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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.
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Mycophenolate Mofetil: A Friend or a Foe with PTCy and Tacrolimus Prophylaxis in HLA-Matched donors?
Mehta, R. S., Saliba, R. M., Hayase, E., Jenq, R. R., Abraham, S., Rashid, A., Rondon, G., Al-Atrash, G., Bashir, Q., Hosing, C. M., et al
Transplantation and cellular therapy. 2022
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Editor's Choice
Abstract
Adapted from the haploidentical literature, post-transplantation cyclophosphamide (PTCy) is increasingly being used with HLA-matched donors, generally with a calcineurin inhibitor, such as tacrolimus (Tac) with or without mycophenolate mofetil (MMF). Owing to its immunosuppressive, potentially antitumor, and antimicrobial properties, MMF is an attractive drug; however, it remains unclear how much benefit is gained when used with PTCy/Tac. To assess that, we compared PTCy/Tac (n=242) to PTCy/Tac/MMF (n= 144) in recipients of HLA-matched donors. In multivariate analysis, the PTCy/Tac/MMF group had a significantly higher risk of grade II-IV acute graft-versus-host disease (GVHD; hazard ratio (HR) 2.1, 95% confidence interval (CI) 1.6-2.8, p<0.001), and steroid-refractory/dependent acute GVHD (HR 4.8, 95% CI 2.4-9.6, p<0.001), yet a significantly lower risk of relapse (HR 0.5, 95% CI, 0.3-0.9, p=0.009) and better progression-free survival (PFS; HR 0.7, 95% CI 0.5-0.9, p=0.04). There was no difference in the risk of grade III-IV acute GVHD, chronic GVHD, non-relapse mortality, or overall survival. MMF was associated with prolonged neutrophil engraftment by 2 days, and a higher risk of bacterial infections. In an exploratory stool microbiome analysis (n=16), we noted a higher relative abundance of β-glucuronidase-producing bacteria in the MMF group, which may have a role in the pathogenesis of MMF-related GVHD. Our data suggest that the addition of MMF to PTCy/Tac for HLA-matched donor HCT does not provide any advantage for GVHD prevention. Further studies are needed to decipher this mechanism, and understand its role with PTCy-based prophylaxis.
PICO Summary
Population
Adults with haematological malignancy who had first transplant with HLA-matched donor (n=386)
Intervention
Post-transplant cyclophosphamide with tacrolimus and mycophenalate mofetil (PTCy/Tac/MMF, n= 144)
Comparison
Post-transplant cyclophosphamide with tacrolimus only (PTCy/Tac, n=242)
Outcome
In multivariate analysis, the PTCy/Tac/MMF group had a significantly higher risk of grade II-IV acute graft-versus-host disease (GVHD; hazard ratio (HR) 2.1, 95% confidence interval (CI) 1.6-2.8), and steroid-refractory/dependent acute GVHD (HR 4.8, 95% CI 2.4-9.6), yet a significantly lower risk of relapse (HR 0.5, 95% CI, 0.3-0.9) and better progression-free survival (PFS; HR 0.7, 95% CI 0.5-0.9). There was no difference in the risk of grade III-IV acute GVHD, chronic GVHD, non-relapse mortality, or overall survival. MMF was associated with prolonged neutrophil engraftment by 2 days, and a higher risk of bacterial infections. In an exploratory stool microbiome analysis (n=16), we noted a higher relative abundance of β-glucuronidase-producing bacteria in the MMF group, which may have a role in the pathogenesis of MMF-related GVHD.
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Post-Transplantation Cyclophosphamide vs Tacrolimus and Methotrexate Graft-versus-Host Disease Prophylaxis For HLA-Matched Donor Transplantation
Mehta, R. S., Saliba, R. M., Rondon, G., Al-Atrash, G., Bashir, Q., Hosing, C. M., Kebriaei, P., Khouri, I., Nieto, Y., Oran, B., et al
Transplantation and cellular therapy. 2022
Abstract
BACKGROUND The use of post-transplantation cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis is increasing in patients undergoing HLA-matched sibling (MSD) or unrelated (MUD) donor hematopoietic cell transplantation (HCT), but data about its comparative efficacy against the traditional GVHD prophylaxis are scarce. OBJECTIVES Two broad questions assessed in this study were: (a) comparison of PTCy-based GVHD prophylaxis vs Tac/MTX (without ATG) in the MSD and (b) comparison of PTCy-based GVHD prophylaxis vs Tac/MTX (with ATG) in the MUD group. STUDY DESIGN This retrospective single-center study analyzed the outcomes of 964 patients who received Tac/MTX (n=578) vs PTCy-based (n=386) GVHD prophylaxis. All MUD recipients in the Tac/MTX group also received ATG; thus, separate analyses were conducted for MSD (n=412) and MUD (n=552) cohorts. In the MUD cohort, 306 patients received Tac/MTX/ATG and 246 received PTCy-based GVHD prophylaxis. In the MSD cohort, 272 received Tac/MTX and 140 received PTCy-based prophylaxis. RESULTS Both PTCy groups included somewhat older patients than the Tac/MTX groups and more patients had myeloid malignancy (85-90% vs 59-64%, respectively). A majority of patients in all groups received myeloablative conditioning and peripheral blood graft. Both PTCy groups had a significantly delayed neutrophil engraftment, higher risk of hemorrhagic cystitis, and higher risk of bacterial infections than the Tac/MTX groups. The risks of viral infections and related deaths were significantly higher in Tac/MTX group in the MUD cohort. In multivariate analysis, the risk of grade III-IV acute GVHD was similar in PTCy and Tac/MTX groups in both MSD and MUD cohorts, but the risk of chronic GVHD was significantly lower with PTCy in the MSD cohort. PTCy was associated with a significantly lower risk of non-relapse mortality and better progression-free survival in the MUD. PTCy was associated with improved GRFS in both MSD and MUD groups. CONCLUSIONS Our data suggest a benefit of using PTCy-based GVHD prophylaxis in both MSD (vs Tac/MTX) and MUD (vs Tac/MTX/ATG) HCT.
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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
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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.
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Acute graft-versus-host disease is the foremost cause of late nonrelapse mortality
Ramdial, J. L., Mehta, R. S., Saliba, R. M., Alousi, A. M., Bashir, Q., Hosing, C., Kebriaei, P., Olson, A. L., Oran, B., Qazilbash, M. H., et al
Bone marrow transplantation. 2021
Abstract
Despite low nonrelapse mortality (NRM) at day 100 after allogeneic hematopoietic cell transplantation (HCT), NRM at 1 year remains substantial. In this study, we retrospectively analyzed 199 patients who were treated on a phase II clinical trial assessing safety and efficacy of myeloablative fractionated busulfan and fludarabine conditioning regimen for hematologic malignancies. The goal of the study was to identify factors associated with NRM occurring between days 101 and 365 post-HCT and generate a hypothesis for future studies to reduce the risk of NRM at 1 year. We found that a vast majority (83%) of patients who experienced NRM between days 101 and 365 had prior grade II-IV acute graft-versus-host disease (GVHD), which was the leading cause of death either by itself (33.3%) or complicated by infections (37.5%). In multivariate analysis, grade II-IV acute GVHD (hazard ratio (HR) 2.9, 95% confidence interval (CI) 1.3-6.6, p?=?0.01) was the only significant predictor of NRM between days 101 and 365. Measures to reduce the risk of acute GVHD could lower the risk of NRM at 1 year and improve overall survival.
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Randomized phase II trial of extracorporeal phototherapy and steroids vs. steroids alone for newly diagnosed acute GVHD
Mehta, R. S., Bassett, R., Rondon, G., Overman, B. J., Popat, U. R., Hosing, C. M., Rezvani, K., Qazilbash, M. H., Anderlini, P., Jones, R. B., et al
Bone marrow transplantation. 2021
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Editor's Choice
Abstract
Steroids remain the initial therapy for acute graft-vs.-host disease (AGVHD). Strategies to improve response and minimize steroid exposure are needed. We report results of a randomized, adaptive, Bayesian-designed, phase II trial of prednisone with or without extracorporeal photopheresis (ECP) as an initial therapy for patients with newly diagnosed AGVHD. The primary endpoint was success at day 56 defined as: alive, in remission, achieving AGVHD response without additional therapy, and on <1?mg/kg at day 28 and <0.5?mg/kg on day 56 of steroids. Eighty-one patients were randomized to the ECP arm (n?=?51) or steroids alone (n?=?30). Median age was 54 years (range: 17-75); 90% had grade II AGVHD and 10% had grades III and IV AGVHD, with skin (85%), upper (22%)/lower (22%) gastrointestinal, and liver (10%) involvement. The ECP arm had a higher probability of success (0.815) and exceeded the predefined threshold for determining the investigational arm promising. ECP was potentially more beneficial than steroids-alone in skin-only AGVHD (response rate: 72% vs. 57%, respectively) than for visceral-organ AGVHD (47% vs. 43%, respectively). The addition of ECP to steroids may result in higher GVHD response as initial therapy for AGVHD, especially for patients with skin-only involvement.
PICO Summary
Population
Patients with newly-diagnosed acute graft-versus-host disease (AGVHD, n=81)
Intervention
Prednisone with extracorporeal photopheresis (ECP, n=51)
Comparison
Prednisone alone (n=30)
Outcome
The ECP arm had a higher probability of success (0.815) and exceeded the predefined threshold for determining the investigational arm promising. ECP was potentially more beneficial than steroids-alone in skin-only AGVHD (response rate: 72% vs. 57%, respectively) than for visceral-organ AGVHD (47% vs. 43%, respectively).
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Pentostatin therapy for steroid-refractory acute graft versus host disease: identifying those who may benefit
Ragon, B. K., Mehta, R. S., Gulbis, A. M., Saliba, R. M., Chen, J., Rondon, G., Popat, U. R., Nieto, Y., Oran, B., Olson, A. L., et al
Bone marrow transplantation. 2018;53(3):315-325
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Abstract
We report outcomes of 60 patients with steroid-refractory (SR)-aGVHD treated with pentostatin. Almost half (47%) of patients had grade 4 GVHD-22% had stage 3-4 liver GVHD and 51% had stage 3-4 lower gastrointestinal tract (LGI) GVHD. Patients received a median of 3 courses (range, 1-9) of pentostatin. Day 28 overall response rate (ORR) was 33% (n = 20) (complete response 18% (n = 11), partial response 15% (n = 9)). Non-relapse mortality was 72% (95% confidence interval (CI) 61-84%) and overall survival (OS) was 21% (95% CI 12-32%) at 18 months. On univariate analysis, age >60 years (HR 1.9, 95% CI 1.01-3.7, p = 0.045) and presence of liver GVHD (HR 1.9, 95% CI 1.9, 95% CI 1.5-3.3, p = 0.03) were significant predictors of poor OS while patients with LGI GVHD had superior OS than those without (HR 0.4, 95% CI 0.2-0.8, p = 0.01). On stratified analysis, patients <60 years with isolated LGI GVHD had the best outcomes with an ORR of 48% and OS of 42% at 18 months. Among older patients, OS was 14% in those with isolated LGI aGVHD and 0% in others. Pentostatin remains a viable treatment option for SR-aGVHD, especially in patients 60 years or younger with isolated LGI involvement.
Clinical Commentary
What is known?
NIHMS1717745
What did this paper set out to examine?
What did they show?
What are the implications for practice and for future work?
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8.
Histologic Grade 1 Is Associated With Increased Nonrelapsed Mortality in Lower Gastrointestinal Graft Versus Host Disease
Im, J. S., Abraham, S. C., Saliba, R. M., Rondon, G., Ross, W. A., Rashid, A., Shpall, E. J., Popat, U., Qazilbash, M. H., Hosing, C., et al
American Journal of Surgical Pathology. 2017;41(11):1483-1490
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Abstract
Histologic confirmation is considered a standard practice to diagnose gastrointestinal graft versus host disease (GI GVHD) and is often used in making treatment decisions. A histologic grade is often determined in cases that are diagnosed with GI GVHD. Although extensive crypt loss (histologic grade 4) is associated with high nonrelapse mortality (NRM), the prognostic value for the more common grade 1 is poorly understood. As clinical decisions are made on the degree of histologic evidence, it is important to establish its prognostic significance. Therefore, we evaluated 309 patients who underwent endoscopic biopsy for suspected GI GVHD within 6 months posttransplant between 2009 and 2012. The presence of histologic grade 1 was associated with increased NRM (hazard ratio=2.7, P=0.02) when compared with one of negative biopsy in patients with lower but not isolated upper GI GVHD. Multivariate competing-risk regression analysis confirmed the independent impact of histologic grade 1 in patients with early clinical stages of lower GI GVHD (stage 0 to 2) (hazard ratio=2.7, P=0.044). When compared with advanced histologic grades, histologic grade 1 did not lessen the adverse outcome for patients with advanced lower GI GVHD (stage 3 to 4) (cumulative incidence NRM of 84%). In conclusion, the presence of histologic grade 1 is associated with increased NRM in patients presenting with lower GI GVHD (stages 0 to 2) and is sufficient evidence for decision to initiate therapy. At the same time, histologic grade 1 does not lessen the markedly adverse impact of advanced lower GI GVHD (stage 3 to 4) and is not synonymous with "mild" GVHD.
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Prognostic value of response after upfront therapy for acute GVHD
Saliba, R. M., Couriel, D. R., Giralt, S., Rondon, G., Okoroji, G. J., Rashid, A., Champlin, R. E., Alousi, A. M.
Bone Marrow Transplant. 2012;47(1):125-31
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Abstract
One challenge in designing clinical trials for treatment of acute GVHD (aGVHD) is the lack of an established standardized end point to measure the success of therapies. To facilitate assessment of end points in clinical trials for treatment of aGVHD in the current allo-SCT era, a national workshop was recently organized. In this study, which was presented at the workshop, we evaluated the prognostic value of response to upfront therapy in a cohort of 83 patients who had been enrolled on two clinical trials testing novel therapies for aGVHD at our institution. Our results indicate that patients whose aGVHD has a CR or PR by day 28 after initiation of systemic therapy have a significantly lower 6-month cumulative incidence of non-relapse mortality (NRM) (16%) than patients whose aGVHD did not respond to therapy by day 28 (48%, P=0.005). Multivariate analysis based on the Cox proportional hazards regression analysis showed that the impact of response on NRM is independent of patient and aGVHD characteristics. Our data confirm the validity of using day-28 response as a primary end point in clinical trials for upfront therapy for aGVHD.