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1.
Outcomes of toxoplasmosis after allogeneic hematopoietic stem cell transplantation and the role of antimicrobial prophylaxis
Malek, A. E., Al-Juhaishi, T., Milton, D. R., Ramdial, J. L., Daher, M., Olson, A. L., Srour, S. A., Alatrash, G., Oran, B., Mehta, R. S., et al
Bone marrow transplantation. 2024
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2.
Incidence and Risk Factors of Early Onset VOD/SOS Differ in Younger vs Older Adults After Stem Cell Transplantation
Marcoux, C., Saliba, R. M., Wallis, W., Khazal, S. J., Ragoonanan, D., Rondon, G., Tewari, P., Popat, U. R., Oran, B., Olson, A. L., et al
Blood advances. 2024
Abstract
Veno-occlusive disease (VOD) is a rare but potentially life-threatening complication following allogeneic hematopoietic stem cell transplantation (allo-SCT). While increasing awareness and modern transplant techniques have mitigated risk, the interaction of historic risk factors in the current era with post-transplant cyclophosphamide (PTCy) is unknown. We performed a retrospective single center analysis of adult patients 18 years or older undergoing allo-SCT (N=1561) using predominately PTCy as GVHD prophylaxis (72%). We found a higher rate of VOD at 16.8% (20/119) in those aged ≤ 25 years compared to 3.8% (55/1442) in those >25 years, with unique predictors of VOD within each cohort. Multivariate classification and regression tree (CART) analysis confirmed age as the primary independent determinant of the rate of VOD. Within patients aged 18-25 years, disease risk index (DRI) (31% with high/very high DRI vs 12% low/intermediate DRI; p=0.03) and prior lines of chemotherapy (24% with >1 vs 6% with ≤1, p=0.03) were the strongest predictors of VOD. Incidence of VOD in patients > 25 years of age consistently ranged between 3-5% across most risk factors evaluated, with only hepatic factors (baseline elevation of bilirubin, aspartate transferase (AST), alanine aminotransferase (ALT)) or gemtuzumab exposure associated with increased rates of VOD. There was no significant difference in rates of VOD in those receiving PTCy compared to those receiving alternate GVHD prophylaxis. Our data highlight the differences in incidence and predictors in VOD between younger (≤25) and older (>25) adults undergoing allo-SCT.
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3.
Azacitidine Post-transplant Maintenance Improves Disease Progression in High-Risk Acute Myeloid Leukemia and Myelodysplastic Syndrome
Pasvolsky, O., Saliba, R. M., Popat, U. R., Alousi, A., Mehta, R., Yeh, J., Al-Atrash, G., Adeel, M., Ramdial, J., Marin, D., et al
Clinical lymphoma, myeloma & leukemia. 2024
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Editor's Choice
Abstract
BACKGROUND Maintenance after allogeneic hematopoietic cell transplantation (alloHCT) with hypomethylating agents has yielded conflicting results. MATERIALS AND METHODS We conducted a single center retrospective matched-control analysis with the study group (5-azacitidine [AZA] group) including adults with FLT3-negative acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) who received post-transplant AZA maintenance off clinical trial (n = 93). A matched control group was comprised of contemporaneous AML/MDS patients who did not receive any maintenance (n = 357). Primary endpoint was disease progression. RESULTS The AZA and control groups had comparable patient and disease characteristics except for older age (median: 61 vs. 57 years, P = .01) and lower hematopoietic comorbidity index (median: 2 vs. 3, P = .04) in the AZA group. The 3-year cumulative incidence of progression in the AZA and control groups was 29% vs. 33% (P = .09). The protective effect of AZA on progression was limited to patients with high-risk AML/MDS (HR = 0.4, 95% CI = 0.2-0.8, P = .009). This led to improved progression-free survival both in high-risk AML and MDS patients with maintenance (HR = 0.2, 95% CI = 0.1-0.6, P = .004 and HR = 0.4, 95% CI = 0.2-0.9, P = .04). CONCLUSION AZA maintenance was associated with a lower progression rate in patients with high-risk FLT3-negative AML or MDS, and AZA maintenance should be considered for post-alloHCT maintenance in this subset.
PICO Summary
Population
Adults with FLT3-negative acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS)
Intervention
Post-transplant 5-azacitidine (AZA) maintenance off clinical trial (n = 93).
Comparison
Contemporaneous AML/MDS patients who did not receive any maintenance (n = 357)
Outcome
The AZA and control groups had comparable patient and disease characteristics except for older age (median: 61 vs. 57 years) and lower hematopoietic comorbidity index (median: 2 vs. 3) in the AZA group. The 3-year cumulative incidence of progression in the AZA and control groups was 29% vs. 33%. The protective effect of AZA on progression was limited to patients with high-risk AML/MDS (HR = 0.4, 95% CI = 0.2-0.8). This led to improved progression-free survival both in high-risk AML and MDS patients with maintenance (HR = 0.2, 95% CI = 0.1-0.6, and HR = 0.4, 95% CI = 0.2-0.9).
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4.
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.
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5.
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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External Validation of the HIGH-2-LOW Model: A Predictive Score for Venous Thromboembolism after Allogeneic Transplant
Li, A., Martens, K. L., Nguyen, D., Basom, R., Rondon, G., Jin, S., Young, E., Amos, C. I., Lee, S. J., Davis, C., et al
American journal of hematology. 2022
Abstract
In patients undergoing hematopoietic cell transplantation (HCT), venous thromboembolism (VTE) remains a serious complication that lacks validated risk assessment models (RAM) to guide thromboprophylaxis. To address this dilemma, we performed a temporal and external validation study of the recently derived HIGH-2-LOW RAM. We selected adult patients undergoing allogeneic HCT from Fred Hutchinson Cancer Research Center (FHCRC) and MD Anderson Cancer Center (MDACC). Patients who died, received anticoagulation, or did not engraft platelets by day 30 were excluded. Primary outcomes were defined as overall VTE and pulmonary embolism +/- lower-extremity deep venous thromboembolism (PE/LE-DVT) by day 180. Covariates were weighted according to the original model, except that grade 2-4 GVHD was substituted for grade 3-4. Discrimination and calibration were assessed. A total of 765 patients from FHCRC and 954 patients from MDACC were included. Incident VTE by day 180 was 5.1% at FHCRC and 6.8% at MDACC. The HIGH-2-LOW score had a c-statistic of 0.67 (0.59-0.75) for VTE and 0.75 (0.64-0.81) for PE/LE-DVT at FHCRC, and 0.62 (0.55-0.70) for VTE and 0.70 (0.56-0.83) for PE/LE-DVT at MDACC. Twenty-five percent and 23% of patients were classified as high-risk (2+ points) in the two cohorts, respectively. High vs. low-risk was associated with OR of 2.80 (1.46-5.38) for VTE and 4.21 (1.82-9.77) for PE/LE-DVT at FHCRC, and OR of 3.54 (2.12-5.91) for VTE and 6.82 (2.30-20.16) for PE-LE-DVT at MDACC. The HIGH-2-LOW RAM identified allogeneic HCT recipients at high-risk for VTE in both validation cohorts. It can improve evidence-based decision-making for thromboprophylaxis post-transplant. This article is protected by copyright. All rights reserved.
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Vorinostat combined with Busulfan, Fludarabine, and Clofarabine Conditioning Regimen for Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Acute Leukemia: Long-term Study Outcomes
Alatrash, G., Saberian, C., Bassett, R., Thall, P. F., Ledesma, C., Lu, Y., Daher, M., Valdez, B. C., Kawedia, J., Popat, U., et al
Transplantation and cellular therapy. 2022
Abstract
BACKGROUND Conditioning regimens play a major role in determining disease outcomes following allogeneic hematopoietic stem cell transplantation (allo-HSCT). The use of intravenous (IV) busulfan (Bu) as part of the conditioning chemotherapy has been shown to be effective in controlling disease relapse. However, disease relapse remains a major cause of death following allo-HSCT. OBJECTIVE To determine the long-term outcomes of vorinostat with IV Bu plus dual nucleoside analogs clofarabine (Clo) and fludarabine (Flu) in the conditioning regimen for patients undergoing allo-HSCT. STUDY DESIGN This was a rapid dose escalation phase I/II study designed to determine whether the addition of vorinostat would improve the efficacy of standard IV Bu Flu Clo conditioning regimen. This report presents the long-term disease outcomes of this combination in 68 patients with high risk leukemia, including 31 (46%) with acute lymphoblastic leukemia (ALL) and 37 (54%) with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). RESULTS Fifty-eight patients (85%) were in morphologic complete remission at time of transplant and 38 patients (56%) received matched unrelated donor grafts. Over the median follow up of 37.6 months, among the 68 patients, 29 (43%) died, and the non-relapse mortality (NRM) rate was 22% (n=15). Median overall survival (OS) and median NRM were not reached. Nineteen patients (28%) experienced disease progression. Median PFS was 36.8 months. Thirty-seven patients (57%) developed grade 2-4 acute GVHD and 20 patients (31%) developed chronic GVHD. CONCLUSION Our results suggest a lack of benefit from adding a short course of vorinostat to IV Bu/Flu/Clo conditioning regimen for leukemia patients undergoing allo- HSCT.
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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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10.
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.