2. Leukemia
Leukemia is a tumorous disease of the blood system with
primarily affected bone marrow and subsequent
generalization of the process.
Classification of leukemia is based on morphological and
cytochemical characteristics of cells that make up the
tumors substrate. If the leukemia substrate is made up of
mature (blast) cells, such forms are defined as acute
leukemia. In chronic leukemia, maturing and mature cells
proliferate.
3. Classification of leukemia
Acute leukemias are subdivided onto lymphoblastic and
nonlymphoblastic.
Chronic leukemias are subdivided into myeloproliferative
and lymphoproliferative.
Chronic myeloproliferative leukemia include:
- Chronic myelogenous leukemia;
- Myelofibrosis;
- Essential thrombocytosis;
- True polycythemia (erythremia).
Chronic lymphoproliferative leukemia include:
- Chronic lymphocytic leukemia;
- Paraproteinemic hematoloblastoses (multiple myeloma,
Waldenstrom's macroglobulinemia)
4. Acute leukemia is a rapidly progressive form of
leukemia, characterized by replacement of the normal
bone marrow with immature blast cells without
differentiating them into normal mature cells.
The entire tumor mass is represented - only by
blasts.
5. Etiology
1. Normally, the body constantly mutates cells →
the main mechanism of evolution →
undesirable mutations → APOPTOSIS;
2. Mutation of cells → undesirable mutations →
apoptosis does not work → non-controlled cell
growth – TUMOR.
8. Pathogenesis
1) Mutation in one of the cells of the bone
marrow;
2) Cells lose the ability to differentiate;
3) Mutant cells are completely autonomous and
with a very high rate of mitosis;
4) From the moment of mutation of one cell to
the appearance of the first clinical and
laboratory appearance - takes about 2 months;
9. During this period, the tumor increases from one
cell to 1 kg;
Rapid displacement of the normal bone marrow;
Development of severe pancytopenia;
Continuous appearance of new chromosomal
abnormalities;
Pathogenesis
10. Forms of onset of acute leukemia
sharp beginning;
The beginning of the disease with severe
hemorrhagic phenomena
slow asymptomatic (latent) onset
11. Main clinical leukemia syndromes
1) Hyperplastic syndrome
Рainless enlarged lymph nodes, liver, spleen, tonsils
(up to the violation of breathing) and syndrome of
compression;
Аn increase in the lymph nodes of the mediastinum
(compression of the superior vena cava),
Gingival hyperplasia with the development of
ulcerative necrotic stomatitis;
Pronounced soreness with the effleurage of bones,
Development of leukemic skin infiltration, in the form
of leukemia
15. The defeat of the lungs - cough, hemoptysis, dyspnea,
diarrhea in a restive type, clinic of pneumonia,
pleurisy, compression of the bronchi with enlarged
lymph nodes;
The defeat of the heart - a violation of rhythm and
conductivity, pericarditis;
Defeat of the endocrine system;
Lesion of the musculoskeletal system - pain in the
bones.
Development of multiple organ failure.
16. 2) Anemic Syndrome
Mechanism of anemia in hemoblastoses
Bone marrow - initial period
Leukemia
Replacement of the red blood-forming germ
17. 3) Hemorrhagic syndrome
-thrombocytopenia - exclusion of bone marrow;
-increased permeability of blood vessels:
Severe anemia - disruption of endothelial nutrition and
vascular wall vasa vasorum
violation of the synthesis of plasma coagulation factors -
Severe anemia - the failure of the liver and its functions;
Different degrees of severity. In 15-20% of cases is the
main reason to measure patients.
19. 4) Immunodeficiency syndrome;
5) Intoxication syndrome - due to the
syndrome of lysis of the tumor mass
and attachment of the infectious
process;
20. Features of fever in leukemia
body temperature daily higher than 38-39 ° C;
duration of fever more than 2 weeks;
there are no clinical manifestations of infection
Blood and urine cultures on bacteria fungal flora, viral
infection negative;
There is no positive therapeutic response to empirical
antibiotic therapy;
Quickly disappears after taking naproxen and other non-
steroidal anti-inflammatory drugs;
Programmed treatment of acute leukemia with
cytostatic agents causes a persistent normalization of
body temperature.
21. Clinical symptoms of
neuroleukemia
Clinical symptoms of neuroleukemia are made up of the
symptoms of intracranial hypertension and of local
symptoms caused by specific infiltration of the cerebral
tissue and of its meninges by tumor cells. Characteristic
symptoms of neuroleukemia: headache, nausea, vomiting,
elevated blood pressure, dizziness, blurred vision
(development of strabismus, diplopia, flickering flies, loss
of field of vision, photophobia).
22. Neuroleukemia
Infiltration of the meninges,
leading to damage to the
facial nerve and unilateral
paralysis of facial muscles
Edema and
hemorrhages in the
retina as a result of
diffuse infiltration of
the meninges
23. Stages of the AL
Acute leukemia has several stages:
1: The first attack of the disease,
2: Stage of remission,
3: Recurrence stage
4: Terminal stage.
24. The parameters of the general blood test for acute
leukemia
anemia;
Reticulocytopenia;
thrombocytopenia;
Leukocytosis or leukopenia;
Blastemia;
Neutropenia
phenomenon of "failure"
Disappearance of basophils and eosinophils;
Increased ESR;
25. Values of the leukocyte formula
Leukocytes
(4 - 9*109/l)
Young
( 0% )
Eos
(1-5)
Bas
(0-1)
Stab
neutro
phils
(1-6)
Segmen
-ted
neutro-
phils
(47-72)
Lim
(19-37)
Mon
(2-8)
50,5
43%
- - -
- 57
-
Acute leukemia
blasts
ESR – 25-56 mm/h
phenomenon of "failure"
26. Values of the leukocyte formula
Leukocytes
(4 - 9*109/l)
Young
( 0% )
Eos
(1-5)
Bas
(0-1)
Stab
neutro
phils
(1-6)
Segmen
ted
neutrop
hils
(47-72)
Lim
(19-37)
Mon
(2-8)
50,5
43%
- - -
57 -
-
Acute leukemia
blasts
ESR – 25-56 mm/h
phenomenon of "failure"
27. In the myelogram :
- Blasts 20% or more
- Expressed reduction of all normal blood sprouts.
28. Normal bone marrow Acute lymphoblastic
leukemia
Аcute myeloblastic
leukemia
Picture of red bone marrow
29. !!!!!! Trepanobiopsy !!!!!;
Biochemistry of blood;
Radiography of chest organs;
Ultrasound of the abdominal cavity;
Cytochemical analysis of sternal punctate is
the basis for verifying the type of acute
leukemia (myelo - or lymphoblastic);
30. The technique of sternal puncture
(trepanobiopsy)
The sternum area
The iliac region
31. Differential diagnosis of acute leukemia
Acute lymphoblastic
leukemia
Acute myeloblastic
leukemia
Age Children and young Median - 64 years
Leukemids More pronounced less often
Enlargement of
lymph nodes
there is Less common and
smaller
Stomatitis no always
Neuroleukemia always less often
Cytochemical
reaction
Positive for glycogen Positive for
myeloperoxidase
32. Specific features of some forms of acute
leukemia:
1. Acute myeloid leukemia. The disease is characte-
rized by rapid development of intoxication, anemic
and hemorrhagic syndromes. The syndrome of
neoplastic proliferation is less common than in ALL.
2. Acute promyelocytic leukemia. The clinical picture
is characterized by development of severe syndrome
of disseminated intravascular coagulation, which
earlier led to a fatal outcome in almost all patients.
Prognosis has changed nowadays due to the use of
monochemotherapy with trans-retinoic acid (ATRA,
vitamin A derivatives).
33. Specific features of some forms of acute
leukemia:
3. Acute erythroleukemia. At the onset of the
disease, there are "rheumatic" symptoms
(arthralgia, serositis), as well as persistent
anemia. The treatment is less effective than in
other variants of AML.
4. Acute lymphoblastic leukemia. Frequent
incidence of tumor cell proliferation syndrome
and of neuroleukemia. Cytogenetic
abnormalities are noted in more than a half of
ALL patients.
35. The main stages of therapy
Specific treatment (Polychemotherapy, (PCT);
Symptomatic therapy;
Bone marrow transplantation.
36. Treatment of acute leukemia
Treatment of acute leukemia is a complicated and
protracted process. There are several principles in the
treatment of AL:
1. Staging. Four stages: induction of remission,
consolidation of remission, neuroleukemia prevention,
supportive treatment;
2. Program approach. Courses of programmed
chemotherapy (PCT) based on the AL form;
monochemotherapy with trans-retinoic acid in the
promyelocytic type are administered. Calculation of
dosage for cytostatic medication is performed on the
account of the patient's body surface area.
37. Treatment of acute leukemia
3. Duration of treatment. Currently, treatment of acute lymphoid
leukemia takes 2 years. Recently developed programs for treating
of myeloid forms are aimed at reduction of treatment duration to
1 year due to the intensification of the induction and
consolidation of remission;
4. Complexity. Polychemotherapy should be combined with
supportive treatment, including therapy with antibacterial and
antifungal agents, detoxication, substitution therapy (transfusion
of washed erythrocytes, platelets, plasma), inhibitors of
proteolysis and uric acid, and other symptomatic agents. In
invasive aspergillosis, voriconazole (itraconazole) is the therapy
of choice. In order to prevent tumor lysis syndrome, beginning
from the first day of chemotherapy course, the volume of the
infused fluid is increased to 3 liters/m2 per day with stimulation
of diuresis with diuretics.
38. Tactics conducting PCT
1 2 3 4 5 6 7 8 9
induction
of
remission
remission
consolidation
remission
consolidation
Maintenance therapy
The interval between the courses is 28-32 days
39. The basic clinical and laboratory concepts
Complete remission - in the myelogram 5% or less
blasts, with complete normalization of the general
blood analysis - at least 1 month;
Recovering - complete remission lasting 5 years or
more.
40. Scheme 7 + 3
rubomycin
cytosar
Days
Schemes of PCT in AML
41. General principles of therapy ALL
Use in the period of induction of at least 4 cytotoxic
drugs;
Compulsory combination with the
glucocorticosteroids ;
Prophylaxis of neiroleukemia;
High-dose consolidation;
Prolonged maintenance therapy
43. Selective decontamination of the intestine
Selective decontamination of the intestine is indicated in
chemotherapy courses, which are characterized by the
development of "deep" and / or prolonged (more than 5-
7) days of neutropenia.
It is spent to patients:
- acute myeloblastic leukemia,
- acute lymphoblastic leukemia,
- myelodysplastic syndrome
- aplastic anemia (treatment with antibiotics,
antilymphocytic globulin)
- recipients of bone marrow
- lymphogranulomatosis, lymphosarcoma, chronic
myeloid leukemia during intensive courses of therapy.
44. Antibacterial drugs used for decontamination:
unabsorbed antibiotics (1 or 2:
kanamycin 1.5 g / day,
polymyxin B or M (0.5 x 4 times a day),
gentamicin (200 mg / day)
trimethoprim-sulfamethoxazоl (960 mg x 2 times
daily)
ciprofloxacin (250 mg x 2 times a day)
45. Empirical antibiotic therapy in patients with
hemoblastosis
Indications for the prescription of antibiotics of the 1st
stage :
an increase in temperature of more than 38°C, which lasts for 2
hours and is not associated with the administration of
pyrogenic preparations (blood components, growth factors)
and / or the presence of a foci of infection (pneumonia,
paraproctitis).
myelotoxic agranulocytosis (leukocytes less than 1000 in 1 μl or
neutrophils less than 500 in 1 μl).
46. Stage I of empirical antibiotic therapy
Monotherapy (one of these drugs is prescribed).
Ceftazidime ("Fortum") - cephalosporin III generation 2 g x 3
times
Cefepime ("Maksipim") cephalosporin IV generation.
Dosing - 2 g x 2 or 3 times a day.
Meropenem (Meronem) - carbapenem. Dosage of 1.0 x 3
times a day.
Imipenem / cilastatin ("Tienam") - carbapenem. Dosage of
0.5 x 4 times a day for 30 minutes.
47. Combination Therapy
Cephalosporins III / IV generation + aminoglycosides:
Ceftazidime ("Fortum") + aminoglycoside.
Cefoperazone ("Cefobide") + aminoglycoside.
Cefepime (Maxipim) + aminoglycoside
Cefoperazone / sulbactam ("Culperazone") + aminoglycoside
The aminoglycosides used are amikacin, netilmicin,
tobramycin. Because of the high frequency of resistance of
bacteria to gentamicin, the use of the latter should be as
rare as possible.
Aminoglycosides are administered once (once a day, a daily
dose or 2/3 of a daily dose is administered) or 3 times a day.
49. Bone marrow transplantation
The main stages of transplantation :
- Bone marrow collection from a patient or donor;
- Complete destruction of the patient's bone marrow
(medication and radiation exposure);
- Introduction of bone marrow - intravenously;
50. Types of transplants
Autologous - the brain of the patient;
Allogeneic - from a donor or a twin.
May be!
"Graft versus host"
"Rejection reaction"
51. Several skin punctures are required in both femurs and
multiple bone punctures to obtain a sufficient amount of
bone marrow.
The amount of bone marrow required for transplantation
depends on the size of the patient and the concentration of
bone marrow cells in the substance taken. Usually they
take from 950 to 2000 milliliters of a mixture consisting of
bone marrow and blood-in fact, it is only about 2% of the
human bone marrow and the body of a healthy donor
replenishes it within four weeks.
52. Bone marrow transplantation - iv mixture in the ward;
2-4 weeks critical period - the reaction of the body and
bone marrow;
The main is symptomatic therapy
53. The main criteria for the remission:
1. Presence of less than 5% blast cells in the bone marrow
punctate;
2. Absence of blasts in blood; neutrophil level should be
higher than 1.5x109/l, platelet count to be higher than
100x109/l;
3. Absence of extramedullary foci of leukemic growth.
54. The most severe complication of cytostatic therapy is
the development of cytostatic disease.
56. Myeloproliferative disease (MPD)
Myeloproliferative disease" (MPD) based on
a generalized proliferation of the bone
marrow cells induced by unknown stimuli
58. Chronic Myeloproliferative
Leukemia
Chronic Myeloproliferative Leukemia is a
myeloproliferative disease characterized by lesions of a
cell-predecessor of myelopoiesis, which is common for
granulocytic, erythroid and megakaryocytic stems of
hematopoiesis
59. Ph-chromosome
The specific
chromosomal anomaly:
the so-called
Philadelphia
chromosome (Ph-
chromosome).
The long arm of
chromosome 22 is
translocated to the
chromosome 9, while a
piece of chromosome 9
is translocated to
chromosome 22.
60. Stages of Chronic myelogenous
leukemia (CML)
1. Chronic stage,
2. Progressive (accelerated phase)
3. Terminal stage (blast transformation
stage).
Most (>90%) CML patients present in chronic phase.
CML is often diagnosed incidentally during routine
examination or examination for another illness.
61. Nonspecific symptoms
Nonspecific symptoms include:
sub-febrile fatigue,
weight loss,
loss of appetite,
general malaise,
dyspepsia,
ossalgia.
62. Specific symptoms
Splenomegaly (the spleen is enlarged, solid
and bumpy on palpation).
hepatomegaly
Skin itch associated with basophil
hyperhystaminemia
Anemic and hemorrhagic syndrome in
terminal stage
68. Laboratory diagnostic in CML
The blood test: hyperleykocytosis with immature
cell neutrophilia (a sharp left shift to
promyelocytes, myelocytes, metamyelocytes,
single blast cells), presence of eosinophilic-
basophilic association.
In the bone marrow: high cellularity with
hyperplasia and rejuvenation of the granulocytic
stem, thrombocytosis and elevated megakaryocyte
count are likely.
69. General blood analysis
Chronic Myeloproliferative Leukemia,
chronic phase
Еr. Hb Tr.
4,5 х 1012
/l 128 g/l
200,0 х
109
/l
Le х 109
/l
Bas. Eos.
Myelo
cytes
young
Stab.
n.
Segment
n.
Lymf. Mon.
187,0 х
109
/l 3 7 25 15 10 28 5 2
Promyelocytes – 3 %
Blasts – 2 %
a lot of young granulocytes
70. General blood analysis
Chronic Myeloproliferative Leukemia,
terminal phase
Еr. Hb Tr.
2,1 х 1012
/l 75 g/l
80,0 х 109
/l
Le х 109
/l
Bas. Eos.
Myelo
cytes
young
Stab.
n.
Segment
n.
Lymf. Mon.
140,0 х
109
/l 9 6 10 9 6 28 10 -
Blasts – 22 %
71. Myelogram
Hypercellular bone marrow
Hyperplasia of the neutrophilic
germ (leucoerythroblastic ratio
reaches 10-20: 1
The number of cells of the
basophilic and eosinophilic series
is increased, anomalous forms are
often encountered; can be
increased and the number of
megakaryocytes
76. Костный мозг при хроническом мие-
лолейкозе.
а — в развернутой стадии;
74. Accelerated Phase
Transition into the accelerated stage is characterized by
development of resistance to the monotherapy and
emergence of signs of leukemia progression (elevated
leukocytosis, increased percentage of immature
granulocytes, including percentage of blast cells,
elevated platelet)
75. Signs of the terminal stage:
1. The fever is resistant to antibiotics.
2. Emergence of extramedullary foci of hematopoiesis:
myeloid metaplasia of the lymph nodes, of the skin,
mammary glands, and others.
3. Rapidly enlargement of the spleen, recurrent spleen
infarctions.
4. Proliferation of myelocytes, promyelocytes, monocytes
and blast cells in the blood.
5. Considerable increase in blast cell count in the bone
marrow (20%).
6. Emergence of anemia, thrombocytopenia.
7. Refractory response to cytostatic therapy.
78. Earlier various chemotherapeutic medications were
used for the treatment of CML: mielosan,
hydroxyurea, purinethol. Interferon type medications
were used both as monotherapy and in combination
with chemotherapy. However, the use of such
medications can provide only clinical and
hematological improvement, but not eliminate the
tumor clone.
Treatment (CML)
79. The contemporary standard used fir the treatment of
CML is the use of a new generation of medications
(tyrosine kinase inhibitors): imatinib, nilotinib,
dasatinib. The therapy with these medications
provides not only hematologic and cytogenetic
remissions, but also complete destruction of the tumor
clone. During the blastic crisis stage, a combined PCT
is performed depending on the nature of the crisis, like
in the corresponding type of acute leukemia.
Transfusion, hemostatic and antibacterial agents,
detoxication therapy are used in a complex treatment
of patients with CML.
Treatment (CML)
80. The duration of treatment in CML
3 months – complete hematologic remission
6 months– major cytogenetic response
12 months–18 months– major molecular response
81. Treatment. Chronic phase
Allogenic stem cell transplantation (SCT) before
the age of 50 from an HLA matching sibling offers a
70% chance of cure in the chronic phase.
HLA-matched unrelated donor (MUD) SCT is less
successful in curing the disease because of higher
morbidity and mortality.
83. POLYCYTHEMIA VERA (Erythremia)
Erythremia (polycythemia vera) is a tumor-induced
disease of hematopoietic tissue, the substrate for which
are mature and maturing cells of the three stems of the
bone marrow: erythroid, granulocytic and
megakaryocytic.
84. Epidemiology
0,6-1,6 cases per 100,000 persons per year
Men are affected more often than women.
The age range varies from 40 to 60 years.
85. Pathogenesis
Plethora: increased mass of circulating erythrocytes
and its consequences: condensation and enhanced
viscosity of the blood.
Increased blood viscosity leads to the development of
thromboses in the organs
Increased production of granulocytes, including
basophils and platelets
86. The clinical syndrome of Erythremia
Plethoric syndrome (weakness and decreased
work performance, headache, vision loss, a sensation
of "sand" in the eyes, hearing loss, angina pain in the
heart)
myeloproliferative syndrome (splenomegaly,
skin itch associated with taking water procedures,
disordered uric acid metabolism: hyperuricemia,
nephrolithiasis, gout).
hemorrhagic syndrome (nasal, gingival,
gastrointestinal hemorrhages )
87. Polycythemia vera: patient with plethora
(erythrocyanotic changes of the skin color (on the face,
neck, on the back, fingertips and toes) and sclera
92. Complications of Erythremia
1. thrombotic complications (necrosis of the fingers,
thromboses of the larger arteries of the lower and
upper limbs, thrombophlebitis, an ischemic stroke,
infarction of the myocardium and in the organs).
2. hemorrhagic complications (nasal, gingival,
gastrointestinal hemorrhages) due to
thrombocytopathy (platelets are tumorous and
functionally defective).
93. Stages of erythremia:
Stage 1 (initial) is characterized by presence of
absolute erythrocytosis and clinical plethoric
syndrome
Stage 2 (erythremic) - plethoric syndrome, enlarged
spleen, thrombotic complications, hemorrhagic and
myeloproliferative syndromes. In the blood: pancytosis
Stage 3 (terminal) - myelofibrosis, chronic
myelogenous leukemia, acute leukemia, anemia
94. BASIC diagnostic criteria for
erythremia:
Increased hemoglobin content (more than 185 g/l in
men and more than 165 g/l in women);
• Elevated erythrocyte count (more than 6.0x1012/l in
men and more than 5.7x1012/l in women);
• Elevated hematocrit index (more than 52% in men
and more than 48% in women);
• Splenomegaly;
• Presence of mutation in the Jak2 gene (95% cases or
more).
95. Supplementary criteria:
Leukocytosis is more than 12.0x109/l
Thrombocytosis is more than 400.0x109/l
Three-stem proliferation in the bone marrow;
Erythropoietin level below the normal.
96. General blood analysis
Erythremia
Еr. Hb Tr.
5,8 х 1012
/l 190 g/l
450,0 х
109
/l
Le х 109
/l
Bas. Eos.
Myelo
cytes
young
Stab.
n.
Segment
n.
Lymf. Mon.
14,0 х
109
/l 2 6 - - 8 72 12 -
Ht – 58%
ESR – 1 mm/h
97. Differential diagnosis of erythremia
Classification of the secondary erythrocytoses:
I. Physiological erythrocytoses.
2. Secondary absolute erythrocytosis
3. Secondary relative erythrocytosis
4. Familial erythrocytoses
98. Physiological erythrocytoses
1. In the inhabitants of mountainous areas.
2. In athletes.
3. Work at high or low atmospheric pressure (pilots,
divers and others).
99. Secondary absolute erythrocytosis
(due to increased production of
erythropoietin)
Chronic obstructive pulmonary diseases, bronchial
asthma, bronchiectasis,
Congenital "blue" heart defects,
Carboxyhemoglobinemia (in smokers);
Paraneoplastic erythrocytoses
In local renal hypoxia: polycystic renal disease,
hydronephrosis, rejection of a kidney transplant, renal
artery stenosis
Induced by intake of androgens or metabolic steroids
100. Secondary relative erythrocytosis
dehydration (vomiting, diarrhea, diabetes insipidus),
massive burns,
Gaisbock’s syndrome (arterial hypertension, obesity,
plethora, tendency to uric acid diathesis in middle-
aged men with signs of autonomic dysfunction),
stress-induced polycythemia,
work at high temperature
overdosage of the diuretics.
101. Familial erythrocytoses
They are caused by a genetic defect in the bone
marrow.
They have a benign course, do not progress, do not
affect the overall development, the spleen is not
enlarged.
In blood: elevated erythrocyte and hemoglobin level,
with normal leukocyte and platelet count,
In the bone marrow: normal.
102. Treatment of erytremia
The goal of therapy for erythremia is reduction of risk
of thrombosis and of vascular complications.
1. Blood exfusions or Erythrocytaphereses
Blood exfusions are administered at 400-500 ml every
other day (through the day).
Erythrocytaphereses more effective than blood
exfusions because after centrifugation, part of the
plasma portion is reinfused to the patient
103. Treatment of erytremia
2. Antiplatelet therapy (aspirin, curantil,
trental, pentoxifylline)
3. Cytostatic therapy (hydroxyurea).
Indications for cytostatic therapy:
thrombocytopenia and leukocytosis.
4. If the itchy skin is prescribed
antihistamines
104. Potential outcomes of the
erythremia
myelofibrosis,
chronic myelogenous leukemia,
acute leukemia
105. Prognosis
Median survival is about 16 years.
Up to 30% of patients develop myelofibrosis .
Acute myeloid leukaemia occurs in up to 5% of
patients
