Leukemia & Lymphoma, July 2014; 55(7): 1694–1696 © 2014 Informa UK, Ltd. ISSN: 1042-8194 print / 1029-2403 online DOI: 10.3109/10428194.2013.853302


Rituximab: how evidence based medicine can change our clinical practice Michael Mian1, Stefan Gritsch2, Ines Wasle1, August Zabernigg3 & Michael Fiegl1 1Department of Hematology & Oncology, Medical University of Innsbruck, Innsbruck, Austria, 2Hospital Pharmacy,

University Hospital Innsbruck, Innsbruck, Austria and 3Department of Internal Medicine, Hospital of Kufstein, Kufstein, Austria

Rituximab, a chimeric monoclonal antibody against the CD20 surface protein, has become one of the most important targeted therapies in the fight against hematologic and autoimmune diseases. The Food and Drug Administration (FDA) approved this drug in 1997 for the treatment of relapsed or refractory, CD20⫹, B-cell low-grade nonHodgkin lymphoma, as a single agent, and 1 year later approval was granted for follicular lymphoma in the European Union. Since then, rituximab has become a backbone of therapy in all CD20-positive lymphomas [1–3]. Due to the profound immunomodulatory effects determined by B-cell depletion, its efficacy in autoimmune diseases [4], inflammatory diseases [5] and even in graft-versus-host disease [6] has been confirmed in a plethora of trials. Interestingly, there exists only one study evaluating the pharmacoepidemiology, meaning the spectrum of diagnoses in which rituximab is administered, in the setting of pediatric patients [7], and none in adult patients. The proportions of patients treated by rituximab for the different indications in real-life are unknown. We also investigated how rapidly research data can change our daily practice. Herein, we present pharmacoepidemiologic data of our rituximab registry covering the whole province of Tyrol in Austria. We retrospectively assessed all patients (n ⫽ 1336) who started treatment with rituximab between 1998 and 2012 in Tyrol. In this province, nine hospitals, of which one is specialized in bone marrow transplant, administer rituximab and contributed to this evaluation. We evaluated both the spectrum of indications over time and the number of rituximab administrations over all therapy lines. The diagnoses at the start of rituximab-based therapy were recorded. This is important to mention since the indication for repeated use of ritruximab may change during the clinical course, for example in a low-grade lymphoma that transforms into highgrade lymphoma. Graphs were drawn using Microsoft Excel and the Statistical Package for the Social Sciences (SPSS) software v.17.0.1 (SPSS, Chicago, IL).

Overall, 1336 patients received 9644 doses of rituximab (median 6 doses, range 1–54). Use of the monoclonal antibody increased steadily over the years, reaching its maximum in 2009–2010 [Figure 1(A)]. In fact, there was a stepwise extention of treatment indications for this drug, so that this targeted therapy has become important for the treatment of several disorders caused by B-cell deregulation [Figure 1(B)]. The overall number of patients for each setting in which rituximab was administered is presented in Table I. In order to provide data reflecting current use, we specified the number of patients treated with the drug in the last 3 years (2010–2012). Despite the monoclonal antibody being used in a plethora of different diseases, it was mainly administered to patients affected by lymphoma, consisting mostly of diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) (Table I). From a dynamic perspective, the approval of rituximab in different settings was always translated immediately into extensive clinical use, reflecting the efficacy of this drug. Thus, pivotal studies revealed the important contribution of rituximab in the treatment of DLBCL [8], chronic lymphocytic leukemia [9] and rheumatoid arthritis [10], which led to the extension of approval for these indications subsequently. However, rituximab has also been used increasingly in an off-label setting to treat autoimmune diseases [4] other than rheumatoid arthritis, such as immune thrombocytopenia [11] or autoimmune hemolytic anemia [12]. In the setting of transplant, the monoclonal antibody was introduced very early and has gained importance over the years. It has proved to be efficient for in vivo purging before stem cell collection for autologous transplant [13], and in treatment of post-transplant lymphoproliferative disease [14] and graft-versus-host disease (GvHD) [15]. To highlight the quick translation of study results into clinical routine in a Western industrialized state, the number of patients according to the different treatment indications is plotted in Figure 1(B), focusing on four categories, namely lymphoma, autoimmune diseases, GvHD and others. The

Correspondence: Michael Mian, MD, Department of Hematology & Oncology, Medical University of Innsbruck, Innsbruck, 6020 Austria. Tel: 0043-512504-24003. Fax: 0043-512-504-25615. E-mail: [email protected] Received 22 August 2013; revised 29 September 2013; accepted 3 October 2013


Letter to the Editor 1695

Number of administeres doses

(A)1400 1156






1000 840 800

727 613


526 374

400 200 21





0 1998
















Number of Patients



Treatment Indications GvHD Other Autoimmune Diseases NHL



0 1998 2000 2002 2004 2006 2008 2010 2012 1999 2001 2003 2005 2007 2009 2011


Figure 1. (A) Number of rituximab administrations for each year from 1998 until 2012. (B) Number of patients according to the different treatment indications. Table I. Patient numbers for each setting in which rituximab was administered for the whole time period and for the last 3 years (2010–2012). 1998–2012 (n ⫽ 1336) Treatment indication Diffuse large B-cell lymphoma Follicular lymphoma grade I/II Chronic lymphocytic leukemia/small lymphocytic lymphoma Mantle cell lymphoma Follicular lymphoma grade III Autoimmune diseases, NOS Mucosa associated tissue lymphoma/marginal zone lymphoma Graft-versus-host disease after allogeneic bone marrow transplant Primary immune thrombocytopenic purpura Rheumatologic diseases, NOS Other lymphomas* Lymphoplasmacytic lymphoma/Waldenström macroglobulinemia Other hematologic diseases Post-transplant lymphoproliferative disease Rheumatoid arthritis Burkitt lymphoma/B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma Autoimmune hemolytic anemia Autoimmune hemolytic anemia associated with lymphoproliferative disease Richter syndrome Neurodegenerative disease Immune thrombocytopenic purpura associated with lymphoproliferative disease Unknown Thrombotic thrombocytopenic purpura Nodular lymphocyte predominant Hodgkin lymphoma Other diseases† Myasthenia gravis Epstein–Barr virus-associated non-Hodgkin lymphoma

2010–2012 (n ⫽ 428)





401 170 139 64 59 57 50 49 39 36 33 32 28 27 24

30 12.7 10.4 4.8 4.4 4.3 3.7 3.7 2.9 2.7 2.5 2.4 2.1 2 1.8

110 36 45 13 12 38 19 22 21 2 17 12 15 8 7

25.7 8.4 10.5 3 2.8 8.9 4.4 5.1 4.9 0.5 4 2.8 3.5 1.9 1.6

22 21 19 15 12 8 10 7 6 3 3 2

1.6 1.6 1.4 1.1 0.9 0.6 0.8 0.5 0.4 0.2 0.2 0.1

12 4 3 4 10 0 6 3 3 3 3 0

2.8 0.9 0.7 0.9 2.3 0 1.4 0.7 0.7 0.7 0.7 0

*B-prolymphocytic leukemia (n ⫽ 2), hairy cell leukemia (n ⫽ 3), HIV-associated lymphoma (n ⫽ 4), Hodgkin lymphoma (n ⫽ 4), low-grade non-Hodgkin lymphoma, NOS (n ⫽ 6), lymphoblastic lymphoma (n ⫽ 3), non-Hodgkin lymphoma, NOS (n ⫽ 9), plasmacytoma, clinical trial (n ⫽ 1), non-Hodgkin lymphoma with a low-grade and a high-grade component (n ⫽ 1). †HCV-associated glomerulonephritis, minimal change nephropathy with nephrotic syndrome, nephrotic syndrome with unknown cause (n ⫽ 1 each). NOS, not otherwise specified; HIV, human immunodeficiency virus; HCV, hepatitis C virus.


M. Mian et al.

subsequent slight decrease after 2010 [Figure 1(A)] may be explained by the advent of novel monoclonal antibodies for the treatment of relapsed/refractory B-cell lymphoma such as ofatumumab. Our registry has the potential for more detailed analyses, such as of treatment response, survival and toxicities, and including rare conditions. For example, we presented a case with toxic pneumonitis during rituximab-containing therapy (R-CHOP; rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) with concomitant filgrastim administration [16]. A subsequent review of the literature revealed that this rare condition might be characteristic and should be considered [16]. A rare but typical rituximab-related disorder is the occurrence of progressive multifocal leukoencephalopathy (PML) due to a JC virus infection [17]. In 2003, one of our patients developed a confirmed JC virus infection resulting in a PML [18]. A recent screening of the International Classification of Diseases (ICD) database of the Innsbruck University Hospital did not reveal any other case of PML after rituximab administration. Another safety concern related to the immunosuppressive activity of the anti-CD20 antibody is the reactivation of a past hepatitis B virus (HBV) infection [19]. Therefore, in virtually all patients, HBV serology is performed, and in the case of a positive result, antiviral prophylaxis is administered. In conclusion, our data offer a realistic estimate of the routine use of rituximab nowadays, potentially contributing to adaptation of health policies. Our next step will be the study of the therapeutic benefits and treatment related toxicities of rituximab in a real-world setting. Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.

References [1] Lunning MA , Vose JM. Management of indolent lymphoma: where are we now and where are we going. Blood Rev 2012;26:279–288. [2] Witzens-Harig M, Hess G, Atta J, et al. Current treatment of mantle cell lymphoma: results of a national survey and consensus meeting. Ann Hematol 2012;91:1765–1772. [3] Armitage JO. How I treat patients with diffuse large B-cell lymphoma. Blood 2007;110:29–36. [4] Gurcan HM, Keskin DB, Stern JN, et al. A review of the current use of rituximab in autoimmune diseases. Int Immunopharmacol 2009;9:10–25.

[5] Carr DR, Heffernan MP. Off-label uses of rituximab in dermatology. Dermatol Ther 2007;20:277–287. [6] Van Hoef ME. Towards a rational graft-versus-host disease (GVHD) prophylaxis: rituximab should not be forgotten. Haematologica 2013;98:e40–e41. [7] Kavcic M, Fisher BT, Seif AE, et al. Leveraging administrative data to monitor rituximab use in 2875 patients at 42 freestanding children’s hospitals across the United States. J Pediatr 2013;162: 1252–1258.e1. [8] Coiffier B, Lepage E, Brière J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 2002;346:235–242. [9] Keating MJ, O’Brien S, Albitar M, et al. Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. J Clin Oncol 2005;23:4079–4088. [10] Emery P, Fleischmann R, Filipowicz-Sosnowska A , et al. The efficacy and safety of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment: results of a phase IIB randomized, double-blind, placebo-controlled, dose-ranging trial. Arthritis Rheum 2006;54:1390–1400. [11] Saleh MN, Gutheil J, Moore M, et al. A pilot study of the anti-CD20 monoclonal antibody rituximab in patients with refractory immune thrombocytopenia. Semin Oncol 2000;27:99–103. [12] Zecca M, De Stefano P, Nobili B, et al. Anti-CD20 monoclonal antibody for the treatment of severe, immune-mediated, pure red cell aplasia and hemolytic anemia. Blood 2001;97:3995–3997. [13] Buckstein R, Imrie K, Spaner D, et al. Stem cell function and engraftment is not affected by “in vivo purging ” with rituximab for autologous stem cell treatment for patients with low-grade nonHodgkin’s lymphoma. Semin Oncol 1999;26:115–122. [14] Faye A , Van Den Abeele T, Peuchmaur M, et al. Anti-CD20 monoclonal antibody for post-transplant lymphoproliferative disorders. Lancet 1998;352:1285. [15] Ratanatharathorn V, Carson E, Reynolds C, et al. Anti-CD20 chimeric monoclonal antibody treatment of refractory immunemediated thrombocytopenia in a patient with chronic graft-versus-host disease. Ann Intern Med 2000;133:275–279. [16] Mian M, Rass C, Hutarew G, et al. Extensive organizing pneumonia during chemo-immunotherapy containing rituximab and G-CSF in a patient with diffuse large B-cell lymphoma: case report and review of the literature. Leuk Lymphoma 2006;47: 1683–1685. [17] Tavazzi E, Ferrante P, Khalili K. Progressive multifocal leukoencephalopathy: an unexpected complication of modern therapeutic monoclonal antibody therapies. Clin Microbiol Infect 2011;17:1776–1780. [18] Steurer M, Clausen J, Gotwald T, et al. Progressive multifocal leukoencephalopathy after allogeneic stem cell transplantation and posttransplantation rituximab. Transplantation 2003;76:435–436. [19] Tsutsumi Y, Kanamori H, Mori A , et al. Reactivation of hepatitis B virus with rituximab. Expert Opin Drug Saf 2005;4:599–608.

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Rituximab: how evidence based medicine can change our clinical practice.

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