Management of Busulfan-Induced Lung Injury in Pediatric Patients with High-Risk Neuroblastoma

Abstract

Background/Objectives: Integrating the cytotoxic drug busulfan into a high-dose chemotherapy regimen prior to autologous hematopoietic stem cell rescue in patients with high-risk neuroblastoma has improved the survival of children battling this deadly disease. Busulfan-induced toxicities can, however, be severe. Here, we describe the diagnosis and successful treatment of acute pulmonary injury by total-body-weight-adjusted busulfan therapy in two children with high-risk neuroblastoma. Case series: Patient 1 developed life-threatening biphasic acute respiratory failure on days +60 and +100 after busulfan therapy, requiring intubation and invasive mechanical ventilation. Despite intensive anti-inflammatory and immunomodulatory therapy, including systemic corticosteroids, topical inhalation regimens, azithromycin, nintedanib and extracorporal photopheresis, patient 1 required extended intensive care measures and non-invasive respiratory support for a total of 20 months. High-resolution computed tomography showed diffuse intra-alveolar and interstitial patterns. Patient 2 developed partial respiratory failure with insufficient oxygen saturation and dyspnea on day +52 after busulfan therapy. Symptoms were resolved after 6 months of systemic corticosteroids, topical inhalation regimens and azithromycin. High-resolution computed tomography showed atypical pneumonic changes with ground-glass opacities. While both patients fully recovered without evidence of pulmonary fibrosis, cancer therapy had to be paused and then modified until full recovery from busulfan-induced lung injury. Conclusions: Busulfan-induced lung injury requires prompt diagnosis and intervention. Symptoms and signs are nonspecific and difficult to differentiate from other causes. Therapeutic busulfan drug level monitoring and the identification of patients at risk for drug overdosing through promoter polymorphisms in the glutathione S-transferase alpha 1 gene encoding the main enzyme in busulfan metabolism are expected to reduce the risk of busulfan-induced toxicities.

Keywords: busulfan; busulfan-induced lung injury; high-dose chemotherapy; neuroblastoma; pediatric cancer; pharmacogenomics; restrictive lung disease; therapeutic drug monitoring.

Figure 1

Schematic diagram illustrating the medical interventions for busulfan-induced lung injury in patient 1 and its consequences for cancer therapy. Induction polychemotherapy was administered in accordance with the rapid platinum-containing induction schedule (carboplatin, cisplatin, vincristine, etoposide, cyclophosphamide) according to the SIOPEN HR-NBL1 protocol (NCT01704716). Consolidation therapy consisted of weight-adjusted high-dose chemotherapy with i.v. busulfan and melphalan (HD BuMel). Maintenance immunotherapy included five cycles of the monoclonal anti-GD2 antibody dinutuximab beta. Radiotherapy of the preoperative tumor bed was administered at 21.6 Gy. Acute respiratory failure and acute respiratory distress syndrome due to busulfan-induced lung injury required invasive mechanical ventilation (IMV) including nitric oxide supplementation followed by prolonged weaning employing non-invasive ventilation (NIV). A total of eight methylprednisolone pulses were administered. Oral prednisolone (2 mg/kg/d) was given in between pulses and was carefully tapered. RIST, molecularly targeted multimodal therapy consisting of metronomic courses of rapamycin/dasatinib and irinotecan/temozolomide. S, surgery. The red dashed line indicates the interruption of the standard oncological treatment of patient 1 due to busulfan-induced lung injury.

Figure 2

Chest X-rays from patient 1 demonstrating signs of busulfan-induced lung injury on day +62 (A) and day +74 (B) after high-dose chemotherapy.

Figure 3

High-resolution computed tomography findings of busulfan-induced lung injury in patient 1 at diagnosis (A) and at follow-up eight months after start of the anti-inflammatory and immunomodulatory therapy (B).

Figure 4

Schematic diagram illustrating the medical interventions for busulfan-induced lung injury in patient 2 and its consequences for the treatment of high-risk neuroblastoma according to the GPOH NB2017 Guidance. Induction polychemotherapy was administered in accordance with the GPOH induction schedule (3xN5 cycle: vindesine, cisplatin, etoposide; 3xN6 cycle: vincristine, dacarbazine, ifosfamide, doxorubicin). Consolidation therapy consisted of weight-adjusted high-dose chemotherapy with i.v. busulfan and melphalan (HD Bu/Mel). Maintenance immunotherapy included five cycles with the monoclonal anti-GD2 antibody dinutuximab beta. Radiotherapy was given at 21.6 Gy to the preoperative tumor bed. Acute partial respiratory failure due to busulfan-induced lung injury required continuous oxygen supplementation. Oral prednisolone was started at 2 mg/kg/d, then gradually tapered. IT and rapamune, multimodal therapy consisting of metronomic courses of rapamune and irinotecan/temozolomide modified from the RIST scheme (NCT01467986), with the multityrosine kinase inhibitor dasatinib replaced by third-generation ALK tyrosine kinase inhibitor lorlatinib; S, surgery. The red dashed line indicates the interruption of the standard oncological treatment of patient 2 due to busulfan-induced lung injury.

Figure 5

High-resolution computed tomography findings of busulfan-induced lung injury in patient 2 at diagnosis (A) and six months after start of the anti-inflammatory therapy (B). (A) Shown are atypical pneumonic changes, characterized by ground-glass opacification and patchy consolidation in the lower lobes. (B) Shown is the regression of consolidations and opacities. There is no evidence of pulmonary fibrosis.