COVID-19 and Pediatric ALL: Frequently Asked Questions

(Version 3.0; last updated January 29, 2021)

Input from Mignon Loh, MD; Andre Baruchel, MD; Andrea Biondi, MD; Steve Hunger, MD; Atsushi Manabe, MD, PhD; Rob Pieters, MD, PhD, MSc; Ching-Hon Pui, MD; Elizabeth Raetz, MD; Martin Schrappe, MD; David Teachey, MD; Ajay Vora, MD; and Kjeld Schmiegelow, MD.

Note: Please review ASH's disclaimer regarding the use of the following information.

Are you changing your approach to initial induction and intensive post-remission therapy?

Severe coronavirus disease (COVID-19) remains rare in healthy children. There continue to be relatively few COVID-19 positive ALL cases reported during the pandemic, and courses have generally been mild.^1-3 Thus, the major threat to children with ALL, particularly those in remission when they acquire COVID-19, is the malignancy itself. Indeed, delays in diagnosis have led to increased morbidity and mortality. Treatment needs to be individualized based on local conditions, whether the patient is already enrolled in a clinical trial, and whether new trial enrollment is feasible. Thus, it is appropriate to consult local and national regulatory bodies for guidance on management for patients enrolled on trials.

Newly diagnosed ALL is highly curable in children and most adolescents and young adults (AYA). Brief (1-2 weeks) interruptions of therapy may be appropriate for those in remission with asymptomatic/presymptomatic or mild COVID-19 infections as occurs with other serious viral infections. Longer interruptions may be indicated in cases with more severe, symptomatic infection. Patients who have COVID-19 at ALL presentation, during ALL induction or while in overt relapse should have their therapy individualized to balance the risk of leukemia vs COVID-19 complications. An international group recently published consensus guidelines on the treatment of the most common childhood cancers during the pandemic with particular emphasis on the challenges that face physicians in resource constrained countries.⁴

Some of the investigational therapies used to treat COVID-19 are immune modulatory and may increase the risk of opportunistic infection in immunocompromised patients. Other investigational therapies can interact with agents commonly used to treat leukemia. Accordingly, additional supportive care measures and dose modifications may be warranted to address the risk of such complications.

To minimize the risk of infection, efforts to avoid clinic visits unless necessary to deliver chemotherapy or supportive care are warranted. Dose modifications, especially pre-maintenance, should be very cautiously approached and generally avoided, as it is unknown whether the current excellent cure rates can be preserved with modified therapy. Importantly, it is unclear if modifying pre-maintenance therapy will lessen the severity, or risk of, contracting COVID-19. Adherence to self-isolation measures, good handwashing, and the use of face masks is paramount. Extreme vigilance to other causes of infection in this population must be maintained.

Are you changing your recommendations for Philadelphia chromosome positive ALL?

No, we continue to recommend multi-drug induction and TKI given the rarity of COVID-19 in younger patients and the importance of early achievement of MRD negative response in pediatric Ph+ ALL. While some practitioners suggest TKI treatment with minimal steroid exposure as initial therapy for adults, we recommend induction for children.

Are you changing your recommendations for infant ALL?

No, national or international protocols for this population should be followed although the risk of serious forms of COVID19 in children under the age of one year has been reported. Testing for COVID-19, possibly repeated, even without symptoms, is strongly recommended, but it is recognized that this will be country dependent.

Are you changing your recommendations for ALL in children with Down syndrome?

No, however vigilance is essential in these children who are susceptible to infections in general, even if this susceptibility has been rarely described for viral infections. Few cases of severe SARS-CoV-2 infection have been reported in children with Down syndrome, generally associated with comorbidities.⁵ Maximal supportive care, including potential mandatory hospitalization until signs of count recovery, is practiced by some.

Are you changing your recommendations for adolescents and young adults?

No, although considerations for leukemia therapy must include the presence of co-morbid risk factors observed in adults with fatal COVID-19, such as asthma, obesity, or diabetes. See ASH's FAQ on COVID-19 and Adult ALL.

How are data about pediatric ALL and COVID-19 being captured?

Global registries that are capturing incidence and outcomes of COVID-19 in childhood cancer patients on a self-reported basis are being collected by several groups, including one housed at St Jude Children’s Research Hospital. The ASH Research Collaborative is also collecting data on patients with malignant and non-malignant hematologic disease who have COVID-19.

In general, while cases of Covid-19 and asymptomatic SARS-CoV-2 positive tests have been documented in children and AYA with ALL, the general observation is that most patients clear their infections with few complications. However, there have been serious cases of COVID-19 associated with mortality and as such, clinical vigilance should be practiced. The impact of treatment delays due to COVID-19 should also be explored.

Should pediatric ALL patients receive a vaccine for SARS-CoV-2?

In general, it is considered safe and appropriate for patients with ALL to receive vaccines, as long as they are not live, attenuated-virus vaccines. Specific to SARS-CoV-2, data regarding the safety and efficacy of vaccines in immunocompromised patients have not yet been released. As a general statement, we are likely to support older children with ALL who otherwise meet the age eligibility (currently 16 years of age for the Pfizer vaccine and 18 years of age for the Moderna vaccine) receiving a SARS-CoV-2 vaccine (non-live) although they may not mount an effective immune response, but we await trial results.

In addition, for those patients who have developed an allergy to PEG-asparaginase during primary treatment, it should be noted that both the Pfizer and Moderna vaccines contain elements of a form of polyethylene glycol (PEG), PEG2000 that is slightly different than the PEG that is conjugated to asparaginase (PEG5000). There are strong data to support that patients who develop an allergic reaction to PEG-Asparaginase are reacting to the PEG moiety as opposed to the asparaginase, particularly early in therapy.^6-8 For patients who have had serious anaphylaxis to a dose of PEG-asparaginase, we would recommend skin testing such patients to PEG and if not tolerated, would advise against receiving the mRNA vaccines.9 It would be reasonable to proceed with the vaccine per local guidelines if patients had mild reactions to PEG-asparaginase and had tolerated other medications containing PEG (laxatives, pegylated G-CSF, some cosmetics and skin care products, etc). Finally, there is some consensus that older patients should not be vaccinated against COVID-19 until completion of asparaginase containing phases and other intensive phases of therapy.

For more information about SARS-CoV-2 vaccines and immunocompromised patients, see the ASH FAQs on this topic.

References

1. Lu X, Zhange L, Du H, et al. SARS-CoV-2 Infection in Children. N Engl J Med. 2020;382:1663-1665.
2. Hrusak O, Kalina T, Wolf J, et al. Flash survey on severe acute respiratory syndrome coronavirus-2 infections in paediatric patients on anticancer treatment. Eur J Cancer. 2020;132:11-16.
3. Balduzzi A, Brivio E, Rovelli A, et al. Lessons after the early management of the COVID-19 outbreak in a pediatric transplant and hemato-oncology center embedded within a COVID-19 dedicated hospital in Lombardia, Italy. Estote parati. Bone Marrow Transplant. 2020;55:1900-1905.
4. Sullivan M, Bouffet E, Rodriguez-Galindo C, et al. 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. Pediatr Blood Cancer. 2020;67:e28409.
5. Kantar A, Mazza A, Bonanomi E, et al. COVID-19 and children with Down syndrome: is there any real reason to worry? Two case reports with severe course. BMC Pediatr. 2020;20:561.
6. Khalil A, Würthwein G, Golitsch J, et al. Pre-existing antibodies against polyethylene glycol reduce asparaginase activities on first administration of pegylated E. coli asparaginase in children with acute lymphocytic leukemia. Haematologica. 2020; doi:10.3324/haematol.2020.258525. [Online ahead of print.]
   
   

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