Acute Lymphoblastic Leukemia

Front 1

Acute lymphoblastic leukemia (ALL)

Back 1

a malignant (clonal) disease of the bone marrow in which early lymphoid precursors proliferate and replace the normal hematopoietic cells of the marrow.

Front 2

organ affected by ALL

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the bone marrow

Front 3

Cells affected by ALL

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early lymphoid precursors proliferate and replace the normal hematopoietic cells of the marrow.

(((lymphoblasts))) :arrested in an early stage of development

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ALL frequency

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most common type of cancer and leukemia in children in the United States.

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ALL symptoms

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1-local : bone pain

2-BM infiltrate : infection/fever

anemia (SOB/fatigue)

low plt (Bruises / bleeding/dizz)

3-periphral blood infiltrate : DIC ((unusual thrombosis ))

Leukostasis

tumor lysis

renal failure

4-organ infiltrate : LN // Spleen // mediastinum

skin rash

Front 6

ALL Signs ??

Back 6

fever

decrease LOC : leukostasis

pallor

bleeding / epistaxis / vaginal

lymphadenopathy

SVO : superior vena cava obstruction

spleenomegally

pneumonia

bruises

skin rash

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% of DIC in ALL at diagnosis ??

Back 7

10 %

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superior mediastinal mass is common in which type of ALL ??

Back 8

T cell ALL

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bone charachteristic in ALL ??

Back 9

sever

and

atypical

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spleenomegaly in ALL ??

Back 10

10 - 20 %

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leukostasis symptomes

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respiratory distress

altered mental status

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petechiae most common site in ALL ??

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lower limbs

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work up for ALL ??

Back 13

1-blood tests

2-cultures

3-imaging

4-biopsy

5-special tests

6-ECG or MGUA

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blood tests in ALL ??

Back 14

- CBC

-KFT

-LFT

-coagulation profile

-LDH

-Uric Acid

-cultures / fever

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imaging

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CXR

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Biopsy

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bone marrow biopsy is a MUST for confirmation

Front 17

other special labs

Back 17

immunhistochemistry

cytogenetics

flow cytometry

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PCR

gene expression profile

Front 18

Management

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chemotherapy :

1- induction

2-consolidation

3-maintinance

CNS prophylaxis

supportive

1-blood products

2-Abx

3-G-CSF

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special manegment for special types

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Mature B-cell ALL

Ph+ ALL

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ALL in older children and younger adults

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Relapsed ALL

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ALL in patients with hyperuricemia or at high risk for tumor lysis syndrome

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how to differentiate betw other lymphoid malignancies and ALL ??

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by cell markers

Immunochemistry, cytochemistry, and cytogenetic markers

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pathophysiology

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lymphoblasts ::

are arrested in an early stage of development.

This arrest is caused by ::

an abnormal expression of genes, often as a result of chromosomal translocations.

The lymphoblasts replace the normal marrow elements, resulting in a marked decrease in the production of normal blood cells.

The lymphoblasts also proliferate in organs other than the marrow, particularly the liver, spleen, and lymph nodes.

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Etiology ??

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most adults : no risk factors known

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MOST acute leukemia that is secondary to other

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(( AML )) not ALL

(like : radiation // MDS // ttt with topoisomerase II

Front 24

ALL in children

frequency

Back 24

75 % of all leukemia in children

25 % of all cancers up to age of 14 yo

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male to female ratio ??

in ALL

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slightly higher in males

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Worldwide, the highest incidence of ALL occurs in ................??

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Italy

United States

Switzerland, and Costa Rica.

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% of cure with today's regimens ??

Back 27

only

20- 40 % of adults

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how to classify pt with ALL ??

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risk / prognostic category

Front 29

risk categories ??

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1-good risk

2-intermediate risk

3-and poor risk.

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Good risk criteria include the following:

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Age younger than 30 years

No adverse cytogenetics

White blood cell (WBC) count of less than 30,000/μL

Complete remission within 4 weeks

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Intermediate risk

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includes those whose condition does not meet the criteria for either good risk or poor risk.

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Poor risk criteria

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Age older than 60 years

Adverse cytogenetics – ---Translocations t(9;22), t(4;11)

Precursor B-cell WBCs with WBC count greater than 100,000/μL

Failure to achieve complete remission within 4 weeks

Front 33

which age represent good prognosis

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< 30 yo

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which age represents bad prognosis

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> 60 yo

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which WBC count is good

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< 30,000

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which WBCs count is bad

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precurser B-cell count > 100,000

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duration of induction remission represents good prognosis

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< 4 weeks

Front 38

adverse cytogenatics in ALL

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philadilphia t(9;22)

t(4;11)

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extremely poor prognosis

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Patients with precursor B-cell ALL

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ttt of choice for ((extremely poor prognosis ))

Patients with precursor B-cell ALL

&

t (4;11)

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((allogenic)) transoplantation

otherwise ((chemo / autologus trans .. no survival benefit ))

Front 41

special categories

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B-cell

T-cell

with meyloid lineage

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T cell / ALL

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younger age

male sex,

mediastinal mass

higher WBC count and hemoglobin level

longer survival

longer disease-free survival

Front 43

ALL cells expressing myeloid antigens

Back 43

same prognosis

Front 44

patient eduacation

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seek advice if ::

fever

signs of bleeding

avoid crowded areas

advice for neutropenic diet

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neutropenic diet

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No fresh fruits or vegetables may be eaten

All foods must be cooked

Meats are to be cooked until well done

Front 46

most common cause of death in ALL ??

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infections

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every fever must be assumed to be due to ...........and treated accordingly

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infection

Front 48

spleenomegaly symptomes ??

Back 48

- early satiety

- UQ fullness

Front 49

frequency of leukostasis in comparison to AML ??

Back 49

less common

needs higher WBCs count ( hundred of thousands)

Front 50

renal impairment with high WBC count

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think of leukemia with high tumor burden leading to hyperuricemia and even tumor lysis

Front 51

history taking ??

Back 51

bone pain

constitutional symptomes

anemia sx

recurrent pneumonia / infection

oral ulcers / dysphagia

recurrent bleeding

bruises

upper Q pain / fullness / early satiety

neck masses / LN

bone pain

Front 52

physical exam

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- fever / hypotension

- pallor

-mucositis

-neck LN

-SVCO signs (dilated veins / plethora )

-flow murmur / anemia

-cosolidation signs

-spleenomegaly

-bruises / petechiae

- DVT (UL / LL)

-skin rash

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types of leukemia that must be considered in ALL diagnosis

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acute biphenotypic leukemia

natural killer (NK)-cell leukemia.

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cute biphenotypic leukemia

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1

Front 55

natural killer (NK)-cell leukemia.

Back 55

1

Front 56

ALL approach

Back 56

1-confirm diagnosis

2- risk stratification/ prognosi / genetics

Front 57

to diagnose ALL you nedd the following ??

Back 57

1- BM

2-flow cytometry immunophenotype

Front 58

Bone marrow biopsy/aspirate studies

Back 58

- > 20 % lymphoblast

-Wright/Giemsa–stained bone marrow aspirate

- Hematoxylin and eosin (H&E)–stained bone marrow core biopsy and clot sections

-with flow cytometry

Front 59

risk stratification and treatment planning in patients with ALL

labs / studies

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Cytogenetics – Karyotyping ::: of G-banded metaphase chromosomes

Interphase fluorescence in situ hybridization (FISH)

Reverse transcriptase polymerase chain reaction (RT-PCR) for fusion genes (eg, BCR-ABL)

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WBC's count in ALL

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high

normal

low (WBC)

_________________________________

((((but they usually exhibit neutropenia)))

Front 61

infection expected when ??

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ANC < 500

esp. sever < 100

Front 62

PT / PTT /INR

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if high they indicate DIC

Front 63

DIC indicators

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high INR

high PT / PTT

high LDH

high D-Dimer

low Fibrinogen

drop in plt / Hb

schistocytes in blood film

Front 64

LDH in ALL

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usually high

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uric acid in ALL

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usuallu high

Front 66

CXR findings i n ALL ?

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infiltrate : pneumonia

mediastinum : wide / prominant : T cell ALL

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before starting chemo in ALL you must do .........as baseline

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ECG or Multiple-gated acquisition (MUGA)

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Multiple-gated acquisition (MUGA)

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1

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% of blast in marrow to diagnose ALL

FAB classification

WHO classifiaction

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30 % in FAB ((old classification sys)

20 % in WHO

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bone marrow

stains

studies

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Wright or Giemsa

terminal deoxynucleotidyl transferase (TdT)

myeloperoxidase (MPO) (or Sudan black)

flow cytometry

cytogenetics.

Front 71

Wright or Giemsa used for ??

Back 71

morphology

to identify blasts

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myeloperoxidase (MPO) (or Sudan black)

Back 72

1

Front 73

terminal deoxynucleotidyl transferase (TdT)

Back 73

1

Front 74

flow cytometry

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1

Front 75

cytogenetics.

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2

Front 76

% of +ve philadilphia chrom t(9;22)

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15 %

Front 77

WHO classification

histological classification

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1-precursor B lymphoblastic leukemia/lymphoblastic lymphoma

2-precursor T lymphoblastic leukemia/lymphoblastic lymphoma

3-mature B-cell neoplasms

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how to confirm the lineage ??

Back 78

two methods

1- stains ((MPO vs TdT )

2-flow cytometry / cytogenetics

Front 79

how to diagnose lymphoid lineage according to the MPO / TdT stain

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negative myeloperoxidase (MPO) stain and a positive and terminal deoxynucleotidyl transferase (TdT)

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is MOP / TdT stain is enough for lineage confirmation

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no ,, flow cyto must be done

becoz MPO / TdT are not specific

Front 81

AML type that stain negative for MPO ??

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AML (M0)

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myeloid markers

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CD33

Front 83

lymphoid markers

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CD3 (T-lineage ALL)

CD19 (B-lineage ALL)

Front 84

cytogenetic abnormalities

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- balanced translocation

- bnormalities of chromosome number (hypodiploidy, hyperdiploidy)

Front 85

the importance of cytogenetics

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help in choosing regimen for specific mutations

Front 86

types of ALL acoording to blast type

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- T-cell

-B-cell (( 85 %))

Front 87

B-cell ALL

types

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Early B-precursor ALL

precursor B ALL

Mature B cell (Burkitt) ALL

Front 88

T cell ALL

types

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early T-precursor AL

T-cell ALL

Front 89

Polymerase Chain Reaction or Cytogenics

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to diagnose ph+ve ( t(9;22)) ALL

Front 90

the supportive care measures that must be present in the facility treating ALL

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- high-level blood banking

- leukapheresis

Front 91

the main four component of ALL chemo ttt

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1-induction

2-consolidation

3-maintinanc

4-maintenance

5-central nervous system (CNS) prophylaxis

Front 92

Induction Chemotherapy

common regimens

Back 92

4 chemo based

(((vincristine, prednisone, anthracycline, and cyclophosphamide/or/ L -asparaginase))

5 chemo based

((vincristine, prednisone, anthracycline, cyclophosphamide, and L -asparaginase))

Front 93

induction phase

duration

Back 93

over 4-6 weeks

Front 94

Consolidation Therapy

Back 94

4-5 drugs

usually include consolidation therapy with Ara-C in combination with an anthracycline or epipodophyllotoxin

Front 95

Maintenance Therapy

Back 95

Intensification of maintenance therapy from a 12-month course of a four-drug regimen compared with a 14-month course of a seven-drug regimen did not show a difference in disease-free survival between the two groups

Front 96

CNS Prophylaxis

% of ALL pt that present with meningeal infiltration at diagnosis

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minority

Front 97

CNS Prophylaxis

% of ALL pt that present with meningeal infiltration at relaps

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frequent

Front 98

induction regimens

Back 98

1---ALL-2 protocol

((the Memorial Acute Lymphoblastic Leukemia – 2 ))

2-- the hyper-CVAD

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ALL-2 protocol

Back 99

high-dose, mitoxantrone-based,

combined with high-dose cytosine arabinoside (Ara-C)

Front 100

Hyper-CVAD regimen

Back 100

hyperfractionated cyclophosphamide

Front 101

ALL philadilphia +ve

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add imatinib

Front 102

CD20 +ve ALL

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add rituximab

Front 103

Transplantation

in ALL

indications

Back 103

1-young with poor prognostic factors

2-young with good prognostic @ relapse

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ttt of relapse

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1- transplantation / if young

2-re-induction

bad prognosis

Front 105

type of blood products that must be given to ALL pt

Back 105

All blood products must be irradiated

Front 106

why the blood products must be irradiated??

Back 106

to prevent transfusion-relatedgraft versus host disease

Front 107

Hb level for transfusion ??

Back 107

Hb 7-8

higher if cardio/respiratory disease

Front 108

platelet transfusion

when ??

Back 108

< 10,000

Front 109

plt transfusion if pulmonary Hrg

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<50.000

Front 110

plt transfusion if GI hrg

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<50.000

Front 111

plt transfusion with CNS hrg

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<100.000

Front 112

indication for FFP

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a significantly prolonged prothrombin time (PT).

Front 113

indications for Cryoprecipitate ??

Back 113

fibrinogen level is less than 100 g/dL

Front 114

Supportive Care - Therapy and Prophylaxis for Infection

role no#1

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all febrile pt must take Abx

Front 115

minimum Abx used in febrile pt

Back 115

3rd generation cephalo / equivelant

++

aminoglycoside ((amikacin / genta / tobra) for G-ve

Front 116

if fever continue after 3-5 days despite Abx

Back 116

add anti-fungal

1-ampho

2-azoles / new generation

3-echinocandin

Front 117

when to suspect aspergillus ??

Back 117

sinuses complaints

pulmonary complaints

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add anti-aspergillus

Front 118

ALL pt during ttt commonly present with fever without specific sign s / sx to suggest site of infection , why ??

Back 118

use of steroids in their chemo

Front 119

do we have to use prophylactic Abx before induction w/o fever

Back 119

?? controversial

A commonly used regimen includes the following

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Ciprofloxacin (oral [PO] 500 mg twice daily [bid])

Fluconazole (200 mg PO daily), itraconazole (200 mg PO bid), or posaconazole (200 mg PO three times daily [tid])

Acyclovir (200 mg PO 5 times/d) or valacyclovir (500 mg PO daily)

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once pt become febrile switch to IV forms

Front 120

G-CSF use ??

forms

Back 120

studies about the early use of GCSF

Filgrastim (Neupogen)

Front 121

Tumor lysis syndrome common in which tumors ??

Back 121

potentially life-threatening complication that may be seen in patients receiving chemotherapy for acute leukemias and high-grade non-Hodgkin lymphomas.

Front 122

tumor lysis

labs

Back 122

lab tests

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high Uric acid

high K

high phosphorus

low Ca

______________________________

clinical

1-renal impairment

2-cardiac arrythmia / sudden death

3-seizure

Front 123

high Uric acid

Back 123

> 8 mg/dl

or

> 50 % ibncrease over baseline

Front 124

pottasium

Back 124

> 6

or

>50 % of baseline

Front 125

phosphorus

Back 125

>1.45

or

> 25 % of baseline

Front 126

calcium

Back 126

< 1.75

or

> 25 % of baseline drop

Front 127

allopurinol use

Back 127

is indicated during induction till blasts are cleared

Front 128

allopurinol dose ??

Back 128

300 mg / 1-3 times

Front 129

rasburicase

when to use

Back 129

High-risk patients (those with very high lactate dehydrogenase [LDH] or leukemic infiltration of the kidneys

Front 130

long term manegment / during maintinance

Back 130

all must be on : TMP/SMZ (to prevent PCP)

oral nystatin

clotrimazole troches for candidiasis prevention