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Axicabtagene Ciloleucel (Axi-cel) CD19 Chimeric Antigen Receptor (CAR) T-Cell Therapy for Relapsed/Refractory Large B-Cell Lymphoma: Real World Experience

Loretta J. Nastoupil, Michael D. Jain, Jay Y. Spiegel, Armin Ghobadi, Yi Lin, Saurabh Dahiya, Matthew A. Lunning, Lazaros J. Lekakis, Patrick M. Reagan, Olalekan O. Oluwole, Joseph P. McGuirk, Abhinav Deol, Alison R. Sehgal, Andre Goy, Brian T. Hill, Charalambos Andreadis, Javier Munoz, Jason R. Westin, Julio C. Chavez, Amanda F Cashen, Nora N Bennani, Aaron P. Rapoport, Julie M. Vose, David B. Miklos, Sattva S. Neelapu and Frederick L. Locke

Abstract

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Introduction

Axi-cel is an autologous anti-CD19 CAR T-cell therapy approved by the US FDA 10/18/2017, for the treatment of adults with relapsed or refractory (r/r) large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma (PMBCL), transformed lymphoma (tFL), and high-grade B-cell lymphoma (HGBCL) who have failed at least two prior systemic lines of therapy. In the pivotal ZUMA-1 trial, 108 patients (pts) with r/r DLBCL were treated with axi-cel: the best overall response rate (ORR) was 82% and complete response (CR) rate was 58%. At a median follow-up of 15.4 months, 42% of the pts had ongoing remission (Neelapu and Locke et al. NEJM 2017). Grade 3 or higher cytokine release syndrome (CRS) by Lee criteria and neurologic events (NEs) occurred in 13% and 31% of the pts, respectively. Here, we evaluated the real world outcomes of pts treated with standard of care axi-cel under the commercial FDA label.

Methods and Results

Seventeen US academic centers contributed data to this effort independently of the manufacturer. As of 6/30/2018, 211 pts were leukapheresed with intention to manufacture commercial axi-cel. Of these, 165 (78%) pts completed axi-cel infusion as of 6/30/18 and a further 23 (11%) pts are scheduled for axi-cel infusion in July 2018. Of the 23 remaining pts, 7 (3%) received axi-cel therapy on ZUMA-9 expanded access trial (NCT03153462) due to non-conforming cell therapy product, 15 (7%) pts died before axi-cel infusion (14 from lymphoma progression and 1 from sepsis) and 1 (1%) patient attained CR from bridging therapy and was not infused.

Safety was evaluable in 163 pts receiving axi-cel. Grade ³3 CRS and NEs occurred in 7% and 31% of pts. Tocilizumab was administered in 62% of pts and 57% received corticosteroids. Outside of lymphoma progression, 3 deaths occurred post-axi-cel; 1 due to HLH, 1 due to systemic candidiasis, and a third due to septic shock. There were no grade 5 NEs observed.

Response assessment was done for pts infused with axi-cel and who were re-staged at day 30 and/or day 100, or were deemed to have clinical progression. Of 112 pts evaluable at day 30, ORR was 79% with 50% CR, 29% PR, 6% SD and 14% with PD. Of 39 pts evaluable at day 100, 59% of pts had ongoing response (CR 49%, PR 10%).

At the time of abstract submission, more detailed patient characteristics and treatment course data were available in 134/165 pts infused. Median age was 59 (range 21-82) with 57% male. Performance status (PS) was ECOG 0-1 (81%), ECOG 2 (16%) and ECOG 3 (3%). By histology, 61% of pts had DLBCL including HGBCL, 31% had tFL and 8% PMBCL. Thirty-one percent had a prior autologous stem cell transplant. Bridging therapy between apheresis and infusion was given in 56% of patients, the majority of which consisted of chemotherapy. Sixty-six of 134 (49%) would not have met eligibility criteria for ZUMA-1 at the time of leukapheresis. Common criteria that would have made these patients ineligible for ZUMA-1 included ECOG PS >1 (n = 22), platelets <75k (n = 17), GFR <60 (n =12), active DVT/PE (n = 13), liver enzyme abnormalities (n = 10), a history of CNS lymphoma (n = 8), recent checkpoint inhibitor therapy (n = 7), ejection fraction <50% (n = 4), prior CD19 CAR T therapy (n = 4), and prior allogeneic transplant (n=2). Median time from leukapheresis to start of conditioning chemotherapy was 21 days and median time from leukapheresis to axi-cel infusion was 26 days. Median hospitalization period was 14 days.

Conclusions

This multicenter retrospective study delineates the real world outcomes of axi-cel CAR T-cell therapy for r/r aggressive B-cell lymphoma when used as a standard of care. Though limited by relatively short follow up, 30 day responses in the real world setting are comparable to the best responses observed on the pivotal ZUMA-1 clinical trial (Table 1). Importantly, safety appears comparable to the ZUMA-1 trial despite nearly half the pts failing to meet ZUMA-1 eligibility criteria. Updated results including PFS and OS will be presented at the meeting.

L.J.N. and M.D.J. contributed equally; D.B.M., S.S.N. and F.L.L. contributed equally.

Disclosures Nastoupil: Merck: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; TG Therappeutics: Research Funding; Karus: Research Funding; Genentech: Honoraria, Research Funding; Janssen: Research Funding; Gilead: Honoraria; Juno: Honoraria; Novartis: Honoraria; Spectrum: Honoraria. Lunning: Celgene: Consultancy; Spectrum: Consultancy; Portola: Consultancy; Genzyme: Consultancy; Janssen: Consultancy; Seattle Genetics: Consultancy; Kite: Consultancy; Juno: Consultancy; AbbVie: Consultancy; Astra-Zeneca: Consultancy; Genentech: Consultancy; Gilead: Consultancy; Genentech: Consultancy; Bayer: Consultancy; TG Therapeutics: Consultancy; Verastem: Consultancy. Reagan: Seattle Genetics: Research Funding. McGuirk: Gamida Cell: Research Funding; Astellas Pharma: Research Funding; Fresenius Biotech: Research Funding; Bellicum Pharmaceuticals: Research Funding; Novartis Pharmaceuticals Corporation: Honoraria, Other: speaker, Research Funding; Kite Pharma: Honoraria, Other: travel accommodations, expenses, speaker ; Pluristem Ltd: Research Funding. Deol: Novartis: Consultancy; Kite Pharmaceuticals: Consultancy. Hill: Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Andreadis: Gilead: Consultancy; Genentech: Consultancy, Employment; Astellas: Consultancy; Bayer: Consultancy; Celgene: Consultancy; Seattle Genetics: Consultancy; Pharmacyclics: Consultancy; Juno: Research Funding; Kite: Consultancy; Novartis: Consultancy, Research Funding. Munoz: Pfizer: Consultancy; Bayer: Consultancy, Speakers Bureau; Juno: Consultancy, Honoraria; Janssen: Consultancy; Genentech: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy; Pharmacyclics: Consultancy, Honoraria; Kite: Consultancy, Honoraria, Speakers Bureau; Alexion: Consultancy; Gilead: Speakers Bureau. Westin: Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees; Celgen: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Apotex: Membership on an entity's Board of Directors or advisory committees. Vose: Kite Pharma: Research Funding; Acerta Pharma: Research Funding; Celgene: Research Funding; Novartis: Honoraria, Research Funding; Roche: Honoraria; Seattle Genetics, Inc.: Research Funding; Legend Pharmaceuticals: Honoraria; Merck Sharp & Dohme Corp.: Research Funding; Abbvie: Honoraria; Epizyme: Honoraria; Bristol Myers Squibb: Research Funding; Incyte Corp.: Research Funding. Miklos: Genentech: Research Funding; Kite - Gilead: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pharmacyclics - Abbot: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy, Research Funding. Locke: Kite Pharma: Other: Scientific Advisor; Cellular BioMedicine Group Inc.: Consultancy; Novartis Pharmaceuticals: Other: Scientific Advisor.

  • * Asterisk with author names denotes non-ASH members.

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