Acalabrutinib, venetoclax, and obinutuzumab in relapsed/refractory CLL: final efficacy and ctDNA analysis of the CLL2-BAAG trial.

ABSTRACT: The phase 2 CLL2-BAAG trial tested the measurable residual disease (MRD)-guided triple combination of acalabrutinib, venetoclax, and obinutuzumab after optional bendamustine debulking in 45 patients with relapsed/refractory chronic lymphocytic leukemia (CLL). MRD was measured by flow cytometry (FCM; undetectable MRD <10-4) in peripheral blood (PB) and circulating tumor DNA (ctDNA) using digital droplet polymerase chain reaction of variable-diversity-joining (VDJ) rearrangements and CLL-related mutations in plasma. The median number of previous treatments was 1 (range, 1-4); 18 patients (40%) had received a Bruton tyrosine kinase inhibitor (BTKi) and/or venetoclax before inclusion, 14 of 44 (31.8%) had TP53 aberrations, and 34 (75.6%) had unmutated immunoglobulin heavy-chain variable region genes. With a median observation time of 36.3 months and all patients off-treatment for a median of 21.9 months, uMRD <10-4 in PB was achieved in 42 of the 45 patients (93.3%) at any time point, including 17 of 18 (94.4%) previously exposed to venetoclax/BTKi and 13 of 14 (92.9%) with TP53 aberrations. The estimated 3-year progression-free and overall survival rates were 85.0% and 93.8%, respectively. Overall, 585 paired FCM/ctDNA samples were analyzed and 18 MRD recurrences (5 with and 13 without clinical progression) occurred after the end of treatment. Twelve samples were first detected by ctDNA, 3 by FCM, and 3 synchronously. In conclusion, time-limited MRD-guided acalabrutinib, venetoclax, and obinutuzumab achieved deep remissions in almost all patients with relapsed/refractory CLL. The addition of ctDNA-based analyses to FCM MRD assessment seems to improve early detection of relapses. This trial was registered at www.clinicaltrials.gov as #NCT03787264.

Reassessing the chronic lymphocytic leukemia International Prognostic Index in the era of targeted therapies.

ABSTRACT: We evaluated the chronic lymphocytic leukemia International Prognostic Index (CLL-IPI) in patients with CLL treated first line with targeted drugs (n = 991) or chemoimmunotherapy (n = 1256). With a median observation time of 40.5 months, the 3-year progression-free survival (PFS) rates for targeted drug-treated patients varied by CLL-IPI risk group: 96.5% (low), 87.6% (intermediate), 82.4% (high), and 78.7% (very high). Differences between consecutive CLL-IPI risk groups were observed for intermediate vs low and high vs intermediate, but not very high vs high. CLL-IPI factors ß2-microglobulin, immunoglobulin heavy variable (IGHV) status, and TP53 status each retained prognostic value for PFS. The 3-year overall survival (OS) rates by CLL-IPI risk groups were 100%, 96%, 93.9%, and 89.4%, respectively, with no differences between consecutive risk groups. Age, Binet stage, ß2-microglobulin, and TP53 status each retained prognostic value for OS. In chemoimmunotherapy patients (median observation time, 66.9 months), 3-year PFS rates for CLL-IPI risk groups were 78.1%, 51.4%, 40.1%, and 16.5%, respectively; corresponding 3-year OS rates were 97.4%, 93.1%, 81.8%, and 57.3%. In a matched-pair analysis, PFS differences in targeted therapies (n = 812) vs chemoimmunotherapy (n = 812) across all risk groups and OS differences in all but patients at low risk were demonstrated. The CLL-IPI maintains its prognostic value in predicting PFS outcomes with targeted drugs, but its impact in predicting survival appears diminished. Targeted therapies showed enhanced outcomes over chemoimmunotherapy, highlighting their effectiveness across various risk groups. Our findings support ongoing assessment of prognostic tools in CLL treatment evolution. These trials were registered at www.ClinicalTrials.gov as #NCT02345863, #NCT02401503, #NCT02689141, #NCT02445131, #NCT02758665, #NCT02950051, #NCT02242942, #NCT00262782, #NCT00281918, and #NCT01010061.

Funcion de distintas formas de fibronectina en el desarrollo de foliculos bovinos in vitro / Role of different forms of fibronectin in in vitro bovine follicular development

En el presente estudio, se analizó la posibilidad de que las distintas formas de fibronectina (FN), producidas como resultado de la maduración alternativa (alternative splicing) del mensajero, ejerzan funciones diferenciales en el desarrollo folicular. En particular se determinó la presencia de la región ED-I, ausente en la FN plasmática, tanto a nivel de mensajero como de proteína, durante este proceso. El análisis de los niveles de FN en fluidos foliculares correspondientes a distintas etapas de desarrollo mostró marcadas variaciones en la concentración de FN ED-I+ y los de permanecieron relativamente constantes. En folículos corespondientes a la fase de selección se observó una correlación inversa entre los niveles de FN ED-I+ y los de estradio (p<0.001). El tratamiento con estradiol no tuvo efecto sobre el splicing alternativo de FN en cultivos de células de la granulosa bovinas, mientras que el AMPc tuvo un efecto inhibitorio sobre la incorporación de ED-I. Por otra parte, el factor de crecimiento transformante tipo beta (TGF-beta) estimuló tanto la produción de FN total como la inclusión de la región ED-I. Este efecto fue verificado tanto a nivel de la proteína (Western blots) como del ARN mensajero (Northern blots). Un péptido correspondiente a la región ED-I tuvo un efecto estimulatorio sobre el crecimento de una línea de células de la granulosa bovinas (BGC-1) mientras que el péptido correspondiente e las regiones flanqueantes no tuvo efecto. Los datos presentados en este estudio plantean una nueva forma de regulación mediante la cual cambios cualitativos en la estructura primaria de la FN podrían mediar algunas de las acciones de gonadotrofinas y factores intraováricos durante el desarrollo folicular.