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

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

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

Hematopoieticstem cell

Neutrophils

Eosinophils

Basophils

Monocytes

Platelets

Red cells

Myeloidprogenitor

Lymphoidprogenitor

B-lymphocytes

T-lymphocytes

Plasmacells

naïve

ALL

AML

Types of Leukemia Acute Lymphoblastic Leukemia (ALL)

Acute Myeloblastic Leukemia (AML)

Chronic Lymphocytic Leukemia (CLL)

Chronic Myelocytic Leukemia (CML)

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

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

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.

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

Chronic Myeloid Leukaemia The myeloproliferative diseases (MPDs)

are clonal stem cell disorders characterised by leukocytosis, thrombocytosis, erythrocytosis, splenomegaly, and bone marrow hypercelularity

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

Bone Marrow Pathology

Acute Leukemia

accumulation of blasts in the marrow

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

Acute leukemias - clinical features1. Bleeding2. Fever/infection3. Bone/joint pain4. Hepatomegaly5. Splenomegaly6. Lymphadenopathy7. CNS involvement

Acute leukemias - Laboratory findings

1. Cytochemical stains2. Immunophenotyping3. Cytogenetics4. Molecular studies

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

Acute Leukemia:Clinical Manifestations

Constitutional & Metabolic effects:

Weight loss Fever Hyperkalemia Hyperuricemia

Acute Leukemia:Clinical Manifestations Marrow replacement, organ

infiltration & metabolic effects

Marrow replacement Neutropenia: infection Anemia: pallor, fatigue, dyspnea Thrombocytopenia: abnormal

bruising and bleeding

Acute Leukemia:Clinical Manifestations Organ infiltration

Bone pain Hepatosplenomegaly Lymphadenopathy Gingival hypertrophy Leukemic meningitis

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

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

AML – M1 Note the myeloblasts and the auer rod:

AML – M2 Note myeloblasts and hypogranulated

PMNs:

AML – M3 Note hypergranular promyelocytes:

AML – M4 Note monoblasts and promonocytes:

AML – M5A Note monoblasts:

AML – M6 Note M1 type monoblasts

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

FAB ClassificationL1

Small, uniform lymphoblastsScant cytoplasm, indistinct nucleoli, occassional clefting of nucleus, chromatin is clumpedAffects primarily children

FAB Classification: L2L2

Large, pleomorphic lymphoblastsAbundant cytoplasm, predominant nucleoli, nuclear clefting and indentationAffects adults

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

CHRONIC LEUKEMIAS

Definition: Neoplastic proliferations of mature haemopoeitic cells.

Types: Chronic lymphocytic leukemia (CLL) Chronic myeloid leukemia (CML)

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.

SYMPTOMS of CLL

Weakness, fatigue, vague sense of

being ill

Night sweat

Infections esp pneumonia

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

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.

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)

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

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)

Treatment

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

(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

(Treatment of acute leukemia)

Consolidation• Different or same drugs to those used during

induction

• Higher doses of chemotherapy

• Advantage: Delays relapse and improved survival

(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.

(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

ALL vs AMLALL

Induction

Consolidation

Maintenance

CNS prophylaxis all patients

AML

Induction

Consolidation

No maintenance

CNS – Selected group only

DRUGS USED TO TREAT ACUTE MELOBLASTIC LEUKEMIA ( AML) AnthracyclineDaunorubicinDoxorubicinIdarubicinMitoxantrone

AntimetaboliteCladribineCytarabineFludarabineHydroxyureaMethotrexate6-Mercaptopurine6-Thioguanine

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

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

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 )

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

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.

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

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.

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 )

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.

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

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

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

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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