leukemia and emergencies associated with leukemia in pediatrics.

1. LEUKEMIA II
Dr: Inayat Ullah
PG Paeds
Shifa International Hospital Islamabad.

2. OVERVIEW
• AML
• CML
• INFANTILE LEUKEMIA
• DOWN SYNDROME AND ACUTE LEUKEMIA & TRANSIENT
MYELOPROLIFERATIVE DISORDERS
• JUVENILE MYELOMONOCYTIC LEUKEMIA
• EMERGENCIES ASSOCIATED WITH LEUKEMIA

3. Classification
• Classified based on cell type involved and the
clinical course
– Acute :
• ALL
• AML
– Chronic :
• CLL
• CML
3

4. Acute Myeloid Leukemia
- Clonal expansion of myeloid precursor cells
with reduced capacity to differentiate
- As opposed to ALL/CLL, it is limited to the
myeloid cell line
– differentiated from ALL based on morphology,
cytogenetics, cytochemical analysis, cell surface
markers

5. Etiology
• Unknown / De-novo In majority
• Predisposing factors:
– Ionizing radiation exposure
– Previous chemotherapy : alkylating agents
– Occupational chemical exposure : benzene
– Genetic factors: Down’s Syndrome, Bloom’s,
Fanconi’s Anemia
– Viral infection ( HTLV-1)
– Paroxysmal nocturnal hemoglobinurea.
5

6. Hereditary Disorders Associated With
an Increased Risk of AML
• Down syndrome
• Ataxia telangiectasia
• Li-Fraumeni syndrome
• Klinefelter’s syndrome
• Fanconi’s anemia
• Wiskott-Aldrich syndrome
• Bloom syndrome
• NF-1
• Shwachman-Diamond syndrome
• Kostmann syndrome.
6

7. Epidemiology
• M > F
• 11% of childhood leukemia
• ALL which predominantly affects younger
individuals
• AML – adults and the elderly
• Median age group-65yr
7

8. Hematopoietic
stem cell
Neutrophils
Eosinophils
Basophils
Monocytes
Platelets
Red cells
Myeloid
progenitor
Lymphoid
progenitor
B-lymphocytes
T-lymphocytes
Plasma
cells
naïve
ALL
AML

9. Myeloid maturation
myeloblast promyelocyte myelocyte metamyelocyte band neutrophil
MATURATION
Adapted and modified from U Va website

10. WHO Classification
• AML with certain genetic abnormalities
– t(8;21), t(16), inv(16), chromosome 11 changes
– t(15;17) as usually seen with AML M3
• AML with multilineage dysplasia (more than one abnormal myeloid cell type is involved)
• AML related to previous chemotherapy or radiation
• AML not otherwise specified
– undifferentiated AML (M0)
– AML with minimal maturation (M1)
– AML with maturation (M2)
– acute myelomonocytic leukemia (M4)
– acute monocytic leukemia (M5)
– acute erythroid leukemia (M6)
– acute megakaryoblastic leukemia (M7)
– acute basophilic leukemia
– acute panmyelosis with fibrosis
– myeloid sarcoma (also known as granulocytic sarcoma or chloroma)
• Undifferentiated or biphenotypic acute leukemias (leukemias that have both lymphocytic
and myeloid features. Sometimes called ALL with myeloid markers, AML with lymphoid
markers, or mixed lineage leukemias.)

11. Clinical symptoms
• Due to the excessive proliferation of myeloid
precursor cells in bone marrow, followed by
marrow replacement and failure certain
symptoms/lab findings are expected (e.g. as
a result of pancytopenia)
1. Functional neutropenia – fever, chills
(INFECTION)
2. Thrombocytopenia – bleeding, bruising
3. Anemia – weakness, fatigue

12. Specific
• Chloroma:-presents as a mass lesion ‘tumor of
leukemic cells’
• DIC indicative of APL.
• Infiltration of soft tissues, gum infiltration, skin
deposits ,Meningeal involvement-headache,
vomiting, eye symptoms
• Subcutaneous nodules or blue berry muffin
lesions in skin
• CNS involvement is more common in AML then
ALL
12

13. Diagnosis
• Blood count : WBC usually elevated (50,000- 1,00,000 / cmm
); may be normal or low; often anemia & thrombocytopenia
• Bone marrow: Bone marrow aspirate & trephine:
Hypercellular,
–blast cells ( > 20%),
–presence of Auer rods - AML type
• Cytochemistry : Special stains to differentiate AML from ALL
Positivity with Sudan black & Myeloperoxidase (MPO) in AML
13

14. P. Smear AML

15. MPO (right) & Sudan black (left)
showing intense localised positivity in
blasts

16. Confirmation of diagnosis
• Confirmation:
–Immunophenotyping
–Molecular genetics
–Cytogenetics: Chromosomal abnormalities
16

17. MANAGEMENT
• SPECIFIC THERAPHY:
–Chemotherapy : Aggressive multiagent
chemotherapy is successful in approx 85-90%.
– Survival has increased from 15% in 1970 to 60-
70% with modern therapy.
– Targeting therapy to genetic markers may be
benefecial.
– Upto 5% of patients die of either infection or
bleeding before remission can be achieved.
17

18. TREATMENT
• Matched-sibling bone marrow or stem cell
transplantation after remission achieves long
term disease free survival in 2/3rd .
• Continued chemo for those who don’t have
matched donor is less effective than
transplant, but curative in half patients.
• Matched unrelated stem cell transplant may
be effective but there is risk of GVHD

19. TREATMENT CONTINUED
• Acute promyelocytic leukemia APL
charaterized by gene rearrangement involving
retinoic acid receptor is very responsive to
retinoic acid with anthracycline.
• Increased supportive care :
Anemia correction, filgrastim(GMCSF), platelets
transfusion, antibiotics, antifungal
prophylactic.
19

20. DOWN SYNDROME AND ACUTE
LEUKEMIA/TRANSIENT
MYELOPROLIFERATIVE DISORDERS.
• 15-20 times higher than in general population.
• AML:ALL Ratio is the same.
• Outcome of ALL to treatment is inferior.
• Higher sensitivity to MTX and antimetabolite
so higher risk of toxicity
• Better outcome than non down syndrome
>80% long term survival.

21. Transient leukemia
• Develops in 10 % neonates with Down
syndrome
• High TLC, Blast cells on P.Film, anemia,
thrombocytopenia and hepatosplenomegaly.
• Resolve within 1st 3 months of life.
• Require temporary transfusion support and no
chemotherapy.
• Require close follow-up 20-30 % will develop
typical leukemia by 3 yr of life

22. Chronic myeloid leukemia (CML)
• Clonal disorder of hematopoeitic tissue
accounting for 2-3 % of all cases of childhood
leukemia.
• 99% cases are characterized by translocation
of specific chromosome t(9;22)(q34:q11)
known as Philadelphia chromosome resulting
in BCR-ABL fusion protein.

23. (CML) SIGNS SYMPTOMS
• Nonspecific: fever, fatigue, weight loss, and
anorexia
• Splenomegaly with pain in right upper
quadrant.
• CNS menifistation from hyperleukocytosis
resulting in increased blood viscosity and
decreased CNS perfusion.

24. (CML) DIAGNOSIS
• CBC: High WBC count, anemia, and
thrombocytosis
• High myeloid cells at all stages of
differentiation in peripheral blood and bone
marrow
• Confirmed by cytogenetic and and molecular
studies that demonstrate Philadelphia
chromosome and BCR-ABL gene
rearrangement

25. (CML) TREATMENT
• Imatinib (Gleevec), an agent which inhibit
BCR-ABL tyrosine kinase, produce major
cytogenetic response in > 70% of patients
• 2nd generation tyrosine kinase inhibitor
dasatinib have improved remission rate in
adults and now being studied in children.
• HLA matched family donor allogenic stem cell
transplant produces cure in upto 80 % of
children.

26. Juvenile myelomonocytic leukemia
(JMML)
• Previously called juvenile CML is clonal
proliferation of stem cell affects children <2 yr
• JMML< 1% of all childhood leukemia.
• Present with rash, lymphadenopahy,
splenomegaly, and hemorrhagic
menifestation.
• Patient with Noonan syndrome, NF-1 have a
predilection for this leukemia.

27. JMML Diagnosis Treatment
• CBC: shows leukocytosis esp monocytosis,
thrombocytopenia, and anemia with presnece
of blasts.
• BM shows myelodysplastic pattern, with
blasts accounting for < 20%.
• Stem cell transplantation offer the best
opportunity of cure but much less than for
classic CML.

28. Infantile leukemia
• 2% of childhood leukemia occures in children
<1 year of age.
• Ratio of ALL:AML is 2:1
• Leukemic cells have been noted in cord blood
at birth
• Chromosomal translocaton can also occur in
utero during fetal hematopoiesis.

29. INFANTILE LEUKEMIA
• Presentation is usually with hyperleukocytosis
and extensive tissue infiltration with
organomegaly.
• Subcutanous nodules , leukemia cutis and
tachypnoea caused by leukemic cells
pulmonary infiltration
• leukemic cell morphology shows irregular
lymphoblasts with phenotype negative for
CD10

30. INFANTILE LEUKEMIA
• TREATMENT:
• Intensive chemotheray.
• Stem cell transplantation
• None of them satisfactory.
• Meticulous supportive care is necessary
because of the young age and aggressive
therapy needed in these patients.

31. HEMATO/ONCOLOGIC EMERGENCIES

32. Leukostasis
• Leukostasis – predominantly in those with WBC
counts > 100,000 (10% of patients); can also be seen
in patients with WBC > 50,000
– Most common in those with M4 or M5 leukemia
– Function of the blast cells being less deformable than
mature myeloid cells. As a result, intravascular plugs
develop.
– High metabolic activity of blast cells and local production
of various cytokines contribute to underlying hypoxia

33. Leukostasis in AML
Thornton, KA, Levis, M. FLT3 Mutation and Acute Myelogenous Leukemia with Leukostasis. N Engl J Med 2007; 357:1639. Copyright ©2007
Massachusetts Medical Society

34. Leukostasis
• Common symptoms
– Pulmonary: dyspnea, chest pain
– CNS: headaches, altered mentation, CN palsies,
ocular symptoms
– Priapism
– Myocardial Infarction

35. Leukostasis
• Transfuse platelets to keep count above 20,000/μL.
• Avoid (RBC) transfusions because they will raise viscosity
(keep Hb ≤10 g/dL). If RBCs are required, consider partial
exchange transfusion.
• Hydration, alkalinization, and allopurinol should be initiated .
• Administer fresh frozen plasma (FFP) and vitamin K for
coagulopathy.
• Before cytotoxic therapy, consider leukapheresis or exchange
transfusion to lower WBC count if CNS or pulmonary
symptoms exist.
• Start disease treatment as soon as patient is clinically stable.

36. Leukostasis
• Leukapheresis
– Limited affect on established vascular plugs
– Limited benefit in those with underlying pulmonary
symptoms following chemotherapy. Symptoms in this case
related to leukocyte lysis and subsequent inflammatory
response
– Should not be used as a single modality agent in patients
with leukostasis.
– May consider as adjunct to chemoterapy in patients with
WBC >100,000 and symptoms suggestive of leukostasis

37. Tumor Lysis Syndrome
• Characterized by metabolic derangements
caused by massive release of cellular
components following lysis of malignant cells
• Commonly seen in malignancies with high
rates of cell proliferation (esp. ALL, Burkitt’s
lymphoma); also can be seen with AML

38. Tumor Lysis Syndrome
• Hyperuricemia, hypocalcemia, hyperkalemia,
hyperphosphatemia.
• Can lead to acute kidney injury due to precipitation
of uric acid crystals and/or calcium phosphate
crystals in renal tubules and micovasculature,
respectively.

39. Tumor Lysis Syndrome
• Release of intracellular proteins →catobilized to hypoxanthine
→ xanthine → uric acid → Crystalization of uric acid and in
renal tubules → impaired renal function
• Release of phosphate from malignant cells → calcium
phosphate precipitation and further renal impairment along
with hypocalcemia and resultant symptoms from ↓Ca
– Hyperphosphatemia: nausea, vomiting, diarrhea, seizures, lethargy
– Hypocalcemia: arrhythmia, hypotension, tetany, cramps
– Hyperkalemia: arrhythmia, cramps, paresthesia

40. Tumor Lysis Syndrome
• Hydration: Dextrose 5% (D5) 1/4 normal saline (NS) ± 40 mEq/L
NaHCO3 (without K) at double maintenance. Keep urine
specificgravity <1.010 and urine output >100mL/m2/hr.
• Hyperuricemia: Allopurinol inhibits formation of uric acid and can
be given (PO) or (IV) Rasburicase converts uric acid to the more
soluble allantoin. Use in higher-risk patients, especially those with
uric acid >7.5 mg/dL.
• Monitor K+, Ca2+, phosphate, uric acid, and urinalysis closely (up to
Q2 hr for high-risk patients). There is an increased risk of calcium
phosphate precipitation when Ca × Phos > 60
• Consider stopping alkalinization after uric acid levels return to
normal to facilitate calcium phosphate excretion.

41. SPINAL CORD COMPRESSION
• Etiology: Intrinsic or extrinsic compression of spinal
cord; occurs most commonly with brain tumors,
sarcomas, leukemia with lymphomatous
involvement, lymphoma, and neuroblastoma.
Presentation: Back pain (localized or radicular),
weakness, sensory loss, change in bowel or bladder
function.
Prognosis for recovery based on duration and level of
disability at presentation.

42. DIAGNOSIS
• Magnetic resonance imaging (MRI [preferred])
or computed tomography (CT) scan of spine.
• A plain film of spine has good specificity but
detects only two thirds of abnormalities

43. MANAGEMENT
• Management: (Steroids may prevent acurate diagnosis of
leukemia/lymphoma; plan diagnostic procedure as soon as
possible)
• Bolus dexamethasone 1–2mg/kg/day IV and obtain an
emergent MRI of the spine in case of severe symptoms
• In mild sign and symptoms lower dose of dexamethasone,
0.25–0.5 mg/kg/dayPO, divided Q6 hr. Perform MRI of
spine within 24 hours.
• If cause of tumor is known, emergent radiotherapy or
chemotherapy is indicated for sensitive tumors; otherwise,
emergent neurosurgery consultationis warranted.
• If cause of tumor is unknown or debulking may remove
most or all of tumor, surgery is indicated to decompress the
spine.

44. RESPIRATORY DISTRESS AND SV
SYNDROME
• Etiology: Mediastinal mass, edema, or
thrombosis; typically seen with Hodgkin
disease, non-Hodgkin lymphoma (e.g.,
lymphoblastic lymphoma), ALL (T-lineage),
germ cell tumors
• Presentation: Orthopnea, headaches, facial
swelling, dizziness, plethora, acute respiratory
distress or failure

45. DIAGNOSIS AND TREATMENT
Diagnosis: Chest radiograph. Consider CT or MRI to
assess airway.
• Attempt diagnosis of malignancy (if not known) by
least invasive method possible. Avoid sedation or
general anesthesia if unstable, high risk.
Management:
• a. Control airway
• b. Biopsy (e.g., bone marrow, pleurocentesis,
lymphnode biopsy) before therapy if patient can
tolerate sedation or general anesthesia
• Empiric therapy: radiotherapy, steroids, chemotherapy

46. NEUTROPENIC TYPHLITIS
Etiology: Inflammation of bowel wall, usually
localized to cecum. Occurs most often in
association with prolonged neutropenia.
Presentation: Right lower quadrant abdominal
pain, nausea, diarrhea, fever (fever may be
absent early in course
Neutropenic patient with abdominal pain
warrants evaluation for typhlitis .

47. DIAGNOSIS MNAGEMENT
Diagnosis:
• Careful serial abdominal examinations
• X-ray may show pneumatosis intestinalis, bowel wall
edema
• CT (IV and PO contrast) most sensitive imaging; may
reveal bowel walll thickening, pneumatosis intestinalis
Management:
• Keep(NPO), IV fluids; consider NG decompression.
• Broad anaerobic and gram-negative antibiotic
coverage (consider coverage for Clostridium difficile).
• Follow closely with surgery consult.

48. FEVER NEUTROPENIA
• Etiology: Presumed infection (bacterial, viral,
or fungal) in a neutropenic host. Bacterial
infection is the most common documented
infection.
• Occassionally, fevers may be due to
medications.

49. PRESNTATION AND DIGNOSIS
Presentation: Fever, fatigue, chills, rigors,
listlessness, lethargy, tachypnea,tachycardia,
localized pain.
Diagnosis: Fever (temperature [T] > 38.3°C or T
> 38.0°C for >1 hour) in the setting of
neutropenia (ANC < 500 cells/μL, or < 1000
cells but expected to drop to <500 in the next
48 hours).

50. FEBRILE
NEUTROPENIA
MANAGEMNE
T