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.

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.

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.

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.

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.

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.

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.

The efficacy of pirtobrutinib was comparable to continuously administered venetoclax monotherapy in patients with R/R CLL previously treated with a cBTKi. Pirtobrutinib was associated with improved ORR and favorable overall safety profile for most TEAEs compared to venetoclax. This study raises questions regarding optimal treatment sequencing of pirtobrutinib and venetoclax in cBTKi treated CLL, but the lack of prospective direct comparisons and limited long-term follow-up preclude definitive conclusions.

Within R/R CLL, single-agent ibrutinib was evaluated in 3 randomized phase 3 trials: RESONATE (vs ofatumumab), ALPINE (vs zanubrutinib), and ELEVATE-RR (vs acalabrutinib in patients with del(11q) or del(17p) mutations). In phase 3 randomized trials in R/R CLL, continuous ibrutinib treatment was associated with robust PFS and ORR benefits. Ibrutinib outcomes were consistent between RESONATE and ELEVATE-RR; however, significant differences in the performance of ibrutinib within ALPINE were identified. Indirect comparisons have limitations,since each trial, protocol, and patient profile are unique; however, these results highlight the need for further research on which elements of protocol design, center selection, or treatment delivery may lead to a significant impact on the performance of a given BTKi in clinical trials.

Background: The Bruton's tyrosine kinase inhibitor (BTKi) ibrutinib is the standard of care in relapsed or refractory chronic lymphocytic leukemia (RR CLL) and was compared in head-to-head randomized clinical trials (RCTs) with second- generation BTKis: acalabrutinib in ELEVATE-RR and zanubrutinib in ALPINE. Acalabrutinib and zanubrutinib have a similar efficacy in patients with RR CLL, while acalabrutinib has a lower risk of grade ≥ 3 hemorrhage, any grade and grade ≥ 3 hypertension and dose reduction due to AEs vs zanubrutinib. Limitations of MAIC analyses mean the results should be viewed as hypothesis-generating. Meta-analysis, Bruton's tyrosine kinase inhibitor (BTKi), Chronic lymphocytic leukemia

The efficacy of pirtobrutinib was comparable to continuously administered venetoclax monotherapy in patients with R/R CLL previously treated with a cBTKi. Pirtobrutinib was associated with improved ORR and favorable overall safety profile for most TEAEs compared to venetoclax. This study raises questions regarding optimal treatment sequencing of pirtobrutinib and venetoclax in cBTKi treated CLL, but the lack of prospective direct comparisons and limited long-term follow-up preclude definitive conclusions.

Nearly 67% of patients were still receiving orelabrutinib after almost a 3-year follow-up. In conclusion, Orelabrutinib demonstrated compelling efficacy as well as safety profiles, with a noteworthy number of patients obtaining complete response in refractory or relapsed CLL/SLL.

Distinct TR repertoire profiles were identified in groups of patients with CLL bearing different genomic aberrations, alluding to distinct selection processes. Abnormal protein expression and gene dosage effects associated with recurrent genomic aberrations likely represent a relevant source of CLL-specific selecting antigens.

Rituximab (R) was administered as either 375 mg/m2 weekly; 750 mg/m2 daily on days 1, 2 and 3; or 750 mg/m2 weekly times during cycle one and daily times three for cycle two and three. Obinutuzumab (G) and ofatumumab (O) were administered per FDA standard dosing...Some Pts who achieved a partial response (PR) to initial therapy underwent alemtuzumab (Alem) consolidation, 10mg, administered three times a week for a total of eight weeks. All Pts received anti-microbial prophylaxis consisting of fluconazole, bactrim and acyclovir...Patients without progression at 36 months were found to have higher serum IgA levels. While the Tx landscape for CLL has dramatically changed, the addition of HDMP to an anti-CD20 mAB can be a Tx option for patients desiring short course of Tx, requiring bridging to more definite therapy, or debulking strategy prior to venetoclax based Tx.

The results of this final analysis confirm the earlier reports of acalabrutinib efficacy and were later confirmed by similar outcomes of response durability and long-term tolerability in the pivotal ASCEND phase 3 trial in patients with R/R CLL/SLL (Jurczak et al. J Clin Oncol. 2022; 40[suppl 16]:7538).

The final data from ACE-CL-001 further support the long-term efficacy and safety of acalabrutinib monotherapy, with high response rates and rapid, durable responses seen in patients with TN CLL regardless of high-risk genomic features. With over 6 years of follow-up, this study firmly establishes the tolerability and safety profile of acalabrutinib seen consistently in subsequent studies, with a low incidence of atrial fibrillation/flutter seen and no new long-term safety issues identified.

Thirty (68%) pts went on to receive further treatment (19 pts on BTK based regimens, 2 pts received venetoclax monotherapy, 5 pts received combined venetoclax and ibrutinib, 3 pts received chemoimmunotherapy, and 1 pt received obinutuzumab monotherapy). The PFS was similar to that of similarly designed trials with rituximab monotherapy and rituximab in combination with alemtuzumab, respectively. Further internal matched analysis is being conducted to compare time to second treatment.

Index BTKi treatments were given as: first line (27%), second line (33%), third line (18%), fourth line (12%), fifth or greater line (9%) of therapy (Figure 1); patients were treated with either ibrutinib (88%, 51% as monotherapy and 12% in combination with anti-CD20 mAb) or acalabrutinib (12%, all monotherapy). In this retrospective study characterizing CLL/SLL patients at a large academic center who received covalent BTKi mostly in early lines of therapy, BTKi discontinuation was most commonly driven by adverse events (55%), with CLL/SLL disease progression (35%) the second most common reason. These findings are consistent with earlier studies, although notably we observed a relatively low incidence of Richter's transformation (5%). Following BTKi discontinuation, many patients received venetoclax-based regimens, yet with a median follow-up of 5.4 years, 40% patients died.

Our results demonstrated increased telomere erosion in AA CLL compared to EA CLL, even after accounting for other known prognostic factors. Telomere length has been described as an independent prognostic factor in multiple cancers. In CLL, telomere shortening can lead to a selective pressure for loss of function of DNA damage checkpoint genes, becoming permissive to further cell proliferation and telomere shortening.

This study found that first-line single-agent ibrutinib therapy was associated with significantly longer TTNT than CIT regimens in real-world patients with high-risk CLL. The results support the use of ibrutinib in high-risk patients. INFOGRAPHIC.

Currently available treatment approaches for CLL offer the opportunity to individualize therapy for every single patient with CLL. Inhibitors of B-cell receptor (BCR) signalling pathways and antiapoptotic proteins are nowadays the treatment of choice for most CLL patients, but CIT can be an option for younger and fit patients with low-risk disease [mutated IGHV, no del(11q) or del(17p)/TP53 mutations].

Here we show a high sensitivity, specificity, and NPV when comparing targeted sequencing with FISH. FISH panel testing is widely used in clinical practice to characterize highly prognostic chromosomal abnormalities in CLL. Comprehensive genetic profiling with NGS has become increasingly important in the work up of hematologic malignancies and provides additional prognostic and predictive information, including clinically relevant mutations such as TP53, SF3B1 , and NOTCH1, tumor mutation load and mutations associated with resistance to chemo-immunotherapy and targeted therapies, such as BTK or BCL2 inhibitors, that FISH cannot offer.

Previous therapy for CLL included ibrutinib, n=4; chlorambucil + OBIN and then acalabrutinib, n=1; BR, n=1; one pt had no prior therapy for CLL)...R/R RT (n=1) : One pt (58-year-old male) with previously untreated CLL (unmutated IGHV, del(17p), TP53 mutation, NOTCH1 mutation) developed RT and received R-CHOP for 3 cycles with no response... Treatment with combined VEN, OBIN and atezolizumab leads to high rates of remission in pts with previously untreated RT; all 7 pts achieved a remission and 3 pts proceeded to allo-SCT. With the limitation of small numbers, these results are encouraging in relation to combined ibrutinib plus nivolumab in previously untreated RT (7/14, 50% response rate; Jain, ASH 2018). Enrollment in the trial continues and updated data will be presented at the ASH meeting.

In this fully accrued study, U2 was added to ibrutinib in 26 patients. Median age was 63 years (range, 48-81) and 77% were male. Disease characteristics included del(17p) in 8%, del(11q) in 12%, and unmutated IGHV in 31%.

The AMPK inhibitor dorsomorphin, the ULK1/2 inhibitor MRT68921, and the autophagosome-lysosome fusion inhibitor chloroquine demonstrated concentration-dependent and time-dependent cytotoxicity against CLL cells, even in those from hard-to-treat patients who carried del(11q) and del(17p). Additionally, MRT68921 alone induced G2 arrest, but when combined with venetoclax, it triggered caspase-dependent cytotoxicity. These data provide the rationale to target autophagy and for autophagy inhibitors as potential treatments for patients with CLL.