Pediatric Leukemia

and COVID-19
STEFANUS GUNAWAN
INDONESIAN PEDIATRIC SOCIETY NORTH SULAWESI BRANCH

Online Symposium IDAI

Covid-19 and Pediatric Immune System
August 22nd, 2020
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 DISCLOSURE
NO CONFLICT OF INTEREST

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 Structures
Disease burden
Signs & symptoms
Diagnosis
Risk factors
Treatment
Impact of Covid-19 pandemic
Management in Covid-19 pandemic

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Childhood cancer is rare but not
uncommon

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 Leukemia is the most common malignancy of childhood,
accounting for 30% of cases of childhood cancer

Leukemia Classification % of Childhood Leukemia

Based on cellular morphology and clinical
features
Acute lymphoid (ALL) 80
Acute myeloid (AML) 17
Chronic myeloid (CML) 3
Chronic lymphoid (CLL) Virtually none

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Distribution (%) of leukemia subtypes in children diagnosed
during 1995–2009 by continent

Lancet Haematol 2017. https://doi.org/10.1016/S2352-3026(17)30052-2

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The incidence of ALL is approximately 30 cases per 1 million
persons
This incidence varies among different ethnic groups
Indonesia
◦ Sistem Registrasi Kanker di Indonesia (SriKanDI) in 2005-2007,
predicts the incidence of childhood (0-17 years) leukemia ~2,8 per
100,000
◦ By statistics, roughly 1,900 pediatric leukemia/year

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Pathophysiology
The progenitor cell becomes genetically
altered and undergoes dysregulated
proliferation, with clonal expansion (but,
maturation arrest).

The clonal proliferation of leukemic blasts

prevents normal production of red blood
cells, platelets, and neutrophils.

Riether C, et al. Cell Death Differ 2015;22:187–98.

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 Leukemia Clinical Signs, Symptoms, or Complications
abnormality
Anemia Pallor, fatigue, dyspnea on exertion, headache, dizziness, near
syncope, decreased appetite; congestive heart failure with
extremely severe anemia
Neutropenia Fever (should be part of the work up of fever of unknown origin);
risk of overwhelming infection increases with severity of
neutropenia
Thrombocytopenia Petechial, ecchymosis, mucosal bleeding; but serious bleeding is
rare
Coagulation factor Increased bleeding; disseminated intravascular coagulation with
deficiencies severe factor deficiencies occurs frequently in the acute
promyelocytic leukemia

Leukemic infiltration Bone pain, back pain, limp, or refusal to walk

Lymphadenopathy, hepatomegaly, splenomegaly

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Diagnosis
History taking and physical examinations Blood chemistry
◦ Electrolytes
CBC and blood smear
◦ Uric acid, LDH
Chest X-Ray ◦ Kidney & liver function
LP  CSF analysis ◦ Coagulation profile

Echocardiography
Immunohistochemistry
Immunophenotyping
Karyotyping
DNA analysis

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Complete blood count findings at diagnosis of childhood leukemia

Jaime-Pérez JC, et al. Hematol Transfus Cell Ther. 2019;41:57–61

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Bone marrow aspiration
Cytomorphology
FAB classification
◦ ALL L-1, L-2, L3
◦ AML M0-M7

Bone marrow showing

◦ At least 30% blast (FAB)
◦ At least 20% blast (WHO)

Pictures from emedicine.medscape.com and UpToDate.com

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Immunophenotyping
Usually from bone marrow aspiration
Recent studies using peripheral blood sample
Immunophenotypic classification by PBFC is accurate (>98%) in
almost all cases of pediatric leukemia
◦ Sensitivity (100 vs. 93.8%; P = 0.002) and positive predictive value (100 vs.
93.8%; P = 0.002) favoring BMA over PBFC among those with absence of
circulating morphologic blasts
◦ Metrock LK, et al. Pediatr Blood Cancer 2017. doi: 10.1002/pbc.26526
◦ Cheng J et al. Pediatr Blood Cancer 2018. doi.org/10.1002/pbc.27453

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Genetic profiling
Estimated frequency of specific genotypes of ALL in children

Indonesia: hyperdiploid>50:11.46%; hypodiploidy 7.29%

Gunawan s, et al. SIOP abstracts 2011.
Doi.Org/10.1002/pbc.23299
Mullighan CG. Seminars Hematol 2013;50:314–24

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Questions after diagnosis
Any Covid19??
prevention?

What’s
the cause? Any risk factors? Any cures?

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Risk Factors for Childhood Leukemia
GENETIC ENVIRONMENT

Genetic syndromes Radiation exposure

◦ Down syndrome (trisomy 21)
Exposure to chemotherapy and
◦ Li-Fraumeni syndrome
Immune system suppression
Inherited immune system problems Exposure to certain other chemicals
◦ Ataxia-telangiectasia
◦ Wiskott-Aldrich syndrome
◦ Bloom syndrome
◦ Shwachman-Diamond syndrome

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Elevated risks of childhood ALL and AML with home use of pesticides before and
after birth
Maternal occupational exposure childhood AML
Preconception paternal exposure  childhood ALL

Metayer C, et al. Pediatrics 2016;138;S45

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Elevated risks of childhood ALL were observed mainly when
fathers reported smoking both before and after birth

Metayer C, et al. Pediatrics 2016;138;S45

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Elevated risks of childhood ALL and AML with use of paints at home, but
not at the workplace

Metayer C, et al. Pediatrics 2016;138;S45

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 Exposure from power lines
No increase in risk of leukemia among children
who lived within any distance (including < 50 m)
to power lines of all voltages combined

Amoon AT, et al. Br J Cancer 2018;119:364–73 Two-stage meta-analysis < 50 m vs. 300 + m to 200 + kV line*

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 Childhood Leukemia and Magnetic Fields in Infant Incubators

High levels of magnetic field exposure experienced over a short time

period early in life are unlikely to affect childhood leukemia risk
Söderberg KC, et al. Epidemiology 2002;13:45-49

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Even small doses of radiation from pediatric CT
scans produce a small, but detectable increase in
leukemia risk

Nikkilä A, et al. Haematologica 2018.

Doi:10.3324/haematol.2018.187716

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Increased risk of childhood ALL after prelabour caesarean delivery

Marcotte EL, et al. Lancet Haematol 2016; 3: e176–85

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Elective CS rather than emergency CS increases the risk of
lymphoblastic leukemia in offspring

Jiang L. et al. World J Pediatr (2020). https://doi.org/10.1007/s12519-020-00338-4

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Increased risk of Infant ALL following CD

Marcotte EL, et al. Cancer Epidemiol Biomarkers Prev 2018;27; 473–8

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 Promoting breastfeeding for 6 months or more may
help lowering childhood leukemia incidence

Amitay EL, et al. JAMA Pediatr. 2015;169(6):e151025.

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Hypotheses
The population-mixing hypothesis (Kinlen hypothesis)
◦ Abnormal reaction to a low pathogenicity common infection in a population at risk
◦ Due to migration and mixing in the context of a lack of herd immunity

‘Delayed infection' hypothesis

◦ Microbial exposures earlier in life are protective but, in their
absence, later infections trigger the critical secondary mutations
that cause leukemia

Greaves M. Nature Rev Cancer, 2018; DOI: 10.1038/s41568-018-0015-6

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Prognostic factors of pediatric leukemia

Madhusoodhan PP, et al. Curr Probl Pediatr Adolesc Health Care 2016;46:229-41

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Treatment of pediatric leukemia
Children generally are treated at pediatric cancer centers
ALL AML

Risk stratification Not yet has risk stratification

◦ Standard risk vs. High risk
Different protocol for APL
Phases of therapy: induction, consolidation,
No maintenance
(interim maintenance), delayed intensification,
maintenance Allogenic stem cell transplantation is mostly
needed
Central Nervous System (CNS) directed
therapy

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Treatment for pediatric ALL typically consists of remission-induction therapy
with steroids, vincristine, and asparaginase with or without anthracycline
CNS directed therapy: IT therapy, (CNS irradiation)
Followed by multi‐agent consolidation including high‐dose methotrexate and
re‐induction therapy
After consolidation, less intensive maintenance therapy is required for 1–2 years
to maintain event‐free survival

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Indonesian protocol: ALL

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 Indonesian
AML Protocol

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Emergency Management
Hyperleucocytosis (WBC >100,000/cmm)

Hyperhydration D5W 1/2NS 2 to 3 l/m2 /d, or 200 ml/kg/d

+ 40mEq/L NaHCO3  moderate alkalinization of urine (pH 7.5-8)  urine
output >4 ml/kg/h for infants and 100 ml/m2/h for older patients
Potassium must not be added to the hydration fluid
Allopurinol or Rasburicase to prevent hyperuricemia
If hemoglobin <6 g/dl, lower fluid volumes to prevent congestive heart failure
Diuretics not indicated
Daily weights and urine output should be measured in assessing fluid balance

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 Outcomes of Pediatric Leukemia
The overall 5-year survival rate of children with leukemia:
◦ ALL about 90%
◦ AML improving around 65% to 70%; APL better outcome >80%
◦ CML in the range of 60% to 80%
◦ JMML about 50%

In low-middle income countries, outcomes varies

◦ The 5-year overall survival rate for ALL 55-80%
◦ Abdelmabood S, et al. J Pediatria (Rio J) 2020;96:108-16
◦ Wijayanti LP, Supriyadi E. Indonesian J Cancer 2017.doi: 10.33371/ijoc.v11i4.532
◦ Jaime-Pérez JC, et al. Arch Med Res 2016; 47: 668-76
◦ Güneş AM, et al. Ann Hematol 2014;93:1677-84

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Covid-19 Pandemic in Pediatric Oncology Population
Covid-19 in ped-oncol appears to be rare
◦ Prevalence in ped-oncol 0-18 years: 1.3%
◦ 27% of them from nosocomial infections!
◦ de Rojas, et al. PBC 2020, doi: 10.1002/pbc28397

Clinically milder & have better prognosis than adults, in line with general
pediatric
However, be aware of a higher risk of severe forms due to immunocompromised
Lu X, et al. NEJM 2020; 382:1663-65
André N, et al. PBC 2020, doi:10.1002/pbc.28392
Boulard F, et al. JAMA Oncol 2020. doi:10.1001/jamaoncol2020.2028

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Survey of Ped-Oncology centers in Latin America
◦ 95% chemo continued
◦ 58% delays of outpatients procedures
◦ 45% delays of cancer surgeries
◦ 33% delays of radiotherapy
◦ 60% decreased staff due to covid-19 infection or quarantine
◦ 79% shortage of blood products

Vasquez L, et al. Lancet Oncol 2020, doi:10.1016/s1470-2045(20)30280-1

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 Chidren with blood cancer in
Hubei Province

Fever, respiratory symptoms,

gastrointestinal symtoms

No

To be admitted to Yes
hospital for Suspend the
chemotherapy ? chemotherapy

No Yes

At home as planned,
Taking Blood routine Pulmonary Other
chemotherapy drug test + CRP Imaging Pathogenic Tests

Subspecialty Group of Hematology and Oncology, Society of Pediatrics of Hubei. Whether the condition
Zhongguo Dang Dai Er Ke Za Zhi. 2020;22(3):177‐182.
of suspected case is met

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 chemotherapy drug test + CRP Imaging Pathogenic Tests

Whether the condition

of suspected case is met

No Yes
Complete the treatment as planned Suspected case
Given to those infected with other
etiological infections
Corresponding treatment, close
monitoring
Consult to the expert
and complete viral
nucleic acid detection

2 times
negative

Positive

Confirmed cases
Normal Lung CT Pulmonary CT
can be excluded can’t exclude
COVID-19 à
Subspecialty Group of Hematology Continue to Transfer to designated
and Oncology, Society of Pediatrics isolate and tract hospital for treatment
of Hubei.
Zhongguo Dang Dai Er Ke Za Zhi.
2020;22(3):177‐182. Figure 2. Management flow chart of children with hematological
tumors in Hubei Province during the COVID-19 epidemic
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The COVID‐19 pandemic: A rapid global response for children with cancer
from SIOP, COG, SIOP‐E, SIOP‐PODC, IPSO, PROS, CCI, and St Jude Global

The burden will fall particularly heavy on children, their families, and
cancer services in low‐ and middle‐income countries
ALL is the most common single childhood cancer, with the longest
duration of treatment
The major threat to children with ALL may be COVID‐19–related
interruption of treatment, or treatment non-completion

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Sullivan M, et al. PBC 2020. https://doi.org/10.1002/pbc.28409
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Sullivan M, et al. PBC 2020. https://doi.org/10.1002/pbc.28409

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General Recommendations
1. Treatment needs to be individualized based on local conditions
2. Test for SARS-CoV-2 before starting intensive chemotherapy for ALL patients, with or
without symptoms
3. Brief (1-2 weeks) interruptions may be appropriate for those in remission with
asymptomatic or mild COVID-19 infections
4. Longer interruptions may be indicated in more severe symptomatic infection
5. Dose modifications, especially pre-maintenance, should be approached very cautiously
and avoided generally
6. Avoid clinic visits unless necessary
7. “Over-isolate” a child COVID-negative to securely advance in the treatment (facial
mask, barrier measures, no contact with suspect COVID or COVID+ for 3 weeks, etc.)
ASH. https://www.hematology.org/covid-19/covid-19-and-pediatric-all
French (SFCE) Recommendations. . Bull Cancer 2020, doi:10.1016/j.bulcan.2020.04.003

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Childhood Leukemia: Is it Time for Primary Prevention?
The accumulating evidence that environmental exposures increase
the risk of childhood leukemia
◦ Based on case-control studies; yet, required of prospective cohort study
design
However, a causal biological mechanism for carcinogenicity has not
yet been found
Education of clinicians and the public on primary prevention to
reduce exposure during prepregnancy, pregnancy, and early
childhood to environmental/chemicals associated with childhood
leukemia — could occur now

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Take Home Message
Malignancy is a primary danger
◦ Early detection
◦ Primary prevention?

Preventive measures of covid-19 should not hinder

its treatment
◦ Hrusak O, et al. Eur J Cancer 2020, doi:10.1016/j.ejca.2020.03.021

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