NE Oncology Issue – May 2011

Screen Shot 2015-08-18 at 10.33.22 AMCanadianizing a New Standard of Care in CLL

Treatment with rituximab in combination with fludarabine plus cyclophosphamide (FCR) has dramatically improved the outcome of patients with chronic lymphocytic leukemia (CLL). For patients who can tolerate it, first-line treatment with FCR is now considered to be the standard of care in CLL across Canada. Despite the success of the FCR regimen, a number of questions exist on its optimal administration. The following paper is the second of a series examining key challenges faced in the administration of FCR in Canada. Future papers will address issues such as supportive care for patients receiving FCR and use of the oral formulations of fludarabine and cyclophosphamide. By addressing the challenges related to the administration of FCR, patients are more likely to complete all treatment cycles, thereby increasing efficacy and resulting in improved outcomes.

Tina Crosbie, BSc Pharm, ACPR;1 Michelle Delbaere, BA, BSP, ACPR2

1The Ottawa Hospital, Ottawa, Ontario

Medical Writer: Meenakshi Kashyap, PhD, New Evidence

Download PDF


Chronic lymphocytic leukemia (CLL), an indolent disease of neoplastic B cells, is the most common adult leukemia in western countries. The age-standardized incidence rate in Canada is 5.01 per 100,000, with the highest rate found in Alberta (6.82/100,000), followed by Saskatchewan (6.34/100,000), and Ontario (5.27/100,000).1,2

Although CLL still remains incurable, considerable advances have been made in the past decade. The combination of purine analogues and alkylating drugs, especially fludarabine and cyclophosphamide (FC), improved response rates and progression-free survival (PFS).3,4

More recently, chemoimmunotherapy, in particular the addition of the monoclonal antibody rituximab to standard chemotherapy, has shifted treatment goals toward overall survival (OS).1 The German CLL Study Group’s phase III, randomized CLL-8 trial, which compared fludarabine, cyclophosphamide, and rituximab (FCR) with FC in fit, treatment-naïve CLL patients, demonstrated a significant OS benefit for FCR over FC at three years (FCR 87% versus FC 83%, p = 0.012).5 FCR has now become the first-line standard of care for fit patients with CLL.1

Based on results of the CLL-8 study, the FCR regimen has been approved for funding in all provinces as firstline treatment for CLL, with the exception of British Columbia, where FR is recommended first-line, and Quebec, where FCR is funded on a case-by-case basis.

CLL presents specific challenges for rituximab dosing and administration

Although the recommended dosing for rituximab in combination with chemotherapy in the treatment of non-Hodgkin’s lymphoma (NHL) is 375 mg/m2 iv per cycle for a total of eight cycles,6 CLL requires higher dosages due to the low expression of the CD20 antigen on leukemic cells characteristic of the disease.5 Consequently, rituximab was administered at a dose of 375 mg/m2 for the first cycle and 500 mg/m2 for the second to sixth cycles in the CLL-8 trial. The rituximab product monograph recommends administering rituximab 375 mg/m2 for the first cycle and 500 mg/m2 for the second to sixth cycles when used in combination with chemotherapy.5,6

Infusion-related reactions

Rituximab dosing for CLL is further complicated by the fact that patients with CLL who have a high number (>25 x 109/L) of circulating malignant cells, elevated white blood cell (WBC) counts, and high tumour burden may be at greater risk of developing infusion-related reactions due to severe cytokine release syndrome.6 In these patients, both the Cancer Care Ontario (CCO) drug formulary and the rituximab product monograph recommend a slow rate for the first infusion or splitting the dose of rituximab over two days with or without the addition of corticosteroids during the first cycle and any subsequent cycles if the lymphocyte count is still greater than 25 x 109/L.6,7 In the CLL-8 study, at the investigators’ discretion, the rituximab dose could be split between the first and second day of the first cycle or could be omitted until the second cycle.5

Neutropenia and leukopenia

CLL patients who develop neutropenia and/or leukopenia during treatment may need to have their therapy interrupted until their blood counts improve or to have the dose of therapeutic drug reduced. As a result, these patients do not receive optimal benefit from treatment with FCR.

Current CCO guidelines do not recommend the routine use of granulocyte colony-stimulating factor (GCSF) as either a primary or secondary prophylaxis in patients with CLL. However, the authors of the guidelines do state that selected patients with recurrent infections who are experiencing some benefit from their chemotherapy may benefit from GCSF to reduce infectious morbidity.8 In the CLL-8 study, 45% of patients in the FCR group and 23% of patients in the FC group received GCSF.5 Administration of GCSF was mandated in the event of grade 3/4 neutropenia with fever >38.5 °C or hypothermia, either with or without suspected or documented infection.

Purpose of this document

At the present time, no Canadian consensus on the best approach to administering the FCR regimen in patients with CLL has been established. The lack of consensus on best practices for preventing and managing infusion-related reactions and hematological adverse events, such as neutropenia or cytopenia, has led hospitals across Canada to develop FCR treatment algorithms that can provide the optimal benefit for their patients. While dose reductions for renal toxicities appear to be standard across most hospitals, there are variations in practices for preventing and managing infusion-related reactions in CLL patients with high tumour burden and elevated WBC counts.

In order to facilitate discussion toward establishing a Canadian consensus, this paper will discuss some Canadian practices for managing infusion-related reactions, with a focus on a meeting which took place in Ottawa on November 2010 and the subsequent development at The Ottawa Hospital (TOH) of a novel treatment algorithm for the administration of the FCR regimen in CLL.

Current options used to modify the rituximab administration protocol for CLL

Various options have been tried to minimize the risk of cytokinedependent infusion-related reactions. These options include administering rituximab at a reduced infusion rate for the first infusion, splitting the dose over two days for the first cycle, or omitting rituximab from the first cycle. However, limited data exist in the literature to guide clinicians on how to optimally administer rituximab when treating CLL.

The approach to managing patients at high risk of developing an infusion reaction differs from centre to centre within Ontario. For example, the current practice for rituximab infusions in patients with CLL at the Juravinski Hospital and Cancer Centre (JHCC) in Hamilton is to split the dose of rituximab over two days in patients who have absolute lymphocyte counts ≥25 x 109/L. In these patients, rituximab (50 mg/m2) is given on day 1 and rituximab (325 mg/m2) is given on day 2. For patients who do not exhibit a reaction with the first infusion, subsequent infusions may be given as a rapid infusion. In contrast, the preference at Princess Margaret Hospital (PMH) in Toronto is to slow down the rate of infusion in patients with high WBC counts. (Table 1)

The Ottawa Hospital meeting

In May 2010, CCO approved funding of rituximab in Ontario for the first-line treatment of CLL when combined with a fludarabine-based regimen. CCO funding has resulted in an increased use of rituximab across Ontario, but clear guidelines for its administration in CLL are lacking.

In November 2010, a meeting of pharmacists and nurses from TOH was convened to discuss the optimal manner in which the FCR regimen could be administered in treatmentnaïve patients with CLL. Topics tabled for discussion at the meeting included:

  • Pre-medications to prevent infusion reactions;
  • Managing patients with high tumour burden;
  • Managing hematological toxicities, infectious complications, and renal and hepatic impairment;
  • Oral fludarabine versus intravenous fludarabine for dosing flexibility.

During the discussion, participants agreed that since patients with CLL tend to exhibit more reactions to rituximab in cycle 1 (and sometimes even in cycle 2), the team would focus their immediate efforts on refining the FCR treatment protocol to prevent infusion-related reactions.

Developing a new strategy for FCR administration at The Ottawa Hospital

Since the November meeting, TOH has developed a novel approach to administering rituximab in patients with CLL receiving FCR therapy, leading to a new TOH algorithm for FCR administration.

Initial approach to rituximab administration in patients with CLL

Initially, the protocol for rituximab administration in CLL patients during cycle 1 of treatment was adopted from the CCO drug formulary. The formulary suggests considering either a slower infusion rate or split dosing over days 1–2 (± corticosteroids) for any cycle where the tumour load is high or the WBC is >25 x 109/L.7

For all patients with CLL receiving cycle 1 of FCR treatment at TOH, rituximab (375 mg/m2) was diluted in 1 litre of NaCl 0.9%. Infusion rates started at 50 mL/hour and were increased according to the TOH protocol and a nurse’s evaluation of the patient. Pre-medication with acetaminophen and diphenhydramine, and a saline bolus were used. For patients known to have a WBC count >25 x 109/L, steroids were added to the pre-medication regimen. For this patient population, the rituximab infusion rate was increased at a slower pace as per the nurse’s discretion.

Collection of data from 28 CLL patients receiving rituximab in combination with a fludarabinebased regimen

Data was collected to help assess the effectiveness of the treatment algorithm based on the CCO drug formulary. Twenty-eight (28) patients with CLL who had received a fludarabine-based regimen in combination with rituximab since May 2010 were available for review. Modifications of the algorithm occurred throughout the year to help minimize infusion- related reactions. The goal for the treatment algorithm was improved tolerability of each cycle.

Assessment of the TOH data showed that patients with CLL tended to react to rituximab more often than patients receiving rituximab for other indications. Reactions included chills, rigors, rash, hypotension, throat soreness or tightness, and heaviness in the chest.

Assessment and modification of the rituximab administration protocol for cycle 1

Sixteen (16) of the 28 patients reacted during their first infusion. Four of these patients did not exhibit signs of tumour burden and were not expected to react. The remaining 12 patients had an elevated WBC count at the time of rituximab infusion.

Based on these results, it was decided to repeat acetaminophen and diphenhydramine four hours after the initial dose for all cycle 1 patients. Intravenous steroids were also added to the pre-medication regimen for all cycle 1 patients.

This intervention was not completely successful, as the majority of patients (n = 7/13) still reacted, despite steroids and a second dose of acetaminophen and diphenhydramine. (Figure 1)

Assessment and modification of the rituximab administration protocol for cycle 2

Patients who completed cycle 1 of rituximab treatment subsequently received rituximab during cycle 2 at 500 mg/m2 in 250 mL NaCl 0.9%. The rituximab infusion was initially given at 100 mL/hour for 30 minutes. If the vital signs and the patient were stable, the rate was then increased to 300 mL/hour for the remainder of the infusion. This cycle exposed the patient to a higher dose of rituximab in a more concentrated form and at a faster rate of infusion.

Three patients experienced infusion-related reactions during cycle 2. Two of these patients had been pre-medicated with steroids. In two of the three patients, the reaction occurred before the infusion rate was increased. All three patients required the rate to be capped at 100 mL/hour in order to complete the infusion.

Following assessment of patients receiving cycle 2 of rituximab treatment, the protocol was modified to cap the rate at 100 mL/hour for all cycle 2 infusions. If cycle 2 proceeded without incident, rituximab was then administered according to the TOH lymphoma-based rapid infusion protocol for cycle 3 onward.

Interestingly, two of the three patients who experienced infusion-related reactions during cycle 2 had not had a reaction during cycle 1. Consequently, steroids were included in the protocol as a pre-medication for cycle 2. Most patients had already been scheduled to receive steroids as a premedication for cycle 2, because they had reacted during cycle 1. However, this change resulted in one extra patient receiving steroids prior to cycle 2. No infusion-related reaction was observed in this patient.

Assessment of other protocol modifications

Of the 28 TOH patients with CLL included in the review, those who had elevated WBC counts experienced the greatest number of infusion-related reactions during cycle 1 of rituximab therapy, despite steroid pre-medication and a slow rate of dose escalation. Two other strategies to minimize infusion-related reactions were therefore tried with eight of the patients: dividing the rituximab dose over two days for cycle 1 or omitting rituximab from cycle 1.

In both groups, 50% of patients still experienced infusionrelated reactions. Also, the split-dose regimen required a twelve-hour bed to be available for two consecutive days. If this option were to be chosen, initiating treatment could be delayed. Finding a twelve-hour appointment on two consecutive days is extremely difficult, due to limited capacity and other scheduled treatments.

Arriving at a new TOH rituximab administration protocol for patients with CLL

While searching for ways to minimize patient reactions during rituximab infusions, TOH decided to administer rituximab on day 3 of cycle 1 for patients with high WBC counts. This approach, however, did not capture patients with low WBC counts who had reacted to treatment with rituximab. Additionally, some patients who did not have elevated WBC counts at the time of evaluation in the clinic did have high WBC counts on the day of treatment. Therefore, in February 2011, the TOH rituximab treatment protocol was modified to administer rituximab on day 3 rather than day 1 for all cycle 1 patients. Rituximab would then be given on day 1 for subsequent cycles. (Figure 2)

None of the three patients who received rituximab on day 3 experienced infusion-related reactions. Of note, all three patients had an elevated WBC count >25 x 109/L.

Conclusions and Future Direction

The review of TOH patients who received rituximab for CLL showed it to be difficult to predict which patients would experience an infusion-related reaction. This observation is corroborated by the 2003 Byrd et al. study, which concluded that none of the pre-treatment variables (age, stage, β2M level, leukocyte count) could predict which patients would have severe infusion-related toxicity.9

Deferring rituximab to the final day of treatment for cycle 1 appeared to eliminate infusion-related reactions at TOH. The team at TOH will continue to collect data to determine if this trend continues and if further refinements to the treatment algorithm are needed.

Although the number of patients in the TOH review was small, the TOH experience may help improve tolerability so that patients can receive the proven benefit of the addition of rituximab to a fludarabine-based regimen. In the ongoing discussion toward a Canadian consensus on the administration of FCR in patients with CLL, the TOH experience is an important step.


The authors would like to acknowledge the contribution of Lisa Buchner, BSc Pharm, ACPR and Darcy McLurg, BSc Pharm, ACPR, malignant hematology pharmacists at TOH, for their aid in developing the TOH FCR administration protocol.

References: 1. Smolej, L. Modern concepts in the treatment of chronic lymphocytic leukemia. Hematology 2009;14(5):249–254. 2. Public Health Agency of Canada. Cancer surveillance on-line: chronic lymphocytic leukemia, both sexes combined, all ages, 2007. cancer/c_quik-eng.php. Accessed April 2011. 3. Flinn IW, Neuberg DS, Grever MR, et al. Phase III trial of fludarabine plus cyclophosphamide compared with fludarabine for patients with previously untreated chronic lymphocytic leukemia: US Intergroup Trial E2997. J Clin Oncol 2007;25:793–98. 4. Catovsky D, Richards S, Matutes E, et al. Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF CLL4 Trial): a randomised controlled trial. Lancet 2007;370:230–39. 5. Hallek M, Fischer K, Fingerle-Rowson, et cal. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 4 trial. Lancet 2010;376:1164–1174. 6. Hoffman-La Roche Ltd. PrRITUXAN® product monograph. January, 2011. 7. Cancer Care Ontario. Drug formulary. Chemotherapy regimens in CLL: rituximab treatment (in combination with fludarabine-based regimes). Accessed April 2011. 8. Kouroukis GT and Haynes AE. The prophylactic use of filgrastim in patients with hematological malignancies. Cancer Care Ontario Special Advice Report #14-1, September 23, 2009. http://www.cancercare. Accessed April 2011. 9. Byrd JC, Peterson BL, Morrison VA, et al. Randomized phase 2 study of fludarabine with concurrent versus sequential treatment with rituximab in symptomatic, untreated patients with B-cell chronic lymphocytic leukemia: results from Cancer and Leukemia Group B 9712 (CALGB 9712). Blood 2003;101:6–14.

Download Journal


Presentations and Commentaries

Joseph M. Connors, MD, FRCPC
Dr. Joseph Connors is a clinical professor in the Department of Medicine, Division of Medical Oncology, at the University of British Columbia and the Clinical Director of the BC Cancer Agency Centre for Lymphoid Cancer. He is best known for his clinical investigations into the treatment of Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, chronic lymphocytic leukemias and multiple myeloma. He serves as a member of the executive committee of the Hematology Site Group for the National Cancer Institute of Canada Clinical Trials Group, as chair of the Educational Affairs Committee of the American Society of Hematology, and on the scientific advisory boards of the Lymphoma Foundation Canada and the Lymphoma Research Foundation of the United States. Dr. Connors has published over 250 peer-reviewed scientific articles addressing various aspects of research into lymphoid cancers.

Martin Dreyling, MD, PhD
Dr. Martin Dreyling is an attending physician and associate professor in the Medical Department of the University of Munich, Grosshadern, Germany. His primary interests include the molecular biology and clinical care of lymphoma. Dr. Dreyling’s research activities relate to the molecular basis of malignant transformation, cell cycle dysregulation in mantle cell lymphoma (MCL), secondary genetic alterations and biological prognostic factors in malignant lymphoma, and innovative therapeutic approaches in indolent lymphoma. He is actively involved in a number of national and European study groups, and is currently the Coordinator of the European MCL Network. Dr. Dreyling has co-authored over 300 scientific papers, book chapters and published abstracts in international peer-reviewed journals.

Gilles Salles, MD
Dr. Gilles Salles is a Professor in the Department of Hematology at the Centre Hospitalier Lyon-Sud, Lyon, France, and Head of the Research Unit Pathologie des Cellules Lymphoïdes at the University of Lyon. He served as Chairman of the Scientific Committee of GELA (Groupe d’Etude des Lymphomes de l’Adulte) until 2007 and is presently acting as vice-president of this group. He is also a member of several professional societies, including the American Society of Hematology, the American Society of Clinical Oncology, and the European Hematology Association. Professor Salles has been especially interested in the clinical and biological study of malignant lymphoma, and major focuses of his work include the description and validation of prognostic factors as well as clinical trials in indolent lymphomas. He has been involved as a coordinator or co-investigator in many clinical trials and studies within his field, and has published numerous articles in international peer-reviewed journals.

James Johnston, MD, FRCP
Dr. James Johnston is a professor in the Department of Internal Medicine at the University of Manitoba and a Hematologist at CancerCare Manitoba. He is primarily interested in the treatment of chronic lymphocytic leukemia (CLL) and is responsible for the CLL clinic at CancerCare Manitoba. He is also the Clinical Director of the Manitoba CLL Tumour Bank. Dr. Johnston’s research activities relate to the epidemiology of CLL and to the mechanism of action of anti-tumour agents in this disease. He is involved in a number of educational activities related to CLL and with Dr Spencer Gibson organizes the “Canadian CLL Meeting” which is held annually in Winnipeg.