*2.5.3 COVID-19 experience in pediatric oncology*

Early data from China revealed that children positive for COVID-19 had a low (2.8%) rate of severe disease [29]. However, in COVID-19 positive children, ICU admission rates were 33.2% in the COVID-NET group study and 35% in another study [30, 31]. Furthermore, in a systemic review (June 2020), the survival rate was %100 among children with cancer and COVID-19 [32].

In a multicenter, retrospective study of 578 children with cancer, 98 were positive for COVID-19. Asymptomatic (n = 25), mild (n = 45), moderate (n = 11), severe (n = 17) disease were observed. Twenty-eight were hospitalized, seven needed mechanical ventilation. Hydroxychloroquine (n = 15), azithromycin (n = 15), tocilizumab (n = 5), remdesivir (n = 4) were given [17]. In a systematic review of 204 children with cancer, 96 were hospitalized because of COVID-19 infection. Thirtytwo percent had oxygen requirements. Pneumothorax, pleural effusion, pulmonary arterial hypertension, bronchiolitis obliterans, diffuse alveolar hemorrhage, septic shock, and acute respiratory distress syndrome are other complications. Forty-one patients received hydroxychloroquine; nine took steroids, five took lopinavir/ ritonavir combination. Azithromycin (n = 4), remdesivir (n = 4), and tocilizumab (n = 3) were used. Twenty-one required intensive care unit admission. Out of 15 deaths, four of them were not related to COVID-19. Thus, the mortality rate was 4.9% [33]. Millen et al. reported 54 positive children of COVID-19 with cancer. The majority (53.7%) of the patients had ALL (acute lymphoblastic leukemia). Four of them had acute myeloid leukemia, five had central nervous system tumors, six had neuroblastoma. None of them died of COVID-19 disease. Twenty-one percent were taking very myelosuppressive chemotherapy; twenty-one were receiving a less intense regimen. Twenty-six had targeted therapies. None received high-dose chemotherapy and stem-cell transplantation within 28 days of this infection [34]. In a resource-limited country, Peru, the epidemiologic data was similar. Among 69 children with cancer, 36 had ALL, 5 had NHL (non-Hodgkin lymphoma), 5 had brain tumors, and COVID 19. Ivermectin, azithromycin, corticosteroids were used for COVID-19 treatment. Unfortunately, seven of them died and, COVID-19 lethality is 10% in this study [35]. Graetz et al. reported that out of 79 countries and 213 centers, 88% had SARS-CoV2 testing opportunities, 43% of centers declined in new cancer diagnosis. Reduction in surgery (72%), chemotherapy changes (57%), disruption in radiotherapy (28%) has been a great deal. In low-middle income countries, unavailability of chemotherapy agents, lag in treatment, and radiotherapy was more common [36].

In another cross-sectional study, 51 children with cancer were examined, and they had COVID-19. Sixty point eight percent had hematologic malignancies; six underwent stem cell transplantation, 17 had moderate or severe disease, nine had a critical illness. Delay in treatment (chemotherapy, radiotherapy, surgery) and reduction in chemotherapy doses were reported in 40-58% of the cases [37]. Kebudi et al. said the mortality rate was 1.9% in COVID-19 infection of pediatric oncology patients. Hematologic malignancies, HSCT, a mixed condition, increased the severity of COVID-19 disease [38]. COVID-19 recommendations are rapidly changing, guidelines of the Ministry of health were used in this study. Recent proposals for immunocompromised children in this guideline are; mild cases with possible worsening respiratory failure should be treated. Here, drug interactions should be carefully examined. These patients older than twelve receive favipiravir with a loading dose of 1600 mgr twice a day, and a maintenance dose of 600 mg,

once a day. Hydroxychloroquine ± azithromycin is deleted currently but previously given in this guideline [39].

## **2.6 Managing hematologic malignancies in COVID-19 pandemic**

European Society for Blood and Marrow Transplantation (EBMT) reported their recommendations (June 2020). Steroids that may cause viral rebounds and adverse events are the main component of acute lymphoblastic leukemia treatment. Dose reduction is not recommended in prophase, induction, and consolidation. Asparaginase has thrombotic complications that are also observed in COVID infections. Treatment delay is not recommended for drugs, blinatumomab or inotuzumab. Tyrosine kinase inhibitors are the mainstay treatment in Philadelphiapositive ALL; this treatment should not be delayed. As well as acute promyelocyte leukemia should be treated immediately. Acute myeloid leukemia with adverse cytogenetic risks and a suitable donor for allogeneic stem cell transplantation needs intensive therapy. Patients with favorable or intermediate-risk factors should also be treated, but some modifications in doses can be preferred after induction. This procedure cannot be postponed for patients with a risk of progression or relapse without allogeneic stem cell transplantation. Controversial indications should be reconsidered [40]. Passamonti et al. reported that outcomes were worse in hematological malignancies with COVID-19. The leading diagnoses with worse survival were acute myeloid leukemia, indolent NHL, aggressive NHL, or plasma cell neoplasms. In addition, the mortality rate of hematological malignancies was four times higher than the general population with COVID-19. This rate was also 41 times higher than the hematologic malignancies without COVID-19. Thus, disease type and status are essential for outcome [41]. Retrospective studies support a mortality rate up to %62 in hematological malignancies with COVID-19. Prolonged persistence of the RNA up to 32.7 days is reported.

Acute leukemias, especially acute myeloid leukemia (AML), myeloproliferative neoplasms, myelodysplastic syndromes, lymphomas, have the worst complications and outcomes. Chemotherapy was not generally associated with worse results. PCR ± C.T. of the chest is recommended before treatment. Induction treatment should not be delayed. In case of a positive test, a multidisciplinary team containing a pediatric hematology-oncologist and pediatric infectious diseases specialists should decide the time of others courses. With a positive test, the period of chemotherapy can be postponed for two weeks. In high-risk AML, allogeneic stem cell transplantation should not be delayed. Recommendations of EBMT should be followed [42]. Tyrosine kinase inhibitors (TKIs) are the mainstay treatment in chronic myeloid leukemia (CML). The cessation of these drugs needs a deep and stable response to treatment and close follow-up. In the COVID-19 pandemic, termination of therapy is not a helpful approach. The interaction of remdesivir with imatinib, dasatinib, and nilotinib is essential. In CML blastic phase, TKIs plus intensive chemotherapy is an urgent treatment [42].

Newly diagnosed aggressive NHL like Burkitt lymphoma and Diffuse large B cell Lymphoma need acute treatment, and delay is inappropriate. DA-EPOCH-R (dose-adjusted etoposide, cyclophosphamide, vincristine, doxorubicin, prednisone) is the standard treatment for PMBCL (primary mediastinal B-cell lymphoma). Because of the severe immunosuppressive effect of this regimen, alternatives are recommended, like R-CHOP with radiotherapy consolidation. RICE (rituximab, ifosfamide, carboplatin, etoposide) can be given as a salvage regimen in a relapsed refractory setting. However, less myelotoxic regimens can be preferred. In Hodgkin lymphoma treatment, bleomycin and checkpoint inhibitors have adverse pulmonary toxicity events. In adults, the omission of bleomycin can

be an option for complete remission after the second course. Guidelines for radiotherapy should be followed [39]. Bendamustine as an option in relapsed refractory patients is associated with mortality in COVID-19 positive lymphomas [43].
