Acute Acute lymphoblastic lymphoblastic leukemialeukemia in childrenin children

Dragana JanićUniversity Chldrens Hospital, Belgrade, Serbia

EPIDEMIOLOGY OF ALLEPIDEMIOLOGY OF ALL IN IN CHILDRENCHILDREN

• Malignancie in children – 1% of all malignancies

• ALL 1/3 of all - 40/1 million children/y• Slightly more frequent in males, except for

infants (females > males)• Peak incidence 2-5 years• 85% cure rate vs none some 60y ago

LEUKEMOGENESIS - LEUKEMOGENESIS - EEnvironmental factors

• Ionizing radiation– Risk of ALL increased to 1:60 during 12 years after

nuclear bomb explosion– Intrauterine exposure to X-rays (historical data) for

diagnostics increases relative risk of ALL to 1.5

• Role of infection– Protective at an early age– Increasing the incidence when populations mix

LEUKEMOGENESIS - LEUKEMOGENESIS - Genetic factors

Congenital gene aberrations– Inherited syndromes (Down, neurofibromatosis type I. Bloom,

ataxia telangiectasia, Schwachman) – Family clustering - Li Fraumeni sy: TP53

Acquired gene aberrations: detected in up to 50% by cytogenetics and far more with molecular genetics

– Hypodyploidy <44 chr– High hyperdyploidy 51-65 chr– BCR-ABL t(9;22), ETV6/RUNX1 t(12;21), MLL 11q 23 mostly

resulting from t(4;11)– iAMP 21– Oher reccurent abnormalities

FREQUENCY OF SPECIFIC GENE FREQUENCY OF SPECIFIC GENE

ALTERATIONS IN ALTERATIONS IN ALLALL

Pui et al. NEJM. 2004

10%2%

7%

3%

25%

53%

ADULTDECA

25%

3%5%

8%

22%

37%HyperdiploidyTEL/AML1MLL/AF4BCR/ABLE2A/PBX1Other

CHILDREN

Acquired gene aberrations inAcquired gene aberrations in explaining explaining ALLALL

• Prenatal origin of leukemogenic event &Prenatal origin of leukemogenic event & theory of placental metastasistheory of placental metastasis

• ““Two-hit theory” (two leukemogenic events)Two-hit theory” (two leukemogenic events)

Prenatal origin of leukemogenic eventPrenatal origin of leukemogenic event && theory of placental metastasistheory of placental metastasis

58% of identical twins share the placenta, monochorionic, blood vessel anastomosis.

Clarkson BD. Boyse EA Possible explanation of the high concordance for acute leukaemia in monozygotic twins. Lancet. 1971 Apr 3;1(7701):699-701.

1617 NN: De Wikkelkinderen (The Swaddled Twins). The Muiderslot castle near Amsterdam

““Two-hit” theoryTwo-hit” theory

first mutation

first mutation

second mutationsecond

mutation

External factors

External factors

in uteroin utero

postnatalpostnatal

Monozygotic twinsGuthrie test cards

Greaves MF. et al. Leukemia in twins: lessons in natural history Blood. 1 October 2003. Vol. 102. No. 7. pp. 2321-2333

ALL

RetrospeRetrospectivective analysis of Guthrie analysis of Guthrie cards for fusion genescards for fusion genesGuthrie catds from the

1950s used for PKU• The same mutation found

on card as in leukemia patient (TEL-AML1)

• Prenatal initiation – first hit

• Latency 3 years

• Not all leukemias are initiated in utero - t(1;19), negative on cards

Second hitSecond hit

• Different age in other twin with leukemia (latency 3 years)

• 1% of healthy children bear TEL-AML1, never to develop leukemia

DIDIAGNOSISAGNOSIS

• History

• Physical examination

• Lab

HistoryHistory

Short duration

• Fatigue

• Fever

• Bone and joint pain

• Hemorrhagic syndrome

ALL common presentation

Findings % pts

Hepatosplenomegaly 70

Splenomegaly 65

Fever 60

Bleeding 50

Lymphadenopathy 50

Pain/swelling bone/joint 25

Lab % pts

WBC (mm3)

10 000 55

10 000 – 49 000 30

50 000 15

Hgb (g/dL)

70 45

70 – 110 45

110 10

PLT (mm3)

20 000 30

20 000 – 99 000 50

100 000 20

ALL uncommon presentation

CNS - 5%

Increased preassure

Sight disturbances

Paralysis of cranial

nerves

Vertigo

Hearing disturbances

Cerebelar disturbances

Hyperpnea

Less than 1%

• BM aplasia

• Hypereosinophilia

• Hypercalcemia

• Cyclic neutropenia

• SLE

• Renal failure

• IHA

The most common presentations of The most common presentations of ALLALL

1. B cell precursor ALL

2. T-ALL (15% of ALL)

3. ALL in infants and small children

B CELL PRECURSOR ALLB CELL PRECURSOR ALL

Common ALL,

CALLA+, CD10+

Most common IPH

Age 2-5 yrs

Best prognosis

Up to 5% may be

BCR-ABL+

T-ALLT-ALL

Older age

Male predominance

Mediastinal mass,

hyperleukocytosis,

CNS affection

INFANT ALLINFANT ALL

Hyperleukocytosis,

organomegaly, CNS

Early pre-B cells, coexpression

of myeloid antigens

Structural alterations in

11q23 (MLL gene), most

commonly t(4;11)

Lab analysisLab analysis

• Complete blood count

• Bone marrow– morphology– cytochemistry– immunophenotype– bone marrow cytogenetics– molecular genetics

Bone marrow morphologyBone marrow morphology

• % of leukoblasts

• FAB morphology classification

L1 L2 L3

Bone marrow cytochemistryBone marrow cytochemistry

• Specific dyes– PAS– Sudan black– Myeloperoxidase...

PAS+ Sudan Black Myeloperoxidase

Bone marrow immunophenotypeBone marrow immunophenotype

• Classification• T (15%) (CD3, CD2, CD5 and CD7)

– Early (CD34, CD7, CD5, CD2, cyCD3, TdT) – Medium (CD4 and CD8, CD3) – Late (either CD4 or CD8)

• B– Pre-pre-B-ALL (CD10, CD19, CD24, CD34, HLA-DR, cyCD22,

CD79a, CD79b and nu-TdT)– Pre-B-ALL (CD19, CD20, HLA-DR, CD10 in 90% (CALLA-

Common ALL antigen)• Mature B ALL (1-2%) (IgM, CD20, CD19, HLA-DR, CD21)

Cytogenetics andCytogenetics and molecular geneticsmolecular genetics

• Numeric and structural aberrations

• Methods:

2. FISH

3. PCR4. micro array

1. karyotype

Case reviews

Case №1

• Boy aged 7

• Presented with:– Fever– Lymphadenopathy– Splenomegaly

of short duration

• CBC showed WBC↑ 20.000/mm3, moderate anemia and thrombocytopenia

Case №1

• Differential diagnosis– Infectious mononucleosis– Malignancy?

• Diagnostic work-up– CBC with peripheral smear– BM aspiration– Immunophenotype

• Dg: T - ALL

Case №2

• 6 year old girl

• Presented with:– Bone and joint pain with a limp– Knee swelling– Thrombocytopenia

Case №2

• Diagnostic work-up:– CBC with peripheral smear revealed Plt↓– Careful re-examination revealed

splenomegaly

• Dg: B cell precursor ALL

Case №3

• 4 year old girl

• Presented with:– Fever– Severe aphthous stomatitis– “Strange” lesions on the skin– Pancytopenia– Hepatosplenomegaly

Case №3

• CBC with peripheral smear showed pancytopenia with scarce leukoblasts

• BM aspiration with immunophenotyping showed B-cell precursor ALL

• Skin biopsy: atypical form of pyoderma gangrenosum (paraneoplastic neutrophilic dermatosis – very rare in children!)

Case №4

• 3 year old boy

• Presented with:– Leucocytosis– Anemia– Thrombocytopenia– Massive hepatosplenomegaly– Scrotal swelling

Case №4

• Diagnostic work-up:– BM aspiration with immunophenotype– Abdominal and testicular US

• Dg: B cell precursor ALL with testicular infiltration

Special therapy for subtypes?

IV Balkan Hematology Days, Sept. 2009, Sofia

From: Acute lymphoblastic leukaemia. Pui CH, Robison LL, Look AT. Lancet 2008.

PROGNOSTIPROGNOSTICC FA FACCTORTORSS

Gene

alterations

Age, WBC, Tx response

Imnunophenotype: pre-B and T

I-BFM SG

ChemotherapyChemotherapy--treatment treatment protoprotoccolol

General principles of ALL therapy

InductionCNS-directed therapy and consolidationReinductionMaintenance

General principles of ALL therapy: Induction

98% - morphological remission and restauration of hematopoesis

4-6w of 4 sistemic drugs (glucocorticoids, vincristine, anthracycline andL-asparaginase) + IT therapy with MTX or MTX, hydrocortisone and cytarabine

General principles of ALL therapy: CNS-directed therapy and

consolidation

Prevention of CNS relapsesHigh-dose MTX and 6-MP + IT ThT ALL with high WBC, high-risk pts - 12GyCNS involvement -18Gy

General principles of ALL therapy: Reinduction or delayed

intensification

Introduction of reinduction therapy brought the major improvement in EFS rates

Therapy repeats the elements of induction

General principles of ALL therapy: Maintenance

Oral daily 6-MP and weekly MTX for total therapy duration of 2 to 3 years

Adjusting the doses of the drugs in order to keep the WBC count between 1500 and 3000/mm3, which requires frequent check-ups because of high inter-individual variability

Selected randomized studies comparing Pred with Dexa in the treatment of childhood

ALL

Trial Years Outcome

CALGB 7111 1971-1974

Isolated CNS relapse rates:

Pred 25.5%

Dexa 14.3%

CCG 1922 1993-1995EFS at 6 y:

Pred 77%

Dexa 85%

UK MRC ALL97 and ALL97/99

1997-2002EFS at 5y:

Pred 76%

Dexa 84%

Stanulla M, Schrappe M. Treatment of childhood acute lymphoblastic leukemia. Semin Hematol. 2009;46(1):52-63

Randomized trials of 6-MP and 6-TG for childhood ALL

Trial Years Outcome Toxicity

COALL-92 1992-1997EFS at 6.6y: 6-MP 79%

6-TG 78%

6-TG: prolonged myelosuppression

with marked thrombocytopenia

UK MRC ALL97 and ALL97/99

1997-2002EFS at 6.6y: 6-MP 81%

6-TG 80%

6-TG: non-fatal hepatotoxicity with features of VOD at

11% pts

CCG-1952 1996-2000

EFS at 5y:

6-MP 77%

6-TG 85%

6-TG: reversible VOD at 20% pts;

portal hypertension as a late effect

Stanulla M, Schrappe M. Treatment of childhood acute lymphoblastic leukemia. Semin Hematol. 2009;46(1):52-63

Choosing treatment protocol -Serbian experience

In 2002, all Serbian centers treating pediatric ALL achieved consent to participate in the randomized study of ALL treatment

Concerning our long-term experience in providing treatment according to BFM-based protocols, we participated in ALL IC BFM 2002 protocol and became members of I-BFM-SG

Janic et al. Rezultati lečenja dece obolele od akutne limfoblastne leukemije po modifikovanom BFM protokolu. Srp arh celok lek 2004; 132:17-22

SCG National Group for ALL IC-BFM 2002

Dragana Janić, National Coordinator

Intensive chemotherapy for childhood acute lymphoblastic leukemia: results of the randomized intercontinental trial ALL IC-BFM 2002.

Stary J, Zimmermann M, Campbell M, Castillo L, Dibar E, Donska S, Gonzalez A, Izraeli S, Janic D, Jazbec J, Konja J, Kaiserova E, Kowalczyk J, Kovacs G, Li CK, Magyarosy E, Popa A, Stark B, Jabali Y, Trka J, Hrusak O,

Riehm H, Masera G, Schrappe M.

J Clin Oncol. 2014 Jan 20;32(3):174-84

EXPERIENCE IN PROTOCOL ADMINISTRATION

Novi Sad

Belgrade

Banja Luka

Niš

Serbia

Adriatic sea

Bosnia and Herzegovina

Croatia

Hungary

Romania

Bulgaria

FYR Macedonia

AlbaniaImmunophenotyping

Cytogenetics

Immunophenotyping

BMT

Molecular genetics

Podgorica

Montenegro

NEGATIVES

HEAVY WORK LOAD!

Conclusions

ALL displays an enormous biological variety which is not yet fully elucidated

Great expectations that molecular genetic methods will enable us to recognize new risk factors related to biology of the disease

Being involved in one of the large international studies is probably the best way toward optimizing the treatment of each individual patient

SupSuppportivortivee treatmenttreatment

• Blood component transfusion

• Infection prophylaxis and treatment

• Psychosocial

• Nutrition

• Various disease and treatment related complications