Childhood acute leukemia

Wisdom of the Land

Childhood acute leukemia

4th August, 2019

Kleebsabai Sanpakit, MD Division of Hematology/Oncology

Department of Pediatrics Faculty of Medicine, Siriraj Hospital

Mahidol University

Topic outline

Conditions Predisposing to childhood leukemia Diagnosis and classification Risk stratification Treatment in pediatric leukemia Indications for HSCT Summary

Age-adjusted incidence rates for childhood cancer by ICCC Group, 2003-2005

Wiangnon S,et al. Asian Pacific J Cancer Prev, 2011

Total 2,792 cases Age<15 yrs, Both Sexes

N=266 ~ 9.5% of all childhood cancer

N = 1421 cases ~ 50.9%

Bidwell SS, et al. Pedatric Blood & Cancer 2019

Total 3,574 cases Age<19 yrs, Both Sexes Leukemia 1,245 cases 34.8%

Diagnosis

Breems D’s presentation

WHO ALL: lymphoblast blasts in BM > 25% of TNC ANLL: myeloblast blasts in BM > 20% of TNC

Diagnosis

Patients with clonal cytogenetic abnormalities

including t(8;21) (q22;q22), inv(16) (p13;q22) or

t(16;16) (p13;q22) and t(15;17)(q22;q12) are

considered to have AML regardless of % blasts

1. Environmental

- Ionizing radiation

- Chemical exposure: Benzene/Petroleum, Herbicides/Pesticides

- Drugs: Alkylating agents typically present within 3-5 years after

Rx, AML with poor-risk cytogenetics

Epidophyllotoxin typically present 6-36 months after Rx,

FAB M4 or M5, often involves MLL gene rearrangement (11q.23)

- Infections: EBV - Burkitt’s lymphoma

HTLV I - T cell ALL

Risk factors

Risk factors

2. Predisposing conditions - Noninherited syndrome:

Aplastic anemia, PNH, MDS AML

Immunodificiencies (drug/viral) ALL

Immune suppression: previous organ transplant

- Siblings of children with leukemia, especially among identical twins

Risk factors

Condition Inheritance Leukemia

Down Syndrome

Trisomy 21

< 3 yrs. AML > ALL > 3 yrs. AML = ALL

Ataxia Telangiectasia AR ALL Wiskott-Aldrich X – linked ALL Bloom Syndrome AR AML > ALL Fanconi Anemia AR AML > ALL Kostmann’s Syndrome AR AML Schwachman Syndrome AR AML > ALL NF1 AR AML > ALL Klinefelter Syndrome Extra X ALL > AML

- Inherited syndrome:

, JMMoL

FAB classification in ALL

L1 L2 L3

Immunophenotype

Lanzkowsky’s manual of Pediatric Hematology and Oncology, 6th edition. 2016

Childhood ALL

Lanzkowsky’s manual of Pediatric Hematology and Oncology, 6th edition. 2016

Estimated frequencies of specific genotypes

Bennett, et al. BJH 1976 Breems D’s presentation

Breems D’s presentation,

Mechanism of genetic and molecular mutation resulting in AML

Redner A, et al. Lanzkowsky 2016

Precursor stage CD34, CD117, CD133, HLA-DR

Pan-leukocyte markers CD45

Lanzkowsky’s manual of Pediatric Hematology and Oncology, 6th edition. 2016

WHO classification 2016

5-15%, FAB M1/M2, ass with high rate of long term

remission

2-11%, FAB M4Eo, favorable prognosis,

CNS leukemia

5-13%, FAB M4, M5a, infant or young adult, high WBC 6-15%

WHO classification 2016

WHO classification 2016

Myeloid sarcoma Tumor mass consisting of myeloid blasts with or without maturation Common sites: head, orbit, skin, CNS, paraspinal area Common in patient < 1 year old high initial WBC t(8;21), inv(16), 11q23 (MLL rearrangements) FAB M4, M5

Myeloid proliferations related to Down syndrome

Transient abnormal myelopoiesis (TAM)

- Association with Trisomy 21, Mosaicism may be present - Clonal expansion of myeloblasts, Mainly GATA1 gene mutation - Usually occur in first few days of life, 4-10% occur within 1 yr - Indistinguishable from congenital AML - Majority of patients have spontaneous regression in 1-3 months - Some have severe life-threatening symptoms exchange transfusion and/or low-dose cytarabine - 20-30 % of pts develop AML in 2-4 yrs

WHO classification 2016

WHO classification 2016

Myeloid proliferations related to Down syndrome Myeloid leukemia associated with Down syndrome

- 10-20 times more likely to develop leukemia

- For first 3 yrs : AML > ALL

- MDS prodrome frequent

- M7 subtype ~ 500 times more common

- Myelofibrosis is common in M7

- Superior outcome compare to non-DS AML

- Patients > 4 years old had a significantly worse EFS

Risk-adapted Rx based on prognostic factors and Rx response

Prognostic factors: Genetic abnormalities Response to Therapy Cytogenetic abnormalities found in 70-80% of children with AML

Induction in Pediatric AML

One or 2 courses of induction therapy Standard induction therapy 3 days of anthracycline 7-10 days of cytarabine “3+7” or “3+10” >85% of patients achieve CR - Failure to achieve CR after 1st induction is associated with a poor outcome in de novo and relapsed AML. - Achievement of 2nd CR in relapsed AML is the most important prognostic factor of OS.

Daunorubicin 60 mg/m2/day Idarubicin 10-12 mg/m2/day Mitoxantrone 10-12 mg/m2/day

Cytarabine 100-200 mg/m2/day

CNS leukemia

5-10% of pediatric AML: CNS involvement at diagnosis and at relapse

Factors Associated with CNS disease - Younger age < 2 years - Hyperleukocytosis (>100,000/cumm) - Monocytic leukemia (FAB M4 or M5) - APL with PML/RARA in relapse - Certain molecular/cytogenetic findings (eg, FLT3-ITD; AML with inv(16) or chrom 11 abnormalities; complex karyotypes) - Expression of CD56 on the surface of blast cells - Elevated LDH Not affect OS, although increased incidence of isolated

CNS relapse

CNS Therapy

No prospective studies comparing the use of IT chemotherapy and cranial radiation in patients with CNS involvement

In general, triple IT chemotherapy is preferred in patients with CNS involvement without neurological deficits

Radiation therapy may be considered in CNS involvement with focal neurological deficits Tumor mass impinges on important structure such as

spinal cord Failure to respond to IT chemotherapy (CNS +ve after 4 x IT-chemotherapy)

MRD is a strong prognostic factor in pediatric acute leukemia

ATRA+/- ATO and anthracycline are standard of care

Prognosis of APL

Poor prognosis if initial white count ( > 10,000 cumm) platelet count ( < 40,000 cumm) PLZF-RARa (not respond to ATO and ATRA)

FLT3-ITD or additional cytogenetic not significantly related to adverse outcome.

De Botton S, et al. British journal of haematology. 2000;111(3):801-6.

Indications for HSCT 1. Acute myeloid leukemia in remission

2. Acute lymphoblastic Leukemia (ALL)

CR1: Philadelphia chromosome, T cell with initial WBC >100,000/cumm, Hypodiploidy chromosome, Induction failure, Infant ALL with age < 6 months or initial WBC > 300,000/cumm to intermediate and high risk infant ALL

CR2

3. Chronic myeloid leukemia in all stages

4. Juvenile myelo/monocytic leukemia (JMML)

Disease status at HSCT is a significant predictor of recurrence and OS.

5-year overall survival of acute leukemia 57%

51%

Bidwell SS, et al. Pedatric Blood & Cancer 2019

Summary

Improvements in survival rates of pediatric leukemia

- Defining risk stratification based on cytogenetic and

molecular markers and response to therapy

- Optimizing of chemotherapy regimens to reduce toxicity for

patients who can be cured with less intensity and intensify

therapy for patients who remain at high risk of relapse

- Monitoring response to therapy using MRD

- Better salvage options including HSCT

- Good supportive care

Thank you for your attention