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1.
Impact of donor age and relationship on outcomes of peripheral blood haploidentical hematopoietic cell transplantation
Pruitt, A., Gao, F., De Togni, E., Cochran, H., Godbole, S., Slade, M., Abboud, R.
Bone marrow transplantation. 2023
Abstract
Here we describe a retrospective analysis of outcomes in 299 patients who underwent peripheral blood haplo-HCT with PTCy from July 2009 through May 2021 and their association with donor characteristics. Patients had mostly acute leukemias and high or very high DRI. Multivariate analyses were conducted examining OS, NRM, relapse, cytokine release syndrome, acute and chronic GVHD. Donor characteristics included age, sex, relationship, ABO status, CMV status, and HLA match grade. Our analysis revealed increasing donor age was associated with higher NRM (compared to age <30; age 30-44 HR, 1.65; P = 0.110, age >44 HR, 1.80; P = 0.056) but lower relapse risk (compared to age <30; age 30-44 HR, 0.61; P = 0.034, age > 44 HR, 0.71; P = 0.132). There were no differences in CRS, aGVHD or cGVHD. We found no difference in outcomes based on the donor-recipient relationship. No differences were found based on HLA match grade or DRB1 match status. Increasing donor age was associated with lower relapse risk but higher NRM, resulting in no difference in OS based on donor age. Other donor factors including relationship (parent/sibling/child/ maternal), CMV status, donor sex, HLA match grade, and DRB1 status were not associated with outcomes.
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2.
The Role of Allogeneic Transplant for Adult Ph+ ALL in CR1 with Complete Molecular Remission: A Retrospective Analysis
Ghobadi, A., Slade, M., Kantarjian, H. M., Alvarenga, J., Aldoss, I., Mohammed, K., Jabbour, E. J., Faramand, R. G., Shah, B. D., Locke, F. L., et al
Blood. 2022
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Editor's Choice
Abstract
Historically, Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) has been associated with poor outcomes and allogeneic hematopoietic cell transplantation (allo-HCT) is recommended in first complete remission (CR1). However, in the tyrosine kinase inhibitor (TKI) era, rapid attainment of a complete molecular remission (CMR) is associated with excellent outcomes without allo-HCT, suggesting transplant may not be required for these patients. To test this hypothesis, we retrospectively identified adult patients with Ph+ ALL treated with induction therapy including TKIs and attained CMR within 90 days of diagnosis at 5 transplant centers in the United States. We compared outcomes of those who did and did not receive allo-HCT in first remission. We identified 230 patients (Allo-HCT: 98, non-HCT: 132). The allo-HCT cohort was younger with better performance status. On multivariable analysis (MVA), allo-HCT was not associated with improved overall survival (aHR 1.05, 95% C.I. 0.63 - 1.73) or relapse-free survival (aHR: 0.86, 95% C.I. 0.54 - 1.37) compared to non-HCT treatment. Allo-HCT was associated with a lower cumulative incidence of relapse (aHR 0.32, 95% C.I. 0.17 - 0.62) but higher non-relapse mortality (aHR: 2.59, 95% C.I. 1.37 - 4.89). Propensity score matching analysis confirmed results of MVA. Comparison of reduced-intensity HCT to non-HCT showed no statistically significant difference in any of the above endpoints. In conclusion, adult patients with Ph+ ALL who achieved CMR within 90 days of starting treatment did not derive a survival benefit from allo-HCT in CR1 in this retrospective study.
PICO Summary
Population
Adults with Philadelphia chromosome-positive acute lymphoblastic leukaemia (Ph+ALL) from five centres in the USA (n=230)
Intervention
Allogeneic transplant in first remission (Allo-HCT, n=98)
Comparison
No allogeneic transplant in first remission (non-HCT, n=132)
Outcome
The allo-HCT cohort was younger with better performance status. On multivariable analysis (MVA), allo-HCT was not associated with improved overall survival (aHR 1.05, 95% C.I. 0.63 - 1.73) or relapse-free survival (aHR: 0.86, 95% C.I. 0.54 - 1.37) compared to non-HCT treatment. Allo-HCT was associated with a lower cumulative incidence of relapse (aHR 0.32, 95% C.I. 0.17 - 0.62) but higher non-relapse mortality (aHR: 2.59, 95% C.I. 1.37 - 4.89). Propensity score matching analysis confirmed results of MVA. Comparison of reduced-intensity HCT to non-HCT showed no statistically significant difference in any of the above endpoints.
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Ixazomib, lenalidomide and dexamethasone consolidation with randomized ixazomib or lenalidomide maintenance after autologous transplant in newly diagnosed multiple myeloma
Slade, M., Martin, T. G., Nathwani, N., Fiala, M. A., Rettig, M. P., Gao, F., Deol, A., Buadi, F. K., Kaufman, J. L., Hofmeister, C. C., et al
Leukemia. 2022
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The Effect of Donor Type on Outcomes in Adults with Acute Myeloid Leukemia after Reduced Intensity Hematopoietic Peripheral Blood Cell Transplant
Rashid, N., Slade, M., Abboud, R., Gao, F., DiPersio, J. F., Westervelt, P., Uy, G., Stockerl-Goldstein, K., Romee, R., Schroeder, M. A.
Transplant international : official journal of the European Society for Organ Transplantation. 2020
Abstract
We retrospectively analyzed outcomes in patients with acute myeloid leukemia (AML) receiving reduced intensity conditioning (RIC) hematopoietic stem cell transplants (HCT) from a peripheral blood (PB) source. We identified 46 haploidentical HCT (haplo), 59 matched unrelated donor HCT (MUD), and 40 matched related donor HCT (SIB) patients at a single institution. Haplo had improved overall survival (OS) when compared to MUD, HR 2.03 (p=0.01) but not SIB, HR 1.17, (p=0.61). There were no differences in relapse rates or treatment related mortality (TRM). Haplo had higher rates of acute graft versus host disease (GVHD) grade II-IV at day 180 than MUD (44% vs 25%, p=0.03) and SIB (44% vs 13% p<0.01). Rates of acute GVHD III-IV and chronic GVHD were similar among the groups. Haplo had slower engraftment rates compared to MUD with neutrophil engraftment at 87% vs 93%, (p<0.01) and platelet engraftment at 59% vs 86%, (p<0.01) at 28 days. Although patients receiving haplo had higher acute GVHD II-IV and slower engraftment, they did not have increased TRM. These data may suggest that patients receiving haplo have improved OS compared to MUD for AML patients receiving RIC transplants. This should be confirmed using a larger cohort.
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The Predicted Indirectly Recognizable HLA Epitopes (PIRCHE) Score for HLA Class I Graft-Versus-Host Disparity Is Associated with Increased Acute Graft-Versus-Host Disease in Haploidentical Transplantation with Post-Transplant Cyclophosphamide
Rimando, J., Slade, M., DiPersio, J. F., Westervelt, P., Gao, F., Liu, C., Romee, R.
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
Abstract
The Predicted Indirectly Recognizable HLA Epitopes (PIRCHE) score quantifies the number of PIRCHE between patient and donor pairs and represents an in silico measure of indirect alloreactivity. This biologic process is defined as T cell recognition of epitopes derived from mismatched, allogeneic HLA peptides that are subsequently presented by shared HLA molecules. Its association with clinical outcome has not been examined in haplo-HCT with PTCy. We hypothesized that PIRCHE scores would correlate with indirect alloreactivity and predict graft-versus-host disease (GvHD) risk and incidence of relapse after haplo-HCT with PTCy. To address this, we retrospectively analyzed 148 patients who received peripheral blood, T cell-replete haplo-HCT with PTCy at a single center between 2009 and 2016. PIRCHE scores (PS) were calculated using the PIRCHE online matching tool. PS were categorized by class and vector. The median class I graft-versus-host (GvH) PS was 11 (range, 0-56), while the median class I host-versus-graft (HvG) PS was 10 (range 0-51). The class I GvH PS was associated with increased grade II-IV aGvHD (adjusted HR or aHR 1.03 per PS unit increase; 95% CI 1.01-1.05; p=0.008) but not chronic GvHD or incidence of relapse. PIRCHE scores represent a novel strategy to predict clinical outcome in haplo-HCT. Further studies using registry data and prospective cohorts are warranted to validate these findings.
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Propensity Score Analysis of Conditioning Intensity in Peripheral Blood Haploidentical Hematopoietic Cell Transplantation
Huselton, E., Slade, M., Trinkaus, K. M., DiPersio, J. F., Westervelt, P., Romee, R.
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2018
Abstract
T-cell replete HLA-haploidentical hematopoietic cell transplantation (haplo HCT) with post-transplant cyclophosphamide was originally described using a reduced-intensity conditioning (RIC) regimen. Given that myeloablative conditioning (MAC) is more effective at preventing disease relapse, we compared outcomes of patients receiving MAC and RIC regimens. We evaluated overall survival (OS), disease free survival (DFS), relapse, non-relapse mortality (NRM), and graft versus host disease (GvHD) of 148 patients that underwent haplo HCT with either MAC (n = 61) or RIC (n = 87). Propensity score adjustment (PSA) was used to balance baseline characteristics between groups and more effectively compare outcomes based on conditioning intensity. After the PSA analysis, relapse was significantly decreased with MAC (HR 0.47, 95% CI 0.31-0.70), but was associated with higher NRM (HR 1.74, 1.13-2.67). OS and DFS were not significantly different between groups (HRs for MAC vs. RIC were 0.87, 95% CI 0.64-1.18 and 0.90, 95% CI 0.68-1.18, for OS and DFS, respectively). Rates of acute and chronic GvHD were not significantly different between groups. This analysis suggests that both MAC and RIC regimens are effective in haplo HCT and that MAC regimens may result in less relapse in selected patients. These results need to be verified in a larger registry study.
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7.
HLA epitope mismatch in haploidentical transplantation is associated with decreased relapse and delayed engraftment
Rimando, J., Slade, M., DiPersio, J. F., Westervelt, P., Gao, F., Liu, C., Romee, R.
Blood advances. 2018;2(24):3590-3601
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Editor's Choice
Abstract
HLA disparity is traditionally measured at the antigen or allele level, and its impact on haploidentical hematopoietic cell transplantation (haplo-HCT) with high-dose posttransplant cyclophosphamide (PTCy) is unclear. To the best of our knowledge, the relationship between HLA eplet-derived epitope mismatch (EM) and clinical outcome has not been examined in haplo-HCT. We retrospectively analyzed 148 patients who received a peripheral blood, T-cell-replete haplo-HCT with PTCy at a single center. HLA EM was quantified using an HLAMatchmaker-based method and was stratified by class and vector. The primary outcome was incidence of relapse. The total number of mismatched epitopes (MEs) per patient-donor pair in our patient population ranged from 0 to 51 (median, 24) in the graft-versus-host (GVH) direction and 0 to 47 (median, 24) in the host-versus-graft (HVG) direction. Higher HLA class II EM in the GVH direction was associated with a significantly reduced risk of relapse (adjusted hazard ratio [HR], 0.952 per ME; P = .002) and improved relapse-free survival (adjusted HR, 0.974 per ME; P = .020). Higher HLA class II EM in the HVG direction was associated with longer time to neutrophil (adjusted HR, 0.974 per ME; P = .013) and platelet (adjusted HR, 0.961 per ME; P = .001) engraftment. In peripheral blood haplo-HCT patients, increased HLA EM was associated with a protective effect on the risk of relapse in the GVH direction but a negative effect on time to count recovery in the HVG direction. HLA EM based on the HLA Matchmaker represents a novel strategy to predict clinical outcome in haplo-HCT.
PICO Summary
Population
Population 148 patients who received a peripheral blood, T-cell-replete haplo-HCT with high-dose posttransplant cyclophosphamide
Intervention
Intervention Measurement of epitope mismatch
Comparison
Comparison N/A
Outcome
Outcome Higher HLA class II EM in the GVH direction was associated with a significantly reduced risk of relapse and improved relapse-free survival. Higher HLA class II EM in the HVG direction was associated with longer time to neutrophil and platelet engraftment. In peripheral blood haplo-HCT patients, increased HLA EM was associated with a protective effect on the risk of relapse in the GVH direction but a negative effect on time to count recovery in the HVG direction
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8.
Untreated donor specific antibodies against HLA are associated with poor outcomes in peripheral blood haploidentical hematopoietic cell transplantation
Zou, J., Romee, R., Slade, M., Phelan, D., Keller, J., Mohanakumar, T., Grossman, B. J.
Bone Marrow Transplantation. 2017;52(6):898-901
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9.
Haploidentical Transplantation with Post-Transplantation Cyclophosphamide for High-Risk Acute Lymphoblastic Leukemia
Srour, S. A., Milton, D. R., Bashey, A., Karduss-Urueta, A., Al Malki, M. M., Romee, R., Solomon, S., Nademanee, A., Brown, S., Slade, M., et al
Biology of Blood & Marrow Transplantation. 2017;23(2):318-324
Abstract
Haploidentical transplantation performed with post-transplantation cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis has been associated with favorable outcomes for patients with acute myeloid leukemia and lymphomas. However, it remains unclear if such approach is effective for patients with acute lymphoblastic leukemia (ALL). We analyzed outcomes of 109 consecutively treated ALL patients 18 years of age and older at 5 institutions. The median age was 32 years and the median follow-up for survivors was 13 months. Thirty-two patients were in first complete remission (CR1), while the rest were beyond CR1. Neutrophil engraftment occurred in 95% of the patients. The cumulative incidences of grades II to IV and III and IV acute GVHD at day 100 after transplantation were 32% and 11%, respectively, whereas chronic GVHD, nonrelapse mortality, relapse rate, and disease-free survival (DFS) at 1 year after transplantation were 32%, 21%, 27%, and 51%, respectively. Patients in CR1 had 52% DFS at 3 years. These results suggest that haploidentical transplants performed with PTCy-based GVHD prophylaxis provide a very suitable alternative to HLA-matched transplantations for patients with ALL.
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10.
Cardiomyopathy in patients after posttransplant cyclophosphamide-based hematopoietic cell transplantation
Lin, C. J., Vader, J. M., Slade, M., DiPersio, J. F., Westervelt, P., Romee, R.
Cancer. 2017;123(10):1800-1809
Abstract
BACKGROUND The use of posttransplant cyclophosphamide (PT-Cy) has contributed significantly to the success of haploidentical hematopoietic cell transplantation (HCT). Furthermore, several studies have shown promising results in the human leukocyte antigen-matched setting. However, the use of high-dose cyclophosphamide has been associated with the development of cardiomyopathy. There is a paucity of data concerning posttransplant cardiac complications in patients undergoing PT-Cy-based HCT. METHODS A retrospective analysis of 176 patients undergoing HCT with PT-Cy was performed. The overall survival, left ventricular ejection fractions, brain natriuretic peptide levels, and cardiac comorbidities were reviewed. The associations between comorbidities and the onset of heart failure were assessed with a Cox proportional hazards model. RESULTS Pretransplant cardiomyopathy was found in 16 patients (9.1%) but had no effect on their posttransplant overall survival. Thirty-five patients (21.9%) developed posttransplant cardiomyopathy, which correlated with increased mortality, but this was not statistically different from the frequency-matched non-PT-Cy cohort. The majority of these cardiomyopathies occurred in the setting of an infectious milieu. An age greater than 60 years and an HCT comorbidity index score equal to or greater than 4 were the only risk factors that correlated with posttransplant cardiomyopathy. CONCLUSIONS The presence of pretransplant cardiomyopathy does not negatively affect overall survival for patients who undergo HCT with PT-Cy. Furthermore, cardiomyopathy in PT-Cy patients is not caused by PT-Cy but is mostly concurrent with infectious complications and is associated with reduced overall survival. Traditional cardiovascular risk factors do not fully predict the occurrence of posttransplant cardiomyopathy. Future research is required to unravel predictive factors for cardiomyopathy after PT-Cy-based HCT. Cancer 2017;123:1800-1809. © 2017 American Cancer Society.