ALBERT

Description: BH3 mimetics are promising drugs for hematologic malignancies that trigger cell death by promoting the release of proapoptotic BCL2 family members from antiapoptotic proteins. Multiple myeloma is considered to be a disease dependent mainly on MCL1 for survival, based mostly on studies using cell lines. We used a BH3-mimetic toolkit to study the dependency on BCL2, BCLXL, or MCL1 in malignant plasma cells from 60 patients. Dependencies were analyzed using an unbiased BH3 mimetics cell-death clustering by k-means. In the whole cohort of patients, BCL2 dependency was mostly found in the CCND1 subgroup (83%). Of note, MCL1 dependence significantly increased from 33% at diagnosis to 69% at relapse, suggesting a plasticity of the cellular dependency favoring MCL1 dependencies at relapse. In addition, 35% of overall patient samples showed codependencies on either BCL2/MCL1 or BCLXL/MCL1. Finally, we identified a group of patients not targeted by any of the BH3 mimetics, predominantly at diagnosis in patients not presenting the common recurrent translocations. Mechanistically, we demonstrated that BAK is crucial for cell death induced by MCL1 mimetic A1210477, according to the protection from cell death observed by BAK knock-down, as well as the complete and early disruption of MCL1/BAK complexes on A1210477 treatment. Interestingly, this complex was also dissociated in A1210477-resistant cells, but free BAK was simultaneously recaptured by BCLXL, supporting the role of BCLXL in A1210477 resistance. In conclusion, our study opens the way to rationally use venetoclax and/or MCL1 BH3 mimetics for clinical evaluation in myeloma at both diagnosis and relapse.

Description: Objectives: To evaluate the therapeutic response to treatment with transcriptional therapy that combines hydralazine / valproate(Transkrip) in cancer patients with cutaneous T-cell lymphoma Determine toxicity, duration of response and time to progression of epigenetic therapy with hydralazine / valproate in patients with T-cell lymphomas Material and methods an open-label, phase II, prospective and longitudinal in the National Cancer Institute of Mexico was carried out, recruiting patients diagnosed with Cutaneous T based on WHO classification 2008, newly diagnosed untreated, demographic data were analyzed and vital and somatometry signs, assessment of efficacy was established according to the therapeutic response in lymphomas measured at each visit at the affected sites for each patient, using the m-SWAT system sorted in complete response (CR), partial response (PR ), stable disease (SD) and progression (PE) and is considered response to patients with complete or partial response, these data were collected in the form of case report at baseline in the first consultation, during treatment and at the end the study at each visit to the doctor. Statistical analysis was performed with SPSS version 13.0 software. results 16 patients were selected with diagnosis of cutaneous T-cell lymphoma, one patients discontinued the study at baseline and 4 patients had disease progression during the first months of the study, a total of 10 patients who completed 18 months of study continuing the compassionate use treatment. The median age of patients was 45.8 years analyzed (18-83 years) of which 8 are women (53%) and 7 men (47%) with an ECOG 1 in 93.3% of patients, with an average weight of 72.5 ± 15.99 kg, height 1.6 ± 0.1 m, body mass index 28.3 ± 5.7 kg / m2, 46.7% of overweight patients, systolic blood pressure an average of 116.2 ± 14.3 mmHg and diastolic 75.1 ± 11.04 mmHg with respiratory rate 19.43 ± 1.74 resp / min and 77.8 ± 12.3 cardiac beats / min. Of the 10 patients who completed the study, 100% had complete or partial response itching to 6 month continuing unchanged at month 18, the dream as an adverse event occurred in 33% of patients, this being more frequent, adverse events attributed to the drug were known, expected and mild. From 6 months of treatment, the percentage of partial response and complete response of m-SWAT and pruritus were greater than 90% of patients. conclusions: Hydralazine/Valproate (Transkrip) is a medication that offers patients with cutaneous T-cell lymphoma, both first-line and refractory, a therapeutic alternative with high efficiency and good safety profile. Disclosures No relevant conflicts of interest to declare.