|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Originally published as JCO Early Release 10.1200/JCO.2006.09.7311 on February 20 2007 © 2007 American Society of Clinical Oncology. Phase I Study of Intraventricular Administration of Rituximab in Patients With Recurrent CNS and Intraocular Lymphoma
From the Division of Hematology/Oncology, and the Departments of Epidemiology and Biostatistics, Pathology, Neurological Surgery, and Division of Ocular Oncology, University of California, San Francisco, San Francisco, CA; and Memorial Sloan-Kettering Cancer Center, New York, NY Address reprint requests to James L. Rubenstein, MD, PhD, University of California, San Francisco, Division of Hematology/Oncology, M1282 Box 1270, San Francisco, CA 94143; e-mail: jamesr{at}medicine.ucsf.edu
Purpose: We previously determined that intravenous administration of rituximab results in limited penetration of this agent into the leptomeningeal space. Systemic rituximab does not reduce the risk of CNS relapse or dissemination in patients with large cell lymphoma. We therefore conducted a phase I dose-escalation study of intrathecal rituximab monotherapy in patients with recurrent CNS non-Hodgkin's lymphoma (NHL). Patients and Methods: The protocol planned nine injections of rituximab (10 mg, 25 mg, or 50 mg dose levels) through an Ommaya reservoir over 5 weeks. The safety profile of intraventricular rituximab was defined in 10 patients. Results: The maximum tolerated dose was determined to be 25 mg and rapid craniospinal axis distribution was demonstrated. Cytologic responses were detected in six patients; four patients exhibited complete response. Two patients experienced improvement in intraocular NHL and one exhibited resolution of parenchymal NHL. High RNA levels of Pim-2 and FoxP1 in meningeal lymphoma cells were associated with disease refractory to rituximab monotherapy. Conclusion: These results suggest that intrathecal rituximab (10 to 25 mg) is feasible and effective in NHL involving the CNS.
CNS dissemination of non-Hodgkin's lymphoma (NHL) is an important cause of morbidity and death in patients with high-grade disease.1 The majority of CNS lymphomas are large, B-cell neoplasms that express CD20.2 The prognosis associated with primary CNS lymphoma is markedly worse than other localized extranodal NHLs. New therapies are needed to prevent and treat the CNS dissemination of NHL because established therapies are arcane and highly toxic.3 We previously conducted an analysis of the safety and pharmacokinetics (PK) of intrathecal rituximab administration in nonhuman primates.4 This constitutes the basis for the current phase I study of intraventricular rituximab administration in patients with recurrent primary or secondary CNS lymphoma. The rationale for this study is multifold: (1) CSF levels of rituximab in patients are only approximately 0.1% of matched serum levels after intravenous administration; (2) intrathecal administration of rituximab in cynomologus monkeys produced therapeutic CSF levels without evidence of major toxicity4; (3) though intravenous administration of rituximab contributes to prolonged survival in patients with systemic large B-cell lymphoma, intravenous rituximab does not impact CNS relapse.5 Our goals were to: (1) evaluate the safety and pharmacokinetics of intrathecal distribution of rituximab at each of three dose levels; (2) evaluate the effects of intrathecal rituximab in the treatment of recurrent NHL involving the brain, intraocular, and leptomeningeal compartments; (3) gain insight into the molecular basis of rituximab activity as well as into resistance in the treatment of CNS lymphomas.
Study Design We performed a phase I open label sequential dose-escalation study to define the safety, PK, and efficacy of rituximab following intraventricular administration. The study population consisted of 10 patients at two centers with relapsed or refractory CD20-positive CNS lymphoma arising from systemic NHL or primary CNS lymphoma. Eligibility mandated patient age older than 17 years, Karnofsky performance status greater than 50%, HIV seronegative status, granulocyte concentration of at least 1,500/µL, and platelet concentration of at least 50,000/µL. No patient received concurrent systemic or other intrathecal therapy; all patients were on a stable or tapering dose of glucocorticoids during pretreatment staging and intrathecal rituximab therapy. Other intrathecal and/or radiation therapy was completed at least 8 days before pretreatment CSF assessment and initiation of intraventricular rituximab; in three patients with particularly aggressive recurrent disease, treatment was initiated within 5 days of prior therapy, with institutional internal review board–approval for these protocol exceptions. The study was conducted under BB-IND Approval No. 10155. All patients signed informed consent indicating that they were aware of the investigational nature and potential risks and benefits of the study, in accordance with institutional internal review boards and the Declaration of Helsinki. Pretreatment staging included physical and ocular slit lamp examination and baseline magnetic resonance imaging (MRI) of brain and spine. Patency within the ventricular system was demonstrated in all patients by CSF flow studies; these were performed within 1 week of the initiation of intrathecal rituximab in eight patients and within 3 weeks of its initiation in two patients. Baseline laboratory studies included complete blood count, electrolytes, CSF cell count, differential, protein and glucose, and cytospins of CSF reviewed for malignant lymphoma cells. Enrollment was onto one of three rituximab dose cohorts: three patients at 10 mg (dose level 1), three patients at 25 mg (dose level 2), and a maximum of four patients at 50 mg (dose level 3). Accrual goal was 10 patients. CSF was evaluated with every intrathecal injection, at intervals of twice per week; cytology was evaluated during the second injection every week. Serum laboratory studies were repeated at the time of the second injection every week. Maximum number of intrathecal injections of rituximab was nine over a 5-week period. Rituximab was administered once on study week 1 and twice per week thereafter (day 1 and day 4) for 4 weeks for a maximum of nine doses through an Ommaya reservoir. At dose levels 1 and 2, rituximab stock solution (10 mg/mL) was diluted in 0.9% saline to a total volume of 5 mL. At dose level 3, rituximab was directly injected without dilution (5 mL of a 10 mg/mL solution) slowly over a period of 1 to 5 minutes. All patients received acetaminophen, diphenhydramine, and famotidine or cimetidine 30 minutes before intrathecal injection. At least 5 mL of CSF were removed before each intrathecal rituximab injection, after which manual pressure was applied to the skin over the Ommaya device to facilitate delivery into the brain ventricles. On completion of the 5-week course of treatment, at restaging, rituximab was administered by lumbar puncture (LP) as part of the protocol to three patients (10 mg, n = 1; 25 mg, n = 2). Patients subsequently maintained recumbent posture for 90 minutes so that we could assess the distribution of rituximab through the cranial-spinal axis from the lumbar region into the brain ventricles. Toxicities of intrathecal rituximab were evaluated according to the National Cancer Institute (NCI) Common Toxicity Criteria (version 2.0) scale. Patients were assessed for toxicity on receipt of at least one dose of intraventricular rituximab. All patients underwent lymphoma restaging at week 6, including repeat neuroimaging of brain (and spine if clinically indicated). Repeat ophthalmologic examinations were performed if intraocular lymphoma was demonstrated at pretreatment. Responses were assessed as defined.6 Complete responders received extended dosing per protocol, as clinically indicated.
Pharmacokinetic Sampling CSF samples for drug analysis were placed in cryovials for frozen storage. Blood samples were allowed to clot at room temperature for approximately 45 minutes then were centrifuged at 1,300 g. CSF and serum were frozen within 1 hour of collection and stored at –20°C until analysis for rituximab concentration.
Bioanalysis
Gene Expression Profile Analysis
Patient Characteristics and Rituximab Treatment: Toxicity, Adverse Events, and Efficacy Patient characteristics and assigned treatment are listed in Tables 1, 2, and 3. Three patients were treated at the 10 mg dose level, five patients at the 25 mg dose level, and two patients at the 50 mg dose level.
Patients 1, 2, and 3 each received 10 mg of intrathecal rituximab. Patient 1 experienced early neurologic decline and was removed from the study after receiving two doses; patients 2 and 3 received all nine doses. Patients 4, 5, and 6 received the full nine-dose course of treatment at 25 mg. Five patients received all nine scheduled intraventricular injections of rituximab (10 mg and 25 mg doses) without major or dose-limiting toxicity. However, in one patient, who was asymptomatic, focal changes in white matter were detected on restaging MRI, raising the possibility of leukoencephalopathy. Similar abnormalities on MRI were not seen in four other patients at restaging. Dose-limiting toxicity (grade 3 hypertension) was reproducibly experienced by both patients (patients 7 and 8) treated at the 50 mg dose level. In addition to hypertension, patient 7 experienced transient diplopia and nausea and vomiting. Patient 8 experienced hypertension, abdominal cramping, and diffuse chest discomfort without evidence for cardiac ischemia or bronchospasm. In each case, symptoms resolved within 20 minutes with medical management, which for patient 8, included administration of labetelol. Because dose-limiting toxicity at the 50 mg dose level had been identified, the two remaining patients (patients 9 and 10) were treated with 25 mg of intrathecal rituximab. Each of these two patients exhibited tumor progression before completion of the protocol: Patient 9 received only one dose of intrathecal rituximab and patient 10 received a total of six doses. None of the five patients treated with intraventricular rituximab at 25 mg exhibited toxicity. At post-treatment restaging on week 6, three patients were treated with intrathecal rituximab via LP per protocol. Patients 2, 4, and 5 received single LP administrations of 10, 25, and 25 mg of rituximab, respectively. One patient experienced paresthesias in the sacral distribution after LP administration of rituximab at 25 mg; the symptom began approximately 5 minutes after drug administration and resolved within 10 minutes without sequelae. During the course of the study, six patients exhibited cytologic responses detected within both ventricular and lumbar CSF compartments after intra-Ommaya rituximab administration; the longest durable cytologic response was 9 months (patient 3). However, in two instances, despite clearance of malignant lymphoma cells from the CSF there was progressive neurologic deterioration consistent with unabated brain tumor progression. Each of two patients with concurrent intraocular lymphoma exhibited resolution of intraocular disease and/or clinical improvement confirmed by complete ophthalmologic examination after intrathecal rituximab (25 mg dose). In one patient, this intraocular response was durable, lasting over 6 months (vision improved from legal blindness, 20/400 to 20/100 in the right eye, and from 20/50 to 20/40 in the left eye). One patient exhibited complete resolution of a focus of brain parenchymal lymphoma involving the left frontal subcortical white matter (Fig 1). Overall, after 5 weeks of intraventricular rituximab monotherapy, four patients exhibited complete responses at all sites of disease in the neuroaxis at week 6 restaging (Table 2 and Table 3).
CSF Rituximab Concentration Profiles and Pharmacokinetic Parameters CSF rituximab concentrations rapidly declined after the first dose and exhibited a biphasic profile indicating distribution into at least two distinct biologic spaces. Mean CSF and serum profiles are shown for the 10 and 25 mg rituximab dose levels in Figures 2A and 2B. Predose and 1 hour postdose CSF concentrations appeared to be at steady-state after the first two doses (day 1 of weeks 1 and 2) at the 25 mg dose level. After the first dose, CSF rituximab concentrations peaked at 1 hour postdose at 149 and 259 µg/mL for the 10 and 25 mg dose levels, respectively. Over the entire course of treatment, CSF concentrations 1 hour postdose rose to means of 214 and 472 µg/mL for the 10 and 25 mg dose levels, respectively. Predose (trough) concentrations ranged from 0.197 to 1.32 µg/mL at 10 mg and from 0.726 to 25.3 µg/mL at 25 mg.
All patients were included in the PK analysis of CSF rituximab concentrations following the first dose during week 1. Preliminary estimates of initial distribution half-life averaged 2.0 hours after the 10 mg rituximab dose and 3.0 hours after the 25 mg dose. Initial half-life could not be estimated for the 50 mg dose level. Estimated elimination half-life averaged 21.9, 34.9, and 13.5 hours for the 10, 25, and 50 mg rituximab dose levels, respectively.
LP Samples and LP Administration At the completion of rituximab treatment, CSF was obtained predose from both LP and the Ommaya reservoir in three patients. Ninety minutes after LP administration, rituximab had distributed to the ventricular space; Ommaya CSF concentrations had risen 11-, 4.9-, and 2.6-fold from predose to 90 minutes postdose (Fig 2D).
Serum Rituximab Concentration Profiles For those patients without prior rituximab systemic treatment, serum rituximab concentrations following intraventicular administration exhibited a slow and steady rise over the course of the study (Fig 2A). Concentrations were far lower in serum compared with CSF (< 3% of CSF concentrations on average) and peaked much later than CSF concentrations, indicating a slow input rate from CSF to serum. On multiple dosing twice weekly at 10 and 25 mg, serum concentrations rose steadily and were still increasing at the time of the last intraventricular dose, but were still far below CSF concentrations. Final serum concentrations were between 5 and 7 µg/mL for the 10 mg dose level and between 12 and 16 µg/mL for the 25 mg dose level.
Gene Expression of Meningeal Lymphoma
We predicted that genes associated with the activated B-cell (ABC) type would be associated with rituximab-failure in meningeal lymphoma. Previously, we used the subtype assignments of Rosenwald et al16 to perform a molecular sub-classification of primary CNS lymphoma.12 We evaluated ABC genes from this overlapping subset, which were also expressed in meningeal lymphomas for differential expression related to outcome. The genes most highly expressed at the RNA level in tumors refractory to intrathecal rituximab and with short survival are Pim-2 kinase and Forkhead transcription factor P1 (FoxP1). Expression levels of these genes was each at least seven-fold higher in the nonresponding cases and were each associated with significant P values for differential expression at the 5% level after adjustment for multiple testing (Appendix, online-only).15 FoxP1 is an established marker of adverse outcome in large B-cell lymphoma at diagnosis.17,18 Both genes are established markers of activated B-cells.19
This study demonstrates the feasibility of intraventricular administration of rituximab in patients with refractory CNS lymphomas. Our data suggest that toxicity of intrathecal rituximab is dose-related and that the maximum tolerated dose of intraventricular rituximab is 25 mg as a 1:1 dilution in preservative-free normal saline. Intrathecal rituximab at 50 mg was associated with grade 3 infusion-related hypertension in two consecutive patients. The physiologic basis for this toxicity may relate to nonspecific effects on the autonomic nervous system caused by rituximab excipients as these distribute through the ventricular system. Because these results are preliminary, we will continue to evaluate potential toxicity carefully in future studies. To our knowledge, this study represents the first PK analysis of a naked monoclonal antibody administered into the CSF in humans. Intraventricular rituximab injection at 10 to 50 mg reproducibly results in concentrations within the ventricules that are similar to peak levels in the serum achieved after standard intravenous injection of rituximab.20 Rituximab is distributed throughout the cranio-spinal CSF space after intraventricular or LP administration. The concentration-time profiles and estimate for initial distribution half-life of rituximab determined for intraventricular rituximab in this first study in humans were similar to those obtained in cynomologus monkeys in which rituximab was injected directly into the suboccipital space and measured from this site at repeat time intervals.4 Intraventricular rituximab monotherapy was associated with encouraging anti-CNS lymphoma activity and clinical benefit in a heavily pretreated population of patients. Meningeal responses were detected in six patients, two patients exhibited intraocular responses, and one patient exhibited the resolution of brain parenchymal lymphoma. This is the first report of successful treatment of intraocular lymphoma by rituximab. In patient 4, the leptomeningeal response was detected in the lateral ventricle where there was persistent lymphoma 4 days after completing a course of radiation to the lower cervical spine to treat a symptomatic focus of disseminated disease. The duration of remission and improved functional status experienced by patient 4 during intrathecal rituximab monotherapy exceeded the only previous remission that occurred after whole-brain irradiation. Intravenous methotrexate in combination with systemic rituximab previously failed to produce a remission in this CNS lymphoma patient. In patient 10, intrathecal rituximab was also associated with the resolution of persistent malignant cytology in the lateral ventricles, detected 5 days after completing irradiation to the brain. It is possible that the response could be partially attributed to the delayed effects of the previous treatment (Table 3). Pim-2 kinase confers apoptotic resistance in hematopoeitic cells, possibly through phosphorylation of the BH3 protein BAD.21-23 Our evidence for high expression of Pim-2 in recurrent CNS lymphomas refractory to rituximab awaits validation in additional trials. These results constitute the basis for a successor trial to examine the safety, pharmacokinetics, and efficacy of intra-CSF injection of rituximab plus methotrexate in the treatment of recurrent CNS and ocular lymphomas. The rationale for this approach is underscored by the increasing body of evidence that suggests that rituximab may sensitize malignant or autoimmune B cells to apoptosis induced by genotoxic therapy.24,25
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment: N/A Leadership: N/A Consultant: James L. Rubenstein, Genentech Stock: Lloyd Damon, Genentech Honoraria: N/A Research Funds: James L. Rubenstein, Genentech Testimony: N/A Other: N/A
Conception and design: James L. Rubenstein, Marc Shuman Financial support: James L. Rubenstein Administrative support: James L. Rubenstein Provision of study materials or patients: James L. Rubenstein, Lauren Abrey Collection and assembly of data: James L. Rubenstein, Lauren Abrey, Arthur Shen, Jon Karch, Samar Issa, Michael Prados, Michael McDermott, Joan O'Brien, Chris Haqq Data analysis and interpretation: James L. Rubenstein, Jane Fridlyand, Lauren Abrey, Endi Wang, Lloyd Damon, Michael Prados, Joan O'Brien, Chris Haqq Manuscript writing: James L. Rubenstein, Jane Fridlyand, Samar Issa, Lloyd Damon, Joan O'Brien, Marc Shuman Final approval of manuscript: James L. Rubenstein, Jane Fridlyand, Lauren Abrey, Arthur Shen, Jon Karch, Endi Wang, Samar Issa, Lloyd Damon, Michael Prados, Michael McDermott, Joan O'Brien, Chris Haqq, Marc Shuman
We are grateful to the patients who participated in this study. We are also grateful to Dan Combs and to Cynthia Woods for rituximab pharmacokinetic analysis and to Paula O'Connor for helpful discussions.
published online ahead of print at www.jco.org on February 20, 2007. Supported by a National Cancer Institute (NCI) Research Career Award, by the National Institutes of Health Brain Tumor SPORE (Grant No. P50 CA097257), and by grants from the American Society of Clinical Oncology, the University of California, San Francisco Mt Zion Health Fund (J.L.R.), by NCI Grant No. RO1 CA101042-01 (C.H.), and by the General Clinical Research Center with funds provided by the National Center for Research Resources (Grant No. M01 RR-00079). Presented in abstract form at the 9th International Conference on Malignant Lymphoma, Lugano, Switzerland, June 8-11, 2005, and at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5-8, 2004. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Van Besien K, Ha CS, Murphy S, et al: Risk factors, treatment and outcome of central nervous recurrence in adults with intermediate-grade and immunoblastic lymphoma. Blood 91:1178-1184, 1998 2. Rubenstein JL, Treseler P, O'Brien JM: Pathology and genetics of primary central nervous system and intraocular lymphoma. Hematol Oncol Clin North Am 19:705-717, 2005[CrossRef][Medline] 3. Shah G, DeAngelis L: Treatment of primary central nervous system lymphoma. Hematol Oncol Clin North Am 19:611-627, 2005[CrossRef][Medline] 4. Rubenstein JL, Combs D, Rosenberg J, et al: Rituximab in CNS lymphoma: Targeting the leptomeningeal compartment. Blood 101:466-468, 2003 5. Feugier P, Virion J, Tilly H, et al: Incidence and risk factors for central nervous system occurrence in elderly patients with diffuse large-B-cell lymphoma: Influence of rituximab. Ann Oncol 15:129-133, 2004 6. Abrey LE, Batchelor TT, Ferreri AJ, et al: Report of an international workshop to standardize baseline evaluation and response criteria for primary CNS lymphoma. J Clin Oncol 23:5034-5043, 2005 7. Wiestner A, Rosenwald A, Barry TS, et al: ZAP-70 expression identifies a chronic lymphocytic leukemia subtype with unmutated immunoglobulin genes, inferior clinical outcome, and distinct gene expression profile. Blood 101:4944-4951, 2003 8. Alizadeh AA, Eisen MB, Davis RE, et al: Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 403:503-511, 2000[CrossRef][Medline] 9. Wright G, Tan B, Rosenwald A, et al: A gene expression-based method to diagnose clinically distinct subgroups of diffuse large B cell lymphoma. Proc Natl Acad Sci U S A 100:9991-9996, 2003 10. Maloney DG, Grillo-Lopez AJ, Bodkin DJ, et al: DEC-C2B8: Results of a phase I multiple-dose trial in patients with relapsed non-Hodgkin's lymphoma. J Clin Oncol 15:3266-3274, 1997[Abstract] 11. Dobson AT, Raja R, Abeyta MJ, et al: The unique transcriptome through day 3 of human preimplantation development. Hum Mol Genet 13:1461-1470, 2004 12. Rubenstein J, Fridlyand J, Shen A, et al: Gene expression and angiotropism in primary CNS lymphoma. Blood 107:3716-3723, 2006 13. Ithaka R, Gentleman RR: A language for data analysis and graphics. J Comput Graph Stat 5:299-314, 1996[CrossRef] 14. Smyth GK: Linear models and empirical bayes methods for assessing differential expression in microarray experiments. Stat Appl Genet Mol Biol 3:1-26, 2004 15. Holm S: A simple sequentially rejective multiple test procedure. Scand J Statist 6:65-70, 1979 16. Rosenwald A, Wright G, Chan WC, et al: Lymphoma/leukemia molecular profiling project: The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med 346:1937-1947, 2002 17. Banham AH, Connors JM, Brown PJ, et al: Expression of the FOXP1 transcription factor is strongly associated with inferior survival in patients with diffuse large B-cell lymphoma. Clin Cancer Res 11:1065-1072, 2005 18. Barrans SL, Fenton JA, Banham A, et al: Strong expression of FOXP1 identifies a distinct subset of diffuse large B-cell lymphoma (DLBCL) patients with poor outcome. Blood 104:2933-2935, 2004 19. Wright G, Tan B, Rosenwald A, et al: A gene expression-based method to diagnose clinically distinct subgroups of diffuse large B cell lymphoma. Proc Natl Acad Sci U S A 100:9991-9996, 2003 20. Maloney DG, Grillo-Lopez AJ, Bodkin DJ, et al: IDEC-C2B8: results of a phase I multiple-dose trial in patients with relapsed non-Hodgkin's lymphoma. J Clin Oncol 15:3266-3274, 1997[Abstract] 21. Fox CJ, Hammerman PS, Cinalli RM, et al: The serine/threonine kinase Pim-2 is a transcriptionally regulated apoptotic inhibitor. Genes Dev 17:1841-1854, 2003 22. Hammerman PS, Fox CJ, Cinalli RM, et al: Lymphocyte transformation by Pim-2 is dependent on nuclear factor-kappa B activation. Cancer Res 64:8341-8348, 2004 23. Yan B, Zemskova M, Holder S, et al: The PIM-2 kinase phosphorylates BAD on serine 112 and reverses BAD-induced cell death. J Biol Chem 278:45358-45367, 2003 24. Edwards JC, Szczepanski L, Szechinski J, et al: Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med 350:2572-2581, 2004 25. Coiffier B, Lepage E, Briere J, et al: CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 346:235-242, 2002 Submitted October 30, 2006; accepted January 4, 2007. Related Correspondence
This article has been cited by other articles:
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
