Written in Blood
Preventing Hepatitis B Virus Reactivation During
Immunochemotherapy for Lymphoma
Administering prophylactic antiviral treatment
is effective in preventing hepatitis B virus
(HBV) reactivation in patients with B-cell
non-Hodgkin lymphoma (NHL) being treated
with an anti-CD20 monoclonal antibody.
However, overexposure to antiviral medication
can lead to adverse events and drug resistance.
In a study published in Blood, researchers
evaluated an alternative approach to treating
these patients with antiviral medications: using
monthly DNA monitoring to determine which
patients with resolved HBV infection are at
the highest risk of developing HBV-related
hepatitis while receiving obinutuzumab or
rituximab.
Shigeru Kusumoto, MD, PhD, from the
Nagoya City University Graduate School of
Medical Sciences in Japan, and authors found
that detectable HBV DNA at baseline was
strongly associated with later HBV reactivation,
according to their analysis of patients receiving
obinutuzumab- or rituximab-containing
immunochemotherapy enrolled in the phase
III GOYA and GALLIUM trials. Administering
pre-emptive nucleoside analog treatment
(NAT) based on HBV-positive DNA results
prevented most, but not all, patients from
developing HBV-related hepatitis.
HBV assessments were performed at base-
line and then monthly thereafter, until at least
one year after the last dose of the study drug
was administered. HBV DNA was measured in
serum using a quantitative, real-time poly-
merase chain reaction (PCR) assay.
When patients were determined to have
a virus reactivation (defined as HBV DNA
≥29 IU/mL), immunochemotherapy was held
and NAT (including entecavir, lamivudine,
adefovir, and tenofovir) was started. If HBV
DNA became undetectable or if reactivation
was not confirmed, immunochemotherapy was
restarted; if HBV DNA exceeded 100 IU/mL
while a patient was on NAT, immunochemo-
therapy was discontinued.
Prophylactic NAT was allowed by investiga-
tor discretion.
Among the 326 patients with resolved
HBV infection, 27 patients (8.2%) had HBV
“Considering all these points,
pre-emptive nucleoside
analog treatment guided
by HBV DNA monitoring
appears to be a reasonable
strategy for most patients
with resolved HBV infection.”
—SHIGERU KUSUMOTO, MD, PhD
56
ASH Clinical News
reactivation, including 21 (6.4%)
with HBV DNA ≥100 IU/mL.
Reactivation occurred a median
of 125 days (range = 85-331
days) after the first dose of either
obinutuzumab or rituximab.
For the 16 participants who
experienced an HBV reactivation
during immunochemotherapy,
12 withheld study treatment
but no patients discontinued
immunochemotherapy due to
HBV reactivation, the authors
reported.
Of the 27 patients with HBV
reactivation, 25 were in the group
of patients who did not receive
prophylactic NAT (n=25/232;
10.8%). In this group, HBV DNA
levels reached a median peak of
342 IU/mL (range = 101-1,230
IU/mL). The researchers added that “HBV-
related hepatitis was not observed among these
25 patients, although relatively high-peak HBV
DNA levels … were seen in three patients.”
However, nine patients of the 25 patients
had late HBV reactivation, occurring a median
of 196 days (range = 153-310) after completion
of immunochemotherapy. “The observation
of [delayed] HBV reactivation … suggests that
HBV DNA monitoring is necessary for at least
one year after completion of lymphoma treat-
ment,” the authors wrote.
Among the 94 patients who received pro-
phylactic NAT, two (2.1%) had HBV reactiva-
tion: One at 18 months after stopping NAT and
one while on NAT.
Estimated HBV reactivation rates were
lower among those who received prophylactic
NAT, compared with those who did not:
• 1 year: 1.5% vs. 10.6%
• 2 years: 1.5% vs. 11.9%
This translated to a reduced risk of HBV reac-
tivation in patients who received prophylactic
NAT (hazard ratio [HR] = 0.09; 95% CI 0.02-
0.41; p=0.002).
In multivariate analyses (accounting for
baseline age and sex), the following factors
were associated with a higher risk for HBV
reactivation:
• older age (by decade; HR=1.63; 95% CI
1.00-2.37; p=0.035)
• seronegative for hepatitis B surface
antibodies (anti-HBs) at baseline
(HR=4.00; 95% CI 1.71-9.37; p=001)
• a diagnosis of diffuse large B-cell
lymphoma (DLBCL)
• detectable baseline HBV DNA levels
(HR=18.22; 95% CI 6.04-54.93; p<0.001)
Based on these results, the authors concluded
that, “pre-emptive NAT avoids unnecessary anti-
viral treatment thereby reducing drug costs.”
However, for patients with clearly defined risk
factors for HBV reactivation (i.e., anti-HBs
seronegativity or detectable HBV DNA at base-
line), prophylactic NAT may be appropriate.
Also, “as prophylactic NAT cannot be contin-
ued indefinitely in patients with resolved HBV
infection, HBV DNA monitoring is necessary
after stopping prophylactic NAT to diagnose
delayed HBV reactivation.”
When the researchers looked across each
trial’s drug regimen, they did not observe
any significant difference in the risk of HBV
reactivation between obinutuzumab- and
rituximab-based immunochemotherapy. How-
ever, this analysis was limited by the imbalance
of baseline risk factors between the two groups
of trial participants, “which was unsurprising
given that HBV reactivation was not a major
endpoint in either trial.” They added that each
trial also used slightly different approaches to
managing HBV reactivation and in defining the
criteria for initiating pre-emptive NAT, which
may have confounded results.
“Considering all these points, pre-emptive
NAT guided by HBV DNA monitoring appears
to be a reasonable strategy for most patients
with resolved HBV infection,” they concluded.
“Further basic research and clinical trials are
now warranted to improve our understand-
ing of the pathogenesis of HBV reactivation in
[patients with DLBCL] who receive anti-CD20
antibodies with chemotherapy and to deter-
mine whether DLBCL truly increases the risk
of reactivation compared with other lymphoma
types,” the researchers noted.
Authors report financial relationships with
Chugai Pharmaceutical Co. and Roche. ●
REFERENCE
Kusumoto S, Arcaini L, Hong X, et al. Risk of HBV reactivation in patients with
B-cell lymphomas receiving obinutuzumab or rituximab immunochemotherapy.
Blood. 2018 October 19. [Epub ahead of print]
December 2018