leukemia
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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
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