Ofatumumab is a recombinant human monoclonal antibody to CD20 a cell surface antigen found on pre-B and mature B lymphocytes and which is approved for use in resistant chronic lymphocytic leukemia. Ofatumumab therapy has not been associated with serum enzyme elevations during therapy or to cases of idiosyncratic, clinically apparent liver injury. However, ofatumumab has potent immunosuppressive activity and its use has been reported to be associated with cases of reactivation of inactive hepatitis B which can be severe and can result in fatality.


Ofatumumab (oh” fa toom’ ue mab) is a human monoclonal IgG1 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 chronic lymphocytic leukemia (CLL). CD20 is not present on pro-B cells, hematopoietic stem cells, normal plasma cells or other normal lymphocytes, circulating cells or tissues. Engagement of ofatumumab with CD20 leads to B cell lysis and depletion of circulating and tissue B cells for an extended period, up to 6 to 8 months. There is an accompanying mild decrease in IgM, but no change in IgG or IgA levels. Ofatumumab was approved for use in previously treated, resistant chronic lymphocyte leukemia in the United States in 2009. Ofatumumab is available in liquid solution in single use vials of 100 and 1000 mg (20 mg/mL) under the brand name Arzerra. The dose and regimen varies by indication, but it is usually given intravenously in 300 to 2000 mg amounts in 28 day cycles. Common side effects include infusion reactions, chills, fever, nausea, diarrhea, fatigue, dyspnea, cough, bronchitis, pneumonia, skin rash, neutropenia and infections. Less common, but potentially severe side effects include cutaneous reactions (Stevens Johnson syndrome), tumor lysis syndrome, prolonged neutropenia, thrombocytopenia and anemia. Because of the potential severity of infusion reactions, premedication with antihistamines, acetaminophen and corticosteroids is recommended, and ofatumumab should be administered under close medical observation.


Serum aminotransferase elevations are uncommon during ofatumumab therapy and rarely mentioned in large clinical trials of its use in CLL and autoimmune diseases. Clinically apparent liver injury has not been reported with ofatumumab therapy either in prelicensure clinical trials or subsequent to its more widescale clinical use.

On the other hand, ofatumumab is a potent immunosuppressive agent and has been reported to cause reactivation of hepatitis B by the FDA. However, there have been no examples of reactivation published in the medical literature and specific features of the reactivation caused by ofatumumab have not been described. Typically, HBV reactivation is associated with acute hepatocellular injury similar to acute viral hepatitis that can be severe and lead to acute liver failure and death or need for emergency liver transplantation. If detected early, however, therapy with antiviral agents can blunt the severity of injury. In contrast, rituximab, another monoclonal antibody to CD20 that has been extensively used for several decades, is perhaps the best and mostly commonly described cause of HBV reactivation. Because ofatumumab, like rituximab, is a monoclonal antibody to CD20, it should have a similar effect on inactive or latent hepatitis B.

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 onset of liver injury is delayed and may occur after 3 to 6 monthly courses of immunosuppressive therapy. The usual sequence of events is appearance of rising levels of HBV DNA in serum shortly after chemotherapy is started, followed by a rise in levels of HBsAg and HBeAg. When therapy is stopped and immune reconstitution has begun, serum ALT and AST levels start to rise followed by symptoms and jaundice. 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.

Reactivation of HBV in persons who have resolved hepatitis B (anti-HBc without HBsAg in serum) is usually referred to as “reverse seroconversion”, and reactivation in persons with preexisting HBsAg in serum as “typical” or classical HBV reactivation. The two forms of reactivation have somewhat different clinical, biochemical and virology courses. In general, patients with reverse seroconversion have received more rigorous immunosuppression, the latency until onset is longer, peak levels of HBV DNA are lower, and the disease course is more severe than in patients with typical reactivation. The time to appearance of clinically apparent reactivation tends to be 3 to 6 months in patients with typical reactivation, but 12 to 36 months in those with reverse seroconversion. Outcomes may also be different, reverse seroconversion tending to be more severe and more likely to resolve with disappearance of HBsAg than typical reactivation. Exceptions occur in both situations; however, some patients with reverse seroconversion do not revert back to being HBsAg negative, particularly those who have had hematopoietic cell transplantation (HCT). In addition, some patients with classic reactivation of hepatitis B ultimately clear HBsAg as a result of the acute liver injury. Both forms of reactivation appear to be ameliorated by early intervention with oral antiviral therapy, but institution of therapy after appearance of clinical disease and jaundice may not be effective and many instances of fatal reactivation have occurred despite treatment with oral antiviral agents. Many cases of reverse seroconversion have been reported with rituximab therapy; the occurrence with ofatumumab has been implied, but specific cases have not been published.

Likelihood score: E* (unproven but suspected cause of clinically apparent liver injury).

Mechanism of Injury

The mechanism of liver injury in reactivation of hepatitis B appears to be a brisk immunological response to viral antigens. Injury generally arises after immunosuppressive or cancer chemotherapy has stopped or between courses of treatment. Rituximab is also known to cause an acute autoimmune-like hepatitis, unrelated to reactivation. Ofatumumab has not been shown to cause this type of drug-induced liver injury.

Outcome and Management

Guidelines for management of patients who are to receive ofatumumab 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. This approach, however, is problematic in that reactivation may occur late during chemotherapy or even after it is completed. The choice of antiviral agents includes lamivudine, telbivudine, adefovir, tenofovir or entecavir. All are given once a day and are extremely well tolerated. Lamivudine is less expensive than the other agents, but is associated with a high rate of antiviral resistance, particularly if given for more than 6 months. Tenofovir and entecavir are the most potent and have high barriers to antiviral resistance, which is important if long term therapy is planned. However, there are no prospectively acquired controlled studies to support use of one of these agents over another. Finally, the appropriate duration of treatment is unclear. The typical recommendation is to continue antivirals for at least 6 months after stopping cancer chemotherapy, but cases of reactivation following withdrawal of antiviral therapy (including fatal instances) have been described and some degree of monitoring during withdrawal of antiviral therapy is appropriate with early re-intervention of HBV DNA levels rise. In patients with anti-HBc without HBsAg, boosting titers of anti-HBs before or in-between treatment courses may be helpful in preventing reactivation. However, patients with lymphoma or autoimmune conditions and those who are receiving ofatumumab generally have poor responses to vaccination and this approach has not been critically evaluated in prospective controlled studies.

Drug Class: Antineoplastic Agents, Monoclonal Antibodies



Ofatumumab – Arzerra®


Antineoplastic Agents


Product labeling at DailyMed, National Library of Medicine, NIH



References updated: 15 April 2020

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