SYMPATICO Trial: Ibrutinib Plus Venetoclax Improves Progression-Free Survival in Relapsed Mantle Cell Lymphoma

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The combination of ibrutinib and venetoclax has led to an improved progression-free survival rate in patients with relapsed or refractory mantle cell lymphoma (MCL), according to findings presented at the 2023 American Society of Hematology (ASH) Annual Meeting & Exposition.1

Interim analysis of the phase III SYMPATICO trial showed a median progression-free survival of 31.9 months with the ibrutinib/venetoclax combination compared with 22 months when ibrutinib was used with placebo (hazard ratio [HR] = 0.65; P = .0052). There was also a significant improvement in overall response rate across the entire study population with the combination regimen, with 82% of patients responding to the intervention compared with 74% of those given ibrutinib plus placebo.

Given the challenging treatment landscape of relapsed mantle cell lymphoma, where available therapies often have short-lived effects, these findings may signal a major advance for patients in need of treatment options. However, many experts noted, ibrutinib is no longer approved for MCL in the United States.

Michael Wang, MD

Michael Wang, MD

“The ibrutinib/venetoclax combination achieved a statistically significant improvement in progression-free survival compared with ibrutinib alone, and this combination showed a robust benefit across all sensitivity analyses,” said lead study author Michael Wang, MD, Professor in the Department of Lymphoma and Myeloma at The University of Texas MD Anderson Cancer Center, Houston. “While the overall survival was not statistically significant at this interim analysis, the improved response rates and safety profile in patients with relapsed or refractory MCL suggest this combination therapy should be considered a new standard treatment in countries where ibrutinib is indicated.”

Ibrutinib, an oral Bruton’s tyrosine kinase inhibitor, and venetoclax, a BCL2 inhibitor, have been individually approved in several countries for the treatment of different types of blood cancers. Emerging evidence suggests the synergistic antitumor activity of these two agents may be leveraged for the treatment of relapsed or refractory MCL.

Study Details

The double-blind, multinational, placebo-controlled, phase III ­SYMPATICO study sought to investigate the efficacy and tolerability of the combination of ibrutinib and venetoclax in adults with relapsed or refractory MCL who had one to five prior treatments. Patients were randomly assigned to receive oral ibrutinib concurrently with venetoclax or placebo, followed by a continuous treatment phase for 24 months until progressive disease or unacceptable toxicity. Investigators stratified patients based on Eastern Cooperative Oncology Group performance status, prior lines of therapy, and tumor-­lysis syndrome risk based on tumor burden and creatinine clearance.


  • The combination of ibrutinib and venetoclax yielded significant improvement in progression-free survival in patients with relapsed mantle cell lymphoma, according to an interim analysis of the phase III SYMPATICO trial.
  • The safety profile of the combination therapy was consistent with the previously known adverse events for each single agent.

In addition to the improvements in duration of response seen with ibrutinib/venetoclax, the investigators reported a statistically significant improvement in complete response rates, with 54% of the combination group achieving a complete response vs 32% of the placebo group. Long-term assessment and follow-up also showed a significantly longer median duration of response with the combination (42.1 months) vs venetoclax plus the placebo (27.6 months).

The median overall survival in the combination group was 49.9 months vs 38.6 months in the placebo group. Although these results were not statistically significant at the interim analysis, Dr. Wang emphasized that longer follow-up data would be obtained.

The safety profile of the combination therapy was consistent with the known adverse events of each single agent, noted Dr. Wang, and he suggested there were no new safety signals. The most frequent adverse events included diarrhea, neutropenia, nausea, and fatigue.

According to Dr. Wang, these findings may herald a new era of better treatment options for patients with relapsed MCL. 

DISCLOSURE: Dr. Wang has consulted for AbbVie, Acerta Pharma, ADC Therapeutics America, Amphista Therapeutics Limited, AstraZeneca, BeiGene, bE Biopharma, BioInvent, Bristol Myers Squibb, Deciphera, Genentech, InnoCare, Janssen, Kite Pharma, Lilly, Merck, Miltenyi Biomedicine, Oncternal, Parexel, Pepromene Bio, and Pharmacyclics; has recieved research funding from Acerta Pharma, AstraZeneca, BeiGene, BioInvent, Celgene, Genmab, Genentech, Innocare, Janssen, Juno Therapeutics, Kite Pharma, Lilly, Loxo Oncology, Molecular Templates, Oncternal, Pharmacyclics, and Vincerx; and has received honoraria from AbbVie, Acerta Pharma, AstraZeneca, BeiGene, BioInvent, Bristol Myers Squibb, CAHON, Catamount Medical Education, Dava Oncology, Genmab, Janssen, Kite Pharma, MJH Life Sciences, Merck, MSC National Research Institute of Oncolgy, NIH, Nurix, Pharmacyclics, Physicians Education Resources (PER), Research to Practice, Scripps, Studio ER Congressi, South African Clinical Hematology Society, and WebMD.


1. Wang M, Jurczak W, Trněný M, et al: Ibrutinib combined with venetoclax in patients with relapsed/refractory mantle cell lymphoma. 2023 ASH Annual Meeting & Exposition. Abstract LBA-2. Presented December 12, 2023.


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