Chr del(17p) + Chr del(11q)

Background: Treatment with combined covalent BTK-inhibitor (cBTKi such as ibrutinib, acalabrutinib, zanubrutinib) withBCL2-inhibitor, venetoclax +/- CD20 monoclonal antibody obinutuzumab showed high rates of undetectableMRD (U-MRD) remission in patients (pts) with CLL (Jain, NEJM 2019; Munir NEJM 2023; Wierda, JCO 2021; Kater, NEJM Evidence 2022). We report the first results for first-line combined pirtobrutinib, venetoclax, and obinutuzumab in pts with CLL. Avery high rate of bone marrow U-MRD at 10-6 sensitivity was noted at 6-months of combined treatment. Adverse event profile was similar to what was noted in previous studies with these agents.

Our analysis revealed that specific genetic mutations and chromosomal alterations are strongly associated with the disease's course and patient prognosis. Particularly, the presence of unmutated IGHV and TP53 mutations emerged as key indicators of a more aggressive disease course and shorter treatment-free intervals. These findings underscore the critical role of advanced genetic testing in identifying patients who may require more intensive treatment and monitoring.

Background: A phase II trial has shown, first-line treatment with iFCG (ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab) led to a bone marrow (BM) undetectable minimal residual disease (uMRD) rate of 98% (44/45) as best response in treatment-naïve patients with chronic lymphocytic leukemia/small lymphocytic leukemia (CLL/SLL). This is the first clinical trial exploring the efficacy and safety of the second generation BTKi plus chemoimmunotherapy in patients with CLL. The OFCG regimen shows a rapid and deep molecular remission with a pleasant safety profile in the TN CLL patients including the ones with unfavorable factors.

Using a comprehensive list of matching variables, this MAIC compares the performance of ibrutinib across ALPINE and ELEVATE-RR trials and demonstrates no evidence of a difference. Comparing the common comparator arms of 2 trials (ibrutinib vs ibrutinib) instead of the different investigational arms (zanubrutinib vs acalabrutinib) allows for eliminating some of the residual confounding that is inherent in MAICs. Despite decreased estimated sample size due to considering a comprehensive list of variables in the adjustment, results were consistent across multiple scenarios tested.

In this real-world study using a large community healthcare dataset, CLL/SLL patients with high-risk molecular-cytogenetic features (del[17p], or del[11q], or unmutated IGHV) treated with 1L ibrutinib had similar OS compared to patients without high-risk features. Importantly, similar findings were observed in the high-risk sensitivity analysis and the Medicare subgroup.

With a planned 24 evaluable pts in phase II, the target ORR will be 60%, which was selected due to a recent phase I/II study of pirtobrutinib enrolling a similar CLL pt population demonstrating an ORR of the drug ~63%. ORR will be summarized by the observed proportion and an exact one-sided 95% confidence interval (Clopper-Pearson method). With 24 evaluable pts, the lower bound of the confidence interval will be approximately 17-20% below the observed proportion for observed ORR near 60%, which is an acceptable level of precision in a dose expansion cohort.

IGLV3-21R110 was identified as an independent prognostic factor for shorter EFS in early stage CLL with intermediate/high risk score and was associated with reduced ibrutinib efficacy in the CLL12 trial.

To gain further insight into the genetic mechanisms of cBTKi resistance in a randomized population of pts with CLL, we performed next-generation sequencing (NGS) on samples from pts who had progression on zanubrutinib (zanu) or ibrutinib (ibr) in the phase 3 ALPINE study (NCT03734016; Brown et al. Of the 52 pts, most (82.6%) did not have acquired BTK or PLCG2 mutations. Among the zanu pts, 3/24 (12.5%) developed non-C481 BTK mutations. This rate was lower than that reported by Woyach et al (ICML 2023); shorter follow-up and fewer prior therapies in the ALPINE study may explain this discrepancy.

Sponsored by AstraZeneca Background: The 1 st -generation Bruton’s Tyrosine Kinase inhibitor (BTKI) ibrutinib compared in randomized clinical trials (RCTs) with 2 nd -generation BTKIs Acala (ELEVATE-RR) & Zanu (ALPINE). Acala & Zanu have a similar efficacy in patients with RR CLL, while Acala has a lower risk of grade ≥ 3 hemorrhage, any grade and grade ≥ 3 hypertension and dose reduction due to AEs vs Zanu.

In phase 3 randomized trials in R/R CLL, ibrutinib was associated with robust PFS and ORR benefits. Ibrutinib outcomes were consistent between RESONATE and ELEVATE-RR; however, differences were identified between RESONATE and ALPINE. Indirect comparisons have limitations (each trial, protocol, and patient profile are unique), but these results highlight the need to investigate elements of protocol design, center selection, or treatment delivery that may impact BTKi trial performance.

Also, the goodness of model fit was enhanced (χ2 = 20.1, P=0.002), indicating its improved performance above the basic prognostic model. In conclusion, DSAF-GS identified a group of significant genes for CLL prognosis, suggesting future directions for bio-molecular research.

Acalabrutinib seems to determine, like Ibrutinib, an increase of ALC immediately after the starting of therapy. Therefore, lymphocytosis appears as a cBTKi-class effect. Despite this, the kinetics of lymphocytosis is not overlapping when comparing the two drugs.