LEUKEMIA

Candra WibowoNephrology Division, Medical School of Trisakti University Jakarta

DEFINITION OF LEUKEMIA

• Cancer of the white blood cells (leukocytes) or their precursors

• Affects ability to produce normal blood cells• Bone marrow makes abnormally large number of

immature white blood cells called blasts• Accumulation or proliferation of leukocytes in the

bone marrow• Acute or Chronic• May or may not have increased leukocyte count

in the peripheral blood

HISTORY OF LEUKEMIA

• Means “white blood” in Greek

• Discovered by Dr. Alfred Velpeau in France, 1827

• Named by pathologist Rudolf Virchow in Germany, 1845

MAIN TYPES OF LEUKEMIA

• Acute Lymphocytic Leukemia (ALL)

• Acute Mylogenous Leukemia (AML)

• Chronic Lymphocytic Leukemia (CLL)

• Chronic Mylogenous Leukemia (CML)

Acute no maturation

beyond blast

Chronic maturation beyond

blast

Lymphocytic T or B lineage ALL CLL

Myeloid (granulocytes, monocytes, erythrocytes, platelets)

AML CML

MAIN TYPES OF LEUKEMIA

The peripheral blood WBC in leukemia

White CellCount

Differential White Cell Count

Acute Low, normalor high

If high, blast cellspredominate. If normal or low,may be very few blasts

Chronic High Mature cells predominate.Blasts less than 10%

Demographics of Leukemia Patients (2001 Data)

ALL11%

CLL26%

AML31%

CML15%

others17%

Total Reported Cases = 31,500Sources from Leukemia, Lyphoma, Myeloma Facts 2001

CLL=Chronic Lymphocytic

ALL=Acute Lymphocytic

CML=Chronic Mylogenous

AML=Acute Mylogenous

SYMPTOMS

• When there are excessive white blood cells Infections

• When there are few red blood cells: Paleness Anemia

• When there are few platelets Excessive bleeding

TESTS FOR DIAGNOSIS

• Finger prick

• Blood sample

• Blood dye

• Bone marrow sample

• Spinal Tap/Lumbar Puncture

Pictures Of Blood

Normal human blood

White Cell Red Cell

Platelet

Blood with leukemia

BlastsRed Cell

Platelet

White Cell

Sources from Arginine.umdnj.eduSources from beyond2000.com

EFFECTS ON THE BODY

• Attacks the immune system

• Infections

• Anemia

• Weakness

• No more regular white blood cells, red blood cells, and platelets

• Blasts clog blood stream and bone marrow

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 Sources from Leukemia, by D. Newton and D. Siegel

CAUSES

• High level radiation/toxin exposure

• Viruses

• Genes

• Chemicals

• Mostly unknown

• Can’t be caught

TREATMENT

• Chemotherapy

• Immunotherapy

• Radiation

• Bone marrow transplant

RESEARCH

• New drugs

• Cord blood and planceta

CHRONIC LYMPHOCYTIC LEUKEMIA

• Clonal proliferation & accumulation of B cell

neoplastic in liver, spleen, nnll, bone marrow

• Commonest leukemia in adults (65 yr)

older is more freq

• Does not affect children

• Approximately 25% of all leukemias

• Male > female

• Caucasian

• Survival rate : 5 yrs after diagnosis

US SEER data – annual cases/100,000

PATHOLOGY

• Genetic change in B-cell clone• Slow proliferation exceeds apoptosis• Gradual accumulation of neoplastic B –

lymphocytes• Neoplastic B-lymphocyte accumulation

– blood lymphocytosis– marrow failure – lymphadenopathy (lymphocytic lymphoma)– Spleenomegaly– hepatomegaly

CLINICAL FEATURES

• Asymptomatic• Marrow failure• Symptoms

– weight loss– night sweats– tired– fevers

• Lymphadenopathy (general 50%)• Splenomegaly, hepatomegaly (25-50%)• Obstruction

BLOOD COUNT

WBC x 109/L 150.0 [4-11]Hb g/L 98 [120-160]MCV fl 87 [79-98]Platelets x 109/L 48 [150-450]

Neuts x 109/L 1.5 [2-7.5]Lymphs x 109/L 130.0 [1.5-4]Monos x 109/L 0.5 [0.2-0.8]Eos x 109/L - [0-0.7]Basos x 109/L - [0-0.1]

Smudge cells x 109/L 28.0 [0]

Film Comment: appearances suggest CLL

lymphocytes

lymphocytes

‘smudge’ cells

DIAGNOSIS

• Increase in blood lymphocyte count (95%) : small lymphocyte & smudge cell dominan

• Infiltration lymphocytes to bone marrow (>30% lymphocytes) : interstitial, nodolar, difus

• Demonstrate presence of a B-lymphocyte clone of appropriate immunophenotype– Surface marker analysis – ‘flow cytometry’ (CD5+,

CD19+, CD20+,CD23+, CD22-/+)

COMPLICATIONS

• Hypogamaglobulinemia (66%) : all of Ig class (IgG, IgM, IgA), neutrophilia bacteria infection

• Failure of humoral and cellular immunity– Opportunistic infection common profilactic

• eg shingles, pneumocystis carinii, bacteria (M. tbc, Listeria sp.), fungi (candida, aspergilus), CMV

• Malignancy transformation : to become Richter syndrome, prolimphocytic leukemia, plasma cell leukemia, MM, Hodgkin lymphoma

• Malignancy secondary : skin, lung, GIT• Autoimmune diasese

– warm autoimmune hemolytic anemia– autoimmune thrombocytopenia– pure red cell aplasia– agranulositosis

PRINCIPLES OF TREATMENT

• Incurable• No treatment is needed for asymptomatic

patients without marrow failure• Control of the disease with chemotherapy is

the goal in symptomatic patients• Individualized treatment based on biological

and genetic risk factors is probably coming

MEDIAN SURVIVAL (years)

• Early - lymphocytosis alone (>10y)

• Late - marrow failure (3-4y)

Montserrat, E. Hematology 2006;2006:279-

284

Overall survival of patients with CLL according to Binet stages (Barcelona

series)

frequency of CLL-like clones in peripheral blood

Normals >40 y 3%

Males > 40 y 6%

Healthy 1st degree CLL relatives

10-15%

Essential Monoclonal Lymphopathy

Oligoclonal B-cell expansions in normal aging individuals and family members

of patients with B-CLL

CHRONIC MYELOID LEUKEMIA

• 1st leukemia which found; 20% of leukemias (II)• Adult 30-50 yr old• A neoplasm of hemopoietic stem cells caused by the ‘Philadelphia’ chromosome t(9;22)• Granulocyte proliferation with differentiated cell •A three-phase disease

–Chronic (3-5 yrs)–Accelerated–Blast crisis (3-6 mth)

PATHOLOGY

• Chronic Phase– Accumulation of myeloid cells

• bone marrow• peripheral blood• spleen and liver• elsewhere

• Accelerated Phase BLAST CRISIS– Further genetic changes in the stem cell

leading eventually to acute transformation (ie acute leukemia) and death

“The findings suggest a causal relationship between the chromosome abnormality observed and chronic granulocytic leukemia.”

He found 22q chromosome or 22 chromosome with loss of long arm

Peter Nowell, 1960

The Philadelphia Chromosome

Janet Rowley

1973

bcr

abl

fusion 9abl/bcr

fusion 22bcr/abl

CLINICAL FEATURES OF CHRONIC PHASE

• Peak age 20 to 40 years

• Weight loss, night sweats

• Big spleen

• Gout

• Often found by chance

WBC x 109/L 122.0 [4-11]Hb g/L 98.5 [120-160]MCV fl 87 [79-98]Platelets x 109/L 843 [150-450]

Neuts x 109/L 80.0 [2-7.5]Lymphs x 109/L 2.0 [1.5-4]Monos x 109/L 2.0 [0.2-0.8]Eos x 109/L 1.0 [0-0.7]Basos x 109/L 5.0 [0-0.1]

Blasts x 109/L 2.0 [0]Promyelocytes x 109/L 4.0 [0]Myelocytes x 109/L 20.0 [0]Metamyelocytes x 109/L 4.0 [0]

Nucleated RBC x 109/L 2.0 [0]

Film Comment: appearances suggest CML

BLOOD COUNT

basophil blast

neutrophils and precursors

promyelocyte

DIAGNOSIS

• Blood count

• Genetic analysis (RT-PCR or FISH)

• Bone marrow in selected cases

ACCELERATED PHASE

• Was inevitable – now prevented by imatinib

• 1/3 ALL; 2/3 AML

• Clinical features– sweats, weight loss, bone pain, enlarging spleen– bone marrow failure, and blasts in the blood

• Onset and course rapid, outcome fatal.

• Imatinib mesylate to achieve a ‘Major Molecular Remission’ (by Q-RT-PCR)

• Allogeneic transplantation

• Hydroxyurea

PRINCIPLES OF TREATMENT

• No treatment (3)

• Suppressive chemotherapy (4)

• Imatinib mesylate (90% alive at 5 yrs)

• Transplant (5+)

MEDIAN SURVIVAL (years)

Druker B et al. N Engl J Med 2006;355:2408-2417

Kaplan-Meier Estimates of the Rates of Event-free Survival and Progression to the Accelerated Phase or Blast Crisis of CML for Patients Receiving Imatinib

European BMT data 1980 - 90

Chronic myeloid leukemia

• The myeloproliferative diseases (MPDs) are clonal stem cell disorders characterised by leukocytosis, thrombocytosis, erythrocytosis, splenomegaly, and bone marrow hypercelularity

• They are divided into polycythemia vera (PV), essential thrombocytosis (ET), agnogenic myeloid metaplasia or myelofibrosis and chronic myelogenous leukemia (CML)

• CML results from a somatic mutation in a pluripotential lymphohematopoietic cell

• CML is a MPD characterized by increased granulocytic cell line, associated with erythroid and platelet hyperplasia

• The disease usually envolves into an accelerated phase that often terminates in acute phase

chronic phase 3-5 yearsaccelerated phaseblastic phase 3-6 months

Etiology

• Exposure to high- dose ionizing radiation• Chemical agents have not been established as a cause

Epidemiology

• CML accounts for approximately 15 percent of all cases of leukemia and approximately 3 percent of childhood leukemias

• The median age of onset is 53 years

Pathogenesis Hematopoietic abnormality• Expansion of granulocytic progenitors and a decreased sensitivity of the progenitors to regulation – increased white cell count• Megakaryocytopoiesis is often expanded• Erythropoiesis is usually deficient• Function of the neutrophils and platelet is nearly normal

Pathogenesis Genetic abnormality• CML is the result of an acquired genetic abnormality• A translocation between chromosome 9 and 22 [t(9;22)] – the Philadelphia chromosome• The oncogene BCR-ABL encodes an enzyme – tyrosine phosphokinase (usually p210)

Translocation t(9;22)(q34;q11)

Translocation t(9;22)(q34;q11)

Philadelphia Chromosome• More than 95% of patients with CML has Philadelphia

(Ph) chromosome A subset of patients with CML lack a detectable Ph

chromosome but have the fusion product for the bcr/abl translocation detectable by reverse transcriptase- polymerase chain reaction (RT-PCR)

The bcr/abl fusion protein

• Uncontrolled kinase activity

1. Deregulated cellular proliferation

2. Decreased adherence of leukemia cells to the bone marrow stroma

3. Leukemic cells are protected from normal programmed cell death (apoptosis)

Clinical features

• 30 percent of patient are asymptomatic at the time of diagnosis

• Symptoms are gradual in onset: easy fatigability, malaise, anorexia, abdominal

discomfort, weight loss, excessive sweating● Less frequent symptoms: Night sweats, heat intolerance- mimicking

hyperthyroidism, gouty arthitis, symptoms of leukostasis (tinnitus, stupor), splenic infartion (left upper-quadrant and left shoulder pain), urticaria (result of histamine release)

● Physical signs: Pallor, splenomegaly, sternal pain

Laboratory features

• The hemoglobin concentration is decreased

• Nucleated red cells in blood film

• The leukocyte count above 25000/μl (often above 100000/μl), granulocytes at all stages of development

• Hypersegmentated neutrophils

• The basophiles count is increased

• The platelet count is normal or increased

• Neutrophils alkaline phosphatase activity is low or absent (90%)

Laboratory features (2)

• The marrow is hypercellular (granulocytic hyperplasia)• Reticulin fibrosis• Hyperuricemia and hyperuricosuria• Serum vitamin B12-binding proteine and serum vitamin

B12 levels are increased• Pseudohyperkalemia, and spurious hypoxemia and

hypoglycemia• Cytogenetic test- presence of the Ph chromosome• Molecular test – presence of the BCR-ABL fusion gene

Differential diagnosis

• Polycythemia vera• Myelofibrosis• Essential thrombocytemia• Extreme reactive leukocytosis

Treatment

• New treatment options - - individualisation of treatment decisions based on

the risk category in which a patiens resides

TreatmentPrognostic factors

• Sokal score = = (11x age + 35x spleen + 89x blasts + 0,4x platelet –

550)/1000

• Euro scale = = (0,666x age /0 when age <50, 1 when >/ + 0,0420x

spleen + 0,0584x blasts + 0,0413x eosinophils + 0,2039x basophils /0 when basophils <3%, 1 when basophils >3%/ + 1,0956x platelet /0 when platelet <15000G/l, 1 when >/) x 1000

Sokal EuroLow risk <0,8 <780Moderate risk 0,8-1,2 781-1479High risk >1,2 >1480

Treatment

• Oral chemotherapeutic agents (hydroxyurea, busulfan)

• Interferon alfa• Imatinib mesylate (Glivec, Gleevec)• Allo- SCT

TreatmentHydroxyurea

• Often used initially for white cell count reduction• Dose: 1-6g/d orally, depending on the hight of the

white cell count• The dose should be decreased to 1-2g/d when the

leukocyte count reaches 20000/µl• Drug should be stopped if the white count falls to

5000/µl• Side effects: suppression of hematopoiesis, often with

megaloblastic erythropoiesis• It does not alter long-term prognosis

Treatment Interferon-alfa

• Patients with low risk (Sokal/Euro score) and high TRM, patient not eligible for alloSCT

• Side effects are more intensive above 60 years of age• Dose: 3million units/m² subcutaneously 3 days per

week, and after 1 week – 5 million u/m². Maximal dose: 5 million u/m² per day. After maximal response (6-8 months) 3-5 million u/m² once or twice weekly

• Dose should be reduced or teporarily discontinued if the white cell count less than 5000/µl or platelet count less than 50000/µl

• The higher the dose tolerated the greater the cytogenetic response

Treatment Interferon alfa

• Initial side effects of INFalfa: fever, fatigue, sweats, anorexia, headache, muscle pain, nausea, and bone pain – 50% of patients

• Later effects: apathy, insomnia, depression, bone and muscle pain, hepatic, renal and cardiac dysfunction, immunemediated anemia, thrombocytopenia, hypothyroidism, hypertriglyceridemia

• A polyethylene glycol-conjugated interferon-alfa (PEG-interferon)- better toleration, treatment once per week

• Prolong the chronic phase of CML more likely than hydroxyurea

• Hematologic improvement – 75% of patients, cytogenetic remission – 10%, molecular remission- 2%

• If after 6 months no or poor responce – Imatinib or alloSCT

Criteria of cytogenetic response

Cytogenetic response

% of Ph in bone marrow

complete 0

maior 1-35

minor 36-95

lack of response >95

Criteria of molecular response

Complete molecular response:

BCR/ABL transcript undetectable in PCR

Maior molecular response:

≥3-log reduction of BCR/ABL transcript in RQ-PCR

Treatment Interferon with Cytarabine

• Cytarabine (Ara-C, cytosine arabinoside) has activity against CML cells

• Dose: 20-40mg/m² subcutaneously over 10 days per month combined with interferon-alfa

• Combined therapy can improve the results of treatment

TraetmentImatinib mesylate (Gleevec)

• Inhibits activity of mutant tyrosine kinase by blocking ATP binding

• Very useful in older patients or patients intolerant or resistance to interferon-alfa

• Imatinib has less toxicity, is easier to administer , and induces higher hematologic (90 percent vs. 75percent), cytogenetic (40 percent vs. 10 percent) and molecular (7 percent vs. 2 percent) types of remission

• Dose: 400mg/d orally (maximal dose 600-800mg/d in two divided doses)

• Usually after 3-9 months of treatment – cytogenetic response

TreatmentImatinib mesylate

• Side effects: nausea, vomiting, edema, muscle cramps, diarrhea, headache, abdominal pain- usually low-grade

• The drug can be used prior the alloSCT if eligible, or nonmyeloablative SCT for older patient

TreatmentEarly alloSCT

• The early mortality in younger patient (below 40 years of age) – 15 percent

• 5-year survival can be achieved in 60 percent of patients in chronic phase (some can be cured)

• There is 20 percent chance of relapse of CML in the years after succesful transplantation

• Donor lymphocyte infusion (DLI) can produce remission in transplanted patiens who have relapse of their disease

TreatmentPrognostic factors

• Sokal score = = (11x age + 35x spleen + 89x blasts + 0,4x platelet –

550)/1000

• Euro scale = = (0,666x age /0 when age <50, 1 when >/ + 0,0420x

spleen + 0,0584x blasts + 0,0413x eosinophils + 0,2039x basophils /0 when basophils <3%, 1 when basophils >3%/ + 1,0956x platelet /0 when platelet <15000G/l, 1 when >/) x 1000

Sokal EuroLow risk <0,8 <780Moderate risk 0,8-1,2 781-1479High risk >1,2 >1480

TreatmentRisk of transplant-related mortality

(TRM)A Donor Score

HLA-matched sibling donor 0Unrelated donor 1

B Phase of diseaseChronic 0Accelerated 1Blastic 2

C AgeBelow 20 years 020-40 years 1Above 40 years 2

D Donor/acceptor combination of sexOther 0Women donor for man acceptor 1

E Time between CML diagnosis and alloSCT<12 months 0>12 months 1

TreatmentDecision making in the imatinib area

How does one treat the younger CML patients with a possible allogeneic donor?

OPTION 1: give all patients an initial trial of imatinib

OPTION 2: Offer early allograft to selected patients and trial of imatinib to other patients

TreatmentAlgorithm for treating CML (Option 1)- 2004

DIAGNOSIS

Imatinib for all

Response to imatinib‘Failed” response

to imatinib

Continue Consider for SCT

TreatmentAlgorithm for treating CML (Option 2) - 2004

DIAGNOSIS

Decision point

Define category of patients for initial allo-SCT

Not for initial allografting

Allo - SCTInitial trial of imatinib

(or combination)

If imatinib fails, proceed to allo-SCT

TreatmentOption 2 – Proposed indications for early

allo-SCT

• CML-CP up to age 45 with sibling donor• CML-CP up to age 35 with molecularly

matched unrelated donor

Treatment

• Splenic radiation- useful in marked splenomegaly and splenic pain (marked splenomegaly usully asociated with acute transformation of the disease)

• Splenectomy- helpful in patient with thrombocytopenia and massive splenomegaly refractory to therapy (postoperative complications)

• Radiotherapy for extramedullary granulocytic tumors• Leukapheresis – useful in patients in early pregnancy

Accelerated phase of CML

• Most patients eventually became resistant to therapy and the disease enters a more agressive phase

• Criteria of accelerated phase1. Blasts in blood or bone marrow-10-19%2. Basophilia ≥ 20%3. Thrombocytopenia <100G/l4. Thrombocytaemia >1000G/l5. Additional chromosomal aberrations6. refractory splenomegaly or refractory

leucocytosis

Blast phase (blast crisis) of CML

• Criteria of blast phase

1. Blasts ≥20%

2. extramedullary tumors

• Phenotype of blasts

1. Mieloblasts - 50%

2. Limphoblasts - 30%

3. Megakarioblasts – 10%

4. Acute myelofibrosis

Treatment of patients with AML phenotype

• Start with Imatinib 600mg/d, if tolerated can increase to 400mg twice a week.

• If remission develops consider allogeneic stem cell transplant

• If relapse on Imatinib therapy consider an AML drug protocol depending on patient´s age and condition

Treatment of patients with ALL phenotype

• Start with Imatinib 600mg/d orally- maximal dose 400mg twice a day. If remission develops consider allogeneic stem cell transplantation

• If relapse after imatinib consider ALL drug protocol:

Vincristine sulfate 1,4mg/m² iv once per week

+ prednisone 60mg/m² per day orally

one-third of patiens reenters the chronic phase, but remission lasts usually about 4 months

• Allogeneic stem cell transplantation can prolong remission in blasts crisis