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LEUKEMIAS

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Precursor T acute lymphoblastic leukemia/lymphoma 2- Burkitt's leukemia/lymphoma Synonyms:Former FAB L3 3- Biphenotypic acute leukemia Treatment: ... – PowerPoint PPT presentation

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Title: LEUKEMIAS


1
LEUKEMIAS
By
Prof. Dr. Sameh Shamaa
2
Conditions characterised by abnormal
proliferation of leucopoietic tissue and
appearance of immature forms of white cells in
the peripheral blood.
3
Acute Leukemias Results from proliferation
of young forms of leucocytes at a stage when
they do not enter the circulation as readily as
they do when more mature.
4
Classification
acute lymphoblastic L.



-----gt more common
acute myeloblastic L. acute monocytic L.
5
ACUTE LEUKEMIAS Def Heterogenous group of
neoplastic discases characterized. by
proliferation of atypical elements which
originates from the stem cells of the
hematopoietic system. the
uncontrolled and progressive proliferation of
these cells lead to- - Replacement of
normal marrow - Invasion of peripheral
blood -Infiltration of various organs and tissues
6
Relative frequency -
Adults gt14 years Children ( 14 years) Type

10-25 65-80 Lymphoblastic
20 6-25 Myeloblastic
20 2-6 Myelomonocytic
1-10 2-6 Monocytic
10 1-2 Promyelocytic
3 0-1 Erythroid
1 0-1 Megakaryocytic
7
  • Etiology-
  • Unknown, some factors seem to be implicated -
  • A- Environmental factors-
  • Ionizing radiation mainly AML but ALL less
    important
  • Chemical substances prolonged exposure to
    certain
  • substances (benzene, phenylbutazone,
    chloramphenicol,
  • anticancer drugs, alkylating agents, natulan)
    ---gt incidence of leukemia mainly AML
  • Onset often preceeded by a state of bone marrow
    hypoplasia, peripheral pancytopenia
  • (preleukemic syndrome).

8
B-Genetic- May act by facilitating
envirnomental factors. C- Viruses- Based on
experiments with laboratory animal, has never
proved humans. Typical products of viruses have
been identified in some adult patients. With T.ALL
- HTLV (human T cell lymphotrophic virus) in T
cell ALL and hairy cell leuk.
9
D- Immunological Factors - Patient with
acquired or congenital immune deficiency
syndrome or subjected to prolonged
immunosuppresive treatment has ? incidence of
leukemia.
10
Differential Diagnosis  -------------------------
------------------ D.D. between various forms of
acute leukemia is mainly on cytomorphologic,
cytochemical criteria rather than on clinical
data, which are often superimposable. age may
accur at any age but in general -A.L.L --- gt the
peak incidence in 1st 6 years of life. Uncommon
after age of 20 -A.M.L.--- gtmore commonly at
slightly older age groups centering around the
teen-age or adolescent period -A. Monocytic leuk.
---gtno specific age group.
11
Clinical Picture 1- Fever moderate or high
grade, usually irregular and shoots up when 2ry
infection occur 2-rapidly developing marked
asthenia. 3- rapidly developing severe anaemia
---gt marked pallor. 4-severe bone ache allover
the body 5-Severe sore throat 6- bleeding
tendency from ---gt----- gt gums.
-------gt skin --------gt orifices
---------gtint. organs. 7-tender
bones 8- joint pain (bleeding
infiltration) 9-L.N. enlargement in ---gt------gt
A.L.L. ----gtA.M.L. ----gtA. Monocytic
L. 10-spleen Liver enlargement. 11-Chloromas -
more in A.M.L. (subperiosteal tumor like
masses) 12-C.N.S ---gtFocal Hge or infection of
nerves or meningies.
12
Blood Picture - A.L.L R.B.Cs ---gt
severe form of normocytic ncrmochromic anemia
occurs early. W.B.cs ---gt
( ) 10,000 --- 100,000 Or more but 40 are
leukopenic - Lymphocytes are likely to be the
predominant cells. - The diagnosis is established
by detecting lymphoblastes in the peripheral
smear. (N.B. Lymphoblastes large cells with
clear cytoplasm, prominant nucleus, definite
nucleole. Diff. From mycloblastes - absent
specific granules of cytoplasm, -ve peroxidase
stain -PAS ve - Sudan Black -ve or weekly ve
platelets usually lt 100.000 may be
completetly absent.
13
2- Myeloblastic Leuk - W.B.Cs. count as
A.L.L. - Leukopenia is as likely to occur as
A.L.L - The cells are peroxidase ve, PAS ve,
Sudan black ve , acid
phosphatase ve - In 10 - 20 Auer bodies are
present rod like structures.
in cytoplasm of------------gt myeloblast
-------------gt
monoblast 3- Monocytic Leukemia
- monoblast in the peripheral blood. Stain PAS
-ve, Sudan B ve, Peroxidase -ve acid phosphatase
ve
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Bone marrow aspiration Massive proliferation of
blast cells even when leukopenia exist.
A.L.L-----gt lymphoblast A.M.L----gtmyeloblast A.
monocytic----gt monoblasts and monocytes. Radiolo
gy - -Sketetat involvement in almost all
children and 50 of dults. diffuse
osteoprosis periosteal elevation
osteolytic lesions radiolucent
metaphyseal bands.
18
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19
Diff- diagnosis - The combination of anemia

thrombocytopenia
bone marrow prolif. è primitive white cells
is found only in leukemia.
20
  • From other causes of sore throat Fever as-
  • vincent angina.
  • diphtheria.
  • infectious, mononucleosis.
  • aplastic anemia.
  • agranulocytosis.
  • (2) from other causes of parpura -
  • I.T.P
  • Aplastic anemia.

21
(3) Lymphadenopathy splenomegally-
infective mononucleosis H.D.
.N.H.L. (by blood picture).. (4) Lymphocytosis
in . whooping
caugh infective lyrmphocytosis. (white cells
mature, R.B.Cs and platelets are
normal). (5) Rheumtic Fever
22
Name Description ICD-O
AML with characteristic genetic abnormalities Includes AML with translocations between chromosome 8 and 21 t(821) (ICD-O 9896/3) RUNX1/RUNX1T1 AML with inversions in chromosome 16 inv(16) (ICD-O 9871/3) CBFB/MYH11 AML with translocations between chromosome 15 and 17 t(1517) (ICD-O 9866/3) RARAPML Patients with AML in this category generally have a high rate of remission and a better prognosis compared to other types of AML. Multiple
AML with multilineage dysplasia This category includes patients who have had a prior myelodysplastic syndrome (MDS) or myeloproliferative disease (MPD) that transforms into AML. This category of AML occurs most often in elderly patients and often has a worse prognosis. M9895/3
AML and MDS, therapy-related This category includes patients who have had prior chemotherapy and/or radiation and subsequently develop AML or MDS. These leukemias may be characterized by specific chromosomal abnormalities, and often carry a worse prognosis. M9920/3
AML not otherwise categorized Includes subtypes of AML that do not fall into the above categories. M9861/3
23
aaa Name Cytogenetics
M0 minimally differentiated acute myeloblastic leukemia
M1 acute myeloblastic leukemia, without maturation
M2 acute myeloblastic leukemia, with granulocytic maturation t(821)(q22q22), t(69)
M3 promyelocytic, or acute promyelocytic leukemia (APL) t(1517)
M4 acute myelomonocytic leukemia inv(16)(p13q22), del(16q)
M4eo myelomonocytic together with bone marrow eosinophilia inv(16), t(1616)
M5 acute monoblastic leukemia (M5a) or acute monocytic leukemia (M5b) del (11q), t(911), t(1119)
M6 acute erythroid leukemias, including erythroleukemia (M6a) and very rare pure erythroid leukemia (M6b)
M7 acute megakaryoblastic leukemia t(122)
M8 acute basophilic leukemia
24
The FAB classificationSubtyping of the various
forms of ALL used to be done according to the
French-American-British (FAB) classification,18
which was used for all acute leukemias (including
acute myelogenous leukemia, AML). ALL-L1 small
uniform cells ALL-L2 large varied cells
ALL-L3 large varied cells with vacuoles
(bubble-like features) Each subtype is then
further classified by determining the surface
markers of the abnormal lymphocytes, called
immunophenotyping. There are 2 main immunologic
types pre-B cell and pre-T cell. The mature
B-cell ALL (L3) is now classified as Burkitt's
lymphoma/leukemia. Subtyping helps determine the
prognosis and most appropriate treatment in
treating ALL
25
WHO proposed classification of acute
lymphoblastic leukemia The recent WHO
International panel on ALL recommends that the
FAB classification be abandoned, since the
morphological classification has no clinical or
prognostic relevance. It instead advocates the
use of the immunophenotypic classification
mentioned below. 1- Acute lymphoblastic
leukemia/lymphoma SynonymsFormer Fab L1/L2 i.
Precursor B acute lymphoblastic
leukemia/lymphoma. Cytogenetic subtypes19
t(1221)(p12,q22) TEL/AML-1 t(119)(q23p13)
PBX/E2A t(922)(q34q11) ABL/BCR T(V,11)(Vq23)
V/MLL ii. Precursor T acute lymphoblastic
leukemia/lymphoma 2- Burkitt's leukemia/lymphoma
SynonymsFormer FAB L3 3- Biphenotypic acute
leukemia
26
Treatment- Combination chemotherapy in order
to - obtain synergestic
action minimize side effects. attacks
leukemic cells in different phases of mitosis.
delay the onset of resistance of the malignant
cells.
27
Acute L. Leuk. effective drugs are 1-
vincristine-----gt arrest cell mitosis 2-
predinsone ----gt Lyrmpholysis 3-6.M.P.
----gt inhibit DNA synthesis.
4-Methotrexate ----gt inhibit RNA and protein
synthesis 5-Doxorubich
(adriamycin)----gt inhibit DNA synthesis
6-L- asparaginase
28
Phase Description Agents
Remission induction The aim of remission induction is to rapidly kill most tumor cells and get the patient into remission. This is defined as the presence of less than 5 leukemic blasts in the bone marrow, normal blood cells and absence of tumor cells from blood, and absence of other signs and symptoms of the disease. Combination of Prednisolone or dexamethasone (in children), vincristine, asparaginase, and daunorubicin (used in Adult ALL) is used to induce remission
29
Intensification Intensification uses high doses
of intravenous multidrug chemotherapy to further
reduce tumor burden. Since ALL cells sometimes
penetrate the Central Nervous System (CNS), most
protocols include delivery of chemotherapy into
the CNS fluid (termed intrathecal chemotherapy).
Some centers deliver the drug through Ommaya
reservoir (a device surgically placed under the
scalp and used to deliver drugs to the CNS fluid
and to extract CNS fluid for various tests).
Other centers would perform multiple lumbar
punctures as needed for testing and treatment
delivery. Typical intensification protocols use
vincristine, cyclophosphamide, cytarabine,
daunorubicin, etoposide, thioguanine or
mercaptopurine given as blocks in different
combinations. For CNS protection, intrathecal
methotrexate or cytarabine is usually used
combined with or without cranio-spinal
irradiation (the use of radiation therapy to the
head and spine). Central nervous system relapse
is treated with intrathecal administration of
hydrocortisone, methotrexate, and cytarabine.
30
Maintenance therapy The aim of maintenance
therapy is to kill any residual cell that was not
killed by remission induction, and
intensification regimens. Although such cells are
few, they will cause relapse if not eradicated.
For this purpose, daily oral mercaptopurine, once
weekly oral methotrexate, once monthly 5-day
course of intravenous vincristine and oral
corticosteroids are usually used. The length of
maintenance therapy is 3 years for boys, 2 years
for girls and adults.
31
These drugs must be used sequentially and in
combinations- a-Induction therapy- To
obtain apparent clinical hematological
remission 2 or 3 drugs used - Vincristine
1.4 mg/m2 I.V. once weekly for 4 weeks... -
prednisone lmg/kg body weight P.O. daily - L.
asparaginase or Adriamycin
32
b- Consolidation theraby- to decrease total
no. of residual malignant cells to 10G cells or
less. e.g. Methotrexate 15 mg/m2I.M. daily
For 3 - 5 days.. followed by cystarabine 100 mg/
m2 I.V. twice daily for 3-5 days.
33
c- C.N.S. prophylaxis by cranial
irradiation 1800 2400 R Intra thecal
(l.T.) Methotrexate in mg/ m2 for 5 injection.
(twice weekly).
34
d- Prolonged maintenance 2-3 years
Methotrexate 15 mg/ m2 once or twice weekly
I.M. 6 M.P 1-2.5 mg/kg daily P.O. Cyclophospham
ide 200mg/ m2 p.o. weekly.
35
Acute Non Lymphoblastic L. -The initial
objectives is the induction of a CR. (reduction
of marrow blasts to less than 5, increase in
neutrophils in the peripheral blood to l.5x 106
/L. or more and of platelets to 100x 106/L. or
more.). -Then consolidation therapy follows, for
which identical drugs are used (the aim is
further reduction of leukemic cells). - Both in
induction and consolidation, high dosage of drugs
are given to produce temporary marrow aplasia.
36
  • After the marrow have recovered from
    consolidation therapy, maintenance therapy is
    given at monthly intervals usually for 2-3 years,
    aiming for a further stepwise reduction of
    remaining leukemic cells without making the
    marrow splastic
  • -The cornerstone of remission induction and
    consolidation chemotherapy is a combination of
    cytosine-arabinoside and daunorubicin resulting
    in 50 CR rates.
  • -Drugs used for maintenance cytosine-arabinoside,
    6-thioguanine, cyclophosphamide and
    daunarubicin.
  • However the value of maintenance
    treatment is marjinal.

37
complications - (1)Severe bone ache or massive
C.N.S infiltration. ---- gt Local
irradiation (2)C.N.S. involvement ----gt
intrathecal Mtx. 12 mg I.T./3 days cranial
irradiation (3)Fever. (4)Hge. (6)Hyperuricemia
38
Prognosis (1) A.L.L -----gtC.R. ----gt 90 of
children. ----gt 60 of adults.
----gt Cure in 70 of children. and 35
of adults. Allogenic bone marrow
transplantation is the only form of therapy for
patients with drug -resistant disease (2)
A.N.L.L.-----gtC.R is up to 50 - only about 25
remain disease free after 5 years and can expect
to be cured - However, bone marrow
transplantation if preformed during First
remission can improve survival and it has been
suggested to be preformed in all patients younger
than 50 years and who have available HLA
identical donor
39
Risk Category Abnormality 5-year survival Relapse rate
Favorable t(821), t(1517), inv(16) 70 33
Intermediate Normal, 8, 21, 22, del(7q), del(9q), Abnormal 11q23, all other structural or numerical changes 48 50
Adverse -5, -7, del(5q), Abnormal 3q, Complex cytogenetics 15 78
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edit Prognosis The survival rate has improved
from zero four decades ago, to 20-75 percent
currently, largely due to clinical trials and
improvements in bone marrow transplantation (BMT)
and stem cell transplantation (SCT)
technology. Five-year survival rates evaluate
older, not current, treatments. New drugs, and
matching treatment to the genetic characteristics
of the blast cells, may improve those rates. The
prognosis for ALL differs between individuals
depending on a variety of factors Sex females
tend to fare better than males. Ethnicity
Caucasians are more likely to develop acute
leukemia than African-Americans, Asians and
Hispanics and tend to have a better prognosis
than non-Caucasians. Age at diagnosis children
between 110 years of age are most likely to
develop ALL and to be cured of it. Cases in older
patients are more likely to result from
chromosomal abnormalities (e.g. the Philadelphia
chromosome) that make treatment more difficult
and prognoses poorer. White blood cell count at
diagnosis of less than 50,000/µl Cancer spread
into the Central_nervous_system (brain or spinal
cord) has worse outcomes. Morphological,
immunological, and genetic subtypes Patient's
response to initial treatment Genetic disorders
such as Down's Syndrome
42
Cytogenetics, the study of characteristic large
changes in the chromosomes of cancer cells, is an
important predictor of outcome.13 Some
cytogenetic subtypes have a worse prognosis than
others
43
Cytogenetic change Risk category
Philadelphia chromosome Poor prognosis
t(411)(q21q23) Poor prognosis
t(814)(q24.1q32) Poor prognosis
Complex karyotype (more than four abnormalities) Poor prognosis
Low hypodiploidy or near triploidy Poor prognosis
High hyperdiploidy (specifically, trisomy 4, 10, 17) Good prognosis
del(9p) Good prognosis
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