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Rituximab for the treatment of chronic lymphocytic leukaemia

Source agency:

LBI -HTA

Date of Submission:

20/11/2009

Date of Printing:

03/09/2010

Disclaimer:

This report is work in progress and should not be used for external distribution without permission from the originating agency. Users should be aware that reports are based on information available at the time of research and often on a limited literature search.

Technology, Company & Licensing

Technology name:

Rituximab, Rituxan®, MabThera®

Technology - description:

Rituximab belongs to the pharmacotherapeutic group of antineoplastic agents and monoclonal antibodies (ATC code: L01XC02).
Rituximab is a chimeric murine/human anti-CD20 monoclonal antibody targeted against the cluster of differentiation (CD) 20 antigen expressed on the surface of human B-cells. By binding to the CD20 antigen it promotes antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity and induces lysis and apoptosis of normal and malignant hu-man B- cells. Furthermore, it sensitises malignant B-cells to the cytotoxic effect of chemotherapy.

The recommended treatment regimen consists of six treatment cycles of rituximab in combination with fludarabine and cyclophosphamide at intervals of 28 days (= 1 cycle). Rituximab is administered only once at the beginning of every cycle with an initial starting dose of 375mg/m2 body surface area (BSA) intravenously (IV) (Cycle 1), followed by 500mg/m2 IV (Cycle 2-6).

Company or developer:

Hoffmann-La Roche Ltd. , Genentech, Inc., and Biogen Idec

Reason for database entry:

major health benefit expected, high costs & additional therapy - major financial impact

Technology - stage in early warning process:

Assessment complete

Technology - stage of development:

Established

Licensing, reimbursement and other approval:

Rituximab (MabThera®) was approved by the European Medicines Agency (EMEA)

- for the first-line treatment of patients with CLL in combination with chemotherapy in January 2009.

- for the treatment of NHL (first approval was granted in 1998 with subsequent extensions of indication), including

- previously untreated patients with stage III-IV follicular lymphoma in combination with chemotherapy.

- maintenance therapy of patients with relapsed/refractory follicular lymphoma responding to induction therapy with chemotherapy with or without rituximab.

- monotherapy of patients with stage III-IV follicular lymphoma who are chemoresistant or are in their second or subsequent relapse after chemotherapy.

- patients with CD20-positive, diffuse large B-cell NHL in combination with cyclophosphamide, doxorubicin, vincristine, prednisolone (CHOP) chemotherapy.

- in combination with methotrexate for adult patients with severe active rheumatoid arthritis who have had an inadequate response or intolerance to other disease-modifying anti-rheumatic drugs including one or more tumour necrosis factor inhibitor therapies in June 2006.

In addition, the Committee for Medicinal Products for Human Use of the EMEA adopted a positive opinion to recommend MabThera® in combination with chemotherapy for the treatment of patients with relapsed/ refractory CLL in July 2009.

Technology - type(s):

Drug

Technology - use(s):

Therapeutic

Patient Indication & Setting

Patient indications:

Rituximab is indicated for the first-line treatment of patients with chronic lymphocytic leukaemia (CLL) in combination with chemotherapy.

Disease description and associated mortality and morbidity:

Chronic lymphocytic leukaemia (CLL) belongs to the entity of indolent B-cell non-Hodgkin lymphomas (NHL) and is the most common adult leu-kaemia in the Western World. It accounts for 40% of all leukaemias in individuals aged more than 65 years with men being affected twice as often as women. The median age of presentation is 70 to 74 years.
Risk factors for developing CLL include older age, male sex, white ethnicity, family history of CLL or other blood and bone marrow cancers and exposure to certain chemicals, such as herbicides and insecticides.
In the majority of cases CLL is diagnosed incidentally by routine complete blood count examination. Most patients are asymptomatic at the time of diagnosis. The most common symptom is lymphadenopathy, followed by so called “B” symptoms, including fever, night sweats and weight loss. The life expectancy of patients with early stage disease at diagnosis is greater than ten years but decreases with advanced disease at diagnosis to a median survival of less than one year.
According to the recently updated National Cancer Institute-Working Group 1996 guidelines for the diagnosis and treatment of chronic lymphocytic leukaemia, the diagnosis of CLL requires a B lymphocytosis of ≥5.0 x 109/L with characteristic morphology and immunophenotype in the peripheral blood for at least three months. Interphase fluorescence-in situ hybridization (FISH) is recommended at diagnosis to identify cytogenetic lesions, such as deletion in the short arm of chromosome 17 (del(17p)) which is associated with resistance to standard chemotherapy regimens and poor prognosis.
There are two classification systems for the clinical staging of CLL, depending on standard laboratory tests and physical examination, including the Rai classification and the Binet staging system. The Rai classification distinguishes low (formerly Rai stage 0), intermediate (formerly Rai stage I or II) and high (formerly Rai stage IV and V) risk disease, whereas the Binet staging is subdivided into stage A, B and C.
The prognosis of CLL depends upon several factors und might be worsened by advanced disease stage, short lymphocyte doubling time, higher levels of beta-2-microglobulin, absence of immunoglobulin variable region heavy chain mutation, ZAP-70 (zeta-chain associated protein kinase 70) positivity, FISH chromosomal abnormalities and CD38 positivity.
Standard treatment options for patients with CLL comprise watchful waiting, radiation therapy, chemotherapy, corticosteroids, and monoclonal anti-body therapy.
The initiation of treatment is not recommended for asymptomatic early-stage disease (Rai 0, Binet A). In these patients a watch-and-wait strategy with controls of blood cell counts and clinical examination every three to six months is recommended until there is evidence of disease progression. In patients with intermediate and high risk disease, according to the Rai classification as well as patients with Binet stage B or C disease, the initiation of treatment is recommended, whereas some patients with intermediate disease or Binet stage B might as well be monitored until disease progresses. Disease progression requiring treatment is based on certain criteria, such as increasing adenopathy, hepatosplenomegaly, development of auto-immune cytopenias, and marrow failure.

Number of Patients:

In Austria the overall incidence of all forms of leukaemia (C91-C95 accord-ing to the World Health Organization’s International Classification of Diseases - 10 was 7.3/100,000/y in 2006. Among males, the incidence was 8.6/100,000/y, whereas among females it was 6.3/100,000/y in 2006. The overall death rate of all forms of leukaemia was 4.6/100,000/y in Austria in 2006. Within men, the death rate was 5.9/100,000/y and within women it was 3.7/100,000/y in 2006.

Technology - specialities(s):

Oncology & radiotherapy, Haematology & blood products

Technology - setting(s):

General hospital and ambulatory care, Specialist hospital

Setting - further information:

 

Impact

Alternative and/or complementary technology:

Additive or complementary technology

Current Technology:

There are various treatment options for CLL depending on disease stage, patient’s age, presence of cytogenetic lesions, concomitant diseases and – with second line therapy – duration of response, including (ordered from the least to the most toxic options)
- Observation watchful waiting
- Oral alkylating agents (chlorambucil) with or without corticoster-oids
- Purine analogs (fludarabine, 2-chlorodeoxyadenosine, pentostatin)
- Combination chemo(immuno)therapy (e.g. fludarabine + cyclo-phosphamide (FC), cyclophosphamide + vincristine + prednisone (COP), cyclophosphamide + doxorubicin + vincristine + prednisone (CHOP), fludarabine + cyclophosphamide + mitoxantrone (FCM), bendamustine, besides others)
- Involved-field radiation therapy
- Radioimmunotherapy
- Anti-CD52 monoclonal antibody (alemtuzumab)
- Bone marrow and peripheral stem cell transplantations are cur-rently under clinical evaluation in patients younger than 60 years with adverse prognostic factors
The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology provide detailed information on current treatment options for both first- and second-line therapy of CLL.

Health Impact:

 

Diffusion:

 

Cost, infrastructure and economic consequences:

In Austria rituximab is marketed by Roche Austria, Vienna. One package of 100mg rituximab (10mg/ml) concentrate for solution for infusion consisting of two single-use vials is € 616.15. In addition, one package of 500mg rituximab (10mg/ml) concentrate for solution for infusion containing one single-use vial is € 1,492.75.
Assuming an average body surface area, based on height and weight, of 1.7 m2 for both men and women, total treatment costs for the recommended ri-tuximab regimen can be estimated. The first cycle of rituximab infusion would be € 2,109, followed by € 2,725 for cycle two to six (assuming that two packages containing two 100mg vials are used) which would add up to total treatment costs of € 15,734 in addition to chemotherapy.

Ethical, social, legal, political and cultural impact:

 

Evidence & Policy

Clinical evidence and safety:

Phase III studies:

Sponsor: Hoffmann-La Roche Ltd, Basel, Switzerland

Country: Multicentre – International (190 study sites across 11 countries)

Design: Prospective, randomised, open-label, active control
(Randomisation stratified by country and disease stage according to the Binet staging system), crossover (patients with stable disease or progressive disease after three cycles of treatment were withdrawn from study treatment and eligible to receive alternative treatment, including rituximab-containing regimens)

Participants characteristics:
n=817 patients (pts) (I: 408 vs. C: 409); median age I: 61y (30-80y), C: 61y (36-81y)

Treatment:
I(ntervention): Rituximab +Fludarabine + Cyclophosphamide for a total of six treatment cycles at intervals of 28 days
Rituximab IV infusion before FC infusion
Cycle 1: 375mg/m2 IV; d0
Cycle 2-6 : 500mg/m2 IV ; d1
Fludarabine IV infusion over three days for six treatment cycles (25mg/m2/day IV; d1-d3)
Cyclophosphamide IV infusion over three days for six treatment cycles (250mg/m2/day IV; d1-d3)
C(ontrol): Fludarabine + Cyclophosphamide
Fludarabine IV infusion over three days for six treatment cycles (25mg/m2/day IV; d1-d3)
Cyclophosphamide IV infusion over three days for six treatment cycles (250mg/m2/day IV; d1-d3)

In-/exclusion criteria:
Inclusion criteria: Patients with untreated, active B-cell CLL and good physical fitness (CIRS1 score ≤6), Binet stage B and C requiring treatment (certain criteria have to be fulfilled), age ≥18 years, expected survival >6 months, EC OG2 performance status 0-1
Exclusion criteria: Binet stage A, prior chemotherapy and/or radiotherapy, clinically significant auto-immune cytopenia, Coombs-positive haemolytic anaemia as judged by the treating physician

Follow-up:
Median follow-up 25.4 months

Outcomes:
Primary: Progression-free survival (PFS)
Secondary: Overall survival (OS), response rates, rates of treatment-related adverse effects

Key results:
Primary:
Median PFS at 25.4 months: I: 42.8 months vs. C: 32.5 months (p<0.001), HR3= 0.60 (95% CI4 0.48 – 0.76; p<0.001)
PFS at 25.5 months: I: 76.6% vs. C: 62.3% (p<0.001)
PFS at 26.4 months: I: 37.1 months vs. C: 30.8 months (p<0.001), HR=0.6 (95% CI 0.47 – 0.75; p<0.0001)
Secondary:
OS at 25.4 months: HR=0.72 (95% CI: 0.48, 1.09; p=0.13), at 25.5. months I: 91% vs. C: 88% (p=0.18);
Mean OS at 26.4 months: I: 47.7 months vs. C: 48.2 (p=0.18)
Response to treatment: Overall response rate I: 95% vs. C: 88% [p=0.001]; complete remission I: 44.5% vs. C: 22.9% [p<0.01]; partial remission I: 39.6% vs. C: 50.4% [p<0.01], progressive disease I: 3.3% vs. C: 8.1% [p<0.01]

Adverse effects:
Grade 3/4 CTC5 adverse events (I vs. C)
Overall: 309 (77.5%) vs. 248 (62.6%) [p<0.0001]; Hematological toxicity 55.7% vs. 39.4% [p<0.0001] Neutropenia 33.7% vs. 21% [p<0.0001]
Leukocytopenia 24% vs. 12.1% [p<0.0001]
Thrombocytopenia 7.4% vs. 10.9%
Anemia 5.4% vs. 6.8%
Infection 18.8% vs. 14.9%
Tumour Lysis Syndrome 0.2% vs. 0.5%
Cytokine release syndrome 0.25% vs. 0.0%
Treatment related mortality 2.0% vs. 1.5%
Commentary 7 pts. were excluded from all analyses due to missing informed consent. The ITT6 population included 810 pts. (I: 403 vs. C: 407)

Commentary:
As shown in multivariate analyses certain factors, including age, gender, Binet stage, CIRS score and renal function, were independently predicting PFS or OS [1-6].

Sponsor:
Biogen Idec.
Collaborators: Hoffmann-La Roche, Genentech

Countries: Multicentre – International (88 study sites across 17 countries)

Design: Randomised, open-label , active control

Participant characteristics:
n=552 patients (pts) (I:276 vs. C:276); median age I: 63y (35-83y), C: 62y (35-81y)

Treatment:
I(ntervention):Rituximab + Fludarabine + Cyclophosphamide for a total of six treatment cycles at intervals of 28 days
Rituximab IV infusion before FC infusion
Cycle 1: 375mg/m2 IV; d0
Cycles 2-6: 500mg/m2 IV; d1
Fludarabine IV infusion over three days for six treatment cycles (25mg/m2/day IV; d1-d3)
Cyclophosphamide IV infusion over three days for six treatment cycles (250mg/m2/day IV; d1-d3)
C(ontrol): Fludarabine + Cyclophosphamide
Fludarabine IV infusion over three days for six treatment cycles(25mg/m2/day IV; d1-d3)
Cyclophosphamide IV infusion over three days for six treatment cycles (250mg/m2/day IV; d1-d3)

In-/exclusion criteria:
Inclusion criteria: relapsed or refractory patients with B-cell CLL and ≤one previous chemotherapy, Binet stages A, B, C, ECOG2 Performance Status 0-1, age ≥18 years, expected survival >6 months, acceptable hematologic status, liver function, renal function and pulmonary function
Exclusion criteria: prior treatment with Interferon, rituximab or other monoclonal antibody, prior allogeneic or autologous bone marrow transplant or peripheral stem cell transplant or patients who are considered to be candidates for those procedures as assessed by their treating physicians, severe grade 3 or 4 non-hematological toxicity or prolonged (>2 weeks) grade 3 or 4 cytopenia on prior fludarabine or nucleoside analogue regimen, history of fludarabine-induced or clinically significant autoimmune cytopenia

Follow-up:
Median follow-up 25.3 months

Outcomes:
Primary: Progression-free survival (PFS)
Secondary: Overall survival (OS), response rates

Key results:
Primary:
Median PFS: I: 30.6 months vs. C: 20.6 months [p=0.0002], HR3= 0.65 (95% CI4: 0.51, 0.82)
Secondary:
Median OS: I: not reached vs. C: 51.9 months
Response to treatment: Overall response rate I: 69.9% vs. C: 58.0% (p=0.0034); complete remission I: 24.3% vs. C: 13.0% [p=0.0007]; partial remission I: 45.7% vs. C: 44.9%; progressive disease I: 2.5% vs. C: 5.4%

Adverse events:
Grade 3/4 CTC5 adverse events (I vs. C)
Overall: 65pts (23.6%) vs. 60pts (21.7%)
Infusion-related (d1-2 of first cycle): 6pts (2.2%) vs. 4pts (1.5%)
Tumour Lysis Syndrome: 2pts (0.7%) vs. 3pts (1.1%)
Neutropenia 42pts (15.2%) vs. 40pts (14.5%)
Febrile Neutropenia: 15pts (5.4%) vs. 12pts (4.3%)
Thrombopenia: 11pts (4%) vs. 9pts (3.3%)
Autoimmune haemolytic anaemia: 5pts (1.8%) vs. 12pts (4.3%)
Infections: 17pts (6.2%) vs. 19pts (6.9%)
Hepatitis B: 2pts (0.7%) vs. 0 pts (0%)
Benign or malignant neoplasms: 7pts (2.5%) vs. 3pts (1.1%) [2,3,7,8]

Economic evaluation:

 

Ongoing research:

There are a number of ongoing phase III trials of rituximab, such as
NCT00769522: German CLL study group, Germany; CLL first-line therapy; primary outcome: progression-free survival; results ex-pected 2018.
NCT00645606: GOELAMS and FCGCLL/WM, France; CLL mainte-nance; primary outcome: progression-free survival; results ex-pected 2012.

Ongoing or planned HTA:

 

Web link:

http://eprints.hta.lbg.ac.at/860/

References and sources:

1. European Medicines Agency. EPARs for authorised medicinal products for human use. 2009 [cited 2009, September 8]; Available from: http://www.emea.europa.eu/humandocs/Humans/EPAR/mabthera/mabthera.htm.
2. Roche. Trial Results Search. Clinical Trial Results: MabThera/Rituxan [rituximab]. 2009 [cited 2009 September 10,]; Available from: http://www.roche-tri-als.com/patient/trialresults/druglst_MabTheraRituxan_rituximab.html.
3. Roche. Investor science event from ASH 2008, San Francisco 9 December 2008. 2008 [cited 2009, September 7 ]; Available from: http://www.roche.com/irp081209.pdf
4. Deutsche CLL Studiengruppe. CLL8 Protocol of the DCLLSG. 2004 [cited 2009, September 7]; Available from: http://www.dcllsg.de/en/cll8/index.php.
5. American Society of Hematology. 50th ASH Annual Meeting and Exposi-tion: Online Program and Abstracts: 325 Immunochemotherapy with Fludarabine (F), Cyclophosphamide (C), and Rituximab (R) (FCR) Ver-sus Fludarabine and Cyclophosphamide (FC) Improves Response Rates and Progression-Free Survival (PFS) of Previously Untreated Patients (pts) with Advanced Chronic Lymphocytic Leukemia (CLL). 2008 [cited 2009, September 7]; Available from: http://ash.confex.com/ash/2008/webprogram/Paper9237.html.
6. NHS National Institute for Health and Clinical Excellence. NICE technol-ogy appraisal guidance 174: Rituximab for the first-line treatment of chronic lymphocytic leukaemia. 2009 [cited 2009, September 2]; Avail-able from: http://www.nice.org.uk/TA174.
7. U.S. National Institutes of Health. ClinicalTrials.gov: FCR Versus FC Alone in the Treatment of Chronic Lymphocytic Leukemia (CLL). 2009 [cited 2009, September 10, ]; Available from: http://clinicaltrials.gov/ct2/show/record/NCT00090051.
8. American Society of Hematology. 50th ASH Annual Meeting and Exposi-tion: Online Program and Abstracts: LBA-1 Rituximab, Fludarabine, and Cyclophoshpamide (R-FC) Prolongs Progression Free Survival in Re-lapsed or Refractory Chronic Lymphocytic Leukemia (CLL) Compared with FC Alone: Final Results from the International Randomized Phase III REACH Trial. 2008 [cited 2009, September 7]; Available from: http://ash.confex.com/ash/2008/webprogram/Paper15742.html.

Notes:

CLL is the most common leukaemia in adults in industrialised countries and despite several treatment options still considered incurable except in a small group of patients eligible for allogeneic bone marrow transplantation. In addition to available treatment regimens, rituximab was approved by the EMEA for the first-line treatment of CLL patients in combination with chemotherapy. Moreover, a positive opinion concerning the second-line treatment of CLL patients in combination with chemotherapy has been issued by the EMEA in July 2009.
The CLL-8 trial demonstrated favourable outcomes in terms of PFS and complete remission rates for patients receiving FCR over patients receiving FC. In spite of encouraging results regarding improved overall survival in an interim analysis, the study failed to maintain this advantage during follow-up, but the authors argue that this might have been due to subsequent lines of treatment as well as cross-over. The incidence of grade 3/4 adverse events, mainly haematological reactions occuring particularly during the first treatment cycles, was higher in the intervention than in the control group. Moreover, serious adverse events, the most common of which was febrile neutropenia, were observed in 46% of the FCR arm and in 41% in the FC arm. However, the percentage of deaths judged to be related to treatment was 2% in FCR and 1.5% in FC.
The choice of treatment regimen for CLL depends upon several factors, such as patient’s age, disease stage, presence of cytogenetic lesions, concomitant diseases and - with second-line treatment – duration of response. Chemotherapy mainly provides a treatment option for patients aged less than 70 years and in good clinical condition. With Rituximab in combination therapy response rates increased by about 10%, PFS by 7 to 10 months, no effect on OS has been proven yet. As response rates and progression-free survival are believed to lead to a substantial gain in quality of life (while the effect from PFS on increased overall survival is under debate), FCR might be a treatment option for those patients but at the expense of increased toxicity. In contrast, as the majority of patients are diagnosed at the age of 70 or above, only a limited number of CLL patients might be suitable for this treatment. Of note, the trials presented in this report included mainly younger and fitter patients, making it difficult to judge possible positive and negative consequences for older individuals.
Overall, the chosen study populations as well as the comparator (FC only) in the two phase IIl studies seem to be appropriate for the intended target group but the study populations were younger and fitter than CLL patients in clinical practice [24]. Therefore, to assess the value of rituximab in older individuals with comorbidities who make up the majority of CLL patients, further trials both in comparison to and in combination with chlorambucil and other less aggressive regimens than FC are needed. Furthermore, rituximab is a potential add-on to any other CLL chemotherapy regimen other than FC because most of the FCR toxicity is caused by the FC part of the schedule.
Because rituximab is an add-on to existing CLL treatment regimens and CLL is on the rise in Austria due to an ageing population, the financial impact of the licensure of rituximab for the treatment of CLL will be substantial.