Tositumomab is the combination of a monoclonal antibody to CD20 and iodine-131 which is used to treat refractory, advanced non-Hodgkin lymphoma. Tositumomab has not been associated with significant serum enzyme elevations during therapy or to cases of idiosyncratic, clinically apparent liver injury. However, tositumomab has potent immunosuppressive activity and is probably capable of causing reactivation of hepatitis B in susceptible patients.


Tositumomab (toe si tue’ moe mab) is a monoclonal antibody to the cell surface antigen CD20 (also known as human B lymphocyte restricted differentiation antigen: Bp35) which is found on mature B cells as well as 90% of neoplastic B cell such as occur in non-Hodgkin lymphoma. Engagement of tositumomab with CD20 leads to cell lysis and depletion of circulating and tissue B cells for 6 to 8 months. Tositumomab is given in combination with iodine-131 radiolabeled tositumomab which provides additional antineoplastic activity. Tositumomab and tositumomab I-131 were approved for use in previously treated, resistant non-Hodgkin lymphoma in the United States in 2003. Because of declining use and the availability of other anti-CD20 monoclonal antibodies, however, tositumomab was discontinued by its sponsor in 2014. Tositumomab was previously available in liquid solution in single use vials of 35 and 225 mg (14 mg/mL) and as Iodine 131 tositumomab solutions of varying concentrations. Dosing required a 2 part dosimetric step followed 7 to 14 days later by a 2-part therapeutic step. Tositumomab was meant to be given only for a single course. Common side effects included infusion reactions, chills, fever, nausea, fatigue, anemia, thrombocytopenia, neutropenia and infections. Less common but potentially severe side effects included severe allergic reactions, anaphylaxis, marked bone marrow suppression, thyroid abnormalities and radiation exposure.


Serum aminotransferase elevations are uncommon during tositumomab therapy and rarely mentioned in large clinical trials of its use in non-Hodgkin lymphoma. Clinically apparent liver injury has not been reported with tositumomab therapy either in prelicensure clinical trials or subsequent to its general clinical use.

On the other hand, other monoclonal antibodies to CD20 such as rituximab and ofatumumab are well known to cause reactivation of hepatitis B. Specific features of the reactivation caused by tositumomab have not been published, but HBV reactivation is typically associated with acute hepatocellular injury that can be severe and lead to acute liver failure and death or need for emergency liver transplantation. Reactivation typically occurs in patients who are HBsAg carriers with inactive hepatitis B who undergo chemotherapy for cancer. Reactivation can also occur in persons who have recovered from hepatitis B, who have no detectable HBsAg, but have antibody to hepatitis B core antigen (anti-HBc) with or without antibody to HBsAg (anti-HBs) in serum. The usual sequence of events is appearance of rising levels of HBV DNA in serum shortly after chemotherapy is started followed by rise in levels of HBsAg and HBeAg. When therapy is stopped and immune reconstitution has begun, serum ALT and AST levels rise, which is followed by symptoms and jaundice. The onset of liver injury is delayed and may occur months after 3 to 6 courses of therapy. Reactivation of hepatitis B tends to be severe and the mortality rate in jaundiced cases exceeds 10%. Liver histology demonstrates an acute hepatitis like pattern with focal or confluent necrosis and prominent lymphocytic infiltrates of activated T cells, which is compatible with an immune mediated hepatic injury. Restarting chemotherapy can result in recurrence of injury, although concurrent antiviral treatment may block recurrence. Many cases of hepatitis B reactivation have been reported with rituximab therapy; the occurrence with tositumomab has been implied but specific cases have not been published.

Likelihood score: E* (unproven but suspected rare cause of clinically apparent liver injury and possibly reactivation of hepatitis B).

Mechanism of Injury

The mechanism of liver injury in reactivation of hepatitis B appears to be a brisk immunological response to newly expressed viral antigens on hepatocytes. Injury generally arises after immunosuppressive or cancer chemotherapy has stopped or between courses of treatment.

Outcome and Management

Guidelines for management of patients who are to receive tositumomab recommend routine screening for hepatitis B before starting treatment. Screening should include tests for HBsAg and anti-HBc (and perhaps also anti-HBs as this may help in management). Prophylaxis with a potent oral, antiviral agent effective against hepatitis B is recommended for all persons who have HBsAg in serum and is suggested for those with anti-HBc without HBsAg. An alternative approach is careful monitoring for HBV DNA during therapy and early institution of antiviral therapy if levels rise.

Drug Class: Antineoplastic Agents, Monoclonal Antibodies



Tositumomab – Bexxar®


Antineoplastic Agents


Product labeling at DailyMed, National Library of Medicine, NIH



References updated: 15 April 2020

Abbreviations: TNF, tumor necrosis factor.

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    (Review of adverse event reports made to the FDA and WHO for tositumomab demonstrated an increase after 2003 to a peak in 2005 and subsequent gradual decrease, correlating with change in usage; most common adverse events were myelodysplastic syndrome, fever, acute myeloid leukemia, fatigue and nausea; liver injury and ALT elevations were not mentioned).
  • Shadman M, Li H, Rimsza L, Leonard JP, Kaminski MS, Braziel RM, Spier CM, et al. Continued excellent outcomes in previously untreated patients with follicular lymphoma after treatment with CHOP plus rituximab or CHOP plus (131)I-tositumomab: long-term follow-up of phase III randomized study SWOG-S0016. J Clin Oncol. 2018;36:697–703. [PMC free article: PMC6553811] [PubMed: 29356608]
    (Long term follow up of trial comparing R-CHOP to CHOP with tositumomab [Press 2013] found radiotherapy resulted in better progression-free survival but similar overall survival, the occurrence of deaths from leukemia and myelodysplastic syndrome with radiation exposure being greater; no mention of hepatotoxicity or liver related deaths).
  • Hadid T, Raufi A, Kafri Z, Mandziara M, Kalabat J, Szpunar S, Kolizeras K, et al. Safety and efficacy of radioimmunotherapy (RIT) in treatment of non-Hodgkin's lymphoma in the community setting. Nucl Med Biol. 2016;43:227–31. [PubMed: 27067042]
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    (Among 15 patients with non-Hodgkin lymphoma treated with tositumomab after completing 6 cycles of CHOP, the response rate increased from 60% to 80% and adverse events included bone marrow suppression as well as fatigue [72%], dyspnea, headache and pain; no mention of ALT elevations or hepatotoxicity).