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

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

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

Leukemia: Etiology

Chromosomal abnormalities/changes

Congenital disorders

Environmental factors

Family history

Chemical agents

Chemotherapeutic agents

Viruses

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

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

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

Leukemia: Approach to Diagnosis

Medical history and physical

CBC with differential

Chemistry panel

Bone marrow biopsy and aspiration

Immunophenotyping

Cytogenetics

Leukemia: Major Types

Acute Lymphocytic Leukemia (ALL)

Acute Myelogenous Leukemia (AML)

Chronic Lymphocytic Leukemia (CLL)

Chronic Myelogenous Leukemia (CML)

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

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

Acute Leukemias

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

ALL: Treatment Phases

CNS Therapy (intrathecal chemotherapy)

AML: Treatment Phases

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

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

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

Chronic Leukemias

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

CLL: Treatment Phases

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

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

Chronic Myelogenous Leukemia

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)

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

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

CML: Treatment

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

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

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