Fatal neurological side‐effects with necrosis of spinal cord following nelarabine treatment in a child with relapsed T‐cell acute lymphoblastic leukemia

Abstract

The article by Kawakami et al. demonstrated severe and irreversible neurological side effects in patients who received nelarabine prior to haploidentical stem cell transplantation 1. We report an 11-year-old boy with a second combined bone marrow (BM) and central nervous system (CNS) relapse of his T cell acute lymphoblastic leukemia (T-;ALL) who suffered severe and fatal neurological side-effects after one cycle of nelarabine treatment. Histopathologic examinations revealed severe necrotic changes in the nervous system corresponding to alterations in the MRI. At admission, the boy was in a good general condition without neurological deficits. Chemotherapy according to the recommendation by Commander et al. 2 including cyclophosphamide, etoposide, nelarabine, and one dose of intrathecal cytarabine, MTX, and prednisolone was started. BY day 5 of chemotherapy strong muscle pain in the limbs developed and two days later the boy suffered from a tonic-clonic seizure. Focal and generalized seizures reappeared over the next days. By day 12 of chemotherapy, the patient developed a Guillain–Barré-like syndrome with hyperreflexia of both arms and hyporeflexia of both legs. Within the next eight days the patient lost sensitivity and reflexes of the lower limbs, developed painful dysesthesia of the arms and lost motor control. After a severe aspiration and cardio-pulmonary reanimation he was transferred to the intensive-care unit, requiring mechanical ventilation. Visual, auditory, and somatosensory evoked potentials were not detectable. By day 20 of chemotherapy, complete remission in the BM and CNS was observed. However, because of the severe neurological symptoms, chemotherapy was stopped. The patient died in a blast crisis eleven weeks after start of chemotherapy without recovery of the neurological symptoms. Longitudinal MRI at days 6 through 74 after initiation of nelarabine treatment showed progressive T2-hyperintense lesions of the spinal cord, including the medial lemniscus and eventually involving its whole cross-sectional diameter. In addition, T2 signal changes of several cranial nerves were observed which were characterized by restricted water diffusion, suggesting cytotoxic edema (Fig. 1). Investigation of post-mortem samples of the nervous system revealed macrophage invasion, gliosis and tissue sponginess in the basal ganglia, thalamus, mammillary bodies, and occipital white matter. Alterations were more pronounced in the fiber tracts of the brain stem and the spinal cord was completely necrotic. Anterior spinal nerve roots showed advanced demyelination while the posterior roots appeared intact. Peripheral nerves exhibited segmental demyelination. Electron microscopy of brain tissue demonstrated macrophages loaded with myelin debris and whole degenerating myelinated axons (Fig. 2). Severe and even fatal neurological toxicities have been described after nelarabine therapy in several patients 1, 3. However, to our knowledge neuropathological changes like in the present case were not even detected in preclinical studies in primates suffering from nelarabine associated neurotoxicity 4. Other causes of neurotoxicity can be excluded since the patient never received spinal irradiation, cranial irradiation dated back more than one year and no infection occurred after nelarabine treatment 5, 6. The patient received a single dose of intrathecal MTX, which may cause neurotoxicity. However, a single dose makes MTX as sole cause unlikely. In summary, our observations confirm the reported neurotoxicity observed by Kawakami et al. BH wrote the manuscript, UL wrote the manuscript and is responsible for MRI performance, CH wrote the manuscript and is responsible for histopathological examination, GE wrote the manuscript and was the responsible clinical physician. Authors are grateful to Dr. Rudolf Laas, Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, for helpful discussions on the manuscript. Bernd Hartz,1 Ulrike Löbel,2 Christian Hagel,3 and Gabriele Escherich1 1Clinic of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany 2Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany 3Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany