Rationale for the combination of venetoclax and ibrutinib in T-prolymphocytic leukemia
Bibliographic record
Abstract
Rationale for the combination of venetoclax and ibrutinib in T-prolymphocytic leukemia T-prolymphocytic leukemia (T-PLL) is an aggressive mature T-cell neoplasm that responds poorly to conventional chemotherapy and has a dismal outcome. 1 Patients with active T-PLL present with an exponential rise of post-thymic T cells with prolymphocytic morphology, hepatosplenomegaly, skin rash, lymphadenopathy, and effusions.1 T-PLL cells commonly demonstrate rearrangements involving T-cell leukemia/lymphoma 1 (TCL1) family genes TCL1A, MTCP1 (mature T-cell proliferation), or TCL1B as molecular hallmarks.2 The anti-CD52 antibody alemtuzumab has improved initial responses up to 90%; however, nearly all cases eventually relapse, and allogeneic stem cell transplantation remains the only curative treatment option for a small subset of patients.3 Recently, we and others have demonstrated in vitro activity and clinical efficacy of the Bcl-2 inhibitor venetoclax as a single agent in relapsed/refractory T-PLL (r/r-T-PLL).4,5 Since clinical responses were transient, we set out to identify effective combination partners for venetoclax.We probed putative mechanisms and demonstrated clinical feasibility and activity of a putative combination by treating two patients with active, r/r-T-PLL.We employed combinatorial drug screening to identify synergistic combination partners to enhance the efficacy of venetoclax in T-PLL patients.Twenty-four candidate compounds were selected based on their clinical approval status, literature data, and mechanisms of drug action.Venetoclax was used in pairwise combinations (Figure 1A) in primary T-PLL samples with a mean post-thawing viability of 93% and mean purity of 94% (Table 1).Drug screening was performed as previously described.4 Here ibrutinib demonstrated the strongest synergism with
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.003 | 0.009 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.002 | 0.003 |
| Scholarly communication | 0.003 | 0.002 |
| Open science | 0.002 | 0.001 |
| Research integrity | 0.024 | 0.031 |
| Insufficient payload (model declined to judge) | 0.006 | 0.005 |
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 source (direct Gemma or distilled Codex), 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".