Written in Blood
Does Cytomegalovirus Reactivation Protect Against AML Relapse?
cant risk factor for NRM for AML and ALL
patients (p<0.001 for both), but not for CML or
MDS patients (p=0.64 and 0.69, respectively).
Other risk factors for increased NRM included
older age, higher disease risk category, human
leukocyte antigen incompatibility, and use of
peripheral blood stem cell graft.
CMV reactivation was associated with inferior OS among all disease groups in a multivariate analysis (TABLE 5). In addition, Mr. Teira
and colleagues identified several factors that
were also associated with lower OS, including:
• Higher NRM among those with AML and
ALL (but not those with CML and MDS)
• Positive CMV serology in low-risk
(p<0.0001) and high-risk (p=0.013) AML
There is conflicting evidence regarding the role
that cytomegalovirus (CMV) reactivation plays
in the relapse risk of acute myeloid leukemia
(AML) patients after they have undergone allogeneic hematopoietic cell transplantation (AlloHCT). Though prior studies have shown an
association between CMV reactivation within
100 days post-AlloHCT and a lower incidence
of relapse, other reports indicate a higher risk
of relapse and poorer overall survival (OS) in
patients with positive CMV serology.
In an analysis of the Center for International Blood and Marrow Transplant Research
(CIBMTR) database published in Blood, Pierre
Teira, from the Sainte Justine Hospital and
University of Montreal in Quebec, Canada, and
colleagues found that CMV reactivation puts
patients at risk for poor post-transplant outcomes and does not confer protection against
relapse of hematologic cancers.
Mr. Teira and researchers evaluated the
effect of CMV serostatus and reactivation on
the following outcomes post-AlloHCT: hematologic disease relapse, OS, and non-relapse
mortality (NRM).
All patients received their first AlloHCT between 2003 and 2010. A total of 9,469 patients
were included in the study: 5,310 patients with
AML, 1,883 with acute lymphocytic leukemia
(ALL), 1,197 with myelodysplastic syndromes
(MDS), and 1,079 with chronic myeloid leukemia (CML).
Patients were excluded from the study if:
• Post-transplant infection or CMV
serostatus data were missing
• They were enrolled at centers where more
than 30 percent of patient forms were
incomplete
• Information was obtained without a
signed in formed consent form
• A 100-day follow-up form was missing
• An identical twin donor was used
• Multiple donor grafts were received
• Death occurred before HCT
The median time to CMV reactivation was 41
days (range = 1-362) and nearly all reactivation
occurred before 100 days post-HCT (98%). The
incidence of reactivation was higher for groups
with CMV serology–negative donors (D–) and
CMV serology–positive recipients (R+; 34%)
and D+/R+ (32%), while D+/R− patients were
most protected against reactivation (11%).
CMV serology had a limited effect on the
risk of hematologic relapse at three years. There
was no effect on risk of relapse among AML,
CML, or MDS patients, and “paradoxically, for
ALL patients, positive D/R serology increased
relapse risk compared with negative D/R serology (p=0.004),” the authors observed. “Multivariate analysis also found several classical risk
factors for disease relapse,” including higher-risk
hematologic disease and reduced-intensity conditioning regimen (in AML and MDS patients).
In contrast, CMV was strongly associated
with NRM at three years, and positive serology
among either donor or recipient was a signifi-
Effect of CMV Reactivation on Overall Survival by
Hematologic Disease
TABLE 5.
Relative Risk
p Value (95% CI)
AML
1.27
<0.0001 (95% CI 1.17-1.38)
ALL
1.46
<0.0001 (95% CI 1.25-1.71)
MDS
1.31
0.003 (95% CI 1.09-1.57)
CML
1.49
0.0005 (95% CI 1.19-1.88)
CMV = cytomegalovirus; AML = acute myeloid leukemia; ALL = acute lymphocytic leukemia; MDS = myelodysplastic syndrome; CML = chronic myeloid leukemia
36
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• D+/R+ groups with high-risk disease
(relative risk [RR] = 1.19; 95% CI 1.001.41; p=0.04) and D−/R+ groups with lowrisk disease (RR=1.44.; 95% CI 1.25-1.66;
p<0.0001)
• Positive donor and recipient serology in
patients with ALL (RR=1.39; 95% CI 1.171.64; p=0.0001)
“Overall, CMV reactivation resulted in
increased NRM and decreased disease-free survival, translating into poorer OS in each disease
category,” the authors noted, outlining three
ways through which CMV adversely effects
transplant outcomes:
• Increased risk for bacterial and fungal coinfections
• Increased organ toxicity directly via CMV
infection and indirectly via associated side
effects of antiviral therapy
• Increased incidence and severity of graftversus-host disease
Limitations of the study are inherent to its
registry design, such as a lack of data on how
CMV reactivation was monitored and institutional cut-off values applied for implementing
pre-emptive therapy. Therefore, inaccurate
reporting for CMV reactivation was possible.
Institutional practices for pre-emptive and
prophylactic therapy also varied, affecting the
ability to assess efficacy of initial therapy and
duration of CMV reactivation.
“Acquiring additional relevant data from
participating transplant centers within the CIBMTR would have enhanced statistical analyses in
the current study and enabled more meaningful
interpretation of results,” the authors concluded.
“Collecting such supplemental data might also be
used to establish evidence-based guidelines for
CMV prophylaxis and treatment and improve
practice consistency among transplant centers.” ●
REFERENCE
Teira P, Battiwalla M, Ramanathan M, et al. Early cytomegalovirus reactivation
remains associated with increased transplant related mortality in the current
era: a CIBMTR analysis. Blood. 2016 February 16. [Epub ahead of print]
April 2016