LEUKEMIA

Candra Wibowo
Nephrology 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)

MAIN TYPES OF LEUKEMIA

Acute
no maturation beyond blast

Chronic
maturation beyond blast

Lymphocytic
T or B lineage

ALL

CLL

Myeloid
(granulocytes, monocytes, erythrocytes, platelets)

AML

CML

The peripheral blood WBC in leukemia

W eC hit ell C ount Acut e Low normal , or high High

Different ial W e Cell C hit ount If high, blast cells predominate. If normal or low , may be very fewblast s Mature cells predominat e. Blast s less t han 1 0%

C hronic

Demographics of Leukemia
Patients (2001 Data)
CLL=Chronic Lymphocytic ALL=Acute Lymphocytic CML=Chronic Mylogenous AML=Acute Mylogenous
CML 15% CLL 26% others 17% ALL 11%

AML 31%

Sources from Leukemia, Lyphoma, Myeloma Facts 2001

Total Reported Cases = 31,500

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
Platelet
White Cell Red Cell White Cell Red Cell Platelet Blasts

Normal human blood

Sources from Arginine.umdnj.edu

Blood with leukemia

Sources 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

Legend

White Cell Red Cell Platelet Blast Germ

Stage 5a- Anemia

Stage 4- Worsening
Sources from Leukemia, by D. Newton and D. Siegel

Stage 5b- Infection

CAUSES
High level radiation/toxin exposure
Viruses Genes Chemicals Mostly unknown Cant 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
W x 1 9/L BC 0

Hb g/L MC fl V Plat elet s x 1 9/L 0 Neu s x 1 9/L t 0 L phs x 1 9/L ym 0 Mon x 1 9/L os 0 Eos x 1 9/L 0 Basos x 1 9/L 0 Sm udge cells x 1 9/L 0

1 50.0 98 87 48 1 .5 1 30.0 0 .5 28.0

[4-1 ] 1 [1 20-1 0] 6 [79-98] [1 50-450] [2-7.5] [1 .5-4] [0.2-0.8] [0-0.7] [0-0.1 ] [0]

Film C m t : ap om en pearances su est CL gg L

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)

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

Montserrat, E. Hematology 2006;2006:279-284

Essential Monoclonal Lymphopathy

Oligoclonal B-cell expansions in normal aging individuals and family members of patients with B-CLL
frequency of CLL-like clones in peripheral blood 3% 6% 10-15%

Normals >40 y Males > 40 y Healthy 1st degree CLL relatives

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

1973

Janet Rowley

fusion 22 bcr/abl

abl
bcr

fusion 9 abl/bcr

CLINICAL FEATURES OF CHRONIC PHASE

Peak age 20 to 40 years Weight loss, night sweats Big spleen Gout Often found by chance

BLOOD COUNT
W BC x 1 9 /L 0 Hb g/ L MC fl V Plat elet s x 1 9 /L 0 Neut s x 1 9 /L 0 Lym phs x 1 9 /L 0 Monos x 1 9 /L 0 9 Eos x 1 /L 0 Basos x 1 9 /L 0 Blast s x 1 9 /L 0 Prom yelocyt es x 1 9 /L 0 9 Myelocyt es x 1 /L 0 Met am yelocyt es x 1 9 /L 0 Nucleat ed RBC x 1 9 /L 0 1 22.0 9 8 .5 87 8 43 8 0 .0 2.0 2.0 1 .0 5.0 2.0 4.0 20 .0 4.0 2.0 [4-1 ] 1 [1 -1 0 ] 20 6 [79-9 8 ] [1 -450 ] 50 [2-7.5] [1 .5-4] [0 .2-0 .8 ] [0 -0 .7] [0 -0 .1 ] [0 ] [0 ] [0 ] [0 ] [0 ]

Film C om ment : appearan ces suggest C ML

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.

PRINCIPLES OF TREATMENT
Imatinib mesylate to achieve a Major Molecular Remission (by Q-RT-PCR) Allogeneic transplantation Hydroxyurea

MEDIAN SURVIVAL (years)

No treatment (3) Suppressive chemotherapy (4) Imatinib mesylate (90% alive at 5 yrs) Transplant (5+)

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

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

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 accelerated phase blastic phase 3-5 years 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

1. 2. 3. Uncontrolled kinase activity Deregulated cellular proliferation Decreased adherence of leukemia cells to the bone marrow stroma 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/l (often above 100000/l), 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

Treatment Prognostic 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
Low risk Moderate risk High risk Sokal <0,8 0,8-1,2 >1,2 Euro <780 781-1479 >1480

Treatment

Oral chemotherapeutic agents (hydroxyurea, busulfan) Interferon alfa Imatinib mesylate (Glivec, Gleevec) Allo- SCT

Treatment Hydroxyurea
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/l Drug should be stopped if the white count falls to 5000/l 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/m subcutaneously 3 days per week, and after 1 week 5 million u/m. Maximal dose: 5 million u/m per day. After maximal response (6-8 months) 3-5 million u/m once or twice weekly Dose should be reduced or teporarily discontinued if the white cell count less than 5000/l or platelet count less than 50000/l 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 (PEGinterferon)- 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 complete

% of Ph in bone marrow 0

maior
minor lack of response

1-35
36-95 >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/m subcutaneously over 10 days per month combined with interferon-alfa Combined therapy can improve the results of treatment

Traetment Imatinib 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

Treatment Imatinib 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

Treatment Early 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

Treatment Prognostic 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
Low risk Moderate risk High risk Sokal <0,8 0,8-1,2 >1,2 Euro <780 781-1479 >1480

Treatment Risk of transplant-related mortality (TRM)

A Donor HLA-matched sibling donor Unrelated donor Phase of disease Chronic Accelerated Blastic Age Below 20 years 20-40 years Above 40 years Donor/acceptor combination of sex Other Women donor for man acceptor Time between CML diagnosis and alloSCT <12 months >12 months Score 0 1 0 1 2 0 1 2 0 1 0 1 B

Treatment Decision 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

Treatment Algorithm for treating CML (Option 1)- 2004

DIAGNOSIS

Imatinib for all

Response to imatinib

Failed response to imatinib

Continue

Consider for SCT

Treatment Algorithm for treating CML (Option 2) - 2004

DIAGNOSIS

Decision point

Define category of patients for initial allo-SCT

Not for initial allografting

Allo - SCT

Initial trial of imatinib (or combination)

If imatinib fails, proceed to allo-SCT

Treatment Option 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

1. 2. 3. 4. 5. 6. Most patients eventually became resistant to therapy and the disease enters a more agressive phase Criteria of accelerated phase Blasts in blood or bone marrow-10-19% Basophilia 20% Thrombocytopenia <100G/l Thrombocytaemia >1000G/l Additional chromosomal aberrations refractory splenomegaly or refractory leucocytosis

Blast phase (blast crisis) of CML

1. 2. Criteria of blast phase Blasts 20% extramedullary tumors

1. 2. 3. 4.

Phenotype of blasts Mieloblasts - 50% Limphoblasts - 30% Megakarioblasts 10% 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 patients 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/m iv once per week + prednisone 60mg/m 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