65. Leukemia in children and adolescent

Question 1

Acute lymphoblastic leukemia (ALL)

Answer 1

Malignant proliferation of lymphoid cells at an early stage of differentiation.
Most common malignancy in childhood.
Most common age group: 2-5 yrs
Etiology: genetic (Down syndrome) and environmental factors (radiation, viral infections e.g. EBV)

Question 2

ALL classification

Answer 2

Morphological FAB classification:
L1- small lymphoblasts with sparse cytoplasm
L2- large cells with abundant cytoplasm & differentiated nucleolus
L3- basophilic cytoplasm & vacuoles

Immunophenotypic classification:
B-cell (80-85%)
T-cell (15%) poor prognosis

Genetic classification: enriches diagnosis, treatment choice and prognosis

Question 3

ALL symptoms

Answer 3

Symptom duration varies from days to months.
anemia- pallor, fatigue
thrombocytopenia- hemorrhagic manifestations
neutropenia- infections
anorexia
bone pain
lymphadenomegaly (in T-cell leukemia mediastinal lymph nodes often affected—> resp failure or superior vena cava syndrome)
hepatomegaly
splenomegaly
CNS involvement- increases ICP, seizures
Infiltrative changes in kidneys, testicles, skin- rare

Question 4

ALL diagnosis

Answer 4

CBC- leukocytosis, anemia, thrombocytopenia

Bone marrow aspiration biopsy

high lactate dehydrogenase
high uric acid level
dyselectrolytemia
coagulation abnormalities

CSF cytology- confirms CNS involvement

Question 5

ALL differential diagnoses

Answer 5

other hematologic diseases
infectious diseases
bone diseases
rheumatoid diseases
solid tumors with bone marrow infiltration

Question 6

ALL treatment

Answer 6

induction phase- to achieve remission (blasts <5% in bone marrow)

early intensification- to eliminate residual leukemic populations

consolidation/CNS prevention- to consolidate achieved remission and prevent CNS involvement

late intensification- repetition of induction and early intensification phase

maintenance- low dose cytostatics to control cellular proliferation

Target therapy: tyrosine kinase inhibitors
Immune therapy

Hematopoietic stem cell transplantation (HSCT)- only in some cases

Question 7

ALL relapse

Answer 7

In 20% of cases there is relapse
leukemic cells in bone marrow &/or extramedullary (CNS, testes, skin)
Relapse can be:
early- during treatment & up to 6 months after end of treatment
late

Tx: Allogenic HSCT

Question 8

ALL late complications

Answer 8

secondary neoplasms (other leukemias, solid tumors)
neurotoxicity
cardiotoxicity
endocrine abnormalities
bone toxicity

Question 9

Acute myeloid leukemia

Answer 9

<15% of all acute leukemia cases in childhood.

Question 10

AML classification

Answer 10

Morphological FAB classification:
M0-M7
In promyelocytic myeloid leukemia (M3)- DIC is frequent
Megakaryoblastic leukemia (M7)- more common in Down syndrome children

Immunophenotypic classification

Question 11

AML symptoms

Answer 11

acquired immune deficiency
anemia
thrombocytopenia
extramedullary spread and infiltration less pronounced compared to ALL, subcut nodes, gingival infiltration, “granulocyte sarcoma”

Question 12

AML diagnosis

Answer 12

specific peripheral blood
bone marrow test

Question 13

AML treatment

Answer 13

Induction phase with combination of chemotherapeutics

Consolidation phase with high dose cytostatics

Intensification phase
(Intensive chemo may cause tumor lysis syndrome)

Maintenance phase- low dose cytostatics

In M3- retinoic acid, arsenic derivatives

Target therapy- MABs, specific inhibitors

Question 14

AML relapse

Answer 14

Higher risk of relapse than ALL
Lower survival rate (40-50%)

Tx: myeloablative chemotherapy & allogenic HSCT

HSCT- associated with significant risks, but has a higher definitive success than chemo alone

Question 15

Chronic leukemia

Answer 15

Myeloproliferative diseases caused by clonal disorder of hematopoietic stem cells.

Only CML has clinical significance in children.
Chronic lymphocytic leukemia (CLL)- doesn’t occur in childhood.

Juvenile myelomonocytic leukemia (JMML)- rare, but exclusively in children

Polcythemia vera, essential thrombocythemia & primary myelofibrosis- myeloproliferative diseases occasionally seen in children

Question 16

Chronic myeloid leukemia (CML)

Answer 16

3% of leukemia in childhood
Average age of onset: 11-12 yrs
Slight male prevalence

Etiology: reciprocal translocation of genes between chromosomes 9 & 22 t(9;22) Philadelphia chromosome
Leads to production of overactive enzyme- tyrosine kinase
Induces & maintains high rate myeloid proliferation

Phases of CML: chronic, acceleration & blast transformation (mainly to AML, but switch to ALL is possible)

Question 17

CML symptoms

Answer 17

painful splenomegaly

Question 18

CML diagnosis

Answer 18

peripheral blood- high num of myeloid cells
bone marrow- high num of myeloid cells
cytogenetic or molecular methods- to prove t(9;22)

Question 19

CML treatment

Answer 19

Targeted therapy- TKI

Long term remission with TKI= >70%

Question 20

Juvenile myelomonocytic leukemia (JMML)

Answer 20

Clonal proliferation of hematopoietic stem cells.
Age of onset: <2 yrs
1% of all childhood leukemias

Etiology: mutations associated with activation of RAS oncogene pathway

Sx: skin rash, lymphadenomegaly, splenomegaly, hemorrhagic manifestations

Dx: Peripheral blood
leukocytosis - monocytosis
thrombocytopenia
anemia with erythroblastosis
Philadelphia chromosome negative!!!

Bone marrow
myelodysplastic features
blast cells<20%

Tx: cytostatic combinations
allogenic HSCT- definitive