key: cord-0999995-qxjrp1wm
authors: Rouger-Gaudichon, Jérémie; Bertrand, Yves; Boissel, Nicolas; Brethon, Benoit; Ducassou, Stéphane; Gandemer, Virginie; Halfon-Domenech, Carine; Leblanc, Thierry; Leverger, Guy; Michel, Gérard; Petit, Arnaud; Ray-Lunven, Anne-France; Rohrlich, Pierre-Simon; Schneider, Pascale; Sirvent, Nicolas; Strullu, Marion; Baruchel, André
title: COVID19 and acute lymphoblastic leukemias of children and adolescents: updated recommendations (Version 2) of the Leukemia Committee of the French Society for the fight against Cancers and leukemias in children and adolescents (SFCE)
date: 2021-03-11
journal: Bull Cancer
DOI: 10.1016/j.bulcan.2021.02.004
sha: a8ed6c6ce25ca2df9fa043d6c47ef086376015db
doc_id: 999995
cord_uid: qxjrp1wm

Since the emergence of the SARS-CoV-2 infection, many recommendations have been made. However, the very nature of acute lymphoblastic leukemias and their treatment in children and adolescents led the Leukemia Committee of the French Society for the fight against Cancers and leukemias in children and adolescents (SFCE) to propose more specific recommendations. Here is the second version of these recommendations updated according to the evolution of knowledge on COVID19. Depuis l’émergence de l’infection à SARS-CoV-2, de très nombreuses recommandations ont été émises. Cependant la nature de la maladie et la spécificité du traitement des leucémies aiguës lymphoblastiques de l’enfant et de l’adolescent ont conduit le Comité Leucémies de la Société Française de lutte contre les Cancers et leucémies de l’Enfant et de l’adolescent (SFCE) à proposer des recommandations propres. Voici la deuxième version de ces recommandations prenant en compte l’évolution des connaissances sur l’infection COVID19.

Depuis l'émergence de l'infection à SARS-CoV-2, de très nombreuses recommandations ont été émises. Cependant la nature de la maladie et la spécificité du traitement des leucémies aiguës lymphoblastiques de l'enfant et de l'adolescent ont conduit le Comité Leucémies de la Société Française de lutte contre les Cancers et leucémies de l'Enfant et de l'adolescent (SFCE) à proposer des recommandations propres. Voici la deuxième version de ces recommandations prenant en compte l'évolution des connaissances sur l'infection COVID19.

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The situation of the current COVID-19 pandemic is continuously evolving. We thus have taken the more recent knowledge into account to update the previous recommendations from the Leukemia committee of the Société Française de lutte contre les cancers et leucémies de l'enfant et de l'adolescent (SFCE) (1) .

Despite an increasing number of publications concerning severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in pediatric oncology and hematology, data in children with cancer are still limited (Table 1) . Published recommendations most often relies on an expert-opinion basis (2, 3) . While some early studies in adults with cancers suggested that the risk of severe COVID-19 is higher in this population (4, 5) , more recent data indicate that patients with cancer may not be at greater risk than others when matched for comorbidities (6, 7) . However, mortality appears to be higher in adults with haematological malignancies (8, 9) .

In pediatric oncology, most reports have been limited to cases or small sample populations (10) (11) (12) (13) (14) (15) (16) (17) while larger clinical studies have recently been published and/or are still ongoing (18) (19) (20) . These reports suggest that COVID-19 is generally asymptomatic, mild or moderate in children receiving anti-cancer therapy. Thus children with cancer appear to have a similar risk of developing severe COVID-19 to those in their healthy counterparts. However, some severe cases have been described, mostly in children highly immunocompromised and/or with severe oncologic conditions (14, 15, 18, 21, 22 

Are you changing your approach to initial induction?

Corticosteroids are a key part of induction therapy and, more generally, of ALL treatments. Initial outcomes of the use of corticosteroids in SARS-CoV-2 infection were controversial. Recent data suggested that dexamethasone is effective in severe COVID-19 in immunocompetent patients (29) . The benefit of using corticosteroids in immunocompromised patients with severe COVID-19 is less clear and has not been proven yet. Still, ALL is life-threatening and very probably more than COVID-19 in most situations. Thus, we consider that the riskbenefit ratio calls for regular protocol induction. However, chemotherapy doses and scheduled administration should be weighted with the clinical status and oxygen saturation of the patient, as well as the results of chest computed tomography scan, which should be performed in all patients during this induction phase. In case of significant desaturation (e.g. < 94% of oxygen), signs of respiratory distress and/or more than a 50% lung parenchyma impairment, we recommend pausing chemotherapy. Chemotherapy doses may also be delayed/reduced. Overall, we recommend a multidisciplinary discussion and / or with the protocol coordinators. After completion of chemotherapy, the use of G-CSF in a SARS-CoV-2-positive patient can be discussed to reduce the duration of neutropenia, in the absence of inflammatory signs attributable to COVID-19.

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 being SARS-CoV-2 carriers. A strict policy for family members is obviously to be established.

Note that the risk of needing an intensive care bed during induction therapy of ALL is low (probably <5%). However, in certain regions and/or time frames, the decrease in the number of pediatric ICU beds (transformed into adult resuscitation beds) implies that the pediatric need is being forcefully reexpressed.

a. Philadelphia chromosome ALL: some adult hematologists (see ASH adult ALL COVID19 recommendations) offer treatment with a tyrosine kinase inhibitor with minimal steroid exposure rather than aggressive induction with multidrug therapy for the initial treatment, in the hope of avoiding prolonged hospitalization during the pandemic (30) . However, the recommendation to keep on including our patients in the EsPhall 2017 protocol with a regular use of imatinib, still seems appropriate to us.

b. 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.

c. Adolescents and young adults: clinicians may consider adolescents and young adults with a particular attention also taking into account the risk factors observed in adults, such as asthma, obesity and diabetes. To insist on compliance with treatment in general but also on adherence to barrier gestures and general sanitary measures is of paramount importance.

d. Children with Down syndrome: vigilance is essential in these children susceptible to infections in general, even if this susceptibility rarely concerns viral infections. Some reports suggest that patients with Down syndrome have a greater risk of developing severe COVID-19 (31) . Of note this group benefits from an induction with "only" 3 drugs in the CAALL-F01 protocol, including dexamethasone.

Are you changing the approach to intensive post-remission therapy (consolidation, delayed intensification)?

In the absence of data, our recommendation is to follow the protocol, including for corticosteroid therapy. As said in the general recommendations paragraph, each intensive course is to be preceded by a test.

For patients with high-risk ALL, an individualized 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. In case of symptoms, COVID19 testing the day before should be performed: if COVID +, then postpone the pulse for about 2 weeks and perform another test before performing the pulse.

-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, minimizing hospital visits seems appropriate. Home blood tests are to be preferred and partial use of telemedicine may be considered. However, a physical examination should be performed regularly to avoid any delay in the diagnosis of treatment complications or relapse. Of course, such an attitude is beneficial only if preventive measures are also applied at home.

Patients with relapsed ALL may be at greater risk of severe COVID-19 (23) . Test must be performed before starting a chemotherapy block, and postponing chemotherapy in case of positive test should be discussed in accordance with each specific situation and benefits/risks ratio regarding the leukemia.

 First relapse: we propose to include all eligible patients and/or to follow the INTREALL protocol as much as possible. Patients who reach complete remission n°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: most if not all academic or industrial promoters ask now for SARS-CoV2 testing before inclusion. Any positivity is an at least temporary exclusion criterion.

• CAR-T cells: The indication for treatment with CAR-T cells must be weighed with the center which would perform the procedure: feasibility of performing apheresis (systematic patient testing, problem of using an operating room for apheresis central line placement for example)?

Manufacturing feasibility? Feasibility of administration according to the possible rooms in intensive care unit ? (32, 33) 

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 described, most of the experience is currently reassuring (19, 20, 23)  Any "specific" treatment must be discussed with the infectious diseases team.

Potential interactions:

They are described in Table 2 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 covid19 infection is generally the one of aggravation, and often involves hospitalization in ICU. Chemotherapy, except for steroids, is obviously interrupted at this stage.

As underlined above, any specific anti-COVID-19 treatment should be considered and discussed with the infectious diseases team. Great efforts have been made to evaluate the efficacy of repurposed drugs against SARS-CoV-2 infection (Table 2 and 3) . Accordingly with the recently published interim analysis of the Solidarity study, there is no clear evidence of efficacy on COVID-19-related mortality of any antiviral agent (34) . Though hydroxychloroquine and lopinavir/ritonavir therapeutic should be abandoned, remdesivir use could eventually be considered. In children, remdesivir may be proposed to positive patients who present potential risk factors of severe COVID-19 and should be given as early as possible in the course of the infection, for 10 days. Above 40 kg of weight, children may receive 200 mg the first day and 100 mg per day the next nine days. Below 40 kg of weight, children may receive 5 mg/kg on the first day and then 2.5 mg/kg once a day until 10 days of treatment (35) . Interestingly evidence of prolonged viral shedding has been shown in immunosuppressed patients and could lead to discuss a more prolonged administration (36) (37) (38) .

Among therapies acting on immune system and inflammation, there is no clear evidence that tocilizumab or anakinra are effective. However, dexamethasone use has been proven to be effective (29) . Convalescent plasma use may be safe and beneficial (29, (39) (40) (41) . Convalescent plasma may especially be useful in immunosuppressed patients (42) , but it may not be easily available and, at best, should be considered in a clinical trial setting.

Food and Drug Administration (FDA) has delivered in November an emergency use authorization for the specific monoclonal antibodies casirivimab and imdevimab against SARS-CoV-2, which may prevent aggravation of COVID-19 in patients who present a high risk of a severe of the disease (43, 44) . An emergency use authorization has also been delivered for a Janus kinase inhibitor, baricitinib, which may be beneficial for patients requiring non-invasive ventilation in association with remdesivir (45) . Interestingly pediatric data are available for baricitinib in the setting of auto-inflammatory diseases (46, 47) . It is too soon to claim that the monoclonal antibodies and baricitinib are really effective. Their utilization should ideally be considered in a clinical trial context which is nevertheless unlikely to occur in the pediatric setting.

SARS-CoV-2 infection is associated with hypercoagulability and an increased risk of thrombosis, which participates to disease morbidity and mortality (48) . In children infected with SARS-CoV-2, hemostasis parameters also suggest a state of hypercoagulability, though the thrombotic risk is not well established in this population (49) . D-dimers and fibrinogen should be dosed and disseminated intravascular coagulation should be sought in the case of proven infection, and such dosages should be repeated during the course of COVID-19 (50) . The combination of the prothrombophilic status of the leukemia, the use of asparaginase and the presence of central venous line potentially increase the COVID-19-related thrombotic risk. Therefore, preventive anticoagulation with low molecular weight heparin should be considered. In case of suggestive symptoms, cerebral thrombophlebitis or any other thrombotic complication should be searched for, even in patients treated with preventive anticoagulation.

There are currently no specific marker to predict COVID-19 complications. However, COVID-19 may be complicated by inflammation dysregulation and macrophage activation syndrome that may require a higher level of care. Thus, one could recommend to monitor ferritin levels, fibrinogen as well as hepatic enzymes and triglyceride levels, especially for patients who may be at a greater risk. Unfavorable outcomes may also be correlated to high SARS-CoV-2 viremia for which monitoring may be beneficial (51) . Tests may also be repeated until virus clearance, since virus shedding seems to be prolonged in the most immunocompromised patients (37) . Although its prognostic value is less clear in children, lymphopenia is associated with severe SARS-CoV-2 infection in both immunocompetent and immunocompromised adults (52) (53) (54) . Lymphopenia is common in children treated with chemotherapy, making difficult to clearly associate it with severe COVID-19. However, closely monitoring lymphocyte counts may be interesting in that context.

The recent availability of several vaccines brings a great hope among global population, even if evidence of long-term efficacy and safety are lacking (55, 56, 57) . The availability of such vaccines will still be limited in the next months and the priority use will be determined by HTAs (Health Technology Assessments) such as the Haute Autorité de Santé in France. Health care providers aged 50 years or more, or with comorbidities, are the first professionals in France to receive the vaccine. Those working in our hem-onc units should be seen as an example for all health care providers and finally parents and families. Indeed when available, we may recommend to perform the vaccination of parents and siblings of patients who are the most at risk of developing COVID-19 complication (e. g. patients with recent HSCT history, relapsed leukemia under intensive treatment and any patient with significant comorbidity). A recent study suggests that patients with solid tumors may have an effective immune response to SARS-CoV-2, making vaccination in these patients a feasible option (38) . However, the immune response of patients with hematological cancers seems to be impaired, particularly those with B-cell malignancies, which on the one hand may explain their vulnerability and on the other hand argues in favour of vaccination of their relatives (38) . Another issue is the age, since the Marketing Authorization has been only given according to trial populations age range (lower age limit of 16 and 18 years for the Pfizer and Moderna vaccines respectively). The final issue is that those 2 first vaccines contain polyethylene glycol (PEG), which could be a problem, leading to raise anti-PEG antibodies in children receiving pegylated asparaginase.

Despite extremely rapid advances obtained in less than one year, our knowledge of SARS Cov2 and its complications is still incomplete. We presented here an updated version of previous recommendations of the Leukemia committee of the SFCE (1). We can anticipate that this current version will need an update in the next few months.

(Version 2.0; last update 18.01. 2021) 

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