1.
Systematic Evaluation of Donor-KIR/Recipient-HLA Interactions in HLA-matched Hematopoietic Cell Transplantation for AML
Fein, J. A., Shouval, R., Krieger, E., Spellman, S. R., Wang, T., Baldauf, H., Fleischhauer, K., Kröger, N., Horowitz, M. M., Maiers, M., et al
Blood advances. 2023
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Editor's Choice
Abstract
In acute myeloid leukemia (AML), donor NK-cell killer immunoglobulin-like receptors (KIR) and recipient HLA interactions may contribute to the graft-versus-leukemia effect of allogeneic hematopoietic cell transplantation (HCT). Analyses of individual KIR/HLA interactions however have yielded conflicting findings, and their importance in the HLA-matched unrelated donor (MUD) setting remains controversial. We systematically studied outcomes of individual donor-KIR/recipient-HLA interactions for HCT outcomes and empirically evaluated prevalent KIR genotypes for clinical benefit. Adult AML patients (n=2025) transplanted in complete remission who received MUD grafts reported to the Center for International Blood and Marrow Transplantation were evaluated. Only the donor-2DL2present/recipient-HLA-C1present pair was associated with reduced relapse (hazard ratio 0.79 [95% confidence interval: 0.67, 0.93], p = 0.006) compared with donor-2DL2absent/recipient-HLA-C1present. However, no association were found when comparing HLA-C groups among KIR-2DL2present-graft recipients. We identified nine prevalent donor KIR genotypes in our cohort and screened them for association with relapse risk. Genotype (G)5 in all recipients and G3 in Bw4present recipients were associated with decreased relapse risk (HR 0.52 [0.35, 0.78], p = 0.002; 0.32 [0.14, 0.72], p = 0.006, respectively) and G2 (HR 1.63 [1.15, 2.29], p = 0.005) with increased relapse risk C1-homozygous recipients, compared to patients with the same ligand. However, we could not validate these findings in an external dataset of 796 AML transplants from the German transplantation registry. Neither a systematic evaluation of known HLA-KIR interactions nor an empiric assessment of prevalent KIR genotypes demonstrated clinically actionable associations, therefore not supporting these KIR-driven strategies for MUD selection in AML.
PICO Summary
Population
Adults with acute myeloid leukaemia who underwent matched unrelated donor (MUD) transplantation in complete remission, identified from the CIBMTR registry (n=2025)
Intervention
Evaluation of individual donor-KIR/recipient-HLA interactions for HCT outcomes and empirically evaluated prevalent KIR genotypes for clinical benefit.
Comparison
Independent validation cohort of 796 AML transplants from the German transplantation registry (n=796)
Outcome
Only the donor-2DL2+/recipient-HLA-C1+ pair was associated with reduced relapse (hazard ratio 0.79 [95% confidence interval: 0.67, 0.93]) compared with donor-2DL2-/recipient-HLA-C1+. However, no association were found when comparing HLA-C groups among KIR-2DL2+-graft recipients. We identified nine prevalent donor KIR genotypes in our cohort and screened them for association with relapse risk. Genotype (G)5 in all recipients and G3 in Bw4+recipients were associated with decreased relapse risk (HR 0.52 [0.35, 0.78]; 0.32 [0.14, 0.72], respectively) and G2 (HR 1.63 [1.15, 2.29]) with increased relapse risk C1-homozygous recipients, compared to patients with the same ligand.
2.
Post-Transplant Cyclophosphamide (PTCy) is Associated with Increased Cytomegalovirus Infection: A CIBMTR Analysis
Goldsmith, S. R., Abid, M. B., Auletta, J. J., Bashey, A., Beitinjaneh, A., Castillo, P., Chemaly, R. F., Chen, M., Ciurea, S. O., Dandoy, C. E., et al
Blood. 2021
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Editor's Choice
Abstract
Prior studies suggest increased CMV infection following haploidentical donor transplantation with post-transplant cyclophosphamide (HaploCy). The role of allograft source and PTCy in CMV infection and disease is unclear. We analyzed the effect of graft source and PTCy on incidence of CMV infection as well as transplant outcomes as it relates to CMV serostatus and occurrence of CMV infection by d180. We examined patients reported to CIBMTR between 2012-2017 who had received HaploCy (n = 757), Sib with PTCy (SibCy, n=403), or Sib with calcineurin inhibitor-based prophylaxis (SibCNI, n=1605) for AML/ALL/MDS. Cumulative incidences of CMV infection by d180 were 42% (99% CI, 37-46), 37% (31 - 43), and 23% (20 - 26), respectively [p<0.001]. CMV end-organ disease was statistically comparable. CMV infection risk was highest for CMV-Seropositive recipients (R+), but significantly higher in PTCy recipients regardless of donor [HaploCy (n=545): HR 50.3 (14.4 - 175.2); SibCy (n=279): HR 47.7 (13.3 - 171.4); SibCNI (n=1065): HR 24.4 (7.2 - 83.1); p<0.001]. D+/R- patients also had increased risk for CMV infection. Among seropositive recipients or those developing CMV infection, HaploCy had worse OS and NRM. Relapse was unaffected by CMV infection or serostatus. PTCy was associated with lower chronic GVHD overall, but CMV infection in PTCy recipients was associated with higher cGVHD (p=0.006). PTCy, regardless of donor, is associated with higher incidence of CMV infection, augmenting the risk of seropositivity. Additionally CMV infection may negate the cGVHD protection of PTCy. This study supports aggressive prevention strategies in all patients receiving PTCy.
PICO Summary
Population
Patients with acute myeloid leukaemia, acute lymphoblastic leukaemia or myelodysplastic synrome (n=2765)
Intervention
Haploidentical transplantation with post-transplant cyclophosphamide (HaploCy, n=757),
Comparison
Sibling donor with post-transplant cyclophosphamide (SibCy, n=403), or Sibling donor with calcineurin inhibitor-based prophylaxis (SibCNI, n=1605)
Outcome
Cumulative incidences of CMV infection by day 180 were 42% (HaploCy), 37% (SibCy), and 23% (SibCNI), respectively. CMV end-organ disease was statistically comparable. CMV infection risk was highest for CMV-Seropositive recipients (R+), but significantly higher in PTCy recipients regardless of donor [HaploCy (n=545): HR 50.3; SibCy (n=279): HR 47.7; SibCNI (n=1065): HR 24.4. D+/R- patients also had increased risk for CMV infection. Among seropositive recipients or those developing CMV infection, HaploCy had worse OS and NRM. Relapse was unaffected by CMV infection or serostatus. PTCy was associated with lower chronic GVHD overall, but CMV infection in PTCy recipients was associated with higher cGVHD. PTCy, regardless of donor, is associated with higher incidence of CMV infection, augmenting the risk of seropositivity. Additionally CMV infection may negate the cGVHD protection of PTCy.
3.
Post-Transplant cyclophosphamide is associated with increase in Non-CMV Herpesvirus infections in Acute leukemia and MDS patients
Singh, A., Dandoy, C. E., Chen, M., Kim, S., Mulroney, C. M., Kharfan-Dabaja, M. A., Ganguly, S., Maziarz, R. T., Kanakry, C. G., Kanakry, J. A., et al
Transplantation and cellular therapy. 2021
Abstract
BACKGROUND There is increasing use of post-transplant cyclophosphamide (PTCy) for GVHD prophylaxis for both haploidentical and fully matched transplants. Published studies have reported an increased incidence of CMV infection with the use of PTCy. Limited data exist regarding the incidence and outcomes of infection with non-CMV herpes viruses (NCHV) in this setting. OBJECTIVE The aim of this study was to evaluate the cumulative incidence of NCHV infections and the association of NCHV infections with transplant-specific outcomes in patients receiving haploidentical transplant with PTCy(HaploCy), matched sibling donor transplant with PTCy (SibCy) or matched sibling donor transplant with calcineurin inhibitor based prophylaxis (SibCNI). We hypothesized that, like CMV infection, patients receiving haploidentical transplant with PTCy will have higher risk of NCHV infections. STUDY DESIGN Using the CIBMTR database, we analyzed patients (HaploCy, n=757; SibCNI, n=1605; SibCy, n=403) receiving first hematopoietic stem-cell transplant between 2012 and 2017 for acute myeloid leukemia, acute lymphoblastic leukemia and myelodysplastic syndrome. RESULTS The cumulative incidence of non-CMV herpes virus infection at six months post-transplant in the HaploCy, SibCy and SibCNI were 13.9% (99%CI=10.8-17.3%), 10.7% (99%CI=7.1-15%), and 5.7% (99%CI=4.3-7.3%), p<0.001 respectively. This was primarily due to a higher frequency of HHV-6 viremia reported in patients receiving PTCy. Incidence of Epstein-Barr viremia was low in all groups and no cases of post-transplant lymphoproliferative disorder were seen in PTCy groups. The incidence of non-CMV herpes virus organ disease was low in all three cohorts. Development of NCHV infection was associated with increased treatment-related mortality, particularly in the HaploCy group. There was no association with the development of GVHD, relapse, and disease-free survival. Patients in PTCy cohorts who did not develop non-CMV herpes virus infection had lower rates of cGVHD. CONCLUSIONS This study demonstrates that the use of PTCy is associated with increased risk of NCHV infection. Development of NCHV infection is associated with increased non-relapse mortality, especially in HaploCY group. Prospective trials should consider viral surveillance strategies in conjunction with assessment of immune reconstitution for better understanding of the clinical relevance of viral reactivation in different transplant settings.