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Guidelines for the use of Rituximab in Non-Hodgkins Lymphoma.pdf

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					             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 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).




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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


                                                                                                  2
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.


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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.




                                                                                                      4
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.




                                                                                                    5
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.




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                Side Effects
                       The side effect profile is based on pooled data from 315 patients who received rituximab in single agent clinical trials.
                                                                            Fever                                                             The reactions occurred within 30 minutes to 2 hours after
                                                                            Chills/Rigors                                                     beginning the first infusion - limited to duration of infusion –
Infusion-Related Symptoms                                                   Nausea/Vomiting                                                   resolved with slow or interruption of infusion and supportive
                                                                            Asthenia                                                          care (IV saline, diphenhydramine and acetaminophen).
                                                                            Headaches                                                         Incidence decreased from 80% (7% grade3\4) during from
                                                                            Urticaria                                                         first infusion to approximately 40% (5-10% grade 3\4) with
                                                                            Pruritus                                                          subsequent infusions.
                                                                            Bronchospasm
                                                                            Dyspnea                                                           Recommendation
                                                                            Angioedema                                                             Premedicate with acetaminophen 650 mg po, and
                                                                            Rhinitis                                                               diphenhydramine 25 mg po, 30-60 minutes prior to
                                                                            Hypotension                                                            infusion
                                                                            Flushing                                                               Bronchodilators may be given for bronchospasm
                                                                            Pain at Disease Site                                                   (- 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                Recommend:
                                                                           positive cells. Tumour lysis syndrome has been reported to         Identify patient at risk and follow closely with laboratory
                                                                           occur within 12 to 24 hours after the first infusion in patients   monitoring and treatment.
                                                                           with high numbers of circulating malignant lymphocytes.
                                                                           Patients with bulky lesion may also be at risk.
                                             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



                                                                                                                                                                                                            7
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
                                 Department of Medicine




                                                                                                    8
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