Reply to: Ibrutinib plus venetoclax for patients with relapsed or refractory mantle cell lymphoma: an editorial on the phase 3 SYMPATICO trial
We thank Dr. Reef and Dr. Grover for their thoughtful commentary on the results of the SYMPATICO study (1), which were recently published in Lancet Oncology (2). We agree that ibrutinib combined with venetoclax provides a valuable treatment option for patients with mantle cell lymphoma (MCL), particularly those with TP53 mutations.
Although TP53 mutation status was unknown in 25% of patients, the 40 patients with TP53 mutations treated with ibrutinib plus venetoclax in the randomized phase of SYMPATICO represent the largest single-study cohort of patients with MCL and TP53 mutations reported to date. Median progression-free survival (PFS) in the randomized phase was 19.8 months with ibrutinib plus venetoclax vs. 10.9 months with ibrutinib plus placebo. Additional patients with TP53 mutations were treated with ibrutinib plus venetoclax in the safety run-in phase (n=5) and in the treatment-naive cohort (n=29) for a total of 74 patients across all three cohorts of the SYMPATICO study (3). Results for these 74 patients were presented at the 2024 annual meeting of the American Society of Clinical Oncology and reinforced the high complete response (CR) rates and durable remissions achieved with ibrutinib plus venetoclax in patients with TP53 mutations (3).
Progression of disease within 24 months (POD24) is an independent predictor of worse overall survival (OS) in patients with MCL (4). In SYMPATICO, POD24 after first-line therapy was identified (based on date of progression or start of next-line therapy) in 52 patients in the ibrutinib plus venetoclax arm vs. 55 patients in the ibrutinib plus placebo arm. Among these patients, median PFS was 15.9 vs. 11.0 months, and 6-month PFS estimates were 67% vs. 56% (Table 1). Median OS was 23.2 vs. 17.1 months, the overall response rate was 69% vs. 64%, and the CR rate was 39% vs. 24% (Table 1). Although not statistically significant, these data suggest an advantage with ibrutinib plus venetoclax vs. ibrutinib plus placebo in patients with a prior history of early progression.
Table 1
| Outcomes | Ibrutinib plus venetoclax (n=59) | Ibrutinib plus placebo (n=67) |
|---|---|---|
| PFS | ||
| Median PFS (95% CI), months | 15.9 (7.3–29.5) | 11.0 (5.5–22.1) |
| 6-month PFS rate [95% CI], % | 67 [52–78] | 56 [42–68] |
| Hazard ratio (95% CI) | 0.71 (0.45–1.12) | |
| P value | 0.14 | |
| OS | ||
| Median OS (95% CI), months | 23.2 (12.7–50.5) | 17.1 (12.0–35.7) |
| Hazard ratio (95% CI) | 0.76 (0.47–1.23) | |
| P value | 0.27 | |
| ORR | ||
| ORR [95% CI], % | 69 [55–81] | 64 [50–76] |
| Rate ratio (95% CI) | 1.055 (0.808–1.378) | |
| P value | 0.70 | |
| CR | ||
| CR [95% CI], % | 39 [25–53] | 24 [13–37] |
| Rate ratio (95% CI) | 1.626 (0.901–2.904) | |
| P value | 0.10 | |
CI, confidence interval; CR, complete response; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; POD24, progression of disease within 24 months.
Dr. Reef and Dr. Grover note a small increase in grade 5 cardiac and hemorrhagic adverse events (AEs) with ibrutinib plus venetoclax relative to ibrutinib plus placebo. Of the four grade 5 cardiac AEs in the ibrutinib plus venetoclax arm, one event (cardiac arrest) was considered possibly related to ibrutinib; the other three events were deemed unrelated to either study drug (Table 2). These four cases were confounded by liver transplant and cardiac risk factors in one patient, multiple cardiac risk factors in two other patients, and advanced age in the 4th patient. Overall, treatment-emergent cardiac disorders (identified by system organ class) were balanced across treatment arms, with events of any grade reported in 35/134 patients (26%) with ibrutinib plus venetoclax vs. 35/132 patients (27%) with ibrutinib plus placebo, grades 3–4 events in 14/134 (10%) vs. 17/132 (13%), and grade 5 events in 2/134 (1%) vs. 1/132 (1%). Treatment-emergent cardiac arrhythmias [identified by Cardiac Arrhythmia Standardized MedDRA Query (SMQ) excluding “atrial fibrillation”] were slightly increased with ibrutinib plus venetoclax vs. ibrutinib plus placebo, with events of any grade reported in 30/134 (22%) vs. 18/132 (14%) patients, grades 3–4 events in 7/134 (5%) vs. 6/132 (5%), and grade 5 events in 4/134 (3%) vs. 0. Neither of the two grade 5 hemorrhagic AEs were considered related to study treatment (Table 2). These two cases appeared to be related to anticoagulation therapy in one case and to a mechanical fall in the other case. Overall, there was a slight increase in treatment-emergent bleeding events (identified by Hemorrhage SMQ, excluding laboratory terms) with ibrutinib plus venetoclax vs. ibrutinib plus placebo, with events of any grade reported in 61/134 (46%) vs. 50/132 (38%) patients, grades 3–4 events in 8/134 (6%) vs. 7/132 (5%), and grade 5 events in 2/134 (1%) vs. 0.
Table 2
| Event (age/sex) | Related to study drug (yes/no) | Clinical course |
|---|---|---|
| Cardiac arrest (69 years/male) | Yes | Medical history of HCV/HBV cirrhosis and liver transplant with multiple cardiac risk factors (diabetes mellitus, arterial hypertension, high cholesterol) |
| Found dead at home on day 323 | ||
| Cause of death reported as cardiac arrest | ||
| Cardiac arrest (77 years/male) | No | Multiple cardiac risk factors (atrial fibrillation, arterial hypertension, coronary artery disease, hyperlipidemia, diabetes mellitus, pulmonary embolism) |
| Hospitalized for bilateral pleural effusions; persistent atrial fibrillation/flutter observed during admission | ||
| Multiple episodes of atrial fibrillation and cardiac arrhythmias reported during the study | ||
| Transferred to hospice due to continued clinical decline and died 2 days later on day 108 due to cardiac arrest | ||
| Cardiac death (68 years/male) | No | Multiple cardiac risk factors (arterial hypertension, coronary artery disease, coronary angioplasty, right bundle branch block, myocardial infarction, myocardial ischemia, obesity) |
| Found dead at home on day 15 | ||
| Resuscitation team noted “asystole” | ||
| Sudden death (86 years/male) | No | No cardiac risk factors |
| Found dead at home on study day 636 | ||
| Cause of death reported as sudden death by the investigator who found the patient | ||
| Subarachnoid hemorrhage (76 years/male) | No | Received study drugs for only 21 days without reaching target dose of 400 mg venetoclax; stopped dosing during the ramp up in week 3 with a dose of 100 mg |
| Medical history of atrial fibrillation, COPD, osteoarthritis | ||
| On rivaroxaban for atrial fibrillation | ||
| Grade 2 atrial flutter on day 15, grade 3 atrial flutter on day 20, grade 4 subarachnoid hemorrhage on day 21, died on day 23 | ||
| Intracranial bleeding (67 years/male) | No | Medical history of diabetes mellitus, arterial hypertension, obesity |
| Grade 2 cardiac decompensation on day 77, ongoing until death | ||
| Fall with grade 5 intracranial bleeding on day 195 |
COPD, chronic obstructive pulmonary disease; HBV, hepatitis B virus; HCV, hepatitis C virus.
With an increasing proportion of patients receiving first-line BTK inhibitor-based therapy, Dr. Reef and Dr. Grover justifiably raise the question of appropriate treatment sequencing for MCL. Unfortunately, results from SYMPATICO do not provide insight into the efficacy of ibrutinib plus venetoclax after prior BTK inhibitors because patients were excluded if they had previously received BTK inhibitors or BCL2 inhibitors. However, we note that European Society of Medical Oncology guidelines recommend the use of covalent BTK inhibitors alone or combined with venetoclax in patients with relapsed/refractory MCL, including in those who have relapsed after first-line BTK inhibitor-based treatment (5).
To date, limited data are available regarding combinations of venetoclax with second-generation BTK inhibitors in patients with MCL, and we caution against extrapolation of data from SYMPATICO to inform the use of such combinations. Phase 2 trials are currently ongoing to evaluate combinations of venetoclax with acalabrutinib (NCT03946878), zanubrutinib (NCT05168930), or pirtobrutinib (NCT05529069) in patients with relapsed/refractory MCL, with results expected in 2026–2027. In the first-line setting, results from the treatment-naive cohort of SYMPATICO showed high CR rates and durable remissions in patients ≥65 years or of any age with a TP53 mutation (6). Several phase 2 trials are ongoing to evaluate triplet combinations of BTK inhibitors with anti-CD20 antibodies and venetoclax for MCL, including ibrutinib plus anti-CD20 plus venetoclax (OASIS II; NCT04802590) (7), acalabrutinib plus venetoclax plus rituximab (TrAVeRse; NCT05951959) (8), acalabrutinib plus venetoclax plus obinutuzumab (MAVO; NCT04855695) (9), and zanubrutinib plus obinutuzumab plus venetoclax (BOVen; NCT03824483) (10). Preliminary results from these studies were recently reported, showing high rates of CR (63% to 100%) and MRD negativity (79% to 100%) in patients with previously untreated MCL (7-10). Additionally, the ongoing phase 1/2 GLOVe study (NCT05861050) is evaluating the combination of glofitamab, lenalidomide, and venetoclax in patients with previously untreated MCL; preliminary results in 20 evaluable patients showed CR in 100% of patients and MRD negativity in 95% (11).
The combination of ibrutinib and venetoclax has an important role in the treatment of MCL globally and is approved for relapsed/refractory MCL in several countries.
Acknowledgments
AbbVie and the authors thank the patients who participated in the study and their supportive families, as well as the investigators, study coordinators, study teams, and nurses who cared for the patients. Medical writing support was provided by Melanie Sweetlove, MSc, and funded by AbbVie.
Footnote
Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article did not undergo external peer review.
Funding:
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-26-0007/coif). M.W. reports honoraria from Acerta Pharma, Anticancer Association, AstraZeneca, BeiGene, BGICS, BioInvent, CAHON, Chinese Medical Association, Clinical Care Options, Dava Oncology, Eastern Virginia Medical School, Epizyme, Hebei Cancer Prevention Federation, Imedex, Janssen, Kite Pharma LLC, TS Oncology, Miltenyi Biomedicine GmbH, Moffitt Cancer Center, Mumbai Hematology Group, Newbridge Pharmaceuticals, OMI, OncLive, Physicians Education Resources (PER), Practice Point Communications (PPC), Scripps, The First Affiliated Hospital of Zhejiang University, and Pharmacyclics LLC, an AbbVie Company; consulting/advisory role for AstraZeneca, Bayer Healthcare, BeiGene, BioInvent, CStone, DTRM Biopharma (Cayman) Limited, Epizyme, Genentech, InnoCare, Janssen, Juno Therapeutics, Kite Pharma, Loxo Oncology, Miltenyi Biomedicine GmbH, Oncternal, VelosBio, and Pharmacyclics LLC, an AbbVie Company; research funding from Acerta Pharma, AstraZeneca, BeiGene, BioInvent, Celgene, Genentech, InnoCare, Janssen, Juno Therapeutics, Kite Pharma, Lilly, Loxo Oncology, Molecular Templates, Oncternal, VelosBio, and Pharmacyclics LLC, an AbbVie Company; travel/accommodations/expenses from Physician Education Resources (PER), Kite, Janssen, AstraZeneca, Acerta Pharma, Juno Therapeutics, Celgene, Loxo Oncology, VelosBio, Verastem, Molecular Templates, BioInvent, Oncternal, and Pharmacyclics LLC, an AbbVie Company. J.K.N. reports employment and stock or other ownership with AbbVie. C.S.T. reports honoraria from Janssen, AbbVie, LOXO, and BeiGene; and research funding from Janssen, AbbVie, and BeiGene. All authors had access to relevant data and participated in the drafting, review, and approval of this publication. No honoraria or payments were made for authorship. The authors have no other conflicts of interest to declare.
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References
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Cite this article as: Wang M, Neuenburg JK, Tam CS. Reply to: Ibrutinib plus venetoclax for patients with relapsed or refractory mantle cell lymphoma: an editorial on the phase 3 SYMPATICO trial. AME Clin Trials Rev 2026;4:21.
