Chr del(11q)

P1, N=20, Completed, Noah Merin | Active, not recruiting --> Completed | N=30 --> 20 | Trial completion date: Nov 2031 --> Nov 2024

This study supports the use of MRD testing to guide duration of Ven / Obin therapy in the 1L setting. Early discontinuation of Ven/Obin for pts who are uMRD6 at C9 achieves similar PFS to pts who completed 12C of Ven/Obin and have uMRD5 status before entering TFO. In this study, concordance rate between PB and BM was relatively low (approximately two-thirds concordance) at 10-6 (C9) and 10-5 (C12) sensitivities.

Patients with neuroblastoma characterized by these genetic characteristics often have suppressed T cell response and an overabundance of immunosuppressive cells and cytokines in the peripheral blood. This imbalance is significantly associated with poor EFS. Moreover, if these patients show an elevated levels of immunosuppressive cytokines such as IL-10, the prognosis will be worse.

We identified a potential connection between XPB gain and chemoresistance of NB. The findings help elucidate the molecular profiles of high-risk NB with 11q deletion in pre- and post-chemotherapy tumor samples, which may reflect unique profiles in poor response to treatment.

The EBV-DNA load could be used as a prognostic factor in the initial examination of CLL patients to better characterize the disease outcome and prognosis.

In conclusion, the identification of specific miRNAs as predictors of TTFT holds promise for enhancing risk stratification in CLL to predict therapeutic needs. However, further validation studies and in-depth functional analyses are required to confirm the robustness of these observations and to facilitate their translation into meaningful clinical utility.

P2, N=42, Active, not recruiting, Jennifer Woyach | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024

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.

Time limited AO was well tolerated and resulted in deep remissions allowing for time limited BTKi tx. 40% ofpts achieved U-MRD with 13C of tx, 86% of these patients maintained U-MRD 3 cycles post completion of tx. This study is fully accrued.

Our findings highlight the diverse prognostic influence of genetic aberrations depending on the IGHV status in symptomatic CLL patients receiving first-line CIT. The prognosis of gene mutations and cytogenetic abnormalities needs to be investigated with a compartmentalized methodology, taking into account the IGVH status of patients receiving first-line BTK and/or BCL2 inhibitors.

The combination of ofatumumab, HDMP, and lenalidomide was effective and relatively well tolerated in treatment-naive CLL/SLL. Its role in the frontline setting remains unclear given the current available and effective treatment options.

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.

A comprehensive analysis of genetic prognostic factors provides a more precise information on the outcome of CLL patients. In addition to FISH cytogenetic aberrations, IGHV and TP53 mutations, IGHV gene families, and CK information could help clinicians in the decision-making process.

The most important breakpoints appear to be at 17q12 and 17q21. The former distinguishes between whole and partial chromosome 17q gain; the latter is a site of IGF2BP1 and NME1 genes that appear to be the main oncogenes responsible for the functional effects of 17q gain.

P2, N=78, Recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024

TERT was frequently placed in juxtaposition to a previously established gene in neuroblastoma tumorigenesis or cancer in general. Given the importance of high-risk neuroblastoma, means for mitigating active telomere maintenance must be therapeutically explored.

P3, N=533, Active, not recruiting, Acerta Pharma BV | Trial completion date: Oct 2026 --> Jan 2028

After 4 years of follow-up, ibrutinib-venetoclax continues to significantly prolong progression-free survival (vs chemoimmunotherapy) in patients with previously untreated chronic lymphocytic leukaemia, supporting its use as a first-line option.

The initial patient, a 74-year-old male with CLL (unmutated IGHV, del(11q), BTK C481S mutation) and 3 prior lines of therapy (FCR, ibrutinib, venetoclax + rituximab), received a LD regimen of cyclophosphamide 500 mg/m 2 and fludarabine 24 mg/m 2 (daily for 3 days) followed by a starting dose of 60 million CAR+ SC291 cells (of which approximately 80% are fully HIP engineered cells). Immune assays demonstrated that the CD19 HIP CAR T cell subpopulation effectively evades the host adaptive and innate immune responses and could overcome the allogeneic barrier in humans. Additional data from the ARDENT study will be presented at the time of the conference.

Background: Fludarabine, cyclophosphamide, and rituximab (FCR) is the standard first-line therapy for fit (physically active, with no major health problems and normal renal function) treatment-naive patients with chronic lymphocytic leukemia (CLL) (Eichhorst et al...2016) investigated FCR and bendamustine + rituximab (BR), while the SEQUOIA trial compared zanubrutinib to BR (NCT03336333; Tam et al... Our findings suggest that zanubrutinib offers clinically meaningful benefits in PFS over FCR in fit treatment-naive patients with CLL. MAICs rely on reporting of relevant patient characteristics in published studies. In the current study, ZAP-70 methylation and TP53 mutation, which were considered treatment effect modifiers, were not reported in CLL10 and were not accounted for in the propensity model.

Using genome wide sequencing, we identify increasing genomic deletions as a feature of enhanced-high risk del17p. While deletion burden cut-offs identified here are specific to our research method and require further validation in additional independent cohorts, EHR subgroup remained significant after adjusting for other known prognostic variables .

ATM, KAP1, and H2AX phosphorylation levels were examined after etoposide or irradiation (IR) exposure, by western blot or flow cytometry, in primary CLL cells with or without ATM aberrancy...CLL cells with ATM aberrancies had ATM pathway dysfunction, and those with biallelic ATM aberrancies were more sensitive to the PARP inhibitor, talazoparib, than WT. This work could potentially lead to additional avenues for treatment based on differential sensitivities of CLLs with ATM aberrancy. Further studies are needed to characterize specific ATM germline variants with or without somatic ATM events.

In conclusion, by assessing the individual contribution of DME and TL to disease survival, we found that both variables offer valuable independent prognostic information when included in statistical models with poor-risk genomic lesions. TL and DME could help identify IGHV-mutated patients destined to respond poorly to (immuno-)chemotherapy, that might be more favourably treated with targeted agents.

3%), mainly rituximab, and those based on BTK inhibitors (33. 3%), mainly ibrutinib...The different time of drug access in Italy, typically delayed after the EU approval, may also have affected the limited use of venetoclax-based treatment. The continuous accrual of pts in this study will allow to obtain a close-to-registry vision of CLL management in Italy over time, in terms of coverage of the entire country but enriched with the granularity of the data and flexibility of the collection typical of a real-world study.

Introduction: Venetoclax in combination with rituximab (VenR) along with either ibrutinib or acalabrutinib monotherapy represent the most common regimens currently used for the treatment of relapsed/refractory (RR) chronic lymphocytic leukemia (CLL) in the Czech Republic...Bendamustine and rituximab followed by fludarabine, cyclophosphamide and rituximab were the most common regimens used in the firs-line treatment... In terms of high-risk prognostic markers, a higher prevalence of del 17p and/or TP53 mutation, and del 11q were observed in the BTKi cohort. In contrast, frequency of the unmutated IGVH gene was comparable in both groups. Difference in median PFS and OS was not statistically significant within the current follow-up period.

Adverse events in general were manageable and mainly related to gastrointestinal and liver toxicity, and patient died during treatment from complications from COVID-19 pneumonia. After an initial 12 weeks of continuous duvelisib treatment, the incorporation of intermittent dosing appears to be a viable option for patients with previously treated CLL/SLL.

SEQUOIA study demonstrated superior efficacy of frontline zanubrutinib than bendamustine-rituximab combination, and ALPINE study showed improved overall response rate (ORR) and progression free survival (PFS) of zanubrutinib than ibrutinib in relapsed/refractory chronic lymphocytic leukemia (R/R CLL). Despite an improved safety profile, AE remained the main reason of zanubrutinib dose reduction, and dose reduction significantly associated with shorter PFS and OS. Therefore, better treatment strategies such as combined targeted therapy are required to improve the outcomes of these pts.

P3, N=553, Active, not recruiting, AstraZeneca | Phase classification: P3b --> P3

Iron chelation therapy : Exjade from 2019 to 2022, now suspended. Total number of MDS-RS patients treated with Luspatercept 15 Age years, median (range) 74 (52-83) Sex, n (%) Male 10 (67) Female 5 (33) Cytogenetic, n Normal 11 8 1 Y 1 del 11q 1 del 20q 1 IPSS-R Classification, n (%) Very Low Risk 1 (15) Low Risk 7 (47) Intermediate Risk 6 (38) Mutation status, detected by NGS SF3B1, n (%) 14 (92) Vaf , %, median (range) 39 (21,4-46,3) Patients with others concomitant mutations 11 (73%) IPSS M Classification, n (%) Very Low Risk 2 (13) Low Risk 8 (54) Moderatly Low Risk 4 (26) Intermediate Risk 1 (7) Duration of EPO traitment before Luspatercept Months, median, range 21, 6-104 Transfusion burden sec. IWG 2018 Low Trasfusion Burden, n (% ) 7 (46) High transfusion burden , n (%) 8 (54)

Of the 29 patients with PD, 19 have required retreatment (single-agent ibrutinib, n = 16, or ibrutinib plus venetoclax, n = 3); 17 achieved partial response or better, 1 achieved stable disease, and 1 is pending response assessment. First-line fixed-duration combination treatment with ibrutinib plus venetoclax may mitigate development of resistance mechanisms associated with continuous single-agent targeted therapies, allowing for effective retreatment.

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.

We performed whole exome sequencing on matched tumor and normal samples from 19 CLL patients treated with BTK inhibitors (Ibrutinib, Ibr, 42% (8/19); Acalabrutinib, Acala, 21% (4/19) and Pirtobrutinib, Pirto, 37% (7/19))...The ibr cohort had no prior BTKi therapy whereas 1 patient in the acala cohort had received spebrutinib, another cBTKi...The approach of combining WES data with growth pattern modeling can help unravel the complexities of tumor evolution and drug resistance for the different classes of BTKi. Data on comparative clone growth rates will be presented at the meeting.

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.

Ibrutinib, Zanubrutinib, Orelabrutinib were administered in 55.3%,18.3% and 17.9% of patients respectively, in addition to 6 patients with Acalabrutinib and one with Loxo-305, among them 47.7% (125/262) received BTKi as first line treatment...Venetoclax-based regimen might be an effective salvage therapy which could showed a benefit trend in PFS as compared to other post BTKi therapy (10.1 months vs 3.1 months, p= 0.1818)...Acquired BTK/PLCG2 mutations remained to be key drivers of BTKis resistance and BTKC481S mutation was the dominant mutation, while BTKT474 mutation was only detected in Orelabrutinib-resistant patients. The prognosis was rather poor for relapsed patients especially for RTs, treatment strategy after disease progression remains to be optimized.

Only 2 pts developed VTE during active R2 and both were not taking prophylactic aspirin. In this long-term pooled f/u analysis of CLL pts, we found that R2 provided high ORR, modest PFS and OS benefit, and tolerable long-term toxicities. The ORR of R2 in this study (82.3%) compares favorably to ORR of R monotherapy in previous studies (51%, Hainsworth et al, JCO 2003). The absence of secondary myeloid neoplasms suggests that len may not substantially increase cumulative secondary malignancy risk—the cumulative cutaneous neoplasm incidence may reflect elevated baseline risk in CLL pts.

5 pts have started subsequent therapy (acalabrutinib, n=4; ibrutinib, n=1; all are clinically responding); 1 pt has not yet started therapy. We report long term follow-up of combined IBR and VEN in first-line CLL (n=120) with a 5-year PFS of 90.1%. The 5-year PFS for pts with del(17p)/TP53 mutation is 86.1%. Retreatment with BTK inhibitor appears effective for pts with disease relapse.

Figure 1. Frequency of mutations Graph shows frequency of mutations among patients with autoimmune diseases (AD) in MDS versus those without AD.* p<0.05, **p<0.001.

In sum, our study of the molecular landscape of c-CBL mutations highlights that these lesions occur mainly during disease development with majority of the cases carrying subclonal hits with a weaker effect on disease phenotype and prognosis. Such mutations can be present in both primary and secondary AML (in contrast with previous reports) and additive effects can be observed when c-CBL mutations co-occur with more than one RAS gene in these disease groups. In some cases, especially in non-canonical mutations, c-CBL could also act as ancestral event and as an independent leukemic driver.

Among the 160 patients with symptomatic or progressive lymphadenopathy/splenomegaly or extranodal disease, the treatments administered include: mAb alone (n=35), chemotherapy alone (n=33), chemoimmunotherapy (n=57), targeted agent (n=33; Bruton tyrosine kinase inhibitor [BTKi] based n=28; venetoclax-based n=3, BTKi + venetoclax n=2), and other (n=2)...Trisomy 12 was the most frequently detected abnormality on peripheral blood FISH testing. Treatment with novel agents achieved durable TFS and OS.

Higher mutational burden is associated with worsened TTFT in CLL pts independently of other genomic events. In this cohort we did not see co-occurrence of specific mutations.

In this population of pts with CLL with high-risk disease features predictive of need for earlier treatment, LEN resulted in a prolonged time to subsequent therapy, even in cases of LEN discontinuation. The incidence of gr ≥3 INFs and SN were as expected for this population supporting that LEN does not increase risk for these complications.