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Home , Mantle cell lymphoma, Multiple myeloma

Horizon Scanning Centre September 2013

Lenalidomide (Revlimid) for mantle cell

SUMMARY NIHR HSC ID: 4375

Lenalidomide (Revlimid) is intended to be used as therapy for relapsed or refractory . If licensed, it will provide an additional treatment option for this patient group. Lenalidomide is a small molecule immunomodulatory drug and a structural analogue of . It is currently licensed in the EU for . This briefing is Mantle cell lymphoma is a rare form of non-, affecting B based on lymphocytes in the lymph nodes. Diagnosis peaks at around age 65 and the information majority of patients present with advanced disease. The one- and five-year available at the time survival rates are 71% and 27%, respectively. Most patients will respond to of research and a treatment, however mantle cell lymphoma typically progresses and median limited literature survival is around 3 years. search. It is not intended to be a Treatment for mantle cell lymphoma is dependent on stage, grade, definitive statement performance status and whether or not patients are eligible for stem cell or on the safety, marrow transplant. There is no standardised care and entry into a efficacy or clinical trial is recommended for eligible patients. Lenalidomide is currently in effectiveness of the phase II clinical trials comparing its effect on progression-free survival health technology against treatment with the investigating clinician’s choice of single agent. covered and should not be used for commercial purposes or commissioning without additional information.

This briefing presents independent research funded by the National Institute for Health Research (NIHR). The views expressed are those of the author and not necessarily those of the NHS, the NIHR or the Department of Health.

NIHR Horizon Scanning Centre, University of Birmingham Email: [email protected] Web: http://www.hsc.nihr.ac.uk NIHR Horizon Scanning Centre

TARGET GROUP

• Mantle cell lymphoma (MCL): relapsed or refractory.

TECHNOLOGY

DESCRIPTION

Lenalidomide (Revlimid; CC-5013) is a small molecule immunomodulatory drug and a structural analogue of thalidomide. Its mechanism of action is yet to be defined but includes antineoplastic, anti-angiogenic, pro-erythropoietic and immunomodulatory properties1. In clinical trials, lenalidomide was administered orally at 10mg or 25mg, once daily for 21 days of a 28 day cycle2 .

Lenalidomide is licensed in the EU for multiple myeloma (in combination with ) and myelodysplastic syndromes. Recognised adverse effects (≥10%) include infections, thrombocytopenia, neutropenias, anaemia, haemorrhage, leucopenias, hypokalaemia, decreased appetite, peripheral neuropathies, dizziness, tremor, dysgeusia, , blurred vision, venous thromboembolic events, dyspnoea, nasopharyngitis, pharyngitis, bronchitis, epistaxis, constipation, diarrhoea, abdominal pain, nausea, vomiting, rashes, dry skin, pruritus, muscle spasms, , musculoskeletal and connective tissue pain and discomfort, arthralgia, myalgia, , oedema, pyrexia and influenza-like illness syndrome3.

Lenalidomide is also in phase III clinical trials for: • chronic lymphocytic leukaemia • diffuse large B-cell lymphoma • • multiple myeloma • myelodysplastic syndromes • prostate and in phase II trials for: • acute myeloid leukaemia, • T-cell leukaemia-lymphoma • chronic lymphocytic leukaemia • glioblastoma • myelofibrosis • non-Hodgkin’s lymphoma

INNOVATION and/or ADVANTAGES

If licensed, lenalidomide will provide an additional treatment option for this patient group.

DEVELOPER

Celgene.

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AVAILABILITY, LAUNCH OR MARKETING

In phase III clinical trials.

PATIENT GROUP

BACKGROUND

MCL is a rare form of non-Hodgkin lymphoma (NHL) affecting B lymphocytes in the lymph nodes4. The most common symptoms are one or more painless swellings in the neck armpit or groin, caused by enlarged lymph nodes5,6. Usually, more than one group of nodes is involved, and other areas of the body may also be affected, such as the , bowel, stomach, liver or spleen5. Other systemic symptoms, known as B-cell symptoms, may occur in some people, including loss of appetite and , fatigue, and fevers5,6. MCL has an aggressive course with a pattern of resistant and relapsing disease, which typically renders it incurable with current standard pharmaceutical therapy7.

NHS or GOVERNMENT PRIORITY AREA

This topic is relevant to: Improving Outcomes: A Strategy for Cancer (2011).

CLINICAL NEED and BURDEN OF DISEASE

NHL is the sixth most common cancer in the UK8, with 10,875 new diagnoses in England and Wales in 20109. MCL accounts for around 3-10% of all NHLs (equating to around 326- 1,087 new diagnoses in England and Wales). Diagnosis peaks at around age 65, patients are predominantly male (male to female ratio of around 4:1)4 and the majority present with advanced disease6. The one- and five-year survival rates for MCL are 71% and 27%, respectively10. Around 50-70% of patients respond to treatment, however MCL typically progresses and the median survival is around 3 years11. In 2011-12, there were 178 hospital admissions for MCL (ICD-10: C83.1) in England, accounting for 182 finished consultant episodes and 395 bed days12, and in 2011, there were 236 deaths registered in England and Wales13.

PATIENT PATHWAY

RELEVANT GUIDANCE

NICE Guidance

• NICE technology appraisal in development. in combination with for the first line treatment of mantle cell lymphoma (ID609). Expected date of issue to be confirmed14. • NICE technology appraisal. Rituximab for the first line treatment of stage III-IV follicular lymphoma: (review of NICE technology appraisal guidance 110) (TA243). January 201215. • NICE cancer service guidance. Improving outcomes in haemato- cancer (CSGHO). October 200316.

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Other Guidance

• McKay P, Leach M, Jackson R et al. Guidelines for the investigation and management of mantle cell lymphoma. 20127. • British Committee for Standards in Haematology. Best practice in lymphoma diagnosis and reporting. 201017.

EXISTING COMPARATORS and TREATMENTS

Treatment for MCL is dependent on stage, grade, performance status and whether or not patients are eligible for stem cell or bone marrow transplant6,7. There is no standardised treatment and entry into a clinical trial is recommended for eligible patients7,18.

Current options include5,6,7,18: • Combination regimens ° R-CHOP – vincristine, , , prednisolone and rituximab ° FC-R – , cyclophosphamide and rituximab ° FCM-R – fludarabine, cyclophosphamide, and rituximab ° R-HCVAD – cytarabine, cyclophosphamide, doxorubicin, vincristine, dexamethasone and rituximab (for younger patients) ° R-maxi-CHOP/H Ara-C – vincristine, doxorubicin, cyclophosphamide, cytarabine, prednisolone and rituximab (for younger patients) ° Single may be offered – bendamustine, chlorambucil, cyclophosphamide, fludarabine (with or without rituximab) • Bone marrow or stem cell transplant (intensive chemotherapy in combination with stem cell transplant is considered standard of care in younger relapsed patients19 • Radiotherapy

EFFICACY and SAFETY

Trial SPRINT, NCT00875667, CC-5013-MCL- EMERGE, NCT00737529, CC-5013- 002; lenalidomide vs clinician’s choice of MCL-001; lenalidomide; phase II. single agent; phase II. Sponsor . Celgene. Status Ongoing. Ongoing. 20 Source of Trial registry2. Trial registry . information Location EU (incl UK), Israel, Russia. EU (incl UK), USA and other countries. Design Randomised, active-controlled. Single arm, uncontrolled. Participants n=254 (planned); aged ≥18 years; mantle n=134 (planned); aged ≥18 years; mantle cell lymphoma, refractory or relapsed up cell lymphoma; relapsed, refractory or to 3 times; progressive disease. progressive disease following treatment with . Schedule Randomised to lenalidomide, oral, 10mga All participants receive lenalidomide, oral, or 25mgb, once daily for 21 days of 28 25mg, once daily for 21 days of 28 day day cycle; or clinician’s choice of single cycle. agentc.

a Patients with clearance of ≥30mL/min but <60mL/min. b Patients with creatinine clearance of ≥60mL/min. c Chloramucil, rituximab, cytarabine, gemcitabine or fludarabine.

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Follow-up Active treatment until disease Not reported. progression; follow-up not reported. Primary Progression free survival. Tumour response; duration of response. outcome/s Secondary Overall response; duration of response; Safety; time to progression; OS. outcome/s tumour control rate; time to progression; time to treatment failure; time to tumour response; overall survival (OS); safety; quality of life. Expected Not reported. Not reported. reporting date

ESTIMATED COST and IMPACT

COST

The cost of lenalidomide for MCL is not yet known. However, lenalidomide (Revlimid) is already marketed for the treatment of multiple myeloma; 25mg daily for 21 days of a 28 day cycle would cost £4,368 per cycle21.

IMPACT - SPECULATIVE

Impact on Patients and Carers

 Reduced mortality/increased length of survival  Reduced symptoms or disability

 Other:  No impact identified

Impact on Services

 Increased use of existing services  Decreased use of existing services: oral treatment option.

 Re-organisation of existing services  Need for new services

 Other:  None identified

Impact on Costs

 Increased drug treatment costs  Reduced drug treatment costs

 Other increase in costs:  Other reduction in costs:

 Other: uncertain unit cost compared to  None identified existing treatments

Other Issues

 Clinical uncertainty or other research question  None identified identified:

REFERENCES

1 Habermann TM, Lossos IS, Justice G et al. Lenalidomide oral monotherapy produces a high response rate in patients with relapsed or refractory mantle cell lymphoma. British Journal of Haematology 2009;145:344-349.

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2 ClinicalTrials.gov. A study to determine the efficacy of lenalidomide versus investigator’s choice in patients with relapsed or refractory mantle cell lymphoma (MCL) (Sprint). http://clinicaltrials.gov/ct2/show/NCT00875667?term=nct00875667&rank=1 Accessed 15 August 2013. 3 Electronic Medicines Compendium.SPC. Revlimid. http://www.medicines.org.uk/emc/medicine/19841/SPC/Revlimid/ Accessed 15 August 2013. 4 Orpha.net. Mantle cell lymphoma. http://www.orpha.net/consor/cgi- bin/Disease_Search.php?lng=EN&data_id=10693&Disease_Disease_Search_diseaseGroup=ma ntle-cell- lymphoma&Disease_Disease_Search_diseaseType=Pat&Disease%28s%29/group%20of%20dis eases=Mantle-cell-lymphoma&title=Mantle-cell-lymphoma&search=Disease_Search_Simple Accessed 15 August 2013. 5 Macmillan Cancer Care. Mantle cell lymphoma. http://www.macmillan.org.uk/Cancerinformation/Cancertypes/Lymphomanon- Hodgkin/TypesofNHL/Mantlecell.aspx#DynamicJumpMenuManager_6_Anchor_2 Accessed 15 August 2013. 6 Cancer Research UK. Mantle cell lymphoma. http://www.cancerresearchuk.org/cancer- help/type/non-hodgkins-lymphoma/about/types/mantle-cell-lymphoma Accessed 15 August 2013. 7 McKay P, Leach M, Jackson R et al. Guidelines for the investigation and management of mantle cell lymphoma. British Journal of Haematology 2012;159:405-426. 8 Cancer Research UK. Non-Hodgkin lymphoma (NHL) key facts. http://www.cancerresearchuk.org/cancer-info/cancerstats/keyfacts/non-hodgkin-lymphoma/ Accessed 15 August 2013. 9 Cancer Research UK. Non-Hodgkin lymphoma incidence statistics. http://www.cancerresearchuk.org/cancer-info/cancerstats/types/nhl/incidence/ Accessed 15 August 2013. 10 Cancer Research UK. Non-Hodgkin lymphoma survival statistics. http://www.cancerresearchuk.org/cancer-info/cancerstats/types/nhl/survival/ Accessed 15 August 2013. 11 National Institute for Health and Clinical Excellence. Lymhoma (mantle cell) – bendamustine (1st line, with rituximab): final scope. London: NICE; December 2012. 12 Health and Social Care Information Centre. Hospital episode statistics for England. Inpatient statistics, 2011-12. www.hscic.gov.uk 13 Office for National Statistics. Mortality statistics: deaths registered in England and Wales (Series DR), 2011. www.ons.gov.uk 14 National Institute for Health and Care Excellence. Bendamustine in combination with rituximab for the first line treatment of mantle cell lymphoma (ID609). Technology appraisal in development. Expected date of issue to be confirmed. 15 National Institute for Health and Clinical Excellence. Rituximab for the first line treatment of stage III-IV follicular lymphoma: (review of NICE technology appraisal guidance 110). Technology appraisal TA243. London: NICE; January 2012. 16 National Institute for Health and Clinical Excellence. Improving outcomes in haemato-oncology cancer. CSGHO. London: NICE; October 2003. 17 British Committee for Standards in Haematology. Best practice in lymphoma diagnosis and reporting. London: BCSH; April 2010. 18 Map of Medicine. Aggressive non-Hodgkin lymphoma (NHL). http://app.mapofmedicine.com/mom/1/page.html?department-id=3&specialty-id=1007&pathway- id=14307&page-id=14318 Accessed 16 August 2013. 19 National Institute for Health Research Horizon Scanning Centre. Borezomib (Velcade) for newly diagnosed mantle cell lymphoma – first line. www.hsc.nihr.ac.uk/ 20 ClinicalTrials.gov. A study to determine the efficacy and safety of lenalidomide in patients with mantle cell NHL who have relapsed or progressed after treatment with bortezomib or are refractory to bortezomib. The EMERGE trial. http://clinicaltrials.gov/ct2/show/NCT00737529?term=NCT00737529&rank=1 Accessed 16 August 2013. 21 British Medical Association and Royal Pharmaceutical Soceity of Great Britain. British National Formulary. BNF 65. London: BMJ Group and RPS Publishing, March 2013.

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