Ofatumumab for the treatment of chronic lymphocytic leukaemia in patients who are refractory to fludarabine and alemtuzumab: a critique of the submission from GSK

Article history

The research reported in this article of the journal supplement was commissioned and funded by the HTA programme on behalf of NICE as project number 09/96/01. The assessment report began editorial review in June 2010 and was accepted for publication in September 2010. See the HTA programme website for further project information (www.hta.ac.uk). This summary of the ERG report was compiled after the Appraisal Committee’s review. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors’ report and would like to thank the referees for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report. The views expressed in this publication are those of the authors and not necessarily those of the HTA programme or the Department of Health.

Declared competing interests of authors

none

Copyright statement

© Queen’s Printer and Controller of HMSO 2011. This work was produced under the terms of a commissioning contract issued by the Secretary of State for Health. This journal is a member of and subscribes to the principles of the Committee on Publication Ethics (COPE) (http://www.publicationethics.org/). This journal may be freely reproduced for the purposes of private research and study and may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NETSCC, Health Technology Assessment, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK.

2011 Queen’s Printer and Controller of HMSO

Description of the underlying health problem

Chronic lymphocytic leukaemia (CLL) is a malignant disorder of white blood cells (lymphocytes). CLL causes abnormal lymphocytes to proliferate, which, in turn, causes anaemia and increased susceptibility to infection. CLL often remains undiagnosed either until it is well advanced or until a chance test shows abnormally high levels of lymphocytes in the blood. It is a chronic and incurable disease. CLL is the most common form of leukaemia in the UK. In England, 1961 cases of CLL were diagnosed in 2004. In England and Wales, CLL caused 1019 deaths in 2007. It mainly affects older people, with 75% of diagnoses being made in people over the age of 60 years. Overall incidence is approximately three cases per 100,000 of the population per year. Twice as many men as women are affected. CLL is genetically heterogeneous, with median survival ranging from about 3 to 12 years depending on the genetic subtype and the stage at which the disease is diagnosed. Other prognostic factors include age at onset, spread of disease and response to treatment. 2

In the UK, first-line medical management of CLL usually involves chemotherapy with fludarabine and cyclophosphamide, with or without the addition of rituximab, or, in some cases, chlorambucil is used. Refractory CLL is generally considered to be disease that has not responded adequately to treatment or that has relapsed within 6–12 months of an adequate response. Refractory CLL is associated with a poorer prognosis. People whose disease is refractory to first-line treatment with fludarabine combination therapies may be given alternative non-fludarabine therapies, such as cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP) with or without rituximab, or may be given non-chemotherapy treatments, such as alemtuzumab or high-dose steroids. Some people with refractory disease will receive best supportive care (BSC). There is an ongoing appraisal of rituximab in combination with chemotherapy for relapsed or refractory CLL. 2

Scope of the evidence review group report

The purpose of the ERG report was to comment on the validity of the manufacturer’s submission (MS) on the technology of interest. The scope for this submission, and hence the scope for the ERG report, is shown in Table 1.

Summary of submitted clinical evidence

The submission from GlaxoSmithKline (GSK) included one study: a non-randomised, single-arm study (Hx-CD20-406) of ofatumumab. From a total of 138 patients, treatment effectiveness is taken from the 59 patients defined as ‘double refractory’ (DR; refractory to both fludarabine and alemtuzumab treatment). After week 28, disease status evaluation (physical examination, spleen and liver measurement, and blood samples) took place every 3 months until month 24.

Two other studies were identified, Tam et al. 4 and Dungarwalla et al. ,5 which were ruled out because they are non-comparative and provide evidence for therapies other than ofatumumab.

In the Hx-CD20-406 study the overall response rate (ORR) was 58% (99% confidence interval 40% to 74%, p < 0.001). Complete resolution of constitutional symptoms and improved performance status occurred in 57% of patients. Median progression-free survival (PFS) and overall survival (OS) times were 5.7 and 13.7 months, respectively.

The most common adverse events (AEs) during treatment were infusion reactions, which were primarily grade 1 or 2 events. The AE profile is consistent with that seen with other monoclonal antibody therapies.

Summary of submitted cost-effectiveness evidence

The manufacturer used a cohort-based ‘area-under-the-curve’ model to project expected clinical and economic outcomes for patients with DR CLL who received either ofatumumab or BSC. The model had three states: ‘alive pre-progression’, ‘alive post progression’ and ‘dead’.

GlaxoSmithKline’s base-case analysis produced an incremental cost-effectiveness ratio (ICER) of £38,241 per quality-adjusted life-year (QALY). When we updated GSK’s model with what we thought were more appropriate assumptions of the utilities for PFS and progressive disease (PD), and included the 17p and 11q chromosomal deletions, the base-case ICER increased to at least £81,500 per QALY.

Commentary on the robustness of submitted evidence

Areas of uncertainty

Several areas of uncertainty were identified:

• The true effect of ofatumumab on ORR, PFS and OS is uncertain. Although it is not self-evident that modelling patients on BSC as non-responders in the single arm trial of ofatumumab will necessarily lead to an overestimate of the treatment effect, it is superficially tempting to conclude that this is the most likely impact of the bias.

• In the absence of a control arm, it is not known whether AEs experienced by the treated population are related to the condition or the treatment.

• It is difficult to determine the impact of ofatumumab on global quality of life as it has not been measured.

• The impact on the measured effect of outcomes, for example infection, which could be attributable to lack of response or to AEs of ofatumumab.

There was considerable uncertainty concerning the base-case ICER for the following reasons:

• The effectiveness of the ofatumumab and BSC treatment arms was not taken from a randomised trial. Instead, the effectiveness for BSC was taken from non-responders in the single-arm ofatumumab trial, which is methodologically very dubious. However, as the survival data for the non-responder group in the ofatumumab trial are very similar to those in the Tam et al. observational study,4 this offers some support for the use of this group as an appropriate proxy for the BSC arm.

• There was extensive extrapolation of OS, with approximately 40% of patients still alive at maximum follow-up.

• There was considerable uncertainty surrounding the methodology of the study from which the utilities are taken. 6 This is important because cost-effectiveness is sensitive to the utilities. The valuation of health-state descriptions in the Ferguson et al. study6 uses the time trade-off method (which is appropriate), from a representative sample of the general public (n = 60). However, the health-state descriptions were taken from the literature, the clinical guidelines and specialist nurses/clinicians, but the NICE reference case1,7 explicitly states that health-state descriptions should come from patients. Further information on the health-state descriptions, particularly the domains covered, was not available.

• GlaxoSmithKline’s probabilistic sensitivity analyses overestimate the extent of parameter uncertainty in cost-effectiveness because GSK have assumed that the two parameters of the Weibull distributions for PFS and separately for OS are independent, whereas they will be correlated to some extent.

Key issues

The key issues for consideration by the appraisal committee were thus suggested to be as follows:

• The use of a non-randomised, single-arm study makes it difficult to determine the nature and extent of the bias in the treatment effect of ofatumumab relative to BSC.

• It is difficult to determine the impact of ofatumumab on global quality of life, as it has not been measured.

• The impact on the measured effect of outcomes, for example infection, which could be attributable either to lack of response or to AEs of ofatumumab.

Summary of NICE guidance issued as a result of the STA

The final appraisal determination was issued by NICE in September 2010 and states:

1. 1.1 Ofatumumab is not recommended for the treatment of chronic lymphocytic leukaemia that is refractory to fludarabine and alemtuzumab.

2. 1.2 People currently receiving ofatumumab for the treatment of chronic lymphocytic leukaemia that is refractory to fludarabine and alemtuzumab should have the option to continue treatment until they and their clinician consider it appropriate to stop.

Disclaimers

The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the Department of Health.