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Clinical Trial
. 2022 Mar;57(3):423-430.
doi: 10.1038/s41409-021-01551-z. Epub 2021 Dec 24.

Results of a multicenter phase I/II trial of TCRαβ and CD19-depleted haploidentical hematopoietic stem cell transplantation for adult and pediatric patients

Wolfgang A Bethge  1 , Matthias Eyrich  2 , Stephan Mielke  3   4 , Roland Meisel  5 , Dietger Niederwieser  6 , Paul G Schlegel  2 , Ansgar Schulz  7 , Johann Greil  8 , Donald Bunjes  9 , Arne Brecht  10 , Jurgen Kuball  11 , Michael Schumm  12   13 , Vladan Vucinic  6 , Markus Wiesneth  14 , Halvard Bonig  15 , Kasper Westinga  16 , Stefanie Biedermann  17 , Silke Holtkamp  18 , Sandra Karitzky  18 , Michaela Malchow  18 , Christiane Siewert  17 , Rupert Handgretinger  13 , Peter Lang  19
Affiliations
Clinical Trial

Results of a multicenter phase I/II trial of TCRαβ and CD19-depleted haploidentical hematopoietic stem cell transplantation for adult and pediatric patients

Wolfgang A Bethge et al. Bone Marrow Transplant. 2022 Mar.

Abstract

Hematopoietic stem cell transplantation (HSCT) from haploidentical donors is a viable option for patients lacking HLA-matched donors. Here we report the results of a prospective multicenter phase I/II trial of transplantation of TCRαβ and CD19-depleted peripheral blood stem cells from haploidentical family donors after a reduced-intensity conditioning with fludarabine, thiotepa, and melphalan. Thirty pediatric and 30 adult patients with acute leukemia (n = 43), myelodysplastic or myeloproliferative syndrome (n = 6), multiple myeloma (n = 1), solid tumors (n = 6), and non-malignant disorders (n = 4) were enrolled. TCR αβ/CD19-depleted grafts prepared decentrally at six manufacturing sites contained a median of 12.1 × 106 CD34+ cells/kg and 14.2 × 103 TCRαβ+ T-cells/kg. None of the patients developed grade lll/IV acute graft-versus-host disease (GVHD) and only six patients (10%) had grade II acute GVHD. With a median follow-up of 733 days 36/60 patients are alive. The cumulative incidence of non-relapse mortality at day 100, 1 and 2 years after HSCT was 5%, 15%, and 17% for all patients, respectively. Estimated probabilities of overall and disease-free survival at 2 years were 63% and 50%, respectively. Based on these promising results in a high-risk patient cohort, haploidentical HSCT using TCRαβ/CD19-depleted grafts represents a viable treatment option.

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Conflict of interest statement

WB: Consultancy and Research Funding—Miltenyi Biotec; Advisory Boards—Celgene, Novartis, Janssen, Gilead. ME: Clinical trial support and advisory boards—Bristol-Myers-Squibb. SM: Data safety monitoring board—Miltenyi, Immunicum; expert panel—Gilead/Kite, Bellicum; speaker’s fee—Novartis, DNA Prime SA, Cellex, Celgene, Kiadis Pharma, Jazz, Miltenyi; travel support—Cellex, Gilead/Kite, MSD, Celgene, Kiadis Pharma, Miltenyi. RM: Consulting or Advisory Role—Bluebird Bio, Bellicum Pharmaceuticals, Novartis; Travel, Accommodations, Expenses—Jazz Pharmaceuticals. DN: Advisory board—Cellectis; speakers bureau—Novartis, Daiichi; manuscript preparation support—Novartis. PGS: Advisory board—Bluebird Bio, not related to the topic of this publication. JK: Shareholder Gadeta and inventor on multiple patents dealing with gdT cell-related topics as well as CAR T isolation strategies; Research Support—Miltenyi Biotec, Novartis. HB: Research support: Bayer, Chugai, Erydel, Miltenyi, Polyphor, Sandoz-Hexal (a Novartis Company), Stage (a Celgene Company), Terumo BCT, Uniqure; honoraria/speakers‘ fees—Chugai, Fresenius, Genzyme, Kiadis, medac, Miltenyi, Novartis, Sandoz-Hexal, Terumo BCT; consultancy and advisory boards—Boehringer-Ingelheim, Celgene, Genzyme, medac, Novartis, Sandoz-Hexal, Stage, Terumo BCT; royalties—medac; stocks—Healthineers. KW: Advisory board—Novartis AG, not related to the topics of this publication. SB and CS are employees of Miltenyi Biotec. SH, SK, and MM are employees of Miltenyi Biomedicine. RH: Speakers’ honoraria—Miltenyi Biotec; co-patent holder of the TcR alpha-beta depletion. AB, DB, JG, PL, AS, MS, VV, MW: no conflict of interest.

Figures

Fig. 1
Fig. 1. Performance of the TCRαβ- and CD19 depletion.
Median logarithmic depletion of TCRαβ+T- and CD19+ B cells in 87 depletion procedures with the CliniMACS Plus device.
Fig. 2
Fig. 2. Cumulative incidence of virus reactivation.
Patients were screened for adenovirus (ADV) DNA (stool, urine, and blood) and for cytomegalovirus (CMV) DNA (blood, stool, and throat); cumulative incidences of positive findings are shown for the adult (a) and pediatric (b) patient cohort, respectively, and for donor/recipient pairs with CMV IgG seropositive recipient (D−R+/D+R+); no events occurred in seronegative recipients (D−R−/D+R−).
Fig. 3
Fig. 3. Non-relapse mortality.
Cumulative incidence of non-relapse mortality (NRM) until 2 years posttransplant.
Fig. 4
Fig. 4. Immune reconstitution of different lymphocyte subsets after HSCT.
Reconstitution of CD3+ T-cells, CD3+CD4+ T-cells, and CD3+CD8+ T-cells (a), TCRαβ+ and TCRγδ+ T-cells (b) and CD19+ B- and CD56+ NK-cells (c) after transplantation of TCRαβ/CD19-depleted allografts. Points represent the mean values ± standard deviations at each time point.
Fig. 5
Fig. 5. Relapse rate, overall survival, disease-free survival, and GVHD-relapse-free survival for the whole patient cohort.
a Relapse rates in patients with leukemia/myelodysplastic syndrome (MDS) transplanted in complete remission (CR) versus patients with leukemia/MDS transplanted in non-remission. b Disease-free survival (DFS), overall survival (OS), and GVHD-, relapse-free survival (GRFS) of the whole patient group. c DFS of patients with leukemia/MDS transplanted in CR versus patients with leukemia/MDS transplanted in non-remission.
Fig. 6
Fig. 6. Relapse rate, overall survival, disease-free survival, and GVHD-relapse-free survival for adult patients.
a Relapse rates in adult patients with leukemia/myelodysplastic syndrome (MDS) transplanted in complete remission (CR) versus patients with leukemia/MDS transplanted in non-remission. b Disease-free survival (DFS), overall survival (OS), and GVHD-, relapse-free survival (GRFS) of the adult cohort. c DFS of adult patients with leukemia/MDS transplanted in CR versus adult patients with leukemia/MDS transplanted in non-remission.
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