RITUXAN maintenance following first-line R-CHEMO—proven in a Phase III trial of more than 1,000 follicular NHL patients
PRIMA TRIAL DESIGN1,2
- To ensure that all patients received an equal number of courses of RITUXAN prior to maintenance randomization, an additional 2 courses of RITUXAN were given to R-CHOP– and R-FCM–treated patients. For the R-CHOP patients, the 2 additional courses were given on Day 1 of Cycles 7 and 8; for the R-FCM patients, the 2 additional courses were given on Day 15 of Cycles 1 and 4.2
- PRIMA=Primary RItuximab and MAintenance; R=RITUXAN; NHL=non-Hodgkin’s lymphoma; CHOP=cyclophosphamide, doxorubicin, vincristine, and prednisone; CVP=cyclophosphamide, vincristine, and prednisone; FCM=fludarabine, cyclophosphamide, and mitoxantrone; PFS=progression-free survival; PR=partial response; CR=complete response.
- The PRIMA dosing schedule was chosen based on its potential to maintain a target serum level of RITUXAN3
- This once-every-2-months dosing schedule was also supported by data from earlier Phase II clinical trials4,5
Patient population was diverse and well balanced across both arms
|Baseline characteristics before induction*||
|Bone marrow involvement||Involved Not involved Unspecified Not done||
|Extranodal involvement||<2 sites ≥2 sites||
|ECOG performance status||0 1 2||
|FLIPI score||≤1 2 ≥3||
|Induction therapy||R-CHOP R-CVP R-FCM||
- *For patients (N=1,018) who were randomized to the maintenance portion of the trial.2
- †Percentages are rounded and may not add up to 100%.
- ECOG=Eastern Cooperative Oncology Group; FLIPI=Follicular Lymphoma International Prognostic Index.
- The PRIMA trial’s diverse patient population included2:
- Patients with bulky disease—98% of the PRIMA population had bulky disease prior to induction therapy
- Higher-risk patients—43% had a FLIPI score of ≥3
- Lower-risk patients—57% had a FLIPI score of ≤2
RITUXAN maintenance following first-line R-CHEMO nearly doubled the likelihood of remaining progression-free at 2-year median follow-up
PFS AT 2-YEAR MEDIAN FOLLOW-UP1,2
- CI=confidence interval.
In a Kaplan-Meier PFS curve, when the patient population gets smaller, either due to availability for analysis or progression, a single event can result in a drastic drop in the curve. PFS assessment after 27 months is based on <10% of the patient population and the plot cannot be used to reliably predict PFS beyond this time point.
A prespecified interim analysis demonstrated the superiority of RITUXAN maintenance vs observation following first-line R-CHEMO. FDA approval was based on an independent review committee (IRC) assessment of the study results2:
- RITUXAN maintenance provided a 46% reduction in the risk of progression, relapse, or death (p<0.0001)2
- RITUXAN maintenance significantly improved PFS at 2 years—78% vs 62%2
- Results from the investigator’s analysis showed a similar 2-year PFS improvement in the RITUXAN maintenance arm—82% vs 66% (p<0.0001; HR: 0.50; 95% CI: 0.39–0.64)
Safety for single-agent RITUXAN as maintenance for follicular NHL after first-line RITUXAN-based chemotherapy
- Detailed safety data collection was limited to Grade ≥2 infections, Grade ≥3 adverse reactions, and serious adverse reactions
- The most frequently reported adverse reaction was infections. In patients receiving RITUXAN as single-agent maintenance therapy following RITUXAN plus chemotherapy, infections were reported more frequently compared with the observation arm (37% vs 22%). Most infections reported with RITUXAN maintenance were Grade 2
- The most common Grade 3-4 adverse reactions occurring at a higher incidence (≥2%) in the RITUXAN arm than in the observation arm were infections (4% vs 1%) and neutropenia (4% vs <1%)
- RITUXAN® (Rituximab) full prescribing information, Genentech, Inc., 2012.
- Data on file, Genentech, Inc.
- Berinstein NL, Grillo-López AJ, White CA, et al. Association of serum rituximab (IDEC-C2B8) concentration and anti-tumor response in the treatment of recurrent low-grade or follicular non-Hodgkin's lymphoma. Ann Oncol. 1998;9:995-1001.
- Ghielmini M, Hsu Schmitz SF, Cogliatti SB, et al. Prolonged treatment with rituximab in patients with follicular lymphoma significantly increases event-free survival and response duration compared with the standard weekly ×4 schedule. Blood. 2004;103:4416-4423.
- Gordan LN, Grow WB, Pusateri A, et al. Phase II trial of individualized rituximab dosing for patients with CD20-positive lymphoproliferative disorders. J Clin Oncol. 2005;23:1096-1102.
RITUXAN® (Rituximab) is indicated for the treatment of patients with:
- Relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL as a single agent
- Previously untreated follicular, CD20-positive, B-cell NHL in combination with first-line chemotherapy and, in patients achieving a complete or partial response to RITUXAN in combination with chemotherapy, as single-agent maintenance therapy
- Non-progressing (including stable disease), low-grade, CD20-positive, B-cell NHL, as a single agent, after first-line CVP chemotherapy
- Previously untreated diffuse large B-cell, CD20-positive NHL in combination with CHOP or other anthracycline-based chemotherapy regimens
- Previously untreated and previously treated CD20-positive CLL in combination with fludarabine and cyclophosphamide (FC)
RITUXAN is not recommended for use in patients with severe, active infections.
Important Safety Information
WARNING: FATAL INFUSION REACTIONS, TUMOR LYSIS SYNDROME (TLS), SEVERE MUCOCUTANEOUS REACTIONS, and PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML)
Infusion Reactions: RITUXAN administration can result in serious, including fatal, infusion reactions. Deaths within 24 hours of RITUXAN infusion have occurred. Approximately 80% of fatal infusion reactions occurred in association with the first infusion. Carefully monitor patients during infusions. Discontinue RITUXAN infusion and provide medical treatment for Grade 3 or 4 infusion reactions.
Tumor Lysis Syndrome (TLS): Acute renal failure requiring dialysis with instances of fatal outcome can occur in the setting of TLS following treatment of non-Hodgkin's lymphoma (NHL) with RITUXAN monotherapy.
Severe Mucocutaneous Reactions: Severe, including fatal, mucocutaneous reactions can occur in patients receiving RITUXAN.
Progressive Multifocal Leukoencephalopathy (PML): JC virus infection resulting in PML and death can occur in patients receiving RITUXAN.
Warnings and Precautions
RITUXAN has also been associated with other serious and/or fatal adverse reactions. These include
- hepatitis B reactivation with fulminant hepatitis; hepatic failure resulting in death
- serious, including fatal, bacterial, fungal, and new or reactivated viral infections
- cardiovascular events, including serious or life-threatening cardiac arrhythmias
- severe, including fatal, renal toxicity
- abdominal pain, bowel obstruction and perforation, in some cases leading to death, can occur in patients receiving RITUXAN in combination with chemotherapy
Additional Important Safety Information
- The most frequent Grade 3 or 4 adverse reactions observed in NHL were cytopenias, including lymphopenia. The most common adverse reactions of RITUXAN (incidence ≥25%) observed in clinical trials of patients with NHL were infusion reactions, fever, lymphopenia, chills, infection, and asthenia. The incidence of infusion reactions was highest during the first infusion (77%) and decreased with each subsequent infusion. These infusion reactions typically resolved with slowing or interruption of the infusion and with supportive care
- The most common adverse reactions of RITUXAN (incidence ≥25%) observed in clinical trials of patients with CLL were infusion reactions and neutropenia. Infusion-related adverse reactions occurring during or within 24 hours of the start of infusion included nausea, pyrexia, chills, hypotension, vomiting, and dyspnea
- Most CLL patients treated with R-FC experienced at least one Grade 3 or 4 adverse reaction. The Grade 3 or 4 adverse reactions observed more frequently with R-FC compared with FC alone were neutropenia, leukopenia, febrile neutropenia, thrombocytopenia, infusion reactions, pancytopenia, hypotension, and hepatitis B
- In clinical trials, CLL patients 70 years of age or older who received R-FC had more Grade 3 and 4 adverse reactions compared with younger CLL patients who received the same treatment
Attention Healthcare Provider: Provide Medication Guide to patient prior to RITUXAN infusion.