UOA05-06: Effective treatment of chronic lymphocytic leukaemia
Submitting InstitutionUniversity of Oxford
Unit of AssessmentBiological Sciences
Summary Impact TypeTechnological
Research Subject Area(s)
Medical and Health Sciences: Oncology and Carcinogenesis
Summary of the impact
Research led by University of Oxford scientists has resulted in
widespread use of the humanised therapeutic antibody, Campath
(alemtuzumab), in patients with chronic lymphocytic leukaemia (CLL).
Licensed by both the European and American regulatory authorities in 2004
for the treatment of CLL, Campath is used as first-line treatment for
patients with aggressive forms of the disease and following relapse. It
can induce long-term clinical remission even in cases resistant to other
drugs. Campath has now been used in approximately 15,000 patients, and has
generated revenues of approximately £750 million from the licensed
treatment of CLL.
B-cell chronic lymphocytic leukaemia (B-CLL) is the most common leukaemia
in the Western world and a major health problem, accounting for 25% of
leukaemias and with an annual incidence rate of 4.3 per 100,000 people.
The US National Institutes of Health estimate that in the USA, 15,680
people will be diagnosed with, and 4,580 people will die of CLL in 2013.
Most commonly occurring over the age of 50, in 50% of patients CLL has an
indolent clinical course that may not require treatment for many years. In
the remaining patients, however, CLL progresses rapidly and does not
respond to current therapy. The most frequent form of treatment is
combination chemotherapy. There are, however, patients whose disease is
treatment resistant and the majority of these patients die within one
year. New treatment options are therefore imperative.
In the late 1990s and early 2000s, Professors Herman Waldmann and Geoff
Hale at the University of Oxford, in collaboration with approximately
fifty clinical teams worldwide, designed and coordinated a series of
international clinical trials using Campath in CLL. In 1997, the
researchers showed that Campath, through its action of targeting the CD52
antigen (absent on stem cells but present on normal cells and malignant
white blood cells) was capable of eradicating minimal residual disease in
CLL1. This early trial was critically dependent on Campath that
was manufactured at the University of Oxford.
In 2002, a phase II trial involving the Oxford University team confirmed
the efficacy of Campath as a first-line treatment for CLL2; and
in 2004, Campath was shown to be an effective second-line treatment for
patients who had relapsed following conventional treatment for CLL with
fludarabine3. An important outcome from these trials was the
demonstration that Campath could be administered subcutaneously rather
than intravenously2, 3.
As a result of the research driven by the University of Oxford team,
Campath was approved as a first-line treatment for adult CLL in 20074.
Genzyme (now Sanofi-Aventis/Genzyme) and Bayer Healthcare obtained
exclusive worldwide rights to market Campath.
References to the research
1. Dyer MJS, Kelsey SM, MacKay HJ, Emmett E, Thornton P, Hale G, Waldmann
H, Newland AC, Catovsky D. (1997) In vivo "purging" of residual disease in
CLL with CAMPATH-1H. Brit J Haematol. 97: 669-672. doi:
10.1046/j.1365-2141.1997.1062924.x First report that Campath is
effective in removing residual tumour cells from patients.
2. Lundin J, Kimby E, Bjorkholm M, Broliden P-A, Celsing F, Hjalmar V,
Mollgard L, Rebello P, Hale G, Waldmann H, Mellstedt H, Osterborg A.
(2002) Phase II trial of subcutaneous anti-CD52 monoclonal antibody
alemtuzumab (Campath-1H) as first-line treatment for patients with B-cell
chronic lymphocytic leukaemia (B-CLL). Blood 100: 768-773. doi:
10.1182/blood-2002-01-0159 Example of the use of Campath for the
first-line (initial) treatment of CLL and the efficacy of its
3. Hale G, Rebello P, Brettman L, Fegan C, Kennedy B, Kimby E, Leach M,
Lundin J, Mellstedt H, Moreton P, Rawstron A, Waldmann H, Osterborg A,
Hillmen P. (2004) Blood concentrations of alemtuzumab and antiglobulin
responses in patients with chronic lymphocytic leukaemia following
intravenous or subcutaneous routes of administration. Blood 104: 948-955.
doi: 10.1182/blood-2004-02-0593 Example of Campath (alemtuzumab) as
a treatment for relapsed CLL that had failed prior treatment. The
trial also demonstrated the clinical value of the subcutaneous
administration of Campath.
4. Websites describing the various international approvals for Campath in
CLL. National Cancer Institute. FDA Approval for Alemtuzumab. Available
NCI confirms FDA approval for alemtuzumab in September 2007.
BTG plc: Campath® approved for first-line use in Adult
Leukemia. Available from: http://www.btgplc.com/page/4872/btg-plc-campathsup174/sup-approved-for-first-line-use-in-adult-leukemia
Press release 20 Sep 2007 describing the approval of Campath for
the first-line treatment of CLL.
Funding for research: This research was funded by approximately
£6.3M (until 2007) from the MRC, LeukoSite Inc. and ILEX Oncology.
Details of the impact
Campath is now a treatment of choice for many cases of CLL and for
patients who have relapsed from their disease. It benefits patients
and is cost-effective relative to other agents. Financially, its use in
the treatment of CLL has generated substantial income for both the
pharmaceutical industry and the university sector in the UK.
Benefit to patients with CLL
The specificity of Campath means it is well tolerated compared with
conventional cytotoxic chemotherapy; it is effective at stabilising
disease or inducing clinical remission; and it has been shown to improve
survival and quality of life.
Campath's importance in the treatment of relapsed CLL has been reinforced
by clinical trials showing that its use in combination with chemotherapy
(e.g. fludarabine or methlyprednisolone) and/or rituximab in the treatment
of patients with CLL who had failed all available therapies, resulted in
more effective clinical responses and increased survival5.
Other large international clinical trials studies have shown its efficacy
as first-line treatment for those patients who have CLL6-8,
particularly with genetic abnormalities associated with a poor prognosis,
such as those affecting the tumour suppressor protein p536. The
following quote from this reference states that Campath `combined with
methylprednisolone is the most effective induction regimen hitherto
reported in TP53-deleted CLL' 8. Low dose monotherapy
using subcutaneously administered Campath has also been shown to be
efficacious in poor prognosis CLL8. Subcutaneously
administrated Campath simplifies treatment, opens up the options for
patients requiring maintenance therapy to control their disease, and
More than 70 papers and/or reviews have been published since 2008
reporting the efficacy of Campath in CLL and, as further evidence of its
widespread use for the treatment of CLL, patient access programmes have
been established in 50 countries. In September 2012 Campath was no longer
commercially available for the treatment of CLL, because the manufacturer,
Sanofi- Aventis/Genzyme, made a decision to surrender the licence so that
Campath could be licensed for the treatment of multiple sclerosis (under
the new name Lemtrada)10. Under the US Campath Distribution
Program, Campath is provided free of charge by Sanofi-Aventis/Genzyme to
appropriate patients, to ensure that CLL patients have continued access to
treatment11. Currently, Campath is being used to treat ~1,500
patients/year with CLL12.
Financial benefit to the pharmaceutical and university sectors
The $60,000 per patient average cost of a Campath course of treatment for
CLL brought in a total of $76M in 2011, with cumulative worldwide sales of
approximately $268M between 2010 and 201212. Therefore, the
income for the UK during the REF period is substantial, with 2% going to
the UK university sector (including Oxford University), 2% going to
British Technology Group (BTG, a company assigned rights to Campath), and
2% to GlaxoSmithKline (Campath was originally licensed to Burroughs
Wellcome, a company later merging to form part of GSK).
Sources to corroborate the impact
- Stilgenbauer S, Zenz T, Winkler D, Buhler A, Schlenk R, Groner S, et
al. (2009) Subcutaneous alemtuzumab in fludarabine-refractory chronic
lymphocytic leukemia: Clinical results and prognostic marker analyses
from the CLL2H study of the German Chronic Lymphocytic Leukemia Study
Group. J Clin Oncol. 27: 3994-4001. doi: 10.1200/JCO.2008.21.1128 Report
of the efficacy of the use of Campath in combination with
chemotherapy in a large German multicentre trial.
- Pettitt AR, Jackson R, Carruthers S, Dodd J, Dodd S, Oates M, et al.
(2012) Alemtuzumab in combination with methylprednisolone is a highly
effective induction regimen for patients with chronic lymphocytic
leukemia and deletion of TP53: Final results of the National Cancer
Research Institute CLL206 Trial. J Clin Oncol. 30: 1647-1655. doi:
10.1200/JCO.2011.35.9695 Report of the efficacy of the use of
Campath in combination with chemotherapy in a large UK multicentre
- Montillo M, Tedeschi A, Petrizzi VB, Ricci F, Crugnola M, Spriano M,
et al. (2011) An open-label, pilot study of fludarabine,
cyclophosphamide and alemtuzumab in relapsed/refractory patients with
B-cell chronic lymphocytic leukemia. Blood 118: 4079-4085. doi:
10.1182/blood-2011-05-351833 Report of the efficacy of the use of
Campath in combination with chemotherapy in a large Italian
multicentre trial showing its efficacy in inducing clinical
- Cortelezzi A, Pasquini MC, Gardellini A, Gianelli U, Bossi A, Reda G,
et al. (2009) Low-dose subcutaneous alemtuzumab in refractory
lymphocytic leukaemia (CLL): results of a prospective, single-arm
multicentre study. Leukemia 23: 2027-2033. doi: 10.1038/leu.2009.148
Description of low dose monotherapy using subcutaneously
administered Campath and its efficacy in poor prognosis CLL.
- Wierda WG, Kipps TJ, Keating MJ, Brown JR, Gribben JG, Browning M, et
al. (2011) Self-administered subcutaneous alemtuzumab to treat residual
disease in patients with chronic lymphocytic leukemia. Cancer 117:
116-24. doi: 10.1002/cncr.25379 Report that self-administered
subcutaneous Campath was safe and effective for the treatment of
- Staton T. Sanofi pulls Campath to clear way for higher-priced
Lemtrada. FiercePharma; 2012 A http://www.fiercepharma.com/story/sanofi-pulls-campath-clear-way-higher-priced-lemtrada/2012-08-21
Pharma industry newsletter FiercePharma reporting the costs of
Campath for CLL.
- Genzyme Corporation. US Campath Distribution Program. 2009. Available
of the US Campath programme reporting the distribution programme
enabling Campath to be provided free of charge to CLL patients from
September 2012 (after Campath was renamed Lemtrada for treatment of
- Evaluate Ltd. Campath Worldwide Sales 2010/11 Overview.
Website providing the cumulative sales of Campath 2010-2011.