Introduction
Mechanism of Action of Rituximab
Pharmacodynamics of Rituximab
Pharmacokinetic Profile of Rituximab
Manufacture of Rituximab
Clinical Efficacy of Rituximab
Rituximab in Follicular Lymphoma
Study reference | Line of therapy and no. of patients | Treatment regimen | ORR | CR | PFS, EFS, or other parameter as indicateda
| OS |
---|---|---|---|---|---|---|
GLLSG Hiddemann et al. [63] | 1L (428) | R-CHOP vs CHOP | 96% vs 90%b
| 20% vs 17% | TF (median observation time 18 months): 12.6% vs 29.8%b
| Deaths: 2.7% vs 8.3%b
|
East German Study Group Herold et al. [64] | 1L (201) | R-MCP vs MCP | 92% vs 75%b
| 50% vs 25%b
| EFS: NR vs 26 monthsb
PFS: NR vs 28.8 monthsb
mFU: 47 months | 4-year: 87% vs 74%b
|
Marcus et al. [65] Marcus et al. [66] | 1L (321) | R-CVP vs CVP | 81% vs 57%b
| 41% vs 10%b
| TTF: 27 months vs 7 monthsb
DFS: NR vs 21 monthsb
mFU: 30 months | 4-year: 83% vs 77%b
|
GELA-GOELAMS FL2000 Salles et al. [67] Bachy et al. [68] | 1L (358) | R-CHVP + INF vs CHVP + INF | 81% vs 72%b
| 51% vs 39%b
| EFS: 5.5 years vs 2.8 yearsb
5-year EFS: 53% vs 37%b
8-year EFS: 44% vs 28%b
mFU: 5 and 8.3 years | 5-year: 84% vs 79% 8-year: 79% vs 70% |
FOLL05 Federico et al. [69] | 1L (504) | R-CVP vs R-CHOP vs R-FM | 88% vs 93% vs 91% | 67% vs 73% vs 72% | 3-year TF: 46% vs 62% vs 59% HR 0.62, R-CHOP vs R-CVPb,c, HR 0.63, R-FM vs R-CVPb
3-year PFS: 52% vs 68% vs 63% HR 0.64, R-CHOP vs R-CVPb,c, HR 0.66, R-FM vs R-CVPb,
c
mFU: 34 months | 3-year: 95% (all patients) |
Rummel et al. [70] | 1L (514: 420 NHL, including 279 FL; 94 MCL) | R + benda vs R-CHOP | 93% vs 91% | 40% vs 30%b
| PFS: 69.5 months vs 31.2 months (HR 0.58) mFU: 45 months | Deaths: 16.5% vs 17.8% |
Czuczman et al. [62] | 1L and 2L (38) | R-CHOP | 100% (1L 100%, R/R 100%)d
| 87% (1L 90%, R/R 78%)d
| TTP: 82.3 months mFU: NA | |
EORTC 20981 van Oers et al. [71] | R/R (465) | R-CHOP vs CHOP | 85.1% vs 72.3%b
| 29.5% vs 15.6%b
| PFS: 33.1 months vs 20.2 months (HR 0.65b) mFU: 39.4 months | 3-year: 82.5% vs 71.9% (HR 0.74) |
Study reference | Line of therapy and no. of patients | Induction regimen | RMT regimen and duration | ORR | CR | PFS, EFS, or other parameter as indicateda
| OS |
---|---|---|---|---|---|---|---|
GLLSG Forstpointner et al. [77] | R/R (176, including 105 FL) | R-FCM vs FCMb
| R once weekly for 4 weeks at 3 and 6 months | Inductionb: 95% vs 71%c
| Inductionb: 41% vs 23% | RMT vs OBS in FL patients with R-FCM induction therapy DOR: NR vs 26 monthsc
mOBS: 26 months | – |
EORTC 20981 van Oers et al. [71] van Oers et al. [78] | R/R (334) | R-CHOP vs CHOP | R every 3 months (max. 2 years) | Induction (n = 465): 85% vs 72%c
| Induction (n = 465): 30% vs 16%c
| RMT vs OBS PFS: 51.5 months vs 14.9 months (HR 0.40)c
mFU: 39.4 months and 6 years | RMT vs OBS 3-year: 85.1% vs 77.1% (HR 0.52)c
5-year: 74% vs 65% (HR 0.70) |
SAKK 35/98 Martinelli et al. [79] | R/R (151 randomized) | R | R at 0, 2, 4, and 6 months after end of induction therapy | – | – | RMT vs OBS EFS: 24 months vs 13 monthsc
mFU: 9.5 years | RMT vs OBS Patients died: 32% vs 46% (HR 0.63) |
ECOG 1496 Hochster et al. [72] | 1L (228) | CVP | R once weekly for 4 weeks every 6 months (2 years) | – | Induction: 12% Maintenance: 37% RMT vs 21% OBS | RMT vs OBS 3-year PFS: 64% vs 33%c
PFS: 4.3 years vs 1.3 years (HR 0.4)c
mFU: 3.7 years | RMT vs OBS 3-year: 92% vs 86% (HR 0.6) |
PRIMA | 1L (1018, including 858 confirmed FL) | R + chemotherapy (CVP, CHOP, or FCM)d
| R once weekly every 8 weeks (2 years) | – | RMT vs OBS in all patients 71.5% vs 52.2%c
| RMT vs OBS, all patients 3-year PFS: 74.9% vs 57.6% (HR 0.55)c
6-year PFS: 59.2% vs 42.7% (HR 0.58)c
mFU: 36 and 73 months | RMT vs OBS 6-year: 87.4% vs 88.7% |
Rituximab in Diffuse Large B-Cell Lymphoma
Study reference | Line of therapy and no. of patients | Treatment regimen | ORR | CR | PFS, EFS, or other parameter as indicateda
| OS |
---|---|---|---|---|---|---|
1L: elderly patients | ||||||
GELA, LNH98-5 study, phase III Coiffier et al. [85] | 1L (399), median age 69 years | R-CHOP vs CHOP, 8 cycles | 83% vs 69% | 76% vs 63%b
| 2-year EFS: 57% vs 38% (HR 0.58)b
5-year PFS: 54% vs 30%b
10-year PFS: 37% vs 20%b
mFU: 24 months, 5 years, NA | 2-year: 70% vs 57% (HR 0.64)b
5-year: 58% vs 45%b
10-year: 44% vs 28%b
|
Feugier et al. [89] | ||||||
Coiffier et al. [90] | ||||||
ECOG 4494/CALGB 9793, phase III | 1L (546), median age 69 years (R-CHOP), 70 years (CHOP) | R-CHOP vs CHOP, 6–8 cyclesc
| 77% vs 76% | – | 3-year FFS: 53% vs 46% (HR 0.78)b
mFU: NA | HR 0.83, 95% CI 0.63–1.09 |
Habermann et al. [86] | ||||||
1L: younger patients | ||||||
MInT, phase III | 1L (823), median age 47 years | R-CHOP (or R + CHOP-like chemotherapy) vs CHOP (or CHOP-like chemotherapy), 6 cycles | – | 86% vs 68%b
| At mFU of 34 months: 3-year EFS: 79% vs 59%b
3-year PFS: 85% vs 68%b
At mFU of 72 months: 6-year EFS: 74.3% vs 55.8%b
6-year PFS: 80.2% vs 63.9%b
| 3-year: 93% vs 84% (at mFU of 34 months)b
6-year: 90.1% vs 80.0% (at mFU of 72 months)b
|
Pfreundschuh et al. [87] | ||||||
Pfreundschuh et al. [88] | ||||||
R/R | ||||||
Phase III studies | ||||||
Gisselbrecht et al. [94] | R/R (396) | R-ICE vs R-DHAP | 63.5% vs 62.8% | 36.5% vs 39.3% (including CRu) | 3-year EFS: 26% vs 35% 3-year PFS: 31% vs 42% mFU: 27 months | 3-year: 47% vs 51% |
Vellenga et al. [93] | R/R (225, including 21 other aNHL) | R-(DHAP-VIM-DHAP) vs DHAP-VIM-DHAP; ASCT | 75% vs 54%b
| 2-year PFS: 52% vs 31%b
mFU: 31 months | 2-year: 59% vs 52% | |
Phase II studies | ||||||
Jermann et al. [95] | R/R (50, including 25 DLBCL, 18 TBCL, 7 MCL) | R-EPOCH | 68% | 28% | EFS: 11.8 months (MCL 15 months, TBCL 12.4 months, DLBCL 9.7 months) mFU: 33 months | 17.9 months |
Kewalramani et al. [96] | R/R (36) | R-ICE vs ICE (147 historical controls) + ASCT for responders | 78% vs 71% | 53% vs 27%b
| 2-year PFS: 54% vs 43% (after ASCT) mFU: NA | 2-year: 67% vs 56% (after ASCT) |
Mey et al. [97] | R/R (46) | R-DHAP (23) vs DHAP (23); matched-pair analysis of data from 2 phase II trials | 74% vs 74% | 44% vs 35% | PFS: NR vs 13.0 months 2-year PFS: 52% vs 50% mFU: NA | NR vs 31.3 months 2-year: 57% vs 52% |
Elstrom et al. [98] | R/R (15, including 6 TBCL, 9 DLBCL) | R-DICE + BOR | 60% | 20% | PFS: 3 months mFU: 26 months | 10 months |
Rituximab in Chronic Lymphocytic Leukemia
Study reference | Line of therapy and no. of patients | Treatment regimen | ORR | CR | PFS, EFS, or other parameter as indicateda
| OS |
---|---|---|---|---|---|---|
Phase III studies | ||||||
CLL8 | 1L (817), median age 61/61 years (R-FC/FC) | R-FC vs FC, 6 cycles | 90% vs 80%b
| 44% vs 22%b
| mFU: 3.1 years PFS: 51.8 months vs 32.8 months (HR 0.56)b
3-year PFS: 65% vs 45%b
mFU: 5.9 years PFS: 56.8 months vs 32.9 months (HR 0.59)b
5-year PFS: 47% vs 26%b
| 3-year: 87% vs 83% (HR 0.67)b
mFU: 5.9 years NR vs 86.0 months (HR 0.68)b
|
Hallek et al. [99] | ||||||
Fischer et al. [107] | ||||||
CLL10 | 1L fit (561), median age 62/61 years (R-FC/BR) | R-FC vs BR, 6 cycles | 95% vs 96% | 40% vs 31%b
| mFU: 37.1 months PFS: 55.2 months vs 41.7 months (HR 1.643)b
DOR: 52.7 months vs 38.9 months (HR 1.657)b
EFS: 55.2 months vs 38.5 months (HR 1.626)b
| 3-year: 91% vs 92% (HR 1.034) |
Eichhorst et al. [116] | ||||||
REACH | Previously treated (552), median age 63/62 years (R-FC/FC) | R-FC vs FC, 6 cycles | 69.9% vs 58.0%b
| 24.3% vs 13.0%b
| mFU: 25 months PFS: 30.6 months vs 20.6 months (HR 0.65)b
| NR vs 52 months (HR 0.83)b
|
Robak et al. [100] | ||||||
Phase II studies | ||||||
Keating et al. [105] | 1L (224), median age 58 years | R-FC, 6 cycles | 95% | 70% | 4-year FFS: 69% | mFU: 2 years. Deaths in 8.9% |
Tam et al. [110]c
| 1L (300), median age 57 years | R-FC, 6 cycles | 95% | 72% | mFU: 6 years TTP: 80 months 6-year FFS: 51% | 6-year: 77% |
Wierda et al. [106] | R/R (177), median age 59 years | R-FC, 6 cycles | 73% | 25% | mFU: 28 months TTP: 28 months | mFU: 28 months 42 months |
1L (63), median age 58 years | R-FC lite | 94% | 73% | PFS: 5.8 years 5-year PFS: 66.9% | NR 5-year: 85.5% | |
GCLLSG | 1L (117), median age 64 years | BR, 6 cycles | 88% | 23% | mFU: 27 months EFS: 33.9 months PFS: 33.8 months | mFU: 27 months. 90.5% alive |
Fischer et al. [115] | ||||||
CALGB 9712 | 1L (104), median age 63 years | FR sequentially vs FR concurrently | 84% (all FR patients) | – | mFU: 117 months PFS: 42 months 5-year PFS: 28% 10-year PFS: 13% | mFU: 117 months 85 months 5-year: 71% |
Woyach et al. [113] | ||||||
GCLLSG | R/R (78), median age 67 year | BR, 6 cycles | 59% | 9% | mFU: 24 months EFS: 14.7 months PFS: 15.2 months | mFU: 24 months 33.9 months |
Fischer et al. [114] | ||||||
Foà et al. [117] | 1L (97), median age 70 years | R-Clb vs Clb, 6 cycles (induction); responders randomized to R or OBS | 82.4% (induction) 55.9% R 34.4% OBS | 16.5% (induction) 29.4 R 18.7% OBS | 3-year PFS: 42.7% 3-year EFS: 38.2% For R: over 3-year PFS 48.6% For OBS: over 3-year PFS 31.8% mFU: 34.2 months (34.9 months in randomized population) | NA |
Hillmen et al. [118] | 1L (100), median age 70 years | R-Clb, 6 cycles (6 additional cycles in nonresponders) | 84% | 10% | Median PFS: 23.5 months mFU: 30 months | NR |
Other B-Cell Malignancies
Development of Resistance to Rituximab
Safety and Tolerability of Rituximab in Patients with Hematologic Malignancies
Overview of the Safety Profile
Safety in Patient Subpopulations
Management and Prevention Strategies for Rituximab-Associated Adverse Events
Pharmacoeconomic Considerations
Study reference | Setting | Country, year of costing, and perspective | Methodology/data sources | Costs included | Cost-effectiveness |
---|---|---|---|---|---|
Follicular lymphoma | |||||
Deconinck et al. [147] | R/R, RMT, or OBS after induction therapy (R-CHOP or CHOP) | France (2006, national healthcare system perspective) | Markov model PFS and OS data from EORTC 20981, French official cost data, literature, expert opinion | Direct: drug acquisition, drug administration, treatment of AEs, FU visits (clinical examination, diagnostics), investigations, radiotherapy, routine patient management | RMT vs OBS €71,314 vs €62,251 (lifetime costs) ICER/LYG: €7612 ICER/QALY gained: €8729 |
Ray et al. [148] | 1L, R + chemotherapy (MCP, CVP, CHOP, or CHVP) vs chemotherapy | UK (2008, national healthcare system perspective) | Markov model Event rate data from four phase III clinical trials, life table data, National Health Service references and published literature | Direct: drug acquisition, drug administration, routine patient management and surveillance | R + chemotherapy vs chemotherapy £28,582 to £33,513 vs £20,708 to £29,621 (lifetime costs) ICER/LYG: £6503 (R-MCP), £7473 (R-CVP), £9294 (R-CHOP), £7370 (R-CHVP) ICER/QALY gained: £7455 (R-MCP), £8613 (R-CVP), £10,676 (R-CHOP), £8498 (R-CHVP) |
Soini et al. [149] | R/R, R-CHOP (induction), R-CHOP-R (induction + maintenance), or CHOP | Finland (2008, national healthcare system perspective) | Markov model PFS and OS data from EORTC 20981, official drug cost listings, Finnish case-mix-adjusted national unit costs for healthcare resources | Direct: drug acquisition, drug administration (including traveling), relapse management, routine treatment, treatment of AEs | R-CHOP vs R-CHOP-R vs CHOP €59,521 vs €68,331 vs €49,562 (lifetime costs) ICER/LYG: R-CHOP-R vs R-CHOP €16,380; R-CHOP-R vs CHOP €13,041; R-CHOP vs CHOP €11,049 ICER/QALY gained: R-CHOP-R vs R-CHOP €18,147; R-CHOP-R vs CHOP €14,360; RCHOP vs CHOP €12,123 |
Griffiths et al. [150] | 1L (elderly) R + chemotherapy (CVP, CHOP) vs chemotherapy (CVP, CHOP) | USA (2009, Medicare perspective) | Observational cohort SEER registry data, Medicare claims data | Direct: drug acquisition, cancer care, noncancer care (all total direct costs to Medicare) | R + chemotherapy vs chemotherapy Incremental total cost: $18,695 (costs over 4 years) ICER/LYG: €102,142 |
Hornberger et al. [151] | RMT or OBS (after 1L R + chemotherapy) | USA (NA, payer perspective) | Markov model Event rate data from PRIMA and EORTC 20981, Centers for Disease Control and Prevention data, Centers for Medicare and Medicaid Services data, published literature | Direct: drug acquisition, drug administration, management of AEs, outpatient monitoring, postprogression care | RMT vs OBS $183,963 vs $145,418 (lifetime costs) ICER/LYG: $31,934 ICER/QALY gained: $34,842 |
Blommestein et al. [152] | R/R, RMT vs OBS (3 scenarios: trial efficacy + costs, trial efficacy + matched real-world costs, real-world efficacy + costs) | Netherlands (2012, healthcare system perspective) | Markov model PFS and OS data from EORTC 20981, population-based registries, Netherlands Cancer Registry, literature, national reference list for drug prices | Direct: drug acquisition, hospital inpatient days, day treatment, outpatient days, AEs, postprogression care | RMT vs OBS Trial efficacy + costs €17,425, trial efficacy + real-world costs €32,668, real-world efficacy + costs €23,736 (lifetime incremental costs) ICER/LYG: trial efficacy + costs €11,259, trial efficacy + real-world costs €21,202, real-world efficacy + costs €10,591 ICER/QALY gained: trial efficacy + costs €12,655, trial efficacy + real-world costs €23,821, real-world efficacy + costs €11,245 |
Chen et al. [153] | 1L, RMT vs OBS | USA (2013, payer perspective) | Markov models PFS and OS data from PRIMA and ECOG 1496, literature, Medicare physician fee schedule, Centers for Medicare and Medicaid Services database, life table data, expert opinion | Direct: drug acquisition, drug administration, monitoring, blood tests, CT scans, AEs, hospitalization | RMT vs OBS lifetime costs: PRIMA $112,781 vs $68,856; ECOG 1496 $124,406 vs $72,066 ICER/LYG: PRIMA $39,968; ECOG 1496 $37,627 ICER/QALY gained: PRIMA $40,335; ECOG 1496 $37,412 |
Prica et al. [154] | 1L, RIT + RMT vs RIT (only) vs WW | Canada (2012, payer perspective) | Markov model Survival, response and QOL data from clinical trials, cost data from published literature and databases, Statistics Canada life tables | Direct: drug acquisition, cost of patient FU, physician, nursing, pharmacy laboratory, and radiology services, AEs, salvage chemotherapy, palliative care | RIT + RMT vs RIT vs WW $67,489 vs $59,953 vs $75,895 (costs over 30 years) ICER/QALY gained: $62,360 (RMT vs RIT) |
Diffuse large B-cell lymphoma | |||||
Johnston et al. [155] | 1L, R-CHOP vs CHOP | Canada (2006, NA) | Observational cohort BCCA Lymphoid Cancer Database, BCCA Provincial Systemic Therapy Drug Database, literature | Direct: drug acquisition, radiotherapy, palliative care, assessment, hospitalization, outpatient care, stem cell transplantation | R-CHOP vs CHOP $46,337 vs $36,765 (age <60 years); $42,892 vs $34,968 (age ≥60 years) (costs over 15 years) ICER/DF-LYG: $11,965 (age <60 years), $4313 (age ≥60 years) ICER/QALY gained: $19,144 (age <60 years), $5853 (age ≥60 years) |
Griffiths et al. [156] | 1L, R + chemotherapy vs chemotherapy (elderly) | USA (2009, payer perspective) | Observational cohort SEER registry, Medicare claims | Direct: immunochemotherapy, other cancer and noncancer costs (not specified) | R-CHOP vs CHOP Mean cost difference over 4 years $23,097 ICER/LYG: $62,424 |
Khor et al. [157] | 1L, R-CHOP vs CHOP | Canada (2009, healthcare system perspective) | Observational cohort Population-based administrative healthcare databases, cancer-specific databases, health insurance plan databases for costs | Direct: drug acquisition, hospitalization, laboratory tests, imaging services, emergency department visits, homecare services, rehabilitation, palliative care | R-CHOP vs CHOP $85,293 vs $68,995 (costs over 5 years) ICER/LYG: $61,984 (all patients), $31,789 (age <60 years), $80,601 (age 60–79 years), $110,071 (age ≥80 years) |
Chronic lymphocytic leukemia | |||||
Hornberger et al. [158] | 1L, R-FC vs FC | USA (NA, payer and societal perspective) | Markov model Event rate data from CLL8, general US population data, Centers for Medicare and Medicaid Services reimbursement data, literature | Direct: drug acquisition, drug administration, AEs, salvage therapy Indirect: caregiver costs, lost work productivity | R-FC vs FC Payer perspective $110,267 vs $83,240 (lifetime costs) ICER/LYG: $12,558 ICER/QALY: $23,530 Societal perspective $205,147 vs $172,565 (lifetime costs) ICER/LYG: $15,140 ICER/QALY: $31,513 |
Adena et al. [159] | 1L and R/R, R-FC vs FC | Australia (2009, healthcare perspective) | Markov model Event rate data from CLL8 and REACH, treatment guidelines, expert opinion, literature, Australian prescription data | Direct: drug acquisition, administration, AEs, routine monitoring | R-FC vs FC $62,365 vs $22,097 (costs over 15 years) ICER/LYG: $36,387 ICER/QALY gained: $42,906 |
Mandrik et al. [160] | 1L and R/R, R-FC vs FC | Ukraine (2014, healthcare system perspective) | Markov model Event rate data from CLL8 and REACH, literature, clinical guidelines, utility data (UK), resource utilization/costs (Ukraine) Impact of lower life expectancy in Ukraine (1L only) also assessed | Direct: drug costs, hospitalization, AEs, salvage therapy costs | R-FC vs FC ICER/QALY gained: US$8704 (1L), US$11,056 (R/R), US$13,000 (based on higher mortality of Ukrainian population) |
Müller et al. [161] | 1L, R-FC vs FC | Germany (2014, payer perspective) | Markov model Event rate data from CLL8, treatment guidelines, hospital/hematologic practice patterns, physicians, fee scale within statutory health insurance scheme, German pharmacy reference sources | Direct: drug acquisition, drug administration, AEs (FU visits, tumor assessments, routine management excluded) | R-FC vs FC €28,384 vs €8118 (costs over 5.9 years) ICER/LYG: €15,773 ICER/QALY gained: €17,979 |