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First-Line Follicular Lymphoma Patients Who Responded to R-Chemo

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Prima Trial Design
Efficacy
Response Rates in the Randomized Population
Select Important Safety Information

Prima: A Proven Maintenance Strategy for First-Line Follicular Lymphoma

Prima Trial Design1,2*

First-Line Follicular Lymphoma Prima Trial Design

*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

†CRu defined as the following: a) disappearance of all detectable evidence of disease as well as disease-related symptoms and normalization of NHL-related biochemical abnormalities, b) reduction in size of enlarged organs palpable on physical examination in addition to the following features: i) regression of lymph node (greater than 1.5 cm in its greatest transverse diameter) by more than 75% in sum of the products of the greatest diameters and/or ii) indeterminate bone marrow.2

The PRIMA Dosing Schedule Was Chosen Based In Part On Its Potential To Maintain A Target Serum Level Of RITUXAN. This Level Was Derived From Pharmacokinetic Data In The Pivotal McLaughlin Trial In Relapsed Or Refractory Low-Grade Or Follicular Lymphoma.2-4

  • At 3 months post-RITUXAN treatment, median serum levels in responding and non-responding patients were 25.4 μg/mL and 5.9 μg/mL, respectively (P<0.001)2
  • Based on these pharmacokinetic data, a once-every-2-months PRIMA dosing regimen was developed to help increase the likelihood of patients maintaining a serum concentration of 25 μg/mL2

Efficacy

RITUXAN Maintenance Therapy Reduced the Risk of Progression, Relapse, or Death by 46% and Extended Time in Remission1

RITUXAN (rituximab) Maintenance Therapy Efficacy Chart

‡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.

  • The risk of progression, relapse, or death nearly doubled (1.85x) for patients in the observation arm (P<0.0001)§

 §The risk of progression, relapse, or death for the observation arm of the PRIMA trial was calculated using the formula 1/HR.

RITUXAN MAINTENANCE FOLLOWING A RESPONSE TO FIRST-LINE R-CHEMO SHOWED HIGHER RESPONSE RATES AT 2 YEARS VS OBSERVATION2,5

Response Rates in the Randomized Population Based on Investigator Analysis2,5||

Response Rates to R-Chemo Induction Chart

||Patients who did not respond to induction were not randomized to the maintenance or observation stage in PRIMA.

N values do not include the patients (n=231) still undergoing RITUXAN maintenance or observation at the time of the interim analysis.2

  • Two-year response rates were a prespecified secondary endpoint in the PRIMA trial5

SELECT IMPORTANT SAFETY INFORMATION

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 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%)
  • 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%)

CHOP=cyclophosphamide, doxorubicin, vincristine, and prednisone; CR=complete response; CRu=complete response, unconfirmed; CVP=cyclophosphamide, vincristine, and prednisone; ECOG=Eastern Cooperative Oncology Group; FCM=fludarabine, cyclophosphamide, and mitoxantrone; FLIPI=Follicular Lymphoma International Prognostic Index; HR=hazard ratio; CI=confidence interval; IRC=Independent Review Committee; NHL=non-Hodgkin’s lymphoma; ORR=overall response rate; PFS=progression-free survival; PR=partial response; PRIMA=Primary RItuximab and MAintenance; R-CHEMO=RITUXAN plus chemotherapy; R=RITUXAN;

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IMPORTANT SAFETY INFORMATION & INDICATIONS

INDICATIONS

RITUXAN® (rituximab) is indicated for the treatment of adult 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 a rituximab product 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)

BOXED WARNINGS

WARNING: FATAL INFUSION-RELATED REACTIONS, SEVERE MUCOCUTANEOUS REACTIONS, HEPATITIS B VIRUS REACTIVATION and PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY

  • Infusion-related reactions: RITUXAN administration can result in serious, including fatal infusion-related reactions. Deaths within 24 hours of RITUXAN infusion have occurred. Approximately 80% of fatal infusion-related reactions occurred in association with the first infusion. Monitor patients closely. Discontinue RITUXAN infusion for severe reactions and provide medical treatment for Grade 3 or 4 infusion-related reactions
  • Severe Mucocutaneous Reactions: Severe, including fatal, mucocutaneous reactions can occur in patients receiving RITUXAN
  • Hepatitis B Virus (HBV) Reactivation: HBV reactivation can occur in patients treated with RITUXAN, in some cases resulting in fulminant hepatitis, hepatic failure, and death. Screen all patients for HBV infection before treatment initiation, and monitor patients during and after treatment with RITUXAN. Discontinue RITUXAN and concomitant medications in the event of HBV reactivation
  • Progressive Multifocal Leukoencephalopathy (PML), including fatal PML, can occur in patients receiving RITUXAN

Warnings and Precautions

Infusion-related Reactions

  • RITUXAN can cause severe, including fatal, infusion-related reactions. Severe reactions typically occurred during the first infusion with time to onset of 30-120 minutes
  • RITUXAN-induced infusion-related reactions and sequelae include urticaria, hypotension, angioedema, hypoxia, bronchospasm, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, cardiogenic shock, anaphylactoid events, or death
  • Premedicate patients with an antihistamine and acetaminophen prior to dosing. Institute medical management (e.g. glucocorticoids, epinephrine, bronchodilators, or oxygen) for infusion-related reactions as needed. Depending on the severity of the infusion reaction and the required interventions, temporarily or permanently discontinue RITUXAN. Resume infusion at a minimum 50% reduction in rate after symptoms have resolved
  • Closely monitor the following patients: those with pre-existing cardiac or pulmonary conditions, those who experienced prior cardiopulmonary adverse reactions, and those with high numbers of circulating malignant cells (≥25,000/mm3)

Severe Mucocutaneous Reactions

  • Mucocutaneous reactions, some with fatal outcome, can occur in patients treated with RITUXAN. These reactions include paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis
  • The onset of these reactions has been variable and includes reports with onset on the first day of RITUXAN exposure. Discontinue RITUXAN in patients who experience a severe mucocutaneous reaction. The safety of readministration of RITUXAN to patients with severe mucocutaneous reactions has not been determined

Hepatitis B Virus Reactivation

  • Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, can occur in patients treated with drugs classified as CD20-directed cytolytic antibodies, including RITUXAN. Cases have been reported in patients who are hepatitis B surface antigen (HBsAg) positive and also in patients who are HBsAg negative but are hepatitis B core antibody (anti-HBc) positive. Reactivation also has occurred in patients who appear to have resolved hepatitis B infection (i.e., HBsAg negative, anti-HBc positive and hepatitis B surface antibody [anti-HBs] positive)
  • HBV reactivation is defined as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level or detection of HBsAg in a person who was previously HBsAg negative and anti-HBc positive. Reactivation of HBV replication is often followed by hepatitis, i.e., increase in transaminase levels. In severe cases increase in bilirubin levels, liver failure, and death can occur
  • Screen all patients for HBV infection by measuring HBsAg and anti-HBc before initiating treatment with RITUXAN. For patients who show evidence of prior hepatitis B infection (HBsAg positive [regardless of antibody status] or HBsAg negative but anti-HBc positive), consult with physicians with expertise in managing hepatitis B regarding monitoring and consideration for HBV antiviral therapy before and/or during RITUXAN treatment
  • Monitor patients with evidence of current or prior HBV infection for clinical and laboratory signs of hepatitis or HBV reactivation during and for several months following RITUXAN therapy. HBV reactivation has been reported up to 24 months following completion of RITUXAN therapy
  • In patients who develop reactivation of HBV while on RITUXAN, immediately discontinue RITUXAN and any concomitant chemotherapy, and institute appropriate treatment. Insufficient data exist regarding the safety of resuming RITUXAN treatment in patients who develop HBV reactivation. Resumption of RITUXAN treatment in patients whose HBV reactivation resolves should be discussed with physicians with expertise in managing hepatitis B

Progressive Multifocal Leukoencephalopathy

  • JC virus infection resulting in PML and death can occur in RITUXAN-treated patients with hematologic malignancies or with autoimmune diseases. The majority of patients with hematologic malignancies diagnosed with PML received RITUXAN in combination with chemotherapy or as part of a hematopoietic stem cell transplant. Most cases of PML were diagnosed within 12 months of their last infusion of RITUXAN
  • Consider the diagnosis of PML in any patient presenting with new-onset neurologic manifestations. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture. Discontinue RITUXAN and consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML

Tumor Lysis Syndrome

  • Acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, or hyperphosphatemia from tumor lysis, some fatal, can occur within 12−24 hours after the first infusion of RITUXAN in patients with NHL. A high number of circulating malignant cells (≥25,000/mm3) or high tumor burden, confers a greater risk of TLS
  • Administer aggressive intravenous hydration and anti-hyperuricemic therapy in patients at high risk for TLS. Correct electrolyte abnormalities, monitor renal function and fluid balance, and administer supportive care, including dialysis as indicated

Infections

  • Serious, including fatal, bacterial, fungal, and new or reactivated viral infections can occur during and following the completion of RITUXAN-based therapy. Infections have been reported in some patients with prolonged hypogammaglobulinemia (defined as hypogammaglobulinemia >11 months after rituximab exposure)
  • New or reactivated viral infections included cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus, West Nile virus, and hepatitis B and C. Discontinue RITUXAN for serious infections and institute appropriate anti-infective therapy
  • RITUXAN is not recommended for use in patients with severe, active infections

Cardiovascular Adverse Reactions

  • Cardiac adverse reactions, including ventricular fibrillation, myocardial infarction, and cardiogenic shock may occur in patients receiving RITUXAN. Discontinue infusions for serious or life-threatening cardiac arrhythmias. Perform cardiac monitoring during and after all infusions of RITUXAN for patients who develop clinically significant arrhythmias, or who have a history of arrhythmia or angina

Renal Toxicity

  • Severe, including fatal, renal toxicity can occur after RITUXAN administration in patients with NHL. Renal toxicity has occurred in patients who experience tumor lysis syndrome and in patients with NHL administered concomitant cisplatin therapy during clinical trials. The combination of cisplatin and RITUXAN is not an approved treatment regimen. Monitor closely for signs of renal failure and discontinue RITUXAN in patients with a rising serum creatinine or oliguria

Bowel Obstruction and Perforation

  • Abdominal pain, bowel obstruction and perforation, in some cases leading to death, can occur in patients receiving RITUXAN in combination with chemotherapy. In postmarketing reports, the mean time to documented gastrointestinal perforation was 6 (range 1−77) days in patients with NHL. Evaluate if symptoms of obstruction such as abdominal pain or repeated vomiting occur

Immunization

  • The safety of immunization with live viral vaccines following RITUXAN therapy has not been studied and vaccination with live virus vaccines is not recommended before or during treatment
  • For patients treated with RITUXAN, physicians should review the patient’s vaccination status and patients should, if possible, be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating RITUXAN and administer non-live vaccines at least 4 weeks prior to a course of RITUXAN

Embryo-Fetal Toxicity

  • Based on human data, RITUXAN can cause fetal harm due to B-cell lymphocytopenia in infants exposed to rituximab in-utero. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception while receiving RITUXAN and for 12 months after the last dose

Additional Important Safety Information

  • The most common Grade 3 or 4 adverse reactions in clinical trials of NHL and CLL were infusion-related reactions, neutropenia, leukopenia, anemia, thrombocytopenia, and infections. Additionally, lymphopenia and lung disorder were seen in NHL trials; and febrile neutropenia, pancytopenia, hypotension, and hepatitis B were seen in CLL trials
  • The most common adverse reactions (incidence ≥25%) in clinical trials of NHL and CLL were infusion-related reactions. Additionally, fever, lymphopenia, chills, infection, and asthenia were seen in NHL trials; and neutropenia was seen in CLL trials
  • Pregnancy and Nursing Mothers: Based on human data, RITUXAN can cause adverse developmental outcomes including B-cell lymphocytopenia in infants exposed to RITUXAN in-utero. Advise pregnant women of the risk to a fetus. There are no data on the presence of rituximab in human milk, the effect on the breastfed child, or the effect on milk production. Since many drugs including antibodies are present in human milk, advise a lactating woman not to breastfeed during treatment and for 6 months after the last dose of RITUXAN due to the potential for serious adverse reactions in breastfed children

For additional safety information, please see the full Prescribing Information including BOXED WARNINGS and Medication Guide.

Attention Healthcare Provider: Provide Medication Guide to patient prior to RITUXAN infusion.

You may report side effects to the FDA at 800-FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at 888-835-2555.

    • RITUXAN® (rituximab) full Prescribing Information, Genentech, Inc., 2021.

      RITUXAN® (rituximab) full Prescribing Information, Genentech, Inc., 2021.

    • Data on file, Genentech, Inc.

      Data on file, Genentech, Inc.

    • McLaughlin P, Grillo-López AJ, Link BK, et al. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol. 1998;16:2825-2833.

      McLaughlin P, Grillo-López AJ, Link BK, et al. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol. 1998;16:2825-2833.

    • 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.

      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.

    • Salles G, Seymour JF, Offner F, et al. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet.2011;377:42-51.

      Salles G, Seymour JF, Offner F, et al. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet.2011;377:42-51.

    • Hochster H, Weller E, Gascoyne RD, et al. Maintenance rituximab after cyclophosphamide, vincristine, and prednisone prolongs progression-free survival in advanced indolent lymphoma: results of the randomized phase III ECOG 1496 study. J Clin Oncol. 2009;27:1607-1614.

      Hochster H, Weller E, Gascoyne RD, et al. Maintenance rituximab after cyclophosphamide, vincristine, and prednisone prolongs progression-free survival in advanced indolent lymphoma: results of the randomized phase III ECOG 1496 study. J Clin Oncol. 2009;27:1607-1614.

    • Dakhil S, Hermann R, Schreeder MT, et al. Phase III safety study of rituximab administered as a 90-minute infusion in patients with previously untreated diffuse large B-cell and follicular lymphoma. Leuk Lymphoma. 2014;55(10):2335-2340. doi:10.3109/10428194.2013.877135.

      Dakhil S, Hermann R, Schreeder MT, et al. Phase III safety study of rituximab administered as a 90-minute infusion in patients with previously untreated diffuse large B-cell and follicular lymphoma. Leuk Lymphoma. 2014;55(10):2335-2340. doi:10.3109/10428194.2013.877135.

    • Marcus R, Imrie K, Belch A, et al. CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma. Blood. 2005;105:1417-1423.

      Marcus R, Imrie K, Belch A, et al. CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma. Blood. 2005;105:1417-1423.

    • Feugier P, Van Hoof A, Sebban C, et al. Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: a study by the Groupe d’Etude des Lymphomes de l’Adulte. J Clin Oncol. 2005;23:4117-4126.

      Feugier P, Van Hoof A, Sebban C, et al. Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: a study by the Groupe d’Etude des Lymphomes de l’Adulte. J Clin Oncol. 2005;23:4117-4126.

    • Piro LD, White CA, Grillo-López AJ, et al. Extended rituximab (anti-CD20 monoclonal antibody) therapy for relapsed or refractory low-grade or follicular non-Hodgkin's lymphoma. Ann Oncol. 1999;10:655-661.

      Piro LD, White CA, Grillo-López AJ, et al. Extended rituximab (anti-CD20 monoclonal antibody) therapy for relapsed or refractory low-grade or follicular non-Hodgkin's lymphoma. Ann Oncol. 1999;10:655-661.

    • Davis TA, Grillo-López AJ, White CA, et al. Rituximab anti-CD20 monoclonal antibody therapy in non-Hodgkin's lymphoma: safety and efficacy of retreatment. J Clin Oncol. 2000;18:3135-3143.

      Davis TA, Grillo-López AJ, White CA, et al. Rituximab anti-CD20 monoclonal antibody therapy in non-Hodgkin's lymphoma: safety and efficacy of retreatment. J Clin Oncol. 2000;18:3135-3143.

    • MMIT Analysis.

      MMIT Analysis.

    • IQVIA Plantrak Corticosteroid Data.

      IQVIA Plantrak Corticosteroid Data.

    • HLI lives database.

      HLI lives database.

    • Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Chronic Lymphocytic Leukemia V.4.2019. © National Comprehensive Cancer Network, Inc. 2019. All rights reserved. Accessed October 21, 2020. To view the most recent and complete version of the guideline, go online to NCCN.org.

      Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Chronic Lymphocytic Leukemia V.4.2019. © National Comprehensive Cancer Network, Inc. 2019. All rights reserved. Accessed October 21, 2020. To view the most recent and complete version of the guideline, go online to NCCN.org.

    • Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Hodgkin's Lymphoma V.1.2019. © National Comprehensive Cancer Network, Inc. 2019. All rights reserved. Accessed October 21, 2020. To view the most recent and complete version of the guideline, go online to NCCN.org.

      Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Hodgkin's Lymphoma V.1.2019. © National Comprehensive Cancer Network, Inc. 2019. All rights reserved. Accessed October 21, 2020. To view the most recent and complete version of the guideline, go online to NCCN.org.