Lenalidomide (Revlimid) for myelodysplastic syndrome - National ...

Lenalidomide (Revlimid) for
myelodysplastic syndrome
August 2010
This technology summary is based on information available at the time of research
and a limited literature search. It is not intended to be a definitive statement on the safety, efficacy or
effectiveness of the health technology covered and should not be used for commercial purposes.
The National Horizon Scanning Centre Research Programme is part of the
National Institute for Health Research

August 2010
Lenalidomide (Revlimid) for myelodysplastic syndrome
Target group
• Myelodysplastic syndrome (MDS): low or intermediate-1 risk; associated with
deletion 5q (del5q) cytogenetic abnormality; red blood cell (RBC) transfusion
dependent – first line.
Background
MDS is a heterogeneous group of haematopoietic disorders, predominately affecting
older individuals. It is characterised by hypercellular or hypocellular bone marrow with
abnormal cell morphology, maturation and function, and peripheral blood cytopenias.
MDS may be classified as primary (no known exposure) or secondary to complications
from aggressive cancer treatments or other mutagenic agents, or evolve from other
haematological clonal disorders (such as myeloproliferative disorders). It is caused by a
cumulative acquisition of genetic errors in the bone marrow 1 . Common abnormalities
include chromosomal deletions in 5q, 7, 20q, Y and trisomy 8. MDS is a premalignant
condition progressing to acute myeloid leukaemia (AML) in a subgroup of patients if
additional genetic abnormalities are acquired 2 . This occurs in approximately 30% of
MDS patients 3 (less common in patients with the del5q abnormality than other forms of
MDS 4
).
Technology description
Lenalidomide (Revlimid, CC-5013) is a structural analogue of thalidomide. It is an
immunomodulatory drug that inhibits tumour necrosis factor-alpha and interleukin-1 beta
and stimulates anti-inflammatory cytokine interleukin-10. Lenalidomide is in
development for the treatment of patients with MDS associated with a del5q cytogenetic
abnormality who are dependent on RBC transfusion. It is administered orally at 10mg
once daily for 21 consecutive days of a 28 day cycle.
Lenalidomide is licensed in the EU for the second line treatment of multiple myeloma in
combination with dexamethasone. Common adverse events (>10%) reported include
venous thromboembolism, neutropenia, fatigue, asthenia, constipation, muscle cramp,
thrombocytopenia, anaemia, diarrhoea and rash 5
.
Lenalidomide in currently in development for:
Phase III
• Multiple myeloma; first line; newly diagnosed patients not eligible for autologous
stem cell transplant.
• Multiple myeloma: consolidation therapy post stem cell transplant.
• Chronic lymphocytic leukaemia (CLL); first line; in older patients.
• CLL; maintenance after second line therapy.
• Diffuse large B-cell lymphoma.
• Painful lumbar radiculopathy.
Phase II
• CLL; early stage; first line.
• Acute myeloid leukaemia.
• Cutaneous T-cell lymphoma; adjuvant therapy.
• Mantle cell lymphoma; with rituximab or as monotherapy (IV formulation).
• Non-Hodgkin’s lymphoma; combination therapy or monotherapy.
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August 2010
Innovation and/or advantages
Lenalidomide is a new class of drug for the treatment of MDS associated with a del5q
cytogenetic abnormality. If licensed, it may potentially offer improved RBC transfusion
independence (TI) and quality of life.
Developer
Celgene Corporation.
Availability, launch or marketing dates, and licensing plans
Lenalidomide is a designated orphan drug for chronic lymphocytic leukaemia, multiple
myeloma and MDS in the EU and USA.
In phase III clinical trials.
NHS or Government priority area
This topic is relevant to the NHS Cancer Plan (2000) and Cancer Reform Strategy (2007).
Relevant guidance
• NICE technology appraisal in development. Myelodysplastic syndromes – azacitidine.
Expected date of issue to be confirmed 6
.
• NICE cancer service guideline. Improving outcomes in haemato-oncology cancer.
7
2003 .
• British Committee for Standardisation in Haematology. Guidelines for the diagnosis
8
and therapy of adult myelodysplastic syndromes. 2003 .
Clinical need and burden of disease
The annual incidence of MDS is estimated at 4 per 100,000, but many cases remain
undiagnosed 2 . This figure increases to 30 per 100,000 per year for patients over 70 years
of age 8 . Around 2,000 people are diagnosed with MDS each year in the UK 9 . The
deletion of chromosome 5q is one of the most common cytogenetic abnormalities in
MDS, occurring in between 16% to 28% of patients 10 . In England, MDS (ICD-10: D46)
resulted in 35,290 finished consultant episodes in 2008-09, and 97% of patients required
admission 11 . Prognosis is based on the International Prognostic Scoring System (IPSS),
which uses the percentage of blast cells, number of cytopenias and cytogenetics to
calculate risk score. Multiple cytogenetic abnormalities are associated with a worse
prognosis 12 . There are 4 risk groups which range from low to high with median survivals
of 5.7 to 0.4 years respectively. In England and Wales, 963 people died due to an
underlying cause of MDS in 2008, 867 (90%) of these patients were 70 years or older 13
.
Existing comparators and treatments
Management of MDS is based on the patient’s IPSS score wherever possible 8 . Currently
the only potentially curative treatment for MDS is haematopoietic stem cell
transplantation, but this is only suitable in a small percentage of patients and where an
adequate donor is available. The majority of treatment focuses on symptom relief:
reducing cytopenias; treating persistent/recurring infection; improving quality of life
(QoL); and prolonging survival. Many patients become transfusion dependent, so one
major goal of treatment is to achieve TI, resulting in improved QoL and prolonged
survival.
The following drugs can be used to reduce or eliminate the transfusion need in specific
subsets of MDS patients 3,8,14
.
• Erythropoietin (EPO, used in the majority of patients).
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August 2010
• Darbopoetin.
• Azacitidine 15
(only used in advanced disease).
• Decitabine (not licensed in UK).
• Antithymocyte globulin (ATG, used in hypocellular MDS).
• Cyclosporin.
• Imatinib.
Efficacy and safety
Trial CC-5013-MDS-003, NCT00065156; CC-5013-MDS-003, NCT00074126;
lenalidomide; phase II.
lenalidomide; phase II extension.
Sponsor Celgene Corporation. Memorial Sloan-Kettering Cancer Center.
Status Trial complete and published. Trial complete and published in abstract 16 .
Source of Trial registry
information
16 , publication 10 and
abstracts 17,18,19
20
Trial registry .
.
Location USA and Germany. USA.
Design Single arm, open label. Single arm, open label.
Participants n=148; adults; MDS; low or
n=36; adults; MDS; low or intermediate-1
and schedule intermediate-1 risk; associated del5q risk; associated del5q cytogenetic
cytogenetic abnormality; RBC
abnormality; RBC transfusion-dependent
transfusion-dependent anaemia. anaemia; completed trial NCT00065156.
Lenalidomide 10mg on days 1-21 of a Lenalidomide 10mg on days 1-21 of a 28
28 day cycle or continuous dosing, for
up to 6 cycles.
day cycle, for up to 6 cycles.
Follow-up Treatment period up to 24 weeks (or
continued until disease progression).
-
Primary
outcome
RBC TI a
.
RBC TI.
Secondary Duration of TI; frequency of minor Safety.
outcome erythroid; cytogenetic and pathological
abnormalities; safety.
Key results For both dosing schedules, at week 24
TI was achieved by 99 patients (67%).
Median time to TI 4.6 weeks.
At median follow-up of 104 weeks,
53/99 patients remained TI.
-
Expected
reporting date
- Not known.
Adverse Neutropenia (55%) and
-
effects (AEs) thrombocytopenia (44%) were the most
common AEs. 11 patients died whilst
receiving treatment, 3 possibly
treatment-related (neutropenic
infection).
Trial CC-5013-MDS-004, NCT00179621; CC-5013-MDS-007, NCT00812968;
lenalidomide vs placebo; phase III. lenalidomide; phase II.
Sponsor Celgene Corporation. Celgene Corporation.
Status Trial ongoing. Published.
Source of
information
Trial registry 21
.
22 23
Trial registry and publication .
Location EU (inc UK) and Israel. Japan.
a
Transfusion independence (TI): defined as a period of at least 56 consecutive days during which no transfusions
were given and the haemogloblin concentration increased by at least 1g/dL.
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August 2010
Design Randomised, placebo-controlled. Single arm, open label.
Participants
and schedule
n=162 (planned); adults; MDS; low or
intermediate-1 risk; associated del5q
cytogenetic abnormality; RBC
transfusion-dependent anaemia.
Randomised to lenalidomide 5mg every
day, or lenalidomide 10mg on days 1-21
of a 28 day cycle, or placebo, for 16
weeks.
Follow-up Initial treatment period 16 weeks, then
further 52 weeks depending on disease
progression. Open label treatment may
continue for further 2 years. Total
treatment period no greater than 3 years.
Primary
outcome
Secondary
outcome
RBC TI for ≥26 weeks. Safety at 24 weeks.
Erythroid response, duration of RBC TI,
blood cell counts, bone marrow response,
overall survival, time to AML
transformation.
n=11; adults; MDS; low or intermediate-1
risk; associated del5q cytogenetic
abnormality; RBC transfusion-dependent
anaemia or symptomatic anaemia
(haemoglobin [Hb]

August 2010
Estimated cost and cost impact
Lenalidomide is administered at a 10mg once daily dose for 21 consecutive days in a 28
day cycle. The cost per cycle is therefore £3,780.
Claimed or potential impact – speculative
Patients
Reduced mortality or increased
length of survival
Reduction in associated morbidity
or Improved quality of life for
patients and/or carers
Other: None identified
Services
Increased use
Decreased use e.g. fewer
admissions and shorter length of
stay, reduced need for
transfusions.
Costs
Increased unit cost compared to
alternative
New costs:
References
Quicker, earlier or more accurate
diagnosis or identification of
disease
Service organisation Staff requirements
Other: None identified
Increased costs: more patients
coming for treatment
Savings: reduction in hospital
admissions due to reduced
morbidity and need for
transfusions.
Increased costs: capital
investment needed
Other:
1 eMedicine. Myelodysplastic syndrome. http://emedicine.medscape.com/article/207347-overview Accessed 13
July 2010.
2 Killick SB. Myelodysplastic disorders. Medicine 2009;37:186-189.
3 The Myelodysplastic Syndromes Foundation. Understanding myelodysplastic syndromes: A patient handbook.
http://www.mds-foundation.org/patientinfo.htm
4
eMedicine. Myelodysplastic syndromes associated with isolated del(5q).
http://emedicine.medscape.com/article/1644073-overview Accessed 13 July 2010.
5
Electronic Medicines Compendium (eMC). Summary of Product Characteristics (SPC) – Revlimid.
http://www.medicines.org.uk
6
National Institute for Health and Clinical Excellence. Myelodysplastic syndromes – azacitidine. Technology
appraisal in development. Expected unknown.
7 National Institute for Health and Clinical Excellence. Improving outcomes in haemato-oncology cancer. Cancer
Service Guideline CSGHO. London: NICE;October 2003.
8 Bowen D. Guidelines for the diagnosis and therapy of adult myelodysplastic syndromes. British Journal of
Haematology 2003;120:187-200.
9 Leukaemia & Lymphoma Research. Myelodysplastic syndromes. http://www.beatbloodcancers.org/patientinformation/myelodysplastic-syndromes-mds
Accessed 14 July 2010.
10 List A, Dewald G, Bennett J. Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion.
The New England Journal of Medicine 2006;355:1456-1465.
11 Health Episode Statistics (HES) Online. Primary diagnosis: 3 character 2008-09. www.hesonline.nhs.uk
12 Patient UK. Myelodysplastic syndromes (MDS). http://www.patient.co.uk/doctor/Myelodysplastic-syndromes-
(MDS).htm Accessed 13 July 2010.
13 Office of National Statistics (ONS). Mortality statistics: deaths registered in 2008. www.statistics.gov.uk
14 Schiffer CA. Myelodysplasia: The good, the fair and the ugly. Best Practice and Research Clinical
Haematology 2007;20:49-55.
15 Electronic Medicines Compendium (eMC). Summary of Product Characteristics (SPC) – Vidaza 25mg/ml
powder for suspension for injection. http://www.medicines.org.uk
16 ClinicalTrials.gov. Lenalidomide safety/efficacy in myedysplastic syndromes (MDS) associated with a
deletion 5q cytogenetic abnormality. http://www.clinicaltrials.gov/ct2/show/study/NCT00065156 Accessed 09
July 2010.
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August 2010
17 List AF, Dewald G, Bennett J et al. Hematologic and cytogenic (CTG) response to lenalidomide (CC-5013) in
patients with transfusion-dependent (TD) myelodysplastic syndrome (MDS) and chromosome 5q31.1 deletion:
results of the multicenter MDS-003 study. Journal of Clinical Oncology 2005;23(16 Suppl):5.
18 List AF, Moffitt L, Gewald G et al. Results of the MDS-002 and -003 international phase II studies evaluating
lenalidomide (CC-5013; Revlimid) in the treatment of transfusion-dependent (TD) patients with
myelodysplasia syndrome (MDS). European Hematology Association (EHA) Conference June 2005; Abs
0772.
19 List A, Moffitt HL, Dewald G et al. Clinical benefit from 2 phase II trials evaluating lenalidomide (revlimid)
in lower-risk myelodysplastic syndrome patients with or without del 5q cytogenetic abnormalities. European
Hematology Association (EHA) Conference June 2006; Abs 1032.
20 ClinicalTrials.gov. CC-5013 in treating patients with red blood cell transfusion-dependent myelodysplastic
syndromes and cytogenetic abnormality. http://www.clinicaltrials.gov/ct2/show/NCT00074126 Accessed 09
June 2010.
21 ClinicalTrials.gov. Lenalidomide versus placebo in myelodysplastic syndromes with a deletion 5qabnormality.
http://www.clinicaltrials.gov/ct2/show/NCT00179621 Accessed 09 June 2010.
22 ClinicalTrials.gov. Study of CC-5013 to evaluate safety, pharmokinetics and effectiveness for Japanese
patients with symptomatic anaemia associated with myelodysplastic syndrome with a del(5)(q31-33)
abnormality. http://www.clinicaltrials.gov/ct2/show/NCT00812968 Accessed 09 June 2010.
23 Harada H, Watanabe M, Suzuki K et al. Lenalidomide is active in Japanese patients with symptomatic
anaemia in low- or intermediate-1 risk myelodysplastic syndromes with a deletion 5q abnormality.
International Journal of Haematology 2009;90:353-360.
24 ClinicalTrials.gov. The efficacy and safety of lenalidomide monotherapy in red blood cell transfusion
dependent subjects with myelodysplastic syndrome (MDS) associated with del (5q) abnormality.
http://www.clinicaltrials.gov/ct2/show/NCT00874978 Accessed 09 June 2010.
25 ClinicalTrials.gov. Safety of lenalidomide and markers for disease progression in patients with international
prognostic scoring system (IPSS) low- or intermediate-1 risk myelodysplastic syndromes (MDS) with isolated
del5q (MDS-LE-MON-5). http://www.clinicaltrials.gov/ct2/show/NCT01081431 Accessed 09 June 2010.
The National Institute for Health Research National Horizon Scanning Centre Research
Programme is funded by the Department of Health.
The views expressed in this publication are not necessarily those of the NHS, the NIHR or the
Department of Health
The National Horizon Scanning Centre,
Department of Public Health and Epidemiology
University of Birmingham, 90 Vincent Drive, Edgbaston, Birmingham, B15 2SP, England
Tel: +44 (0)121 414 7831 Fax +44 (0)121 414 2269
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