Efficacy and safety of ibrutinib plus venetoclax in patients with mantle cell lymphoma (MCL) and <i>TP53</i> mutations in the SYMPATICO study.
Bibliographic record
Abstract
7007 Background: TP53 mutations confer high risk of early progressive disease (PD) and poor outcomes with standard chemoimmunotherapy in patients (pts) with MCL. To date, data on novel treatment options for these pts are limited to small single-arm analyses. The phase 3 SYMPATICO study is evaluating ibrutinib (Ibr) + venetoclax (Ven) in 3 cohorts of pts with MCL. Primary analysis of the randomized phase showed superior PFS with Ibr+Ven vs Ibr+placebo (Pbo) in pts with relapsed/refractory (R/R) MCL (Wang M et al, ASH 2023) with similar hazard ratios for pts with and without TP53mutations (0.57 [95% CI, 0.33–0.97] and 0.52 [95% CI, 0.32–0.82], respectively). Here, we report efficacy and safety of Ibr+Ven in pts with TP53 mutations across cohorts. Methods: The SYMPATICO cohorts are: open-label safety run-in phase to evaluate concurrent initiation of Ibr+Ven in R/R MCL (n=21); randomized phase to evaluate Ibr+Ven (n=134) vs Ibr+Pbo (n=133) in R/R MCL; and open-label cohort to evaluate first-line (1L) Ibr+Ven (n=78). Data were pooled across cohorts for pts with TP53mutations treated with oral Ibr 560 mg once daily and Ven (5-wk ramp-up to 400 mg once daily) for 2 y, then single-agent Ibr 560 mg until PD or unacceptable toxicity. Response was assessed by investigators per Lugano criteria. Results: In total, 74 pts with TP53 mutations received Ibr+Ven in the safety run-in phase (n=5), the randomized phase (n=40), and the 1L cohort (n=29). At baseline, median age was 67 y, 96% of pts had ECOG PS of 0–1, 43% had high-risk simplified MIPI score, 36% had bulky disease ≥5 cm, 64% had bone marrow involvement, and 39% had splenomegaly. With a median time on study of 40.1 mo (range, 0.6+ to 60.7), median PFS was 20.9 mo vs not reached (NR) in pts without TP53 mutations. ORR was 84%, and the CR rate was 57%. Median OS was 47.1 mo. Outcomes were generally comparable in 1L and R/R MCL (Table). Median duration of treatment was 15.9 mo (range, 0.3–58.9); at data cutoff, treatment was ongoing with Ibr in 24% of pts and with Ven in 4%. The most frequent grade ≥3 AEs (in ≥10% of pts) were neutropenia (32%), anemia (15%), and thrombocytopenia (15%). Conclusions: Ibr+Ven demonstrated promising efficacy with high CR rates and durable remissions in high-risk pts with MCL and TP53mutations in SYMPATICO (n=74; 29 1L and 45 R/R), the largest single-study cohort of such pts reported to date. Clinical trial information: NCT03112174 . [Table: see text]
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.003 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".