Risk of hepatitis B reactivation in patients with myeloproliferative neoplasms treated with ruxolitinib

Table 1 Immunosuppressive agents associated with HBVr

Immunosuppressive therapies with high risk of HBVr
B-cell depleting therapies (rituximab and ofatumumab)		Anthracycline derivatives (doxorubicin and epirubicin)	Corticosteroids		TNF-α inhibitors (infliximab, adalimumab, certolizumab)			Anti-CD52 monoclonal antibody (alemtuzumab)
Increased HBVr risk in positive HBsAg and negative HBsAg and anti-HBc subjects by acting against the B-lymphocyte antigen CD20; The Food and Drug Administration has placed a black box warning for rituximab regarding HBVr in rituximab-treated individuals; used to treat CD20+ blood cancers (lymphomas, CLL) and IRD; B cells play a previously underestimated role in HBV immune control by producing neutralizing antibodies; rituximab associated with > 5× increase in HBVr risk (incidence 3%–55%, overall mortality rate 30%–38%)		High-risk for patients with hepatocellular carcinoma and hepatitis B undergoing TACE; used to treat lymphomas and acute leukemias, breast and ovarian cancer, and sarcoma; HBVr rate = 41% in patients with HBsAg positive	Prednisone use > 20 mg p.o. daily > 4 wk		TNF-α can activate the APOBEC antiviral pathway which causes the degradation of cccDNA in HBV-infected cells. HBVr pooled incidence in patients with resolved HBV infection = 3.0% vs 15.4% in HBsAg positive patients			Used for refractory CLL; causes reverse HBsAg seroconversion and reactivation-related hepatitis
Immunosuppressive agents with moderate risk of HBVr
Less potent TNF-α inhibitors (etanercept)	Cytokine or integrin inhibitors (abatacept, ustekinumab, natalizumab, vedolizumab)	Tyrosine kinase inhibitors (imatinib, nilotinib, dasatinib)	Proteasome inhibitors: (Bortezomib)		Histone deacetylase inhibitors (HDIs) (romidepsin)		Prednisone 10-20 mg p.o. daily > 4 wk	Calcineurin inhibitors (cyclosporine or tacrolimus)
Moderate risk of HBVr in patients with HBsAg positive (1%-5%) and even lower in patients with HBsAg negative	Commonly utilized in the treatment of IBD, IRD and dermatologic conditions; inhibit local inflammatory response associated with immune-mediated diseases by blocking the localization and traffic of activated lymphocytes	Standard of treatment for all phases of CML; also used in the treatment of GIST; inhibit various kinase signaling pathways, essential for immune activation and proliferation of lymphocytes, with an important role in immune control of HBV replication; prophylactic antiviral therapy and regular monitoring of HBV DNA and liver enzymes are essential; reported HBVr rates of 26%–34.8%	Used for the treatment of MM and induction therapy for transplant- eligible patients prior to stem cell harvest; target cellular pathways that interfere with the functions of healthy B cells, which are important in HBV immune control		Used in the treatment of T-cell lymphomas; inhibit histone deacetylase, a histone-modifying enzyme that is important for epigenetic regulation of gene expression with possible deacetylation status of silent cccDNA, resulting in active HBV transcription and then HBVr		The mechanism is two-fold: The HBV genome contains a transcription regulatory element responsive to glucocorticoid that is up-regulated by corticosteroids, resulting in increased viral replication; a directly suppressive effect on cytotoxic T cells that are involved in HBV control; risk of HBVr of 10%-15.8% in HBsAg positive individuals	Suppress T cell function by inhibiting calcineurin required for signal transduction of T cell activation and inhibiting transcription of interleukin required for T cell proliferation
Immunosuppressive agents with low risk of HBVr
Methotrexate, azathioprine or 6-mercaptopurine				Intra-articular steroid injections or prednisone < 10 mg p.o. daily
Documented cases of HBVr are rather rare
Novel therapies
Immune checkpoint inhibitors such as anti-PD-L1 (nivolumab) and anti-CTLA4 (ipilimumab)	BTK inhibitor ibrutinib and PI3K delta inhibitor idelalisib	Ruxolitinib	Mogamulizumab	Brentuximab		Obinutuzumab	Hypomethylating agents: Decitabine, azacitidine	Daratumumab
HBVr rarely reporter; anti-HBV prophylaxis is recommended	B-cell receptor signaling modulators; approved by the FDA for the treatment of CLL and certain low-grade NHL; HBVr has been rarely been reported; anti-HBV prophylaxis is recommended	A novel inhibitor of JAK1 and JAK2 that has been approved for the treatment of patients with MPNs; There are reported cases of HBVr	Humanized monoclonal antibody targeting the C-C chemokine receptor 4; Used for ATLL; HBVr cases have been reported	Anti-CD30 drug conjugated antibody; used in the treatment of relapsed or refractory HL and CD30 positive T-cell lymphoma; There are reported cases of HBVr		Newer generation anti-CD20 monoclonal antibody, similar to rituximab but with greater efficacy; FDA has mandated a warning of the risk of HBVr with obinutuzumab and HBVr has been reported	Used in the treatment of AML; anti-HBV prophylaxis is recommended	Monoclonal antibody against CD38; used in the treatment of hematologic malignancies of B cells; HBVr cases have been reported

CML: Chronic myeloid leukemia; GIST: Gastrointestinal stromal tumors; ATLL: Adult T-cell leukemia/lymphoma; AML: Acute myeloid leukemia; CLL: Chronic lymphocytic leukemia; IRD: Inflammatory rheumatic diseases; TACE: transarterial chemoembolization, APOBEC: Catalytic polypeptide-like apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like; MM: Multiple myeloma; NHL: Non-Hodgkin’s lymphomas; HL: Hodgkin’s lymphoma; HBVr: Hepatitis B virus reactivation.