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As part of its Single Technology Appraisal (STA) process, the UK National Institute for Health and Care Excellence (NICE) invited the manufacturer of ibrutinib (Janssen) to submit evidence on the clinical and cost effectiveness of ibrutinib for treating Waldenström's macroglobulinaemia (WM). The School of Health and Related Research Technology Assessment Group at the University of Sheffield was commissioned to act as the independent Evidence Review Group (ERG). The ERG produced a critical review of the evidence for the clinical and cost effectiveness of ibrutinib based on the company's submission to NICE. The clinical evidence was derived from one phase II, single-arm, open-label study of ibrutinib in adult patients with WM who had received at least one prior therapy (Study 1118E) and an indirect comparison using a matched cohort from a retrospective European chart review of patients receiving various treatments for WM. The indirect comparison suggested a hazard ratio for progression-free survival (PFS) of 0.25 (95% confidence interval 0.11-0.57). The ERG had concerns regarding the high risk of bias in Study 1118E, the limited generalisability of the study, and the absence of randomised controlled trial evidence. The company's Markov model assessed the cost effectiveness of ibrutinib versus rituximab/chemotherapy for patients with relapsed/refractory (R/R) WM from the perspective of the National Health Service (NHS) and Personal Social Services (PSS) over a lifetime horizon. Based on the company's original Patient Access Scheme (PAS), the company's probabilistic model generated an incremental cost-effectiveness ratio (ICER) for ibrutinib versus rituximab/chemotherapy of £58,905 per quality-adjusted life-year (QALY) gained. Following a critique of the model, the ERG's preferred analysis, which corrected cost errors and used the observed mortality rate from Study 1118E, generated a probabilistic ICER of £61,219 per QALY gained. Based on this amended model, additional exploratory analyses produced ICERs for ibrutinib that were > £60,000 per QALY gained. Subsequently, the company offered to provide ibrutinib at a price that resulted in ibrutinib being cost effective within the Cancer Drugs Fund (CDF). The Committee recommended ibrutinib for use in the CDF as an option for treating WM in adults who have had at least one prior therapy, only if the conditions in the managed access agreement for ibrutinib are followed.

Background: Current treatment regimens for Waldenstrom macroglobulinemia (WM) are based on the use of oral alkylating agents. Recently, however, other more costly agents have been proposed for the treatment of WM. In the current study, the authors report on results obtained using oral melphalan, cyclophosphamide, and prednisone (MCP) to treat 72 patients with WM, and they compare these results (and the associated costs) with those observed using more aggressive protocols., Methods: Between July 1973 and April 2002, the authors documented overexpression of the immunoglobulin M paraprotein in 317 consecutive patients. Of these, 100 had newly diagnosed WM, and the 72 who were symptomatic were treated using the MCP protocol. Response rate, overall survival (OS), response duration, freedom from progression (FFP), event-free survival (EFS) duration, toxicity, and cost per course in Euro and U.S. dollars were evaluated for patients receiving this regimen., Results: Seventy-one of 72 patients (99%) were evaluable. Of these patients, 55 (77%) achieved a response; 7 others (10%) experienced disease stabilization, and the remaining 9 (13%) experienced disease progression. After a median follow-up of 72 months (range, 3-195 months), the median durations of EFS, FFP, response, and OS were 47, 55, 64, and 66 months, respectively. No World Health Organization Grade III or IV toxicities were observed, and side effects were limited to transient nausea, emesis, and mild neutropenia. The cost per course of the MCP regimen was $16, similar to that of standard protocols involving chlorambucil and much less than that of more aggressive protocols (price range, $91-11091) proposed for the treatment of WM., Conclusions: Like chlorambucil-based protocols, the MCP regimen is a cost-effective and safe option for the treatment of patients with WM. Furthermore, the results obtained do not appear to be inferior to those yielded by more expensive, aggressive, and toxic intravenous protocols., ((c) 2004 American Cancer Society)