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The Use of Natalizumab in Pediatric Patients With Active Relapsing Multiple Sclerosis: A Prospective Study
Pediatric Neurology 70 (2017) 56e60
Contents lists available at ScienceDirect
Pediatric Neurology journal homepage: www.elsevier.com/locate/pnu
Original Article
The Use of Natalizumab in Pediatric Patients With Active Relapsing Multiple Sclerosis: A Prospective Study Raed Alroughani MD, FRCPC a, b, *, Samar Farouk Ahmed MD c, d, Raed Behbehani MD, FRCSC b, e, Jasem Al-Hashel MD, FRCPC c, f a
Division of Neurology, Amiri Hospital, Sharq, Kuwait Neurology Clinic, Dasman Diabetes Institute, Dasman, Kuwait c Department of Neurology, Ibn Sina Hospital, Kuwait City, Kuwait d Department of Neurology and Psychiatry, Minia University, Minia, Egypt e Department of Ophthalmology, Al-Bahar Ophthalmology Center, Kuwait City, Kuwait f Department of Medicine, Kuwait University, Kuwait City, Kuwait b
abstract BACKGROUND: Pediatric multiple sclerosis (MS) has been increasingly recognized. In the absence of approved disease-modifying therapies (DMTs) for pediatric patients, clinicians resort to data extrapolated from clinical trials conducted in adults with MS. The objective of this article was to study the effectiveness and safety of natalizumab in with pediatric MS. METHODS: Patients with pediatric MS (aged less than 18 years) who had been treated with natalizumab were followed up prospectively as part of the national MS registry. Data of relapsing patients who had at least a one-year follow-up were analyzed. The primary outcome measure was the annual relapse rate after natalizumab treatment. Secondary outcomes measures included the mean change in disease progression measured by the expanded disability status scale and the proportion of patients with radiologic activity (gadolinium-enhancing or new T2 lesions) at the last follow-up visit. RESULTS: Thirty-two patients with pediatric MS had been treated with natalizumab for at least 12 months, of whom 72% were females. The mean age at onset and disease duration were 14.9 2.6 and 5.1 3.1 years, respectively. Most patients (n ¼ 21, 66%) had breakthrough disease on first-line disease-modifying therapies. The mean number of natalizumab infusions was 34.5 18. The annual relapse rate was significantly reduced (1.66 0.5 vs 0.06 0.25; P < 0.001), whereas the mean expanded disability status score improved (3.3 1.3 vs 2.2 1.0; P < 0.001) at the last follow-up visits. The proportion of patients with magnetic resonance imaging activity was significantly reduced (93.8% versus 12.5%; P < 0.001). No major adverse events were observed. CONCLUSION: In our pediatric MS cohort with aggressive or breakthrough disease, treatment with natalizumab was effective in reducing clinical and radiologic disease activity. Natalizumab has a similar clinical efficacy and safety profile as in adult MS. Keywords: multiple sclerosis, pediatric, natalizumab, EDSS, Kuwait
Pediatr Neurol 2017; 70: 56-60 Ó 2017 Elsevier Inc. All rights reserved. Introduction
As the criteria for the diagnosis of multiple sclerosis (MS) evolve, MS is being increasingly recognized in children and adolescents. The prevalence of pediatric-onset MS ranges
Article History: Received November 12, 2016; Accepted in final form January 18, 2017 * Communications should be addressed to: Dr. Alroughani; Division of Neurology; Department of Medicine; Amiri Hospital; Arabian Gulf Street; Sharq 13041, Kuwait. E-mail address: [email protected] 0887-8994/$ e see front matter Ó 2017 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pediatrneurol.2017.01.017
from 2.7% to 11.3% of the total MS populations.1-3 Children with MS predominantly present with more frequent relapses and a higher incidence of cognitive deficits than in adult MS cohorts,4 which poses unique challenges in the management, especially given the lack of specific diseasemodifying therapies (DMTs) proved by clinical trials for pediatric MS.5-7 The American and European regulatory agencies have implemented guidelines for the inclusion of pediatric investigation plans for new pharmacologic agents, with the aim of ensuring safe and appropriate access to promising new therapies for children and adolescents.8 Physicians are generally reluctant to use DMTs in children
R. Alroughani et al. / Pediatric Neurology 70 (2017) 56e60
during periods of growth and physical development.9 Firstline medications, namely, interferon beta and glatiramer acetate (GA), are the standard care for patients with pediatric MS.10,11 However, about 30% of treated patients were partial or nonresponders to first-line treatment and later on required a switch to a high-efficacy therapy.12 Several observational studies have shown that natalizumab consistently reduces disease activity in patients with pediatric MS.13-16 However, prospective data are limited, and there have been no regional published data about the use of natalizumab in pediatric cohorts. In our study, we aim to prospectively assess the effectiveness and safety of natalizumab in patients with pediatric MS in Kuwait. Methods We conducted a prospective study utilizing the national MS registry to evaluate patients with pediatric MS (less than 18 years) treated with natalizumab. The registry was established in 2010 in Kuwait and is composed of databases of all major hospitals.17 The diagnosis in patients with pediatric MS was established based on the consensus definition proposed by the International Pediatric Multiple Sclerosis Study Group (IPMSSG).18,19 Patients, who were identified from the registry, were followed up prospectively. As per the registry protocol, patients had at least two visits per year, excluding visits for suspected relapses. Neurological evaluation, including the assessment of expanded disability status scale (EDSS),20 was performed every 6 months. Anti-John Cunningham virus (JCV) antibody (Stratify JCV performed at Unilabs, Denmark)21 was performed every 6 months after the initiation of natalizumab. Magnetic resonance imaging (MRI) (1.5 T) brain and cervical spine with gadolinium were obtained at baseline, biannually for the first year and then annually. Relapses were defined as new or recurrent neurological symptoms not associated with fever or infection that lasted for at least 24 hours and were accompanied by new neurological signs found by the examining neurologist while disease progression was evident by an increase of at least 1.0 point on EDSS score.22 MRI activity was defined as an increase evident by either gadolinium-enhancing or new T2 lesions. According to the hospital protocol, the indications for the institution of natalizumab in patients with pediatric MS were (1) one relapse and evidence of new brain MRI activity or a severe relapse with incomplete recovery despite being on first-line therapies (interferon beta or glatiramer acetate) for at least one year or (2) demonstration of rapidly evolving MS, with at least two relapses in the last year and appearance of new brain MRI activity in naïve patients. Patients received the standard adult dose of natalizumab (300 mg intravenously every 4 weeks). To obtain the annual relapse rate (ARR), we included only relapsing patients with pediatric MS who had at least one-year follow-up after natalizumab institutions. Pretreatment ARR was defined as the number of relapses that occurred in the year before natalizumab initiation, whereas on-treatment ARR was calculated as the number of relapses per duration of therapy. Patients’ demographics (age, gender), clinical characteristics (course of the disease, disease duration, relapse rate, EDSS score), and treatment parameters (prior DMT use, number of natalizumab infusions, adverse events, anti-JCV results) were obtained. The primary outcome measure of the study was to determine the ARR before and after natalizumab treatment. Secondary outcomes measures included the change in disease progression measured by EDSS scores and the proportion of patients with radiologic activity (gadolinium-enhancing or new T2 lesions) at the end of the observational period. Patients with primary or secondary progressive MS were excluded. The study was approved by the institutional ethical committee. Assents and parental consents forms were obtained from all patients. All analyses were performed using SPSS 19 for Windows. Simple descriptive statistical tests (mean and standard deviation) were used to describe the numerical values of the sample. The significance of the differences of mean ARR and EDSS scores before and after treatment were compared by using the paired-sample Student t test, whereas c2
57
tests were used for categorical variables (MRI activity); P value < 0.05 was regarded as significant.
Results
Of 35 patients with pediatric MS who had been treated with natalizumab, three received less than 12 natalizumab infusions and were excluded. Data from 32 relapsing patients with pediatric MS were analyzed. Baseline demographics and clinical characteristics of the studied cohort are outlined in Table. The mean age at onset and disease duration were 14.9 2.6 and 5.1 3.1 years, respectively. Most patients (66%; n ¼ 21) were escalated to natalizumab after having breakthrough disease while on first-line therapies (indication “a”). Natalizumab was initiated in 11 naïve pediatric patients who had a rapidly evolving disease (indication “b”). The mean number of natalizumab infusions was 34.5 18 in the studied cohort. No major adverse events were observed. With respect to the primary outcome measure, the ARR decreased significantly from 1.66 0.5 in the year before natalizumab treatment to 0.06 0.25 (P < 0.001) at the end of the observational period. The mean EDSS in our patients decreased from 3.3 1.29 (range 2-6) at initiation of natalizumab treatment to 2.2 1.0 (range 1-5) at last visit (P < 0.001). The proportion of patients with MRI activity was significantly reduced from 93.8% to 12.5% (P < 0.001) at the end of observational period. The proportion of patients with no evidence of combined clinical and radiologic activities was 84% (Figure). We have not seen any major adverse events, apart from two patients who experienced mild headaches following the infusions, which subsided with acetaminophen, and one patient who experienced mild infusion-related TABLE. Baseline Demographic and Clinical Characteristics of Pediatric MS Who Were Treated With Natalizumab for at Least 1 Year (n ¼ 32)
Variables Gender Female Male Mean age of onset (years) Mean age at start of natalizumab initiation (years) MS duration (years) Mean number of natalizumab infusions Anti-JCV antibody status Negative Positive Prior use of DMTs IFN-b 1a IM IFN-b 1a SC IFN-b 1b SC Others Abbreviations: DMT ¼ Disease-modifying therapy IFN ¼ Interferon IM ¼ Intramuscular JCV ¼ John Cunningham virus MS ¼ Multiple sclerosis N ¼ Number SC ¼ Subcutaneous
n (%), Mean S.D. (Range) 23 9 14.9 2.6 15.7 1.9
(66%) (34%) (8-17) (8-17)
5.1 3.1 (1-11) 34.5 18 (6-79)
29 3 21 6 5 9 1
(90.6) (9.4) (65.6) (18.8) (15.6) (28.1) (3.1)
58
R. Alroughani et al. / Pediatric Neurology 70 (2017) 56e60
FIGURE. Kaplan-Meier estimates for the percentage of patients free from clinical, magnetic resonance imaging (MRI), and combined (clinical þ MRI) disease activity after institution of natalizumab. MS, multiple sclerosis.
reaction, managed (diphenhydramine).
with
intravenous
antihistamine
Discussion
Natalizumab therapy in active relapsing pediatric MS patients was associated with significant improvement in both clinical and radiologic disease activity. This finding is consistent with previous observational studies conducted in other international centers.13-15 The largest published pediatric cohort treated with natalizumab came from the Italian registry, which included 101 patients with a mean natalizumab duration of 34.2 18.3 months, and was comparable with our study (35.2 18 infusions).16 The ARR in the Italian study was higher than that in our study (2.3 vs 1.66), which can be attributed to the younger mean age at the time of natalizumab initiation (14.7 vs 15.7 years). More importantly, the impact of treatment was similar in both cohorts throughout the observational period, as the ARR was reduced significantly to <0.1 and the EDSS score showed improvement by 30%-35%. Other retrospective studies had shown similar results in terms of efficacy and safety.7,14,15 An earlier study that extracted data from the same Italian registry included 55 patients who received natalizumab (median 26 infusions) and showed an improvement in the ARR from 2.4 to 0.01 and reduction in the mean EDSS score from 2.9 to 1.7 (P < 0.001), whereas the MRI activity was observed in 3.7%17.6% of patients depending on the follow-up duration.15 Kornek et al.13 reported comparable efficacy when 20 patients were followed up for a mean period of 20 months after natalizumab treatment. Arnal-Garcia et al.14 reported a series of nine patients who received a median of 17 natalizumab infusions (range 2 to 31). The ARR was reduced from three to zero and the EDSS was reduced from 3.0 to 1.0, and none of the patients had an increased MRI activity on follow-up. There is no uniform definition of treatment failure of first-line therapies; however, several factors were found to be predictive of inadequate treatment response or
suboptimal response to first-line therapies in adult cohorts.23-25 There is general agreement that breakthrough disease/suboptimal response can be defined as the persistence of relapses and/or one or more gadolinium-enhancing lesions. Although most treating physicians use a combination of both clinical and radiologic factors to assess the response to first-line therapy, severe disabling relapses remain a strong indication to escalate to more effective therapy.26,27 In our study, 21 of 32 patients had breakthrough disease, necessitating escalation to natalizumab. This is in line with a multicenter, longitudinal retrospective study that assessed 258 patients during a three-year period for the occurrence of refractory disease in a group of pediatric patients with MS treated with first-line DMTs. Yeh et al.12 observed that 55.8% (n ¼ 144) continued the firstline therapy, whereas 65 (25.2%), 29 (11.2%), and 20 (7.8%) received two, three, or four, or more sequential therapies, respectively. This raises the importance of clinical and radiologic vigilance of pediatric patients while on first-line therapies. More importantly, given the differences in assessing suboptimal or breakthrough disease among patients with MS, a unified consensus of such definition is needed, especially for pediatric cohorts who often have a high relapse rate and active MRI. JCV serostatus is an important factor in the treatment escalation decision because it helps stratification of the risk of progressive multifocal leukoencephalopathy in natalizumab-treated patients. In a large pediatric cohort including 256 patients, 51.6% of patients were found to be seropositive for JCV at the onset of the disease. The study included patients who were not treated with natalizumab. The annual conversion rate was 4.37% after monitoring the serostatus in 154 patients for a period ranging from six to 54 months. The prevalence of anti-JCV antibodies was similar between children under ten years of age and adolescents aged 14 to 17 years at the onset of MS.28 The frequency of patients positive for anti-JCV antibodies in our cohort was 7%, which is lower than other natalizumabtreated cohorts, ranging from 38% to 42%.13,15,16 This could be explained by several factors, including the differences in the number of patients included, duration of follow-ups, rates of JCV infection in our region, and more importantly the stratification methodology with respect to treatment. Natalizumab was well tolerated and no serious adverse events were observed in our study. This result was similar to that in other cohorts, which reported mild and transient events, such as headaches and fatigue.7,13-15 Ghezzi et al.15 reported eight mild hematologic events (primarily leukocytosis), and all the events were transient and resolved spontaneously. In another study, four of nine patients reported mild adverse events and natalizumab was discontinued in one patient because of a hypersensitivity reaction after the second infusion.14 High-titer neutralizing antibodies against natalizumab necessitating discontinuation were found in two patients in a different study.13 Cessation of natalizumab treatment may pose a risk of disease reactivation, especially when the washout period is longer than three months.29,30 Thus, the reasons for discontinuing natalizumab should be justified on the basis of either serious adverse events, such as anaphylactic reaction, or an increased risk of progressive multifocal leukoencephalopathy (PML) development with prior use of
R. Alroughani et al. / Pediatric Neurology 70 (2017) 56e60
immunosuppressants or longer duration (beyond two years) of treatment in JCV-seropositive patients. PML has not been documented in natalizumab-treated pediatric patients. Our study has several limitations. First, the data represent the management in a specialized center where a stratification approach and different second-line therapies, such as fingolimod and rituximab, are available. Initial treatment choices may have been influenced by individual practice patterns and perceived disease severity, thus potentially skewing the results. Second, the number of included patients is small but this is not unusual in most pediatric studies, especially in cohorts treated with second-line therapies. On the other hand, our study was one of the few prospective longitudinal studies that included patients with at least one year of natalizumab treatment. In addition, this is the first regional study conducted in natalizumab-treated pediatric cohorts. Collaborative regional work is needed to further extend the number and longitudinal follow-up of patients with pediatric MS in general and natalizumabtreated patients in particular to study the natural history, the effectiveness of treatment, and more importantly the seroprevalence of JCV in the region, which may be attributed to the exposure to infections, and socioeconomic status. Several practical points need to be addressed. The decision to institute natalizumab in pediatric patients should be discussed thoroughly with the patient and caregivers in a benefit versus risk approach. Despite its high-efficacy profile, treatment with natalizumab may pose a potential PML risk. The treating neurologist has to feel that the benefit/risk ratio is high enough to justify treatment with natalizumab in pediatric patients who have long “patient-years” because treatment for a long duration may increase the risk of PML. The decision to initiate natalizumab should be based on a correct indication. Natalizumab should be considered for either aggressive naïve patients who have rapidly evolving highly active MS or patients who continue to have breakthrough disease despite first-line therapies. It should be emphasized that, despite the positive data of our study, the presented results reflect only a short-term follow-up. Hence, a longitudinal follow-up along with clinical and radiologic vigilance is paramount to assess the sustainability of the efficacy and long-term safety profile. In summary, natalizumab was effective in halting the disease activity in our cohort of patients with pediatric MS who had rapidly evolving or breakthrough disease. Both clinical (ARR and EDSS progression) and radiologic activities were significantly reduced throughout the treatment period. Natalizumab was well tolerated without significant or serious adverse events. We thank the medical and administrative staff in Dasman Diabetes Institute, Amiri, and Ibn Sina hospitals for their comprehensive logistic support in helping to establish the national MS registry. Conflict of interest: The authors declare that there are no conflicts of interest in relation to this manuscript. Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
59
References 1. Simone IL, Carrara D, Tortorella C, et al. Course and prognosis in early-onset MS: comparison with adult-onset forms. Neurology. 2002;59:1922-1928. 2. Renoux C, Vukusic S, Mikaeloff Y, et al. Natural history of multiple sclerosis with childhood onset. N Engl J Med. 2007;356:2603-2613. 3. Alroughani R, Akhtar S, Ahmed SF, Behbehani R, Al-Abkal J, AlHashel J. Incidence and prevalence of pediatric onset multiple sclerosis in Kuwait: 1994-2013. J Neurol Sci. 2015;353:107-110. 4. Cardoso M, Olmo NR, Fragoso YD. Systematic Review of Cognitive Dysfunction in Pediatric and Juvenile Multiple Sclerosis. Pediatr Neurol. 2015;53:287-292. 5. Banwell B, Bar-Or A, Giovannoni G, Dale RC, Tardieu M. Therapies for multiple sclerosis: considerations in the pediatric patient. Nat Rev Neurol. 2011;7:109-122. 6. Narula S, Hopkins SE, Banwell B. Treatment of pediatric multiple sclerosis. Curr Treat Options Neurol. 2015;17:336. 7. Ghezzi A, Pozzilli C, Grimaldi LM, et al. Safety and efficacy of natalizumab in children with multiple sclerosis. Neurology. 2010;75: 912-917. 8. Chitnis T, Tardieu M, Amato MP, et al. International Pediatric MS Study Group Clinical Trials Summit: meeting report. Neurology. 2013;80:1161-1168. 9. Simone M, Chitnis T. Use of Disease-Modifying Therapies in Pediatric MS. Curr Treat Options Neurol. 2016;18:36. 10. Waldman A, Ghezzi A, Bar-Or A, Mikaeloff Y, Tardieu M, Banwell B. Multiple sclerosis in children: an update on clinical diagnosis, therapeutic strategies, and research. Lancet Neurol. 2014;13: 936-948. 11. Tenembaum SN. Treatment of multiple sclerosis and neuromyelitis optica in children and adolescents. Clin Neurol Neurosurg. 2013;115 Suppl 1:S21-S29. 12. Yeh EA, Waubant E, Krupp LB, et al. Multiple sclerosis therapies in pediatric patients with refractory multiple sclerosis. Arch Neurol. 2011;68:437-444. 13. Kornek B, Aboul-Enein F, Rostasy K, et al. Natalizumab therapy for highly active pediatric multiple sclerosis. JAMA Neurol. 2013;70: 469-475. 14. Arnal-Garcia C, Garcia-Montero MR, Malaga I, et al. Natalizumab use in pediatric patients with relapsing-remitting multiple sclerosis. Eur J Paediatr Neurol. 2013;17:50-54. 15. Ghezzi A, Pozzilli C, Grimaldi LM, et al. Natalizumab in pediatric multiple sclerosis: results of a cohort of 55 cases. Mult Scler. 2013; 19:1106-1112. 16. Ghezzi A, Moiola L, Pozzilli C, et al. Natalizumab in the pediatric MS population: results of the Italian registry. BMC Neurol. 2015;15:174. 17. Alroughani R, Ahmed SF, Behbahani R, et al. Increasing prevalence and incidence rates of multiple sclerosis in Kuwait. Mult Scler. 2014; 20:543-547. 18. Krupp LB, Banwell B, Tenembaum S, International Pediatric MSSG. Consensus definitions proposed for pediatric multiple sclerosis and related disorders. Neurology. 2007;68:S7-S12. 19. Krupp LB, Tardieu M, Amato MP, et al. International Pediatric Multiple Sclerosis Study Group criteria for pediatric multiple sclerosis and immune-mediated central nervous system demyelinating disorders: revisions to the 2007 definitions. Mult Scler. 2013;19: 1261-1267. 20. Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology. 1983;33: 1444-1452. 21. Lee P, Plavina T, Castro A, et al. A second-generation ELISA (STRATIFY JCV DxSelect) for detection of JC virus antibodies in human serum and plasma to support progressive multifocal leukoencephalopathy risk stratification. J Clin Virol. 2013;57:141-146. 22. Lublin FD, Baier M, Cutter G. Effect of relapses on development of residual deficit in multiple sclerosis. Neurology. 2003;61:1528-1532. 23. Cohen BA, Khan O, Jeffery DR, et al. Identifying and treating patients with suboptimal responses. Neurology. 2004;63:S33-S40. 24. Freedman MS, Cohen B, Dhib-Jalbut S, et al. Recognizing and treating suboptimally controlled multiple sclerosis: steps toward regaining command. Curr Med Res Opin. 2009;25:2459-2470. 25. Rio J, Nos C, Tintore M, et al. Defining the response to interferon-
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26. Freedman MS, Forrestal FG. Canadian treatment optimization recommendations (TOR) as a predictor of disease breakthrough in patients with multiple sclerosis treated with interferon beta-1a: analysis of the PRISMS study. Mult Scler. 2008;14:1234-1241. 27. Yamout B, Alroughani R, Al-Jumah M, et al. Consensus guidelines for the diagnosis and treatment of multiple sclerosis. Curr Med Res Opin. 2013;29:611-621.
28. Huppke P, Hummel H, Ellenberger D, et al. JC virus antibody status in a pediatric multiple sclerosis cohort: prevalence, conversion rate and influence on disease severity. Mult Scler. 2015;21: 382-387. 29. O’Connor PW, Goodman A, Kappos L, et al. Disease activity return during natalizumab treatment interruption in patients with multiple sclerosis. Neurology. 2011;76:1858-1865. 30. Killestein J, Vennegoor A, Strijbis EM, et al. Natalizumab drug holiday in multiple sclerosis: poorly tolerated. Ann Neurol. 2010;68: 392-395.
The excursion is the same when you go looking for your sorrow as when you go looking for your joy. Eudora Welty
Contents lists available at ScienceDirect
Pediatric Neurology journal homepage: www.elsevier.com/locate/pnu
Original Article
The Use of Natalizumab in Pediatric Patients With Active Relapsing Multiple Sclerosis: A Prospective Study Raed Alroughani MD, FRCPC a, b, *, Samar Farouk Ahmed MD c, d, Raed Behbehani MD, FRCSC b, e, Jasem Al-Hashel MD, FRCPC c, f a
Division of Neurology, Amiri Hospital, Sharq, Kuwait Neurology Clinic, Dasman Diabetes Institute, Dasman, Kuwait c Department of Neurology, Ibn Sina Hospital, Kuwait City, Kuwait d Department of Neurology and Psychiatry, Minia University, Minia, Egypt e Department of Ophthalmology, Al-Bahar Ophthalmology Center, Kuwait City, Kuwait f Department of Medicine, Kuwait University, Kuwait City, Kuwait b
abstract BACKGROUND: Pediatric multiple sclerosis (MS) has been increasingly recognized. In the absence of approved disease-modifying therapies (DMTs) for pediatric patients, clinicians resort to data extrapolated from clinical trials conducted in adults with MS. The objective of this article was to study the effectiveness and safety of natalizumab in with pediatric MS. METHODS: Patients with pediatric MS (aged less than 18 years) who had been treated with natalizumab were followed up prospectively as part of the national MS registry. Data of relapsing patients who had at least a one-year follow-up were analyzed. The primary outcome measure was the annual relapse rate after natalizumab treatment. Secondary outcomes measures included the mean change in disease progression measured by the expanded disability status scale and the proportion of patients with radiologic activity (gadolinium-enhancing or new T2 lesions) at the last follow-up visit. RESULTS: Thirty-two patients with pediatric MS had been treated with natalizumab for at least 12 months, of whom 72% were females. The mean age at onset and disease duration were 14.9 2.6 and 5.1 3.1 years, respectively. Most patients (n ¼ 21, 66%) had breakthrough disease on first-line disease-modifying therapies. The mean number of natalizumab infusions was 34.5 18. The annual relapse rate was significantly reduced (1.66 0.5 vs 0.06 0.25; P < 0.001), whereas the mean expanded disability status score improved (3.3 1.3 vs 2.2 1.0; P < 0.001) at the last follow-up visits. The proportion of patients with magnetic resonance imaging activity was significantly reduced (93.8% versus 12.5%; P < 0.001). No major adverse events were observed. CONCLUSION: In our pediatric MS cohort with aggressive or breakthrough disease, treatment with natalizumab was effective in reducing clinical and radiologic disease activity. Natalizumab has a similar clinical efficacy and safety profile as in adult MS. Keywords: multiple sclerosis, pediatric, natalizumab, EDSS, Kuwait
Pediatr Neurol 2017; 70: 56-60 Ó 2017 Elsevier Inc. All rights reserved. Introduction
As the criteria for the diagnosis of multiple sclerosis (MS) evolve, MS is being increasingly recognized in children and adolescents. The prevalence of pediatric-onset MS ranges
Article History: Received November 12, 2016; Accepted in final form January 18, 2017 * Communications should be addressed to: Dr. Alroughani; Division of Neurology; Department of Medicine; Amiri Hospital; Arabian Gulf Street; Sharq 13041, Kuwait. E-mail address: [email protected] 0887-8994/$ e see front matter Ó 2017 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pediatrneurol.2017.01.017
from 2.7% to 11.3% of the total MS populations.1-3 Children with MS predominantly present with more frequent relapses and a higher incidence of cognitive deficits than in adult MS cohorts,4 which poses unique challenges in the management, especially given the lack of specific diseasemodifying therapies (DMTs) proved by clinical trials for pediatric MS.5-7 The American and European regulatory agencies have implemented guidelines for the inclusion of pediatric investigation plans for new pharmacologic agents, with the aim of ensuring safe and appropriate access to promising new therapies for children and adolescents.8 Physicians are generally reluctant to use DMTs in children
R. Alroughani et al. / Pediatric Neurology 70 (2017) 56e60
during periods of growth and physical development.9 Firstline medications, namely, interferon beta and glatiramer acetate (GA), are the standard care for patients with pediatric MS.10,11 However, about 30% of treated patients were partial or nonresponders to first-line treatment and later on required a switch to a high-efficacy therapy.12 Several observational studies have shown that natalizumab consistently reduces disease activity in patients with pediatric MS.13-16 However, prospective data are limited, and there have been no regional published data about the use of natalizumab in pediatric cohorts. In our study, we aim to prospectively assess the effectiveness and safety of natalizumab in patients with pediatric MS in Kuwait. Methods We conducted a prospective study utilizing the national MS registry to evaluate patients with pediatric MS (less than 18 years) treated with natalizumab. The registry was established in 2010 in Kuwait and is composed of databases of all major hospitals.17 The diagnosis in patients with pediatric MS was established based on the consensus definition proposed by the International Pediatric Multiple Sclerosis Study Group (IPMSSG).18,19 Patients, who were identified from the registry, were followed up prospectively. As per the registry protocol, patients had at least two visits per year, excluding visits for suspected relapses. Neurological evaluation, including the assessment of expanded disability status scale (EDSS),20 was performed every 6 months. Anti-John Cunningham virus (JCV) antibody (Stratify JCV performed at Unilabs, Denmark)21 was performed every 6 months after the initiation of natalizumab. Magnetic resonance imaging (MRI) (1.5 T) brain and cervical spine with gadolinium were obtained at baseline, biannually for the first year and then annually. Relapses were defined as new or recurrent neurological symptoms not associated with fever or infection that lasted for at least 24 hours and were accompanied by new neurological signs found by the examining neurologist while disease progression was evident by an increase of at least 1.0 point on EDSS score.22 MRI activity was defined as an increase evident by either gadolinium-enhancing or new T2 lesions. According to the hospital protocol, the indications for the institution of natalizumab in patients with pediatric MS were (1) one relapse and evidence of new brain MRI activity or a severe relapse with incomplete recovery despite being on first-line therapies (interferon beta or glatiramer acetate) for at least one year or (2) demonstration of rapidly evolving MS, with at least two relapses in the last year and appearance of new brain MRI activity in naïve patients. Patients received the standard adult dose of natalizumab (300 mg intravenously every 4 weeks). To obtain the annual relapse rate (ARR), we included only relapsing patients with pediatric MS who had at least one-year follow-up after natalizumab institutions. Pretreatment ARR was defined as the number of relapses that occurred in the year before natalizumab initiation, whereas on-treatment ARR was calculated as the number of relapses per duration of therapy. Patients’ demographics (age, gender), clinical characteristics (course of the disease, disease duration, relapse rate, EDSS score), and treatment parameters (prior DMT use, number of natalizumab infusions, adverse events, anti-JCV results) were obtained. The primary outcome measure of the study was to determine the ARR before and after natalizumab treatment. Secondary outcomes measures included the change in disease progression measured by EDSS scores and the proportion of patients with radiologic activity (gadolinium-enhancing or new T2 lesions) at the end of the observational period. Patients with primary or secondary progressive MS were excluded. The study was approved by the institutional ethical committee. Assents and parental consents forms were obtained from all patients. All analyses were performed using SPSS 19 for Windows. Simple descriptive statistical tests (mean and standard deviation) were used to describe the numerical values of the sample. The significance of the differences of mean ARR and EDSS scores before and after treatment were compared by using the paired-sample Student t test, whereas c2
57
tests were used for categorical variables (MRI activity); P value < 0.05 was regarded as significant.
Results
Of 35 patients with pediatric MS who had been treated with natalizumab, three received less than 12 natalizumab infusions and were excluded. Data from 32 relapsing patients with pediatric MS were analyzed. Baseline demographics and clinical characteristics of the studied cohort are outlined in Table. The mean age at onset and disease duration were 14.9 2.6 and 5.1 3.1 years, respectively. Most patients (66%; n ¼ 21) were escalated to natalizumab after having breakthrough disease while on first-line therapies (indication “a”). Natalizumab was initiated in 11 naïve pediatric patients who had a rapidly evolving disease (indication “b”). The mean number of natalizumab infusions was 34.5 18 in the studied cohort. No major adverse events were observed. With respect to the primary outcome measure, the ARR decreased significantly from 1.66 0.5 in the year before natalizumab treatment to 0.06 0.25 (P < 0.001) at the end of the observational period. The mean EDSS in our patients decreased from 3.3 1.29 (range 2-6) at initiation of natalizumab treatment to 2.2 1.0 (range 1-5) at last visit (P < 0.001). The proportion of patients with MRI activity was significantly reduced from 93.8% to 12.5% (P < 0.001) at the end of observational period. The proportion of patients with no evidence of combined clinical and radiologic activities was 84% (Figure). We have not seen any major adverse events, apart from two patients who experienced mild headaches following the infusions, which subsided with acetaminophen, and one patient who experienced mild infusion-related TABLE. Baseline Demographic and Clinical Characteristics of Pediatric MS Who Were Treated With Natalizumab for at Least 1 Year (n ¼ 32)
Variables Gender Female Male Mean age of onset (years) Mean age at start of natalizumab initiation (years) MS duration (years) Mean number of natalizumab infusions Anti-JCV antibody status Negative Positive Prior use of DMTs IFN-b 1a IM IFN-b 1a SC IFN-b 1b SC Others Abbreviations: DMT ¼ Disease-modifying therapy IFN ¼ Interferon IM ¼ Intramuscular JCV ¼ John Cunningham virus MS ¼ Multiple sclerosis N ¼ Number SC ¼ Subcutaneous
n (%), Mean S.D. (Range) 23 9 14.9 2.6 15.7 1.9
(66%) (34%) (8-17) (8-17)
5.1 3.1 (1-11) 34.5 18 (6-79)
29 3 21 6 5 9 1
(90.6) (9.4) (65.6) (18.8) (15.6) (28.1) (3.1)
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R. Alroughani et al. / Pediatric Neurology 70 (2017) 56e60
FIGURE. Kaplan-Meier estimates for the percentage of patients free from clinical, magnetic resonance imaging (MRI), and combined (clinical þ MRI) disease activity after institution of natalizumab. MS, multiple sclerosis.
reaction, managed (diphenhydramine).
with
intravenous
antihistamine
Discussion
Natalizumab therapy in active relapsing pediatric MS patients was associated with significant improvement in both clinical and radiologic disease activity. This finding is consistent with previous observational studies conducted in other international centers.13-15 The largest published pediatric cohort treated with natalizumab came from the Italian registry, which included 101 patients with a mean natalizumab duration of 34.2 18.3 months, and was comparable with our study (35.2 18 infusions).16 The ARR in the Italian study was higher than that in our study (2.3 vs 1.66), which can be attributed to the younger mean age at the time of natalizumab initiation (14.7 vs 15.7 years). More importantly, the impact of treatment was similar in both cohorts throughout the observational period, as the ARR was reduced significantly to <0.1 and the EDSS score showed improvement by 30%-35%. Other retrospective studies had shown similar results in terms of efficacy and safety.7,14,15 An earlier study that extracted data from the same Italian registry included 55 patients who received natalizumab (median 26 infusions) and showed an improvement in the ARR from 2.4 to 0.01 and reduction in the mean EDSS score from 2.9 to 1.7 (P < 0.001), whereas the MRI activity was observed in 3.7%17.6% of patients depending on the follow-up duration.15 Kornek et al.13 reported comparable efficacy when 20 patients were followed up for a mean period of 20 months after natalizumab treatment. Arnal-Garcia et al.14 reported a series of nine patients who received a median of 17 natalizumab infusions (range 2 to 31). The ARR was reduced from three to zero and the EDSS was reduced from 3.0 to 1.0, and none of the patients had an increased MRI activity on follow-up. There is no uniform definition of treatment failure of first-line therapies; however, several factors were found to be predictive of inadequate treatment response or
suboptimal response to first-line therapies in adult cohorts.23-25 There is general agreement that breakthrough disease/suboptimal response can be defined as the persistence of relapses and/or one or more gadolinium-enhancing lesions. Although most treating physicians use a combination of both clinical and radiologic factors to assess the response to first-line therapy, severe disabling relapses remain a strong indication to escalate to more effective therapy.26,27 In our study, 21 of 32 patients had breakthrough disease, necessitating escalation to natalizumab. This is in line with a multicenter, longitudinal retrospective study that assessed 258 patients during a three-year period for the occurrence of refractory disease in a group of pediatric patients with MS treated with first-line DMTs. Yeh et al.12 observed that 55.8% (n ¼ 144) continued the firstline therapy, whereas 65 (25.2%), 29 (11.2%), and 20 (7.8%) received two, three, or four, or more sequential therapies, respectively. This raises the importance of clinical and radiologic vigilance of pediatric patients while on first-line therapies. More importantly, given the differences in assessing suboptimal or breakthrough disease among patients with MS, a unified consensus of such definition is needed, especially for pediatric cohorts who often have a high relapse rate and active MRI. JCV serostatus is an important factor in the treatment escalation decision because it helps stratification of the risk of progressive multifocal leukoencephalopathy in natalizumab-treated patients. In a large pediatric cohort including 256 patients, 51.6% of patients were found to be seropositive for JCV at the onset of the disease. The study included patients who were not treated with natalizumab. The annual conversion rate was 4.37% after monitoring the serostatus in 154 patients for a period ranging from six to 54 months. The prevalence of anti-JCV antibodies was similar between children under ten years of age and adolescents aged 14 to 17 years at the onset of MS.28 The frequency of patients positive for anti-JCV antibodies in our cohort was 7%, which is lower than other natalizumabtreated cohorts, ranging from 38% to 42%.13,15,16 This could be explained by several factors, including the differences in the number of patients included, duration of follow-ups, rates of JCV infection in our region, and more importantly the stratification methodology with respect to treatment. Natalizumab was well tolerated and no serious adverse events were observed in our study. This result was similar to that in other cohorts, which reported mild and transient events, such as headaches and fatigue.7,13-15 Ghezzi et al.15 reported eight mild hematologic events (primarily leukocytosis), and all the events were transient and resolved spontaneously. In another study, four of nine patients reported mild adverse events and natalizumab was discontinued in one patient because of a hypersensitivity reaction after the second infusion.14 High-titer neutralizing antibodies against natalizumab necessitating discontinuation were found in two patients in a different study.13 Cessation of natalizumab treatment may pose a risk of disease reactivation, especially when the washout period is longer than three months.29,30 Thus, the reasons for discontinuing natalizumab should be justified on the basis of either serious adverse events, such as anaphylactic reaction, or an increased risk of progressive multifocal leukoencephalopathy (PML) development with prior use of
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immunosuppressants or longer duration (beyond two years) of treatment in JCV-seropositive patients. PML has not been documented in natalizumab-treated pediatric patients. Our study has several limitations. First, the data represent the management in a specialized center where a stratification approach and different second-line therapies, such as fingolimod and rituximab, are available. Initial treatment choices may have been influenced by individual practice patterns and perceived disease severity, thus potentially skewing the results. Second, the number of included patients is small but this is not unusual in most pediatric studies, especially in cohorts treated with second-line therapies. On the other hand, our study was one of the few prospective longitudinal studies that included patients with at least one year of natalizumab treatment. In addition, this is the first regional study conducted in natalizumab-treated pediatric cohorts. Collaborative regional work is needed to further extend the number and longitudinal follow-up of patients with pediatric MS in general and natalizumabtreated patients in particular to study the natural history, the effectiveness of treatment, and more importantly the seroprevalence of JCV in the region, which may be attributed to the exposure to infections, and socioeconomic status. Several practical points need to be addressed. The decision to institute natalizumab in pediatric patients should be discussed thoroughly with the patient and caregivers in a benefit versus risk approach. Despite its high-efficacy profile, treatment with natalizumab may pose a potential PML risk. The treating neurologist has to feel that the benefit/risk ratio is high enough to justify treatment with natalizumab in pediatric patients who have long “patient-years” because treatment for a long duration may increase the risk of PML. The decision to initiate natalizumab should be based on a correct indication. Natalizumab should be considered for either aggressive naïve patients who have rapidly evolving highly active MS or patients who continue to have breakthrough disease despite first-line therapies. It should be emphasized that, despite the positive data of our study, the presented results reflect only a short-term follow-up. Hence, a longitudinal follow-up along with clinical and radiologic vigilance is paramount to assess the sustainability of the efficacy and long-term safety profile. In summary, natalizumab was effective in halting the disease activity in our cohort of patients with pediatric MS who had rapidly evolving or breakthrough disease. Both clinical (ARR and EDSS progression) and radiologic activities were significantly reduced throughout the treatment period. Natalizumab was well tolerated without significant or serious adverse events. We thank the medical and administrative staff in Dasman Diabetes Institute, Amiri, and Ibn Sina hospitals for their comprehensive logistic support in helping to establish the national MS registry. Conflict of interest: The authors declare that there are no conflicts of interest in relation to this manuscript. Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
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