E Jabbour

EL Bollen

G Antonini

G. W. van Imhoff

GD Shah

H Schulz

J. E. C. Bromberg

J. K. Doorduijn

J. W. Baars

JL Rubenstein

K Ostermann

L Recht

M Pfreundschuh

M. J. van den Bent

R. Enting

RW Nelson

S Kim

PubMed

Springer - Publisher Connector

Acute painful lumbosacral paresthesia after intrathecal rituximab

Bromberg, Jacoline

Doorduijn, Jeanette

Baars, JW

van Imhoff, GW

Enting, R

van den Bent, Martin

EUR Research Repository

LETTER TO THE EDITORSAcute painful lumbosacral paresthesia after intrathecal rituximabJ. E. C. Bromberg • J. K. Doorduijn •J. W. Baars • G. W. van Imhoff • R. Enting •M. J. van den BentReceived: 18 May 2011 / Revised: 11 July 2011 / Accepted: 14 July 2011 The Author(s) 2011. This article is published with open access at Springerlink.comDear Sirs,Central nervous system (CNS) recurrence of systemicaggressive B-cell lymphoma carries poor prognosis withmedian survival of 2–4 months and less than 10% 1-yearsurvival after treatment with standard-dose chemotherapyand/or radiotherapy [1, 2]. Aiming to improve on thesetreatment results, we designed a phase II study to evaluatean intensive protocol including myeloablative treatmentin CNS recurrence of systemic B-cell non-Hodgkin’slymphoma (NHL). This study (HOVON 80, NetherlandsTrial Register, no. 1757) is an ongoing phase II study onthe feasibility and efficacy of R-DHAP ? HD-MTX(dexamethasone 40 mg days 1–4, cisplatin 100 mg/m2day 1, cytarabine 2 9 2 g/m2 day 2, rituximab 375 mg/m2day 5, methotrexate 3 g/m2 day 15), followed by autolo-gous stem cell transplantation in patients with recurrentaggressive B-cell lymphoma with CNS localization. Rit-uximab is a chimeric anti-CD-20 antibody which has rad-ically changed prospects for patients with systemic B-celllymphoma [3, 4]. However, after intravenous administra-tion it does not penetrate the blood–brain barrier well, andit has been postulated that intrathecal administration mayimprove results of treatment of leptomeningeal lymphoma[5, 6]. We therefore incorporated intrathecal rituximab intothe protocol.The patients we report herein were all treated accordingto protocol with systemic R-DHAP-MTX as describedabove, for three 28-day cycles. Additionally, intrathecalrituximab, containing no preservatives and without con-current other agents, was administered via lumbar punctureafter premedication with paracetamol 1,000 mg on days -1,4, 8, 11, and 21 in the first cycle, four times in the secondcycle, and three times in the third cycle. The first adminis-tration in each patient consisted of 10 mg rituximab; insubsequent administrations the dose was increased to 25 mgprovided no toxicity had occurred. This dosing was based onprior publications [7, 8]. None of our patients experiencedside-effects after the first intrathecal administration of rit-uximab, except for a minor sensation of pressure in thesacral area in one patient. However, after the first adminis-tration of 25 mg rituximab, 2 of the first 12 treated patientsreported extremely painful paresthesia in the buttocks,legs, and feet immediately after administration, lasting30–60 min. There were no neurologic deficits at the time,nor on follow-up, but blood pressure increased temporarily.After these adverse events the protocol was amended todilution of rituximab in 0.9% saline to 5 mg/ml and addi-tional premedication with antihistamines. The subsequentlytreated, 13th, patient suffered identical symptoms despiteJ. E. C. Bromberg (&)  M. J. van den BentDepartment of Neuro-Oncology, Daniel den Hoed CancerCenter, Erasmus MC, University Medical Center Rotterdam,PO Box 5201, 3008 AE Rotterdam, The Netherlandse-mail: j.bromberg@erasmusmc.nlJ. K. DoorduijnDepartment of Hematology, Daniel den Hoed Cancer Center,Erasmus MC, University Medical Center Rotterdam,PO Box 5201, 3008 AE Rotterdam, The NetherlandsJ. W. BaarsDepartment of Medical Oncology, The Netherlands CancerInstitute, Antoni van Leeuwenhoek Hospital, Amsterdam,The NetherlandsG. W. van ImhoffDepartment of Hematology, University Medical CenterGroningen, Groningen, The NetherlandsR. EntingDepartment of Neuro-Oncology, University Medical CenterGroningen, Groningen, The Netherlands123J NeurolDOI 10.1007/s00415-011-6190-ythe adapted protocol. Clinical characteristics of the patientsare given in Table 1. The pain resolved completely in allpatients within a few hours. However, they all refused fur-ther treatment with intrathecal rituximab, and furtherintrathecal therapy was changed to methotrexate, which wasadministered uneventfully. The rituximab dose in the pro-tocol was subsequently reduced to 10 mg per administra-tion, diluted as described above and combined with 4 mgintrathecal dexamethasone. Twelve additional patients werethus treated, and no further incidents of painful radiculop-athy have occurred.In a phase I study investigating intraventricular/intra-thecal rituximab, the maximum tolerated dose was found tobe 25 mg; at 50 mg, grade III hypertension was the dose-limiting toxicity and one of two patients thus treatedadditionally experienced transient diplopia, nausea, andvomiting [7]. A painful radiculopathy was described afterintrathecal administration of 25 mg via lumbar puncture inone patient; the majority, however, had been treatedintraventricularly. Antonini described one patient treatedwith 40 mg intrathecal rituximab in whom transient head-ache, cramps, back pain, and leg weakness occurred [9].Schulz described six patients treated with 10–40 mgundiluted intra-CSF rituximab for CNS lymphoma, two ofthem via lumbar puncture; one of them suffered transientsevere back pain and paraparesis during the first intrathecaladministration of rituximab (25 mg) [8]. In this patient ahigh tumor load was present in the CSF and the authorsassumed a tumor lysis syndrome. However, in none of ourpatients was high CSF cellularity present, making tumorlysis an unlikely explanation.Both acute and subacute toxicities have been observedafter intrathecal treatment with chemotherapeutic agents[10–13]. For methotrexate as well as (sustained-release)cytarabine an acute, reversible aseptic meningitis withfever, headache, backache, nausea, and vomiting has beendescribed. Symptoms begin several hours after adminis-tration and can be prevented with oral or intrathecaldexamethasone in the majority of patients [10, 11]. Aninflammatory reaction is a likely cause for the asepticmeningitis after methotrexate and cytarabine, but inrituximab the occurrence during or immediately afteradministration make an inflammatory reaction unlikely.We postulate a direct interaction with spinal nervousstructures (radices?) as the most likely explanation for thisadverse reaction to rituximab.This very painful, though completely transient, adverseeffect of intrathecal rituximab precludes intrathecaladministration of higher doses via lumbar puncture. It hasnot been described after intraventricular administration,despite the fact that considerably more patients have beentreated with rituximab via this route.Acknowledgments The rituximab used in the study was providedfree of charge by Roche. Financial support for the HOVON 80 studywas obtained from the Dutch Cancer Society, project no. 2006-11.J.K.D. reports receiving travel grants from Roche.Conflicts of interest Dr. Bromberg reports no conflicts of interestother than the above. Dr. Baars reports no conflicts of interest. Dr.vanImhoff reports no conflicts of interest. Dr.Enting reports no conflictsof interest. Dr. van den Bent has performed consultancy services forRoche.Open Access This article is distributed under the terms of theCreative Commons Attribution Noncommercial License which per-mits any noncommercial use, distribution, and reproduction in anymedium, provided the original author(s) and source are credited.References1. Bollen EL, Brouwer RE, Hamers S, Hermans J, Kluin M, San-katsing SU, Tjak RV, Charvat MV, Kluin-Nelemans JC (1997)Central nervous system relapse in non-Hodgkin lymphoma. Asingle-center study of 532 patients. Arch Neurol 54:854–8592. Recht L, Straus DJ, Cirrincione C, Thaler HT, Posner JB (1988)Central nervous system metastases from non-Hodgkin’s lym-phoma: treatment and prophylaxis. Am J Med 84:425–4353. Pfreundschuh M, Schubert J, Ziepert M, Schmits R, Mohren M,Lengfelder E, Reiser M, Nickenig C, Clemens M, Peter N, Bo-kemeyer C, Eimermacher H, Ho A, Hoffmann M, MertelsmannR, Trumper L, Balleisen L, Liersch R, Metzner B, Hartmann F,Glass B, Poeschel V, Schmitz N, Ruebe C, Feller AC, Loeffler M(2008) Six versus eight cycles of bi-weekly CHOP-14 with orwithout rituximab in elderly patients with aggressive CD20 ? B-cell lymphomas: a randomised controlled trial (RICOVER-60).Lancet Oncol 9:105–116Table 1 Clinical characteristics of affected patientsPatient 1 2 3Age (years) 49 48 58CSF cellularity before i.t. rituximab 16 9 106/l 0.7 9 106/l 8.7 9 106/lCSF lymphoma by cytology and/or flow cytometry ? – Not available/unevaluableCSF cellularity after i.t. rituximab (4 days) 5 9 106/l 1.7 9 106/l Not doneBest result of treatment CRu CR CRuSurvival after AE (months) 8 [26 5.5CRu Complete response unconfirmed, CR complete response, CSF cerebrospinal fluid, AE adverse eventJ Neurol1234. Pfreundschuh M, Trumper L, Osterborg A, Pettengell R, TrnenyM, Imrie K, Ma D, Gill D, Walewski J, Zinzani PL, Stahel R,Kvaloy S, Shpilberg O, Jaeger U, Hansen M, Lehtinen T, Lopez-Guillermo A, Corrado C, Scheliga A, Milpied N, Mendila M,Rashford M, Kuhnt E, Loeffler M (2006) CHOP-like chemo-therapy plus rituximab versus CHOP-like chemotherapy alonein young patients with good-prognosis diffuse large-B-cell lym-phoma: a randomised controlled trial by the MabThera Interna-tional Trial (MInT) Group. Lancet Oncol 7:379–3915. Rubenstein JL, Combs D, Rosenberg J, Levy A, McDermottM, Damon L, Ignoffo R, Aldape K, Shen A, Lee D, Grillo-Lopez A, Shuman MA (2003) Rituximab therapy for CNSlymphomas: targeting the leptomeningeal compartment. Blood101:466–4686. Shah GD, Yahalom J, Correa DD, Lai RK, Raizer JJ, Schiff D,LaRocca R, Grant B, Deangelis LM, Abrey LE (2007) Combinedimmunochemotherapy with reduced whole-brain radiotherapyfor newly diagnosed primary CNS lymphoma. J Clin Oncol25:4730–47357. Rubenstein JL, Fridlyand J, Abrey L, Shen A, Karch J, Wang E,Issa S, Damon L, Prados M, McDermott M, O’Brien J, Haqq C,Shuman M (2007) Phase I study of intraventricular administrationof rituximab in patients with recurrent CNS and intraocularlymphoma. J Clin Oncol 25:1350–13568. Schulz H, Pels H, Schmidt-Wolf I, Zeelen U, Germing U, EngertA (2004) Intraventricular treatment of relapsed central nervoussystem lymphoma with the anti-CD20 antibody rituximab.Haematologica 89:753–7549. Antonini G, Cox MC, Montefusco E, Ferrari A, Conte E, MorinoS, Latino P, Trasimeni G, Monarca B (2007) Intrathecal anti-CD20 antibody: an effective and safe treatment for leptomenin-geal lymphoma. J Neurooncol 81:197–19910. Nelson RW, Frank JT (1981) Intrathecal methotrexate-inducedneurotoxicities. Am J Hosp Pharm 38:65–6811. Kim S, Chatelut E, Kim JC, Howell SB, Cates C, Kormanik PA,Chamberlain MC (1993) Extended CSF cytarabine exposurefollowing intrathecal administration of DTC 101. J Clin Oncol11:2186–219312. Jabbour E, O’Brien S, Kantarjian H, Garcia-Manero G, FerrajoliA, Ravandi F, Cabanillas M, Thomas DA (2007) Neurologiccomplications associated with intrathecal liposomal cytarabinegiven prophylactically in combination with high-dose metho-trexate and cytarabine to patients with acute lymphocytic leuke-mia. Blood 109:3214–321813. Ostermann K, Pels H, Kowoll A, Kuhnhenn J, Schlegel U (2011)Neurologic complications after intrathecal liposomal cytarabinein combination with systemic polychemotherapy in primary CNSlymphoma. J Neurooncol 103:635–640J Neurol123

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EUR Research Information PortalAcute painful lumbosacral paresthesia after intrathecal rituximabPublished in:Journal of NeurologyPublication status and date:Published: 01/01/2012DOI (link to publisher):10.1007/s00415-011-6190-yDocument VersionPublisher's PDF, also known as Version of recordCitation for the published version (APA):Bromberg, J., Doorduijn, J., Baars, JW., van Imhoff, GW., Enting, R., & van den Bent, M. (2012). Acute painful lumbosacralparesthesia after intrathecal rituximab. Journal of Neurology, 259(3), 559-561. https://doi.org/10.1007/s00415-011-6190-yLink to publication on the EUR Research Information PortalTerms and Conditions of UseExcept as permitted by the applicable copyright law, you may not reproduce or make this material available to any third partywithout the prior written permission from the copyright holder(s). Copyright law allows the following uses of this materialwithout prior permission:            • you may download, save and print a copy of this material for your personal use only;            • you may share the EUR portal link to this material.In case the material is published with an open access license (e.g. a Creative Commons (CC) license), other uses may beallowed. Please check the terms and conditions of the specific license.Take-down policyIf you believe that this material infringes your copyright and/or any other intellectual property rights, you may request itsremoval by contacting us at the following email address: openaccess.library@eur.nl. Please provide us with all the relevantinformation, including the reasons why you believe any of your rights have been infringed. In case of a legitimate complaint,we will make the material inaccessible and/or remove it from the website.LETTER TO THE EDITORSAcute painful lumbosacral paresthesia after intrathecal rituximabJ. E. C. Bromberg • J. K. Doorduijn •J. W. Baars • G. W. van Imhoff • R. Enting •M. J. van den BentReceived: 18 May 2011 / Revised: 11 July 2011 / Accepted: 14 July 2011 The Author(s) 2011. This article is published with open access at Springerlink.comDear Sirs,Central nervous system (CNS) recurrence of systemicaggressive B-cell lymphoma carries poor prognosis withmedian survival of 2–4 months and less than 10% 1-yearsurvival after treatment with standard-dose chemotherapyand/or radiotherapy [1, 2]. Aiming to improve on thesetreatment results, we designed a phase II study to evaluatean intensive protocol including myeloablative treatmentin CNS recurrence of systemic B-cell non-Hodgkin’slymphoma (NHL). This study (HOVON 80, NetherlandsTrial Register, no. 1757) is an ongoing phase II study onthe feasibility and efficacy of R-DHAP ? HD-MTX(dexamethasone 40 mg days 1–4, cisplatin 100 mg/m2day 1, cytarabine 2 9 2 g/m2 day 2, rituximab 375 mg/m2day 5, methotrexate 3 g/m2 day 15), followed by autolo-gous stem cell transplantation in patients with recurrentaggressive B-cell lymphoma with CNS localization. Rit-uximab is a chimeric anti-CD-20 antibody which has rad-ically changed prospects for patients with systemic B-celllymphoma [3, 4]. However, after intravenous administra-tion it does not penetrate the blood–brain barrier well, andit has been postulated that intrathecal administration mayimprove results of treatment of leptomeningeal lymphoma[5, 6]. We therefore incorporated intrathecal rituximab intothe protocol.The patients we report herein were all treated accordingto protocol with systemic R-DHAP-MTX as describedabove, for three 28-day cycles. Additionally, intrathecalrituximab, containing no preservatives and without con-current other agents, was administered via lumbar punctureafter premedication with paracetamol 1,000 mg on days -1,4, 8, 11, and 21 in the first cycle, four times in the secondcycle, and three times in the third cycle. The first adminis-tration in each patient consisted of 10 mg rituximab; insubsequent administrations the dose was increased to 25 mgprovided no toxicity had occurred. This dosing was based onprior publications [7, 8]. None of our patients experiencedside-effects after the first intrathecal administration of rit-uximab, except for a minor sensation of pressure in thesacral area in one patient. However, after the first adminis-tration of 25 mg rituximab, 2 of the first 12 treated patientsreported extremely painful paresthesia in the buttocks,legs, and feet immediately after administration, lasting30–60 min. There were no neurologic deficits at the time,nor on follow-up, but blood pressure increased temporarily.After these adverse events the protocol was amended todilution of rituximab in 0.9% saline to 5 mg/ml and addi-tional premedication with antihistamines. The subsequentlytreated, 13th, patient suffered identical symptoms despiteJ. E. C. Bromberg (&)  M. J. van den BentDepartment of Neuro-Oncology, Daniel den Hoed CancerCenter, Erasmus MC, University Medical Center Rotterdam,PO Box 5201, 3008 AE Rotterdam, The Netherlandse-mail: j.bromberg@erasmusmc.nlJ. K. DoorduijnDepartment of Hematology, Daniel den Hoed Cancer Center,Erasmus MC, University Medical Center Rotterdam,PO Box 5201, 3008 AE Rotterdam, The NetherlandsJ. W. BaarsDepartment of Medical Oncology, The Netherlands CancerInstitute, Antoni van Leeuwenhoek Hospital, Amsterdam,The NetherlandsG. W. van ImhoffDepartment of Hematology, University Medical CenterGroningen, Groningen, The NetherlandsR. EntingDepartment of Neuro-Oncology, University Medical CenterGroningen, Groningen, The Netherlands123J NeurolDOI 10.1007/s00415-011-6190-ythe adapted protocol. Clinical characteristics of the patientsare given in Table 1. The pain resolved completely in allpatients within a few hours. However, they all refused fur-ther treatment with intrathecal rituximab, and furtherintrathecal therapy was changed to methotrexate, which wasadministered uneventfully. The rituximab dose in the pro-tocol was subsequently reduced to 10 mg per administra-tion, diluted as described above and combined with 4 mgintrathecal dexamethasone. Twelve additional patients werethus treated, and no further incidents of painful radiculop-athy have occurred.In a phase I study investigating intraventricular/intra-thecal rituximab, the maximum tolerated dose was found tobe 25 mg; at 50 mg, grade III hypertension was the dose-limiting toxicity and one of two patients thus treatedadditionally experienced transient diplopia, nausea, andvomiting [7]. A painful radiculopathy was described afterintrathecal administration of 25 mg via lumbar puncture inone patient; the majority, however, had been treatedintraventricularly. Antonini described one patient treatedwith 40 mg intrathecal rituximab in whom transient head-ache, cramps, back pain, and leg weakness occurred [9].Schulz described six patients treated with 10–40 mgundiluted intra-CSF rituximab for CNS lymphoma, two ofthem via lumbar puncture; one of them suffered transientsevere back pain and paraparesis during the first intrathecaladministration of rituximab (25 mg) [8]. In this patient ahigh tumor load was present in the CSF and the authorsassumed a tumor lysis syndrome. However, in none of ourpatients was high CSF cellularity present, making tumorlysis an unlikely explanation.Both acute and subacute toxicities have been observedafter intrathecal treatment with chemotherapeutic agents[10–13]. For methotrexate as well as (sustained-release)cytarabine an acute, reversible aseptic meningitis withfever, headache, backache, nausea, and vomiting has beendescribed. Symptoms begin several hours after adminis-tration and can be prevented with oral or intrathecaldexamethasone in the majority of patients [10, 11]. Aninflammatory reaction is a likely cause for the asepticmeningitis after methotrexate and cytarabine, but inrituximab the occurrence during or immediately afteradministration make an inflammatory reaction unlikely.We postulate a direct interaction with spinal nervousstructures (radices?) as the most likely explanation for thisadverse reaction to rituximab.This very painful, though completely transient, adverseeffect of intrathecal rituximab precludes intrathecaladministration of higher doses via lumbar puncture. It hasnot been described after intraventricular administration,despite the fact that considerably more patients have beentreated with rituximab via this route.Acknowledgments The rituximab used in the study was providedfree of charge by Roche. Financial support for the HOVON 80 studywas obtained from the Dutch Cancer Society, project no. 2006-11.J.K.D. reports receiving travel grants from Roche.Conflicts of interest Dr. Bromberg reports no conflicts of interestother than the above. Dr. Baars reports no conflicts of interest. Dr.vanImhoff reports no conflicts of interest. Dr.Enting reports no conflictsof interest. Dr. van den Bent has performed consultancy services forRoche.Open Access This article is distributed under the terms of theCreative Commons Attribution Noncommercial License which per-mits any noncommercial use, distribution, and reproduction in anymedium, provided the original author(s) and source are credited.References1. Bollen EL, Brouwer RE, Hamers S, Hermans J, Kluin M, San-katsing SU, Tjak RV, Charvat MV, Kluin-Nelemans JC (1997)Central nervous system relapse in non-Hodgkin lymphoma. Asingle-center study of 532 patients. Arch Neurol 54:854–8592. Recht L, Straus DJ, Cirrincione C, Thaler HT, Posner JB (1988)Central nervous system metastases from non-Hodgkin’s lym-phoma: treatment and prophylaxis. Am J Med 84:425–4353. Pfreundschuh M, Schubert J, Ziepert M, Schmits R, Mohren M,Lengfelder E, Reiser M, Nickenig C, Clemens M, Peter N, Bo-kemeyer C, Eimermacher H, Ho A, Hoffmann M, MertelsmannR, Trumper L, Balleisen L, Liersch R, Metzner B, Hartmann F,Glass B, Poeschel V, Schmitz N, Ruebe C, Feller AC, Loeffler M(2008) Six versus eight cycles of bi-weekly CHOP-14 with orwithout rituximab in elderly patients with aggressive CD20 ? B-cell lymphomas: a randomised controlled trial (RICOVER-60).Lancet Oncol 9:105–116Table 1 Clinical characteristics of affected patientsPatient 1 2 3Age (years) 49 48 58CSF cellularity before i.t. rituximab 16 9 106/l 0.7 9 106/l 8.7 9 106/lCSF lymphoma by cytology and/or flow cytometry ? – Not available/unevaluableCSF cellularity after i.t. rituximab (4 days) 5 9 106/l 1.7 9 106/l Not doneBest result of treatment CRu CR CRuSurvival after AE (months) 8 [26 5.5CRu Complete response unconfirmed, CR complete response, CSF cerebrospinal fluid, AE adverse eventJ Neurol1234. Pfreundschuh M, Trumper L, Osterborg A, Pettengell R, TrnenyM, Imrie K, Ma D, Gill D, Walewski J, Zinzani PL, Stahel R,Kvaloy S, Shpilberg O, Jaeger U, Hansen M, Lehtinen T, Lopez-Guillermo A, Corrado C, Scheliga A, Milpied N, Mendila M,Rashford M, Kuhnt E, Loeffler M (2006) CHOP-like chemo-therapy plus rituximab versus CHOP-like chemotherapy alonein young patients with good-prognosis diffuse large-B-cell lym-phoma: a randomised controlled trial by the MabThera Interna-tional Trial (MInT) Group. Lancet Oncol 7:379–3915. Rubenstein JL, Combs D, Rosenberg J, Levy A, McDermottM, Damon L, Ignoffo R, Aldape K, Shen A, Lee D, Grillo-Lopez A, Shuman MA (2003) Rituximab therapy for CNSlymphomas: targeting the leptomeningeal compartment. Blood101:466–4686. Shah GD, Yahalom J, Correa DD, Lai RK, Raizer JJ, Schiff D,LaRocca R, Grant B, Deangelis LM, Abrey LE (2007) Combinedimmunochemotherapy with reduced whole-brain radiotherapyfor newly diagnosed primary CNS lymphoma. J Clin Oncol25:4730–47357. Rubenstein JL, Fridlyand J, Abrey L, Shen A, Karch J, Wang E,Issa S, Damon L, Prados M, McDermott M, O’Brien J, Haqq C,Shuman M (2007) Phase I study of intraventricular administrationof rituximab in patients with recurrent CNS and intraocularlymphoma. J Clin Oncol 25:1350–13568. Schulz H, Pels H, Schmidt-Wolf I, Zeelen U, Germing U, EngertA (2004) Intraventricular treatment of relapsed central nervoussystem lymphoma with the anti-CD20 antibody rituximab.Haematologica 89:753–7549. Antonini G, Cox MC, Montefusco E, Ferrari A, Conte E, MorinoS, Latino P, Trasimeni G, Monarca B (2007) Intrathecal anti-CD20 antibody: an effective and safe treatment for leptomenin-geal lymphoma. J Neurooncol 81:197–19910. Nelson RW, Frank JT (1981) Intrathecal methotrexate-inducedneurotoxicities. Am J Hosp Pharm 38:65–6811. Kim S, Chatelut E, Kim JC, Howell SB, Cates C, Kormanik PA,Chamberlain MC (1993) Extended CSF cytarabine exposurefollowing intrathecal administration of DTC 101. J Clin Oncol11:2186–219312. Jabbour E, O’Brien S, Kantarjian H, Garcia-Manero G, FerrajoliA, Ravandi F, Cabanillas M, Thomas DA (2007) Neurologiccomplications associated with intrathecal liposomal cytarabinegiven prophylactically in combination with high-dose metho-trexate and cytarabine to patients with acute lymphocytic leuke-mia. Blood 109:3214–321813. Ostermann K, Pels H, Kowoll A, Kuhnhenn J, Schlegel U (2011)Neurologic complications after intrathecal liposomal cytarabinein combination with systemic polychemotherapy in primary CNSlymphoma. J Neurooncol 103:635–640J Neurol123

NARCIS 

Bromberg, J E C

Doorduijn, J K

Baars, J W

van Imhoff, G W

van den Bent, M J

Bromberg, J.E.C. (Jacoline)

Doorduijn, J.K. (Jeanette)

Baars, J.W. (Joke)

Imhoff, G. (Gustaaf) van

Enting, R. (Roelien)

Bent, M.J. (Martin) van den

Erasmus University Digital Repository

LETTER TO THE EDITORS
Acute painful lumbosacral paresthesia after intrathecal rituximab
J. E. C. Bromberg • J. K. Doorduijn •
J. W. Baars • G. W. van Imhoff • R. Enting •
M. J. van den Bent
Received: 18 May 2011 / Revised: 11 July 2011 / Accepted: 14 July 2011 / Published online: 10 August 2011
 The Author(s) 2011. This article is published with open access at Springerlink.com
Dear Sirs,
Central nervous system (CNS) recurrence of systemic
aggressive B-cell lymphoma carries poor prognosis with
median survival of 2–4 months and less than 10% 1-year
survival after treatment with standard-dose chemotherapy
and/or radiotherapy [1, 2]. Aiming to improve on these
treatment results, we designed a phase II study to evaluate
an intensive protocol including myeloablative treatment
in CNS recurrence of systemic B-cell non-Hodgkin’s
lymphoma (NHL). This study (HOVON 80, Netherlands
Trial Register, no. 1757) is an ongoing phase II study on
the feasibility and efficacy of R-DHAP ? HD-MTX
(dexamethasone 40 mg days 1–4, cisplatin 100 mg/m2
day 1, cytarabine 2 9 2 g/m2 day 2, rituximab 375 mg/m2
day 5, methotrexate 3 g/m2 day 15), followed by autolo-
gous stem cell transplantation in patients with recurrent
aggressive B-cell lymphoma with CNS localization. Rit-
uximab is a chimeric anti-CD-20 antibody which has rad-
ically changed prospects for patients with systemic B-cell
lymphoma [3, 4]. However, after intravenous administra-
tion it does not penetrate the blood–brain barrier well, and
it has been postulated that intrathecal administration may
improve results of treatment of leptomeningeal lymphoma
[5, 6]. We therefore incorporated intrathecal rituximab into
the protocol.
The patients we report herein were all treated according
to protocol with systemic R-DHAP-MTX as described
above, for three 28-day cycles. Additionally, intrathecal
rituximab, containing no preservatives and without con-
current other agents, was administered via lumbar puncture
after premedication with paracetamol 1,000 mg on days -1,
4, 8, 11, and 21 in the first cycle, four times in the second
cycle, and three times in the third cycle. The first adminis-
tration in each patient consisted of 10 mg rituximab; in
subsequent administrations the dose was increased to 25 mg
provided no toxicity had occurred. This dosing was based on
prior publications [7, 8]. None of our patients experienced
side-effects after the first intrathecal administration of rit-
uximab, except for a minor sensation of pressure in the
sacral area in one patient. However, after the first adminis-
tration of 25 mg rituximab, 2 of the first 12 treated patients
reported extremely painful paresthesia in the buttocks,
legs, and feet immediately after administration, lasting
30–60 min. There were no neurologic deficits at the time,
nor on follow-up, but blood pressure increased temporarily.
After these adverse events the protocol was amended to
dilution of rituximab in 0.9% saline to 5 mg/ml and addi-
tional premedication with antihistamines. The subsequently
treated, 13th, patient suffered identical symptoms despite
J. E. C. Bromberg (&)  M. J. van den Bent
Department of Neuro-Oncology, Daniel den Hoed Cancer
Center, Erasmus MC, University Medical Center Rotterdam,
PO Box 5201, 3008 AE Rotterdam, The Netherlands
e-mail: j.bromberg@erasmusmc.nl
J. K. Doorduijn
Department of Hematology, Daniel den Hoed Cancer Center,
Erasmus MC, University Medical Center Rotterdam,
PO Box 5201, 3008 AE Rotterdam, The Netherlands
J. W. Baars
Department of Medical Oncology, The Netherlands Cancer
Institute, Antoni van Leeuwenhoek Hospital, Amsterdam,
The Netherlands
G. W. van Imhoff
Department of Hematology, University Medical Center
Groningen, Groningen, The Netherlands
R. Enting
Department of Neuro-Oncology, University Medical Center
Groningen, Groningen, The Netherlands
123
J Neurol (2012) 259:559–561
DOI 10.1007/s00415-011-6190-y
the adapted protocol. Clinical characteristics of the patients
are given in Table 1. The pain resolved completely in all
patients within a few hours. However, they all refused fur-
ther treatment with intrathecal rituximab, and further
intrathecal therapy was changed to methotrexate, which was
administered uneventfully. The rituximab dose in the pro-
tocol was subsequently reduced to 10 mg per administra-
tion, diluted as described above and combined with 4 mg
intrathecal dexamethasone. Twelve additional patients were
thus treated, and no further incidents of painful radiculop-
athy have occurred.
In a phase I study investigating intraventricular/intra-
thecal rituximab, the maximum tolerated dose was found to
be 25 mg; at 50 mg, grade III hypertension was the dose-
limiting toxicity and one of two patients thus treated
additionally experienced transient diplopia, nausea, and
vomiting [7]. A painful radiculopathy was described after
intrathecal administration of 25 mg via lumbar puncture in
one patient; the majority, however, had been treated
intraventricularly. Antonini described one patient treated
with 40 mg intrathecal rituximab in whom transient head-
ache, cramps, back pain, and leg weakness occurred [9].
Schulz described six patients treated with 10–40 mg
undiluted intra-CSF rituximab for CNS lymphoma, two of
them via lumbar puncture; one of them suffered transient
severe back pain and paraparesis during the first intrathecal
administration of rituximab (25 mg) [8]. In this patient a
high tumor load was present in the CSF and the authors
assumed a tumor lysis syndrome. However, in none of our
patients was high CSF cellularity present, making tumor
lysis an unlikely explanation.
Both acute and subacute toxicities have been observed
after intrathecal treatment with chemotherapeutic agents
[10–13]. For methotrexate as well as (sustained-release)
cytarabine an acute, reversible aseptic meningitis with
fever, headache, backache, nausea, and vomiting has been
described. Symptoms begin several hours after adminis-
tration and can be prevented with oral or intrathecal
dexamethasone in the majority of patients [10, 11]. An
inflammatory reaction is a likely cause for the aseptic
meningitis after methotrexate and cytarabine, but in
rituximab the occurrence during or immediately after
administration make an inflammatory reaction unlikely.
We postulate a direct interaction with spinal nervous
structures (radices?) as the most likely explanation for this
adverse reaction to rituximab.
This very painful, though completely transient, adverse
effect of intrathecal rituximab precludes intrathecal
administration of higher doses via lumbar puncture. It has
not been described after intraventricular administration,
despite the fact that considerably more patients have been
treated with rituximab via this route.
Acknowledgments The rituximab used in the study was provided
free of charge by Roche. Financial support for the HOVON 80 study
was obtained from the Dutch Cancer Society, project no. 2006-11.
J.K.D. reports receiving travel grants from Roche.
Conflicts of interest Dr. Bromberg reports no conflicts of interest
other than the above. Dr. Baars reports no conflicts of interest. Dr.van
Imhoff reports no conflicts of interest. Dr.Enting reports no conflicts
of interest. Dr. van den Bent has performed consultancy services for
Roche.
Open Access This article is distributed under the terms of the
Creative Commons Attribution Noncommercial License which per-
mits any noncommercial use, distribution, and reproduction in any
medium, provided the original author(s) and source are credited.
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University of Groningen

ARTS repository - University of Groningen

Central nervous system metastases from non-Hodgkin’s lymphoma: treatment and prophylaxis.

Central nervous system relapse in non-Hodgkin lymphoma. A single-center study of 532 patients.

Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20 ? Bcell lymphomas: a randomised controlled trial (RICOVER-60). Lancet Oncol 9:105–116

Acute painful lumbosacral paresthesia after intrathecal rituximab

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