Horizon Scanning Centre September 2013 Lenalidomide (Revlimid) for mantle cell lymphoma SUMMARY NIHR HSC ID: 4375 Lenalidomide (Revlimid) is intended to be used as therapy for relapsed or refractory mantle cell lymphoma. 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 thalidomide. It is currently licensed in the EU for multiple myeloma. This briefing is Mantle cell lymphoma is a rare form of non-Hodgkin lymphoma, 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, bone 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 dexamethasone) and myelodysplastic syndromes. Recognised adverse effects (≥10%) include infections, thrombocytopenia, neutropenias, anaemia, haemorrhage, leucopenias, hypokalaemia, decreased appetite, peripheral neuropathies, dizziness, tremor, dysgeusia, headache, blurred vision, venous thromboembolic events, dyspnoea, nasopharyngitis, pharyngitis, bronchitis, epistaxis, constipation, diarrhoea, abdominal pain, nausea, vomiting, rashes, dry skin, pruritus, muscle spasms, bone pain, musculoskeletal and connective tissue pain and discomfort, arthralgia, myalgia, fatigue, oedema, pyrexia and influenza-like illness syndrome3. Lenalidomide is also in phase III clinical trials for: • chronic lymphocytic leukaemia • diffuse large B-cell lymphoma • follicular lymphoma • multiple myeloma • myelodysplastic syndromes • prostate cancer 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. 2 NIHR Horizon Scanning Centre 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 bone marrow, bowel, stomach, liver or spleen5. Other systemic symptoms, known as B-cell symptoms, may occur in some people, including loss of appetite and weight loss, fatigue, night sweats 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. Bendamustine in combination with rituximab 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-oncology cancer (CSGHO). October 200316. 3 NIHR Horizon Scanning Centre 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 chemotherapy regimens ° R-CHOP – vincristine, doxorubicin, cyclophosphamide, prednisolone and rituximab ° FC-R – fludarabine, cyclophosphamide and rituximab ° FCM-R – fludarabine, cyclophosphamide, mitoxantrone 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 chemotherapies 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. 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 bortezomib. 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 creatinine clearance of ≥30mL/min but <60mL/min. b Patients with creatinine clearance of ≥60mL/min. c Chloramucil, rituximab, cytarabine, gemcitabine or fludarabine. 4 NIHR Horizon Scanning Centre 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