Does Cytomegalovirus Reactivation Protect Against AML Relapse?

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 informed 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 significant 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). 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
  • D+/R+ groups with high-risk disease (relative risk [RR] = 1.19; 95% CI 1.00-1.41; p=0.04) and D−/R+ groups with low-risk 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 1.17-1.64; 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 co-infections
  • Increased organ toxicity directly via CMV infection and indirectly via associated side effects of antiviral therapy
  • Increased incidence and severity of graft-versus-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]

TABLE. Effect of CMV Reactivation on Overall Survival by Hematologic Disease
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

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