Consolidation with Allogeneic Hematopoietic Cell Transplant Improved Survival Outcomes of Adults with Relapsed / Refractory Acute Lymphoblastic Leukemia Following Response to Memory-Enriched CD19CAR T Cells

Background: CD19-directed chimeric antigen receptor (CD19CAR) T cell therapy produces excellent remission rates in children and adults with relapsed/refractory (r/r) acute lymphoblastic leukemia (ALL). While a small number of adult patients (pts) who respond to CD19CAR T cells have durable remission without additional therapy, most do not, and it remains debatable whether consolidation with allogeneic hematopoietic cell transplantation (alloHCT) after CD19CAR T cells should be offered to every adult responder with r/r ALL, especially in context of a second consolidative alloHCT in pts who relapsed following prior alloHCT. Here we report a subanalysis from our recently completed phase 1/2 prospective study (NCT02146924) using memory-enriched CD19CAR T cells in adults with r/r ALL to assess the role of alloHCT consolidation on outcome.

Methods: This study assessed the safety and efficacy of naïve, stem and central memory (Tn/mem)-derived CAR T cells delivered at the recommended phase 2 dose (RP2D; 200x10⁶ CAR T cells) in adults with r/r ALL. If pts achieved complete remission (CR)/CR with incomplete hematologic recovery (CRi) post CAR T cells, they could receive optional consolidation with alloHCT per the treating physician discretion anytime 4 weeks after infusion. We evaluated the adjusted association between relapse free survival (RFS) and time varying status for alloHCT consolidation, Philadelphia (Ph)-like status, bone marrow blasts at time of lymphodepletion (LD; <5% vs. ≥5%) and presence of extramedullary disease (EMD) at LD among the responders by performing a pre-specified Cox proportional hazards regression model.

Results: We enrolled 58 pts at the RP2D who underwent leukapheresis; 46 pts received CD19CAR T cells. The median age for pts who received CD19CAR T cells was 38 years (range, 22-72), with 15 (33%) pts ≥ 50 years. The median number of prior lines of therapy was 3 (range, 1-9); 29 (63%) pts had prior alloHCT, and 29 (63%) and 15 (33%) pts failed blinatumomab and inotuzumab before enrollment, respectively. Eighteen (39%) had Ph-like genotype and 16 (35%) had EMD at LD. Forty (87%) patients achieved CR/CRi, 1 (2%) progressed and 5 (11%) were unevaluable for response.

Twenty-one (53%) responders proceeded directly to alloHCT consolidation while in CR/CRi post CAR T cell therapy, including 10 pts who received their second alloHCT. Notably, 6/13 pts with EMD at LD who achieved CR/CRi after infusion underwent alloHCT consolidation. The median time to transplant was 79 days (range, 50-192) post CAR T cell infusion. For the 40 responders, with a median follow up of 11.4 months (range, 3.3-65.8) post CAR T cell infusion, median overall survival (OS) was not reached, and median RFS was 17.1 months (95%CI: 6.9 to NA). The 12-month OS and RFS were 63.2% and 52.6%, respectively.

Among responders, 12-month RFS were 81% and 16% for those who did and those who did not undergo consolidation with alloHCT in CR/CRi, respectively. In the prespecified multivariable analysis, only consolidation with alloHCT post CAR T cells was independently associated with superior RFS [adjusted hazard ratio (HR)=0.16; 95% CI: 0.05-0.48; P= 0.001]. Of the 19 pts who responded to CAR T cells and did not have alloHCT consolidation, 11 relapsed with a median time of 3.4 months (range, 2.1-10.3) post CAR T cell infusion, 3 pts died in remission, and 5 pts remained alive and in remission at last contact or date of censoring, with a median follow up of 9.7 months (range, 3.3-51.8) including 1 pt who was censored at day 99 post infusion upon initiating ponatinib maintenance. Of the 21 pts who responded to CAR T cells and underwent alloHCT consolidation, 2 pts relapsed (6.9- and 12.4-months post-transplant) of whom 1 died after relapse and 1 received a second CAR T cell infusion and was censored for OS at the date of second infusion, 3 pts died in remission, and 16 pts remained alive and in remission. (Figure A) The 100-day non-relapse mortality rate post-transplant was 5% (n= 1). OS was comparable for responders who had their first or second alloHCT post CAR T cells (12-months OS= 82% vs 79%, p= 0.9; Figure B).

Conclusion: Outcomes of alloHCT consolidation in adults with high-risk r/r ALL after achieving remission with Tn/mem CD19CAR T cells were promising, including for pts receiving their second alloHCT, and transplant led to improved survival outcomes.

Aldoss:Agios: Consultancy, Honoraria; Amgen: Consultancy; Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Kite: Consultancy; Autolus Limited: Consultancy; AbbVie: Consultancy, Research Funding. Stein:Amgen: Speakers Bureau. Pullarkat:Amgen, Dova, and Novartis: Consultancy, Other: Advisory Board Member; AbbVie, Amgen, Genentech, Jazz Pharmaceuticals, Novartis, Pfizer, and Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Salhotra:BMS: Research Funding; Kadmon: Other: Advisory board meeting ; Orca Bio: Research Funding. Al Malki:NexImmune: Consultancy, Research Funding; Hasna Biopharma: Membership on an entity's Board of Directors or advisory committees; Miltenyi Biotec: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; CareDx: Consultancy, Research Funding; Gilead: Consultancy, Research Funding. Marcucci:Agios: Other: Speaker and advisory scientific board meetings; Abbvie: Other: Speaker and advisory scientific board meetings; Novartis: Other: Speaker and advisory scientific board meetings. Brown:Mustang Bio: Consultancy, Other: IP licensing revenue; Chimeric Therapeutics: Consultancy, Other: IP licensing revenue.