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Internal Medicine Journal 37 (2007) 569571

B R IE F C O M M U N IC AT I O N

Evaluation of the off-label usage of rituximab in a large teaching hospital in New South Wales
R. Sharma,1 L. Koller,2 P. Barclay3 and C. Liddle1
Departments of 1Clinical Pharmacology and 2Pharmacy, Westmead Hospital and 3Department of Pharmacy, Westmead Childrens Hospital, Sydney, New South Wales, Australia

Key words rituximab, off label, cost, drug utilization evaluation. Correspondence Christopher Liddle, Department of Clinical Pharmacology, University of Sydney, Westmead, NSW 2145, Australia. Email: chris_liddle@wmi.usyd.edu.au Received 16 July 2006; accepted 14 February 2007. doi:10.1111/j.1445-5994.2007.01406.x

Abstract
A retrospective review of patients receiving rituximab off label in a large teaching hospital was conducted between July 2002 and January 2006. The indication, dosing regimen, efcacy and cost of rituximab were evaluated. Rituximab was prescribed for three clinical indications; acute organ transplant rejection, posttransplant lymphoproliferative disease and autoimmune disease. On average, 600 mg of rituximab was prescribed weekly for 4 weeks, costing the hospital $108 739.37. We suggest an initial approval for a limited number of doses with subsequent approval dependent on improvement in predened clinical or biochemical end-points. Furthermore, we suggest an Australia-wide central database be established to enable delineation of the optimal dosing schedule, as well as monitoring of clinical outcome.

Rituximab is a genetically engineered chimeric human/ murine monoclonal antibody that binds to the transmembrane antigen CD20. CD20 regulates the early steps of activation and differentiation of B lymphocytes. Rituximab selectively depletes B cells by three mechanisms: antibody-dependent, cell-mediated cytotoxicity, complement-mediated cytotoxicity and CD20+ B-cell apoptosis.13 Rituximab was approved by the Therapeutic Goods Administration (TGA) for the treatment of refractory low-grade or follicular B-cell non-Hodgkins lymphoma (NHL) in July 2002. There is a growing use of rituximab for off-label conditions resulting in a substantial economical cost, $160 907 incurred by Westmead Hospital alone in 6 months. This has been perpetuated by several case controlled studies in conditions as diverse as systemic autoimmune disease and post-transplant lymphoproliferative disease (PTLD). In these diseases, B cells and autoantibodies appear to play an important role in pathophysiology; therefore, there is a rationale for the

Funding: R. Sharma is a recipient of a Cancer Institute of NSW Research Scholarship. Potential conicts of interest: None
2007 The Authors Journal compilation 2007 Royal Australasian College of Physicians

use of an anti-CD20 therapy. Treatment guidelines regarding dose schedule, combination therapy and follow up are unclear and as rituximab is a high-cost medication, restrictions may be required. The aim of this study was to characterize the patterns of usage of rituximab, evaluate the appropriateness of prescribing and to establish guidelines for off-label use. Patients having received rituximab for an off-label indication were identied from pharmacy stock reports. Data were collected retrospectively from the date of TGA registration, July 2002, to January 2006. Patients with a history of low-grade or follicular, CD20+, B-cell NHL were excluded. The number of rituximab infusions, the dosage received and any adverse reactions were noted. Histopathology reports were reviewed and data collected on diagnosis, and the presence of CD20 was accessed. In renal transplant recipients with organ rejection, response was dened as any improvement in serum creatinine concentration (Cr) and/or maintenance of graft function. In patients with autoimmune disorders response was dened as a decrease of 50% or more of the initial disease activity, as determined by relevant biomarkers, or an improvement in symptoms. Twenty-ve cases were identied and their case notes reviewed. Eleven patients received rituximab for
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Table 1 Demographics of patients with acute antibody-mediated organ rejection Case Age Sex Organ Concomitant medication No. Graft plasmaphoresis survival 1 10 0 Yes Yes Yes Return to dialysis Serum Cr before Cr 1 month Cr 1 year after rituximab after rituximab rituximab treatment 172 222 Not applicable 55 Not available Not applicable

1 2 1

54 36 34

F F F

Kidney TAC, PNL Kidney TAC, MMF, PNL Pancreatic TAC, SIR islets

No 372 No 651 Not applicable Not applicable

MMF, mycophenolate mofetil; PNL, prednisolone; SIR, sirolimus; TAC, tacrolimus.

unapproved indications. Case notes for two patients could not be obtained and they were excluded from analysis. One patient experienced a transient decline in total white cell count following the rst infusion of rituximab. Forty-seven administrations of rituximab were prescribed costing $108 739.37, not including pharmacy preparation, administration or management of any adverse events. Three patients were identied, two of which had a diagnosis of acute organ rejection following renal transplantation. Patient demographics and treatment are shown in Table 1. Patient 1 was diagnosed with acute rejection in July 2004 and received antithymocyte globulin (ATG) and basiliximab, followed by a single dose of rituximab with good response. Acute rejection was diagnosed 5 months later and was treated with pulse methylprednisolone and plasmaphoresis followed by rituximab 375 mg/m2 weekly for 4 weeks with improvement in renal function. Patient 2 was diagnosed with acute rejection in July 2005 and received ATG, pulse methylprednisolone followed by 10 episodes of plasmaphoresis before receiving weekly 375 mg/m2 rituximab. To date patient 2 has received three doses with marked improvement in renal function but remains on intermittent dialysis. The nal case is of a patient with pancreatic islet cell transplantation who was diagnosed with insulin resistance based on a rising C-peptide. Before receiving rituximab, C-peptide level was 0.21 and fell after a month to <0.1. A year later this remains <0.1. An average of $8330.74 per patient was spent on the treatment of acute rejection. Five patients had a diagnosis of PTLD of varying degrees. Two patients were excluded as pathology review indicated a diagnosis of CD20+, diffuse NHL. Three remaining patients had undergone renal transplantation. Patient
Table 2 Demographics of patients with PTLD following renal transplantation Case 1 2 3 Age 38 63 62 Sex F M M Concomitant medication TAC, PNL, MMF TAC, PNL Cyclosporine, azathioprine, PNL

demographics are shown in Table 2. Two of the three biopsies were positive for CD20. Patients received weekly infusions of 375 mg/m2 of rituximab for a variable number of infusions (range 16). Two patients responded to treatment with rituximab, whereas the treatment outcome for one patient was not recorded. An average of $13 989.26 per patient was spent on the treatment of PTLD. Two patients had a diagnosis of polymyositis made on muscle biopsy. Both had previously received several immunosuppressants, including azathioprine, mycophenolate mofetil, cyclosporine, prednisolone and monthly intragam. After developing increasing leg weakness, four weekly infusions of 375 mg/m2 of rituximab was given in combination with hydrocortisone 100 mg. Plasma creatine kinase (CK), erythrocyte sedimentation rate, C-reactive protein and CD19 were used as markers of response. Both cases reported reduction in CK and clinical response. No change in the other biomarkers was seen. The last patient was diagnosed with multicentric Castlemans disease in February 2003. She had increasing dyspnoea and lethargy. Chest radiograph showed bilateral interstitial inltrates with parahilar lymphadenopathy. Lymph node biopsy was negative for CD20. Previous treatment included cyclophosphamide followed by prednisolone. Four weekly infusions of rituximab, 375 mg/ m2 in combination with 25 mg prednisolone were given. Symptomatically there was improvement a month after receiving rituximab. Chest radiograph remained unchanged and no real improvements in biomarker measurements were seen. Rituximab was given for another 4 weeks with no improvement in symptoms. The concurrent dose of steroids was not reduced in any of the reported cases. An average of $19 019.12 per patient was spent on the treatment of autoimmune disorders.

Site of disease Axillary lymph node Cerebral Cervical node, tonsil

CD20+ biopsy No + +

Biomarkers assessed Clinical, LDH Imaging LDH, clinical

Response Yes Yes Not available

LDH, lactate dehydrogenase; MMF, mycophenolate mofetil; PNL, prednisolone; PTLD, post-transplant lymphoproliferative disease; SIR, sirolimus; TAC, tacrolimus.
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Evaluation of the off-label usage of rituximab

As there is increasing use of rituximab for unapproved indications, we sought to delineate prescribing patterns to prevent escalating costs to hospital pharmacy budgets. Although most cases of acute organ rejection are T-cell mediated, the presence of B cells in the graft is associated with poor reversibility of graft function and impaired graft survival. Hence, there is a rationale for the use of rituximab as an adjunct to existing therapies. The efcacy of rituximab was illustrated by two studies that reported a dramatic reduction in serum Cr following a single dose of rituximab.4,5 Rituximab alone has no effect on circulating antibodies or plasma cells and therefore although rituximab appears to be efcacious, it may be appropriate to use rituximab in combination with ATG or plasmaphoresis. This report does not attempt any formal pharmacoeconomic analysis; however, the use of rituximab in the management of acute rejection may offset the costs of ATG and plasmaphoresis as well as dialysis. The current role of rituximab for the management of PTLD is even less clear. The largest case series reported a response rate of 69% in patients receiving rituximab therapy, 375 mg/m2 weekly for 4 weeks, and rituximab was shown to be a strong predictor of survival in patients positive for CD20.6,7 There are two main concerns for the use of rituximab in this setting: the potential emergence of CD202 PTLD and, as rituximab does not restore the cellular immune response to EpsteinBarr virus (EBV), recurrence of PTLD with EBV-infected B-cell recovery.8,9 More clinical follow-up data are required to investigate these concepts. B-cell depletion using rituximab may have efcacy in myositis, vasculitis and other autoantibody-associated disorders.1012 Again, there is no consensus as to the optimum dose or duration of treatment. The clinical heterogeneity of these diseases makes it difcult to devise quantitative measures of response to therapy and different studies have used a variety of clinical and biochemical end-points. A 100-mg vial of rituximab costs $943 and a 500-mg vial is $2357.89. On average each patient received 600 mg of rituximab weekly for 4 weeks costing an average of $13 203.56 per patient. Based on the available evidence, rituximab should only be prescribed where there is clear evidence of CD20+ cells on biopsy and/or in the pathophysiology of the disease. What remains unclear is the appropriate dosing regimen. Many studies have extrapolated from the haematological setting and it is unclear whether this is relevant to other areas of clinical practice. Given the small numbers of patients that were treated in this case series, it is difcult to establish guidelines. We suggest an Australia-wide surveillance programme where all patients receiving rituximab for

an off-label indication are entered into a de-identied database. This would enable the delineation of optimal dose and duration of therapy and allow for the monitoring of safety and efcacy based on relevant biomarkers and validated clinical tools.

References
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