Nowadays, due to the worldwide economic crisis, the payer attaches special importance to money allocation in the health care sector. In many countries health technology assessment (HTA) plays an important role in the decision making process of drug reimbursement. In Poland the HTA agency, AHTAPol (Agency for Health Technology Assessment in Poland), was created to support the Minister of Health in the reimbursement decisions. The requirements for the HTA documentation to be fulfilled are described in the AHTAPol HTA guidelines, the latest version dated April 2009. Each new technology has to be proven to be an effective, safe and cost-effective treatment. Additionally the budget impact should be calculated. This applies to all newly introduced drugs and new indications for already used technologies. In 2011 Polish Parliament enacted a new legal act regarding reimbursement procedures, which has been in force since January 2012.
Among other regulations the new Reimbursement Act clearly defines the threshold for cost-effectiveness and cost-utility analysis, which has been set at 3xGDP (Gross Domestic Product) per capita level, taking the mean value for GDP per capita from the last 3 years. For 2012 it has been calculated at 99 543 PLN.
The important implication of such regulation is that there are no exceptions. The threshold remains the same for all technologies, including oncology, rare diseases and orphan drugs. Reviewing the AHTAPol President’s Recommendations it seems very rare and unlikely for an innovative oncology/hematology treatment to meet those criteria.
Mabthera (rituximab) a genetically engineered monoclonal antibody has been registered and approved for use in different indications in hematology (non-Hodgkin’s lymphoma, NHL; chronic lymphocytic lymphoma, CLL) and in rheumatoid arthritis. It has been used successfully in clinical practice for over a decade and is now a renowned and widely studied drug. The economic aspects and cost-effectiveness of Mabthera use have also been subjects of investigations in many countries. Likewise in other countries, in Poland the use of Mabthera in all registered indications and across wide population of patients was consistently proven to be safe and cost-effective.
We have reviewed the analyses prepared for Mabthera in the following indications and submitted for the assessment by AHTAPol:
- previously untreated patients with stage III-IV follicular lymphoma (FL),
- maintenance treatment of follicular lymphoma patients responding to induction treatment (1st and subsequent lines),
- CD20 positive diffuse large B-cell non-Hodgkin’s lymphoma,
Chronic lymphocytic leukemia:
- previously untreated and relapsed/refractory chronic lymphocytic leukemia (1st and 2nd line treatment).
The analyses were performed in line with the AHTAPol guidelines. The cost-effectiveness analyses were preceded by systematic reviews of the literature. Analyses considered Polish clinical treatment practice, standards of care, as well as the adverse events treatment patterns and costs. Data was identified and gathered using a questionnaire filled in by Polish clinical experts from different oncology centers. Corresponding incurred costs were calculated from the Polish public payer (National Health Fund, NHF) perspective. Markov models were used and cost-effectiveness and cost-utility techniques applied to calculate incremental cost-effectiveness and cost-utility ratios. Sensitivity analysis was performed to assess the impact of change in crucial assumptions on the overall results and conclusions.
Previously untreated patients with stage III-IV follicular lymphoma
The treatment of patients with stage III-IV follicular lymphoma with rituximab in combination with chemotherapy is financed by the public payer in Poland through a therapeutic program. Immumochemotherapy is recommended by Polish and international organizations as an effective and safe treatment of FL patients. The analysis aimed at assessing the clinical efficacy, safety and cost-effectiveness of rituximab administered with chemotherapy CVP (cyclophosphamide, vincristine, prednisone) or CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) in the treatment of previously untreated patients diagnosed with stage III-IV follicular lymphoma.
Systematic review of Medline, Cochrane and Embase databases allowed for identification of randomized clinical trials (RCT) directly comparing R-CVP vs. CVP (Marcus 2005, Markus 2008, Markus 2010) and R-CHOP vs. CHOP (Hidemann 2005, Buske 2006) regimens used in the treatment of previously untreated patients diagnosed with stage III-IV follicular lymphoma. Patients received rituximab at 375 mg/m2 day 1 of each 21 day chemotherapy cycle for maximum 6 cycles with CVP and 6-8 cycles with CHOP.
The analysis demonstrated that addition of rituximab to CVP treatment statistically significantly improves: overall survival (OS), time to treatment failure (TTF), median duration of response (RD), median disease free survival (DFS), median time to next lymphoma treatment (TNLT), overall and complete response rate (Tab 1.). The estimated 4-year survival was significantly higher in R-CVP group than in patients receiving CVP alone (83% vs. 77%, p=0.029).The safety profile of R-CVP treatment was favorable. No deaths related to R-CVP were reported. Two patients were withdrawn from the study due to rituximab infusion related reactions. There were no differences between analyzed groups in relation to frequency of infections and neutropenia related sepsis.
Table 1. Results of R-CVP vs. CVP treatment comparison in previously untreated patients diagnosed with stage III-IV follicular lymphoma
|End point||R-CVP (N=162)||CVP (N=159)||RR*** (or HR) (95% CI)||NNT*** (or NNH) (95% CI)||P value^|
|Time to treatment failure (TTF; median, months)||27 (95% CI: 25-37)||7 (95% CI: 6-9)||-||-||<0.0001*|
|Time to progression (TTP; median, months)||34 (95% CI: 25-37)||15 (95% CI: 12-18)||-||-||<0.0001*|
|Duration of response (RD; median, months)||38 (95% CI: 28 - not reached)||14 (95% CI: 9-18)||HR: 0.48 (0.36-0.62)||-||<0.0001**|
|Disease free survival(DFS; median, months)||not reached (95% CI:35 - not reached)||21 (95% CI: 14-38)||-||-||<0.0001*|
|Time to next lymphoma treatment (TNLT) or death (median, months)||49 (95% CI: 32 - not reached)||12 (95% CI: 10-18)||-||-||<0.0001*|
|No overall survival- 4-years follow-up (% patients) #||17%***||23%***||0.74 (0.48-1.15)||-||0.029|
|No overall treatment response ((ORR): CR+CRu+PR; n (%) patients) #||31 (19%)***||69 (43%)***||0.44 (0.31-0.63)||5 (3-7)||<0.0001**|
|Stable disease- 30 month follow-up (SD; n (%) patients) #||150 (93%)***||126 (79%)***||1.17 (1.07-1.28)||NNH: 7 (5-17)||0.0008|
|Disease progression- 30 month follow-up (PD; n (%) patients)||17 (11%)||31 (20%)||0.54 (0.31-0.93)||11 (6-86)||0.03|
|Death (n (%) patients)||31 (19%)||46 (29%)||0.66 (0.44-0.99)||-||0.054***|
|Quality-adjusted time without symptoms of disease or toxicity (Q-TWiST; months)||50.31||41.97||-||-||<0.001|
* Log-rank test stratified by centre, ** Test Î§2, *** calculated based on available data, ^ p value from clinical trials (exc. death rate), # positive endpoints (OS, ORR, SD) were converted into negative endpoints in order to standardize conclusions regarding RR for all analysed endpoints.
Patients receiving rituximab with CHOP regimen had significantly lower risk of experiencing treatment failure, disease progression and disease relapse in comparison to those treated with CHOP alone (Table 2). The overall survival and overall response rates and were also higher in R-CHOP group. The non-hematological adverse events were more frequent with CHOP treatment, however grade 3 and 4 granulocytopenia was observed more often in patients treated with R-CHOP regimen. The probability of disease progression related death was higher in CHOP treated patients.
Table 2. Results of R-CHOP vs. CHOP treatment comparison in previously untreated patients diagnosed with stage III-IV follicular lymphoma
|End point||R-CHOP N=223||CHOP N=205||RR* (95% CI)||NNT* (95% CI)||P value^|
|Treatment failure (TTF; % patients)||32%||65%||0.52 (0.42-0.63)||3 (2-4)||<0.0001|
|No disease response to the treatment (RD; % patients)#||34%||65%||0.54 (0.44-0.67)||3 (3-5)||<0.0001|
|No overall survival (OS; % patients)#||10%||16%||0.61 (0.37-1.02)||-||0.0493|
|No overall treatment response (ORR; % patients) #||3%||9%||0.36 (0.15-0.84)||18 (9-87)||0.005|
|No stable disease (SD; % patients)#||98%||95%||1.04 (1.00-1.08)||-||0.081*|
|Disease progression during therapy (% patients)||1%||3%||0.26 (0.06-1.25)||-||0.14*|
* calculated based on available data, # positive endpoints (OS, ORR, SD, RD) were converted into negative endpoints in order to standardize conclusions regarding RR for all analysed endpoints, ^ p value from clinical trials (exc. stable disease and disease progression during therapy).
Clinical analysis demonstrated that rituximab in combination with CVP or CHOP chemotherapy is an effective and safe treatment for previously untreated patients diagnosed with stage III-IV follicular lymphoma. Moreover, long term follow-up data indicate that treatment with rituximab renders positive and durable effects, with favorable safety profile maintained.
Following confirmation of positive results of treatment with rituximab, cost-effectiveness and cost-utility analysis were performed. Data on clinical practice regarding the therapy of previously untreated patients diagnosed with stage III-IV follicular lymphoma, the therapy of treatment related adverse events and costs were gathered in 5 oncology centers in Poland using a detailed questionnaire. The three state Markov model (disease progression free, disease progression and death) was used to extrapolate clinical efficacy data from clinical trials and to translate experimental efficacy into life years gained (LYG) and quality-adjusted life years (QALY). The public payer’s perspective was assumed as most treatment and treatment related costs are covered from public resources. The analysis time horizon was set at 26 years for both efficacy and cost assessment. The utility data were extracted from the Cost-effectiveness Analysis Registry (CEAR). Following costs were calculated and included:
- 1st line chemotherapy costs (treatment administration costs and drug costs),
- patients’ monitoring and care in disease progression free state,
- patients’ monitoring and care in disease progression state,
- treatment related adverse events therapy.
Costs of active substances were retrieved from NHF and Minister of Health (MoH) published price lists. In line with AHTAPol guidelines cost were discounted at 5% and effects at 3.5%. Deterministic and probabilistic sensitivity analyses were performed to test the results from base case analysis.
The analyses results for both R-CVP vs. CVP and R-CHOP vs. CHOP comparisons show that the incremental cost-effectiveness (ICER, 36 189.31 PLN, 35 392.05 PLN respectively) and incremental cost-utility (ICUR, 41 191.65 PLN, 39 949.48 PLN respectively) ratios are far below assumed in the Poland’s cost-effectiveness threshold. Therefore the use of rituximab in combination with CVP or CHOP regimens in the treatment of previously untreated patients diagnosed with stage III-IV follicular lymphoma is a highly cost effective therapeutic option. The sensitivity analysis indicated that results were sensitive to change in the assumed time horizon, however still the calculated ratios remained far below the threshold.
Table 3. Cost-effectiveness and cost-utility analysis results: R-CVP vs. CVP
|R-CVP||Life year (LY)||9.20520|
|Quality-adjusted life year (QALY)||6.536|
|Total costs (PLN)||152 419.54|
|CVP||Life year (LY)||7.68763|
|Quality-adjusted life year (QALY)||5.203|
|Total costs (PLN)||97 499.66|
|ICER: cost per LYG||36 189.31|
|ICUR: cost per QALY||41 191.65|
Table 4. Cost-effectiveness and cost-utility analysis results: R-CHOP vs. CHOP
|R-CVP||Life year (LY)||10.27610|
|Quality-adjusted life year (QALY)||7.502|
|Total costs (PLN)||139 445.74|
|CVP||Life year (LY)||9.09245|
|Quality-adjusted life year (QALY)||6.454|
|Total costs (PLN)||97 554.12|
|ICER: cost per LYG||35 392.05|
|ICUR: cost per QALY||39 949.48|
Rituximab as a treatment option for previously untreated patients diagnosed with stage III-IV follicular lymphoma should be considered as highly effective and highly cost-effective from the the public payer’s perspective in Poland.
Maintenance treatment of follicular lymphoma
Maintenance treatment aims at maintaining as long as possible the response achieved with the induction therapy, allowing at the same time postponement of subsequent treatment lines. The ESMO (European Society for Medical Oncology) and NCCN (National Comprehensive Cancer Network) guidelines indicate rituximab maintenance as the most optimal and effective strategy to be implemented after induction in patients with follicular lymphoma. This therapeutic approach can be applied instead of watch and wait strategy and, as clinical trials results show, is regarded as highly effective and safe at the same time. The analysis prepared for rituximab assessed efficacy, safety and cost-effectiveness of maintenance monotherapy, both after 1st and subsequent lines of induction treatment, when administered in follicular lymphoma patients.
Maintenance treatment of follicular lymphoma patients responding to 1st line induction treatment
A systematic review was performed in Medline, Embase and Cochrane databases to identify available data on efficacy and safety of maintenance treatment in patients responding to 1st line induction treatment in comparison to watch and wait strategy. One relevant randomized clinical trial was identified. In PRIMA study (Salles 2010) patients received R-CHOP, R-CVP or R-FCM (rituximab, fludarabine, cyclophosphamide, mitoxantron) as an induction therapy and those who achieved response were randomized to either maintenance with rituximab monotherapy or watch and wait strategy. Rituximab in maintenance phase was administered at 375 mg/m2 every 8 weeks for maximum 12 cycles or until disease progression.
The results showed that administration of rituximab as the maintenance therapy reduces the disease progression risk by 45% in comparison to observation during 36 months of the follow-up. A 3-year progression free survival in the rituximab maintenance group was higher than in observation (74.9% vs. 57.6% respectively). Rituximab administered as maintenance treatment after 1st line induction also reduced risk of next anti-lymphoma treatment by 40% and risk of next chemotherapy by 38% in 36 months of the follow-up. It also statistically significantly improved the complete response and complete unconfirmed response rates at 2 years in patients who achieved partial response after induction treatment and at 36 months follow-up. The risk of death was reduced by 13% in rituximab maintenance group; however the results were not statistically significant.
Table 5. Results of clinical analysis: maintenance with rituximab vs. observation in follicular lymphoma patients responding to 1st line induction treatment
|End point||Statistically significant advantage of rituximab maintenance||Statistically significant advantage of observation|
|OR/HR (95% CI)|
|Progression free survival (PFS)||HR=0.55 (0.44; 0.68)||-|
|3-year PFS||OR=2.20 (1.68; 2.87) RD=0.17 (0.12; 0.23) NNT=6 (5; 9)||-|
|Event free survival (EFS)||HR=0.59 (0.48; 0.72)||-|
|Overall survival (OS)||ns|
|Next lymphoma treatment during 36 months follow-up||OR=0.52 (0.39; 0.70); RD=-0.12 (-0.18; -0.07) NNT=9 (6; 15) HR=0.60 (0.47; 0.76)||-|
|Next chemotherapy during 36 months follow-up||OR=0.56 (0.41; 0.76) RD=-0.09 (-0.14; -0.04) NNT=12 (8; 25) HR=0.62 (0.47; 0.81)||-|
|Complete response (CR/CRu) in patients who completed maintenance treatment or observation||OR=2.29 (1.77; 2.97) RD=0.19 (0.13; 0.25) NNT=6 (4; 8)||-|
|Complete response (CR/CRu) during 2 years in patients with partial response after induction||OR=2.56 (1.58; 4.14) RD=0.22 (0.11; 0.33) NNT=5 (4; 10)||-|
|Disease progression during 36 months follow-up in patients qualified to maintenance treatment or observation||OR=0.47 (0.36; 0.61) RD=-0.17 (-0.22; -0.11) NNT=6 (5; 10)||-|
|Disease progression risk during 36 months follow-up||After
|HR=0.51 (0.39; 0.65)||-|
|Patients with CR/CRu after induction||HR=0.57 (0.44; 0.74)||-|
|Patients with PR after induction||HR=0.48 (0.32; 0.72)||-|
|Quality of life||FACT-G||ns|
ns- not statistically significant
The results of the PRIMA study indicated that maintenance treatment with rituximab has an acceptable profile with infections and neutropenia grade 3 and 4 more frequent in the rituximab group. The increased frequency of adverse events (infections and neutropenia) in the rituximab group did not translate into the increased risk of death due to adverse events. The overall results of the clinical efficacy and safety analysis indicate that rituximab should be considered as an option for patients who responded to 1st line induction therapy.
The economic evaluation of rituximab maintenance therapy after 1st line induction treatment was prepared from the public payer’s perspective assuming 25 year (life-time) time horizon to capture all effects and costs that could appear throughout the whole patient’s life. Direct medical costs were assessed based on the data regarding clinical practice of FL treatment and data related to medical resources use gathered in 5 oncology centers in Poland. The following cost categories were identified as important and included in the analysis: cost of drugs and drug administration, treatment-related adverse events costs, lymphoma relapse treatment costs and patient health monitoring costs. Costs were discounted at 5% and effects at 3.5% rate. The four health state Markov model (progression-free 1st line, progression-free subsequent line, progression and death) was used. Sensitivity analysis was performed testing the influence of critical parameters such as utilities values, different costs categories, length of time horizon and patient’s body surface.
Mean number of cycles administered was 10.6 (the PRIMA study). Based on those data and assuming 1.81 m2 body surface area total dose of rituximab and drug administration costs were calculated.
Introduction of 1st line rituximab maintenance therapy resulted in gain of 1.4 life years and 1.3 quality adjusted life years compared to observation. The total incremental costs were 60 707 PLN which corresponded to an incremental cost-effectiveness ratio (ICER) of 43 348 PLN and an incremental cost-utility ratio (ICUR) of 47 357 PLN. Both values are below cost-effectiveness threshold assumed by the Polish public payer for cost-effective technologies.
Table 6. Cost-effectiveness and cost-utility analyses results: rituximab maintenance vs. observation
|Life years gained [LYG]||Incremental cost [PLN]||ICER [PLN/LYG]|
|Rituximab vs. observation||1.400||60 707||43 348|
|Quality adjusted years gained [QALY]||Incremental cost [PLN]||ICUR
|1.282||60 707||47 357|
The results were sensitive to changes in discount rates, utilities values applied to the specific health states, length of time horizon. None of the tested scenarios resulted in values of ICUR and ICER exceeding the 99 543 PLN threshold, providing evidence that the rituximab treatment is cost-effective from the public payer’s perspective. The probability of 1st line maintenance therapy with RTX being cost-effective was 100%.
Rituximab 1st line maintenance treatment of follicular lymphoma patients who responded to induction treatment is an effective, safe and highly cost-effective therapeutic option.
The maintenance therapy prolongs patient’s life and at the same time improves their quality of life. Therefore, need for a structured financing from public resources of maintenance therapy with rituximab should be recognized, so that the option would be available for Polish lymphoma patients.
Maintenance treatment of follicular lymphoma patients responding to 2nd and subsequent lines induction treatment
Maintenance therapy with rituximab of follicular lymphoma patients responding to 2nd and subsequent lines of induction treatment has already been implemented into the daily clinical practice in Poland and is accepted as effective and safe option for patients who would otherwise be subjected to observation only. The therapy is financed from public resources through the therapeutic program. The analyses were prepared to confirm that the decision to finance this option for follicular lymphoma patients was justified and well-funded.
Systematic review of Medline, Embase and Cochrane databases revealed 2 publications of randomized clinical trials results: EORTC 20981- van Oers 2010 (induction with either R-CHOP or CHOP regimens) and Forstpointner 2006 (induction with R-FCM or FCM). Rituximab in maintenance phase was administered every 3 months for 2 years or until disease relapse at 375 mg/m2 dose in van Oers 2010 and in 2 courses, each consisting of 4 doses of 375 mg/m2/day given for 4 consecutive weeks, given 3 and 9 months after completion of salvage therapy in Forstpointner 2006 trial.
Rituximab administered as maintenance therapy reduced risk of disease progression by 45% in comparison to observation. The disease progression risk reduction was also noted in subgroup analysis in patients treated in induction phases with CHOP or R-CHOP regimen and those who achieved complete or partial response after induction treatment. In patients who received rituximab in maintenance therapy the response duration was significantly longer. There were no differences between compared options regarding 5-year survival, however the results were on the border line of statistical significance, therefore trend in improvement of this parameter could be observed as well.
Table 7. Clinical efficacy results: rituximab maintenance vs. observation in follicular lymphoma patients responding to 2nd or subsequent lines of induction treatment
|End point||Statistically significant advantage of rituximab maintenance||Statistically significant advantage of observation|
|OR/HR (95% CI or p value)|
|After CHOP||HR=0.37 (p<0.001)||ns|
|After R-CHOP||HR=0.69 (p=0.043)||ns|
|Patients with PR after induction||HR=0.58 (p<0.001)||ns|
|Patients with CR after induction||HR=0.48 (p=0.003)||ns|
|Duration of response (median)||p=0.035||ns|
The results of the clinical efficacy and safety analysis indicate that rituximab administration as the maintenance strategy in patients with follicular lymphoma, who responded to 2nd or subsequent lines of induction treatment is an effective and safe therapeutic option.
Economic analysis assessed the cost-effectiveness of rituximab maintenance therapy based on the results of clinical analysis. Life-time horizon was assumed as effects and costs of the maintenance strategy can be observed throughout whole patient’s life. The four health state Markov model was used (progression free- induction, progression free- maintenance, progression, death). Discounting was performed at 3.5% for effects and 5% for costs (in the sensitivity analysis those were tested according to AHTAPol guidelines at 5% or 0% for both effects and costs and 0% for effects and 5% for costs). The data regarding utilities were derived from the CEAR. Data on clinical practice and resource utilization were gathered in the 5 oncology centers in Poland. Costs were calculated from the perspective of the public payer’s and included costs of drugs, drug administration costs (induction and maintenance phase), costs of adverse events treatment, costs disease relapse therapy and patient’s health monitoring costs. Sensitivity analysis (one- and multiway) tested changes in various parameters including: utility values, body surface area, administration costs changes, number of treatment cycles induction or maintenance, costs of adverse events therapy, time horizon.
The results showed that administering rituximab in maintenance therapy to patients with follicular lymphoma who responded to 2nd or subsequent line of treatment instead of subjecting them only to observation is not only clinically justified but cost-effective from the public payer’s perspective as well. The ICER was 77 113 PLN/LYG and ICUR 92 612 PLN/QALY. Both results fall below the threshold of 99 543 PLN/QALY or LYG. The sensitivity analysis indicated that the base case results are robust and in all tested scenario cost-effectiveness ratios remained below the threshold.
Table 8. Cost-effectiveness and cost-utility analysis results: rituximab maintenance vs. observation in follicular lymphoma patients responding to 2nd or subsequent lines of induction treatment
|Life years gained [LYG]||Incremental cost [PLN]||ICER [PLN/LYG]|
|Rituximab vs. observation||0.691||53 280||77 113|
|Quality adjusted years gained [QALY]||Incremental cost [PLN]||ICUR
|0.575||53 280||92 621|
The results of analyses for both 1st and 2nd/subsequent lines of maintenance therapy confirm that extending financing from public resources of rituximab in the maintenance phase to patients who responded to 1st line induction treatment should be seriously considered in the nearest future, as this option is not only clinically effective and safe, but also financially sustainable for the public payer.
Chronic lymphocytic leukemia
Chronic lymphocytic leukemia 1st line treatment
In patients with low grade chronic lymphocytic leukemia and slow course of the disease administration of chemotherapy can be postponed for years and watch and wait strategy applied instead. However, in some patients (about 1/3 of all cases) CLL has a more aggressive form and patient’s condition deteriorates very quickly. In such cases chemotherapy should be indicated as soon as possible. The choice of chemotherapy depends on patient’s general health status, age, the disease stage according to Binet or Rai classification and presence of prognostic factors. The treatment aims at achieving complete remission to prolong disease free survival, overall survival and improve quality of life (this is especially important in the older patients). There are several treatment options available; however most clinical recommendations issued by ESMO, NCCN, PUO (Polska Unia Onkologii, Polish Oncology Union) indicate immunochemotherapy with rituximab in combination with fludarabine and cyclophosphamide (R-FC) or chlorambucil monotherapy as the most optimal 1st line treatment in CLL patients. In Poland the use of rituximab in the 1st line treatment of CLL patients is financed from public resources through the catalogue of chemotherapy. The analyses were performed to assess whether the decision to finance this treatment is beneficial for patients and cost-effective from the public payer’s perspective.
The systematic review performed within clinical efficacy and safety analysis helped to identify one randomized clinical trial GCLLSG CLL8 (German Chronic Lymphocytic Lymphoma Study Group) comparing the 1st line R-FC treatment with FC alone. The attempts to identify trials directly comparing R-FC vs. chlorambucil failed. Therefore indirect comparison with Bucher method was performed based on the results of GCLLSG and LFR CLL4 trials results; however due to differences in the characteristics of FC regimens used as a common comparator in both trials the results are prone to be burdened with errors.
In the GCLLSG study rituximab was administered on day 1 of each cycle at 375 mg/m2 (cycle 1) and 500 mg/m2 cycles 2-6 with standard dosages of FC regimen. In the 3-year follow up R-FC therapy prolonged progression free survival (in the general population and in subgroups analyzed: Binet stage B, patients with unfavorable prognostic factors, all age groups). Probability of achieving treatment response and complete remission was statistically significantly higher in R-FC group than in patients treated with chemotherapy alone. The overall survival was also significantly longer in patients receiving R-FC than FC (62.5 months vs. 46.8 months). The positive results for R-FC treatment were also confirmed in the subgroup analysis.
Table 9. Clinical efficacy results: R-FC vs. FC in the 1st line treatment of CLL patients
|Parameter||Hazard ratio (95%CI)||P value|
|Progression free survival||HR=0.56 (95%CI: 0.46; 0.69)||p<0.0001|
|Treatment response||RB=1.13 (95%CI: 1.07; 1.20)||p<0.0001|
|Complete remission||RB=2.05 (95%CI: 1.66; 2.56)||p<0.0001|
|Overall survival||HR=0.67 (95%CI: 0.48; 0.92)||p=0.012|
|Death||RR=0.75 (95%CI: 0.57; 1.01)||p>0.05|
Further analysis showed that the addition of rituximab to FC regimen significantly reduces minimal residual disease levels, which can have impact on the prolongation of progression free survival.
The safety analysis indicated that R-FC increases probability of hematologic grade 3 and 4 adverse events occurrence, including neutropenia and leukopenia, although those incidents do not result in the increased probability of death. Moreover, administration of rituximab as an addition to FC regimen does not negatively influence the patient’s quality of life. The overall safety profile was assessed as favorable.
The economic analysis was performed from the public payer’s perspective for the comparisons of R-FC vs. FC and of R-FC vs. chlorambucil. Data on clinical practice and resources utilization were gathered in 4 oncology and hematology centers in Poland. The Markov model (progression free, progression, death) was used and cost-effectiveness and cost-utility analysis performed. Utility data came from CEAR data base. Only direct medical costs were considered as no other cost categories were identified as important for the payer. The following cost categories were included:
- 1st and 2nd line therapy costs (drugs, drug administration, treatment efficacy assessment costs),
- Monitoring patient’s health in progression free and progression states,
- Grade 3 and 4 adverse events treatment,
- Allogeneic stem cell transplantation costs,
- Cost of transfusion of 1 unit of blood.
Costs of drugs and procedures valuation were derived from NHF and MoH price lists. The time horizon for the analysis of costs and effects was set at 15 years (median survival of CLL patients is 3 to 10 years depending on disease stage). Discounting was applied according to AHTAPol guideline- 5% for costs and 3.5% for effects. The deterministic analysis testing influence of changes in FC and R-FC treatment costs, adverse events treatment costs, utility values, body surface area, time horizon (5 and 10 years) and discounting rates (0% for effects and costs, 5% for effects and costs, 0% for effects and 5% for costs). A probabilistic analysis was also performed.
The results of the economic analysis once again confirmed the value of rituximab treatment. ICER and ICUR values were for both comparisons (vs. FC and vs. chlorambucil) far below the threshold (56 321.18 PLN/LYG, 58 080.35 PLN/QALY and 37 121.16 PLN/LYG and 38 107.03 PLN/QALY respectively).
Table 10. Cost-effectiveness and cost-utility analysis results: R-FC vs. FC and R-FC vs. chlorambucil monotherapy in previously untreated CLL patients
|Parameter||RFC vs. FC||RFC vs. chlorambucyl|
|Incremental costs||51 894.24 PLN||67 782.92 PLN|
|ICER: cost per LYG (PLN)||56 321.18 PLN||37 121.16 PLN|
|ICUR: cost per QALY (PLN)||58 080.35 PLN||38 107.03 PLN|
Sensitivity analysis results confirmed the cost-effectiveness and cost-utility of R-FC regimen. ICER and ICUR values remained far below the threshold in almost all variants of the analysis (except for the scenario when the time horizon was shortened to 5 years). The cost-effectiveness of R-FC vs. FC and of R-FC vs. chlorambucil were close to 100%.
Both clinical efficacy and economic analysis results confirm that rituximab is a beneficial and cost-effective treatment option for previously untreated CLL patients.
Chronic lymphocytic leukemia 2nd line treatment
Similarly as in previously untreated CLL patients, the 2nd line therapy (for patients with relapsed or refractory CLL) is selected by a physician according to patient’s age, health state, lymphoma course and prognostic factors. The treatment aims at this stage at achieving best possible response, progression free survival and prolongation of treatment response duration, without compromising the safety aspects. As the comparators for R-FC scheme FC and bendamustine in monotherapy were selected after reviewing clinical guidelines (ESMO, NCCN). The 2nd line treatment of CLL patients in financed in Poland from public resources through the catalog of chemotherapy. In the systematic review of Medline, Embase, Cochrane data bases, as well as ASCO (American Society of Clinical Oncology), ESMO and ASH (American Society of Hematology) conference abstract databases, one randomized clinical trial (REACH) directly comparing R-FC to FC treatment in patients with relapse or refractory CLL was identified, supplemented with abstract on quality of life of patients from REACH study presented at ASH conference. No trials directly comparing efficacy or safety of R-FC vs. bendamustine treatment were found, therefor an attempt to find data allowing for indirect comparison was made. However also this search was unsuccessful and the analysis authors concluded that there was no possibility to compare R-FC vs. bendamustine.
In REACH trial patients received rituximab on day 1 of each cycle at 375 mg/m2 in cycle 1 and 500 mg/m2 cycles 2-6. Rituximab was combined with the standard doses of FC chemotherapy. Immunotherapy was more efficacious than the FC scheme regarding progression of free survival, treatment response rate, complete and partial treatment response duration of treatment response and time to next lymphoma treatment.
Table 11. Clinical efficacy: R-FC vs. FC in patients with relapsed or refractory CLL
|Parameter||R-FC vs. FC|
|Progression free survival (months); investigator’s assessment||30.6 vs. 20.6; HR=0.65; 95%CI: 0.51; 0.82; p<0.001|
|Progression free survival (months); Independent Reviewing Committee||27.0 vs. 21.9; HR=0.76; 95%CI: 0.60; 0.96; p=0.0218|
|Treatment response; complete or partial; investigator’s assessment||69.9% vs. 58.0%; RB=1.21; 95%CI: 1.06; 1.37; p=0.0034; NNT=9 (6; 26)|
|Complete response rate||24.3% vs. 13.0%; RB=1.86; 95%CI: 1.29; 2.69; p<0.001; NNT=9 (6; 21)|
|Partial treatment response||45,7% vs 44,9%; RB=1,02; 95%CI: 0,84; 1,22; p>0,05|
|Treatment response; complete or partial; Independent Reviewing Committee||61% vs. 49%; RB=1.24; 95%CI: 1.07; 1.45; p=0.0048; NNT=9 (5; 28)|
|Complete response rate; Independent Reviewing Committee||9% vs. 3%; RB=3.125; 95%CI: 1.47; 6.70; p=0.0046; NNT=17 (10; 44)|
|Stable disease||17.0% vs. 22.1%; RR=0.77; 95%CI: 0.55; 1.08; p>0.05|
|Disease progression||2.5% vs 5.4%; RR=0.47; 95%CI: 0.20; 1.09; p>0.05|
|Duration of response; months||39.6 vs. 27.7; HR=0.69; 95%CI: 0.50; 0.96; p=0.0252|
|Median time to next lymphoma treatment; months||Not reached vs. 34.3; HR=0.65; 95%CI: 0.49; 0.86; p=0.0024|
|Overall survival; months||Not reached vs. 52; HR=0.83; 95%CI: 0.59; 1.17; p=0.2874|
|Absence of minimal residual disease||43% vs. 31%; RB=1.38; 95%CI: 0.75; 2.64; p>0.05|
Regarding a safety profile, there are no statistically significant differences between R-FC and FC groups in relation to probability of adverse events occurrence, including grade 3 and 4 adverse events, hematologic adverse events (neutropenia, thrombocytopenia, granulocytopenia or anemia). Quality of life analysis indicated that R-FC therapy prolongs time without disease manifestation, without increasing the risk of treatment related adverse events.
The economic analysis was prepared to assess the cost-effectiveness of R-FC treatment of patients with relapsed or refractory CLL. The calculations were done from the public payer’s perspective with the 15 year time horizon for effects and costs assessment. Only following direct medial costs were considered:
- 2nd and 3rd line therapy costs (drugs, drug administration, treatment efficacy assessment costs),
- Monitoring a patient’s health in progression free and progression states,
- Grade 3 and 4 adverse events treatment,
- Allogeneic stem cell transplantation costs,
- Cost of transfusion of 1 unit of blood.
The three state Markov model was used and cost-effectiveness and cost-utility techniques applied. Utilities were found in the CEAR data base. Deterministic and probabilistic sensitivity analyses were performed. Discounting was performed (5% for costs and 3.5% for effects).
Table 12. Cost-effectiveness and cost-utility analysis results: R-FC vs. FC in patients with relapsed or refractory CLL
|Parameter||RFC vs. FC|
|Incremental costs (PLN)||48 772.15|
|ICER: cost per LYG (PLN)||78 709.13|
|ICUR: cost per QALY (PLN)||79 920.61|
The R-FC treatment of patients with relapsed or refractory CLL was proven to be cost-effective from the public payer’s perspective and moreover highly beneficial for patients. The results of sensitivity analysis provided evidence that conclusions on cost-effectiveness of rituximab treatment were sound and well-based.
Diffuse large B-cell lymphoma treatment
Rituximab in combination with CHOP chemotherapy is regarded as the golden standard of treatment of patients with diffuse large B-cell lymphoma. The R-CHOP regimen is financed from public resources in Poland through therapeutic programme. Immunochemotherapy is deeply set in clinical practice and the analyses were performed to justify the wide use and public financing of rituximab in the treatment of DLBCL patients.
Clinical analysis aimed at assessing the efficacy and safety of immunochemotherapy with rituximab in combination with CHOP regimen vs. CHOP alone in patients with diffuse large B-cell lymphoma. The systematic review covered among other Medline, Embase, Cochrane and CDR data bases and rendered publications on 2 randomized clinical trials for general DLBCL population and DLBCL patients with HIV co-infection. Rituximab was administered at 375 mg/m2 7 and 3 days before cycle 1 and 2 days before cycles 3, 5 and 7 every 21 days with standard dosing of CHOP regimen. Patients who achieved complete remission after four cycles received six cycles in total and those with continued response completed 8 cycles. In the HIV patients rituximab was administered at 375 mg/m2 2 days prior to each CHOP chemotherapy cycle. Patients who achieved partial or complete response received 3 monthly maintenance doses of rituximab also at 375 mg/m2.
The results of the analysis demonstrated that treatment with R-CHOP is effective and safe in all patients, regardless of age or potential HIV co-infection. Immunochemotherapy with rituximab prolonged overall survival, progression free survival, time to event and failure free survival, increased probability of complete and complete unconfirmed response. At the same time R-CHOP in comparison to CHOP alone associated with decreased probability of disease relapse, disease progression and disease progression during treatment, death due to lymphoma or an adverse event. The safety profile in general population and in patients with HIV co-infection was favourable. Although R-CHOP therapy was associated with higher risk of cardio toxicity, infusion related complications and shingles, the overall efficacy outweighed potential negative effects of R-CHOP treatment.
The economic analysis was based on the results of clinical efficacy and safety analysis. The cost-effectiveness and cost-utility analyses were performed from the public payer’s perspective. All costs and effects were estimated in 30 year horizon (life-time). The Markov model was applied with progression, progression free and death health states. The utility data were derived from the CEAR base. Patients were split into two subgroups according to age: ’60 years and ‹60 years. The following costs were identified as crucial from the public payer’s perspective and included in the analysis:
- Cost of drugs (1st and 2nd line chemotherapy),
- Drug administration costs,
- Costs of treatment efficacy assessment,
- Patient’s health monitoring costs,
- Grade 3 and 4 adverse events treatment costs,
- Cost of autologous stem cell transplantation.
Only direct medical costs were included. Prices of drugs and costs of procedures were drawn from NHF and MoH price lists. Data on resource utilization and clinical practice were determined based on a questionnaire study conducted in the 5 Polish oncology and haematology centres. In line with AHTAPol guidelines costs were discounted by 5% and effects by 3.5% in the base case analysis. Deterministic and probabilistic analyses were performed. Various assumptions were checked for their impact on overall analysis results and conclusions.
Both in the under and over 60-year-old population the administration of R-CHOP instead of CHOP regimen alone allowed for gain in LYGs and QALYs. The incremental costs related to R-CHOP vs. CHOP were counterbalanced with efficacy gain rendering ICERs and ICURs values far below the threshold assumed in Poland.
Table 13. Cost-effectiveness and cost-utility analysis results: R-CHOP vs. CHOP in DLBCL over 60 patients
|Parameter||R-CHOP vs. CHOP|
|Incremental cost (PLN)||50 905.10 PLN|
|LYG gain||1.696 LYG|
|QALY gain||1.462 QALY|
|ICER: cost per LYG (PLN)||30 009.60 PLN/LYG|
|ICUR: cost per QALY (PLN)||34 818.82 PLN/QALY|
Table 14. Cost-effectiveness and cost-utility analysis results: R-CHOP vs. CHOP in DLBCL under 60 patients
|Parametr||Porównanie R-CHOP vs CHOP|
|Incremental cost (PLN)||47 825.94 PLN|
|LYG gain||2.721 LYG|
|QALY gain||2.321 QALY|
|ICER: cost per LYG (PLN)||17 577.27 PLN/LYG|
|ICUR: cost per QALY (PLN)||20 602.97 PLN/QALY|
All tested in sensitivity analysis options resulted in ICERs and ICURs (in both under- and over-60- years groups) far below the threshold, thus confirming efficacy and cost-effectiveness of R-CHOP treatment of patients with DLBCL.
Analyses performed for rituximab in combination with CHOP chemotherapy used in the treatment of DLBCL patients indicate that the position of rituximab as the golden standard is justified and sound. Both clinical and economic data show that administration of immunochemotherapy is beneficial for patients and cost-effective for the Polish public payer.
Rituximab has been introduced into the clinical practice several years ago and since then became a standard addition to chemotherapy of patients with FL, DLBCL and CLL. In clinical trials Mabthera has proven its value with significant overall survival, progression free survival, event free survival and overall response time and rates improvement. The treatment with rituximab also allowed for prolongation of time to next lymphoma therapy and had a positive effect on the patient’s quality of life. In terms of economic impact, the analyses that were prepared from the public payer’s perspective in Poland showed that the clinical benefits are linked with very favorable economic results. In all analyzed indications Mabthera was highly cost-effective and conclusions drawn from these analyses justify financing of this treatment option from public resources. The economic results from Polish analyses were consistent with those published worldwide, where treatment with Mabthera was also proven to be cost-effective from the public payers’ perspectives. Independent of health care system in which Mabthera was administered the treatment remained an effective and cost-effective option for the payers and societies (where societal perspective was assumed).
In Portugal analysis conducted for R-CVP vs. CVP treatment in previously untreated FL patients demonstrated that addition of rituximab to CVP regimen is cost-effective from Portuguese National Health System perspective (Braga 2010). Similar findings were published for the UK, where rituximab was added to MCP (mitoxantrone, chlorambucil, prednisolone), CVP, CHOP, and CHVP (cyclophosphamide, etoposide, doxorubicin, prednisolone, interferon alpha) regimens. In all of the analyzed options ICERs far below the threshold assumed for cost-effectiveness in the UK (Ray 2010). In the US were societal perspective was assumed economic analysis results also confirmed that addition of rituximab to chemotherapy is cost-effective in treatment of FL patients (Hornberger 2008). The same conclusions were drawn for maintenance treatment with rituximab after 1st line induction therapy in the Finnish health care system (Soini 2011) and for the maintenance treatment in the management of relapsed or refractory FL patients in French health care setting, where calculated ICERs fell below those observed for other therapies in the oncology (Deconinck 2010). Findings were similar in Sweden (Kasteng 2009).
Published data on cost-effectiveness of 1st line R-FC therapy of CLL patients showed that administration of Mabthera in this indication is cost-effective from a third-party payer and societal perspective in the US (Hornberger 2012). The same conclusions were drawn earlier from analyses conducted in the UK and Spain both for 1st and subsequent lines of CLL patients treatment with R-FC (Main 2010, Dretzke 2010, Casado 2011).
The DLBCL patients’ treatment with rituximab also showed very good economic results in many countries. The analysis prepared by Canadian Centre for Applied Research in Cancer Control (ARCC) and British Columbia Cancer Agency confirmed that R-CHOP treatment in DLBCL patients in a cost-effective option for the payer. Similar results were observed in France (Best 2005) and the US where analyses confirmed that R-CHOP regimen is cost-effective in older patients’ population (Hornberger 2005).
The coherent clinical efficacy and safety data with positive economic analyses results place rituximab in a unique position amongst innovative oncology treatments. Regardless of health care or financing systems rituximab proves its value, even when confronted with rigid HTA requirements. Clinicians and payers have at their disposal highly valuable therapeutic option for patients.
Based on available randomized clinical trials results, numerous conference reports and health technology assessment dossiers prepared for Mabthera in treatment of patients with FL (I line and maintenance, II line maintenance), DLBCL and CLL (I and II line) in Poland it has been proven that it is an clinically effective and beneficial for patients and cost-effective for the public payer treatment option.