Tisagenlecleucel Plus Ibrutinib Deemed “Highly Effective”

The combination of ibrutinib with tisagenlecleucel was “highly effective” in the phase 2 TARMAC trial, according to study presenter Adrian Minson, MBBS, of the University of Melbourne in Australia.2 

The trial (ClinicalTrials.gov Identifier: NCT04234061) included 20 evaluable patients with relapsed/refractory MCL who had received a median of 2 prior lines of therapy (range, 1-5). Half of patients had been exposed to ibrutinib.

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Patients not already taking ibrutinib at baseline started the drug (at 560 mg daily) at least 7 days prior to leukapheresis. Ibrutinib treatment continued through optional bridging therapy, through lymphodepletion (fludarabine and cyclophosphamide), and for at least 6 months after tisagenlecleucel infusion. 

About half of patients had a response to ibrutinib during the manufacturing phase, with the remaining 45% demonstrating refractory disease prior to tisagenlecleucel infusion, Dr Minson said.  

At day 28 after infusion, the overall response rate (ORR) was 85%. Most responders stopped ibrutinib around 6 months after tisagenlecleucel infusion, but 2 patients continued ibrutinib beyond that point due to minimal residual disease positivity.

The study’s primary endpoint was the CR rate at 4 months after tisagenlecleucel infusion. The CR rate was 80% in the overall cohort, 90% in patients who had not previously received ibrutinib and 70% in patients who were previously exposed to ibrutinib. 

At a median follow-up of 13 months, the median progression-free survival (PFS) was not reached. The 12-month PFS rate was 75%. The overall survival rate was 100%. 

Most patients (75%) had cytokine release syndrome (CRS), with 11 patients having grade 1-2 CRS and 4 patients having grade 3 CRS. One patient had grade 2 immune effector cell-associated neurotoxicity syndrome (ICANS), but it resolved. One patient had atrial fibrillation associated with sepsis prior to CAR T-cell infusion. 

Dr Minson said this study “provides strong support for further exploration of the combination of BTK inhibition and T-cell redirecting immunotherapies to better characterize the synergy between these agents and define the optimal role of the combination in treatment sequencing.”

Bispecific Antibody Compares Favorably With Other Therapies

Glofitamab produced durable CRs in a phase 1/2 trial of patients with heavily pretreated MCL, according to study presenter Tycel J. Phillips, MD, of the University of Michigan Medical School in Ann Arbor.3 

Tycel J. Phillips, MD

Glofitamab is a bispecific antibody targeting CD20 and CD3. Dr Phillips and colleagues tested glofitamab in a phase 1/2 trial (ClinicalTrials.gov Identifier: NCT03075696) of 37 patients with MCL. 

The patients had previously received a median of 3 lines of therapy (range, 1-5). In this trial, they received glofitamab at 2.5 mg on day 8 of cycle 1, at 10 mg on day 15 of cycle 1, and at 30 mg on day 1 of subsequent cycles, for a maximum of 12 cycles. Pretreatment with obinutuzumab was given to mitigate the risk of CRS. 

The ORR was 83.8%, and the CR rate was 73%. The median duration of CR was 10.0 months. At the data cutoff, 71.4% of patients with a CR remained in remission. In an analysis that excluded 4 patients who died from COVID-19, the median duration of CR was not reached, with 87% of CRs ongoing. 

The most common treatment-related AEs were CRS (73%), neutropenia (43.2%), anemia (21.6%), and AST increase (21.6%). There were 4 cases of grade 3 CRS and 2 cases of grade 4 CRS. Five patients had ICANS. 

“The duration of response is still currently too immature to compare with brexucabtagene autoleucel but compares favorably with other available options in relapsed MCL patients who had been exposed to a BTK inhibitor, such as chemoimmunotherapy, venetoclax, lenalidomide, or bortezomib,” Dr Phillips said. 

“This therapy may be close to CAR T-cell therapy [with regards to efficacy], with less toxicity and an off-the-shelf approach that would not require travel to a specialized center,” said Dr Hill, who was not involved in this study. “We look forward to the possibility of having bispecific agents such as glofitamab available to patients with relapsed/refractory MCL.”

Combination Zandelisib and Zanubrutinib Shows Early Promise 

Combining the PI3Kδ inhibitor zandelisib and the BTK inhibitor zanubrutinib produced a high ORR in a phase 1b trial of patients with relapsed/refractory MCL, according to study presenter Jacob D. Soumerai, MD, of Massachusetts General Hospital in Boston.4

This phase 1b trial (ClinicalTrials.gov Identifier: NCT02914938) enrolled 19 patients with MCL who had received a median of 1.5 prior lines of therapy (range 1-3). (The trial also enrolled patients with follicular lymphoma, but results for those patients are not reported here.)

The patients received zandelisib at 60 mg daily on days 1-7 of each 28-day cycle and zanubrutinib at 80 mg twice daily every day. Patients were treated until disease progression or intolerance.

The median follow-up was 7.4 months. The ORR was 72.2%, and the CR rate was 8%. The median duration of response was not reached, and the median PFS was 10.1 months.

Dr Soumerai noted that responses appear durable and seem to deepen over time, but additional follow-up is needed.

The most common AEs were diarrhea, neutrophil count decrease, platelet count decrease, blood creatinine increase, and anemia. One patient died from COVID-19-related complications.

Disclosures: The TRIANGLE trial was supported by Janssen, the TARMAC trial was partly supported by Novartis, the glofitamab trial was supported by Hoffmann-La Roche, and the zandelisib-zanubrutinib trial was supported by MEI Pharma, Inc. Disclosures for Dr Dreyling, Dr Phillips, Dr Minson, and Dr Soumerai can be found in the references below. Disclosures for Dr Flowers can be seen here. Dr Hill disclosed affiliations with AbbVie, Genentech, Pharmacyclics, AstraZeneca, Beigene, and Gilead. 


1. Dreyling M, Doorduijn JK, Gine E, et al. Efficacy and safety of ibrutinib combined with standard first-line treatment or as substitute for autologous stem cell transplantation in younger patients with mantle cell lymphoma: Results from the randomized Triangle trial by the European MCL Network. Presented at ASH 2022. December 10-13, 2022. Abstract 1.  

2. Minson A, Hamad N, Cheah CYY, et al. 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. Presented at ASH 2022. December 10-13, 2022. Abstract 75. 

3. Phillips TJ, Dickinson M, Morschhauser F, et al. Glofitamab monotherapy induces high complete response rates in patients with heavily pretreated relapsed or refractory mantle cell lymphoma. Presented at ASH 2022. December 10-13, 2022. Abstract 74. 

4. Soumerai JD, Diefenbach CS, Samaniego F, et al. Safety and efficacy of the PI3Kδ inhibitor zandelisib in combination with the BTK inhibitor zanubrutinib in patients with relapsed/refractory (R/R) follicular lymphoma (FL) or mantle cell lymphoma (MCL). Presented at ASH 2022. December 10-13, 2022. Abstract 78.