Allogeneic CD34-Selected HSCT Following CAR T-Cells Is Associated with Low TRM and Favorable OS in Pediatric/Young Adult Patients with Relapsed/Refractory B-ALL
Authors: Fabrizio Vanessa , Boulad Farid , Cancio Maria I. , Higman Meghan A. , Margossian Steven P. , Mauguen Audrey , Prockop Susan , Scaradavou Andromachi , Shah Niketa C. , Spitzer Barbara , Yeager Nick , Kernan Nancy A. , O'Reilly Richard , Boelens Jaap Jan , Curran Kevin J. 
Published: November 2019

Background: Chimeric antigen receptor (CAR) T-cells have transformed the therapeutic options for patients with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). The tolerability and outcome of allo-HSCT following CAR T-cell therapy is yet to be defined.
Methods: We retrospectively reviewed pediatric and young adult patients with R/R B-ALL who received allo-HSCT following CAR T-cells. Outcomes of interest were overall survival (OS), cumulative incidence of relapse, and transplant-related mortality (TRM). These were estimated using log-rank analysis. Variables of interest were disease status at time of allo-HSCT, time from CAR T-cell therapy to start of allo-HSCT, conditioning regimen, graft source and manipulation, GVHD prophylaxis, donor HLA matching, neutrophil/platelet engraftment, relapse and cause of death.
Results: Sixteen patients, with a median age of 13 (range 1-20), at time of allo-HSCT were included. All patients achieved MRD-negative complete remission (CR) following CAR T-cells and proceeded to allo-HSCT as definitive therapy. CR status included CR1 (n=6), CR2 (n=5), CR3 (n=4), and CR4 (n=1). The median time from CAR T-cells to the start of allo-HSCT conditioning was 46.5 days (range 20 -126). Conditioning was TBI-based (n=13) or chemotherapy only (n=3). Graft source included PBSC (n=8) or BM (n=8). Graft manipulation included CD34-selected T-cell depleted (TCD) (Miltenyi) (n=9) or an un-modified HSCT (n=7). Donors were HLA-matched related (n=8), HLA-matched unrelated (n=3), or HLA-mismatched unrelated (n=5). GVHD prophylaxis in the non-manipulated grafts included a calcineurin inhibitor (CNI) plus MTX (n=5), CNI plus MMF (n=1) or post-transplant cyclophosphamide (n=1). Available data included: 15/15 patients achieved neutrophil engraftment (median 12 days; range 9-29) and 13/15 patients achieved platelet engraftment (median 30 days; range 16-265). The 12-month cumulative incidence of relapse was 0% in patients receiving CD34-selected transplant, versus 25% [95% CI: 0 to 67%] in patients receiving un-modified transplant (log-rank p=0.80) and the 24-month cumulative incidence of relapse for the whole cohort was 25% [0-47%]. Late relapse (>12 months from allo-HSCT) occurred in three (n=3) patients in the CD34-selected TCD cohort with a median time to relapse from allo-HSCT of 24.2 months (range 16.3 - 24.7 months). Two (n=2) patients achieved subsequent MRD-neg/CR following additional CD19-specific CAR T-cell infusions (CRs ongoing at 12.4 and 1.4 months). The other patient (n=1) experienced a CD19-negative relapse and is awaiting infusion of CD22-specific CAR T-cells. Early relapse occurred in one (n=1) patient (4.7 months from allo-HSCT) following un-modified allo-HSCT with subsequent MRD-neg/CR following treatment with CD19-specific CAR T-cells (CR ongoing at 5.2 month). Three (n=3) patients in the un-modified cohort died due to TRM (24-month TRM = 46% [7-86%]), including veno-occlusive disease (multi-organ failure/infection) (n=2) and GVHD (n=1), while no TRM was noted in the CD34-selected TCD cohort (p=0.03). The TRM for the entire cohort was 19% at 24 months [0-39%]. The 24-month OS for the entire cohort was 81% [61 -100%], with 100% OS in CD34-selected TCD recipients and 54% in the un-modified recipients (p=0.03).
Conclusion: CAR T-cells when followed by a CD34-selected TCD allo-HSCT resulted in less TRM and favorable OS when compared to un-modified allo-HSCT. Disease control is not impacted by the type of allo-HSCT and late relapse was seen following CD34-selected TCD. Successful re-treatment with CAR T-cells to induce remission is possible and analysis as to the durability of this response is ongoing.

Disclosures
Margossian: Novartis: Membership on an entity's Board of Directors or advisory committees. Prockop:Atara Biotherapeutics: Other: Support for industry sponsored trails ; Mesoblast: Other: Support for industry sponsored trails . Shah:Jazz pharmaceuticals: Speakers Bureau. Boelens:Takeda: Consultancy; Magenta: Consultancy; Bluerock: Consultancy; Avrobio: Consultancy. Curran:Juno Therapeutics: Consultancy, Research Funding; Novartis: Consultancy.