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B. Wang et al.
chemotherapy for NHL, 27 patients (8.2%) in total had HBV reactivation; of these, 17 had received obinutuzumab and 10 rituximab.35 The mechanism of action of these drugs in causing depletion of circulating B cells and partial depletion in the lymphatic system and bone marrow explains the strong association with HBV reactivation: a fall in anti-HBs antibody titers has been demonstrated in patients undergoing rituximab therapy, with reactivation seen most in those with complete loss of anti-HBs.36 A large meta-analysis of over 800 patients with resolved HBV infection receiving rituximab also demonstrated a protective effect of possessing anti-HBs, with 14% of those who were only anti-HBc positive developing reacti- vation compared with 5% of those also positive for anti- HBs.18 The risk of reactivation associated with this class of drugs also potentially persists for longer than with other therapies. Reactivation events have been reported up to two years after the last dose of rituximab; one prospective study of 63 anti-HBc positive patients with lymphoma reported a cumulative rate of HBV reactivation of 41.5% over two years, with a median time to reactivation of 23 weeks, but a range of up to 100 weeks.12 Again, in this study, possession of anti-HBs antibodies was protective against reactivation, with the 2-year cumulative rate of reactivation being significantly higher in those negative for anti-HBs. The wide range and potential delay in pres- entation of reactivation mirrors the scenario of a hepatic flare after rituximab treatment of HCV-related lym- phomas, and possibly relates to variation in the strength of immune control of HBV in different individuals.37
Monoclonal antibodies directed against other immune cell targets have also been associated with reactivation. Alemtuzumab, a monoclonal antibody against CD52 used for refractory chronic lymphocytic leukemia (CLL) and in HSCT conditioning regimens, has been reported to cause reverse HBsAg seroconversion and significant reactiva- tion-related hepatitis.38,39 Furthermore, as newer agents are developed, emerging cases of HBV reactivation are also being reported, including fatalities: mogamulizumab, a treatment for T-cell lymphoma, and brentuximab vedotin, used in the treatment of refractory or relapsed Hodgkin lymphoma, are two recent examples.40-42 Daratumumab, a monoclonal antibody against CD38 which is over- expressed in B-cell hematologic malignancies, also has the potential for reactivation given its mechanism of action, but so far no reports have emerged.
Hematopoietic stem cell transplantation
Hepatitis B virus reactivation in the context of allogeneic HSCT is well-recognized and represents a high risk, rang- ing from 40% over two years in patients with resolved infection to 70-86% over five years in HBsAg-positive recipients.43,44 Risk factors are similar to those for reactiva- tion in general, including older age (≥50 years) and detectable HBV DNA prior to transplant.45,46 Development of graft-versus-host disease (GvHD) also significantly increases the risk of HBV reactivation, with one study of 85 anti-HBc positive recipients of allogeneic HSCT show- ing a cumulative rate at two years of 79.5% compared with 21%.44 This increased risk is likely associated with the fact that patients with GvHD receive more immuno- suppression therapy, and experience a delay in reconstitu- tion of the immune system for up to 12-18 months.47 HBV reactivation after autologous HSCT is also recognized, although data are more limited. In one study of 32 HBsAg-
positive patients with NHL undergoing high-dose chemotherapy and autologous HSCT, the incidence of hepatitis due to HBV reactivation was 50%.48 In anti-HBc positive patients, the risk is predictably lower; one study found reactivation in 7 out of 107 (6.5%) patients.49
In considering HBV reactivation post HSCT, the HBV status of the donor has been shown to have significant impact. It is known that, in allogeneic HSCT, donor vacci- nation can result in transfer of immunity against a range of infectious antigens, including hepatitis B.50,51 More recent- ly, it has been demonstrated that recipients of HSCT who have chronic or resolved HBV infection can also benefit from donors who have been vaccinated against HBV with a strong anti-HBs response. In one series, 3 HBsAg-posi- tive patients received allogeneic HSCT from vaccinated donors with a high anti-HBs titer. All 3 recipients became HBsAg-negative post transplant and developed a strong humoral HBV-specific response with high titers of anti- HBs antibody as well as detectable T-cell immunity.43 In 2 of the recipients, the underlying hematologic malignancy subsequently relapsed, and in each case, anti-HBs levels declined and the patients again became HBsAg positive with detectable HBV DNA. This demonstrates a unique situation where the risk of HBV reactivation may be mod- ified not only by management of the recipient, but also by careful donor selection.
Other novel agents
With the rapid expansion of treatment options for con- ditions such as multiple myeloma and CLL, there are novel therapies that are worthy of attention as potential causes of HBV reactivation, although evidence is limited to individual reports. Tyrosine kinase inhibitors such as imatinib and nilotinib are thought to be associated with a moderate risk of HBV reactivation.52-55 As tyrosine kinase receptor-mediated signaling pathways are involved in immune activation and proliferation of lymphocytes, it is not unexpected that therapeutic blockade of these path- ways may suppress immune control of HBV and result in reactivation. The newer agents ibrutinib (a Bruton tyro- sine kinase inhibitor) and idelalisib (a PI3K tyrosine kinase inhibitor) are both B-cell receptor signaling modulators used for the treatment of CLL and certain NHLs. Both have been associated with cases of HBV reactivation; a recent recommendation has been issued by manufacturers of ibrutinib acknowledging the risk of HBV reactivation and advising serological testing for HBV prior to starting treatment.56
Bortezomib, a proteasome inhibitor that has revolution- ized the medical management of multiple myeloma, and ruxolitinib, an inhibitor of Janus-activated kinases (JAK) used for treatment of myelofibrosis have both been asso- ciated with reported cases of HBV reactivation.57-59 Bortezomib therapy is often given prior to autologous HSCT, and along with the immune dysfunction associated with multiple myeloma itself, it is difficult to isolate the specific risk attributable to bortezomib alone. Nonetheless, reactivation has been reported both in HBsAg-positive and anti-HBc positive patients.57
Immune checkpoint inhibitors as a group of drugs are increasingly used in the treatment of various non-hemato- logic cancers such as melanoma, renal cell carcinoma and hepatocellular carcinoma.60 Their role in treating hemato- logic malignancies such as Hodgkin lymphoma is also evolving. Their mechanism of action in overcoming T-cell
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haematologica | 2019; 104(3)