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• W4237339845 abstract "In high-risk leukaemias treated using allogeneic peripheral blood stem cell transplantation (PBSCT), significant therapeutic benefit is attributed to a graft-versus-leukaemia (GvL) effect mediated by donor T cells and natural killer (NK) cells (Muller et al, 1999; Ruggeri et al, 1999). In patients lacking a human leucocyte antigen (HLA)-matched donor, a T cell-depleted transplant from an HLA-non-identical donor may be the only therapeutic option. Here, donor T-cell infusions are not feasible because of life-threatening graft-versus-host disease (GvHD) (Aversa, 1996; Muller et al, 1999). However, NK cells may provide anti-leukaemic activity without inducing GvHD (Asai et al, 1998) and this activity may be enhanced by immunotherapy using interleukin 2 (IL-2) (Soiffer et al, 1994; Blaise & Maraninchi, 1998; Vivancos et al, 1999). We explored an experimental therapy protocol applying IL-2 [escalating doses up to 3 million units (MU)/m2 three times a week] to stimulate NK activity early after T cell-depleted HLA-haploidentical PBSCT. Following fully informed consent of both parents – including information on transient neurological side-effects – we treated two boys using this strategy. The patients were seen at least three times a week by a paediatric oncologist and clinical status, including neurology, was assessed. Patient 1 had an early second isolated bone marrow relapse of pre-B-acute lymphoblastic leukaemia (ALL) at the age of 7 years. Therapy before PBSCT included standard protocols (ALL-BFM95-MRG, ALL-REZ-BFM96-S4), as well as an individualized protocol consisting of dexamethasone, high-dose cytarabine, etoposide, mitoxantrone and asparaginase. Patient 2 had an early second isolated bone marrow relapse of common-ALL at the age of 11 years. He received standard therapy before PBSCT (ALL-BFM90-SRG, ALL-REZ-BFM96-S2, ALL-REZ-BFM96-S4). Both patients received the following potentially neurotoxic drugs: steroids, vincristine, high-dose intravenous methotrexate, and intrathecal methotrexate and cytarabine. Patient 1 also received high-dose cytarabine 6 weeks before PBSCT; he was never central nervous system (CNS) irradiated. Patient 2 had undergone prophylactic cranial irradiation with 12 Gy, 18 months before PBSCT. Neither patient had any CNS involvement of leukaemia or any neurological abnormalities. Before conditioning, the neuropsychological status in both patients was normal [adverse event score = grade 0, National Cancer Institute-common toxicity criteria (NCI-CTC) version 2·0], as were cranial magnetic resonance imaging (MRI), and cerebrospinal fluid (CSF) cell and protein content. The electroencephalogram (EEG) was normal in patient 1, and showed 2 spike-wave foci in patient 2 that had been unchanged for 7 years. Both patients were in remission from leukaemia at the time of transplantation. In both patients, HLA-matched donors were not available. Thus, they received haploidentical T cell-depleted PBSCT. Conditioning consisted of total body irradiation (TBI, 12 Gy), thiotepa (300 mg/m2 × 1d), etoposide (40 mg/kg × 1d) and anti-thymocyte globulin (5 mg/kg × 4d). Supportive measures included cotrimoxazole, acyclovir, amphotericin B, complete parenteral nutrition and pre-emptive granulocyte transfusions. Full haematological reconstitution developed within 3 weeks. Toxicity in both patients consisted of mucositis I° only. Patient 1 developed sepsis that responded to antibiotics. After confirmation of full donor cell chimaerism and complete remission, immunotherapy with IL-2 was initiated, first given intravenously, than subcutaneously, in escalating doses up to 3 MU/m2 three times a week (Table I). At d +36, patient 1 presented with fatigue grade 1. From d +42, insomnia (grade 2) developed in connection with restlessness (grade 1). These symptoms remained unchanged for several weeks, while IL-2 medication was continued. At d +64, the boy presented with sudden progression of symptoms including restlessness and involuntary movements (grade 3), insomnia (grade 3), and mood alterations including anxiety (grade 3) followed by self-pinching and persistent crying. He then developed personality changes (grade 1) and speech impairment (grade 2). IL-2 therapy was discontinued on d +64. In patient 2, fatigue (grade 2) was noted at d +57. The symptom remained stable for 12 d. On d +69 the boy suddenly presented with a stupor-like condition. He had muscular hypertonia and hyper-reflexia (grade 3), motor neuropathy (grade 2) with apraxia and speech impairment (grade 3). IL-2 therapy was discontinued on d +69. The syndrome progressed to pyramidal tract dysfunction (grade 4), speech impairment (grade 4) and complete incontinence (d +78). In both patients, the symptoms persisted for 4 weeks, followed by slow improvement over more than 2 months and incomplete recovery. In both patients, the leukaemia subsequently relapsed, leading to death 6 months after transplantation. Laboratory investigations showed normal levels of serum electrolytes, vitamins and trace elements, as well as normal parameters of liver and kidney function. In the CSF protein, lactate and cell counts were normal. Polymerase chain reaction (PCR) tests were negative for cytomegalovirus (CMV), Epstein-Barr virus (EBV), human herpesvirus 6 (HHV6), herpes simplex virus (HSV)1/2, varicella zoster virus (VZV), Enterovirae, Mycoplasma, Chlamydia, Mycobacteria, Candida, Aspergillus and Toxoplasma. The patients showed no clinical signs of GvHD. EEG in both patients showed multifocal dysrhythmia and slowing. Cranial MRI was performed in patient 2, showing irregular patchy signal enhancements (Fig 1). CNS MRI scan, T2-weighed, in patient 2. Irregular patchy signal enhancements, especially in the left occipital lobe, are present. Taken together, both patients developed complex neuropsychiatric syndromes after haploidentical PBSCT, with no evidence of pre-existing neurological disorders, CNS leukaemia, infection or GvHD. Thus, it is probable that the syndromes were induced by components of the experimental therapy protocol. Initially, we suspected somnolence syndrome induced by TBI. However, progression to a complex grade 3–4 neuropsychiatric syndrome including involuntary movements/pyramidal tract dysfunction has never been described after TBI with 12 Gy. Nor do the cytostatic drugs applied in the patients (etoposide, thiotepa) have such neurotoxic potential. Consequently, IL-2 appears to be the most probable agent inducing the unusual complications in our patients. The use of IL-2 at the dosage applied in our patients is established for immunotherapy of malignancies (Soiffer et al, 1994; Blaise et al, 1998). A known side-effect is a flu-like syndrome that occasionally progresses to a capillary-leakage syndrome (Karp et al, 1996; Lerner et al, 1999). In one study, slight dose-dependent and self-limited behavioural changes have been reported in 50% of patients (Lerner et al, 1999). However, in a large cohort of 1500 adult patients, severe encephalopathy was seen in only eight cases, with heterogeneous symptoms that rapidly improved within 1 week following cessation of IL-2 (Karp et al, 1996). The complications in the two patients described here are unique with respect to severity and the prolonged duration after discontinuation of IL-2. It is possible that the age of our patients as well as TBI may have potentiated the neurotoxicity of IL-2. Despite this potential severe neurotoxicity, immunotherapy with IL-2 for induction of NK-mediated GvL effects should be considered for poor prognosis patients early after PBSCT. The optimal dose, however, still needs to be established and early signs of neurotoxicity have to be observed carefully, especially in children. We thank Professor Brambs, University Department for Diagnostic Radiology, Ulm, Germany, for providing the MRI scan figure." @default.
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• W4237339845 title "Severe persistent neuropsychiatric toxicity after a human leucocyte antigen-non-identical peripheral blood stem cell transplantation (total body irradiation, etoposide, thiotepa) and interleukin 2-based experimental therapy for poor prognosis relapse acut" @default.
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• W4237339845 doi "https://doi.org/10.1111/j.1365-2141.2001.2937-3.x" @default.
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