Phase II trial of natalizumab for the treatment of anti-Hu associated paraneoplastic neurological syndromes

Anna E.M. Bastiaansen; Adriaan H.C. De Jongste; Marienke A.A.M. De Bruijn; Yvette S. Crijnen; Marco W.J. Schreurs; Marcel M. Verbeek; Daphne W. Dumoulin; Maarten J. Titulaer; Peter A.E. Sillevis Smitt

doi:10.1093/noajnl/vdab145

Phase II trial of natalizumab for the treatment of anti-Hu associated paraneoplastic neurological syndromes

Anna E.M. Bastiaansen, Adriaan H.C. De Jongste, Marienke A.A.M. De Bruijn, Yvette S. Crijnen, Marco W.J. Schreurs, Marcel M. Verbeek, Daphne W. Dumoulin, Maarten J. Titulaer, Peter A.E. Sillevis Smitt^*

^*Corresponding author for this work

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Abstract

Background: Paraneoplastic neurological syndromes with anti-Hu antibodies (Hu-PNS) have a very poor prognosis: More than half of the patients become bedridden and median survival is less than 12 months. Several lines of evidence suggest a pathogenic T cell-mediated immune response. Therefore, we conducted a prospective open-label phase II trial with natalizumab. Methods: Twenty Hu-PNS patients with progressive disease were treated with a maximum of three monthly natalizumab cycles (300 mg). The primary outcome measure was functional improvement, this was defined as at least one point decrease in modified Rankin Scale (mRS) score at the last treatment visit. In addition, treatment response was assessed wherein a mRS score ≤3 after treatment was defined as treatment responsive. Results: The median age at onset was 67.8 years (SD 8.4) with a female predominance (n = 17, 85%). The median time from symptom onset to Hu-PNS diagnosis was 5 months (IQR 2-11). Most patients had subacute sensory neuronopathy (n = 15, 75%), with a median mRS of 4 at baseline. Thirteen patients had a tumor, all small cell lung cancer. After natalizumab treatment, two patients (10%) showed functional improvement. Of the remaining patients, 60% had a stable functional outcome, while 30% showed further deterioration. Treatment response was classified as positive in nine patients (45%). Conclusions: Natalizumab may ameliorate the disease course in Hu-PNS, but no superior effects above other reported immunosuppressive and immunomodulatory were observed. More effective treatment modalities are highly needed. Trial registration: Https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-000675-13/NL

Original language	English
Article number	vdab145
Journal	Neuro-Oncology Advances
Volume	3
Issue number	1
DOIs	https://doi.org/10.1093/noajnl/vdab145
Publication status	Published - 1 Jan 2021

Bibliographical note

Funding
Erasmus MC University Hospital (Rotterdam, Netherlands) was the sponsor of this investigator initiated trial. Biogen Netherlands B.V. (Badhoevedorp, Netherlands) provided study medication and limited support to conduct the study. Biogen was not involved in study design, analysis or writing of the manuscript.

Publisher Copyright: © 2021 The Author(s). Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.

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Bastiaansen, A. E. M., De Jongste, A. H. C., De Bruijn, M. A. A. M., Crijnen, Y. S., Schreurs, M. W. J., Verbeek, M. M., Dumoulin, D. W., Titulaer, M. J., & Sillevis Smitt, P. A. E. (2021). Phase II trial of natalizumab for the treatment of anti-Hu associated paraneoplastic neurological syndromes. Neuro-Oncology Advances, 3(1), Article vdab145. https://doi.org/10.1093/noajnl/vdab145

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title = "Phase II trial of natalizumab for the treatment of anti-Hu associated paraneoplastic neurological syndromes",

abstract = "Background: Paraneoplastic neurological syndromes with anti-Hu antibodies (Hu-PNS) have a very poor prognosis: More than half of the patients become bedridden and median survival is less than 12 months. Several lines of evidence suggest a pathogenic T cell-mediated immune response. Therefore, we conducted a prospective open-label phase II trial with natalizumab. Methods: Twenty Hu-PNS patients with progressive disease were treated with a maximum of three monthly natalizumab cycles (300 mg). The primary outcome measure was functional improvement, this was defined as at least one point decrease in modified Rankin Scale (mRS) score at the last treatment visit. In addition, treatment response was assessed wherein a mRS score ≤3 after treatment was defined as treatment responsive. Results: The median age at onset was 67.8 years (SD 8.4) with a female predominance (n = 17, 85%). The median time from symptom onset to Hu-PNS diagnosis was 5 months (IQR 2-11). Most patients had subacute sensory neuronopathy (n = 15, 75%), with a median mRS of 4 at baseline. Thirteen patients had a tumor, all small cell lung cancer. After natalizumab treatment, two patients (10%) showed functional improvement. Of the remaining patients, 60% had a stable functional outcome, while 30% showed further deterioration. Treatment response was classified as positive in nine patients (45%). Conclusions: Natalizumab may ameliorate the disease course in Hu-PNS, but no superior effects above other reported immunosuppressive and immunomodulatory were observed. More effective treatment modalities are highly needed. Trial registration: Https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-000675-13/NL ",

author = "Bastiaansen, {Anna E.M.} and {De Jongste}, {Adriaan H.C.} and {De Bruijn}, {Marienke A.A.M.} and Crijnen, {Yvette S.} and Schreurs, {Marco W.J.} and Verbeek, {Marcel M.} and Dumoulin, {Daphne W.} and Titulaer, {Maarten J.} and {Sillevis Smitt}, {Peter A.E.}",

note = "Funding Erasmus MC University Hospital (Rotterdam, Netherlands) was the sponsor of this investigator initiated trial. Biogen Netherlands B.V. (Badhoevedorp, Netherlands) provided study medication and limited support to conduct the study. Biogen was not involved in study design, analysis or writing of the manuscript. Publisher Copyright: {\textcopyright} 2021 The Author(s). Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.",

year = "2021",

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doi = "10.1093/noajnl/vdab145",

language = "English",

volume = "3",

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TY - JOUR

T1 - Phase II trial of natalizumab for the treatment of anti-Hu associated paraneoplastic neurological syndromes

AU - Bastiaansen, Anna E.M.

AU - De Jongste, Adriaan H.C.

AU - De Bruijn, Marienke A.A.M.

AU - Crijnen, Yvette S.

AU - Schreurs, Marco W.J.

AU - Verbeek, Marcel M.

AU - Dumoulin, Daphne W.

AU - Titulaer, Maarten J.

AU - Sillevis Smitt, Peter A.E.

N1 - Funding Erasmus MC University Hospital (Rotterdam, Netherlands) was the sponsor of this investigator initiated trial. Biogen Netherlands B.V. (Badhoevedorp, Netherlands) provided study medication and limited support to conduct the study. Biogen was not involved in study design, analysis or writing of the manuscript. Publisher Copyright: © 2021 The Author(s). Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.

PY - 2021/1/1

Y1 - 2021/1/1

N2 - Background: Paraneoplastic neurological syndromes with anti-Hu antibodies (Hu-PNS) have a very poor prognosis: More than half of the patients become bedridden and median survival is less than 12 months. Several lines of evidence suggest a pathogenic T cell-mediated immune response. Therefore, we conducted a prospective open-label phase II trial with natalizumab. Methods: Twenty Hu-PNS patients with progressive disease were treated with a maximum of three monthly natalizumab cycles (300 mg). The primary outcome measure was functional improvement, this was defined as at least one point decrease in modified Rankin Scale (mRS) score at the last treatment visit. In addition, treatment response was assessed wherein a mRS score ≤3 after treatment was defined as treatment responsive. Results: The median age at onset was 67.8 years (SD 8.4) with a female predominance (n = 17, 85%). The median time from symptom onset to Hu-PNS diagnosis was 5 months (IQR 2-11). Most patients had subacute sensory neuronopathy (n = 15, 75%), with a median mRS of 4 at baseline. Thirteen patients had a tumor, all small cell lung cancer. After natalizumab treatment, two patients (10%) showed functional improvement. Of the remaining patients, 60% had a stable functional outcome, while 30% showed further deterioration. Treatment response was classified as positive in nine patients (45%). Conclusions: Natalizumab may ameliorate the disease course in Hu-PNS, but no superior effects above other reported immunosuppressive and immunomodulatory were observed. More effective treatment modalities are highly needed. Trial registration: Https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-000675-13/NL

AB - Background: Paraneoplastic neurological syndromes with anti-Hu antibodies (Hu-PNS) have a very poor prognosis: More than half of the patients become bedridden and median survival is less than 12 months. Several lines of evidence suggest a pathogenic T cell-mediated immune response. Therefore, we conducted a prospective open-label phase II trial with natalizumab. Methods: Twenty Hu-PNS patients with progressive disease were treated with a maximum of three monthly natalizumab cycles (300 mg). The primary outcome measure was functional improvement, this was defined as at least one point decrease in modified Rankin Scale (mRS) score at the last treatment visit. In addition, treatment response was assessed wherein a mRS score ≤3 after treatment was defined as treatment responsive. Results: The median age at onset was 67.8 years (SD 8.4) with a female predominance (n = 17, 85%). The median time from symptom onset to Hu-PNS diagnosis was 5 months (IQR 2-11). Most patients had subacute sensory neuronopathy (n = 15, 75%), with a median mRS of 4 at baseline. Thirteen patients had a tumor, all small cell lung cancer. After natalizumab treatment, two patients (10%) showed functional improvement. Of the remaining patients, 60% had a stable functional outcome, while 30% showed further deterioration. Treatment response was classified as positive in nine patients (45%). Conclusions: Natalizumab may ameliorate the disease course in Hu-PNS, but no superior effects above other reported immunosuppressive and immunomodulatory were observed. More effective treatment modalities are highly needed. Trial registration: Https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-000675-13/NL

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DO - 10.1093/noajnl/vdab145

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AN - SCOPUS:85126668124

SN - 2632-2498

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JO - Neuro-Oncology Advances

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Phase II trial of natalizumab for the treatment of anti-Hu associated paraneoplastic neurological syndromes

Abstract

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