Guidelines for the use of Rituximab in Non-Hodgkin’s Lymphoma QEII Health Sciences Centre
Background
Non-Hodgkin’s lymphoma (NHL) makes up approximately 85% of all lymphomas. They are a heterogeneous collection of lymphoid malignancies with a progressive increase in incidence with age. It is estimated that there will be 5800 new cases of Non-Hodgkin’s lymphoma in Canada with 195 of these in Nova Scotia in 1999.
The low-grade lymphomas are predominantly B-cell tumours. Low-grade NHL is usually diagnosed as systemic disease and approximately 90% will have Stage III or IV disease. The majority of patients with indolent B-cell lymphoma have progressive disease and cannot be cured presently. Drug development for the treatment of low grade NHL has mainly focused on
cytotoxic drugs. The natural history of the disease is not altered despite continued interventions with conventional single agent chemotherapy, combination chemotherapy, bone marrow or peripheral stem cell transplantation and/or radiation therapy.
Patients with relapsed low grade NHL (follicular being the most common sub-type) do respond to therapy and initially achieve objective clinical responses. However, as further relapses occur, the responses are lower and of shorter duration. The median duration of survival is from 6 to 10 years. In some cases patients will be symptom free for long periods and live an excellent quality of life.
There is continued need for alternate methods of treatment and potential for long-term survival.
Standard Treatment
Low-grade NHL is usually diagnosed as systemic disease. Due to the indolent nature of the disease, the decision to initiate therapy is often difficult. Patients who are treated often respond well to initial therapy with oral alkylator chemotherapy. Eventually patients are exposed to single or combination intravenous chemotherapy and/or radiotherapy. As with other disease sites, the search continues for new agents, particularly with different modes of action. Agents that have a decreased toxicity profile would be of interest as these patients often have diminished marrow function.
With the advent of monoclonal antibody technology, interest has focused on patient-specific antibody production. This would not seem practical for a general application. The antigen CD20, a 32-KD monoglycosylated phosphoprotein, is expressed on greater than 90% of B-cell NHL’s but is not found on hematopoietic stem cells, early pre-B cells, normal plasma cells or other normal tissues. It is expressed at a lower density on B-cell chronic lymphocytic leukemia. Antigen CD20 is involved in the regulation of cell cycle initiation and differentiation and may also function as a calcium ion channel. Antibodies binding to the surface CD20 can cause a variety of effects on the cells which include cell cycle progression and differentiation.
Murine antibodies have limited usefulness in clinical trials due to the immune responses to non-human protein. Genetically engineered chimeric antibodies with murine binding sites and non-human constant regions have lower immunogenicity, longer half-life and are able to lyse tumour cells using human complement or antibody-dependent cell-mediated cytotoxicity (ADCC).
Rituximab, a chimeric human murine anti-human antigen CD20 monoclonal antibody was produced. Rituximab binds specifically to the antigen CD20, a hydrophobic transmembrane protein located on normal, malignant pre-B and mature B-lymphocytes.
Treatment with Rituxan® depletes the pool of circulating B-cells. B-cell recovery begins at approximately 6 months following the completion of treatment and median B-cell levels return to normal by 12 months.
Rituximab (Rituxan®) has been approved by the Food and Drug Administration (FDA) in the U.S.A. in November, 1997. This was the first monoclonal antibody approved in the US to treat malignant disease. Rituxan® has not yet received Health Protection Branch (HPB) approval for commercial use in Canada. The drug is only available on a special access program with specific inclusion/exclusion criteria. Presently, the special access program includes patients with
histologically confirmed low-grade or follicular CD20 positive, B-cell NHL which has relapsed or has failed previous therapy and demonstrates progressive disease.
Clinical Studies
Preclinical studies with the chimeric antibody demonstrated depletion of B-cells in blood and lymph nodes in Macaque monkeys. Dose finding Phase I studies consisted of a dose escalation single dose trial by Maloney et al (1994). Fifteen low-grade B-cell lymphoma patients were allocated to selected doses of antibody. Modest tumour responses and acceptable toxicity profile led to a multiple dose regimen. A Phase I study by Tobinai et al (1998) enrolled 12 patients with relapsed B-cell lymphoma to a four dose regimen of 250 mg/m2 and 375 mg/m2 of antibody. It was determined that the four weekly doses of 375 mg/m2 were safe and that seven responders had lymphoma with follicular histology. Another published Phase I trial by Maloney et al (1997) included patients with relapsed low-grade or intermediate/high-grade lymphoma who were treated with four weekly doses of antibody with escalating dosing regimens of 125, 250, or 375 mg/m2. The overall response rate was in the order of 33% and the antibody appeared to be most active in patients with low-grade or follicular histologies.
The Phase II program utilized the antibody IDEC-C2B8 at a four weekly intravenous infusion of 375 mg/m2. Maloney et al (1997) enrolled 37 patients with relapsed low-grade or follicular NHL. The overall response rate was 46% with TTP of 10.2 months. The adverse event profile was predominantly infusion-related. All clinical remissions in this study were identified in patients with a follicular histology while none of the four patients with small lymphocytic lymphoma responded. One patient with mantle cell histology did not respond. It is also important to note that there appeared to be a correlation between the duration of response to the last chemotherapy and the response to the antibody. Patients with less than a 6 month response to the last
chemotherapy had a 30% response rate while those who had a response duration greater than 6 months demonstrated a 65% response rate.
A larger multicentre Phase II study by Coiffier et al (1998) evaluated the efficacy and tolerability of the antibody in more aggressive lymphoma. Fifty four patients were randomized to an eight weekly infusion at 375 mg/m2, or one 375 mg/m2 infusion followed by 7 weekly infusions of 500 mg/m2. The overall response rate was 31% with no difference between the two doses. Long-term follow-up was not planned in this study, therefore, TTP is unclear. It is known that the median TTP exceeded 3.5 months and that in the group of 17 responders, the TTP exceeded 8.2 months. In the study analysis of prognostic factors for response, it was identified that the response rates were lower in patients with refractory disease, patients not classified as those with diffuse large B-cell lymphoma and patients with a tumour larger than 5 cm in diameter. The mean total infusion time for the first infusion was approximately 5 hours in both arms (range 0.5 to 10.1
hours). Fifteen patients experienced a serious adverse event (AE), however, only two patients were withdrawn from the study due to AE’s and no toxic deaths were observed.
The largest study reported by McLaughlin et al (1998) of 166 patients with relapsed low-grade or follicular lymphomas used the low-dose 375 mg/m2 intravenous weekly program. The overall response rate was 48% with a median TTP of 13 months. The long-term follow-up of this trial reported a median TTP of 13.2 months with a median duration of response of 11.6 months. This is the single largest trial which included the following histologies:
33 patients with small lymphocytic lymphoma 67 with follicular small cleaved
53 with follicular mixed
3 with other low-grade lymphoma variants and 10 with follicular large cell
Significantly lower response rates were noted in the small lymphocytic lymphoma group, positive bone marrow patients, patients with greater than or two extranodal sites and among the follicular lymphoma patients, those without detectable bcl-2 gene rearrangement by PCR in the peripheral blood or bone marrow. It is interesting to note that the patients who had prior stem-cell or bone marrow transplantation had a statistically significant response rate over those who did not (78% vs 43%). Again the majority of adverse events occurred during the first infusion. The median duration of nausea was one hour, fever 3 hours, bronchospasm less than 30 minutes, hypotension 1.6 hours, rash and pruritus 2 hours. The mean duration of the first dose was 5.2 hours (range 2.5 to 20 hours).
A recent published non-randomized Phase II trial by Davis et al, reported on 31 patients with bulky (>10 cm lesion) relapsed or refractory low-grade or follicular NHL. The overall response rate was 43% with a median TTP of 8.1 months.
Various abstracts from recent conferences and meetings have identified the extent to which this monoclonal antibody may be used in hematologic malignancies. A report by Byrd et al (1998) reviewed the response in seven Waldenstrom’s macroglobulinemia (WM) patients. WB is a rare low-grade lymphoproliferative disease which exhibited a 57% response rate with rituximab therapy. The median progression-free survival was 8 months. This was observed in pre-treated patients.
A dose escalation study of rituximab therapy in chronic lymphocytic leukemia (CLL) was conducted by O’Brien et al (1998). There is a concern that results of this study may be similar to the small lymphocytic lymphoma patient population in previous trials. It is postulated that reduced response rates may be related to low density of CD20 antigen and/or higher circulating B-cell counts. This trial is ongoing.
A Phase II retreatment trial was conducted by Davis et al and reported (1998) on 60 patients with low-grade follicular NHL who had previously received and responded to rituximab therapy. The overall response of the group was 41% and the median TTP had not been reached after 10 months. This is a particularly interesting trial in view of the fact that patients usually have lower response rates and shorter durations of disease-free interval with repeated chemotherapy.
Combination studies with such agents as chemotherapy and biologicals have been reported in recent publications and abstracts. In a study by Czuczman et al, 40 low-grade NHL patients were treated with a combination of antibody and CHOP chemotherapy. The overall response rate was 95%. Median duration of response and TTP had not been reached after a median observation time of 29+ months. This study included both newly diagnosed and relapsed/refractory patients.
A combination study of CHOP chemotherapy and rituximab in previously untreated intermediate or high-grade NHL was reported by Link et al (1998). Thirty patients were evaluated for an overall response of 84%. The toxicity profile was tolerable with the adverse events similar to that of the chemotherapy alone. Davis et al (1998) reported a study of alpha interferon and rituximab therapy of 31 refractory or relapsed low-grade follicular NHL patients. The overall response rate of 26 patients evaluable was 58%.
A trial reported by Tsai et al (1998) has identified the value of rituximab therapy in intermediate grade NHL after high dose therapy and stem cell transplant. After antibody therapy, a response rate of 85% was observed. Two patients progressed very early on and was retreated with rituximab. The antibody appears to have significant activity despite high dose therapy and is adequately tolerated.
An induction and maintenance study of 23 patients with untreated low-grade NHL was reported by Hainsworth et al (1999). Patients were treated with the weekly four dose regimen. Patients with objective response or stable disease were then retreated at 6 month intervals for a total of four courses. Objective response rate of 67% was reported and found to be an alternative to initial chemotherapy. Long-term follow-up is pending.
Two abstracts are reported on the economic aspect of rituximab. A retrospective questionnaire-based analysis reviewed the comparative costs of CHOP chemotherapy, fludarabine, and rituximab. All costs included method of administration, antiemetics, antibiotic prophylaxis, management of adverse events, drug costs, intensive care utilization and diagnostic tests. This study suggests that the costs of the use of rituximab appears to be comparable to CHOP and less than fludarabine. This analysis has been done in the United Kingdom and has not been translated into Canadian data. An American one year cost of treatment of rituximab compared to
fludarabine was reported at ASCO, 1999. All costs as described in the abstract included drug cost, infusion supplies, physician visits, laboratory, neutropenic events, radiology, concomitant medications related and non-related hospital visits. The average annual costs were nearly identical for both treatments. These data are preliminary and require a prospective, randomized trial which would include a cost-effectiveness analysis.
Approved Use
1. Patients must have histologically confirmed follicular small cell or follicular mixed cell CD 20 positive B-cell NHL.
2. Monotherapy with a limit of weekly four dose treatment program.
3. Patients may be considered for rituximab monotherapy at symptomatic second relapse or beyond. There may be other treatment alternatives including radiation, chemotherapy and high dose therapy which would provide reasonable treatment alternatives.
4. ECOG performance status of 0-2.
5. Patients must have adequate recovery period from prior surgery, radiation, chemotherapy, immunotherapy or bone marrow transplant.
6. Patients must have adequate cardiac function or absence of MI within the past 6 months. Other serious non-malignant diseases, such as CHF, hydronephrosis, or uncontrolled bacterial, viral or fungal infections, would exclude the use of this agent.
Note: Special approval of rituximab for patients outside the approved use can be sought through the Oncology Therapy Subcommittee (Chair) or their designate. Requests should be submitted in writing with specific references included. Guidelines will be updated and modifications made on the basis of published studies only.
Expected Patient Numbers
It is estimated that for:
Rituximab (based on a BSA = 1.7m2) 375 mg/m2 = 638 mg on Day 1, 8, 15 and 22 Rituximab 10 patients/year will be treated
Drug Estimated Cost/patient/course (i.e. Day 1,8, 15 & 22)
Rituximab $7,200.00
Approximate Drug Cost per Year (1999/2000) Rituximab = $ 144,000.00
*Note: There is currently an associated drug cost as described above for rituximab on the special access program.
Side Effects
The side effect profile is based on pooled data from 315 patients who received rituximab in single agent clinical trials.
Infusion-Related Symptoms Fever Chills/Rigors Nausea/Vomiting Asthenia Headaches Urticaria Pruritus Bronchospasm Dyspnea Angioedema Rhinitis Hypotension Flushing
Pain at Disease Site
The reactions occurred within 30 minutes to 2 hours after beginning the first infusion - limited to duration of infusion – resolved with slow or interruption of infusion and supportive care (IV saline, diphenhydramine and acetaminophen). Incidence decreased from 80% (7% grade3\4) during from first infusion to approximately 40% (5-10% grade 3\4) with subsequent infusions.
Recommendation
Premedicate with acetaminophen 650 mg po, and diphenhydramine 25 mg po, 30-60 minutes prior to infusion
Bronchodilators may be given for bronchospasm (- may recommend not taking blood pressure
medication for 12 hours before infusion) mild to moderate hypotension, stop infusion or use IV saline First infusion – initiate infusion at 50 mg/hour, if
tolerated, escalate rate in 50 mg/hour increments every 30 minutes to a maximum of 400 mg/hour
Subsequent infusion – initiate at 100 mg/hour, escalate rate in 100 mg/hour increments every 30 minutes to a maximum of 400 mg/hour
Potentially fatal serious infusion related events can occur. Between Nov/97 and Dec/98 the manufacturer reported 70 cases of serious infusion related events (out of estimated 12,000-14,000 patients) 8 of
which were fatal. A common pattern of predisposing factors were not identified but patients with a large tumour burden and/or circulating malignant cells (exceeding 50,000/mm3) may be at increased risk of severe reactions
Hematologic Severe Thrombocytopenia 1.3%
Severe Neutropenia 1.9% Severe Anemia 1.0%
Hypersensitivity Management Recommend:
- medications for treatment of hypersensitivity i.e. epinephrine, antihistamine and corticosteroids should be available – A designated physician should be available during the infusion
Cardiac Management Recommend:
- patients who have developed clinically significant arhythmias – have cardiac monitor available
Immunological Events - B-cell depletion occurred in 70-80%
Tumour Lysis Syndrome Rituxan rapidly decreases benign and malignant CD20 positive cells. Tumour lysis syndrome has been reported to occur within 12 to 24 hours after the first infusion in patients with high numbers of circulating malignant lymphocytes. Patients with bulky lesion may also be at risk.
Recommend:
Identify patient at risk and follow closely with laboratory monitoring and treatment.
Dose – 375 mg/m2 IV infusion once weekly days 1, 8, 15 and 22 Single doses higher than 500 mg/m2 have not been tested
Summary
There are many difficult issues to examine when reviewing the use of this agent. Single agent use in the most sensitive follicular histologies, treatment in rare disorders (such as WM) response rates in less responsive histologies (such as small lymphocytic or mantle cell lymphomas) retreatment issues, combination issues, treatment in previously untreated patients, maintenance therapy and post-transplant use. Current data is limited to response and response duration (in some circumstances not reported) only. No long-term outcomes have been reviewed with survival data lacking. Rituximab, a novel monoclonal antibody has shown significant activity in a variety of hematologic malignancies and research will continue in all histologic categories. Presently, one is confined to determine the optimal use of this agent. With the lack of comparative data to standard chemotherapy, the drug has shown the highest response rate in patients with follicular small cell or follicular mixed cell NHL. The treatment is fairly well tolerated with a possible infusion related cytokine release syndrome. Careful monitoring, patient selection and consent is vital.
Restrictions for Use
Restricted to hematologist/medical oncologist for the treatment of patients with relapsed or refractory follicular small cell or follicular mixed cell, CD20 positive, B-cell NHL as per eligibility criteria as defined in the approved use indications.
Treatment Location
Patients will be treated in an out-patient oncology clinic area. Arrangements to have the patient admitted to hospital should be considered in the event of severe infusion related or
hypersensitivity reactions. A small portion of patients may initiate therapy as hospital in-patients.
Original Date Prepared: July, 1999
Review Date: July 2000
Prepared by: Dr. S. Couban, Hematologist/Bone Marrow Transplant
Marlene Sellon, Pharmacist
Reviewed by: Division of Hematology
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