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75 Time-Limited Ibrutinib and Tisagenlecleucel Is Highly Effective in the Treatment of Patients with Relapsed or Refractory Mantle Cell Lymphoma, Including Those with TP53 Mutated and Btki-Refractory Disease: First Report of the Tarmac Study

Program: Oral and Poster Abstracts
Type: Oral
Session: 623. Mantle Cell, Follicular, and Other Indolent B Cell Lymphomas: Clinical and Epidemiological I
Hematology Disease Topics & Pathways:
Research, clinical trials, Biological therapies, Lymphomas, Clinical Research, B Cell lymphoma, Chimeric Antigen Receptor (CAR)-T Cell Therapies, Combination therapy, Diseases, Therapies, Lymphoid Malignancies, Adverse Events, Minimal Residual Disease
Saturday, December 10, 2022: 10:00 AM

Adrian Minson, MBBS1,2,3, Nada Hamad, MBBS, BSc, MSc4, Chan Yoon Y. Cheah, MD5,6, Constantine S. Tam, MD, MBBS1,3,7,8, Piers Blombery, MBBS1,2,3, David A Westerman, MBBS, FRCPA, FRACP1,2,3, Stephen Lade2*, David Ritchie, MB ChB, PhD1,2,3,9, Rachel M Koldej, PhD1,3,9*, Mary Ann Anderson, MBBS, PhD1,2,3,10, Amit Khot, MBBS, MD2,3, John F. Seymour, MBBS, PhD, FRACP1,2,3, Molly Robertson, MN2*, Imogen R Caldwell, FRACP, FRCPA2, Georgina L Ryland, PhD1,2, Jing Xie, PhD2*, Huw Morgan, BSc1,11* and Michael Dickinson, MD1,2,3

1University of Melbourne, Melbourne, Australia
2Peter MacCallum Cancer Centre, Melbourne, Australia
3Royal Melbourne Hospital, Melbourne, Australia
4St Vincent's Hospital, Sydney, NSW, Australia
5Linear Clinical Research and Sir Charles Gairdner Hospital, Perth, WEA, Australia
6University of Western Australia, Crawley, Australia
7Peter MacCallum Cancer Centre, Kew, VIC, Australia
8Alfred Hospital, Melbourne, Australia
9ACRF Translational Research Laboratory, Royal Melbourne Hospital, Parkville, VIC, Australia
10The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia
11ACRF Translational Research Laboratory, Melbourne, Australia


Relapsed or refractory MCL (RR-MCL) is an area of significant unmet need, especially in the presence of high-risk features such as TP53 aberrancy, which is associated with treatment resistance and/or early treatment failure with current therapies. Preclinical and clinical data support the potential role of ibrutinib in apheresis product fitness, cytokine release syndrome (CRS) abrogation, and CAR-T expansion. TARMAC is an investigator-initiated multi-centre trial assessing the efficacy and safety of a time-limited combination of ibrutinib and the anti-CD19 CAR-T product tisagenlecleucel (tisa-cel) in RR-MCL.


Patients (pts) had a centrally confirmed diagnosis of RR-MCL with radiologically measurable or morphologic marrow disease, adequate organ function, and no prior CAR-T. Prior BTKi exposure was allowed. Ibrutinib (560mg daily) was commenced at least 7 days prior to leukapheresis and continued throughout optional bridging, lymphodepletion (fludarabine 25mg/m2 and cyclophosphamide 250mg/m2 each daily x 3) and for 6 months after tisa-cel infusion. Molecular profiling included: FISH for t(11;14) and del(17p); and next generation sequencing. Measurable residual disease (MRD) on peripheral blood (PB) and bone marrow (BM) samples during treatment and follow up was assessed by flow cytometry (sensitivity between 10-4 & 10-5), and high throughput immunoglobulin sequencing (IgHTS) (sensitivity between 10-5 & 10-6; Adaptive Biotechnologies). CAR-T quantitation was by digital PCR. Immunologic profiling of baseline and on-treatment PB samples was described using spectral flow cytometry. The primary endpoint was complete response (CR) rate by Lugano criteria at month 4 (M4) after tisa-cel and key secondary endpoints included safety, rates of MRD negativity, ORR, PFS, DOR and OS.


Twenty-one pts were enrolled, one withdrew consent, and 20 were infused. The median age was 66 years (range 41-74y), 75% were male. Median prior therapies was 2 (range 1-5 lines); 55% had undergone prior autologous transplantation. 10 pts (50%) had prior BTKi, 9 were refractory. 4 pts required bridging: venetoclax (n=1) or chemotherapy (n=3). Genomic results were available for 18 pts with 8/18 (44%) demonstrating one or more TP53 mutations. Eight pts had del(17p), including 7 of the 8 pts also demonstrating a TP53 mutation, suggestive of biallelic TP53 dysfunction.

Ibrutinib therapy was well tolerated with 97% mean dose intensity achieved. After tisa-cel infusion, 75% of pts experienced CRS; 11/15 (73%) grade 1-2, 4/15 (27%) grade 3 with no grade 4 events. One episode of ICANS (grade 2) was observed with complete resolution. Atrial fibrillation was observed in one pt associated with infection. Overall grade 3 and 4 toxicities were seen in 75% and 50% of pts. There were no deaths.

The median follow-up was 13.0 months (range 3.5-21.4). The ORR was 90% (CR 85%, PR 5%), with median time to best response of 1 month (range 1-4). At M4 post-infusion, 16 pts (80%) were in CR and 4 had progressed. Fourteen pts (70% of all pts) demonstrated MRD negativity in PB and BM by flow cytometry; 8/14 were also negative by IgHTS. The CR rate (CRR) at M4 in BTKi naïve and exposed populations were 90% and 70% respectively. Median DOR has not been reached, with an estimated 83% of responding pts retaining their response at 12 months. The estimated PFS rates at 12 months were 75% and OS 100% (Figure 1). Response rates and durability of responses were similar between TP53 wildtype and TP53 mutated pts, with CRR at 12 months of 78% and 71% respectively.

Pts in MRD-negative CR at M4 by flow cytometry (deep responders) demonstrated higher peak CAR-T (Cmax 25.4 vs 8.5 CAR19 copies/1000 RPP30; p=0.032) and CAR-T area under the curve to day 28 (356 vs 141 CAR19 copies/1000 RPP30 x days; p=0.039) compared with progressors or MRD-positive pts. Immunologic profiling of deep responders demonstrated significantly lower baseline and pre-leukapheresis CD8+/HLA-DR-/PD1+ Temra populations, consistent with a less exhausted pre-manufacture T-cell phenotype.


This time-limited combination of ibrutinib and tisa-cel is a highly effective treatment in RR-MCL leading to a high rate of durable responses, irrespective of prior BTKi exposure and/or TP53 status. Deep responses were correlated with more robust CAR-T expansion and a less exhausted baseline T-cell state. The safety profile was favourable.

Disclosures: Minson: Roche: Honoraria, Research Funding; Novartis: Other: Travel support, Research Funding. Hamad: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Cheah: Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Merck Sharp & Dohme: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Eli Lilly and Company: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Beigene: Consultancy, Honoraria. Tam: LOXO: Honoraria; AstraZeneca: Honoraria; Beigene: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Blombery: Adaptive Biotechnologies: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Servier: Honoraria. Lade: EUSA Pharma: Consultancy. Ritchie: BMS: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; MSD: Honoraria. Koldej: CRISPR Therapeutics: Research Funding. Anderson: Roche: Honoraria; Takeda: Honoraria; Novartis: Honoraria; Gilead: Honoraria; Astra Zeneca: Honoraria; Janssen: Honoraria; Abbvie: Honoraria; Walter and Eliza Hall Institute: Current Employment, Other: Employee of the Walter and Eliza Hall Institute which recieves milestone payments in relation to venetoclax to which I am entitled to a share. Khot: BMS: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Roche: Honoraria; Mundipharma: Honoraria; Novartis: Other: Travel Grant. Seymour: Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genor Biopharma: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau; BMS: 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, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees. Dickinson: Roche, BMS, Novartis, Kite, Gilead, NKARTA, AdiCet Bio, Interius, Janssen, MSD: Consultancy; Roche, BMS, Novartis, Kite, Gilead, NKARTA, AdiCet Bio, Interius, Janssen, MSD, Amgen: Honoraria; Roche, Novartis, Kite, Gilead, MSD, Takeda, Celgene: Research Funding.

*signifies non-member of ASH