To the Editor,
We read the letter entitled “Acute lymphoblastic leukemia onset
in a 3-year-old child with COVID-19 ” by Marcia et al . with
great interest and we hereby suggest to start chemotherapy within the
same timeline as for non-COVID-19 acute lymphoblastic leukemia (ALL)
patients, following our experience managing a 3-year-old boy with
concomitant diagnoses of precursor B-ALL and COVID-19. The patient was a
previously healthy boy who presented to our hospital with a two-month
history of intermittent fevers, night sweats, fatigue and cervical
lymphadenopathies. His mother had been tested positive for COVID-19
three months earlier. He had been seen by his family physician by
teleconference at the onset of his symptoms, at which point a COVID-19
infection was suspected but not confirmed. The persistence of symptoms
and new onset of bone pain led his parents to reconsult at our hospital.
At presentation, he had no respiratory symptoms. Physical examination
was remarkable for fever, tachycardia and cervical lymphadenopathies.
Bloodwork revealed pancytopenia and circulating peripheral blasts.
Inflammatory markers were elevated (fibrinogen 7.08 g/L; C-reactive
protein 255 mg/L; sedimentation rate 63 mm/h; ferritin 185 ug/L;
D-dimers 0.51 ug/ml). Capillary gas, renal function, hepatic function,
coagulation studies (INR/aPTT) and cardiac biomarkers (troponin and
pro-BNP) were normal. Chest radiograph (CXR) was normal. COVID-19
testing by nasopharyngeal swab was positive. Bone marrow aspiration
revealed 80% precursor B lymphoblasts of hyperdiploid subtype.
Patient was admitted to a dedicated COVID-19 ward. Given the absence of
SARS-CoV-2 infection’s severity criteria, no COVID-19-specific treatment
was initiated. Chemotherapy was started promptly once the diagnostic
work-up was completed, 6 days following the patient’s confirmed COVID-19
diagnosis. The patient was treated with a three-drug chemotherapy
induction based on National Cancer Institute standard-risk criteria
consisting of methylprednisolone, vincristine and asparaginase.
Supportive treatment consisted of intravenous hydration and allopurinol
for tumor lysis prevention, empirical antibiotics, blood transfusions
and prophylactic low molecular weight heparin for COVID-19-associated
thromboembolic complications. The patient’s clinical course was
favorable; fevers, bone pains, peripheral blasts and inflammatory
markers resolved quickly following the steroid prophase. Persistent and
unexplained tachycardia led to extensive investigations given concerns
for COVID-19-related thromboembolic complications. Troponins, pro-BNP,
electrocardiogram, echocardiography, CXR and chest CT scan were
unremarkable, and the tachycardia improved with packed red blood cell
transfusion. The first negative COVID-19 test was obtained on day 4 of
induction therapy but came back positive 48 hours later. The patient was
discharged on day 13 of induction therapy. Three consecutive
nasopharyngeal swabs were negative on days 21, 23 and 38 following
COVID-19 diagnosis (Fig.1). End-induction bone marrow aspiration was
consistent with morphologic remission and end-induction minimal residual
disease by flow cytometry was positive at 0.025%.
This case demonstrates the feasibility of treating children with newly
diagnosed ALL who tested positive for COVID-19, without chemotherapy
delay or modification, nor specific COVID-19 treatments, as done by
Marcia et al . The province of Quebec constitutes the COVID-19
epicenter in Canada with half of all Canadian cases; the prevalence of
COVID-19-positive cases was 3.3% among children under the age of 10,
5.3% between the age of 10-20 years and 49.2% for people aged 50 years
and above.1 Importantly, no death has been reported
among children in the province of Quebec, while 97.6% of COVID-related
deaths were among individuals over the age of 60
years.1 Children appear to be less affected from
COVID-19 infection and exhibit a milder disease course compared to
adults, although the impact of COVID-19 infection among pediatric
oncology patients remains unknown.2-4 Current
published recommendations in the management of pediatric oncology
patients during the COVID-19 pandemic emphasize on the importance of
pursuing protocol-prescribed chemotherapy regimens based on the curable
nature of most pediatric malignancies and the milder COVID-19 disease
course observed in the pediatric population.4 However,
case reports of severe COVID-19 disease in pediatric oncology patients
start to emerge,5 and management of concomitant
COVID-19 infection and newly diagnosed ALL can be challenging. First,
our patient presented with a multisystem inflammatory syndrome which
made it difficult to discern whether he was symptomatic from the
COVID-19 infection versus the leukemia itself. Furthermore, we
questioned whether the positive COVID-19 test by polymerase chain
reaction (PCR) amplification in our patient truly reflects active
infection since there was a nearly 3-month period between the first
positive test in his family and when our patient was first tested
positive. The positive PCR test could result from prolonged viral
shedding in an immunocompromised patient affected by his leukemia onset.
Alternatively, a positive test does not necessarily indicate the
presence of viable virus as Wolfel and colleagues demonstrated that
virus could not be grown from samples obtained from hospitalized
patients beyond the eighth day of illness.6 Therefore,
the general approach to await a negative result prior to begin
chemotherapy might cause significant therapy delay and adversely impact
outcomes in newly diagnosed ALL patients during the COVID-19 pandemic.
Indeed, our patient took over 23 days to have 2 consecutive negative PCR
tests 48 hours apart. Furthermore, the use of COVID-19-specific
antiviral treatment in non-critically ill children is controversial
given the lack of efficacy in this population.7Antiviral treatment may have significant drug interactions with
chemotherapy and contribute to additive gastrointestinal and
myelosuppressive toxicities. Nevertheless, the benefit of dexamethasone
in COVID-19-positive patients requiring respiratory support in reducing
early mortality8 and the exquisite sensitivity of
lymphoblasts to corticosteroids could be an effective early strategy to
safely initiate therapy in newly diagnosed ALL patients affected with
COVID-19, particularly for those presenting with oncologic emergencies
such as hyperleukocytosis or mediastinal mass. As the COVID-19 pandemic
continues to evolve, pediatric oncologists will be confronted with the
ongoing challenge to manage newly diagnosed cancer patients with
concomitant COVID-19 infection. International COVID-19 registries in
pediatric oncology are actively collecting clinical data to
comprehensively assess the impact of COVID-19 within this patient
population and to develop standardized management
guidelines.9 As for now, an assessment of risks and
benefits to initiate or delay cancer therapy will need to be carefully
balanced on a case-by-case basis according to the patient’s clinical
symptoms, type of malignancy, evidence-based treatment options, and
emerging knowledge of COVID-19’s impact in our young cancer patients.
CONFLICT OF INTEREST: The authors declare no conflict of interest.
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Figure 1. Variation of C-reactive protein (CRP) throughout the
hospitalization course (blue line). COVID-19 test results are identified
in green when positive and red when negative. The day of ALL diagnosis,
the day of chemotherapy start (black arrows), the duration of
hospitalization (red box) and the duration of symptoms (green box) are
indicated. Induction chemotherapy includes: Methylprednisone/prednisone
(Day 1-32), Vincristine (Day 4, 11, 18, 25), PEG-Asparaginase (Day 7)
and intrathecal cytarabine (Day 1 & 18).