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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