Rituximab for the Treatment of Patients with Chronic Lymphocytic Leukemia

PICHON-RIVIERE, A.; AUGUSTOVSKI, F. A.; GARCIA MARTI, S.; GLUJOVSKY, D.; ALCARAZ, A.; LOPEZ, A.; BARDACH, A.; CIAPPONI, A; GONZALEZ, L

Documento de Evaluación de Tecnologías Sanitarias

IECS

Año: 2012 p. 1 - 30

1668-2793

Chronic Lymphocytic Leukemia (CLL) is the most common leukemia affecting Western adults with an estimated incidence of 4.2 every 100,000 inhabitants per year. Survival varies from few months after diagnosis to decades. Stem cell allogeneic transplant is the only curative option, but only few selected patients are considered eligible. Multiples regimes of chemotherapy are available with different efficacy in achieving complete remission and prolonging survival. Most patients experience a relapse with rates of response to rescue chemotherapy ranging from 22% to 34% and survival ranges from 10 to 19 months. The use of rituximab is proposed as treatment for CLL both as first-line treatment and in relapsing or refractory patients.TechnologyRituximab is a monoclonal antibody that binds to the CD20 surface antigen, which expresses both in normal B cells as in tumor cells. By binding, rituximab produces cell death through different mechanisms.PurposeTo assess the available evidence on the efficacy, safety and aspects related to coverage polices of the use of rituximab for the treatment of patients with chronic lymphocytic leukemia.MethodsA bibliographic search was carried out on the main databases: DARE, NHS EED, on Internet general search engines, in health technology evaluation agencies and health sponsors. Priority was given to the inclusion of systematic reviews; controlled, randomized clinical trials (RCTs); health technology assessments and economic evaluations; clinical practice guidelines and coverage policies of other health systems.ResultsIn this report, two meta-analyses, three RCTs, five clinical practice guidelines, two economic evaluations, two health technology assessments and five coverage policies were included.Rituximab in treatment-naive patientsOne RCT published in 2010 randomized treatment-naive patients diagnosed with CLL (n=817) to fludarabine plus cyclophosphamide (FC) versus rituximab in combination with the same scheme (FCR). Survival was longer in the FCR group after 3 years of follow up (87% versus 83%; p=0.01). Time at which 25% of patients died was 62.5 months for the FCR group versus 46.8 for the FC group (p=0.012). Progression-free survival (PFS) was longer in the rituximab group (51.8 versus 32.8 months; p <0.01).One RCT published in 2012 (n=165) randomized patients to FCR or FC plus alemtuzumab (FCA). No significant differences were evidenced in the PFS and GS after three years between both schemes. However, the study was early terminated due to the extremely high mortality informed in the FCA arm.One meta-analysis published in 2012 including a total of 25 RCTs (n=7,926) indirectly compared the efficacy of the different regimes in first-line treatment. There was no evidence that any treatment had been better than the other when assessing overall survival. The two agents with better benefits in PFS were bendamustine (HR 0.23; 95% CI 0.14 to 0.36) and the combined regimes based on fludarabine plus rituximab (HR 0.4; 95% CI 0.15 to 0.40).One meta-analysis published in 2012 which included a total of five RCTs (n=2,431), reported a PFS of 76 months (95%CI 60 to 91) for the patients receiving FCR, 60 months (95%CI, 46 to 73) for FC, 38 months (95%CI 27 to 49) for fludarabine, 24 months (95%CI 15 to 32) for alemtuzumab and 23 months (95%CI 15 to 32) for chlorambucil. This meta-analysis did not assess overall survival.Rituximab in relapsing or refractory patientsOne RCT published in 2010 compared FCR with FC in previously treated CLL patients (n=552). No statistically significant differences were found in overall survival between both groups. PFS was longer in the FCR group (30.6 versus 20.6 months; p<0.01).Adverse EffectsDespite the increased rate of severe neutropenia with the use of FCR, the global incidence of infections including severe ones was not significantly different among the treatment groups.Clinical Practice Guidelines and Coverage PoliciesThere is a general consensus among the main international societies that recommend the use of rituximab for the treatment of CLL both as first line and in relapsing or refractory cases, limiting this recommendation to young patients or adults in good general condition or with mild comorbidities.Some US health insurance companies give coverage to rituximab for the treatment of chronic lymphocytic leukemia both as first line and in relapsing cases. The United Kingdom national health system gives coverage to rituximab only in combination with fludarabine and cyclophosphamide for the treatment of first line and second line treatment, but not in fludarabine-refractory cases or those having previously received rituximab. Rituximab is covered by the Argentine Health Service Superintendency´s Unique Reimbursement System for the treatment of treatment-naive CLL patients, who are relapsing or refractory to a previous treatment.CostsThe cost of adding rituximab to the chemotherapy scheme is approximately AR$152,000 (Argentine pesos October/2012) equivalent to approximately US$ 32,000 (American dollars October/2012) for 6 chemotherapy cycles. Two economic evaluations carried out in Spain and the United States concluded that the inclusion of rituximab to the FC scheme is cost-effective.ConclusionsThe evidence found was of very good methodological quality. In the RCTs reviewed, the FCR combined scheme as first-line treatment has shown a slight increase in overall survival. In the clinical context of relapse and refraction, the benefit of adding rituximab is only evidenced in prolonging PFS and rate of CR. However, it is worth mentioning that these benefits were shown in a highly selected population of mainly young patients, with no comorbidities, at early stages of the disease and with no cytogenetic factors of poor prognosis No RCTs were found that assess the efficacy and safety of rituximab in combination with other chemotherapy regimes, therefore, its usefulness is still to be defined within this context. Despite this important limitation, there is consensus among the most important international societies and health insurance companies on considering the FCR scheme as treatment of choice young patients or adults in good general condition treatment-naive or who have relapsed after two years.