COVID-19 and acute lymphoblastic leukemias of children and adolescents: First recommendations of the Leukemia committee of the French Society for the fight against Cancers and Leukemias in children and adolescents (SFCE)



## Preamble and general recommendations
Few cases of acute lymphoblastic leukemia (ALL) with COVID-19 infection have been reported so far during the pandemic, and the course has been generally mild [bib_ref] SARS-CoV-2 Infection in Children, Lu [/bib_ref] [bib_ref] Flash survey on SARS-CoV-2 infections in pediatric patients on anti-cancer treatment, Hrusak [/bib_ref] [bib_ref] Lessons after the early management of the COVID-19 outbreak in a pediatric..., Balduzzi [/bib_ref]. Thus, the main threat to children with ALL, especially those in remission, remains the ALL itself, even if rare serious and life-threatening infections are emerging.
There are currently insufficient data to support recommendations applicable to all local cases and situations during the care of children and AYA with ALL. The most experienced practitioners of the hematology-oncology unit must therefore help to decide, on a case-by-case basis, for which patients should the leukemia treatment be initiated or continued, or identify those in whom a delay is possible, depending on clinical and tumour biology. For patients in the advanced stage of their disease, the real benefit of the treatment in the context of the risk of COVID-19 must be considered and discussed.
It is recommended to test for SARS-CoV-2 before starting intensive chemotherapy or an intensive phase of treatment, for ALL patients, with or without symptoms. If patients are tested positive for SARS-CoV-2, one should delay systemic treatment if possible (e.g. absence of major hyperleukocytosis). If the SARS-CoV-2 test is not available, carefully look for suggestive symptoms (dry cough, high fever, anosmia, digestive signs) and consider a chest CT scan. As soon as available, serological tests should be implemented in all patients.
It is necessary to insist on the need, in particular in the regions with high prevalence, to "over-isolate'' a child or adolescent COVID-negative to allow him to securely advance in the treatment (facial mask, barrier measures, no contact with suspect COVID or COVID+ for 3 weeks, etc.), in particular, those intended to be allografted.
Patients with ALL in first line, included in the CAALL-F01 protocol or treated according to the FRALLE/EORTC protocols, ESPhALL 2017, INTERFANT 06
Are you changing your approach to initial induction?

## General considerations
There is a controversy about the use of steroids, a key part of induction therapy.
We consider that the risk-benefit ratio calls for regular protocol induction.
If the physician considers that the patient is at high risk of complications, we recommend a multidisciplinary discussion and/or with the coordinators of the protocol with a view to considering reductions in dose or in the number of administrations of certain drugs including potentially steroids. Once all the induction chemotherapy has been administered, the use of G-CSF in a COVID+ patient can be discussed to reduce the duration of neutropenia. The implementation of all or part of treatment on an outpatient basis must be carefully weighed. Indeed, the comings and goings to the ambulatory clinic and blood samplings at home increase the number of contacts at risk. Conversely, return at home could limit contact with caregivers, also possibly contaminated.
In most hospitals, visits are limited to only parents, with only one parent present at a time.
Note that the risk of needing an intensive care bed during induction therapy is low (probably < 5%). However, in certain regions, the decrease in the number of pediatric ICU beds (transformed into adult resuscitation beds) implies that the pediatric need is being forcefully re-expressed.

## Specific populations
Philadelphia chromosome ALL: some adult hematologists (see ASH adult ALL COVID-19 recommendation) offer treatment with a tyrosine kinase inhibitor with minimal steroid exposure rather than aggressive induction with multi-drug therapy for the initial treatment, in the hope of avoiding prolonged hospitalisation during the pandemic. However, the recommendation to include our patients in the EsPhall 2017 protocol seems appropriate to us. Infants under one year of age: the risk of serious forms of COVID-19 in infants has been reported. The test for SARS-CoV-2, possibly repeated, is absolutely necessary here. Again, the recommendation is to follow the current guidelines, i.e. to follow the Interfant 06 protocol. Adolescents and young adults: take into account the risk factors observed in adults, asthma, obesity, diabetes. Insist on compliance with treatment in general but also on that linked to containment measures and barrier gestures. Children with Down syndrome: vigilance is essential in these children susceptible to infections in general, even if this susceptibility rarely concerns viral infections. Of note, this group benefits from an induction with "only'' 3 drugs in the CAALL-F01 protocol.
Are you changing the approach to intensive postremission therapy (consolidation, delayed intensification)?
In the absence of data, our recommendation is to follow the protocol, including for corticosteroid therapy.
For patients with high-risk ALL, an individualised decision regarding transplantation and its timing is necessary, weighing the risks of transplantation in an epidemic context of COVID-19 against the risk linked to ALL.
Are you changing your recommendations for maintenance treatment?
Three problems are mainly to be discussed: intensity of maintenance treatment with 6MP/MTX and targets for leukocytosis/neutrophils/lymphocytes: we suggest to follow the usual recommendations of the protocol; pulses: monthly pulses (CAALL-F01, B-SR group) or every 10 weeks (CAALL-F01, B-MR group) with vincristine and steroids are to be maintained. COVID-19 testing the day before could be useful if feasible: if COVID+ , then postpone the pulse for about 2 weeks; high-dose methotrexate cycles in maintenance for T-ALL with high initial leucocyte count ( 100 G/L) and/or CNS3 status: any concern could be discussed with the protocol coordinators. In addition, minimising hospital visits seems appropriate. Monitor patients as much as possible via telemedicine and home blood tests.
Patients with second line or more ALL first relapse: we propose to include all eligible patients and to follow the INTREALL protocol as much as possible. Patients who reach complete remission n o 2 should be considered promptly for allogeneic transplantation, as indicated in the protocol, despite the pandemic; second relapse and refractory relapses: phase I-II trials: it is likely that almost all academic or industrial promoters will ask for SARS-CoV-2 testing before inclusion and that any positivity will be an exclusion criterion, at least temporarily, CAR-T cells: The indication for treatment with CAR-T cells must be weighed with the centre which would perform them: feasibility of performing apheresis (systematic patient testing, problem of using an operating room for the special catheter placement, for example)? Manufacturing feasibility? Feasibility of administration according to the possible places in intensive care unit?
What to do if an ALL patient is diagnosed with SARS-CoV-2 infection? What are the interactions between ALL chemotherapy and potential COVID-19 therapy?

## General recommendations
The diagnosis of SARS-CoV-2 infection during the treatment of ALL should imply to discuss the stopping and/or postponing of all chemotherapies, according to the severity of the ALL, the stage of treatment and the severity of clinical and/or radiological signs. Even if severe forms have been recently described, most of the experience is currently reassuring [bib_ref] Flash survey on SARS-CoV-2 infections in pediatric patients on anti-cancer treatment, Hrusak [/bib_ref] [bib_ref] Lessons after the early management of the COVID-19 outbreak in a pediatric..., Balduzzi [/bib_ref].
Any "specific'' treatment must be discussed with the infectious disease team.

## Potential interactions
They are described in [fig_ref] 1: Hopital Universitaire Robert-Debre AP-HP, Universite de Paris, service d'hematoimmunologie pediatrique, Paris, France... [/fig_ref] aiming to list some of the treatments with antiviral potential and some of those proposed to act against the inflammatory process. Of note, the inflammatory stage of COVID-19 infection is generally the one of aggravation, and often involves hospitalisation in ICU. Chemotherapy is obviously interrupted at this stage.

## Table 1
Treatments of COVID19 with potential interactions with ALL treatment.
Treatments with antiviral potential

# Conclusion
These recommendations have to be updated in the future with more experience and more data gathered at the national and international level and in the evolving context of the pandemic and the weapons to combat it.

# Funding

## Enfants cancers sante.
Disclosure of interest: the authors declare that they have no competing interest.
[table] 1: Hopital Universitaire Robert-Debre AP-HP, Universite de Paris, service d'hematoimmunologie pediatrique, Paris, France 2. CHU de Lyon, institut d'hemato-oncologie pediatrique, Lyon, France 3. Hopital Saint-Louis, AP-HP, Universite de Paris, unite adolescents et jeunes adultes, Paris, France 4. Groupe hospitalier Pellegrin, unite d'hemato-oncologie pediatrique, Bordeaux, France 5. CHU de Rennes, service d'hemato-oncologie pediatrique, Rennes, France 6. Hopital Armand-Trousseau AP-HP, Sorbonne universite, service d'hematooncologie pediatrique, Paris, France 7. CHU la Timone, service d'hematologie pediatrique, Marseille, France 8. CHU l'Archet, service d'hemato-oncologie pediatrique, Nice, France 9. CHU Charles-Nicolle, service d'hematologie pediatrique, Rouen, France 10. CHU Arnaud-de-Villeneuve, service d'hematologie et oncologie pediatrique, Montpellier, France [/table]