Effect of rabbit ATG PK on outcomes after TCR-αβ/CD19–depleted pediatric haploidentical HCT for hematologic malignancy

•Nonoptimal rATG exposure increases nonrelapse mortality, relapse, and chronic GVHD and worsens DFS in pediatric AB-TCD haploidentical HCT.•Targeting rATG dosing to a predicted exposure may improve immune reconstitution and preserve graft-versus-leukemia. [Display omitted] We hypothesized that the i...

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Published in:Blood advances 2024-12, Vol.8 (23), p.6003-6014
Main Authors: Dvorak, Christopher C., Long-Boyle, Janel R., Holbrook-Brown, Lucia, Abdel-Azim, Hisham, Bertaina, Alice, Vatsayan, Anant, Talano, Julie-An, Bunin, Nancy, Anderson, Eric, Flower, Allyson, Lalefar, Nahal, Higham, Christine S., Kapoor, Neena, Klein, Orly, Odinakachukwu, Maryanne C., Cho, Soohee, Jacobsohn, David A., Collier, Willem, Pulsipher, Michael A.
Format: Article
Language:English
Subjects:
Adolescent
Adult
Animals
Antigens, CD19 - immunology
Antilymphocyte Serum - therapeutic use
Child
Child, Preschool
Female
Hematologic Neoplasms - therapy
Hematopoietic Stem Cell Transplantation - methods
Humans
Infant
Male
Rabbits
Receptors, Antigen, T-Cell, alpha-beta
Transplantation
Transplantation, Haploidentical
Treatment Outcome
Young Adult
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container_end_page 6014
container_issue 23
container_start_page 6003
container_title Blood advances
container_volume 8
creator Dvorak, Christopher C.
Long-Boyle, Janel R.
Holbrook-Brown, Lucia
Abdel-Azim, Hisham
Bertaina, Alice
Vatsayan, Anant
Talano, Julie-An
Bunin, Nancy
Anderson, Eric
Flower, Allyson
Lalefar, Nahal
Higham, Christine S.
Kapoor, Neena
Klein, Orly
Odinakachukwu, Maryanne C.
Cho, Soohee
Jacobsohn, David A.
Collier, Willem
Pulsipher, Michael A.
description •Nonoptimal rATG exposure increases nonrelapse mortality, relapse, and chronic GVHD and worsens DFS in pediatric AB-TCD haploidentical HCT.•Targeting rATG dosing to a predicted exposure may improve immune reconstitution and preserve graft-versus-leukemia. [Display omitted] We hypothesized that the inferior disease-free survival (DFS) seen in older patients who underwent αβ-T-cell/CD19–depleted (AB-TCD) haploidentical hematopoietic cell transplantation (HCT) for hematologic malignancies is caused by excessive exposure to rabbit antithymocyte globulin (rATG; Thymoglobulin). Between 2015 and 2023, 163 patients with a median age of 13 years (range, 0.4-27.4) underwent AB-TCD haploidentical HCT for the treatment of acute lymphoblastic leukemia (n = 98), acute myeloid leukemia/myelodysplastic syndrome (n = 49), or other malignancies (n = 16) at 9 centers in 2 prospective trials. Exposures to rATG before and after HCT were predicted using a validated pharmacokinetic model. Receiver operating characteristic curves were used to identify the optimal target windows for rATG exposure in terms of outcomes. We identified 4 quadrants of rATG exposure, namely quadrant 1 (n = 52) with a high pre-HCT area under curve (AUC; ≥50 arbitrary units [AU] per day per milliliter) and a low post-HCT AUC (
doi_str_mv 10.1182/bloodadvances.2024012670
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[Display omitted] We hypothesized that the inferior disease-free survival (DFS) seen in older patients who underwent αβ-T-cell/CD19–depleted (AB-TCD) haploidentical hematopoietic cell transplantation (HCT) for hematologic malignancies is caused by excessive exposure to rabbit antithymocyte globulin (rATG; Thymoglobulin). Between 2015 and 2023, 163 patients with a median age of 13 years (range, 0.4-27.4) underwent AB-TCD haploidentical HCT for the treatment of acute lymphoblastic leukemia (n = 98), acute myeloid leukemia/myelodysplastic syndrome (n = 49), or other malignancies (n = 16) at 9 centers in 2 prospective trials. Exposures to rATG before and after HCT were predicted using a validated pharmacokinetic model. Receiver operating characteristic curves were used to identify the optimal target windows for rATG exposure in terms of outcomes. We identified 4 quadrants of rATG exposure, namely quadrant 1 (n = 52) with a high pre-HCT area under curve (AUC; ≥50 arbitrary units [AU] per day per milliliter) and a low post-HCT AUC (&lt;12 AU per day per liter); quadrant 2 (n = 47) with a low pre- and post-HCT AUC; quadrant 3 (n = 13) with a low pre-HCT and a high post-HCT AUC; and quadrant 4 (n = 51) with a high pre- and post-HCT AUC. Quadrant 1 had a 3-year DFS of 86.5%, quadrant 2 had a DFS of 64.6%, quadrant 3 had a DFS of 32.9%, and for quadrant 4 it was 48.2%. An adjusted regression analysis demonstrated additional factors that were associated with an increased hazard for worse DFS, namely minimal residual disease (MRD) positivity and cytomegalovirus (CMV) R+/D− serostatus. Nonoptimal rATG exposure exhibited the strongest effect in unadjusted and adjusted (MRD status or CMV serostatus) analyses. High exposure to rATG after HCT was 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. 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All other rights reserved. 2024 The American Society of Hematology</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><orcidid>0000-0003-3665-3102 ; 0000-0002-3729-436X ; 0000-0003-3030-8420 ; 0000-0002-6146-3952 ; 0000-0003-2993-0490 ; 0000-0001-6160-2791 ; 0000-0001-6210-2262 ; 0000-0003-1091-2567</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC11629297/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S247395292400449X$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,3549,27924,27925,45780,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39042892$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Dvorak, Christopher C.</creatorcontrib><creatorcontrib>Long-Boyle, Janel R.</creatorcontrib><creatorcontrib>Holbrook-Brown, Lucia</creatorcontrib><creatorcontrib>Abdel-Azim, Hisham</creatorcontrib><creatorcontrib>Bertaina, Alice</creatorcontrib><creatorcontrib>Vatsayan, Anant</creatorcontrib><creatorcontrib>Talano, Julie-An</creatorcontrib><creatorcontrib>Bunin, Nancy</creatorcontrib><creatorcontrib>Anderson, Eric</creatorcontrib><creatorcontrib>Flower, Allyson</creatorcontrib><creatorcontrib>Lalefar, Nahal</creatorcontrib><creatorcontrib>Higham, Christine S.</creatorcontrib><creatorcontrib>Kapoor, Neena</creatorcontrib><creatorcontrib>Klein, Orly</creatorcontrib><creatorcontrib>Odinakachukwu, Maryanne C.</creatorcontrib><creatorcontrib>Cho, Soohee</creatorcontrib><creatorcontrib>Jacobsohn, David A.</creatorcontrib><creatorcontrib>Collier, Willem</creatorcontrib><creatorcontrib>Pulsipher, Michael A.</creatorcontrib><title>Effect of rabbit ATG PK on outcomes after TCR-αβ/CD19–depleted pediatric haploidentical HCT for hematologic malignancy</title><title>Blood advances</title><addtitle>Blood Adv</addtitle><description>•Nonoptimal rATG exposure increases nonrelapse mortality, relapse, and chronic GVHD and worsens DFS in pediatric AB-TCD haploidentical HCT.•Targeting rATG dosing to a predicted exposure may improve immune reconstitution and preserve graft-versus-leukemia. [Display omitted] We hypothesized that the inferior disease-free survival (DFS) seen in older patients who underwent αβ-T-cell/CD19–depleted (AB-TCD) haploidentical hematopoietic cell transplantation (HCT) for hematologic malignancies is caused by excessive exposure to rabbit antithymocyte globulin (rATG; Thymoglobulin). Between 2015 and 2023, 163 patients with a median age of 13 years (range, 0.4-27.4) underwent AB-TCD haploidentical HCT for the treatment of acute lymphoblastic leukemia (n = 98), acute myeloid leukemia/myelodysplastic syndrome (n = 49), or other malignancies (n = 16) at 9 centers in 2 prospective trials. Exposures to rATG before and after HCT were predicted using a validated pharmacokinetic model. Receiver operating characteristic curves were used to identify the optimal target windows for rATG exposure in terms of outcomes. We identified 4 quadrants of rATG exposure, namely quadrant 1 (n = 52) with a high pre-HCT area under curve (AUC; ≥50 arbitrary units [AU] per day per milliliter) and a low post-HCT AUC (&lt;12 AU per day per liter); quadrant 2 (n = 47) with a low pre- and post-HCT AUC; quadrant 3 (n = 13) with a low pre-HCT and a high post-HCT AUC; and quadrant 4 (n = 51) with a high pre- and post-HCT AUC. Quadrant 1 had a 3-year DFS of 86.5%, quadrant 2 had a DFS of 64.6%, quadrant 3 had a DFS of 32.9%, and for quadrant 4 it was 48.2%. An adjusted regression analysis demonstrated additional factors that were associated with an increased hazard for worse DFS, namely minimal residual disease (MRD) positivity and cytomegalovirus (CMV) R+/D− serostatus. Nonoptimal rATG exposure exhibited the strongest effect in unadjusted and adjusted (MRD status or CMV serostatus) analyses. High exposure to rATG after HCT was 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. 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[Display omitted] We hypothesized that the inferior disease-free survival (DFS) seen in older patients who underwent αβ-T-cell/CD19–depleted (AB-TCD) haploidentical hematopoietic cell transplantation (HCT) for hematologic malignancies is caused by excessive exposure to rabbit antithymocyte globulin (rATG; Thymoglobulin). Between 2015 and 2023, 163 patients with a median age of 13 years (range, 0.4-27.4) underwent AB-TCD haploidentical HCT for the treatment of acute lymphoblastic leukemia (n = 98), acute myeloid leukemia/myelodysplastic syndrome (n = 49), or other malignancies (n = 16) at 9 centers in 2 prospective trials. Exposures to rATG before and after HCT were predicted using a validated pharmacokinetic model. Receiver operating characteristic curves were used to identify the optimal target windows for rATG exposure in terms of outcomes. We identified 4 quadrants of rATG exposure, namely quadrant 1 (n = 52) with a high pre-HCT area under curve (AUC; ≥50 arbitrary units [AU] per day per milliliter) and a low post-HCT AUC (&lt;12 AU per day per liter); quadrant 2 (n = 47) with a low pre- and post-HCT AUC; quadrant 3 (n = 13) with a low pre-HCT and a high post-HCT AUC; and quadrant 4 (n = 51) with a high pre- and post-HCT AUC. Quadrant 1 had a 3-year DFS of 86.5%, quadrant 2 had a DFS of 64.6%, quadrant 3 had a DFS of 32.9%, and for quadrant 4 it was 48.2%. An adjusted regression analysis demonstrated additional factors that were associated with an increased hazard for worse DFS, namely minimal residual disease (MRD) positivity and cytomegalovirus (CMV) R+/D− serostatus. Nonoptimal rATG exposure exhibited the strongest effect in unadjusted and adjusted (MRD status or CMV serostatus) analyses. High exposure to rATG after HCT was 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. These trials were registered at www.ClinicalTrials.gov as #NCT02646839 and #NCT04337515.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>39042892</pmid><doi>10.1182/bloodadvances.2024012670</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0003-3665-3102</orcidid><orcidid>https://orcid.org/0000-0002-3729-436X</orcidid><orcidid>https://orcid.org/0000-0003-3030-8420</orcidid><orcidid>https://orcid.org/0000-0002-6146-3952</orcidid><orcidid>https://orcid.org/0000-0003-2993-0490</orcidid><orcidid>https://orcid.org/0000-0001-6160-2791</orcidid><orcidid>https://orcid.org/0000-0001-6210-2262</orcidid><orcidid>https://orcid.org/0000-0003-1091-2567</orcidid><oa>free_for_read</oa></addata></record>
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2473-9537
2473-9537
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source PubMed Central Free; Elsevier ScienceDirect Journals
subjects Adolescent
Adult
Animals
Antigens, CD19 - immunology
Antilymphocyte Serum - therapeutic use
Child
Child, Preschool
Female
Hematologic Neoplasms - therapy
Hematopoietic Stem Cell Transplantation - methods
Humans
Infant
Male
Rabbits
Receptors, Antigen, T-Cell, alpha-beta
Transplantation
Transplantation, Haploidentical
Treatment Outcome
Young Adult
title Effect of rabbit ATG PK on outcomes after TCR-αβ/CD19–depleted pediatric haploidentical HCT for hematologic malignancy
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