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Your search keyword '"Lalefar, Nahal R."' showing total 12 results
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12 results on '"Lalefar, Nahal R."'

1. Comparison of total body irradiation versus non-total body irradiation containing regimens for de novo acute myeloid leukemia in children

Author

Dandoy, Christopher E, Davies, Stella M, Ahn, Kwang Woo, He, Yizeng, Kolb, Anders E, Levine, John, Bo-Subait, Stephanie, Abdel-Azim, Hisham, Bhatt, Neel, Chewing, Joseph, Gadalla, Shahinaz, Gloude, Nicholas, Hayashi, Robert, Lalefar, Nahal R, Law, Jason, MacMillan, Margaret, O’Brien, Tracy, Prestidge, Timothy, Sharma, Akshay, Shaw, Peter, Winestone, Lena, and Eapen, Mary

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Clinical Sciences, Hematology, Traumatic Brain Injury (TBI), Traumatic Head and Spine Injury, Physical Injury - Accidents and Adverse Effects, Brain Disorders, Transplantation, Rare Diseases, Pediatric, Cancer, Busulfan, Child, Cyclophosphamide, Graft vs Host Disease, Hematopoietic Stem Cell Transplantation, Humans, Leukemia, Myeloid, Acute, Retrospective Studies, Transplantation Conditioning, Whole-Body Irradiation, Cardiorespiratory Medicine and Haematology, Immunology, Cardiovascular medicine and haematology
Abstract

With limited data comparing hematopoietic cell transplant outcomes between myeloablative total body irradiation (TBI) containing and non-TBI regimens in children with de novo acute myeloid leukemia, the aim of this study was to compare transplant-outcomes between these regimens. Cox regression models were used to compare transplant-outcomes after TBI and non-TBI regimens in 624 children transplanted between 2008 and 2016. Thirty two percent (n=199) received TBI regimens whereas 68% (n=425) received non-TBI regimens. Five-year non-relapse mortality was higher with TBI regimens (22% vs. 11%, p

Published
2021

2. Pathobiological signatures of dysbiotic lung injury in pediatric patients undergoing stem cell transplantation

Author

Zinter, Matt S., Dvorak, Christopher C., Mayday, Madeline Y., Reyes, Gustavo, Simon, Miriam R., Pearce, Emma M., Kim, Hanna, Shaw, Peter J., Rowan, Courtney M., Auletta, Jeffrey J., Martin, Paul L., Godder, Kamar, Duncan, Christine N., Lalefar, Nahal R., Kreml, Erin M., Hume, Janet R., Abdel-Azim, Hisham, Hurley, Caitlin, Cuvelier, Geoffrey D. E., Keating, Amy K., Qayed, Muna, Killinger, James S., Fitzgerald, Julie C., Hanna, Rabi, Mahadeo, Kris M., Quigg, Troy C., Satwani, Prakash, Castillo, Paul, Gertz, Shira J., Moore, Theodore B., Hanisch, Benjamin, Abdel-Mageed, Aly, Phelan, Rachel, Davis, Dereck B., Hudspeth, Michelle P., Yanik, Greg A., Pulsipher, Michael A., Sulaiman, Imran, Segal, Leopoldo N., Versluys, Birgitta A., Lindemans, Caroline A., Boelens, Jaap J., and DeRisi, Joseph L.

Abstract

Hematopoietic cell transplantation (HCT) uses cytotoxic chemotherapy and/or radiation followed by intravenous infusion of stem cells to cure malignancies, bone marrow failure and inborn errors of immunity, hemoglobin and metabolism. Lung injury is a known complication of the process, due in part to disruption in the pulmonary microenvironment by insults such as infection, alloreactive inflammation and cellular toxicity. How microorganisms, immunity and the respiratory epithelium interact to contribute to lung injury is uncertain, limiting the development of prevention and treatment strategies. Here we used 278 bronchoalveolar lavage (BAL) fluid samples to study the lung microenvironment in 229 pediatric patients who have undergone HCT treated at 32 children’s hospitals between 2014 and 2022. By leveraging paired microbiome and human gene expression data, we identified high-risk BAL compositions associated with in-hospital mortality (P= 0.007). Disadvantageous profiles included bacterial overgrowth with neutrophilic inflammation, microbiome contraction with epithelial fibroproliferation and profound commensal depletion with viral and staphylococcal enrichment, lymphocytic activation and cellular injury, and were replicated in an independent cohort from the Netherlands (P= 0.022). In addition, a broad array of previously occult pathogens was identified, as well as a strong link between antibiotic exposure, commensal bacterial depletion and enrichment of viruses and fungi. Together these lung–immune system–microorganism interactions clarify the important drivers of fatal lung injury in pediatric patients who have undergone HCT. Further investigation is needed to determine how personalized interpretation of heterogeneous pulmonary microenvironments may be used to improve pediatric HCT outcomes.

Published
2024
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3. Comparison of total body irradiation versus non-total body irradiation containing regimens for de novo acute myeloid leukemia in children

Author

Dandoy, Christopher E, Davies, Stella M, Woo Ahn, Kwang, He, Yizeng, Kolb, Anders E, Levine, John, Bo-Subait, Stephanie, Abdel-Azim, Hisham, Bhatt, Neel, Chewning, Joseph, Gadalla, Shahinaz, Gloude, Nicholas, Hayashi, Robert, Lalefar, Nahal R, Law, Jason, MacMillan, Margaret, O'Brien, Tracy, Prestidge, Timothy, Sharma, Akshay, Shaw, Peter, Winestone, Lena, and Eapen, Mary

Subjects
Myeloid, Physical Injury - Accidents and Adverse Effects, Transplantation Conditioning, Immunology, Graft vs Host Disease, Acute, Traumatic Brain Injury (TBI), Cardiorespiratory Medicine and Haematology, Article, Rare Diseases, Humans, Child, Busulfan, Cyclophosphamide, Traumatic Head and Spine Injury, Cancer, Retrospective Studies, Pediatric, Transplantation, Leukemia, Hematopoietic Stem Cell Transplantation, Hematology, Brain Disorders, nervous system diseases, Leukemia, Myeloid, Acute, nervous system, Whole-Body Irradiation
Abstract

With limited data comparing hematopoietic cell transplant outcomes between myeloablative total body irradiation (TBI) containing and non-TBI regimens in children with de novo acute myeloid leukemia, the aim of this study was to compare transplant-outcomes between these regimens. Cox regression models were used to compare transplant-outcomes after TBI and non-TBI regimens in 624 children transplanted between 2008 and 2016. Thirty two percent (n=199) received TBI regimens whereas 68% (n=425) received non-TBI regimens. Five-year non-relapse mortality was higher with TBI regimens (22% vs. 11%, P

Published
2020

4. Comparable Outcomes for Matched and Mismatched Unrelated Donor (URD) Transplantation with the Addition of Abatacept to Standard Graft Versus Host Disease Prophylaxis

Author

Qayed, Muna, primary, Watkins, Benjamin, additional, Gillespie, Scott, additional, Bratrude, Brandi, additional, Betz, Kayla, additional, Suessmuth, Yvonne, additional, Yu, Alison, additional, Furlan, Scott N, additional, Zhang, Chao, additional, Mccracken, Courtney, additional, Cribbin, Kayla, additional, Choi, Sung, additional, Davis, Jeffrey H, additional, Duncan, Christine, additional, Giller, Roger H., additional, Grimley, Michael S., additional, Harris, Andrew C, additional, Jacobsohn, David A., additional, Yanik, Gregory A., additional, Rogatko, Andre, additional, Tighiouart, Mourad, additional, Bresee, Catherine, additional, Kim, Sungjin, additional, Lalefar, Nahal R, additional, Rhodes, James, additional, Norkin, Maxim, additional, Farhadfar, Nosha, additional, Shenoy, Shalini, additional, Petrovic, Aleksandra, additional, Schultz, Kirk R., additional, Pulsipher, Mike A., additional, Waller, Edmund K., additional, Blazar, Bruce R., additional, Langston, Amelia A., additional, Kean, Leslie S., additional, and Horan, John, additional

Published
2021
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5. Incidence and Outcomes of Patients with Thrombotic Microangiopathy after Transplant: Results of Prospective Screening through a Multi-Institutional Collaborative

Author

Dandoy, Christopher E, primary, Rotz, Seth R., additional, Alonso, Priscila Badia, additional, Lane, Adam, additional, Higham, Christine, additional, Dvorak, Christopher C., additional, Duncan, Christine N., additional, Schoettler, Michelle Long, additional, Lehmann, Leslie E., additional, Cancio, Maria, additional, Killinger, James, additional, Davila, Blachy, additional, Phelan, Rachel, additional, Prasad, Swathi, additional, Mahadeo, Kris Michael, additional, Khazal, Sajad J, additional, Lalefar, Nahal R, additional, Vissa, Madhav, additional, Klunk, Anna, additional, Bhatla, Deepika, additional, Gloude, Nicholas J., additional, Anderson, Eric Jon, additional, Huo, Jeffrey S., additional, Roehrs, Philip A., additional, Auletta, Jeffery J., additional, Davies, Stella M., additional, Chima, Ranjit, additional, and Jodele, Sonata, additional

Published
2020
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6. T Cell Costimulation Blockade with CTLA4-Ig (Abatacept) for Acute Gvhd Prevention in HLA Matched and Mismatched Unrelated Donor Transplantation: Results of the First Phase 2 Trial

Author

Watkins, Ben K., primary, Qayed, Muna, additional, Bratrude, Brandi, additional, Betz, Kayla, additional, Sinclair, Shauna, additional, Suessmuth, Yvonne, additional, Rhodes, James, additional, Yu, Alison, additional, Cribbin, Kayla, additional, Dean, Carol, additional, Narayan, Alexandria, additional, Hunt, Daniel, additional, Schwartz, Naomi, additional, Hebert, Kyle, additional, Pasquini, Marcelo C., additional, Rogatko, Andre, additional, Tighiouart, Mourad, additional, Kim, Sungjin, additional, Bresee, Catherine, additional, Banks, Anglea, additional, Gillespie, Scott, additional, Choi, Sung, additional, Davis, Jeffrey H, additional, Duncan, Chrstine, additional, Giller, Roger, additional, Grimley, Michael S., additional, Harris, Andrew C, additional, Jacobsohn, David A., additional, Lalefar, Nahal R, additional, Norkin, Maxim, additional, Pulsipher, Michael A., additional, Shenoy, Shalini, additional, Petrovic, Aleksandra, additional, Schultz, Kirk R., additional, Blazar, Bruce R., additional, Langston, Amelia A., additional, Horan, John, additional, and Kean, Leslie S., additional

Published
2019
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7. 33 - Comparable Outcomes for Matched and Mismatched Unrelated Donor (URD) Transplantation with the Addition of Abatacept to Standard Graft Versus Host Disease Prophylaxis

Author

Qayed, Muna, Watkins, Benjamin, Gillespie, Scott, Bratrude, Brandi, Betz, Kayla, Suessmuth, Yvonne, Yu, Alison, Furlan, Scott N, Zhang, Chao, Mccracken, Courtney, Cribbin, Kayla, Choi, Sung, Davis, Jeffrey H, Duncan, Christine, Giller, Roger H., Grimley, Michael S., Harris, Andrew C, Jacobsohn, David A., Yanik, Gregory A., Rogatko, Andre, Tighiouart, Mourad, Bresee, Catherine, Kim, Sungjin, Lalefar, Nahal R, Rhodes, James, Norkin, Maxim, Farhadfar, Nosha, Shenoy, Shalini, Petrovic, Aleksandra, Schultz, Kirk R., Pulsipher, Mike A., Waller, Edmund K., Blazar, Bruce R., Langston, Amelia A., Kean, Leslie S., and Horan, John

Published
2021
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8. Wnt3a nanodisks promote ex vivo expansion of hematopoietic stem and progenitor cells

Author

Lalefar, Nahal R., Witkowski, Andrzej, Simonsen, Jens Bæk, Ryan, Robert O., Lalefar, Nahal R., Witkowski, Andrzej, Simonsen, Jens Bæk, and Ryan, Robert O.

Abstract

Background: Wnt proteins modulate development, stem cell fate and cancer through interactions with cell surface receptors. Wnts are cysteine-rich, glycosylated, lipid modified, two domain proteins that are prone to aggregation. The culprit responsible for this behavior is a covalently bound palmitoleoyl moiety in the N-terminal domain. Results: By combining murine Wnt3a with phospholipid and apolipoprotein A-I, ternary complexes termed nanodisks (ND) were generated. ND-associated Wnt3a is soluble in the absence of detergent micelles and gel filtration chromatography revealed that Wnt3a co-elutes with ND. In signaling assays, Wnt3a ND induced β-catenin stabilization in mouse fibroblasts as well as hematopoietic stem and progenitor cells (HSPC). Prolonged exposure of HSPC to Wnt3a ND stimulated proliferation and expansion of Lin- Sca-1+ c-Kit+ cells. Surprisingly, ND lacking Wnt3a contributed to Lin- Sca-1+ c-Kit+ cell expansion, an effect that was not mediated through β-catenin. Conclusions: The data indicate Wnt3a ND constitute a water-soluble transport vehicle capable of promoting ex vivo expansion of HSPC.

Published
2016

11. Effect of Rabbit ATG PK on Outcomes after TCR-αβ/CD19-depleted Pediatric Haploidentical HCT for Hematologic Malignancy.

Author

Dvorak CC, Long-Boyle JR, Holbrook-Brown L, Abdel-Azim H, Bertaina A, Vatsayan A, Talano JA, Bunin NJ, Anderson EJ, Flower A, Lalefar NR, Higham CS, Kapoor N, Klein O, Odinakachukwu MC, Cho S, Jacobsohn DA, Collier W, and Pulsipher MA

Abstract

We hypothesized that inferior disease-free survival (DFS) seen in older patients undergoing αβ/CD19-T-cell depleted (AB-TCD) haploidentical hematopoietic cell transplantation (HCT) for patients with hematologic malignancies was due to excessive exposure to rabbit antithymocyte globulin (rATG; Thymoglobulin®). Between 2015-2023, 163 patients with a median age of 13 years (range, 0.4-27.4) underwent AB-TCD haploidentical HCT for treatment of ALL (n=98), AML/MDS (n=49), or other malignancies (n=16) at nine centers on two prospective trials. Exposures of rATG pre- and post-HCT were predicted with a validated pharmacokinetic (PK) model. ROC curves were used to identify optimal target windows of rATG exposure related to outcomes. We identified four quadrants of rATG exposure - quadrant 1 (n=52): high pre-HCT AUC (≥50 AU*day/mL) and low post-HCT (<12 AU*day/L); quadrant 2 (n=47): both low pre-HCT and post-HCT AUCs, quadrant 3 (n=13): low pre-HCT AUC and high post-HCT, and quadrant 4 (n=51): both high pre- and post-HCT AUCs. Quadrant 1 had a 3-year DFS of 86.5% (95% CI, 76.3-96.7%), compared to quadrant 2 (64.6%; 95% CI, 49.1-80.1%), quadrant 3 (32.9%; 95% CI, 0.1-80.5%) or quadrant 4 (48.2%; 95% CI, 22.1-63.3%) (p<0.001). Adjusted regression analysis demonstrated additional factors associated with increased hazard for worse DFS: MRD-positivity (HR=2.45; 1.36-4.41; p=0.003) and CMV R+/D- serostatus (HR=3.33; 1.8-6.16; p<0.001). Non-optimal rATG exposure exhibited the strongest effect in unadjusted (HR=4.24; 1.79-10.03; p=0.001) and adjusted (MRD status or CMV serostatus) analyses (HR=3.84, 1.63-9.05; p=0.002). High exposure to rATG post-HCT is associated with inferior DFS following AB-TCD haploidentical HCT for pediatric patients with hematologic malignancies. Model-based dosing of rATG to achieve optimal exposure may improve DFS. Clinical trials: NCT02646839 & NCT04337515., (Copyright © 2024 American Society of Hematology.)

Published
2024
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12. Pulmonary microbiome and transcriptome signatures reveal distinct pathobiologic states associated with mortality in two cohorts of pediatric stem cell transplant patients.

Author

Zinter MS, Dvorak CC, Mayday MY, Reyes G, Simon MR, Pearce EM, Kim H, Shaw PJ, Rowan CM, Auletta JJ, Martin PL, Godder K, Duncan CN, Lalefar NR, Kreml EM, Hume JR, Abdel-Azim H, Hurley C, Cuvelier GDE, Keating AK, Qayed M, Killinger JS, Fitzgerald JC, Hanna R, Mahadeo KM, Quigg TC, Satwani P, Castillo P, Gertz SJ, Moore TB, Hanisch B, Abdel-Mageed A, Phelan R, Davis DB, Hudspeth MP, Yanik GA, Pulsipher MA, Sulaiman I, Segal LN, Versluys BA, Lindemans CA, Boelens JJ, and DeRisi JL

Abstract

Lung injury is a major determinant of survival after pediatric hematopoietic cell transplantation (HCT). A deeper understanding of the relationship between pulmonary microbes, immunity, and the lung epithelium is needed to improve outcomes. In this multicenter study, we collected 278 bronchoalveolar lavage (BAL) samples from 229 patients treated at 32 children's hospitals between 2014-2022. Using paired metatranscriptomes and human gene expression data, we identified 4 patient clusters with varying BAL composition. Among those requiring respiratory support prior to sampling, in-hospital mortality varied from 22-60% depending on the cluster (p=0.007). The most common patient subtype, Cluster 1, showed a moderate quantity and high diversity of commensal microbes with robust metabolic activity, low rates of infection, gene expression indicating alveolar macrophage predominance, and low mortality. The second most common cluster showed a very high burden of airway microbes, gene expression enriched for neutrophil signaling, frequent bacterial infections, and moderate mortality. Cluster 3 showed significant depletion of commensal microbes, a loss of biodiversity, gene expression indicative of fibroproliferative pathways, increased viral and fungal pathogens, and high mortality. Finally, Cluster 4 showed profound microbiome depletion with enrichment of Staphylococci and viruses, gene expression driven by lymphocyte activation and cellular injury, and the highest mortality. BAL clusters were modeled with a random forest classifier and reproduced in a geographically distinct validation cohort of 57 patients from The Netherlands, recapitulating similar cluster-based mortality differences (p=0.022). Degree of antibiotic exposure was strongly associated with depletion of BAL microbes and enrichment of fungi. Potential pathogens were parsed from all detected microbes by analyzing each BAL microbe relative to the overall microbiome composition, which yielded increased sensitivity for numerous previously occult pathogens. These findings support personalized interpretation of the pulmonary microenvironment in pediatric HCT, which may facilitate biology-targeted interventions to improve outcomes.

Published
2023
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