Cytomegalovirus (CMV) infections and CMV-specific cellular immune reconstitution following reduced intensity conditioning allogeneic stem cell transplantation with Alemtuzumab

By retrospective analysis of 88 patients from the British Society of Blood and Marrow Transplantation registry, we investigated the effect of in vivo T-cell depletion in HLA-identical sibling reduced-intensity conditioning (RIC) allografts for adult AML by comparing patients who received alemtuzumab with those without alemtuzumab conditioning. Both groups were equivalent for age, sex, karyotype and disease status at transplant. With a median follow-up of 27 months (3-72 months) and 48 months (7-72 months), the 2-and 5-year overall survival, with or without alemtuzumab, is 60 and 60% (P ¼ 0.80) and 61 and 53%, respectively (P ¼ 0.85). The 2-year nonrelapse mortality is 12% with alemtuzumab, and 17% without alemtuzumab (P ¼ 0.49). The 2-year relapse rate is 35% with alemtuzumab compared with 19% without alemtuzumab (P ¼ 0.28). Grades II-IV acute GVHD occurred in 22% (8/37) without alemtuzumab compared with 14% (7/51) given alemtuzumab (P ¼ 0.25). Extensive chronic GVHD occurred in 47% (14/30) not given alemtuzumab compared with 4% (2/45) who were given alemtuzumab (P ¼ 0.001). Among evaluable patients, the risk of infections was higher in those treated with alemtuzumab compared with those not treated with alemtuzumab (79 vs 57%, respectively, P ¼ 0.02). In conclusion, alemtuzumab has a beneficial effect by reducing chronic GVHD without affecting overall survival. Further studies are warranted before alemtuzumab can be recommended as standard in RIC allografts for AML.

Section: Discussionsupporting

confidence: 81%

Alemtuzumab markedly reduces chronic GVHD without affecting overall survival in reduced-intensity conditioning sibling allo-SCT for adults with AML

Malladi

Peniket

Littlewood

et al. 2008

“…There remains debate as to the relative risk of CMV reactivation following non-myeloablative transplantations in comparison to myeloablative programmes 20 and CMV-specific T-cell immune reconstitution can occur promptly even after alemtuzumab-containing conditioning regimens. 21 In our cohort reactivation occurred only in CMV seropositive patients and confirmed similar studies showing the primacy of patient serostatus over donor graft origin in development of viraemia. 22 Relatively few studies have studied the importance of both CMV-specific CD4 þ and CD8 þ T-cell immune reconstitution in relation to reactivation risk.…”

Section: Discussionsupporting

confidence: 74%

Early reconstitution of effector memory CD4+ CMV-specific T cells protects against CMV reactivation following allogeneic SCT

Pourgheysari

Piper

McLarnon

et al. 2008

Reactivation of CMV is a common complication following allogeneic haematopoietic SCT and is associated with significant morbidity and mortality. The relative importance of the CD4 þ and CD8 þ components of the CMVspecific immune response in protection from reactivation is unclear. The CMV-specific CD4 þ and CD8 þ immune response was measured at serial time points in 32 patients following allogeneic HSCT. Intracellular cytokine staining following CMV lysate stimulation and HLA-peptide tetramers were used to determine CMV-specific CD4 þ and CD8 þ responses, respectively. A deficient CMVspecific CD4 þ T-cell immune response within the first 30-50 days post transplant was associated with high risk of viral reactivation. Patients with combined impairment of the CD4 þ and CD8 þ immune response within the first 100 days were susceptible to late viral reactivation. The frequency of CMV-specific CD4 þ T cells correlated with CMV-specific CD8 þ T cells, comprising 10% of the whole T-cell repertoire. Early CMV-specific CD4 þ T-cell reconstitution was dominated by effector memory cells with normal levels of IL-2 resuming 6 months following transplantation. In summary, both CD4 and CD8 CMV-specific immune reconstitution is required for protection from recurrent activation. Measurement of the magnitude of the CMV-specific CD4 þ immune response is useful in managing viral reactivation following HSCT.

“…[23][24][25][26][27] Though previous studies have showed similar patterns of immune reconstitution after non-myeloablative transplantation compared with myeloablative transplants, 28 the use of ATG or alemtuzumab has been shown to delay CMV-specific immune reconstitution. 8,9,10,17 In this study, the OS among patients with CMV reactivation was not significantly lower than patients without CMV reactivation. Previous published data have suggested that recipient CMV seropositivity itself was associated with higher mortality rates.…”

Section: Discussionmentioning

confidence: 73%

“…T-cell depletion of the graft and the addition of T-cell depleting agents reduce the risk of acute GVHD but also impair immune reconstitution and have been shown to be associated with a higher incidence of CMV reactivation especially among RIC transplants. [16][17][18] Although in general, the onset of CMV reactivation was not delayed among RIC transplants compared with MAC transplants, the addition of the T-cell depleting agents, alemtuzumab or ATG to the RIC protocol led to an earlier onset of CMV infection than with a standard RIC regimen. Interestingly, the use of ATG was not associated with an earlier onset of CMV reactivation in MAC transplants.…”

Section: Discussionmentioning

confidence: 99%

Fludarabine-based reduced intensity conditioning transplants have a higher incidence of cytomegalovirus reactivation compared with myeloablative transplants

George

Kerridge

Gilroy

et al. 2009

Two hundred and ten adult CMV seropositive patients undergoing myeloablative conditioning (MAC) [n ¼ 127] or reduced intensity conditioning (RIC) [n ¼ 83] transplants (HCT) were serially monitored for CMV reactivation and disease, using a qualitative polymerase chain reaction (PCR) followed by quantitation with pp65 antigen or quantitative PCR. CMV reactivation occurred in 53 RIC (63.9%) and 61 MAC (48%; P ¼ 0.03) transplants at a median of 47 days (range: 24-1977). Risk factors identified included acute GVHD (P ¼ 0.001), RIC regimen (P ¼ 0.03), unrelated donor (P ¼ 0.02), use of anti-thymocyte globulin/alemtuzumb (P ¼ 0.02) and use of bone marrow in MAC transplants (P ¼ 0.011). On multivariate analysis, RIC transplants and acute GVHD remained independent predictors. Treatment with antiviral drugs resulted in CMV negativity rates of 86.8% in MAC and 88.6% in RIC transplants. CMV disease occurred in 10.8% of RIC and 4.7% of MAC transplants (P ¼ 0.15). At a median follow-up of 26 months (range: 3-88), 48.1% of RIC and 50.3% of MAC transplants are alive. The higher incidence of CMV reactivation among RIC transplants suggests the need for novel prophylactic or pre-emptive strategies in this high-risk group of patients.