Management of patients with acute leukemia during the COVID-19 outbreak: practical guidelines from the acute leukemia working party of the European Society for Blood and Marrow Transplantation

 [bib_ref] Critical care utilization for the COVID-19 outbreak in Lombardy, Italy: early experience..., Grasselli [/bib_ref] [bib_ref] Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in..., Yang [/bib_ref] [bib_ref] Covid-19 in critically ill patients in the Seattle region-case series, Bhatraju [/bib_ref] [bib_ref] Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China, Liang [/bib_ref] [bib_ref] Management of patients with multiple myeloma during the COVID-19 outbreak, Malard [/bib_ref] [bib_ref] Index to predict invasive mold infection in high-risk neutropenic patients based on..., Portugal [/bib_ref] [bib_ref] Association of risk factors, mortality, and care costs of adults with acute..., Halpern [/bib_ref] 

## General principle
Patients should be aware of their frailty to COVID-19 infection and specific hygiene measures and importance of social distancing should be explained.
All journeys outside the hematological department should be discussed and adapted for the situation. For example, it should be ensured that outpatient transportation services bring patients to the scheduled time of their consultation, in order to minimize the time spent in the waiting area. For those requiring oral or subcutaneous treatment administration, one needs to minimize hospital visits. Possible strategies for this are offering telephone or video consultations, cutting nonessential face-to-face follow-up, using home-delivery services for medicines, and using local services for blood tests.

## Screening
Given that percentage of asymptomatic cases of COVID-19 can be high [bib_ref] Estimating the asymptomatic proportion of coronavirus disease 2019 (COVID-19) cases on board..., Mizumoto [/bib_ref] , all newly diagnosed patients with acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) should be screened for COVID-19 infection by PCR and high-resolution thoracic computerized tomography scan before initiating chemotherapy [bib_ref] Correlation of chest CT and RT-PCR testing in coronavirus disease 2019 (COVID-19)..., Ai [/bib_ref] [fig_ref] Table 1: Recommendation for management of patients with acute leukemia during the COVID-19 outbreak [/fig_ref]. The screening should be repeated before each course of chemotherapy. If positive, the decision to initiate or continue the treatment needs to made on a case-by-case basis.

## Clinical research
In terms of clinical research, most clinical trials have been suspended during the pandemic. However, in some cases, clinical trials allow access to off-label drugs or combinations which can be highly beneficial. For patients already included in clinical trials, their participation should, in principle, continue. Nevertheless, the patients' safety must remain the priority and, similarly to the recommendation for those treated outside clinical trials, outpatient visits must be replaced by e-health assessment whenever possible. Furthermore, for those receiving oral treatment in the frame of a clinical trial, most clinical research organizations now organize home delivery of the investigated medication to

## General points
- Screening for COVID-19 infection before initiating chemotherapy.
- Cytogenetics and molecular biology should be awaited before starting treatment.
- MRD molecular remission should be useful to consider omitting one cycle of consolidation.
- Outpatient visits should be as much as possible deferred or substituted with telemedicine visites.

## Allo-hsct
Discuss indication for allo-HCT on case-by-case.
Nonurgent allo-HCT should be deferred as much as possible.
High-risk allo-HCT such as for refractory AL or patient with a high risk of NRM should not proceed.
ALL acute lymphoblastic leukemia, Allo-HSCT allogeneic stem cell transplantation, AML acute myeloid leukemia, MRD measurable/minimal residual disease, "3 + 7" daunorubicin and cytarabine.
avoid hospital visits. Alternatively, hospital pharmacies should be authorized to deliver 2 or 3 months' worth of medication, rather than the standard one. Whenever possible, follow-up by e-health assessment should be preferred to avoid hospital visits.

## Acute myeloid leukemia
Patients fit to receive intensive therapy For patients with favorable or intermediate risk acute myeloid leukemia (AML) [bib_ref] Diagnosis and management of AML in adults: 2017 ELN recommendations from an..., Dohner [/bib_ref] who are fit to receive intensive chemotherapy, the standard "3 + 7" induction should be considered [bib_ref] Cytarabine dose for acute myeloid leukemia, Lowenberg [/bib_ref]. For AML with FLT3ITD mutation, midostaurin may be added to induction and consolidation as it prolongs OS and EFS [bib_ref] Midostaurin in FLT3-mutated acute myeloid leukemia, Stone [/bib_ref]. For consolidation, the dose of cytarabine could be reduced to 1.5 g/m 2 instead of 3 g/m 2 for all patients. Indeed, prospective studies showed that consolidation, in association with anthracycline, with either intermediate or high dose of cytarabine, did not result in significant differences in the 5-year overall survival, whereas prolongation of neutropenia and higher transfusion demands were observed in the high dose cytarabine arm [bib_ref] Cytarabine dose of 36 g/m(2) compared with 12 g/m(2) within first consolidation..., Schaich [/bib_ref] [bib_ref] Attempts to optimize induction and consolidation treatment in acute myeloid leukemia: results..., Burnett [/bib_ref] [bib_ref] A randomized trial of high-versus conventional-dose cytarabine in consolidation chemotherapy for adult..., Bradstock [/bib_ref]. The use of G-CSF should be recommended after each cycle to reduce the duration of neutropenia. In patients who have negative measurable/minimal residual disease (MRD) after two cycles of chemotherapy, omission of the fourth cycle of consolidation should be discussed. In this case, the MRD should be very closely monitored, and maintenance therapy considered, especially in those cases.
Patients with an adverse cytogenetic risk should receive intensive therapy if a real chance of going to allogeneic stem cell transplantation exists.
In the case of acute promyelocyte leukemia (APL), chemotherapy should be initiated without delay. Patients with standard-risk APL (white blood cells <10  10 9 /L) should receive all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) as frontline following the standard guideline for APL management (i.e., avoidance of G-CSF for the risk of differentiation syndrome). For high-risk APL, induction should be performed with idarubicine, ATRA, and ATO.

## Patients unfit to receive intensive therapy
Newly diagnosed patients with AML, who are unfit for intensive treatment, hypomethylating agents (HMA) or lowdose cytarabine monotherapy (LDAC) could be given in the case of no-proliferative disease. The addition of venetoclax should be discussed on a case-by-case basis, considering the positive impact on CR rate and OS in combination with HMA or LDAC, but also the risk of tumor lysis syndrome and myelosuppression (https://www.fda.gov/drugs/fda-a pproves-venetoclax-combination-aml-adults). After the first cycle with this combination, if medullary blast infiltration is <5%, dose adjustments, duration of venetoclax, and/or the use of G-CSF are recommended to avoid prolonged cytopenia. Taking into account age, comorbidities, and disease characteristics, patients could also be managed with supportive care and, possibly, eventually hydroxycarbamide.
For patients with relapsed or refractory AML, each team should carefully assess the risks and benefits of pursuing a curative approach on a case-by-case basis. Molecular targeted therapy (e.g., enasidenib, ivosidenib, sorafenib, gilteritinib, etc.) should be discussed, considering the rate of complete remission and the duration of the response that can be expected, with a view to postponing an intensive treatment or allogeneic hematopoietic cell transplantation (allo-HCT).

## Acute lymphoblastic leukemia
In ALL, one major question is the use of glucocorticoids, as they remain essential components of ALL therapy. They appeared to be effective in reducing immunopathological damage [bib_ref] High-dose hydrocortisone reduces expression of the pro-inflammatory chemokines CXCL8 and CXCL10 in..., Cinatl [/bib_ref] , but there are concerns about their possible promotion of viral rebound and adverse events. Taking into account the major role of glucocorticoids in the treatment of ALL, and the paucity of information on their potential negative role in COVID-19 infections, physicians should use the recommended dose of glucocorticoids, especially during, the prephase, induction, and consolidation, with a major concern on preventing bacterial and fungal infections. The use of asparaginase should be carefully monitored considering the inherent risk of thrombotic complications of this drug, especially knowing that COVID-19 can lead to systemic coagulation disorders, and thrombotic complications. The use of blinatumomab or inotuzumab should not be delayed as their benefit in terms of survival has been established.
For Philadelphia-chromosome positive ALL, inhibitors of tyrosine kinase should be maintained considering their positive impact on OS and EFS.

## Stem cell transplantation
The EBMT recommendations for management of allo-HCT during the COVID-19 outbreak have been recently published [bib_ref] The challenge of COVID-19 and hematopoietic cell transplantation; EBMT recommendations for management..., Ljungman [/bib_ref]. Nonurgent allo-HCT procedures should be deferred as much as possible. Due to the rapidly changing situation, access to a stem cell donor may be restricted by the fact that the donor may become infected at the harvest centers in the middle of a strained health care system, or by travel restrictions across international borders. It is, therefore, strongly recommended to have secured stem cell product access, by cryopreserving the product before the start of conditioning. In situations when this is not possible, an alternative back-up donor should be identified. The impact of COVID-19 on a timely graft availability, on cellular therapy unit organization, and on ICU capacity should be considered for each patient with allo-HCT indication. It is necessary to highlight the yet unknown impact of COVID-19 infection on outcomes, when counseling patients on the benefits and risks of the allo-HCT procedure.
All patients who have a high risk of disease progression without allo-HCT should still be considered candidates for the procedure according to standard clinical practice. More controversial allo-HCT indications such as refractory AL, or patients with a high risk of non-relapse mortality should be avoided.
Overall, the management of patients with AL in the COVID-19 outbreak is a major challenge, as this hematological malignancy requires rapid treatment, which may result in a requirement for admission to an ICU unit. Physicians should therefore carefully balance the risk of COVID-19 infection itself against the benefit of antileukemic intensive treatment on a case-by-case basis, within the individual resources of each medical institution.
[table] Table 1: Recommendation for management of patients with acute leukemia during the COVID-19 outbreak. [/table]