FDA Approval: Rituximab (Rituxan) for Lymphoma

The first of its kind

FDA records show rituximab, sold as Rituxan, was approved on November 26, 1997, under priority review. NCI, which funded its development, describes it as one of the first monoclonal antibody cancer treatments.

The label calls it a CD20-directed cytolytic antibody. Every word there is doing work.

What CD20 is, and why it was a good target

CD20 is a protein on the surface of B lymphocytes, the white blood cells that make antibodies. It appears on immature B cells and on mature ones.

Rituximab binds it. Once bound, the label says, it destroys the B cell. It does this by two routes: complement dependent cytotoxicity, where a cascade of blood proteins punches holes in the cell, and antibody dependent cell mediated cytotoxicity, where other immune cells recognize the antibody coat and kill what it is stuck to.

The choice of target was shrewd. Most non-Hodgkin lymphomas are B-cell cancers, so they carry CD20. The label places the marker on pre-B cells and mature B cells, and B-cell numbers recover after treatment ends.

The label documents that rebuilding. Circulating B cells were depleted within three weeks and stayed low for 6 to 9 months in 83 percent of patients. Recovery started around 6 months, and median levels were back to normal by 12 months.

What the label covers

The lymphoma indications alone are several.

• Relapsed or refractory low-grade or follicular CD20-positive B-cell non-Hodgkin lymphoma, as a single agent.
• Previously untreated follicular CD20-positive B-cell lymphoma, with first-line chemotherapy, and then alone as maintenance for those who responded.
• Non-progressing low-grade CD20-positive B-cell lymphoma, alone, after first-line CVP chemotherapy.
• Previously untreated diffuse large B-cell CD20-positive lymphoma, with CHOP or another anthracycline-based regimen.
• Children aged 6 months and older with mature B-cell lymphoma or mature B-cell acute leukemia, with chemotherapy.

It is also approved for chronic lymphocytic leukemia with fludarabine and cyclophosphamide, and outside cancer for rheumatoid arthritis and several autoimmune conditions.

Our page on R-CHOP chemotherapy explains the combination that became standard for diffuse large B-cell lymphoma. The R is this drug.

The evidence

The original approval rested on three single-arm studies in 296 people with relapsed or refractory CD20-positive lymphoma.

In the largest, 166 people with relapsed or refractory low-grade or follicular disease received the study dose by drip, worked out from body size, once a week for four doses.

The overall response rate was 48 percent, with 6 percent complete responses. The median duration of response was 11.2 months. The median time to a response appearing was 50 days.

There is a detail in that trial worth pulling out. Among the 39 people who had disease-related symptoms at entry, including fever, night sweats and weight loss, those symptoms resolved in 64 percent.

For diffuse large B-cell lymphoma, the evidence is different in kind. Three randomized, controlled, open-label trials enrolled 1,854 people between them, comparing chemotherapy alone against the same chemotherapy with rituximab added. Our page on diffuse large B-cell lymphoma covers where that sits in treatment today.

The boxed warning

The label carries a boxed warning naming four dangers.

Infusion reactions. These can be fatal, and deaths have occurred within 24 hours of a dose. About 80 percent of fatal infusion reactions happened with the first infusion, which is why the first one is given slowly and watched.

Severe skin and mucous membrane reactions, some fatal.

Hepatitis B reactivation. Wiping out B cells can let a dormant hepatitis B infection restart, sometimes causing liver failure and death. The label requires screening every patient before treatment, testing for HBsAg and anti-HBc. Reactivation has been reported up to 24 months after therapy ends.

Progressive multifocal leukoencephalopathy, a rare brain infection that has resulted in death.

When to get checked

Lymphoma has no screening test for the general population. What there is instead is a symptom list. NCI's is short.

• Swelling of lymph nodes in the neck, underarm, groin or stomach.
• Fever for no known reason.
• Drenching night sweats.
• Feeling very tired.
• Weight loss for no known reason.
• A skin rash, or itchy skin.
• Pain in the chest, abdomen or bones for no known reason.

When fever, drenching night sweats and weight loss appear together, NCI calls them B symptoms. That grouping goes into the stage.

Most swollen nodes are infections and settle in a few weeks. One that stays, especially with fever, sweats or weight loss, needs an appointment. Our page on lymphoma covers how the many types differ.

The group picture

SEER figures cover all non-Hodgkin lymphoma across the United States. It is a large family of diseases, so a single figure smooths over real differences.

Five-year relative survival is 74.3 percent for cases from 2016 to 2022. By stage it is 87.6 percent at stage I, 79.7 percent at stage II, 74.0 percent at stage III, and 63.6 percent at stage IV.

Thirty-seven percent are found at stage IV, more than at any other stage. An estimated 79,320 new cases and 19,970 deaths are projected for 2026, and the median age at diagnosis is 68.

What this approval cannot tell you

It cannot say whether the drug fits a particular person. The tumor has to be CD20-positive, and hepatitis B status, prior treatment and the specific lymphoma subtype all matter.

Response rates from single-arm studies are not survival results. A 48 percent response rate says tumors shrank in about half of the people treated. It does not say how long they lived.

And a drug approved in 1997 does not stand alone now. Newer CD20 antibodies, cell therapies and bispecific antibodies have followed. What this approval settled was that an antibody could be a cancer treatment at all.

Sources

• DailyMed, RITUXAN (rituximab) prescribing information — https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b172773b-3905-4a1c-ad95-bab4b6126563
• FDA Drugs@FDA, rituximab (BLA 103705) — https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=103705
• openFDA Drugs@FDA API, BLA103705 submission record (ORIG-1, 1997-11-26, priority review) — https://api.fda.gov/drug/drugsfda.json?search=openfda.application_number:%22BLA103705%22&limit=1
• NCI, Rituximab — https://www.cancer.gov/about-cancer/treatment/drugs/rituximab
• NCI PDQ, Adult Non-Hodgkin Lymphoma Treatment (Patient Version) — https://www.cancer.gov/types/lymphoma/patient/adult-nhl-treatment-pdq
• NCI Stories of Discovery, Development of Rituximab — https://www.cancer.gov/research/progress/discovery/blood-cancer
• SEER Cancer Stat Facts, Non-Hodgkin Lymphoma — https://seer.cancer.gov/statfacts/html/nhl.html

How this article was prepared

An AI-assisted editorial system helped prepare this page. No named medical reviewer has reviewed it unless one is listed.

The National Cancer Information Foundation publishes Cancer Explained. This page is for learning. It is not medical advice and does not suggest a test or treatment.

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