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

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.

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.

© 2021. The Author(s).

Figures

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. 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. Non-relapse mortality.

Cumulative incidence of non-relapse mortality (NRM) until 2 years posttransplant.

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. 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. 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.