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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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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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Impact of autologous stem cell transplantation on long term renal function and associated progression-free and overall survival in multiple myeloma
Abudayyeh, A., Lin, H., Mamlouk, O., Abdelrahim, M., Saliba, R., Rondon, G., Martinez, C. S., Delgado, R., Page, V., Rajasekaran, A., et al
Leukemia & lymphoma. 2020;:1-11
Abstract
The long-term impact of Autologous hematopietic stem cell transplantation (ASCT) on renal function, and the impact of renal function on progression-free survival (PFS) and overall survival (OS) in patients with multiple myeloma are not known. We retrospectively reviewed the records of 885 patients at our institution. We used linear mixed effect models to study the change in estimated glomerular filtration rate (eGFR) and a joint model approach to assess associations between the eGFR, PFS and OS. Sensitivity analyses were conducted at days 0, 100, 180, and 365 post-SCT. eGFR post-ASCT was significantly lower than at day 0 but stabilized at approximately 80?mL/min/1.73?m(2). There was no association between eGFR and PFS or OS.; However, relapsed disease and ISS stage were associated with shorter PFS and OS. This data suggests that although there is a modest decline in eGFR post-ASCT, it is not associated with an adverse impact on PFS or OS. KEY POINTS Advanced MM stage at diagnosis was associated with reduced eGFR at all stages of chronic kidney disease. eGFR was not associated with PFS or OS in any of the analyses, but disease-related factors prior to ASCT were all associated with reduced eGFR, PFS and OS. ASCT did not adversely impact kidney function and mitigated the risk of CKD on outcomes in MM.
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Fracture risk prediction using FRAX in patients following hematopoietic stem cell transplantation
Pundole, X., Murphy, W. A., Ebede, C. C., Karim, E., Manocha, S., Don-Pedro, D., Rondon, G., Leung, C. H., Liu, S., Du, X. L., et al
Archives of osteoporosis. 2018;13(1):38
Abstract
We aimed to study the utility of the FRAX tool in predicting fractures in patient's receiving a hematopoietic stem cell transplantation (HSCT). Our results indicate that the FRAX tool has modest fracture predictive ability in patients greater than 50 years of age at the time of HSCT. PURPOSE Identifying patients at high risk of osteoporotic fractures following HSCT is challenging. We aimed to evaluate the utility of the FRAX tool at the time of HSCT in predicting fractures following transplant. METHODS We conducted a retrospective chart review of adults (> 18 years) who underwent HSCT at MD Anderson Cancer Center from January 1, 2001, to December 31, 2010, and were followed until December 31, 2013, to identify osteoporotic fractures. Multivariate Cox regression models were built using FRAX score thresholds of low risk < 10%, medium risk 10 to 20%, and high risk > 20% probability of osteoporotic fracture. RESULTS We identified 5170 patients who had undergone HSCT, 10% of whom developed an osteoporotic fracture during a median follow-up of 3.2 years. In patients > 65 years of age, those with medium risk (hazard ratio (HR) 2.38, 95% confidence interval (CI) 1.27-4.47) and high risk (HR 3.41, 95% CI 1.73-6.75) had a greater probability of developing an osteoporotic fracture compared to those at low risk. Similar trends were seen in patients 50 to 65 years of age. CONCLUSIONS In patients greater than 50 years, the FRAX tool has modest predictive ability and could be used to aid in preventive treatment decision-making at the time of transplant.
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Symptomatic BK Virus Infection Is Associated With Kidney Function Decline and Poor Overall Survival in Allogeneic Hematopoietic Stem Cell Recipients
Abudayyeh, A., Hamdi, A., Lin, H., Abdelrahim, M., Rondon, G., Andersson, B. S., Afrough, A., Martinez, C. S., Tarrand, J. J., Kontoyiannis, D. P., et al
American Journal of Transplantation. 2016;16(5):1492-502
Abstract
Nephropathy due to BK virus (BKV) infection is an evolving challenge in patients undergoing hematopoietic stem cell transplantation (HSCT). We hypothesized that BKV infection was a marker of kidney function decline and a poor prognostic factor in HSCT recipients who experience this complication. In this retrospective study, we analyzed all patients who underwent their first allogeneic HSCT at our institution between 2004 and 2012. We evaluated the incidence of persistent kidney function decline, which was defined as a confirmed reduction in estimated glomerular filtration rate of at least 25% from baseline using the Chronic Kidney Disease Epidemiology equation. Cox proportional hazard regression was used to model the cause-specific hazard of kidney function decline, and the Fine-Gray method was used to account for the competing risks of death. Among 2477 recipients of a first allogeneic HSCT, BK viruria was detected in 25% (n = 629) and kidney function decline in 944 (38.1%). On multivariate analysis, after adjusting for age, sex, acute graft-versus-host disease (GVHD), chronic GVHD, preparative conditioning regimen, and graft source, BK viruria remained a significant risk factor for kidney function decline (p < 0.001). In addition, patients with BKV infection and kidney function decline experienced worse overall survival. After allogeneic HSCT, BKV infection was strongly and independently associated with subsequent kidney function decline and worse patient survival after HSCT. © Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.