a glimpse into the world of leukemia
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A Glimpse into the World of Leukemia. Jeffrey Bryan, Pharm.D. Clinical Pharmacy Specialist, Leukemia MD Anderson Cancer Center. Objectives. Describe the epidemiology, etiology and pathophysiology of acute and chronic leukemia - PowerPoint PPT PresentationTRANSCRIPT
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A Glimpse into the World of Leukemia
Jeffrey Bryan, Pharm.D.
Clinical Pharmacy Specialist, Leukemia
MD Anderson Cancer Center
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Objectives
Describe the epidemiology, etiology and pathophysiology of acute and chronic leukemia
Discuss the presenting signs and symptoms of adult patients with acute and chronic leukemia
Summarize approaches to the diagnosis of leukemia
Compare the general approaches to the treatment of acute and chronic leukemia patients
Discuss the supportive care issues associated with acute and chronic leukemia patients
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Leukemia: Epidemiology
Hematologic Malignancy Median Age
2009 New Diagnosis
Men Women
Acute lymphocytic leukemia (ALL) 13 3,350 2,410
Acute myelogenous leukemia (AML) 66 6,920 5,890
Chronic lymphocytic leukemia (CLL) 72 9,200 6,290
Chronic myelogenous leukemia (CML) 66 2,930 2,120
http://seer.cancer.gov/statfacts/html/leuks.html
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Leukemia: Etiology
Chromosomal abnormalities/changes
Congenital disorders
Environmental factors
Family history
Chemical agents
Chemotherapeutic agents
Viruses
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Leukemia: Pathophysiology
The pathophysiology of leukemia involves:Abnormal proliferation of leukocytes
Failure of leukocytes to mature
Metabolic complications
Abnormal leukocytes cannot perform the primary function
Abnormal cells crowd the bone marrow, lymph nodes, and spleen
Infection and bleeding are two common perils
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Leukemia: Clinical Presentation
ALL AML CLL CMLSigns/Symptoms
Fatigue, weight loss, night sweats, bruising, bleeding
Fatigue, weight loss, night sweats
White blood cell
High/low High/low High High
Hemoglobin Normal/low
Normal/low Normal/low Normal
Platelets Low Low Normal/high Normal/high
BM Blasts > 20% > 20% None 0-10% Chronic Phase
Spleen/Liver May be enlarged
Normal May be enlarged
May be enlarged
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Leukemia: Clinical Problems
Bone Marrow Failure
AnemiaNeutropeniaThrombocytopenia
Infiltration
Leukemia meningitis HepatosplenomegalyCentral nerve palsy Granulocytic sarcomaLeukemic orchitis Lymphadenopathy
Hyperleukocytosis
Central nervous system leukostasis/strokeRespiratory distress syndrome
Metabolic
Hypercalcemia HyperphosphatemiaHyperkalemia HypercoagulationHyperuricemia Weight loss
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Leukemia: Approach to Diagnosis
Medical history and physical
CBC with differential
Chemistry panel
Bone marrow biopsy and aspiration
Immunophenotyping
Cytogenetics
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Leukemia: Major Types
Acute Lymphocytic Leukemia (ALL)
Acute Myelogenous Leukemia (AML)
Chronic Lymphocytic Leukemia (CLL)
Chronic Myelogenous Leukemia (CML)
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Leukemia: Diagnostic Categories
Acute Morpholgy (FAB) Cytogenetics
Lymphocytic
Acute lymphoblastic
Common typePre-B T-cellB-cell
L1 or L2 Normal, t(4;22), or t(9;22)L1 or L2 Normal, t(1;19), or t(9;22) L1 Normal or t(4;22)L3 t(8;14)
Non-Lymphocytic
Acute myeloid
MyeoblasticPromyelocyticMyelomonocyticMonoblastic/monocyticErythrocyticMegakaryoblastic
M0, M1, M2 Normal, t(8;21)M3 t(15;17)M4 Normal, t(9;11), inv16M5 Normal, t(11q23-25)M6 NormalM7 Normal
FAB: French-American-British
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Leukemia: Diagnostic Categories
Chronic Morpholgy (FAB) Cytogenetics
Lymphocytic
Chronic lymphoblastic
B-CLLT-CLLPLLPlasma cellLymphosarcoma
Small Lymphs Normal, +12,14qSmall Lymphs Normal Prolymphocytes Normal, t(6;12)Plasma cells ----Cleaved lymphs Various
Non-Lymphocytic
Chronic myeloid
Chronic
Myeloid blast crisis Lymphoid blast crisis
Myelocytes, t(9;22)MetamyelocytesM1,M2 t(9;22), -8. iso 17L1,L2 t(9;22), -8. iso 17
FAB: French-American-British
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Acute Leukemias
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Acute Leukemia: Blast Cells
Immature precursors of either lymphocytes (lymphoblasts), or granulocytes (myeloblasts)
Not normally appear in peripheral blood
Large size and primitive nuclei (i.e. the nuclei contain nucleoli)
Presence of Auer Rods
Special stains and surface marker techniques are needed to identify the lineage of the cells
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ALL: Treatment Phases
CNS Therapy (intrathecal chemotherapy)
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AML: Treatment Phases
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Acute Leukemia: Treatment Goals
Induction therapy Rapidly achieve complete response (CR)
Consolidation therapy Maintain CR Eliminate clinically undetectable leukemia Prevent/delay relapse
Maintenance therapy Eliminate residual leukemia
Prolong remission
CNS therapy Prevent relapse
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Acute Leukemia: Remission Criteria
Disappearance of all evidence of leukemia
Bone marrow: > 20% cellularity
Bone marrow: < 5% blasts
Absolute neutrophil count: > 1000
Platelets: > 100x109/L
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Acute Leukemia: Frontline Agents
ALL AML
Class Agents Class Agents
Vinca Alkaloids Vincristine Anthracyclines DaunorubicinIdarubicin
Corticosteroids DexamethasonePrednisone
Pyrimidine Analog
Cytarabine
Anthracyclines DoxorubicinDaunorubicin
Antimetabolite Hydroxyurea
Antimetabolite Methotrexate
Alkylator Cyclophosphamide
Enzyme L-Asparaginase
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Chronic Leukemias
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CLL: Clinical Features of Staging
Rai Classification
Stage Lympho-cytosis
Lymph-adenopathy
Hepatomegaly or Splenomegaly
Hemoglobing/dL
PlateletsX 103/dL
I Yes No No >11 > 100
II Yes Yes No >11 > 100
III Yes Yes/No Yes >11 > 100
IV Yes Yes/No Yes/No < 11 > 100
V Yes Yes/No Yes/No Any < 100
Binet Staging
A Yes < 3 nodal groups
Yes/No >10 > 100
B Yes > 3 nodal groups
Yes/No <10 > 100
C Yes Yes/No Yes/No <10 < 100
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CLL: Treatment Phases
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CLL: Response Criteria
Physical Exam Normal
Symptoms None
Lymphocytes 4x109/L
Neutrophils 1.5x109/L
Platelets > 100x109/L
Hemoglobin > 11 g/dL (untransfused)
Bone marrow lymphocytes < 30%; no nodules
National Cancer Institute Working Group Criteriafor complete remission in CLL
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Chronic Leukemia: Frontline Agents
CLL CML
Class Agents Class Agents
Purine analog Fludarabine Tyrosine kinase inhibitors
Imatinib, DasatinibNilotinib
Steroids Methylprednisolone
Alkylators Cyclophosphamide,Chlorambucil,Bendamustine
Monoclonal antibodies
Rituximab,Alemtuzumab,Ofatumumab
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Chronic Myelogenous Leukemia
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CML: Pathophysiology
CML arises from abnormal hematopoietic stem cells that give rise to progeny that have the Philadelphia chromosome (Ph)
Ph is created from the reciprocal translocation between chromosome 9 and 22 forming a BCR-Abl gene on a shortened chromosome 22
Translocation is termed t(9;22)(q34.1;q11.2)
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CML: Three Clinical Phases
Disease Progression
Estimated Survival
Chronic Phase (CP) Accelerated Phase (AP) Blast Crisis (BC)
3 - 5 years 6 - 12 months 3 - 6 months
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CML: Clinical Presentation
Chronic Accelerated BlastCommon Presenting Sign
None , fatigue, weight loss, night sweats
Loss of control of WBC counts
Bruising, internal bleeding, infection
Chromosome Abnormality
BCR-ABL BCR-ABLChromosome AbnormalitiesGenetic Mutations
BCR-ABL Chromosome AbnormalitiesGenetic Mutations
White blood cell
Elevated High/low High/low
Blasts < 10% 10-19% ≥ 20%ExtramedullaryMyeloid/lymph
Other Abnormalities
Platelets or normBasophils
Abnormal platelet Basophils ≥ 20%
platelet count
Spleen/Liver May be enlarged Likely enlarged Likely enlarged
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CML: Treatment
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CML: Response Criteria
Hematologic Cytogenetic% Ph+ Chromosome
MolecularBCR-ABL
Transcripts
Complete (CHR): Normal PB count WBC < 10x109/L Plts < 450x109/L No immature cells No splenomegaly
Complete: 0%Partial: 1-34%Minor: 35-90%
Complete: PCR -Major: ≥ 3 log
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CML: Tyrosine Kinase Inhibitors
Imatinib (Gleevec™)
Dasatinib (Sprycel™)
Nilotinib (Tasigna™)
Targets BCR-ABL, PDGFR,KIT
BCR-ABL, PDGFR, SRC,KIT
BCR-ABLPDGFR,KIT
Generation First Second Second
FDA Approval Frontline Resistant/Intolerant Resistant/Intolerant
Potency ---- 300x 20-30X
Dosing
CP 400mg/day 100mg/day 400mg BID
AP 600mg/day 140mg/day 400mg BID
BP 600mg/day 140mg/day ----
Administration With food Without Regard Empty Stomach
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Leukemia: Supportive Care
Support ALL AML CLL CML
Hospital admit
Neutropenia XXX XXX X
Transfusions X
Nausea/vomiting
Coagulopathy XXX XXX
Metabolic
Infections
Mucositis
Common Occasional Rare
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