Successful Outcomes of Children Simultaneously Diagnosed with Acute Myeloid Leukemia and Covid-19: The Role of a Mild Chemotherapeutic Induction Regimen
Authors: Lins Mecneide Mendes , Costa Juliana Teixeira , Wanderley Alayde Vieira , Seber Adriana , Rocha Cinthya , Silva Luciana Nunes , Pantoja Laudreisa da Costa , Zamperlini Gustavo , Conter Valentino , Ribeiro Raul 
Published: November 2020

Introduction: Children with newly diagnosed acute myeloid leukemia (AML) may have a high early mortality when resources are limited by infrastructure or by a widespread worldwide crisis, as being faced with the SARS-Cov-2 pandemic. Many elective treatments were postponed, but newly diagnosed AML is a life-threatening disease that needs prompt therapy. With acute shortage of infra-structure as intensive care unit beds, blood supply, medication, healthcare personnel, an optimal therapy must balance anti-neoplastic efficacy and the chance of treatment-related mortality. The induction chemotherapy of pediatric patients with AML living in low- and middle-income countries has been thoroughly discussed because early mortality remains 10%-20%, much higher than in developed counties. Mild treatment schemas have been used in Japan, China and Latin America with impressive results, comparable to other intensive induction regimens. Our objective is to describe the results of this mild induction regimen used in Brazil to treat children simultaneously diagnosed with AML and Covid-19 infections.
Methods: This is a retrospective multicentric trial including Brazilian children diagnosed with AML, also found to have a positive nasal and oropharyngeal PCR for SARS-Cov-2 and uniformly treated with mild induction protocol ("MAG") that included Mitoxantrone at 5 mg/m2, by i.v. infusion over 4 to 6 hours once a day on days 1, 3, and 5 (three doses in total), Cytarabine at 10 mg/m2, subcutaneous (s.c.), q 12 h for 10 days (20 doses in total) and G-CSF 5 𝜇g/kg, s.c., once a day for 10 days (10 doses in total) [Bansal D, et al. Pediatr Blood Cancer. 2019 Nov 27:e28087].
Results: From March 15 to July 1, 2020, nine children from four different institutions were diagnosed with AML (Table 1). Their median age was 9 years (range, 5 to 18), 6 female gender, all but one diagnosed with Covid-19 by nasal PCR; one had typical chest CT and positive IgM. The institutions had previously agreed on following the same induction when treating AML children infected by the SARS-Cov-2. Five of the nine had severe illness, three of them needed mechanical ventilation and one did not need supplementary oxygen despite radiologically diagnosed pneumonia. Two children had mild symptoms and two were completely asymptomatic. All children tolerated MAG chemotherapy. Neutropenia lasted for a median of 29 days (17-33) and none of them had neither thrombotic complications nor acute renal failure. All children recovered from the Covid-19 infection and 8 of 9 already evaluable children achieved complete remission of the leukemia with MRD 0-1% after the two planned cycles. All patients are alive, on therapy.
Table 1: Patients characteristics Pt#AgeGenderAML-FABMolecular BiologyCytogeneticsCNS diseaseSeverelly IllDuration of Neutropenia (days)Response to 1st InductionResponse to 2nd InductionCOVID SymptomsOxygen TherapyCOVID TreatmentStatus19MM0NegativeComplex karyotype with del11NoNo330% blastsMRD 0,12%NoneNoAAlive28FM2Negativet(10,11)NoYes261% blastsToo earlyInflamatory syndromeMechanical VentilationA,C,IVIGAlive317FNOSNegativeNormalNoYes227% blastsMRD 1%PneumoniaMechanical VentilationA,I,O,C,HAlive45MM4EoInv16Inv. 16NoYes222% blastsMRD negativeMildNo-Alive58MM2Amltot(8;21)YesYes190%MRD negativeNoneNoAAlive68FNOSNot doneNot doneNoNo254% blastsMRD negativePneumoniaNoA,O,CAlive710FNOSNot doneTrisomy 22NoYes17Too earlyToo earlyPneumonia, Respiratory DistressMechanical VentilationA,O,C, IVIGAlive810FM5ASXL1NormalNoNo310%Too earlyNoneNoA,I,CiproAlive918FM2NegativeNot doneNoNo270%MRD negativeMildNoAAlive
A - Azythromycin; I - Ivermectin; C - Corticosteroids, O - Oseltamivir; IVIG - Immunoglobulin; H- Heparin; Cipro- Coprofloxacin
Conclusions: Against all odds, MAG was well tolerated in children and adolescents newly diagnosed with AML and active Covid-19, with no treatment-related mortality. All evaluable patients achieved remission and are currently proceeding therapy. The high prevalence of Covid-19 in our country may have to be taken into account in all oncological treatment strategies. With a shorter duration of neutropenia, the absence of mucositis or invasive fungal infections, MAG may be implemented in low- and middle-income countries as an optimal strategy to overcome induction mortality and improve outcome of children and adolescents with AML.

Disclosures
No relevant conflicts of interest to declare.