Rapid Infusion of Rituximab with Or Without Steroid-Containing Chemotherapy: 1-Yr Experience in a Single Institution

Rapid infusion of rituximab with or without steroid-containing chemotherapy: 1-yr experience in a single institution

Salar A, Casao D, Cervera M, Pedro C, Calafell M, Abella E, Alvarez- Antonio Salar, Dolors Casao, Marta Larra´n A, Besses C. Rapid infusion of rituximab with or without Cervera, Carmen Pedro, Montserrat steroid-containing chemotherapy: 1-yr experience in a single institution. Calafell, Eugenia Abella, Alberto Alvarez-Larrn, Carlos Besses Department of Clinical Hematology, Hospital del Mar, Barcelona, Spain

Abstract: We assessed the feasibility of a rapid infusion of rituximab with or without steroid-containing chemotherapy. Inclusion criteria: Key words: rituximab; lymphoma; drug administration; previous infusion of rituximab without grade 3 or 4 toxicity, lymphoid monoclonal antibody cells <5 · 109/L and rituximab dose of 375 mg/m2. Seventy patients Correspondence: Antonio Salar, MD, PhD, Department were treated with a total of 319 rapid rituximab infusions [126 (40%) of Clinical Hematology, Hospital del Mar, Passeig with and 193 (60%) without steroids]. Overall, rapid infusion of ritux- Maritim 25-29, 08003 Barcelona, Spain imab was well tolerated – there were no grade 3 or 4 adverse events. Tel: +34-9324-83341 Only, three patients developed symptoms, all grade 1. In conclusion, Fax: +34-9324-83254 rituximab administration in a 90-min infusion schedule is well tolerated e-mail: [email protected] and safe, both in patients who are administered steroids and in patients who are not. Accepted for publication 12 June 2006

The chimeric monoclonal anti-CD20 antibody containing chemotherapy is safe. The aims of this rituximab is now an integral component of therapy study were to assess the safety of a rapid infusion of for non-Hodgkin’s lymphoma (1). Moreover, ritux- rituximab with or without steroid-containing che- imab is being increasingly used for other non- motherapy schedules and to evaluate the feasibility malignant conditions, such as immune cytopenias, of this schedule in terms of shortening stays in autoimmune diseases, etc (2). Administration of hospital. rituximab can be associated with substantial infusion-related toxicity, including hypersensitivity Patients and methods reactions causing fever, rash, cardiovascular and respiratory compromise and rarely a fatal cytokine The study was carried out at the Department of release syndrome. It is interesting to note that the Clinical Haematology in the Hospital del Mar, a incidence of infusion-related reactions decreases University Hospital in Barcelona, Spain. The with the second and subsequent doses of rituximab recruitment period was from February 2005 to (3). February 2006. Informed consent was obtained in Some recommendations have been made in order all patients. Patients were included in the study if to reduce the risk of these infusion-related reac- they had been diagnosed with a CD20+ lympho- tions. These include the administration of rituxim- proliferative disorder or another disease susceptible ab over a prolonged period, usually 5–6 h for the of treatment with rituximab. All patients had first infusion and 3–4 h for subsequent infusions received previous treatment with a first infusion (4). These extended infusions cause long stays in of rituximab according to prescribing information day units, which are inconvenient for patients and in the Roche Summary of Product Characteristics have significant resource implications. Recently, (4). Patients were excluded if they had lymphocy- Sehn et al. (5) have suggested that a rapid rituximab tosis (>5 · 109/L), experienced toxicity grade ‡3 infusion schedule in combination with steroid- during the previous infusion of rituximab or had to

338 Rapid rituximab infusion receive a dose >375 mg/m2 in their planned Table 2. Rapid rituximab infusions according to schedules of treatment treatment schedule. Rituximab maintenance 122 (38) Patients were treated with rituximab adminis- R-CHOP 85 (27) tered over a total time of 90 min in a total volume Rituximab monotherapy 41 (13) of 250 mL. During the 90-min infusion, 20% of the R-EPOCH 22 (7) dose was given in the first 30 min and the remaining R-fludarabine 16 (5) R-ESHAP 14 (4) 80% was infused over 60 min. Patients who were R-gemcitabine 10 (3) treated with steroid-containing chemotherapy re- R-chlorambucil 9 (3) ceived acetaminophen, diphenhydramine and meth- Values are expressed as n (%). ylprednisolone. The dose of methylprednisolone R, rituximab; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; EPOCH, changed according to the planned immunochemo- etoposide, vincristine, doxorubicin, cyclophosphamide, methylprednisolone; ESHAP, therapy schedule. The equivalent dose of intraven- etoposide, metylprednisolone, cisplatin, cytarabine. ous methylprednisolone was used instead of oral prednisone. This was based on availability issues of our Hospital Pharmacy. Those patients who did from the previous standard infusion. These cases not receive steroid-containing chemotherapy were corresponded to patients who received retreatment only administered acetaminophen and diphenhydr- with rituximab because of progressive disease or amine, and did not receive steroids, either as those who were under rituximab maintenance. premedication or to reduce vomiting. Most of the This rapid rituximab administration schedule infusions were given on an outpatient basis. Vital was very well tolerated. No grade 3 or 4 adverse signs were measured every 15 min during the first events were observed. In 3 (0.9%) rapid infusions, hour or until stable, then hourly until the end of the grade 1 symptoms were recorded, two of these infusion. Secondary adverse effects were prospec- events beginning within the first 30 min. One tively monitored. patient had a sore throat that required a reduction in the infusion speed and a second patient reported abdominal discomfort that disappeared spontane- Results ously. A third patient complained of fever 24 h A total of 70 patients were enrolled into the study. after rituximab infusion. This case was finally Patient characteristics are listed in Table 1. Patients considered an adverse event because no symptoms received a cumulative total of 319 rapid rituximab suggestive of infection were found and cultures infusions. Each patient received a median number from blood and urine were negative. All these of 4 (range: 1–12) rapid infusions. The number of reactions occurred in patients who did not receive rapid rituximab infusions according to the chemo- steroid-containing chemotherapy. The first case therapy regimen is shown in Table 2. A total of 126 was taken off the protocol and despite the fact (40%) rituximab infusions were administered with that successive rituximab infusions were adminis- steroids and 193 (60%) were given without steroids. tered according to standard practice in this patient, The median time from the previous rituximab she complained of mild sore throat in almost all of infusion to the first rapid infusion was 28 d (range: the successive infusions. Of note, the other two 7–272). In 16 of 70 patients (23%), the first rapid patients received rapid rituximab in the subsequent infusion was administered with an interval >90 d infusions without any noteworthy events.

Table 1. Characteristics of the 70 patients Discussion

Age (yr) [median (range)] 64 (28–87) Over the past decade, there has been a considerable £ 60 31 (44) increase in the use of cytotoxic chemotherapy to >60 39 (56) treat cancer, a fact that has had a signiﬁcant impact Gender on the capacity of outpatient chemotherapy clinics. Male 33 (47) Female 37 (53) In the last years, the recommendations for the use Diagnosis of rituximab have increased, and many patients Diffuse large B-cell lymphoma 28 (40) with CD20 lymphoproliferative disorders or auto- Follicular lymphoma 25 (36) immune diseases are now candidates for rituximab MALT lymphoma 8 (11) Mantle-cell lymphoma 4 (5) infusion. Long infusion times for rituximab admin- Post-transplant lymphoproliferative disease 2 (3) istration mean that oncology patients spent many Other lymphomas 2 (3) hours in day units for treatment, and may increase Immune cytopenia 1 (2) patientsÕ waiting times for chemotherapy. Shorten- Values are expressed as n (%). ing the infusion time of rituximab by 1.5–2.5 h was MALT, mucosa-associated lymphoid tissue. preferred by patients as their visits to the hospital

339 Salar et al. were reduced to 2–3 h compared with the 4–5 h observation which could be of interest in candidates schedule needed in case of long infusions. More- for maintenance strategies with rituximab. over, the new infusion schedule has also helped us To summarize, rituximab administration in a 90- to treat our patients more quickly and to improve min infusion schedule in second or subsequent our targets for oncology waiting times. infusions is safe and well tolerated by all patients Although the recommended infusion rate for regardless of whether they were receiving steroid- subsequent infusions is up to double that of the first containing chemotherapy or not. Moreover, addi- infusion, several groups have investigated faster tional benefits include greater patient satisfaction infusion rates of rituximab to allow a reduction in and the optimization of nurse time, particularly in the total administration time (5–7). Other groups the outpatient setting. are making modifications to premedication schedules, such as omitting premedication, to test their References feasibility. No significant increase in adverse events has been reported with rapid infusion when ritux- 1. Grillo-Lo´pez AJ, Hedrick E, Rashford M, Benyunes M. Rituximab: ongoing and future clinical development. Semin imab is combined with chemotherapy that contains Oncol 2002;29:105–112. steroids (5). We decided to investigate the feasibility 2. Rastetter W, Molina A, White CA. Rituximab: expand- of a rapid infusion of rituximab not only in patients ing role in therapy for lymphomas and autoimmune diseases. treated with steroid containing chemotherapy but Ann Rev Med 2004;55:477–503. 3. Byrd JC, Waselenko JK, Maneatis TJ, et al. Rituximab also in patients who were not receiving steroids in therapy in hematologic malignancy patients with circulating their chemotherapy courses. We also explored the blood tumor cells: association with increased infusion-rela- group of patients under rituximab maintenance ted side effects and rapid blood tumor clearance. Blood because the number of patients in this condition is 1999;17:791–795. increasing. Therefore, we tested the tolerance of 4. Mabthera. Summary of Product Characteristics. http://www. emea.eu.int/humandocs/PDFS/EPAR/Mabthera/025998en4. this rapid infusion of rituximab in two clinical pdf (August 2004). situations in which no data have yet been reported. 5. Sehn LH, Donaldson J, Filewich A, et al. Rapid infusion In our experience, rituximab administration in a rituximab in combination with steroid containing chemo- 90-min infusion schedule is safe in all patients who therapy can be given safely and substantially reduces resource utilization. Blood 2004;104:394a [Abstract no. 1407]. met our inclusion criteria regardless of whether 6. Byrd J, Peterson B, Morrison V, et al. Randomized phase they were receiving steroid-containing chemother- 2 study of fludarabine with concurrent versus sequential apy or not. This fact is important because many treatment with rituximab in symptomatic, untreated patients lymphoma patients receive rituximab as mono- with B-cell chronic lymphocytic leukaemia: results from Cancer and Leukaemia Group B 9712 (CALGB 9712). therapy or as maintenance, and some patients with Blood 2003;101:6–14. non-malignant conditions can attain beneficial 7. Byrd J, Murphy T, Howard R, et al. Rituximab using a results from rituximab treatment. No significant thrice weekly dosing schedule in B-cell chronic lymphocytic adverse effects were seen even in patients who had leukaemia and small lymphocytic lymphoma demonstrates clinical activity and acceptable toxicity. J Clin Oncol received rapid rituximab infusions with an interval 2001;19:2153–2164. >90 d from the previous standard infusion, an

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