Abstract
Specific major histocompatibility (MHC) class I alleles dominate anti-CMV responses in a hierarchal manner. These CMV immunodominant (IMD) alleles are associated with a higher magnitude and frequency of cytotoxic lymphocyte responses as compared to other human leukocyte antigen (HLA) alleles. CMV reactivation has been associated with an increased incidence of graft-vs.-host disease and non-relapse mortality, as well as protection from relapse in HLA-matched HSCT settings. Less is known about the impact of CMV reactivation on these major outcomes after haploidentical (HI) HSCT, an increasingly applied therapeutic option. In HI HSCT, the efficiency of the immune response is decreased due to the immune suppression required to cross the MHC barrier as well as MHC mismatch between presenting and responding cells. We hypothesized that the presence of a CMV IMD allele would increase the efficiency of CMV responses after HI HSCT potentially impacting CMV-related outcomes. In this retrospective, multivariable review of 216 HI HSCT patients, we found that CMV+ recipients possessing at least 1 of 5 identified CMV IMD alleles had a lower hazard of death (HR = 0.40, p = 0.003) compared to CMV+ recipients not possessing a CMV IMD allele, and an overall survival rate similar to their CMV– counterparts. The analysis delineated subgroups within the CMV+ population at greater risk for death due to CMV reactivation.
Highlights
CMV reactivation has been associated with protection from relapse in human leukocyte antigen (HLA) matched related and unrelated hematopoietic stem cell transplant (HSCT) settings [1,2,3], most pronounced in patients with acute myeloid leukemia (AML) [4]
In haploidentical HSCT (HI HSCT) regimens using cyclophosphamide (CY) tolerization as graft vs. host disease (GVHD) prophylaxis, CMV reactivation was associated with increased non-relapse mortality (NRM) in one analysis [20] but a causal relationship between CMV reactivation and any major transplant outcome was not found in two others [12, 21, 22]
The primary finding of this multivariable analysis was that the presence of a CMV IMD allele in CMV+ recipients undergoing HI HSCT significantly reduced the hazard of post-transplant death as compared to those not possessing a CMV IMD allele
Summary
CMV reactivation has been associated with protection from relapse in human leukocyte antigen (HLA) matched related and unrelated hematopoietic stem cell transplant (HSCT) settings [1,2,3], most pronounced in patients with acute myeloid leukemia (AML) [4]. CMV Immunodominant Alleles And Transplant increases in non-relapse mortality (NRM) [1, 5] and death [5, 6] Herpesviruses such as CMV share peptide sequence homology with humans resulting in cross-reactive cytotoxic lymphocyte (CTL) responses to both the virus and self, providing an explanation as to why CMV has been associated with graft vs host disease (GVHD) and protection from relapse [7,8,9]. Despite a high reactivation rate after HI HSCT, a clear pattern of relapse protection or survival differences due to CMV has not emerged at least in transplants using CY tolerization approaches
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