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967 Long Term Follow-up after SCRI-CAR19v1 Reveals Late Recurrences As Well As a Survival Advantage to Consolidation with HCT after CAR T Cell Induced Remission

Program: Oral and Poster Abstracts
Type: Oral
Session: 732. Clinical Allogeneic Transplantation: Results I
Hematology Disease Topics & Pathways:
Diseases, Leukemia, ALL, Biological, Therapies, CAR-Ts, Lymphoid Malignancies, transplantation
Monday, December 3, 2018: 4:30 PM
Seaport Ballroom A (Manchester Grand Hyatt San Diego)

Corinne Summers, MD1,2, Colleen Annesley, MD3,4, Marie Bleakley, MBBS, PhD, MMSc2,5, Ann Dahlberg, MD2*, Michael C. Jensen, MD3* and Rebecca Gardner, MD3,6

1Seattle Children's Research Institute, SEattle, WA
2Fred Hutchinson Cancer Research Center, Seattle, WA
3Seattle Children's Research Institute, Seattle, WA
4Seattle Children's Hospital, Seattle, WA
5Fred Hutchinson Cancer Rsch. Ctr., Seattle, WA
6Seattle Children’s Hospital, Seattle, WA

Background: CD19 chimeric antigen receptor (CAR) T cell therapy has demonstrated robust responses in refractory/relapsed subjects with CD19+ acute lymphoblastic leukemia (ALL). Our Phase 1 clinical trial demonstrated a minimal residual disease (MRD) negative complete remission (CR) rate of 93% at 21 days following SCRI-CAR19v1 (a CD19 specific CAR T cell product) infusion (PMID: 29171004). Though remission is frequently attained, approximately half of patients recur. Controversy exists regarding the benefit of hematopoietic cell transplant (HCT) following CD19 CAR T cell therapy. Although not mandated by the study, our current institutional recommendation for relapsed/refractory patients without a history of allogeneic HCT is to undergo a HCT once in remission following SCRI-CAR19v1. Additionally, we have recommended HCT to those who have a short duration of persistence of SCRI-CAR19v1 in vivo regardless of prior HCT status. We report here the leukemia free survival (LFS) of subjects who proceeded to HCT following remission after SCRI-CAR19v1 infusion.

Methods/Results: We analyzed the first 64 subjects on our Phase 1/2 trial, PLAT-02 (NCT02028455), with follow-up of ≥1 year to evaluate the potential benefit of consolidative HCT. We excluded subjects that did not respond (n=5) or relapsed prior to day 63 (n=9). Thirty-two of the evaluated subjects were treated on the Phase I dose finding portion of the study and 18 were treated on the Phase 2 portion at dose level of 1x106cells/kg. Of the 50 evaluable subjects, 33 had a history of at least one prior HCT, whereas 17 had no history of HCT. Figure A demonstrates the LFS for patients that did and did not undergo HCT following SCRI-CAR19v1.

There is a trend towards improved LFS (p-value 0.057; Figure B) in patients who underwent first HCT following SCRI-CAR19v1. Of the 17 patients without a history of HCT, 3 did not pursue HCT following CAR therapy. Of those 3 subjects, only 1 remains in remission at 28 months. The other 2 subjects relapsed at 6 and 7 months with CD19+ and CD19- disease, respectively. Of the 14 patients that underwent first HCT after SCRI-CAR19v1, 2 relapsed following HCT. One had evidence of MRD by flow at the time of HCT and the other subject relapsed with CD19- disease. The role of second HCT following CAR therapy remains unclear. Of the 33 subjects with a history of HCT, 10 underwent a second HCT following SCRI-CAR19v1 infusion, and 5 are alive and remain in remission. The recurrences included 2 lineage switches and 2 CD19+ (1 was MRD positive by deep sequence prior to HCT), and one transplant related mortality (TRM). Of the 23 subjects that did not undergo a second HCT, 8 remain in remission (p-value not significant (NS); Figure C).

We previously reported that subjects with a short duration of B cell aplasia (BCA) ≤63 days following SCRI-CAR19v1 have an increased risk of relapse. Here we show that subjects with short BCA who attained a CR and did not relapse prior to day 63 demonstrate a clear benefit of consolidative HCT (p-value 0.007; Figure D). Of the 15 subjects with short BCA (regardless of HCT history), 6 did not pursue HCT and all recurred (5 CD19+, 1 CD19-). Of the short BCA subjects that underwent HCT, 1 subject died of TRM (2ndHCT for this subject) and 2 subjects relapsed following HCT (1 was MRD positive prior to HCT).

All events in the consolidative HCT group have occurred by 20 months following SCRI-CAR19v1. However, we continue to see late relapses following CAR T cell therapy in the group who did not proceed with HCT. Three subjects have relapsed beyond 2 years: 1 with CD19+ disease at 27months, 1 with CD19- disease at 41 months, and 1 patient with lineage switch AML at 38 months. Further analysis is needed to understand the continued long-term risk of relapse following CD19 CAR T cell therapy and the potential role and timing for consolidative HCT in patients with a previous HCT.

Conclusions: We demonstrate a trend towards improved LFS for subjects without a history of HCT who undergo a consolidative HCT following CD19 CAR T cell therapy on PLAT-02. In addition, HCT appears to benefit subjects who attain a CR but are at increased risk of relapse with short-term BCA. Currently, the benefit of second HCT following CD19 CAR T cell therapy is unclear and may be restricted to those that have short functional persistence of SCRI-CAR19v1. Late relapses after SCRI-CAR19v1 have only occurred in those without consolidative HCT, but longer follow up is needed to confirm these findings.

Disclosures: Jensen: Juno Therapeutics, Inc.: Consultancy, Patents & Royalties, Research Funding.

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