Intrathecal nusinersen treatment for SMA in a dedicated neuromuscular clinic: an example of multidisciplinary and integrated care

Sansone, Valeria; Albamonte, Emilio; Salmin, Francesca; Casiraghi, Jacopo; Pirola, Alice; Bettinelli, Massimo; Rao, Fabrizio; Mancini, Luca; Tovaglieri, Nicola; Fedeli, Fausto; Stoia, Paolo; Heinen, M; Cozzi, Valeria; Carraro, Elena; Lunetta, Christian; Bari, Alessandra Di

doi:10.1007/s10072-018-3622-9

Cited by 18 publications

(13 citation statements)

References 18 publications

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“…Since no evidence for sustained inflammatory cellular reactions or a relevant shift of the cellular composition in the CSF was found, cytological analysis did not reveal safety issues of nusinersen treatment in adult patients with SMA. These findings complement the extensive clinical data demonstrating safety and feasibility of nusinersen therapy (6, 13–15).…”

Section: Discussionsupporting

confidence: 78%

Routine Cerebrospinal Fluid Cytology Reveals Unique Inclusions in Macrophages During Treatment With Nusinersen

et al. 2019

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Background: Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder characterized by degeneration of spinal motor neurons leading to muscular weakness. The antisense oligonucleotide nusinersen was approved for the treatment of patients with 5q-associated SMA. Treatment must be repeatedly administered intrathecally by lumbar puncture. So far, data regarding cerebrospinal fluid (CSF) parameters are sparse and examinations of CSF cytology during nusinersen treatment are completely missing. Methods: 87 CSF samples from 19 adult SMA patients who underwent repeated lumbar punctures for intrathecal injections of nusinersen were investigated. CSF specimens were quantitatively assessed regarding leukocyte subpopulations by routine cytology after Pappenheim staining. A control group with 38 CSF samples from 10 patients with repeated lumbar punctures due to other diseases was used. Results: Treatment with nusinersen did not result in persistent inflammatory cellular changes or a relevant shift of leukocyte subpopulations in the CSF. During nusinersen therapy unique macrophages with numerous sharply defined purple and granular inclusions were detected in all patients. These macrophages were not found in CSF of patients with other diseases who underwent repeated lumbar punctures. Discussion: Routine CSF cytology performed by experienced personnel represents an important and feasible tool for safety monitoring during treatment with intrathecally administered therapeutics. Analysis of leukocyte subpopulations did not raise safety concerns during nusinersen therapy. The potential significance of the unique phagocytic cells for disease course and treatment response needs to be further elucidated in the future.

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Section: Discussionsupporting

confidence: 78%

Routine Cerebrospinal Fluid Cytology Reveals Unique Inclusions in Macrophages During Treatment With Nusinersen

et al. 2019

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“…In our daily routine and as described by others, CT-guided intrathecal delivery of nusinersen in SMA patients with severe scoliosis has been well established. This approach was shown to be safe and well tolerated [20][21][22][23][24]. However, side effects reported in our cohort and other recently published studies mainly resulted from the lumbar puncture procedure itself and were not directly related to the medication [24,25].…”

Section: Discussionsupporting

confidence: 56%

Treatment expectations and patient-reported outcomes of nusinersen therapy in adult spinal muscular atrophy

et al. 2020

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Background The antisense-oligonucleotide (ASO) nusinersen has recently been approved as the first genetically modifying therapy for 5q-associated spinal muscular atrophy (SMA) based on randomized sham-controlled trials in infants and children. The efficacy in adults with long disease history and advanced disease status is still widely unknown; the same applies to specific expectations of adult SMA patients and to what extent they are met and may impact outcome measures. Methods In a longitudinal monocentric study in adult patients with SMA types 2-4, the Stanford Expectations of Treatment Scale (SETS) was assessed prior to and during nusinersen treatment. Treatment outcome was evaluated using patient-reported outcomes (PROs) as well as objectively quantifiable motor outcome measures. Results Adult SMA patients had high expectations of nusinersen treatment effectiveness regarding increase in muscle strength and disease stabilization. Via PROs, 75% stated improvements in muscle strength, endurance and independence under therapy which was in line with slight improvements in quantifiable motor scores during a ten month observation period. In contrast, patients only expressed few negative expectations which further decreased during therapy. Conclusions This study showed mainly positive treatment expectations and PROs in patients undergoing nusinersen treatment along with measurable functional improvement in adult SMA patients. Moreover, treatment expectations did not significantly influence outcome measures. Keywords Spinal muscular atrophy (SMA) • Patient-reported outcomes (PROs) • Stanford expectations of treatment scale (SETS) • Nusinersen • Antisense-oligonucleotide (ASO)

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“…Preliminary safety data on nusinersen use in real-world clinical practice have been reported by several groups [47–50]. In one report based on the experience from seven centers in Germany in children with infantile-onset SMA, SAEs were reported in 54.7% of treated children, severe AEs in 45.3%, and PLPS in 4.9% [48].…”

Section: Discussionmentioning

confidence: 99%

An Integrated Safety Analysis of Infants and Children with Symptomatic Spinal Muscular Atrophy (SMA) Treated with Nusinersen in Seven Clinical Trials

et al. 2019

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BackgroundTreatment with nusinersen has demonstrated significant and clinically meaningful benefits in clinical trials in infants and children with spinal muscular atrophy (SMA).ObjectiveThe objective of this analysis was to characterize the safety of nusinersen across the clinical trial program in infants and children with symptomatic SMA.MethodsAn integrated safety analysis evaluated end of study data from seven completed clinical trials that enrolled infants and children with symptomatic SMA who were treated with intrathecal nusinersen or underwent sham procedures. Two of the studies were conducted in symptomatic infants with infantile-onset SMA (most likely to develop SMA type I or II) and the remaining five in symptomatic children and adolescents with later-onset SMA (have or are most likely to develop SMA type II or III). Safety assessments included incidence of adverse events (AEs), physical and neurological examinations, vital signs, clinical laboratory tests (serum chemistry, hematology, and urinalysis), and electrocardiograms.ResultsData were analyzed from 323 infants and children, including 240 treated with nusinersen (100 with infantile-onset SMA and 140 with later-onset SMA) and 83 who underwent sham procedures (41 infantile-onset, 42 later-onset). Median (range) exposure to nusinersen was 449.0 (6–1538) days (375.9 participant-years). The most common AEs with nusinersen were pyrexia, upper respiratory tract infection, nasopharyngitis, vomiting, headache, and constipation. The incidence of serious AEs was lower with nusinersen than with the sham procedure (41% vs. 61%). The overall incidence of respiratory, thoracic, and mediastinal AEs was higher in participants with symptomatic infantile-onset SMA than those with symptomatic later-onset SMA and similar in nusinersen- versus sham procedure–treated participants. Rates of post–lumbar puncture syndrome and related events were higher with nusinersen versus sham procedure in later-onset SMA participants. No abnormal patterns or trends in laboratory test results were observed.ConclusionsNusinersen demonstrated a favorable safety profile in children with symptomatic infantile- and later-onset SMA. Most reported AEs and serious AEs were consistent with the nature and frequency of events typically seen with SMA or in the context of lumbar puncture procedures.RegistrationNCT01494701, NCT01703988, NCT01839656, NCT02193074, NCT02292537, NCT01780246, NCT02052791.Electronic supplementary materialThe online version of this article (10.1007/s40263-019-00656-w) contains supplementary material, which is available to authorized users.

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Intrathecal nusinersen treatment for SMA in a dedicated neuromuscular clinic: an example of multidisciplinary and integrated care

Cited by 18 publications

References 18 publications

Routine Cerebrospinal Fluid Cytology Reveals Unique Inclusions in Macrophages During Treatment With Nusinersen

Routine Cerebrospinal Fluid Cytology Reveals Unique Inclusions in Macrophages During Treatment With Nusinersen

Treatment expectations and patient-reported outcomes of nusinersen therapy in adult spinal muscular atrophy

An Integrated Safety Analysis of Infants and Children with Symptomatic Spinal Muscular Atrophy (SMA) Treated with Nusinersen in Seven Clinical Trials

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