220 | HIGH EFFICACY OF BRIEF BRAF AND MEK COINHIBITION, ALONE AND COMBINED WITH ANTI‐CD20 IMMUNOTHERAPY, IN RELAPSED/REFRACTORY HAIRY CELL LEUKEMIA: A PHASE‐2 TRIAL
Bibliographic record
Abstract
Introduction: ∼50% of HCL patients (pts) relapse after purine analogs (PA) chemotherapy. Vemurafenib (VEM), an oral inhibitor of the BRAF-V600E kinase mutation (genetic cause of HCL; Tiacci et al. NEJM, 2011), proved active when given for a few months to R/R pts (∼35% complete remissions/CR—Tiacci, Park et al. NEJM, 2015). Still, minimal residual disease/MRD persisted in the bone marrow (BM) even in CR pts and the median progression-free survival (PFS) was ∼1 year. Moreover, BM HCL cells often showed ERK phosphorylation (pERK+) despite ongoing BRAF inhibition by VEM, suggesting bypass MEK/ERK reactivation downstream of BRAF as resistance mechanism. BRAF+MEK coinhibition with dabrafenib + trametinib, given to BRAF inhibitor-naïve pts for an indefinite duration (median ∼3 years), led to 66% CR but still rare MRD-negativity (16%; Kreitman et al. Blood, 2023); such a continuous therapy sustained a high PFS at 2 years (94%) but led to frequent serious toxicities (35% of pts). Adding rituximab/RTX (8 doses) to a short VEM course (8 weeks) yielded 87% CR, frequent MRD-negativity (60%), 78% PFS at ∼3 years of median follow-up, and few clinically relevant toxicities (3% of pts) (Tiacci et al. NEJM, 2021). To improve these results, we tested in R/R HCL a brief BRAF+MEK coinhibition (with VEM + cobimetinib/COB) combined to obinutuzumab/OBI (potentially more active than RTX), after establishing the currently unknown efficacy and safety of VEM+COB in HCL. Methods: We enrolled 19 R/R pts (median age 58 years; median of 3 previous therapies, including BRAF inhibitor ± RTX in 4 pts [21%]) in a phase-2 multicenter trial testing VEM (960 mg bid) + COB (60 mg daily, 21 days on/7days off) for 2–3 cycles (28 days each), followed at disease progression (PD) by another brief course of VEM+COB combined to OBI (8 doses over 6 cycles, starting together with VEM+COB). Results: VEM+COB toxicity was as expected and manageable. Clinical events (i.e., not laboratory-only abnormalities) were mostly grade 1–2, consisting mainly in rash due to either drug; arthralgia and photosensitivity due to VEM; and diarrhoea, oral aphthosis and serous retinopathy due to COB. 17/19 pts responded (89%), and 13 of 18 evaluable pts had a CR (72%; 1/13 MRD-). BM pERK+ HCL cells were detected in only 1/9 (11%) evaluable pts. Median PFS was long, 42 months, and a sizable pts subset (4/19, 21%) is free from PD at > 5 years. Of 12 pts with PD, 5 have not (or not yet) received VEM+COBI+OBI for various reasons, while 7 were treated with this short regimen 22–79 months after VEM+COB. All 7 pts (100%) obtained MRD- CR, and are free from cytopenia recurrence at 4–51 months (n = 6 pts) or had a cytopenia relapse at 44 months (n = 1 pt); only 2 clinically relevant toxicities were recorded. Conclusions: Brief BRAF+MEK coinhibition with VEM+COB, especially if boosted by anti-CD20 immunotherapy through OBI, is very effective in R/R HCL (see Figure), and compares well with other strategies tested in this setting. Encore Abstract: EHA 2025 Keywords: molecular targeted therapies; combination therapies; indolent non-Hodgkin lymphoma No potential sources of conflict of interest.
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 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".