KIR-favorable TCR-αβ/CD19-depleted haploidentical HCT in children with ALL/AML/MDS: primary analysis of the PTCTC ONC1401 trial

Michael A. Pulsipher; Kwang W. Ahn; Nancy J. Bunin; Nahal Lalefar; Eric Anderson; Allyson Flower; Mitchell S. Cairo; Julie An Talano; Sonali Chaudhury; Carrie L. Kitko; Jamie L. Duke; Dimitrios Monos; Wing Leung; Christopher C. Dvorak; Hisham Abdel-Azim

doi:10.1182/blood.2022015959

KIR-favorable TCR-αβ/CD19-depleted haploidentical HCT in children with ALL/AML/MDS: primary analysis of the PTCTC ONC1401 trial

Michael A. Pulsipher^*, Kwang W. Ahn, Nancy J. Bunin, Nahal Lalefar, Eric Anderson, Allyson Flower, Mitchell S. Cairo, Julie An Talano, Sonali Chaudhury, Carrie L. Kitko, Jamie L. Duke, Dimitrios Monos, Wing Leung, Christopher C. Dvorak, Hisham Abdel-Azim

^*Corresponding author for this work

Pediatrics

Research output: Contribution to journal › Article › peer-review

17 Scopus citations

Abstract

We performed a prospective multicenter study of T-cell receptor αβ (TCR-αβ)/CD19–depleted haploidentical hematopoietic cell transplantation (HCT) in children with acute leukemia and myelodysplastic syndrome (MDS), to determine 1-year disease-free survival (DFS) and compare 2-year outcomes with recipients of other donor cell sources. Fifty-one patients aged 0.7 to 21 years were enrolled; donors were killer immunoglobulin-like receptor (KIR) favorable based on ligand mismatch and/or high B content. The 1-year DFS was 78%. Superior 2-year DFS and overall survival (OS) were noted in patients <10 years of age, those treated with reduced toxicity conditioning (RTC) rather than myeloablative conditioning, and children with minimal residual disease <0.01% before HCT. Multivariate analysis comparing the KIR-favorable haploidentical cohort with controls showed similar DFS and OS compared with other donor cell sources. Multivariate analysis also showed a marked decrease in the risk of grades 2 to 4 and 3 to 4 acute graft versus host disease (aGHVD), chronic GVHD, and transplant-related mortality vs other donor cell sources. Ethnic and racial minorities accounted for 53% of enrolled patients, and data from a large cohort of recipients/donors screened for KIR showed that >80% of recipients had a KIR-favorable donor by our definition, demonstrating that this approach is broadly applicable to groups often unable to find donors. This prospective, multicenter study showed improved outcomes using TCR-αβ/CD19–depleted haploidentical donors using RTC for children with acute leukemia and MDS. Randomized trials comparing this approach with matched unrelated donors are warranted. This trial was registered at https://clinicaltrials.gov as #NCT02646839.

Original language	English (US)
Pages (from-to)	2556-2572
Number of pages	17
Journal	Blood
Volume	140
Issue number	24
DOIs	https://doi.org/10.1182/blood.2022015959
State	Published - Dec 15 2022

Funding

This work was supported by National Institutes of Health (NIH), National Cancer Institute (NCI) grant R01 CA181050 (NCI). Additional funding for PTCTC activities was provided by NIH, National Heart, Lung, and Blood Institute grant UG1HL069254 and a Johnny Crisstopher Children’s Charitable Foundation St. Baldrick’s Consortium Grant. Funding support for this article was provided by the NCI (R01 CA181050). Conflict-of-interest disclosure: M.A.P. has served on advisory boards for Novartis, Mesoblast, Equillium, Medexus, and Vertex; has engaged in educational activities for Novartis; and has received study support from Miltenyi (not for this trial) and Adaptive. W.L. is an employee of Miltenyi. C.C.D. has been a consultant to and served on advisory boards of Jazz Pharmaceuticals, Alexion Inc, and Omeros Corporation. J.L.D. receives royalties from Omixon. D.M. is a consultant to, owns stock options in, and receives royalties from Omixon. S.C. has served on advisory boards of AbbVie, Viacord, and Alexion. H.A.-A. received study support from Adaptive. The remaining authors declare no competing financial interests.This work was supported by National Institutes of Health (NIH), National Cancer Institute (NCI) grant R01 CA181050 (NCI). Additional funding for PTCTC activities was provided by NIH, National Heart, Lung, and Blood Institute grant UG1HL069254 and a Johnny Crisstopher Children's Charitable Foundation St. Baldrick's Consortium Grant. Funding support for this article was provided by the NCI (R01 CA181050). Contribution: M.A.P. W.L. H.A.-A. D.M. and K.W.A. conceived and designed the study; M.A.P. N.J.B. N.L. E.A. A.F. M.S.C. J.-A,T. S.C. C.L.K. J.L.D. D.M. C.C.D. and H.A.-A. provided study material or patients; M.A.P. K.W.A. N.J.B. N.L. E.A. A.F. J.-A,T. S.C. C.L.K. J.L.D. D.M. C.C.D. and H.A.-A. collected and assembled the data; M.A.P. K.W.A. D.M. C.C.D. and H.A.-A. analyzed and interpreted the data; M.A.P. K.W.A. D.M. C.C.D. and H.A.-A. wrote the manuscript; and all authors provided final approval of the manuscript.

ASJC Scopus subject areas

Biochemistry
Immunology
Hematology
Cell Biology

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10.1182/blood.2022015959

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Pulsipher, M. A., Ahn, K. W., Bunin, N. J., Lalefar, N., Anderson, E., Flower, A., Cairo, M. S., Talano, J. A., Chaudhury, S., Kitko, C. L., Duke, J. L., Monos, D., Leung, W., Dvorak, C. C., & Abdel-Azim, H. (2022). KIR-favorable TCR-αβ/CD19-depleted haploidentical HCT in children with ALL/AML/MDS: primary analysis of the PTCTC ONC1401 trial. Blood, 140(24), 2556-2572. https://doi.org/10.1182/blood.2022015959

@article{9d241a74260340f5857fdf557a4bb6f7,

title = "KIR-favorable TCR-αβ/CD19-depleted haploidentical HCT in children with ALL/AML/MDS: primary analysis of the PTCTC ONC1401 trial",

abstract = "We performed a prospective multicenter study of T-cell receptor αβ (TCR-αβ)/CD19–depleted haploidentical hematopoietic cell transplantation (HCT) in children with acute leukemia and myelodysplastic syndrome (MDS), to determine 1-year disease-free survival (DFS) and compare 2-year outcomes with recipients of other donor cell sources. Fifty-one patients aged 0.7 to 21 years were enrolled; donors were killer immunoglobulin-like receptor (KIR) favorable based on ligand mismatch and/or high B content. The 1-year DFS was 78%. Superior 2-year DFS and overall survival (OS) were noted in patients <10 years of age, those treated with reduced toxicity conditioning (RTC) rather than myeloablative conditioning, and children with minimal residual disease <0.01% before HCT. Multivariate analysis comparing the KIR-favorable haploidentical cohort with controls showed similar DFS and OS compared with other donor cell sources. Multivariate analysis also showed a marked decrease in the risk of grades 2 to 4 and 3 to 4 acute graft versus host disease (aGHVD), chronic GVHD, and transplant-related mortality vs other donor cell sources. Ethnic and racial minorities accounted for 53% of enrolled patients, and data from a large cohort of recipients/donors screened for KIR showed that >80% of recipients had a KIR-favorable donor by our definition, demonstrating that this approach is broadly applicable to groups often unable to find donors. This prospective, multicenter study showed improved outcomes using TCR-αβ/CD19–depleted haploidentical donors using RTC for children with acute leukemia and MDS. Randomized trials comparing this approach with matched unrelated donors are warranted. This trial was registered at https://clinicaltrials.gov as #NCT02646839.",

author = "Pulsipher, {Michael A.} and Ahn, {Kwang W.} and Bunin, {Nancy J.} and Nahal Lalefar and Eric Anderson and Allyson Flower and Cairo, {Mitchell S.} and Talano, {Julie An} and Sonali Chaudhury and Kitko, {Carrie L.} and Duke, {Jamie L.} and Dimitrios Monos and Wing Leung and Dvorak, {Christopher C.} and Hisham Abdel-Azim",

note = "Funding Information: This work was supported by National Institutes of Health (NIH), National Cancer Institute (NCI) grant R01 CA181050 (NCI). Additional funding for PTCTC activities was provided by NIH, National Heart, Lung, and Blood Institute grant UG1HL069254 and a Johnny Crisstopher Children{\textquoteright}s Charitable Foundation St. Baldrick{\textquoteright}s Consortium Grant. Funding support for this article was provided by the NCI (R01 CA181050). Funding Information: Conflict-of-interest disclosure: M.A.P. has served on advisory boards for Novartis, Mesoblast, Equillium, Medexus, and Vertex; has engaged in educational activities for Novartis; and has received study support from Miltenyi (not for this trial) and Adaptive. W.L. is an employee of Miltenyi. C.C.D. has been a consultant to and served on advisory boards of Jazz Pharmaceuticals, Alexion Inc, and Omeros Corporation. J.L.D. receives royalties from Omixon. D.M. is a consultant to, owns stock options in, and receives royalties from Omixon. S.C. has served on advisory boards of AbbVie, Viacord, and Alexion. H.A.-A. received study support from Adaptive. The remaining authors declare no competing financial interests.This work was supported by National Institutes of Health (NIH), National Cancer Institute (NCI) grant R01 CA181050 (NCI). Additional funding for PTCTC activities was provided by NIH, National Heart, Lung, and Blood Institute grant UG1HL069254 and a Johnny Crisstopher Children's Charitable Foundation St. Baldrick's Consortium Grant. Funding support for this article was provided by the NCI (R01 CA181050). Contribution: M.A.P. W.L. H.A.-A. D.M. and K.W.A. conceived and designed the study; M.A.P. N.J.B. N.L. E.A. A.F. M.S.C. J.-A,T. S.C. C.L.K. J.L.D. D.M. C.C.D. and H.A.-A. provided study material or patients; M.A.P. K.W.A. N.J.B. N.L. E.A. A.F. J.-A,T. S.C. C.L.K. J.L.D. D.M. C.C.D. and H.A.-A. collected and assembled the data; M.A.P. K.W.A. D.M. C.C.D. and H.A.-A. analyzed and interpreted the data; M.A.P. K.W.A. D.M. C.C.D. and H.A.-A. wrote the manuscript; and all authors provided final approval of the manuscript. Publisher Copyright: {\textcopyright} 2022 The American Society of Hematology",

year = "2022",

month = dec,

day = "15",

doi = "10.1182/blood.2022015959",

language = "English (US)",

volume = "140",

pages = "2556--2572",

journal = "Blood",

issn = "0006-4971",

publisher = "Elsevier B.V.",

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}

Pulsipher, MA, Ahn, KW, Bunin, NJ, Lalefar, N, Anderson, E, Flower, A, Cairo, MS, Talano, JA, Chaudhury, S, Kitko, CL, Duke, JL, Monos, D, Leung, W, Dvorak, CC & Abdel-Azim, H 2022, 'KIR-favorable TCR-αβ/CD19-depleted haploidentical HCT in children with ALL/AML/MDS: primary analysis of the PTCTC ONC1401 trial', Blood, vol. 140, no. 24, pp. 2556-2572. https://doi.org/10.1182/blood.2022015959

TY - JOUR

T1 - KIR-favorable TCR-αβ/CD19-depleted haploidentical HCT in children with ALL/AML/MDS

T2 - primary analysis of the PTCTC ONC1401 trial

AU - Pulsipher, Michael A.

AU - Ahn, Kwang W.

AU - Bunin, Nancy J.

AU - Lalefar, Nahal

AU - Anderson, Eric

AU - Flower, Allyson

AU - Cairo, Mitchell S.

AU - Talano, Julie An

AU - Chaudhury, Sonali

AU - Kitko, Carrie L.

AU - Duke, Jamie L.

AU - Monos, Dimitrios

AU - Leung, Wing

AU - Dvorak, Christopher C.

AU - Abdel-Azim, Hisham

N1 - Funding Information: This work was supported by National Institutes of Health (NIH), National Cancer Institute (NCI) grant R01 CA181050 (NCI). Additional funding for PTCTC activities was provided by NIH, National Heart, Lung, and Blood Institute grant UG1HL069254 and a Johnny Crisstopher Children’s Charitable Foundation St. Baldrick’s Consortium Grant. Funding support for this article was provided by the NCI (R01 CA181050). Funding Information: Conflict-of-interest disclosure: M.A.P. has served on advisory boards for Novartis, Mesoblast, Equillium, Medexus, and Vertex; has engaged in educational activities for Novartis; and has received study support from Miltenyi (not for this trial) and Adaptive. W.L. is an employee of Miltenyi. C.C.D. has been a consultant to and served on advisory boards of Jazz Pharmaceuticals, Alexion Inc, and Omeros Corporation. J.L.D. receives royalties from Omixon. D.M. is a consultant to, owns stock options in, and receives royalties from Omixon. S.C. has served on advisory boards of AbbVie, Viacord, and Alexion. H.A.-A. received study support from Adaptive. The remaining authors declare no competing financial interests.This work was supported by National Institutes of Health (NIH), National Cancer Institute (NCI) grant R01 CA181050 (NCI). Additional funding for PTCTC activities was provided by NIH, National Heart, Lung, and Blood Institute grant UG1HL069254 and a Johnny Crisstopher Children's Charitable Foundation St. Baldrick's Consortium Grant. Funding support for this article was provided by the NCI (R01 CA181050). Contribution: M.A.P. W.L. H.A.-A. D.M. and K.W.A. conceived and designed the study; M.A.P. N.J.B. N.L. E.A. A.F. M.S.C. J.-A,T. S.C. C.L.K. J.L.D. D.M. C.C.D. and H.A.-A. provided study material or patients; M.A.P. K.W.A. N.J.B. N.L. E.A. A.F. J.-A,T. S.C. C.L.K. J.L.D. D.M. C.C.D. and H.A.-A. collected and assembled the data; M.A.P. K.W.A. D.M. C.C.D. and H.A.-A. analyzed and interpreted the data; M.A.P. K.W.A. D.M. C.C.D. and H.A.-A. wrote the manuscript; and all authors provided final approval of the manuscript. Publisher Copyright: © 2022 The American Society of Hematology

PY - 2022/12/15

Y1 - 2022/12/15

N2 - We performed a prospective multicenter study of T-cell receptor αβ (TCR-αβ)/CD19–depleted haploidentical hematopoietic cell transplantation (HCT) in children with acute leukemia and myelodysplastic syndrome (MDS), to determine 1-year disease-free survival (DFS) and compare 2-year outcomes with recipients of other donor cell sources. Fifty-one patients aged 0.7 to 21 years were enrolled; donors were killer immunoglobulin-like receptor (KIR) favorable based on ligand mismatch and/or high B content. The 1-year DFS was 78%. Superior 2-year DFS and overall survival (OS) were noted in patients <10 years of age, those treated with reduced toxicity conditioning (RTC) rather than myeloablative conditioning, and children with minimal residual disease <0.01% before HCT. Multivariate analysis comparing the KIR-favorable haploidentical cohort with controls showed similar DFS and OS compared with other donor cell sources. Multivariate analysis also showed a marked decrease in the risk of grades 2 to 4 and 3 to 4 acute graft versus host disease (aGHVD), chronic GVHD, and transplant-related mortality vs other donor cell sources. Ethnic and racial minorities accounted for 53% of enrolled patients, and data from a large cohort of recipients/donors screened for KIR showed that >80% of recipients had a KIR-favorable donor by our definition, demonstrating that this approach is broadly applicable to groups often unable to find donors. This prospective, multicenter study showed improved outcomes using TCR-αβ/CD19–depleted haploidentical donors using RTC for children with acute leukemia and MDS. Randomized trials comparing this approach with matched unrelated donors are warranted. This trial was registered at https://clinicaltrials.gov as #NCT02646839.

AB - We performed a prospective multicenter study of T-cell receptor αβ (TCR-αβ)/CD19–depleted haploidentical hematopoietic cell transplantation (HCT) in children with acute leukemia and myelodysplastic syndrome (MDS), to determine 1-year disease-free survival (DFS) and compare 2-year outcomes with recipients of other donor cell sources. Fifty-one patients aged 0.7 to 21 years were enrolled; donors were killer immunoglobulin-like receptor (KIR) favorable based on ligand mismatch and/or high B content. The 1-year DFS was 78%. Superior 2-year DFS and overall survival (OS) were noted in patients <10 years of age, those treated with reduced toxicity conditioning (RTC) rather than myeloablative conditioning, and children with minimal residual disease <0.01% before HCT. Multivariate analysis comparing the KIR-favorable haploidentical cohort with controls showed similar DFS and OS compared with other donor cell sources. Multivariate analysis also showed a marked decrease in the risk of grades 2 to 4 and 3 to 4 acute graft versus host disease (aGHVD), chronic GVHD, and transplant-related mortality vs other donor cell sources. Ethnic and racial minorities accounted for 53% of enrolled patients, and data from a large cohort of recipients/donors screened for KIR showed that >80% of recipients had a KIR-favorable donor by our definition, demonstrating that this approach is broadly applicable to groups often unable to find donors. This prospective, multicenter study showed improved outcomes using TCR-αβ/CD19–depleted haploidentical donors using RTC for children with acute leukemia and MDS. Randomized trials comparing this approach with matched unrelated donors are warranted. This trial was registered at https://clinicaltrials.gov as #NCT02646839.

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U2 - 10.1182/blood.2022015959

DO - 10.1182/blood.2022015959

M3 - Article

C2 - 35776909

AN - SCOPUS:85144585749

SN - 0006-4971

VL - 140

SP - 2556

EP - 2572

JO - Blood

JF - Blood

IS - 24

ER -

KIR-favorable TCR-αβ/CD19-depleted haploidentical HCT in children with ALL/AML/MDS: primary analysis of the PTCTC ONC1401 trial

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