A case of COVID-19 infection in a child with a tailored treatment strategy for Philadelphia chromosome-positive B-cell acute lymphoblastic leukaemia

Introduction

Paediatric Philadelphia chromosome-positive (Ph-positive) acute lymphoblastic leukaemia (ALL) is a rare malignancy accounting for nearly 2–5% of ALL in children, and it is commonly associated with aggressive disease progression [1, 2]. Due to its resistance to standard chemotherapy, Ph-positive ALL can be effectively treated with a tyrosine kinase inhibitor (TKI). Targeted TKI therapy has led to an improved prognosis in patients with Ph-positive ALL [3, 4]. Although current treatment strategies are becoming increasingly successful, chemotherapy-induced immunosuppression and multi-organ toxicity in children increase the risk of potentially life-threatening infectious diseases. In recent years, SARS-CoV-2 infection has attracted the interest of paediatric haematologists and oncologists. Numerous cases of patients with haematological malignancies confronted with SARS-CoV-2 infection during the course of treatment have been described [5, 6]. Early reports documented that children with haematological malignancies and concomitant COVID-19 infection had worse disease outcomes and survival rates compared to patients without infection [7]. However, recent reviews confirm the predominance of mild courses of SARS-CoV-2 infection in most patients with malignant disease [8–10]. Nevertheless, the management of patients with an aggressive form of acute leukaemia and concomitant COVID-19 infection is a challenge for haematologists worldwide and requires collaboration between haematologists and infectious disease specialists [11, 12].  
In this paper, we present the case of a child with Ph-positive B-cell ALL, who received a tailored modified consolidation chemotherapy regimen and experienced various adverse events during intensive chemotherapy and concomitant SARS-CoV-2 infection. Despite having a high-risk (HR) ALL, he developed a mild COVID-19 infection and recovered within a few days.

Patient presentation

A previously healthy 13-year-old boy presented to the surgical department of the children’s hospital in September 2022 with persistent right hip joint pain due to a right femoral head injury and a single episode of unexplained fever (39oC). Diagnostic magnetic resonance imaging of the hip joints showed abnormal signals in the bone marrow of the pelvic bones, visible vertebrae, and parts of the femur, raising strong suspicion of a haematological malignancy. Over the next few days, the patient developed migratory bone pain and fever. Diagnostic bone marrow biopsy revealed findings consistent with acute lymphoblastic leukemia (ALL), common B-cell type, FAB L2, BCR-ABL positive. The central nervous system (CNS) status at diagnosis was defined as CNS1.
In October-November 2022, induction chemotherapy with TKI (imatinib) at a daily dose of 340 mg/m2 was started from day 15 of chemotherapy according to the EsPhALL2017 protocol, along with supportive care. During induction protocol IA, the patient developed mucositis (grade 3–4), myelosuppression (grade 2–3), grade 3 leukopaenia, grade 2 thrombocytopaenia, and grade 2–3 anaemia. Treatment was complicated by vincristine-induced neuropathy and metoclopramide-induced oculomotor nerve palsy. On day 33, his bone marrow was in morphological remission, and minimal residual disease (MRD) testing showed less than 0.01% blast cells, polymerase chain reaction (PCR) BCR/ABL – 2.3 x 10–3. The patient remained in regular follow-up with the haematology team, and in November-December 2022, he continued early intensification IB phase chemotherapy with imatinib. He experienced febrile neutropaenia, mucositis (grade 2), myelosuppression (grades 3–4), leukopaenia (grade 4), thrombocytopaenia (grade 3), and anaemia (grade 3). Severe bilateral focal pneumonia, stage 2 respiratory failure, angular cheilitis, and secondary hemosiderosis were diagnosed. Minimal residual disease was assessed at the end of induction and was less than 0.01%, PCR BCR/ABL – 1.3 x 10–3. Based on the BCR-ABL gene rearrangement alone, the patient was identified as HR disease group.
The second phase of treatment – consolidation chemotherapy for HR B-ALL – consisted of 3 blocks of HR chemotherapy. The first 2 blocks included high-dose methotrexate (MTX) infusion with the necessary monitoring of MTX serum levels and intensification of leucovorin rescue. According to the protocol, MTX serum levels were determined at 24, 42, and 48 hours after the start of the infusion. Unfortunately, consolidation with HR block 1 and 2 chemotherapy was not possible for this patient due to the inability to determine the patient’s serum MTX levels at the local hospital. During this difficult period caused by the devastating war in Ukraine, the National Specialised Children’s Hospital stopped transferring patients from other hospitals. Following the recommendation of the national experts, the patient was advised to start consolidation with HR block 3.
In February 2023, the patient received HR block 3 according to EsPhALL2017, with good tolerability. After completion of HR block 3, the MRD result was 0.01%, PCR BCR/ABL – 8.8 x 10–4. He again had complications of mucositis (grade 2) and myelosuppression consistent with grade 4. Left-sided aspiration pneumonia, stage 1 respiratory failure, and bilateral subconjunctival haemorrhages were also diagnosed. Four days after the end of HR block 3, he developed fever, which was thought to be due to febrile neutropaenia. Ibuprofen and cephalosporin were administered. The patient reported sharp chest pain and massive epistaxis. A significant deterioration in the patient’s condition and laboratory parameters necessitated transfer to the intensive care unit (ICU). In the ICU, nasal packing, infusions of fresh frozen plasma, and erythrocyte transfusion in combination with thromboconcentrate were performed. After partial clinical improvement and return to the haematology department, the patient presented with significant asthenic symptoms along with signs of bronchial obstruction and subfebrile body temperature. Physical examination revealed fine moist rales in the left lung and decreased oxygen saturation to 92–95%. The complete blood count (CBC) showed red blood cells (RBC) at 2.39 x 1012/l, haemoglobin at 68 g/l, haematocrit at 21.09%, white blood cells (WBC) at 0.04 x 109/l, and platelets at 38 x 109/l. Baseline laboratory results showed abnormal findings of C-reactive protein 155.28 mg/l and ferritin – 1365 ng/ml. The patient was treated with cefepime, ciprofloxacin, oxygen therapy, ipratropium bromide, and intravenous immunoglobulin.
Due to the current pandemic of COVID-19 and his transfer to the ICU, a repeated nasopharyngeal swab PCR test was defined as positive for SARS-CoV-2, while the caregiver’s test was negative.
Despite the progression of COVID-19 infection, his condition and CBC parameters gradually improved. Ten days later, his repeat CBC showed haemoglobin at 95 g/l, haematocrit at 29.05%, WBC at 3.14 x 109/l, and platelets at 53 x 109/l. His C-reactive protein level was at 5.77 mg/l, D-dimer was 1.10 mg/l (the normal limit is < 0.05 mg/l), and the PCR for SARS-CoV-2 was negative.
He was afebrile and stable. All family members and hospital staff exposed to the patient tested negative for COVID-19. Lung ultrasound showed a mild degree of alveolar-interstitial syndrome without parenchymal consolidation. The patient was discharged in stable condition.

Discussion

Since the beginning of the COVID-19 pandemic, oncohaematologists from different countries have reported cases of patients with acute leukaemia who developed SARS-CoV-2 infection during chemotherapy. The incidence of this infection was estimated at 1.3% in children with cancer [13]. The reported cases showed different outcomes, ranging from mild manifestations of infection [12, 14, 15] to severe or critical courses of COVID-19 infection in children with malignancies [13]. Regarding the route of contamination, data showed that most SARS-CoV-2 infections in ALL patients were nosocomial, despite the use of personal protective equipment by healthcare workers and patients, restricted access for visiting relatives, and regular monitoring of nasopharyngeal swabs [16]. This was similar to our case, who acquired SARS-CoV-2 in the clinical setting.
Based on the suggestion of the Children’s Oncology Group and the European Study of Postinduction Treatment of Ph-Positive ALL (EsPhALL) consortium, the combination of chemotherapy and TKI is an effective innovative treatment approach for children with Ph-positive ALL. Consequently, paediatric oncohaematologists are faced with a treatment dilemma in such cases: either to stop chemotherapy or to continue with anticancer treatment in patients with a positive SARS-CoV-2 test result [8, 14]. To date, experts from the American and European haematology associations have recommended continued multidrug induction and TKI in children with Ph-positive ALL infected with SARS-CoV-2 virus. Interestingly, researchers also tried to clarify whether chemotherapy in leukaemia protects against severe COVID-19 infection progression [5]. Furthermore, researchers suggest a possible protective role of TKI treatment against the severity of COVID-19 [16]. Although our patient received a deviated protocol of chemotherapy with high-dose MTX (HDMTX) due to low resource settings, it was associated with TKI. In our case, the tailored treatment strategy was caused by the inability to safely administer and monitor HDMTX. Usually, it can be considered as avoidable, but in this situation the treatment deviation became an unavoidable deviation. In addition, based on retrospective analysis of medical records, researchers reported that significant deviations from HDMTX administration guidelines did not affect remission rates, but led to lower disease-free survival of ALL patients [17, 18].
The current clinical protocol EsPhALL2017 is defined as balanced in treatment-related toxicity of intensive chemotherapy [3]. Although TKI plus EsPhALL chemotherapy is considered safe and effective for children and adolescents with Ph-positive ALL, many drug-induced toxicities remain a challenge [2, 11]. Our patient also developed serious side effects including grade 3–4 myelosuppression, vincristine-induced neuropathy, metoclopramide-induced oculomotor nerve palsy, secondary hemosiderosis, and febrile neutropaenia, despite achieving morphologic remission with MRD. Retrospectively, we concluded that the toxicities in our patient overlapped with the symptoms of COVID-19. In particular, not only typical clinical symptoms of SARS-CoV-2 infection (fever, respiratory distress), but also neuropathy and bleeding tendency, which have already been reported [19, 20], may resemble drug-induced toxicities.

Conclusions

This case demonstrates mild COVID-19 symptoms in a child with Ph-positive ALL during a chemotherapy regimen that deviated from the standard of treatment. Adverse effects of chemotherapy can mimic COVID-19 infection symptoms, which include fever, respiratory distress, neuropathy, and haemorrhage. Clinicians should be aware of the potential for misdiagnosis. With the ongoing global threat from COVID-19, children undergoing chemotherapy should be regularly tested for SARS-CoV-2 infection. The treatment of coexisting ALL and COVID-19 in paediatric patients should be individualised to the patient and disease because there is no standardised approach to modifying chemotherapy. This case also supports the effectiveness of the combination of chemotherapy and TKI in the treatment of children with Ph-positive ALL.

Disclosures

1. Institutional review board statement: Not applicable.
2. Assistance with the article: None.
3. Financial support and sponsorship: None.
4. Conflicts of interest: None.

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