ALL Topic review- Case presentation · Epidemiology Etiology Pathophysiology Signe and symptom Work up Diagnosis 5 years survival rate ... (FAB classification) in childhood acute

ALL Topic review-

Case presentation

26 June 2014

By: Boudor AL-Ghabban

Pharma D student, KSU- college of pharmacy

Outlines:

Topic Review

Introduction

Epidemiology

Etiology

Pathophysiology

Signe and symptom

Work up

Diagnosis

5 years survival rate

Treatment

Case Components

Topic review

Acute lymphoblastic leukemia (ALL)

Introduction

Acute leukemia, the most common form of cancer in children,

comprises approximately 30 percent of all childhood malignancies,

with acute lymphoblastic leukemia (ALL) being five times more

common than acute myeloid leukemia (AML)

-ALL is most common in childhood with a peak incidence at 2–5 years

of age, and another peak in old age.

National Vice President, Intramural Research, American Cancer Society, Atlanta, GA.

Topic review cont.

Introduction cont.

-It is the leukemia most responsive to therapy.

-Poor prognostic indicators are as follows: age <2 or >9; WBC

>l05/mm3 and/or CNS involvement.

-Presence of any of the following is associated with an increased risk

for CNS involvement: B-cell phenotype, increased LDH, rapid

leukemic cell proliferation.

National Vice President, Intramural Research, American Cancer Society, Atlanta, GA.

Topic review cont.

Annual Report Prepared by the Staff of the Tumor Registry Research Unit, Oncology Centre

King Faisal Specialist Hospital and Research Centre,2011

Epidemiology

Topic review cont.

Etiology

Risk Factors/Causes:

Prenatal exposure to x-rays.

Postnatal exposure to high doses of radiation.

** Genetic conditions that include the following:

Down syndrome.

Neurofibromatosis.

Bloom syndrome.

Inherited genetic polymorphisms.

Birth weight and risk for childhood leukemia in Denmark, Sweden, Norway, and Iceland.

Topic review cont. Pathophysiology

Topic review cont. Pathophysiology cont.

Morphology :

According to the FAB system:

●L1 lymphoblasts are small cells with scant cytoplasm, condensed

nuclear chromatin, and indistinct nucleoli . Most children with ALL

cases (85 to 89 %) are classified as having FAB L1.

●L2 lymphoblasts are larger cells with a moderate amount of

cytoplasm, dispersed chromatin, and multiple nucleoli . In some

studies, L2 has been associated with worse prognosis than has L1 .

However, when patients are stratified according to age, sex, and

initial WBC, differences in prognosis between L1 and L2 are no

longer observed 11 to 14 % of cases of ALL in children are

classified as FAB L2 .

Prognostic importance of morphology (FAB classification) in childhood acute lymphoblastic leukaemia

(ALL).

Topic review cont. Pathophysiology cont.

Morphology :

●L3 lymphoblasts have deep cytoplasmic basophilia with prominent

cytoplasmic vacuolation . L3 morphology correlates with a more

guarded prognosis. The L3 cell usually has mature B cell

characteristics and often is treated using drugs effective for highly

aggressive B cell lymphoma variants. Less than 1 % of cases of

ALL in children are classified as FAB L3 .

Prognostic importance of morphology (FAB classification) in childhood acute lymphoblastic leukaemia

(ALL).

Topic review cont. Pathophysiology

Immunophenotype — Leukemia cells in ALL are classified according

to immunophenotype using an extensive panel of monoclonal

antibodies to cell surface "cluster of differentiation" (CD) markers

The genetic basis of early T-cell ,B-cell precursor acute lymphoblastic leukaemia.

Topic review cont.

Signs and symptoms:

They result from the lack of normal and healthy blood cells because

they are crowded out by malignant and immature leukocytes (white

blood cells). Therefore, people with ALL experience symptoms from

malfunctioning of their erythrocytes (red blood cells), leukocytes, and

platelets.

-Anemia

-Generalized weakness and fatigu

-Dizziness

-Breathlessness due to low RBC level

-Pallor

-Headache

-Increased risk of bacterial infection such as pneumonia, urinary tract

infection (due to neutropenia)

Cranial nerve involvement in children with leukemia and lymphoma.

Topic review cont.

Signs and symptoms cont.

-Excessive and unexplained bruising

-Epistaxis due to low platelets

-petechiae

-Bone pain, joint pain (caused by the spread of "blast" cells to the

surface of the bone or into the joint from the marrow cavity)

-Enlarged lymph nodes, liver and/or spleen

-Fever, Weight loss and/or loss of appetite

-CNS involvement-diffuse or focal neurological dysfunction(e.g,

menengitis, seizures)

Cranial nerve involvement in children with leukemia and lymphoma.

Topic review cont.

Diagnosis:

Because the symptoms are so general, many other diseases with similar

symptoms must be excluded.

-Medical history and physical examination

-Complete blood count(anemia, thrombocytopenia, granulocytopenia,

WBC count is variable from 1000/mm3 to 100,000/mm3)

-Blood smears(Blast cells are seen on blood smear in majority of cases).

Brunning RD, Flandrin G, Borowitz M, et al. Precursor B lymphoblastic leukaemia/lymphoblastic lymphoma

(Precursor B-cell acute lymphoblastic leukaemia).

Topic review cont.

Diagnosis cont.

-Bone marrow biopsy is conclusive proof of ALL(replacement of

marrow by blast).

-Lumbar puncture will tell if the spinal column and brain have been

invaded.

-Medical imaging (such as ultrasound or CT scanning) can find

invasion of other organs commonly the lung, liver, spleen, lymph

nodes, brain, kidneys, and reproductive organs.

Brunning RD, Flandrin G, Borowitz M, et al. Precursor B lymphoblastic leukaemia/lymphoblastic lymphoma

(Precursor B-cell acute lymphoblastic leukaemia).

Topic review cont.

Classification:

WHO recognizes two immunophenotypic subtypes of ALL:

Precursor B-cell.

Precursor T-cell.

Brunning RD, Flandrin G, Borowitz M, et al. Precursor B lymphoblastic leukaemia/lymphoblastic lymphoma (Precursor

B-cell acute lymphoblastic leukaemia). In: World Health Organization Classification of Tumours. Pathology and Genetics

of Tumours of Haematopoietic and Lymphoid Tissues, Jaffe ES, Harris NL, Stein H, Vardiman JW (Eds), IARC Press, Lyon

2001. p.111.

Topic review cont.

Treatment:

* Goal:

Cure (absence of detectable cancer cells in the body (usually less than

5% blast cells in the bone marrow).

* Modalities:

Chemotherapy.

Radiation Therapy.

Hematopoietic stem cell transplantation.

Terry L. Schwinghammer _Pharmacotherapy handbook 7th edition_ The McGraw-Hill Companies,US: 2009 chapter

14 p 163

Topic review cont.

Treatment cont:

Duration:Approx. 2-2.5 years of continuation therapy, boys might take longer

time

-The earlier acute lymphocytic leukemia is detected, the more

effective the treatment.

Terry L. Schwinghammer _Pharmacotherapy handbook 7th edition_ The McGraw-Hill Companies,US: 2009 chapter

14 p 163

Topic review cont.

Treatment cont:

. Most ALL patients will receive a the initial treatment of choiceis Chemotherapy

combination of different treatments. There are no surgical options, due to the body-

wide distribution of the malignant cells. Chemotherapy for ALL consists of four

phases:

Induction:

The goal is to induce remission, it lasts 4 weeks.

includes a Glucocorticoid, Vincristine, Asparaginase, and possibly an Anthracycline.

Intensification:

To reduce the leukemic cell burden before the emergence of drug resistance and

relapse.

High dose Methotrexate with continuous Mercaptopurine .

Combinations of Vincristine, Peg-aspargaseor ,Cyclophosphamide ,Mercaptopurine

and Cytarabine.

Terry L. Schwinghammer _Pharmacotherapy handbook 7th edition_ The McGraw-Hill Companies,US: 2009 chapter

14 p 163

Topic review cont.

Treatment cont:

Maintenance:

Non myelosuppressive chemotherapy for 4-8 weeks to maintain remission and allow

the BM to recover, followed by delayed intensification.

Weekly Methotrexate and daily 6- Mercaptopurine, In addition pulses of GC and

Vincristine.

Reintensification:

High risk patients before Hematopoietic stem cell transplantation (HSCT).

Dexamethasone, Etoposide, Cytarabine, Asparginaseand IT (Methotrexate ,

Cytarabine, Hydrocortisone)

Terry L. Schwinghammer _Pharmacotherapy handbook 7th edition_ The McGraw-Hill Companies,US: 2009 chapter

14 p 163

Topic review cont.

Treatment cont.

Radiation therapy is used on painful bony areas, in high disease

burdens, or as part of the preparations for a bone marrow transplant

(total body irradiation).

%90 –80 Survival rate in adult with ALL =

Case contents

General information :

AS is a 9 years old girl known case of pre B low risk ALL diagnosed

on 29/4/2014 on chemotherapy drug

consolidation phase 2 week(6) {not started yet }. There is a history of

moderate oral thrush {chemo was held once only}.

Chief Complaint :

She was presented to the ER on 15-6-2014 complaining of back pain

and fever for 1 day.

History of Present illness:

Patient came to the ER with fever and mild back pain, on

paracetamole(400mg PO).

She was diagnosed with Fever without neutropenia

T=38.5oc

WBC=9.6 10e9 /L (5 – 20 10e9 /L) .

ANC= 4.9 10e9 /L (1- 8.50 10e9/L) .

Negative blood culture .

Past Medical History :

Date of Diagnosis Conditions

29/4/2014Pre B low risk ALL

27/5/ 2014 Treated with

fluconazole

Oral thrush

surgical history: Unremarkable.

Family History : Unremarkable.

Social History : Unremarkable.

Allergies : Not known to have allergy .

Medication History :

IndicationDosing

Regimen

RouteMedication

Constipation 25 mg ODIVLasix

Pain and fever400 mg q 4-6

hours

POParacetamol

FN2000 mg ODIVCeftriaxone

FN650mg ODIVAmikacin

Oral thrush135mg ODPOFluconazole

Oral thrush5ml Q6hPOSpecific mouth

wash

FN190mg ODIVGentamicen

FN2250mg Q6hIVTazocin

Medication History cont. :

IndicationDosing

Regimen

RouteMedication

ALL 1.5 mg /m2

(1.23 mg )for 5 weeks

starting on day 2 and

continuing in day 9

,16,23,30

IVvincristine

ALL1000 iu / m2 (2500 iu)

on Day 4 and 18

IM Pegylated

l- asparaginase

First-line treatment of acute lymphoblastic

leukemia with pegasparaginase cont.

PICO

P: Newly diagnosed ALL patients N= 174.

I: PEG asparaginase.

C: placebo.

O: Relapse-Free Survival {RFS}

(The median follow-up was 36 months ).

First-line treatment of acute lymphoblastic

leukemia with pegasparaginase cont.

Outcome measures

The primary efficacy end point:

Relapse-Free Survival (RFS).

Secondary efficacy end points:

- Overall survival (OS).

- Duration of objective response.

First-line treatment of acute lymphoblastic

leukemia with pegasparaginase cont.

Study designs Randomized, double-blind, placebo-controlled, phase III trial.

First-line treatment of acute lymphoblastic

leukemia with pegasparaginase cont.

Statistical analysis

Primary

end point

Secondary

end point

First-line treatment of acute lymphoblastic

leukemia with pegasparaginase cont.

Statistical analysis

Samples were obtained from 62 patients after a single IV dose (2000/IU/m2) of

pegaspargase. Serum asparagine concentration of less than 3 M is considered

optimal deamination.

** Secodary end point- Duration of objective response-.

First-line treatment of acute lymphoblastic

leukemia with pegasparaginase cont.

Statistical analysis

Samples were obtained from 62 patients after a single IV dose (2000/IU/m2) of

pegaspargase. Serum asparagine concentration of less than 3 M is considered

optimal deamination.

** Secodary end point- Duration of objective response-.

First-line treatment of acute lymphoblastic

leukemia with pegasparaginase cont.

Statistical analysis

** Secodary end point- Duration of objective response-.

First-line treatment of acute lymphoblastic

leukemia with pegasparaginase cont.

Statistical analysis

** Safety of IV pegasparaginase .

First-line treatment of acute lymphoblastic

leukemia with pegasparaginase cont.

Conclusion of the study

In conclusion, pegasparaginase chemotherapy show better

RFS in comparison to placebo with low incidence of serious AEs.

On Physical Examination :

Day of admission ( 15/6/2014)

Looks lethargic, febrile, not dehydratedGen

Oral thrushENT

BP 110/ 62 mm Hg , HR 128 bpm , RR 25 bpm,

T 38.5°C.

VS

S1+S2+0CV

Clear bilaterallyChest

Soft , lax Abdomen

No neurological insult NEURO

Labs and Diagnostic tests (15/6/2014) :

Normal Range Patients

labs

Laboratory data

5 – 20 10e9 /L 9.6 10e9 /L (N)WBC

1- 8.50 10e9/L4.9 10e9 /L (N)NEUT (Absolute neutrophils)

3-5.40 10e12/L2.53 10e12/L (L)RBC

10-18 g/dl7.1 g/dl (L)HGB

0.310-0.550 L0.233 (L)Hct

150-450 10e9/L95 10e9/L (L)Plt

135-145 mmol/L132 mmol/L (L)Na

3.5-5 mmol/L4 mmol/L (N)K

2-7.5 mmol/L8.9 mmol/L (H)Urea

Labs and Diagnostic tests cont.(15/6/2014) :

Normal

Ranges

Patients labs Laboratory data

50-115 umol/L26 umol/L (N)Creatinine

2.22-2.64 mmol/L2.03mmol/L(L)Calcium

2.09-2.55 mmol/L2.33mmol/L(N)Corrected calcium

0.60-1.50 mmol/L1.42 mmol/L(N)Phosphorus

0.74-1 mmol/L1.03 mmol/L(N)Mg

36-51 g/L28 g/L (N)Albumin

2-22 umol/L17 umol/L (N)Bilirubin (total)

2-40 U/L40 U/L (N)ALT

32-180 U/L 145 U/L (N)Alkaline Phosphatase

Problem List:

1-FN .

2-ALL .

3- Oral thrush .

4- Back pain .

Management on day 1 (15 /6/2014)

Assessment:

-Child looks lethargic, febrile T =38.5°C, not dehydrated

not in distress .

-BP 110/ 62 mm Hg , HR 128 bpm , RR 25 bpm

-Lab tests:

ANC= 4.9 10e9 /L (1- 8.50 10e9/L).

Plt=95 10e9/L (150-450 10e9/L).

CRP=4 mg/L Normal: < 0.8 mg/L , Low risk: <1.00 mg/L .

Average risk: 1.00 - 3.00 mg/L .

High risk: >3.00 mg/L .

Management on day 2,3 (16-17/6/2014)

Assessment:

-She looks well, pale, not in distress, febrile T=38.7°C

-BP 92/ 50 mm Hg , HR 130 bpm , RR 25 bpm

-Lab test:

ANC=2.6 10e9/L (1- 8.50 10e9/L)

Plt=93 10e9/L (150-450 10e9/L)

CRP= 4 mg/L Normal: < 0.8 mg/L , Low risk: <1.00 mg/L .

Average risk: 1.00 - 3.00 mg/L .

High risk: >3.00 mg/L .

Normal Ranges Patients labs Laboratory data

5 – 20 10e9 /L 4 10e9 /L (N)WBC

1- 8.50 10e9/L2.6 10e9 /L (N)NEUT (Absolute

neutrophils)

3-5.40 10e12/L2.66 10e12/L (L)RBC

10-18 g/dl7.4 g/dl (L)HGB

0.310-0.550 L0.243 (L)Hct

150-450 10e9/L93 10e9/L (L)Plt

135-145 mmol/L136 mmol/L (N)Na

3.5-5 mmol/L3.3 mmol/L (N)K

2-7.5 mmol/L6.8 mmol/L (H)Urea

Labs and Diagnostic tests

(16-17/6/2014)

Labs and Diagnostic tests cont.

(16-17/6/2014)

Normal Ranges Patients labs Laboratory data

50-115 umol/L24 umol/L (N)Creatinine

2.22-2.64 mmol/L2.09mmol/L(L)Calcium

2.09-2.55 mmol/L2.27mmol/L(N)Corrected calcium

0.60-1.50 mmol/L1.17 mmol/L(N)Phosphorus

0.74-1 mmol/L0.79 mmol/L(N)Mg

36-51 g/L29 g/L (N)Albumin

Assessment:

-She looks well, pale, not in distress, febrile T=38.3°C

-BP 92/ 50 mm Hg , HR 130 bpm , RR 25 bpm

-Lab test:

ANC=2.6 10e9/L (1- 8.50 10e9/L) .

Plt=93 10e9/L (150-450 10e9/L) .

Negative blood culture .

Patient developed diarrhea .

18-20/6/2014

Assessment cont. :

- The diarrhea is watery 4 time /day.

- Patient started on metronidazol 200 mg IV.

Q 8 hours for 7-10 days .

- IVF D5% + 0.45 NS .

- Stool for culture.

18-20/6/2014 cont.

Assessment:

-She looks well, pale, not in distress, febrile T=38.3°C

-BP 91/ 50 mm Hg , HR 130 bpm , RR 25 bpm

-Lab test:

ANC= 3 10e9/L (1- 8.50 10e9/L) .

Plt=95 10e9/L(150-450 10e9/L).

21/6/2014

Assessment cont. :

- Stool is negative Clostridium difficile.

- The frequency of diarrhea become1 time/day.

- Patient started on liposumal Amphotericin B 135 mg IV OD.

21/6/2014 cont.

22-23/6/2014

Assessment:

-She looks well, pale, not dehydrated not in distress, low grade fever

T=37.5°C , diarrhea one time / day .

-BP 91/ 50 mm Hg , HR 130 bpm , RR 25 bpm .

-Lab test:

ANC= 3 10e9/L (1- 8.50 10e9/L).

Plt=95 10e9/L(150-450 10e9/L) .

- Chest and Sinuses CT ordered to role out any viral infection.

- Repeat stool culture .

- Negative blood culture .

24-25/6/2014

Assessment:

-She looks well, pale, not dehydrated not in distress, low grade fever

T=37.5°C , diarrhea one time / day.

Plane:

- Follow up the ordered test.

- Continue the same treatment .

Medication :

IndicationDosing

Regimen

RouteMedication

Pain and fever

- Day 11.

400 mg

q 4-6 hours

POParacetamol

To cover any fungal

infection

- Day 5 .

135 mg OD IV Liposumal

Amphotericin B

Diarrhea

- Day 8 .

200 mg

Q 8 hours

IVMetronidazol

Oral thrush

- Day 11 .

5ml Q6hPOSpecific mouth

wash

FN

- Day 10 .

190mg ODIVGentamicen

FN

- Day 10 .

2250mg Q6hIVTazocin

Thank you