-
1.
Molecular disparity of HLA-DPB1 is associated with the development of subsequent solid cancer after allogeneic hematopoietic stem cell transplantation
Zou, J., Kongtim, P., Oran, B., Srour, S. A., Greenbaum, U., Carmazzi, Y., Rondon, G., Ciurea, S. O., Ma, Q., Shpall, E. J., et al
Cancer. 2023
Abstract
BACKGROUND An increased incidence of subsequent solid cancers (SSCs) has been reported in long-term survivors of allogeneic hematopoietic stem cell transplantation (allo-HSCT), and SSC is associated with inferior mortality and morbidity. Previous studies showed that the incidence of SSC is significantly higher in those who underwent allo-HSCT from HLA-mismatched donors, suggesting that persistent alloimmunity may predispose patients to SSCs. It was recently reported that, in a cohort of patients who received allo-HSCT from an unrelated donor matched at HLA-A, -B, -C, -DRB1/3/4/5, and -DQB1 loci, HLA-DPB1 alloimmunity determined by high mismatched eplets (MEs) and Predicted Indirectly Recognizable HLA Epitopes (PIRCHE) score (PS), was associated with relapse protection and increased risk of acute graft-versus-host disease (GVHD). METHODS In the present study, the impact of HLA-DPB1 alloimmunity assessed by molecular mismatch algorithms on the development of SSCs in a cohort of 1514 patients who underwent allo-HSCT for hematologic malignancies was further investigated. ME load at the HLA-DPB1 locus was measured using the HLAMatchmaker module incorporated in HLA Fusion software, and the PS for mismatched HLA-DPB1 was calculated using the HSCT module from the PIRCHE online matching service. RESULTS In multivariable analysis after adjusting for baseline risk factors, higher ME, PS-I, and PS-II in the GVH direction, but not in the HVG direction, were associated with an increased risk of SSCs (ME: subdistribution hazard ratio [SHR] 1.58, p = .01; PS-I: SHR 1.59, p = .009; PS-II: SHR 1.71, p = .003). In contrast, nonpermissive HLA-DPB1 mismatches defined by the conventional T-cell epitope algorithm were not predictive of the risk of SSCs. Moreover, posttransplant cyclophosphamide-based GVHD prophylaxis was associated with a reduced risk of SSC (SHR 0.34, p = .021). CONCLUSIONS These results indicate for the first time that increased GVH alloreactivity could contribute to the development of SSCs in allo-HSCT survivors.
-
2.
SIRPα Mismatch Is Associated With Relapse Protection and Chronic Graft-Versus-Host Disease After Related Hematopoietic Stem Cell Transplantation for Lymphoid Malignancies
Saliba, R. M., Srour, S. A., Greenbaum, U., Ma, Q., Carmazzi, Y., Moller, M., Wood, J., Ciurea, S. O., Kongtim, P., Rondon, G., et al
Frontiers in immunology. 2022;13:904718
Abstract
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative therapy for hematologic malignancies. Alloreactivity after HSCT is known to be mediated by adaptive immune cells expressing rearranging receptors. Recent studies demonstrated that the innate immune system could likewise sense the non-self signals and subsequently enhance the alloimmune response. We recently demonstrated that the donor/recipient mismatch of signal regulatory protein α (SIRPα), an immunoglobulin receptor exclusively expressed on innate cells, is associated with a higher risk of cGVHD and relapse protection in a cohort of acute myeloid leukemia patients who underwent allo-HSCT. Whether these effects also occur in other hematologic malignancies remains unclear. In the present study, we compared outcomes by SIRPα match status in a cohort of 310 patients who received allo-HSCT from an HLA matched-related donor for the treatment of lymphoid malignancies. Multivariable analysis showed that SIRPα mismatch was associated with a significantly higher rate of cGVHD (hazard ratio [HR] 1.8, P= .002), cGVHD requiring systemic immunosuppressive therapy (HR 1.9, P= .005), a lower rate of disease progression (HR 0.5, P= .003) and improved progression-free survival (HR 0.5, P= .001). Notably, the effects of SIRPα mismatch were observed only in the patients who achieved >95% of donor T-cell chimerism. The mismatch in SIRPα is associated with favorable relapse protection and concurrently increased risk of cGVHD in patients who undergo allo-HSCT for lymphoid malignancies, and the optimal donor could be selected based on the finding of the study to mitigate the risk of GVHD and relapse.
-
3.
Donor selection for KIR alloreactivity is associated with superior survival in haploidentical transplant with PTCy
Zou, J., Kongtim, P., Srour, S. A., Greenbaum, U., Schetelig, J., Heidenreich, F., Baldauf, H., Moore, B., Saengboon, S., Carmazzi, Y., et al
Frontiers in immunology. 2022;13:1033871
Abstract
With the continuous increase in the use of haploidentical donors for transplantation, the selection of donors becomes increasingly important. Haploidentical donors have been selected primarily based on clinical characteristics, while the effects of killer cell immunoglobulin-like receptors (KIRs) on outcomes of haploidentical-hematopoietic stem cell transplantation (haplo-HSCT) with post-transplant cyclophosphamide (PTCy) remain inconclusive. The present study aimed to thoroughly evaluate the effect of KIRs and binding ligands assessed by various models, in addition to other patient/donor variables, on clinical outcomes in haplo-HSCT. In a cohort of 354 patients undergoing their first haplo-HSCT, we found that a higher Count Functional inhibitory KIR score (CF-iKIR) was associated with improved progression-free survival (adjusted hazard ratio [HR], 0.71; P = .029) and overall survival (OS) (HR, 0.66; P = .016), while none of the other models predicted for survival in these patients. Moreover, using exploratory classification and regression tree analysis, we found that donor age <58 years combined with cytomegalovirus-nonreactive recipient was associated with the best OS, whereas donor age >58 years was associated with the worst OS. In the rest of our cohort (80%), cytomegalovirus-reactive recipients with a donor <58 years old, a higher CF-iKIR was associated with superior OS. The 3-year OS rates were 73.9%, 54.1% (HR, 1.84; P = .044), 44.5% (HR, 2.01; P = .003), and 18.5% (HR, 5.44; P <.001) in the best, better, poor, and worse donor groups, respectively. Our results suggest that KIR alloreactivity assessed by CF-iKIR score can help optimize donor selection in haplo-HSCT.
-
4.
Mismatch in SIRPa, a regulatory protein in innate immunity, is associated with chronic GVHD in hematopoietic stem cell transplantation
Saliba, R. M., Greenbaum, U., Ma, Q., Srour, S. A., Carmazzi, Y., Li, L., Oran, B., Moller, M., Wood, J., Ciurea, S. O., et al
Blood advances. 2021;5(17):3407-3417
-
-
Free full text
-
Abstract
Recent compelling evidence showed that innate immune effector cells could recognize allogeneic grafts and prime an adaptive immune response. Signal regulatory protein a (SIRPa) is an immunoglobulin superfamily receptor that is expressed on myeloid cells; the interaction between SIRPa and its ubiquitously expressed ligand CD47 elicits an inhibitory signal that suppresses macrophage phagocytic function. Additional studies showed that donor-recipient mismatch in SIRPa variants might activate monocytic allorecognition, possibly as the result of non-self SIRPa-CD47 interaction. However, the frequency of SIRPa variation and its role in hematopoietic stem cell transplantation (HSCT) remains unexplored. We studied 350 patients with acute myeloid leukemia/myelodysplastic syndrome who underwent HLA-matched related HSCT and found that SIRPa allelic mismatches were present in 39% of transplantation pairs. SIRPa variant mismatch was associated with a significantly higher rate of chronic graft-versus-host disease (GVHD; hazard ratio [HR], 1.5; P = .03), especially de novo chronic GVHD (HR, 2.0; P = .01), after adjusting for other predictors. Those with mismatched SIRPa had a lower relapse rate (HR, 0.6; P = .05) and significantly longer relapse-free survival (RFS; HR, 0.6; P = .04). Notably, the effect of SIRPa variant mismatch on relapse protection was most pronounced early after HSCT and in patients who were not in remission at HSCT (cumulative incidence, 73% vs 54%; HR, 0.5; P = .01). These findings show that SIRPa variant mismatch is associated with HSCT outcomes, possibly owing to innate allorecognition. SIRPa variant matching could provide valuable information for donor selection and risk stratification in HSCT.
-
5.
Treatment of Allosensitized Patients Receiving Allogeneic Transplantation
Ciurea, S. O., Al Malki, M. M., Kongtim, P., Zou, J., Aung, F. M., Rondon, G., Chen, J., Taniguchi, M., Otoukesh, S., Nademanee, A., et al
Blood advances. 2021
-
-
-
Free full text
-
Full text
-
Editor's Choice
Abstract
Donor-specific anti-HLA antibodies (DSA) are a major cause of engraftment failure in patients receiving haploidentical stem cell transplantation (HaploSCT). Effective treatments are needed for these patients who often have no other donor options and/or are in need to proceed urgently to transplantation. We studied a multimodality treatment with alternate day plasma exchange, rituximab, intravenous gamma globulin (IvIg) and an irradiated donor buffy coat for patients with DSA at two institutions. Thirty-seven patients with a median age of 51 years were treated with this desensitization protocol. Treatment outcomes were compared with a control group of HaploSCT patients without DSA (N=345). Majority of patients in the DSA group were females (83.8% vs. 37.1% in controls, p<0.001) and received stem cells from a child as donor (67.6% vs. 44.1%, p=0.002). Mean DSA level before and after desensitization was 10,198 and 5,937 MFI, respectively with mean differences of 4,030 MFI. Fourteen of 30 tested patients (46.7%) had C1q positivity while 8 of 29 tested patients (27.6%) remained positive after desensitization. In multivariable analysis, patients with initial DSA >20,000 MFI and with persistent C1q+ after desensitization had a significantly lower engraftment rate, resulted in a significantly higher non-relapse mortality (NRM) and worse overall survival (OS) than controls whereas graft outcome and survivals of patients with initial DSA <20,000 MFI and those with negative C1q after treatment were comparable with controls. In conclusion, treatment with plasma exchange, rituximab, IvIg and donor buffy coat is effective in promoting engraftment in patients with DSA up to 20,000 MFI.
PICO Summary
Population
Patients with donor specific antibodies (DSAs) from two US centres, receiving allogeneic transplantation (DSA group, n=37)
Intervention
Desensitisation protocol: alternate day plasma exchange, rituximab, intravenous gamma globulin (IvIg) and an irradiated donor buffy coat (n=37)
Comparison
Patients without DSAs undergoing haploidentical transplantation (Control, n=345)
Outcome
The majority of patients in the DSA group were female (83.8% vs 37.1% in controls,) and received stem cells from a child as the donor (67.6% vs 44.1%). Mean DSA level before and after desensitization was 10 198 and 5937 mean fluorescence intensity (MFI), respectively, with mean differences of 4030 MFI. Fourteen of 30 tested patients (46.7%) had C1q positivity, while 8 of 29 tested patients (27.6%) remained positive after desensitization. In multivariable analysis, patients with initial DSA > 20 000 MFI and persistent positive C1q after desensitization had a significantly lower engraftment rate, which resulted in significantly higher non-relapse mortality and worse overall survival (OS) than controls, whereas graft outcome and survival of patients with initial DSA < 20 000 MFI and those with negative C1q after treatment were comparable with controls.
-
6.
Incidence and impact of community respiratory viral infections in post-transplant cyclophosphamide-based graft-versus-host disease prophylaxis and haploidentical stem cell transplantation
Mulroney, C. M., Bilal Abid, M., Bashey, A., Chemaly, R. F., Ciurea, S. O., Chen, M., Dandoy, C. E., Diaz Perez, M. A., Friend, B. D., Fuchs, E., et al
British journal of haematology. 2021
-
-
Free full text
-
Abstract
Community respiratory viral infections (CRVIs) are associated with pulmonary function impairment, alloimmune lung syndromes and inferior survival in human leucocyte antigen (HLA)-matched allogeneic haematopoietic stem cell transplant (HCT) recipients. Although the incidence of viral infections in HLA-haploidentical HCT recipients who receive post-transplant cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis is reportedly increased, there are insufficient data describing the incidence of CRVIs and the impact of donor source and PTCy on transplant outcomes. Analysing patients receiving their first HCT between 2012 and 2017 for acute myeloid leukaemia, acute lymphoblastic leukaemia and myelodysplastic syndromes, we describe comparative outcomes between matched sibling transplants receiving either calcineurin-based GVHD prophylaxis (SibCNI, N = 1605) or PTCy (SibCy, N = 403), and related haploidentical transplants receiving PTCy (HaploCy, N = 757). The incidence of CRVIs was higher for patients receiving PTCy, regardless of donor type. Patients in the HaploCy cohort who developed a CRVI by day +180 had both a higher risk of treatment-related mortality [hazard ratio (HR) 2·14, 99% confidence interval (CI) 1·13-4·07; P = 0·002] and inferior 2-year overall survival (HR 1·65, 99% CI 1·11-2·43; P = 0·001) compared to SibCNI with no CRVI. This finding justifies further research into long-term antiviral immune recovery, as well as development of preventive and treatment strategies to improve long-term outcomes in such patients.
-
7.
Risk classification at diagnosis predicts post-HCT outcomes in intermediate-, adverse-risk, and KMT2A-rearranged AML
Menghrajani, K., Gomez-Arteaga, A., Madero-Marroquin, R., Zhang, M. J., Bo-Subait, K., Sanchez, J., Wang, H. L., Aljurf, M., Assal, A., Bacher, U., et al
Blood advances. 2021
Abstract
Little is known about whether risk classification at diagnosis predicts post-hematopoietic cell transplantation (HCT) outcomes for acute myeloid leukemia (AML) patients. We evaluated 8709 AML patients from the CIBMTR database and, after selection and manual curation of cytogenetics data, 3779 patients in CR1 were included in the final analysis: 2384 with intermediate-risk, 969 with adverse-risk, and 426 with KMT2A-rearranged disease. An adjusted multivariable analysis compared to intermediate-risk patients detected an increased risk of relapse for KMT2A-rearranged and adverse-risk patients (HR 1.27, p = 0.01 and HR 1.71, p < 0.001, respectively). Leukemia-free survival (LFS) was similar for KMT2A and adverse-risk patients (HR 1.26, p = 0.002 and HR 1.47, p < 0.001), as was overall survival (OS) (HR 1.32, p < 0.001 and HR 1.45, p < 0.001). No differences in outcome could be detected when patients were stratified by KMT2A fusion partner. This is the largest study conducted to date on post-HCT outcomes in AML using manually curated cytogenetics for risk stratification. Our work demonstrates that risk classification at diagnosis remains predictive of post-HCT outcomes in AML. It also highlights the critical need to develop novel treatment strategies for patients with KMT2A rearrangements and adverse-risk disease.
-
8.
Impact of graft composition on outcomes of haploidentical bone marrow stem cell transplantation
Saliba, R. M., Veltri, L., Rondon, G., Chen, J., Al-Atrash, G., Alousi, A., Martinez, C., Augustine, L., Hosing, C. M., Oran, B., et al
Haematologica. 2020
-
9.
Molecular disparity in human leukocyte antigens is associated with outcomes in haploidentical stem cell transplantation
Zou, J., Ciurea, S. O., Kongtim, P., Yi, M., Carmazzi, Y., Rondon, G., Srour, S., Partlow, D., Champlin, R. E., Cao, K.
Blood advances. 2020;4(15):3474-3485
-
-
-
Free full text
-
-
Editor's Choice
Abstract
Haploidentical donors are increasingly used for patients requiring hematopoietic stem cell transplantation (HSCT). Although several factors have been associated with transplant outcomes, the impact of HLA disparity in haploidentical HSCT (haplo-HSCT) remains unclear. We investigated the impact of HLA disparity quantified by mismatched eplets (ME) load of each HLA locus on the clinical outcome of 278 consecutive haploidentical transplants. Here, we demonstrated that the degree of HLA molecular mismatches, at individual HLA loci, may be relevant to clinical outcome in the haplo-HSCT. A significantly better overall survival was associated with higher ME load from HLA-A (hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.95-0.99; P = .003) and class I loci (HR, 0.99; 95% CI, 0.97-0.99; P = .045) in the host-versus-graft direction. The apparent survival advantage of HLA-A ME was primarily attributed to reduced risk in relapse associated with an increase in HLA-A ME load (subdistribution HR, 0.95; 95% CI, 0.92-0.98; P = .004). Furthermore, we have identified an association between the risk of grade 3-4 acute graft-versus-host disease (GVHD) and a higher ME load at HLA-B and class I loci in graft-versus-host (GVH) direction. Additionally, GVH nonpermissive HLA-DPB1 mismatch defined by T-cell epitope grouping was significantly associated with relapse protection (subdistribution HR, 0.19; 95% CI, 0.06-0.59; P = .004) without a concurrent increase in GVHD. These findings indicate that alloreactivity generated by HLA disparity at certain HLA loci is associated with transplant outcomes, and ME analysis of individual HLA loci might assist donor selection and risk stratification in haplo-HSCT.
PICO Summary
Population
Patients receiving haploidentical transplantation (n=278)
Intervention
HLA disparity quantified by mismatched eplets (ME)
Comparison
None
Outcome
A significantly better overall survival was associated with higher ME load from HLA-A (hazard ratio [HR], 0.97) and class I loci (HR, 0.99) in the host-versus-graft direction. The apparent survival advantage of HLA-A ME was primarily attributed to reduced risk in relapse associated with an increase in HLA-A ME load (subdistribution HR, 0.95). Furthermore, we have identified an association between the risk of grade 3-4 acute graft-versus-host disease (GVHD) and a higher ME load at HLA-B and class I loci in graft-versus-host (GVH) direction. Additionally, GVH nonpermissive HLA-DPB1 mismatch defined by T-cell epitope grouping was significantly associated with relapse protection (subdistribution HR, 0.19) without a concurrent increase in GVHD.
-
10.
Validation of a Hematopoietic Cell Transplant - Composite Risk (HCT-CR) Model for Post Transplant Survival Prediction in Patients with Hematologic Malignancies
Ciurea, S. O., Kongtim, P., Hasan, O., Ramos Perez, J. M., Torres, J., Rondon, G., Champlin, R. E.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2020
Abstract
PURPOSE Allogeneic hematopoietic stem cell transplantation (AHCT) outcomes depend on disease and patient characteristics. We previously developed a novel prognostic model, hematopoietic cell transplant composite-risk (HCT-CR) by incorporating the refined disease risk index (DRI-R) and hematopoietic cell transplant - comorbidity/age index (HCT-CI/Age) to predict post-transplant survival in patients with AML and MDS. Here we aimed to validate and prove the generalizability of the HCT-CR model in an independent cohort of patients with hematologic malignancies receiving AHCT. MATERIALS AND METHODS Data of consecutive adult patients receiving AHCT for various hematologic maliganacies were analyzed. Patients were stratified into 4 HCT-CR risk groups. The discrimination, calibration performance and clinical net benefit of the HCT-CR model were tested. RESULTS The HCT-CR model stratified patient into 4 risk groups with significantly different OS. Three-year OS was 67.4%, 50%, 37.5% and 29.9% for low, intermediate, high and very high-risk group, respectively (P<0.001). The HCT-CR model had better discrimination on OS prediction when compared with the DRI-R and HCT-CI/Age (C-idindex was 0.69 vs. 0.59 and 0.56, respectively, P<0.001). The decision curve analysis showed that HCT-CR model provided better clinical utility for patient selection for post-transplant clinical trial than the "treat all" or "treat none" strategy and the use of the DRI-R and HCT-CI/Age model separately. CONCLUSIONS The HCT-CR can be effectively used to predict post-transplant survival in patients with various hematologic malignancies. This composite model can identify patients who will benefit the most from transplantation and helps physicians in making decisions regarding post-transplant therapy to improve outcomes.