) still under trials
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Monoclonal Antibodies LENALIDOMIDE : An
immunomodulatory drug currently approved for use in Multiple Myeloma and MDS with deletion of Chr 5q .
Studies have shown response rates of 47 – 38 % with complete response rates of 9 % and elimination MRD have been reported.
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Bone Marrow Transplantation Allogenic bone marrow
transplantation is the only known curative therapy.
Addition of ALEMTUZUMAB to pts receiving hematopoetic stem cell transplantation aids in elimination of MRD ( Minimal Residual Disease )
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Radiotherapy For many decades, irradiation of spleen was primary
treatment of CLL. Useful in pts with bulky lymph nodes compressing
nerves / other organs & massive / painful splenomegaly.
IRRADIATION of mediastinum, extracorporeal irradiation of blood and total body irradiation – may reduce the peripheral blood lymphocyte counts and size of lymph node, spleen and liver.
Total body irradiation plus cyclophosphamide & prednisolone had higher response to those treated with TBI alone.
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Supportive therapy Hypogammaglobulinemia : IV Immunoglobulins
Prednisolone - useful against autoimmune manifestations of disease.
Rituximab alone / in combination : effective in eliminating the B cell clone inducing autoimmune disorders, particularly autoimmune thrombocytopenia
Leukapheresis : removal of leukemic cells reduces tumor load and leukostasis.
Long term antibiotics
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CML-Principles of Treatment
Control & prolong chronic phase (non-curative) - Tyrosine kinase inhibitors-Imatinib - Alpha-Interferon - Oral chemotherapy (Hydroxyurea) Eradicate malignant Clone (curative) - Allogeneic BM/stem cell transplantation - Alpha Interferon - Imatinib? 2nd line TKIs
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TREATMENT OF CML Tyrosine kinase inhibitor (TKI) Imatinib
(Glivec) is the first line treatment In resistent cases 2nd line TKIs (Nilotinib,
Dasatinib, Bosutinib) very useful Allogenic bone marrow trasnsplantation can
be curative in pts resisrant to TKIs but has significant complications & mortality
Accelerated and blast phase Treat like AML or ALL followed by BMT
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Bone marrow or PBSC transplantation in leukemias
Types of transplant1. Autologous transplant2. Allogeneic Transplant Purpose of transplant Autologous -To deliver a high dose of chemo to kill
any residual cancer (lymphoma, multiple myeloma) Allogeneic -To eradicate residual leukemia cells -Graft vs leukemia effect
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THANK YOU